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Aliskiren fumarate, CGP-60536(free base), SPP-100B, SPP-100(

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摘 要:Aliskiren fumarate, CGP-60536(free base), SPP-100B, SPP-100(free base), CGP-60536B,173334-58-2, 173334-57-1 (free base), 173399-03-6 (monohydrochloride),2-C30-H53-N3-O6.C4-H4-O4,(2S,4S,5S,7S)-5-Amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy-2-isoprop
  • 【药物名称】Aliskiren fumarate, CGP-60536(free base), SPP-100B, SPP-100(free base), CGP-60536B
  • 【化学名】(2S,4S,5S,7S)-5-Amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnonanamide hemifumarate
  • 【CAS登记号】173334-58-2, 173334-57-1 (free base), 173399-03-6 (monohydrochloride)
  • 【结构式】Aliskiren fumarate, CGP-60536(free base), SPP-100B, SPP-100(--药物合成数据库
  • 【分子式】2-C30-H53-N3-O6.C4-H4-O4
  • 【分子量】1219.599
  • 【原研厂家】Novartis (Originator), Speedel (Licensee)
  • 【作用类别】CARDIOVASCULAR DRUGS, Heart Failure Therapy, Hypertension, Treatment of, Renal Failure, Agents for, RENAL-UROLOGIC DRUGS, Treatment of Renal Diseases, Renin Inhibitors
  • 【研发状态】Phase II
  • 【合成情况】 
  • 〖来源〗15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh)
  • 〖合成路线〗
  • 〖标题〗Structural modification of the P2' position of 2,7-dialkyl substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octane-carboxamides: Discovery of a potent non-peptide renin inhibitor active after once daily dosing in marmosets
  • 〖合成方法〗Alkylation of 3-hydroxy-4-methoxybenzyl alcohol (I) with 1-bromo-3-methoxypropane (II) gives ether (III). Subsequent conversion of benzyl alcohol (III) into bromide (IV) is carried out using bromotrimetylsilane. The chiral isovaleryloxazolidinone (V) is alkylated with bromide (IV) by means of LiHMDS to afford (VI), which is hydrolyzed to the (S)-2-aryl-2-isopropylpropionic acid (VII) by means of lithium peroxide. The reduction of acid (VII) to the corresponding alcohol with NaBH4/I2 reagent, followed by treatment with PPh3 and NBS, provides bromide (VIII). Alkylation of the chiral dimethoxydihydropyrazin (IX) with bromide (VIII) produces (X). Further hydrolysis of the pyrazine ring of (X) with HCl, followed by Boc protection of the resulting (S,S)-amino ester, yields compound (XI). Reduction of the ester group of (XI) with DIBAL gives aldehyde (XII). This compound is condensed with the Grignard reagent (XIII) to afford the diastereomeric mixture of amino alcohols (XIV). Treatment of mixture (XIV) with 2,2-dimethoxypropane (XV) and TsOH produces a mixture of oxazolidines, from which the required (S,S,S)-isomer (XVI) is isolated by flash chromatography. Hydrogenolitic deprotection of the benzyl ether of (XVI) gives alcohol (XVII).
  • 〖作者〗Rigollier, P.; Stutz, S.; Goeschke, R.; Yamaguchi, Y.; Maibaum, J.; Wood, J.
  • 〖参考〗Rigollier, P.; Stutz, S.; Goeschke, R.; Yamaguchi, Y.; Maibaum, J.; Wood, J.; Structural modification of the P2' position of 2,7-dialkyl substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octane-carboxamides: Discovery of a potent non-peptide renin inhibitor acww.chemdrug.com/extend/view.php?i??=耀?ul class="old_db">li>span>【药物名称】/span>N276-15/li> li>span>【化学名】/span>4-Isopropyl-2-methyl-6-[4-(2-methyl-1H-imidazo[4,5-c]pyridin-1-y
  • 〖出处〗15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh)1998,,():Abst P.230
  • 〖备注〗Treatment of (XIV) with 2,2-dimethoxypropane and p-toluenesulfonic acid produced a mixture of oxazolidines, from which the required (S,S,S)-isomer (XV) was isolated by flash chromatography. Hydrogenolytic deprotection of the benzyl ether of (XV) gave alcohol (XVI). This was oxidized to aldehyde with N-methylmorpholine-N-oxide and tetrapropylammonium perruthenate, and further oxidized to carboxylic acid (XVII) with KMnO4 and tetrabutylammonium bromide. Coupling of (XVII) with aminoamide (XVIII) by means of diethyl cyanophosphonate gave (XIX). Finally, acid hydrolysis of the oxazolidine and Boc protecting groups of (XIX) furnished the corresponding aminoalcohol, which was finally converted to the hemifumarate salt.
  • 〖来源〗Drugs Fut
  • 〖合成路线〗
  • 〖标题〗Aliskiren Fumarate
  • 〖合成方法〗Alkylation of 3-hydroxy-4-methoxybenzyl alcohol (I) with 1-bromo-3-methoxypropane (II) gives ether (III). Subsequent conversion of benzyl alcohol (III) into bromide (IV) is carried out using bromotrimetylsilane. The chiral isovaleryloxazolidinone (V) is alkylated with bromide (IV) by means of LiHMDS to afford (VI), which is hydrolyzed to the (S)-2-aryl-2-isopropylpropionic acid (VII) by means of lithium peroxide. The reduction of acid (VII) to the corresponding alcohol with NaBH4/I2 reagent, followed by treatment with PPh3 and NBS, provides bromide (VIII). Alkylation of the chiral dimethoxydihydropyrazin (IX) with bromide (VIII) produces (X). Further hydrolysis of the pyrazine ring of (X) with HCl, followed by Boc protection of the resulting (S,S)-amino ester, yields compound (XI). Reduction of the ester group of (XI) with DIBAL gives aldehyde (XII). This compound is condensed with the Grignard reagent (XIII) to afford the diastereomeric mixture of amino alcohols (XIV). Treatment of mixture (XIV) with 2,2-dimethoxypropane (XV) and TsOH produces a mixture of oxazolidines, from which the required (S,S,S)-isomer (XVI) is isolated by flash chromatography. Hydrogenolitic deprotection of the benzyl ether of (XVI) gives alcohol (XVII).
  • 〖作者〗Mealy, N.E.; Castaer, R.M.; Silvestre, J.S.; Castaer, J.
  • 〖参考〗Mealy, N.E.; Castaer, R.M.; Silvestre, J.S.; Castaer, J.; Aliskiren Fumarate. Drugs Fut 2001, 26, 12, 1139
  • 〖出处〗Drugs Fut2001,26,(12):1139
  • 〖备注〗Synthesis of Aliskiren Fumarate (EN:267580): Aliskiren can be obtained by several different ways: a) Alkylation of 3-hydroxy-4-methoxybenzyl alcohol (I) with 1-bromo-3-methoxypropane (II) gives ether (III). Subsequent conversion of benzyl alcohol (III) into bromide (IV) is carried out using bromotrimetylsilane. The chiral isovaleryloxazolidinone (V) is alkylated with bromide (IV) by means of LiHMDS to afford (VI), which is hydrolyzed to the (S)-2-aryl-2-isopropylpropionic acid (VII) by means of lithium peroxide. The reduction of acid (VII) to the corresponding alcohol with NaBH4/I2 reagent, followed by treatment with PPh3 and NBS, provides bromide (VIII). Alkylation of the chiral dimethoxydihydropyrazin (IX) with bromide (VIII) produces (X). Further hydrolysis of the pyrazine ring of (X) with HCl, followed by Boc protection of the resulting (S,S)-amino ester, yields compound (XI). Reduction of the ester group of (XI) with DIBAL gives aldehyde (XII). This compound is condensed with the Grignard reagent (XIII) to afford the diastereomeric mixture of amino alcohols (XIV). Treatment of mixture (XIV) with 2,2-dimethoxypropane (XV) and TsOH produces a mixture of oxazolidines, from which the required (S,S,S)-isomer (XVI) is isolated by flash chromatography. Hydrogenolitic deprotection of the benzyl ether of (XVI) gives alcohol (XVII) (Scheme 26758001a). This alcohol is oxidized to aldehyde with NMMO and tetrapropylammonium perruthenate (TPAP), and further oxidized to carboxylic acid (XVIII) with KMnO4 and tetrabutylammonium bromide (TBAB). Coupling of (XVIII) with aminoamide (XIX) by means of diethyl cyanophosphonate and TEA gives (XX). Finally, acid hydrolysis of the oxazolidine ring and Boc protecting groups of (XX) furnishes the corresponding amino alcohol, which is finally converted to the hemifumarate salt (1, 2) (Scheme 26758001b). b) The intermediate g-butyrolactone (XXVIII) has been obtained as follows: Allylation of the imidazolidinone intermediate (V) with allyl bromide (XXI) and LiHMDS in THF gives the chiral intermediate (XXII), which by dihydroxylation and cleavage of the chiral auxiliary with OsO4 and NMMO in tert-butanol/acetone/water yields the lactone alcohol (XXIII). Oxidation of (XXIII) with NaIO4 and RuCl3 in CCl4/acetonitrile/water affords the carboxylic acid (XXIV), which by treatment with (COCl)2 in toluene provides the acyl chloride (XXV). Esterification of (XXV) with benzyl alcohol gives the corresponding benzyl ester as a diastereomeric mixture, from which the desired isomer (XXVI) is separated by flash chromatography. Hydrogenolysis of the benzyl ester (XXVI) with H2 over Pd/C in ethyl acetate yields the carboxylic acid (XXVII), which is treated with oxalyl chloride in toluene to afford the desired g-butyrolactone intermediate (XXVIII) (3) (Scheme 26758001c). The reduction of the chiral propionic acid (VII) with NaBH4 in THF gives the primary alcohol (XXIX), which by reaction with SOCl2 and pyridine in CHCl3 yields the chloride (XXX). Condensation of (XXX) with the butyrolactone intermediate (XXVII) by means of Mg and dibromoethane affords the ketonic adduct (XXXI). Reduction of the exocyclic carbonyl group of (XXXI) with NaBH4 in THF/ methanol provides a 3:1 diastereomeric mixture of the desired chiral alcohol (XXXII) and its OH-epimer (XXXIII) that are separated by flash chromatography. Reaction of (XXXII) with MsCl and TEA, followed by treatment with NaN3, affords the azido derivative (XXXIV), which is condensed with 4-amino-3,3-dimethylbutyramide (XIX) by means of 2-hydroxypyridine and TEA to provide the adduct (XXXV). Finally, the azido group of (XXXV) is reduced with H2 over Pd/ in methanol to yield the target amino alcohol (3) (Scheme 26758001d). An extensive study on the stereoselective reduction of the ketonic adduct (XXXI) has been performed. No better diastereoselectivity than 3:1 has been obtained for the synthesis of the chiral alcohol (XXXII). However, excellent diastereoselectivity (97:3) has been obtained for the synthesis of its OH-epimer, alcohol (XXXIII), with K-selectride in THF, which could potentially provide access to the target amino alcohol via a double inversion protocol. c) Alternatively, the chiral phenylpropyl chloride (XXX) can also be prepared as follows: Reduction of the cinnamic acid (XXXVI) with H2 over Pd/C in ethyl acetate gives the phenylpropionic acid (XXXVII), which is treated with oxalyl chloride to yield the acyl chloride (XXXVIII). Condensation of (XXXVIII) with (+)-pseudoephedrine (XXXIX) by means of NaOH in toluene/water affords the chiral amide (XL), which is enantioselectively alkylated with 2-iodopropane (XLI) by means of LDA in THF to provide the adduct (XLII). Reduction of the amide group of (XLII) with BH3/NH3 in THF gives the already reported primary alcohol (XXIX), which is finally treated with POCl3 in hot toluene to afford the phenylpropyl chloride intermediate (XXX) (4) (Scheme 26758001e). d) The chiral azido intermediate (XXXIV) can also be obtained as follows: Reaction of (+)-pseudoephedrine isovaleramide (XLIII) with allyl bromide (XXI) by means of LDA in THF gives the pentenoyl amide (XLIV), which is treated with NBS in DME/water to yield the spiro compound (XLV). Hydrolysis of the bromomethyl group of (XLV) with tetrabutylammonium acetate and K2CO3 affords the carbinol (XLVI), which is oxidized to aldehyde (XLVII) with SO3/pyridine and TEA in DMSO/dichloro-methane. Condensation of (XLVII) with the propyl chloride intermediate (XXX) by means of Mg, dibromoethane and CeCl3 in refluxing THF provides the already reported chiral hydroxylactone (XXXII), which is treated first with 4-bromobenzenesulfonyl chloride and then with NaN3 to give the desired azido derivative (XXXIV) (4) (Scheme 26758001f). e) Alternatively, the chiral azido intermediate (XXXIV) can also be synthesized as follows: Alkylation of oxazolidinone (V) with 1-chloro-3-iodopropene (XLVIII) by means of LiHMDS in THF gives compound (XLIX), which is condensed with the magnesium derivative of the phenylpropyl chloride (XXX) to yield, after working up, amide (L). Bromination of (L) with NBS and phosphoric acid affords the bromolactone (LI), which by treatment with NaN3 in tripropylene glycol/water provides the azido derivative (XXXIV) (5) (Scheme 26758001g). f) Alternatively, the spiro aldehyde (XLVII) is treated with N-benzylhydroxylamine in dichloromethane to give nitrone (LII), which is submitted to a Grignard reaction with the magnesium derivative of intermediate (XXX) in THF to afford the adduct (LIII) as a mixture of epimers at the amino group. Simultaneous N-dehydroxylation and cleavage of the spiro function of (LIII) by means of Zn, Cu(OAc)2 in AcOH/water gives lactone (LIV), which is condensed with 3-amino-2,2-dimethylpropionamide (XIX) by means of TEA and 2-hydroxypyridine giving the adduct (LV). Finally, the benzylamino group of (LV) is removed with H2 over Pd/C in methanol to yield a mixture of two epimers at the amino group, from which aliskiren is separated (6) (Scheme 26758001h). Manufacturers Novartis Pharma AG (CH); licensed to Speedel Pharma AG (CH). References 1. Gschke, R., Maibaum, J.K., Schilling, W., Stutz, S., Rigollier, P, Yamaguchi, Y., Cohen, N.C., Herold, P. (Novartis AG). d-Amino-g-hydroxy-w-aryl alkanoic acid amides with enzyme especially renin inhibiting activities. EP 0678500, EP 0678503, JP 1996053434, JP 1996081430, US 5559111, US 5627182, US 5646143. 2. Wood, J., Yamaguchi, Y. Rigollier, P., Goeschke, R., Stutz, S., Maibaum, J. Structural modification of the P2' position of 2,7-dialkyl substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octane-carboxamides: Discovery of a potent non-peptide renin inhibitor active after once daily dosing in marmosets. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.230. 3. Reger, H., Stutz, S., Gschke, R., Spindler, F., Maibaum, J. A convergent synthesis approach towards CGP60536B, a non-peptide orally potent renin inhibitor, via an enantiomerically pure ketolactone intermediate. Tetrahedron Lett. 2000, 41: 10085-9. 4. Sandham, D.A., Taylor, R.J., Carey, J.S., Fssler, A. A convergent synthesis of the renin inhibitor CGP60536B. Tetrahedron Lett 2000, 41: 10091-4. 5. Herold, P., Stutz, S., Indolese, A. (Speedel Pharma Inc.). Production of N-substd. 2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoylamides. WO 0109079, WO 0109083. 6. Dondoni, A., De Lathauwer, G., Perrone, D. A convergent synthesis of the renin inhibitor SPP-100 using a nitrone intermediate. Tetrahedron Lett 2001, 42: 4819-23.
  • 〖来源〗15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh)
  • 〖合成路线〗
  • 〖标题〗Structural modification of the P2' position of 2,7-dialkyl substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octane-carboxamides: Discovery of a potent non-peptide renin inhibitor active after once daily dosing in marmosets
  • 〖合成方法〗This alcohol is oxidized to aldehyde with NMMO and tetrapropylammonium perruthenate (TPAP), and further oxidized to carboxylic acid (XVIII) with KMnO4 and tetrabutylammonium bromide (TBAB). Coupling of (XVIII) with aminoamide (XIX) by means of diethyl cyanophosphonate and TEA gives (XX). Finally, acid hydrolysis of the oxazolidine ring and Boc protecting groups of (XX) furnishes the corresponding amino alcohol, which is finally converted to the hemifumarate salt.
  • 〖作者〗Rigollier, P.; Stutz, S.; Goeschke, R.; Yamaguchi, Y.; Maibaum, J.; Wood, J.
  • 〖参考〗Rigollier, P.; Stutz, S.; Goeschke, R.; Yamaguchi, Y.; Maibaum, J.; Wood, J.; Structural modification of the P2' position of 2,7-dialkyl substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octane-carboxamides: Discovery of a potent non-peptide renin inhibitor acww.chemdrug.com/extend/view.php?i??=耀?ul class="old_db">li>span>【药物名称】/span>N276-15/li> li>span>【化学名】/span>4-Isopropyl-2-methyl-6-[4-(2-methyl-1H-imidazo[4,5-c]pyridin-1-y
  • 〖出处〗15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh)1998,,():Abst P.230
  • 〖备注〗Treatment of (XIV) with 2,2-dimethoxypropane and p-toluenesulfonic acid produced a mixture of oxazolidines, from which the required (S,S,S)-isomer (XV) was isolated by flash chromatography. Hydrogenolytic deprotection of the benzyl ether of (XV) gave alcohol (XVI). This was oxidized to aldehyde with N-methylmorpholine-N-oxide and tetrapropylammonium perruthenate, and further oxidized to carboxylic acid (XVII) with KMnO4 and tetrabutylammonium bromide. Coupling of (XVII) with aminoamide (XVIII) by means of diethyl cyanophosphonate gave (XIX). Finally, acid hydrolysis of the oxazolidine and Boc protecting groups of (XIX) furnished the corresponding aminoalcohol, which was finally converted to the hemifumarate salt.
  • 〖来源〗Drugs Fut
  • 〖合成路线〗
  • 〖标题〗Aliskiren Fumarate
  • 〖合成方法〗This alcohol is oxidized to aldehyde with NMMO and tetrapropylammonium perruthenate (TPAP), and further oxidized to carboxylic acid (XVIII) with KMnO4 and tetrabutylammonium bromide (TBAB). Coupling of (XVIII) with aminoamide (XIX) by means of diethyl cyanophosphonate and TEA gives (XX). Finally, acid hydrolysis of the oxazolidine ring and Boc protecting groups of (XX) furnishes the corresponding amino alcohol, which is finally converted to the hemifumarate salt.
  • 〖作者〗Mealy, N.E.; Castaer, R.M.; Silvestre, J.S.; Castaer, J.
  • 〖参考〗Mealy, N.E.; Castaer, R.M.; Silvestre, J.S.; Castaer, J.; Aliskiren Fumarate. Drugs Fut 2001, 26, 12, 1139
  • 〖出处〗Drugs Fut2001,26,(12):1139
  • 〖备注〗Synthesis of Aliskiren Fumarate (EN:267580): Aliskiren can be obtained by several different ways: a) Alkylation of 3-hydroxy-4-methoxybenzyl alcohol (I) with 1-bromo-3-methoxypropane (II) gives ether (III). Subsequent conversion of benzyl alcohol (III) into bromide (IV) is carried out using bromotrimetylsilane. The chiral isovaleryloxazolidinone (V) is alkylated with bromide (IV) by means of LiHMDS to afford (VI), which is hydrolyzed to the (S)-2-aryl-2-isopropylpropionic acid (VII) by means of lithium peroxide. The reduction of acid (VII) to the corresponding alcohol with NaBH4/I2 reagent, followed by treatment with PPh3 and NBS, provides bromide (VIII). Alkylation of the chiral dimethoxydihydropyrazin (IX) with bromide (VIII) produces (X). Further hydrolysis of the pyrazine ring of (X) with HCl, followed by Boc protection of the resulting (S,S)-amino ester, yields compound (XI). Reduction of the ester group of (XI) with DIBAL gives aldehyde (XII). This compound is condensed with the Grignard reagent (XIII) to afford the diastereomeric mixture of amino alcohols (XIV). Treatment of mixture (XIV) with 2,2-dimethoxypropane (XV) and TsOH produces a mixture of oxazolidines, from which the required (S,S,S)-isomer (XVI) is isolated by flash chromatography. Hydrogenolitic deprotection of the benzyl ether of (XVI) gives alcohol (XVII) (Scheme 26758001a). This alcohol is oxidized to aldehyde with NMMO and tetrapropylammonium perruthenate (TPAP), and further oxidized to carboxylic acid (XVIII) with KMnO4 and tetrabutylammonium bromide (TBAB). Coupling of (XVIII) with aminoamide (XIX) by means of diethyl cyanophosphonate and TEA gives (XX). Finally, acid hydrolysis of the oxazolidine ring and Boc protecting groups of (XX) furnishes the corresponding amino alcohol, which is finally converted to the hemifumarate salt (1, 2) (Scheme 26758001b). b) The intermediate g-butyrolactone (XXVIII) has been obtained as follows: Allylation of the imidazolidinone intermediate (V) with allyl bromide (XXI) and LiHMDS in THF gives the chiral intermediate (XXII), which by dihydroxylation and cleavage of the chiral auxiliary with OsO4 and NMMO in tert-butanol/acetone/water yields the lactone alcohol (XXIII). Oxidation of (XXIII) with NaIO4 and RuCl3 in CCl4/acetonitrile/water affords the carboxylic acid (XXIV), which by treatment with (COCl)2 in toluene provides the acyl chloride (XXV). Esterification of (XXV) with benzyl alcohol gives the corresponding benzyl ester as a diastereomeric mixture, from which the desired isomer (XXVI) is separated by flash chromatography. Hydrogenolysis of the benzyl ester (XXVI) with H2 over Pd/C in ethyl acetate yields the carboxylic acid (XXVII), which is treated with oxalyl chloride in toluene to afford the desired g-butyrolactone intermediate (XXVIII) (3) (Scheme 26758001c). The reduction of the chiral propionic acid (VII) with NaBH4 in THF gives the primary alcohol (XXIX), which by reaction with SOCl2 and pyridine in CHCl3 yields the chloride (XXX). Condensation of (XXX) with the butyrolactone intermediate (XXVII) by means of Mg and dibromoethane affords the ketonic adduct (XXXI). Reduction of the exocyclic carbonyl group of (XXXI) with NaBH4 in THF/ methanol provides a 3:1 diastereomeric mixture of the desired chiral alcohol (XXXII) and its OH-epimer (XXXIII) that are separated by flash chromatography. Reaction of (XXXII) with MsCl and TEA, followed by treatment with NaN3, affords the azido derivative (XXXIV), which is condensed with 4-amino-3,3-dimethylbutyramide (XIX) by means of 2-hydroxypyridine and TEA to provide the adduct (XXXV). Finally, the azido group of (XXXV) is reduced with H2 over Pd/ in methanol to yield the target amino alcohol (3) (Scheme 26758001d). An extensive study on the stereoselective reduction of the ketonic adduct (XXXI) has been performed. No better diastereoselectivity than 3:1 has been obtained for the synthesis of the chiral alcohol (XXXII). However, excellent diastereoselectivity (97:3) has been obtained for the synthesis of its OH-epimer, alcohol (XXXIII), with K-selectride in THF, which could potentially provide access to the target amino alcohol via a double inversion protocol. c) Alternatively, the chiral phenylpropyl chloride (XXX) can also be prepared as follows: Reduction of the cinnamic acid (XXXVI) with H2 over Pd/C in ethyl acetate gives the phenylpropionic acid (XXXVII), which is treated with oxalyl chloride to yield the acyl chloride (XXXVIII). Condensation of (XXXVIII) with (+)-pseudoephedrine (XXXIX) by means of NaOH in toluene/water affords the chiral amide (XL), which is enantioselectively alkylated with 2-iodopropane (XLI) by means of LDA in THF to provide the adduct (XLII). Reduction of the amide group of (XLII) with BH3/NH3 in THF gives the already reported primary alcohol (XXIX), which is finally treated with POCl3 in hot toluene to afford the phenylpropyl chloride intermediate (XXX) (4) (Scheme 26758001e). d) The chiral azido intermediate (XXXIV) can also be obtained as follows: Reaction of (+)-pseudoephedrine isovaleramide (XLIII) with allyl bromide (XXI) by means of LDA in THF gives the pentenoyl amide (XLIV), which is treated with NBS in DME/water to yield the spiro compound (XLV). Hydrolysis of the bromomethyl group of (XLV) with tetrabutylammonium acetate and K2CO3 affords the carbinol (XLVI), which is oxidized to aldehyde (XLVII) with SO3/pyridine and TEA in DMSO/dichloro-methane. Condensation of (XLVII) with the propyl chloride intermediate (XXX) by means of Mg, dibromoethane and CeCl3 in refluxing THF provides the already reported chiral hydroxylactone (XXXII), which is treated first with 4-bromobenzenesulfonyl chloride and then with NaN3 to give the desired azido derivative (XXXIV) (4) (Scheme 26758001f). e) Alternatively, the chiral azido intermediate (XXXIV) can also be synthesized as follows: Alkylation of oxazolidinone (V) with 1-chloro-3-iodopropene (XLVIII) by means of LiHMDS in THF gives compound (XLIX), which is condensed with the magnesium derivative of the phenylpropyl chloride (XXX) to yield, after working up, amide (L). Bromination of (L) with NBS and phosphoric acid affords the bromolactone (LI), which by treatment with NaN3 in tripropylene glycol/water provides the azido derivative (XXXIV) (5) (Scheme 26758001g). f) Alternatively, the spiro aldehyde (XLVII) is treated with N-benzylhydroxylamine in dichloromethane to give nitrone (LII), which is submitted to a Grignard reaction with the magnesium derivative of intermediate (XXX) in THF to afford the adduct (LIII) as a mixture of epimers at the amino group. Simultaneous N-dehydroxylation and cleavage of the spiro function of (LIII) by means of Zn, Cu(OAc)2 in AcOH/water gives lactone (LIV), which is condensed with 3-amino-2,2-dimethylpropionamide (XIX) by means of TEA and 2-hydroxypyridine giving the adduct (LV). Finally, the benzylamino group of (LV) is removed with H2 over Pd/C in methanol to yield a mixture of two epimers at the amino group, from which aliskiren is separated (6) (Scheme 26758001h). Manufacturers Novartis Pharma AG (CH); licensed to Speedel Pharma AG (CH). References 1. Gschke, R., Maibaum, J.K., Schilling, W., Stutz, S., Rigollier, P, Yamaguchi, Y., Cohen, N.C., Herold, P. (Novartis AG). d-Amino-g-hydroxy-w-aryl alkanoic acid amides with enzyme especially renin inhibiting activities. EP 0678500, EP 0678503, JP 1996053434, JP 1996081430, US 5559111, US 5627182, US 5646143. 2. Wood, J., Yamaguchi, Y. Rigollier, P., Goeschke, R., Stutz, S., Maibaum, J. Structural modification of the P2' position of 2,7-dialkyl substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octane-carboxamides: Discovery of a potent non-peptide renin inhibitor active after once daily dosing in marmosets. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.230. 3. Reger, H., Stutz, S., Gschke, R., Spindler, F., Maibaum, J. A convergent synthesis approach towards CGP60536B, a non-peptide orally potent renin inhibitor, via an enantiomerically pure ketolactone intermediate. Tetrahedron Lett. 2000, 41: 10085-9. 4. Sandham, D.A., Taylor, R.J., Carey, J.S., Fssler, A. A convergent synthesis of the renin inhibitor CGP60536B. Tetrahedron Lett 2000, 41: 10091-4. 5. Herold, P., Stutz, S., Indolese, A. (Speedel Pharma Inc.). Production of N-substd. 2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoylamides. WO 0109079, WO 0109083. 6. Dondoni, A., De Lathauwer, G., Perrone, D. A convergent synthesis of the renin inhibitor SPP-100 using a nitrone intermediate. Tetrahedron Lett 2001, 42: 4819-23.
  • 〖来源〗Tetrahedron Lett
  • 〖合成路线〗
  • 〖标题〗A convergent synthesis approach towards CGP60536B, a non-peptide orally potent renin inhibitor, via an enantiomerically pure ketolactone intermediate
  • 〖合成方法〗The intermediate gamma-butyrolactone (XXVIII) has been obtained as follows: Allylation of the imidazolidinone intermediate (V) with allyl bromide (XXI) and LiHMDS in THF gives the chiral intermediate (XXII), which by dihydroxylation and cleavage of the chiral auxiliary with OsO4 and NMMO in tert-butanol/acetone/water yields the lactone alcohol (XXIII). Oxidation of (XXIII) with NaIO4 and RuCl3 in CCl4/acetonitrile/water affords the carboxylic acid (XXIV), which by treatment with (COCl)2 in toluene provides the acyl chloride (XXV). Esterification of (XXV) with benzyl alcohol gives the corresponding benzyl ester as a diastereomeric mixture, from which the desired isomer (XXVI) is separated by flash chromatography. Hydrogenolysis of the benzyl ester (XXVI) with H2 over Pd/C in ethyl acetate yields the carboxylic acid (XXVII), which is treated with oxalyl chloride in toluene to afford the desired gamma-butyrolactone intermediate (XXVIII).
  • 〖作者〗Reger, H.; Maibaum, J.; Stutz, S.; Spindler, F.; Gschke, R.
  • 〖参考〗Reger, H.; Maibaum, J.; Stutz, S.; Spindler, F.; Gschke, R.; A convergent synthesis approach towards CGP60536B, a non-peptide orally potent renin inhibitor, via an enantiomerically pure ketolactone intermediate. Tetrahedron Lett 2000, 41, 51, 10085
  • 〖出处〗Tetrahedron Lett2000,41,(51):10085
  • 〖备注〗
  • 〖来源〗Drugs Fut
  • 〖合成路线〗
  • 〖标题〗Aliskiren Fumarate
  • 〖合成方法〗The intermediate gamma-butyrolactone (XXVIII) has been obtained as follows: Allylation of the imidazolidinone intermediate (V) with allyl bromide (XXI) and LiHMDS in THF gives the chiral intermediate (XXII), which by dihydroxylation and cleavage of the chiral auxiliary with OsO4 and NMMO in tert-butanol/acetone/water yields the lactone alcohol (XXIII). Oxidation of (XXIII) with NaIO4 and RuCl3 in CCl4/acetonitrile/water affords the carboxylic acid (XXIV), which by treatment with (COCl)2 in toluene provides the acyl chloride (XXV). Esterification of (XXV) with benzyl alcohol gives the corresponding benzyl ester as a diastereomeric mixture, from which the desired isomer (XXVI) is separated by flash chromatography. Hydrogenolysis of the benzyl ester (XXVI) with H2 over Pd/C in ethyl acetate yields the carboxylic acid (XXVII), which is treated with oxalyl chloride in toluene to afford the desired gamma-butyrolactone intermediate (XXVIII).
  • 〖作者〗Mealy, N.E.; Castaer, R.M.; Silvestre, J.S.; Castaer, J.
  • 〖参考〗Mealy, N.E.; Castaer, R.M.; Silvestre, J.S.; Castaer, J.; Aliskiren Fumarate. Drugs Fut 2001, 26, 12, 1139
  • 〖出处〗Drugs Fut2001,26,(12):1139
  • 〖备注〗Synthesis of Aliskiren Fumarate (EN:267580): Aliskiren can be obtained by several different ways: a) Alkylation of 3-hydroxy-4-methoxybenzyl alcohol (I) with 1-bromo-3-methoxypropane (II) gives ether (III). Subsequent conversion of benzyl alcohol (III) into bromide (IV) is carried out using bromotrimetylsilane. The chiral isovaleryloxazolidinone (V) is alkylated with bromide (IV) by means of LiHMDS to afford (VI), which is hydrolyzed to the (S)-2-aryl-2-isopropylpropionic acid (VII) by means of lithium peroxide. The reduction of acid (VII) to the corresponding alcohol with NaBH4/I2 reagent, followed by treatment with PPh3 and NBS, provides bromide (VIII). Alkylation of the chiral dimethoxydihydropyrazin (IX) with bromide (VIII) produces (X). Further hydrolysis of the pyrazine ring of (X) with HCl, followed by Boc protection of the resulting (S,S)-amino ester, yields compound (XI). Reduction of the ester group of (XI) with DIBAL gives aldehyde (XII). This compound is condensed with the Grignard reagent (XIII) to afford the diastereomeric mixture of amino alcohols (XIV). Treatment of mixture (XIV) with 2,2-dimethoxypropane (XV) and TsOH produces a mixture of oxazolidines, from which the required (S,S,S)-isomer (XVI) is isolated by flash chromatography. Hydrogenolitic deprotection of the benzyl ether of (XVI) gives alcohol (XVII) (Scheme 26758001a). This alcohol is oxidized to aldehyde with NMMO and tetrapropylammonium perruthenate (TPAP), and further oxidized to carboxylic acid (XVIII) with KMnO4 and tetrabutylammonium bromide (TBAB). Coupling of (XVIII) with aminoamide (XIX) by means of diethyl cyanophosphonate and TEA gives (XX). Finally, acid hydrolysis of the oxazolidine ring and Boc protecting groups of (XX) furnishes the corresponding amino alcohol, which is finally converted to the hemifumarate salt (1, 2) (Scheme 26758001b). b) The intermediate g-butyrolactone (XXVIII) has been obtained as follows: Allylation of the imidazolidinone intermediate (V) with allyl bromide (XXI) and LiHMDS in THF gives the chiral intermediate (XXII), which by dihydroxylation and cleavage of the chiral auxiliary with OsO4 and NMMO in tert-butanol/acetone/water yields the lactone alcohol (XXIII). Oxidation of (XXIII) with NaIO4 and RuCl3 in CCl4/acetonitrile/water affords the carboxylic acid (XXIV), which by treatment with (COCl)2 in toluene provides the acyl chloride (XXV). Esterification of (XXV) with benzyl alcohol gives the corresponding benzyl ester as a diastereomeric mixture, from which the desired isomer (XXVI) is separated by flash chromatography. Hydrogenolysis of the benzyl ester (XXVI) with H2 over Pd/C in ethyl acetate yields the carboxylic acid (XXVII), which is treated with oxalyl chloride in toluene to afford the desired g-butyrolactone intermediate (XXVIII) (3) (Scheme 26758001c). The reduction of the chiral propionic acid (VII) with NaBH4 in THF gives the primary alcohol (XXIX), which by reaction with SOCl2 and pyridine in CHCl3 yields the chloride (XXX). Condensation of (XXX) with the butyrolactone intermediate (XXVII) by means of Mg and dibromoethane affords the ketonic adduct (XXXI). Reduction of the exocyclic carbonyl group of (XXXI) with NaBH4 in THF/ methanol provides a 3:1 diastereomeric mixture of the desired chiral alcohol (XXXII) and its OH-epimer (XXXIII) that are separated by flash chromatography. Reaction of (XXXII) with MsCl and TEA, followed by treatment with NaN3, affords the azido derivative (XXXIV), which is condensed with 4-amino-3,3-dimethylbutyramide (XIX) by means of 2-hydroxypyridine and TEA to provide the adduct (XXXV). Finally, the azido group of (XXXV) is reduced with H2 over Pd/ in methanol to yield the target amino alcohol (3) (Scheme 26758001d). An extensive study on the stereoselective reduction of the ketonic adduct (XXXI) has been performed. No better diastereoselectivity than 3:1 has been obtained for the synthesis of the chiral alcohol (XXXII). However, excellent diastereoselectivity (97:3) has been obtained for the synthesis of its OH-epimer, alcohol (XXXIII), with K-selectride in THF, which could potentially provide access to the target amino alcohol via a double inversion protocol. c) Alternatively, the chiral phenylpropyl chloride (XXX) can also be prepared as follows: Reduction of the cinnamic acid (XXXVI) with H2 over Pd/C in ethyl acetate gives the phenylpropionic acid (XXXVII), which is treated with oxalyl chloride to yield the acyl chloride (XXXVIII). Condensation of (XXXVIII) with (+)-pseudoephedrine (XXXIX) by means of NaOH in toluene/water affords the chiral amide (XL), which is enantioselectively alkylated with 2-iodopropane (XLI) by means of LDA in THF to provide the adduct (XLII). Reduction of the amide group of (XLII) with BH3/NH3 in THF gives the already reported primary alcohol (XXIX), which is finally treated with POCl3 in hot toluene to afford the phenylpropyl chloride intermediate (XXX) (4) (Scheme 26758001e). d) The chiral azido intermediate (XXXIV) can also be obtained as follows: Reaction of (+)-pseudoephedrine isovaleramide (XLIII) with allyl bromide (XXI) by means of LDA in THF gives the pentenoyl amide (XLIV), which is treated with NBS in DME/water to yield the spiro compound (XLV). Hydrolysis of the bromomethyl group of (XLV) with tetrabutylammonium acetate and K2CO3 affords the carbinol (XLVI), which is oxidized to aldehyde (XLVII) with SO3/pyridine and TEA in DMSO/dichloro-methane. Condensation of (XLVII) with the propyl chloride intermediate (XXX) by means of Mg, dibromoethane and CeCl3 in refluxing THF provides the already reported chiral hydroxylactone (XXXII), which is treated first with 4-bromobenzenesulfonyl chloride and then with NaN3 to give the desired azido derivative (XXXIV) (4) (Scheme 26758001f). e) Alternatively, the chiral azido intermediate (XXXIV) can also be synthesized as follows: Alkylation of oxazolidinone (V) with 1-chloro-3-iodopropene (XLVIII) by means of LiHMDS in THF gives compound (XLIX), which is condensed with the magnesium derivative of the phenylpropyl chloride (XXX) to yield, after working up, amide (L). Bromination of (L) with NBS and phosphoric acid affords the bromolactone (LI), which by treatment with NaN3 in tripropylene glycol/water provides the azido derivative (XXXIV) (5) (Scheme 26758001g). f) Alternatively, the spiro aldehyde (XLVII) is treated with N-benzylhydroxylamine in dichloromethane to give nitrone (LII), which is submitted to a Grignard reaction with the magnesium derivative of intermediate (XXX) in THF to afford the adduct (LIII) as a mixture of epimers at the amino group. Simultaneous N-dehydroxylation and cleavage of the spiro function of (LIII) by means of Zn, Cu(OAc)2 in AcOH/water gives lactone (LIV), which is condensed with 3-amino-2,2-dimethylpropionamide (XIX) by means of TEA and 2-hydroxypyridine giving the adduct (LV). Finally, the benzylamino group of (LV) is removed with H2 over Pd/C in methanol to yield a mixture of two epimers at the amino group, from which aliskiren is separated (6) (Scheme 26758001h). Manufacturers Novartis Pharma AG (CH); licensed to Speedel Pharma AG (CH). References 1. Gschke, R., Maibaum, J.K., Schilling, W., Stutz, S., Rigollier, P, Yamaguchi, Y., Cohen, N.C., Herold, P. (Novartis AG). d-Amino-g-hydroxy-w-aryl alkanoic acid amides with enzyme especially renin inhibiting activities. EP 0678500, EP 0678503, JP 1996053434, JP 1996081430, US 5559111, US 5627182, US 5646143. 2. Wood, J., Yamaguchi, Y. Rigollier, P., Goeschke, R., Stutz, S., Maibaum, J. Structural modification of the P2' position of 2,7-dialkyl substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octane-carboxamides: Discovery of a potent non-peptide renin inhibitor active after once daily dosing in marmosets. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.230. 3. Reger, H., Stutz, S., Gschke, R., Spindler, F., Maibaum, J. A convergent synthesis approach towards CGP60536B, a non-peptide orally potent renin inhibitor, via an enantiomerically pure ketolactone intermediate. Tetrahedron Lett. 2000, 41: 10085-9. 4. Sandham, D.A., Taylor, R.J., Carey, J.S., Fssler, A. A convergent synthesis of the renin inhibitor CGP60536B. Tetrahedron Lett 2000, 41: 10091-4. 5. Herold, P., Stutz, S., Indolese, A. (Speedel Pharma Inc.). Production of N-substd. 2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoylamides. WO 0109079, WO 0109083. 6. Dondoni, A., De Lathauwer, G., Perrone, D. A convergent synthesis of the renin inhibitor SPP-100 using a nitrone intermediate. Tetrahedron Lett 2001, 42: 4819-23.
  • 〖来源〗Tetrahedron Lett
  • 〖合成路线〗
  • 〖标题〗A convergent synthesis approach towards CGP60536B, a non-peptide orally potent renin inhibitor, via an enantiomerically pure ketolactone intermediate
  • 〖合成方法〗The reduction of the chiral propionic acid (VII) with NaBH4 in THF gives the primary alcohol (XXIX), which by reaction with SOCl2 and pyridine in CHCl3 yields the chloride (XXX). Condensation of (XXX) with the butyrolactone intermediate (XXVII) by means of Mg and dibromoethane affords the ketonic adduct (XXXI). Reduction of the exocyclic carbonyl group of (XXXI) with NaBH4 in THF/ methanol provides a 3:1 diastereomeric mixture of the desired chiral alcohol (XXXII) and its OH-epimer (XXXIII) that are separated by flash chromatography. Reaction of (XXXII) with MsCl and TEA, followed by treatment with NaN3, affords the azido derivative (XXXIV), which is condensed with 4-amino-3,3-dimethylbutyramide (XIX) by means of 2-hydroxypyridine and TEA to provide the adduct (XXXV). Finally, the azido group of (XXXV) is reduced with H2 over Pd/ in MeOH to yield the target amino alcohol. An extensive study on the stereoselective reduction of the ketonic adduct (XXXI) has been performed. No better diastereoselectivity than 3:1 has been obtained for the synthesis of the chiral alcohol (XXXII). However, excellent diastereoselectivity (97:3) has been obtained for the synthesis of its OH-epimer, alcohol (XXXIII), with K-selectride in THF, which could potentially provide access to the target amino alcohol via a double inversion protocol.
  • 〖作者〗Reger, H.; Maibaum, J.; Stutz, S.; Spindler, F.; Gschke, R.
  • 〖参考〗Reger, H.; Maibaum, J.; Stutz, S.; Spindler, F.; Gschke, R.; A convergent synthesis approach towards CGP60536B, a non-peptide orally potent renin inhibitor, via an enantiomerically pure ketolactone intermediate. Tetrahedron Lett 2000, 41, 51, 10085
  • 〖出处〗Tetrahedron Lett2000,41,(51):10085
  • 〖备注〗
  • 〖来源〗Drugs Fut
  • 〖合成路线〗
  • 〖标题〗Aliskiren Fumarate
  • 〖合成方法〗The reduction of the chiral propionic acid (VII) with NaBH4 in THF gives the primary alcohol (XXIX), which by reaction with SOCl2 and pyridine in CHCl3 yields the chloride (XXX). Condensation of (XXX) with the butyrolactone intermediate (XXVII) by means of Mg and dibromoethane affords the ketonic adduct (XXXI). Reduction of the exocyclic carbonyl group of (XXXI) with NaBH4 in THF/ methanol provides a 3:1 diastereomeric mixture of the desired chiral alcohol (XXXII) and its OH-epimer (XXXIII) that are separated by flash chromatography. Reaction of (XXXII) with MsCl and TEA, followed by treatment with NaN3, affords the azido derivative (XXXIV), which is condensed with 4-amino-3,3-dimethylbutyramide (XIX) by means of 2-hydroxypyridine and TEA to provide the adduct (XXXV). Finally, the azido group of (XXXV) is reduced with H2 over Pd/ in MeOH to yield the target amino alcohol. An extensive study on the stereoselective reduction of the ketonic adduct (XXXI) has been performed. No better diastereoselectivity than 3:1 has been obtained for the synthesis of the chiral alcohol (XXXII). However, excellent diastereoselectivity (97:3) has been obtained for the synthesis of its OH-epimer, alcohol (XXXIII), with K-selectride in THF, which could potentially provide access to the target amino alcohol via a double inversion protocol.
  • 〖作者〗Mealy, N.E.; Castaer, R.M.; Silvestre, J.S.; Castaer, J.
  • 〖参考〗Mealy, N.E.; Castaer, R.M.; Silvestre, J.S.; Castaer, J.; Aliskiren Fumarate. Drugs Fut 2001, 26, 12, 1139
  • 〖出处〗Drugs Fut2001,26,(12):1139
  • 〖备注〗Synthesis of Aliskiren Fumarate (EN:267580): Aliskiren can be obtained by several different ways: a) Alkylation of 3-hydroxy-4-methoxybenzyl alcohol (I) with 1-bromo-3-methoxypropane (II) gives ether (III). Subsequent conversion of benzyl alcohol (III) into bromide (IV) is carried out using bromotrimetylsilane. The chiral isovaleryloxazolidinone (V) is alkylated with bromide (IV) by means of LiHMDS to afford (VI), which is hydrolyzed to the (S)-2-aryl-2-isopropylpropionic acid (VII) by means of lithium peroxide. The reduction of acid (VII) to the corresponding alcohol with NaBH4/I2 reagent, followed by treatment with PPh3 and NBS, provides bromide (VIII). Alkylation of the chiral dimethoxydihydropyrazin (IX) with bromide (VIII) produces (X). Further hydrolysis of the pyrazine ring of (X) with HCl, followed by Boc protection of the resulting (S,S)-amino ester, yields compound (XI). Reduction of the ester group of (XI) with DIBAL gives aldehyde (XII). This compound is condensed with the Grignard reagent (XIII) to afford the diastereomeric mixture of amino alcohols (XIV). Treatment of mixture (XIV) with 2,2-dimethoxypropane (XV) and TsOH produces a mixture of oxazolidines, from which the required (S,S,S)-isomer (XVI) is isolated by flash chromatography. Hydrogenolitic deprotection of the benzyl ether of (XVI) gives alcohol (XVII) (Scheme 26758001a). This alcohol is oxidized to aldehyde with NMMO and tetrapropylammonium perruthenate (TPAP), and further oxidized to carboxylic acid (XVIII) with KMnO4 and tetrabutylammonium bromide (TBAB). Coupling of (XVIII) with aminoamide (XIX) by means of diethyl cyanophosphonate and TEA gives (XX). Finally, acid hydrolysis of the oxazolidine ring and Boc protecting groups of (XX) furnishes the corresponding amino alcohol, which is finally converted to the hemifumarate salt (1, 2) (Scheme 26758001b). b) The intermediate g-butyrolactone (XXVIII) has been obtained as follows: Allylation of the imidazolidinone intermediate (V) with allyl bromide (XXI) and LiHMDS in THF gives the chiral intermediate (XXII), which by dihydroxylation and cleavage of the chiral auxiliary with OsO4 and NMMO in tert-butanol/acetone/water yields the lactone alcohol (XXIII). Oxidation of (XXIII) with NaIO4 and RuCl3 in CCl4/acetonitrile/water affords the carboxylic acid (XXIV), which by treatment with (COCl)2 in toluene provides the acyl chloride (XXV). Esterification of (XXV) with benzyl alcohol gives the corresponding benzyl ester as a diastereomeric mixture, from which the desired isomer (XXVI) is separated by flash chromatography. Hydrogenolysis of the benzyl ester (XXVI) with H2 over Pd/C in ethyl acetate yields the carboxylic acid (XXVII), which is treated with oxalyl chloride in toluene to afford the desired g-butyrolactone intermediate (XXVIII) (3) (Scheme 26758001c). The reduction of the chiral propionic acid (VII) with NaBH4 in THF gives the primary alcohol (XXIX), which by reaction with SOCl2 and pyridine in CHCl3 yields the chloride (XXX). Condensation of (XXX) with the butyrolactone intermediate (XXVII) by means of Mg and dibromoethane affords the ketonic adduct (XXXI). Reduction of the exocyclic carbonyl group of (XXXI) with NaBH4 in THF/ methanol provides a 3:1 diastereomeric mixture of the desired chiral alcohol (XXXII) and its OH-epimer (XXXIII) that are separated by flash chromatography. Reaction of (XXXII) with MsCl and TEA, followed by treatment with NaN3, affords the azido derivative (XXXIV), which is condensed with 4-amino-3,3-dimethylbutyramide (XIX) by means of 2-hydroxypyridine and TEA to provide the adduct (XXXV). Finally, the azido group of (XXXV) is reduced with H2 over Pd/ in methanol to yield the target amino alcohol (3) (Scheme 26758001d). An extensive study on the stereoselective reduction of the ketonic adduct (XXXI) has been performed. No better diastereoselectivity than 3:1 has been obtained for the synthesis of the chiral alcohol (XXXII). However, excellent diastereoselectivity (97:3) has been obtained for the synthesis of its OH-epimer, alcohol (XXXIII), with K-selectride in THF, which could potentially provide access to the target amino alcohol via a double inversion protocol. c) Alternatively, the chiral phenylpropyl chloride (XXX) can also be prepared as follows: Reduction of the cinnamic acid (XXXVI) with H2 over Pd/C in ethyl acetate gives the phenylpropionic acid (XXXVII), which is treated with oxalyl chloride to yield the acyl chloride (XXXVIII). Condensation of (XXXVIII) with (+)-pseudoephedrine (XXXIX) by means of NaOH in toluene/water affords the chiral amide (XL), which is enantioselectively alkylated with 2-iodopropane (XLI) by means of LDA in THF to provide the adduct (XLII). Reduction of the amide group of (XLII) with BH3/NH3 in THF gives the already reported primary alcohol (XXIX), which is finally treated with POCl3 in hot toluene to afford the phenylpropyl chloride intermediate (XXX) (4) (Scheme 26758001e). d) The chiral azido intermediate (XXXIV) can also be obtained as follows: Reaction of (+)-pseudoephedrine isovaleramide (XLIII) with allyl bromide (XXI) by means of LDA in THF gives the pentenoyl amide (XLIV), which is treated with NBS in DME/water to yield the spiro compound (XLV). Hydrolysis of the bromomethyl group of (XLV) with tetrabutylammonium acetate and K2CO3 affords the carbinol (XLVI), which is oxidized to aldehyde (XLVII) with SO3/pyridine and TEA in DMSO/dichloro-methane. Condensation of (XLVII) with the propyl chloride intermediate (XXX) by means of Mg, dibromoethane and CeCl3 in refluxing THF provides the already reported chiral hydroxylactone (XXXII), which is treated first with 4-bromobenzenesulfonyl chloride and then with NaN3 to give the desired azido derivative (XXXIV) (4) (Scheme 26758001f). e) Alternatively, the chiral azido intermediate (XXXIV) can also be synthesized as follows: Alkylation of oxazolidinone (V) with 1-chloro-3-iodopropene (XLVIII) by means of LiHMDS in THF gives compound (XLIX), which is condensed with the magnesium derivative of the phenylpropyl chloride (XXX) to yield, after working up, amide (L). Bromination of (L) with NBS and phosphoric acid affords the bromolactone (LI), which by treatment with NaN3 in tripropylene glycol/water provides the azido derivative (XXXIV) (5) (Scheme 26758001g). f) Alternatively, the spiro aldehyde (XLVII) is treated with N-benzylhydroxylamine in dichloromethane to give nitrone (LII), which is submitted to a Grignard reaction with the magnesium derivative of intermediate (XXX) in THF to afford the adduct (LIII) as a mixture of epimers at the amino group. Simultaneous N-dehydroxylation and cleavage of the spiro function of (LIII) by means of Zn, Cu(OAc)2 in AcOH/water gives lactone (LIV), which is condensed with 3-amino-2,2-dimethylpropionamide (XIX) by means of TEA and 2-hydroxypyridine giving the adduct (LV). Finally, the benzylamino group of (LV) is removed with H2 over Pd/C in methanol to yield a mixture of two epimers at the amino group, from which aliskiren is separated (6) (Scheme 26758001h). Manufacturers Novartis Pharma AG (CH); licensed to Speedel Pharma AG (CH). References 1. Gschke, R., Maibaum, J.K., Schilling, W., Stutz, S., Rigollier, P, Yamaguchi, Y., Cohen, N.C., Herold, P. (Novartis AG). d-Amino-g-hydroxy-w-aryl alkanoic acid amides with enzyme especially renin inhibiting activities. EP 0678500, EP 0678503, JP 1996053434, JP 1996081430, US 5559111, US 5627182, US 5646143. 2. Wood, J., Yamaguchi, Y. Rigollier, P., Goeschke, R., Stutz, S., Maibaum, J. Structural modification of the P2' position of 2,7-dialkyl substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octane-carboxamides: Discovery of a potent non-peptide renin inhibitor active after once daily dosing in marmosets. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.230. 3. Reger, H., Stutz, S., Gschke, R., Spindler, F., Maibaum, J. A convergent synthesis approach towards CGP60536B, a non-peptide orally potent renin inhibitor, via an enantiomerically pure ketolactone intermediate. Tetrahedron Lett. 2000, 41: 10085-9. 4. Sandham, D.A., Taylor, R.J., Carey, J.S., Fssler, A. A convergent synthesis of the renin inhibitor CGP60536B. Tetrahedron Lett 2000, 41: 10091-4. 5. Herold, P., Stutz, S., Indolese, A. (Speedel Pharma Inc.). Production of N-substd. 2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoylamides. WO 0109079, WO 0109083. 6. Dondoni, A., De Lathauwer, G., Perrone, D. A convergent synthesis of the renin inhibitor SPP-100 using a nitrone intermediate. Tetrahedron Lett 2001, 42: 4819-23.
  • 〖来源〗Tetrahedron Lett
  • 〖合成路线〗
  • 〖标题〗A convergent synthesis of the renin inhibitor CGP60536B
  • 〖合成方法〗Alternatively, the chiral phenylpropyl chloride (XXX) can also be prepared as follows: Reduction of the cinnamic acid (XXXVI) with H2 over Pd/C in ethyl acetate gives the phenylpropionic acid (XXXVII), which is treated with oxalyl chloride to yield the acyl chloride (XXXVIII). Condensation of (XXXVIII) with (+)-pseudoephedrine (XXXIX) by means of NaOH in toluene/water affords the chiral amide (XL), which is enantioselectively alkylated with 2-iodopropane (XLI) by means of LDA in THF to provide the adduct (XLII). Reduction of the amide group of (XLII) with BH3/NH3 in THF gives the already reported primary alcohol (XXIX), which is finally treated with POCl3 in hot toluene to afford the phenylpropyl chloride intermediate (XXX).
  • 〖作者〗Carey, J.S.; Sandham, D.A.; Taylor, R.J.; Fssler, A.
  • 〖参考〗Carey, J.S.; Sandham, D.A.; Taylor, R.J.; Fssler, A.; A convergent synthesis of the renin inhibitor CGP60536B. Tetrahedron Lett 2000, 41, 51, 10091
  • 〖出处〗Tetrahedron Lett2000,41,(51):10091
  • 〖备注〗
  • 〖来源〗Drugs Fut
  • 〖合成路线〗
  • 〖标题〗Aliskiren Fumarate
  • 〖合成方法〗Alternatively, the chiral phenylpropyl chloride (XXX) can also be prepared as follows: Reduction of the cinnamic acid (XXXVI) with H2 over Pd/C in ethyl acetate gives the phenylpropionic acid (XXXVII), which is treated with oxalyl chloride to yield the acyl chloride (XXXVIII). Condensation of (XXXVIII) with (+)-pseudoephedrine (XXXIX) by means of NaOH in toluene/water affords the chiral amide (XL), which is enantioselectively alkylated with 2-iodopropane (XLI) by means of LDA in THF to provide the adduct (XLII). Reduction of the amide group of (XLII) with BH3/NH3 in THF gives the already reported primary alcohol (XXIX), which is finally treated with POCl3 in hot toluene to afford the phenylpropyl chloride intermediate (XXX).
  • 〖作者〗Mealy, N.E.; Castaer, R.M.; Silvestre, J.S.; Castaer, J.
  • 〖参考〗Mealy, N.E.; Castaer, R.M.; Silvestre, J.S.; Castaer, J.; Aliskiren Fumarate. Drugs Fut 2001, 26, 12, 1139
  • 〖出处〗Drugs Fut2001,26,(12):1139
  • 〖备注〗Synthesis of Aliskiren Fumarate (EN:267580): Aliskiren can be obtained by several different ways: a) Alkylation of 3-hydroxy-4-methoxybenzyl alcohol (I) with 1-bromo-3-methoxypropane (II) gives ether (III). Subsequent conversion of benzyl alcohol (III) into bromide (IV) is carried out using bromotrimetylsilane. The chiral isovaleryloxazolidinone (V) is alkylated with bromide (IV) by means of LiHMDS to afford (VI), which is hydrolyzed to the (S)-2-aryl-2-isopropylpropionic acid (VII) by means of lithium peroxide. The reduction of acid (VII) to the corresponding alcohol with NaBH4/I2 reagent, followed by treatment with PPh3 and NBS, provides bromide (VIII). Alkylation of the chiral dimethoxydihydropyrazin (IX) with bromide (VIII) produces (X). Further hydrolysis of the pyrazine ring of (X) with HCl, followed by Boc protection of the resulting (S,S)-amino ester, yields compound (XI). Reduction of the ester group of (XI) with DIBAL gives aldehyde (XII). This compound is condensed with the Grignard reagent (XIII) to afford the diastereomeric mixture of amino alcohols (XIV). Treatment of mixture (XIV) with 2,2-dimethoxypropane (XV) and TsOH produces a mixture of oxazolidines, from which the required (S,S,S)-isomer (XVI) is isolated by flash chromatography. Hydrogenolitic deprotection of the benzyl ether of (XVI) gives alcohol (XVII) (Scheme 26758001a). This alcohol is oxidized to aldehyde with NMMO and tetrapropylammonium perruthenate (TPAP), and further oxidized to carboxylic acid (XVIII) with KMnO4 and tetrabutylammonium bromide (TBAB). Coupling of (XVIII) with aminoamide (XIX) by means of diethyl cyanophosphonate and TEA gives (XX). Finally, acid hydrolysis of the oxazolidine ring and Boc protecting groups of (XX) furnishes the corresponding amino alcohol, which is finally converted to the hemifumarate salt (1, 2) (Scheme 26758001b). b) The intermediate g-butyrolactone (XXVIII) has been obtained as follows: Allylation of the imidazolidinone intermediate (V) with allyl bromide (XXI) and LiHMDS in THF gives the chiral intermediate (XXII), which by dihydroxylation and cleavage of the chiral auxiliary with OsO4 and NMMO in tert-butanol/acetone/water yields the lactone alcohol (XXIII). Oxidation of (XXIII) with NaIO4 and RuCl3 in CCl4/acetonitrile/water affords the carboxylic acid (XXIV), which by treatment with (COCl)2 in toluene provides the acyl chloride (XXV). Esterification of (XXV) with benzyl alcohol gives the corresponding benzyl ester as a diastereomeric mixture, from which the desired isomer (XXVI) is separated by flash chromatography. Hydrogenolysis of the benzyl ester (XXVI) with H2 over Pd/C in ethyl acetate yields the carboxylic acid (XXVII), which is treated with oxalyl chloride in toluene to afford the desired g-butyrolactone intermediate (XXVIII) (3) (Scheme 26758001c). The reduction of the chiral propionic acid (VII) with NaBH4 in THF gives the primary alcohol (XXIX), which by reaction with SOCl2 and pyridine in CHCl3 yields the chloride (XXX). Condensation of (XXX) with the butyrolactone intermediate (XXVII) by means of Mg and dibromoethane affords the ketonic adduct (XXXI). Reduction of the exocyclic carbonyl group of (XXXI) with NaBH4 in THF/ methanol provides a 3:1 diastereomeric mixture of the desired chiral alcohol (XXXII) and its OH-epimer (XXXIII) that are separated by flash chromatography. Reaction of (XXXII) with MsCl and TEA, followed by treatment with NaN3, affords the azido derivative (XXXIV), which is condensed with 4-amino-3,3-dimethylbutyramide (XIX) by means of 2-hydroxypyridine and TEA to provide the adduct (XXXV). Finally, the azido group of (XXXV) is reduced with H2 over Pd/ in methanol to yield the target amino alcohol (3) (Scheme 26758001d). An extensive study on the stereoselective reduction of the ketonic adduct (XXXI) has been performed. No better diastereoselectivity than 3:1 has been obtained for the synthesis of the chiral alcohol (XXXII). However, excellent diastereoselectivity (97:3) has been obtained for the synthesis of its OH-epimer, alcohol (XXXIII), with K-selectride in THF, which could potentially provide access to the target amino alcohol via a double inversion protocol. c) Alternatively, the chiral phenylpropyl chloride (XXX) can also be prepared as follows: Reduction of the cinnamic acid (XXXVI) with H2 over Pd/C in ethyl acetate gives the phenylpropionic acid (XXXVII), which is treated with oxalyl chloride to yield the acyl chloride (XXXVIII). Condensation of (XXXVIII) with (+)-pseudoephedrine (XXXIX) by means of NaOH in toluene/water affords the chiral amide (XL), which is enantioselectively alkylated with 2-iodopropane (XLI) by means of LDA in THF to provide the adduct (XLII). Reduction of the amide group of (XLII) with BH3/NH3 in THF gives the already reported primary alcohol (XXIX), which is finally treated with POCl3 in hot toluene to afford the phenylpropyl chloride intermediate (XXX) (4) (Scheme 26758001e). d) The chiral azido intermediate (XXXIV) can also be obtained as follows: Reaction of (+)-pseudoephedrine isovaleramide (XLIII) with allyl bromide (XXI) by means of LDA in THF gives the pentenoyl amide (XLIV), which is treated with NBS in DME/water to yield the spiro compound (XLV). Hydrolysis of the bromomethyl group of (XLV) with tetrabutylammonium acetate and K2CO3 affords the carbinol (XLVI), which is oxidized to aldehyde (XLVII) with SO3/pyridine and TEA in DMSO/dichloro-methane. Condensation of (XLVII) with the propyl chloride intermediate (XXX) by means of Mg, dibromoethane and CeCl3 in refluxing THF provides the already reported chiral hydroxylactone (XXXII), which is treated first with 4-bromobenzenesulfonyl chloride and then with NaN3 to give the desired azido derivative (XXXIV) (4) (Scheme 26758001f). e) Alternatively, the chiral azido intermediate (XXXIV) can also be synthesized as follows: Alkylation of oxazolidinone (V) with 1-chloro-3-iodopropene (XLVIII) by means of LiHMDS in THF gives compound (XLIX), which is condensed with the magnesium derivative of the phenylpropyl chloride (XXX) to yield, after working up, amide (L). Bromination of (L) with NBS and phosphoric acid affords the bromolactone (LI), which by treatment with NaN3 in tripropylene glycol/water provides the azido derivative (XXXIV) (5) (Scheme 26758001g). f) Alternatively, the spiro aldehyde (XLVII) is treated with N-benzylhydroxylamine in dichloromethane to give nitrone (LII), which is submitted to a Grignard reaction with the magnesium derivative of intermediate (XXX) in THF to afford the adduct (LIII) as a mixture of epimers at the amino group. Simultaneous N-dehydroxylation and cleavage of the spiro function of (LIII) by means of Zn, Cu(OAc)2 in AcOH/water gives lactone (LIV), which is condensed with 3-amino-2,2-dimethylpropionamide (XIX) by means of TEA and 2-hydroxypyridine giving the adduct (LV). Finally, the benzylamino group of (LV) is removed with H2 over Pd/C in methanol to yield a mixture of two epimers at the amino group, from which aliskiren is separated (6) (Scheme 26758001h). Manufacturers Novartis Pharma AG (CH); licensed to Speedel Pharma AG (CH). References 1. Gschke, R., Maibaum, J.K., Schilling, W., Stutz, S., Rigollier, P, Yamaguchi, Y., Cohen, N.C., Herold, P. (Novartis AG). d-Amino-g-hydroxy-w-aryl alkanoic acid amides with enzyme especially renin inhibiting activities. EP 0678500, EP 0678503, JP 1996053434, JP 1996081430, US 5559111, US 5627182, US 5646143. 2. Wood, J., Yamaguchi, Y. Rigollier, P., Goeschke, R., Stutz, S., Maibaum, J. Structural modification of the P2' position of 2,7-dialkyl substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octane-carboxamides: Discovery of a potent non-peptide renin inhibitor active after once daily dosing in marmosets. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.230. 3. Reger, H., Stutz, S., Gschke, R., Spindler, F., Maibaum, J. A convergent synthesis approach towards CGP60536B, a non-peptide orally potent renin inhibitor, via an enantiomerically pure ketolactone intermediate. Tetrahedron Lett. 2000, 41: 10085-9. 4. Sandham, D.A., Taylor, R.J., Carey, J.S., Fssler, A. A convergent synthesis of the renin inhibitor CGP60536B. Tetrahedron Lett 2000, 41: 10091-4. 5. Herold, P., Stutz, S., Indolese, A. (Speedel Pharma Inc.). Production of N-substd. 2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoylamides. WO 0109079, WO 0109083. 6. Dondoni, A., De Lathauwer, G., Perrone, D. A convergent synthesis of the renin inhibitor SPP-100 using a nitrone intermediate. Tetrahedron Lett 2001, 42: 4819-23.
  • 〖来源〗Tetrahedron Lett
  • 〖合成路线〗
  • 〖标题〗A convergent synthesis of the renin inhibitor CGP60536B
  • 〖合成方法〗The chiral azido intermediate (XXXIV) can also be obtained as follows: Reaction of (+)-pseudoephedrine isovaleramide (XLIII) with allyl bromide (XXI) by means of LDA in THF gives the pentenoyl amide (XLIV), which is treated with NBS in DME/water to yield the spiro compound (XLV). Hydrolysis of the bromomethyl group of (XLV) with tetrabutylammonium acetate and K2CO3 affords the carbinol (XLVI), which is oxidized to aldehyde (XLVII) with SO3/pyridine and TEA in DMSO/dichloromethane. Condensation of (XLVII) with the propyl chloride intermediate (XXX) by means of Mg, dibromoethane and CeCl3 in refluxing THF provides the already reported chiral hydroxylactone (XXXII), which is treated first with 4-bromobenzenesulfonyl chloride and then with NaN3 to give the desired azido derivative (XXXIV).
  • 〖作者〗Carey, J.S.; Sandham, D.A.; Taylor, R.J.; Fssler, A.
  • 〖参考〗Carey, J.S.; Sandham, D.A.; Taylor, R.J.; Fssler, A.; A convergent synthesis of the renin inhibitor CGP60536B. Tetrahedron Lett 2000, 41, 51, 10091
  • 〖出处〗Tetrahedron Lett2000,41,(51):10091
  • 〖备注〗
  • 〖来源〗Drugs Fut
  • 〖合成路线〗
  • 〖标题〗Aliskiren Fumarate
  • 〖合成方法〗The chiral azido intermediate (XXXIV) can also be obtained as follows: Reaction of (+)-pseudoephedrine isovaleramide (XLIII) with allyl bromide (XXI) by means of LDA in THF gives the pentenoyl amide (XLIV), which is treated with NBS in DME/water to yield the spiro compound (XLV). Hydrolysis of the bromomethyl group of (XLV) with tetrabutylammonium acetate and K2CO3 affords the carbinol (XLVI), which is oxidized to aldehyde (XLVII) with SO3/pyridine and TEA in DMSO/dichloromethane. Condensation of (XLVII) with the propyl chloride intermediate (XXX) by means of Mg, dibromoethane and CeCl3 in refluxing THF provides the already reported chiral hydroxylactone (XXXII), which is treated first with 4-bromobenzenesulfonyl chloride and then with NaN3 to give the desired azido derivative (XXXIV).
  • 〖作者〗Mealy, N.E.; Castaer, R.M.; Silvestre, J.S.; Castaer, J.
  • 〖参考〗Mealy, N.E.; Castaer, R.M.; Silvestre, J.S.; Castaer, J.; Aliskiren Fumarate. Drugs Fut 2001, 26, 12, 1139
  • 〖出处〗Drugs Fut2001,26,(12):1139
  • 〖备注〗Synthesis of Aliskiren Fumarate (EN:267580): Aliskiren can be obtained by several different ways: a) Alkylation of 3-hydroxy-4-methoxybenzyl alcohol (I) with 1-bromo-3-methoxypropane (II) gives ether (III). Subsequent conversion of benzyl alcohol (III) into bromide (IV) is carried out using bromotrimetylsilane. The chiral isovaleryloxazolidinone (V) is alkylated with bromide (IV) by means of LiHMDS to afford (VI), which is hydrolyzed to the (S)-2-aryl-2-isopropylpropionic acid (VII) by means of lithium peroxide. The reduction of acid (VII) to the corresponding alcohol with NaBH4/I2 reagent, followed by treatment with PPh3 and NBS, provides bromide (VIII). Alkylation of the chiral dimethoxydihydropyrazin (IX) with bromide (VIII) produces (X). Further hydrolysis of the pyrazine ring of (X) with HCl, followed by Boc protection of the resulting (S,S)-amino ester, yields compound (XI). Reduction of the ester group of (XI) with DIBAL gives aldehyde (XII). This compound is condensed with the Grignard reagent (XIII) to afford the diastereomeric mixture of amino alcohols (XIV). Treatment of mixture (XIV) with 2,2-dimethoxypropane (XV) and TsOH produces a mixture of oxazolidines, from which the required (S,S,S)-isomer (XVI) is isolated by flash chromatography. Hydrogenolitic deprotection of the benzyl ether of (XVI) gives alcohol (XVII) (Scheme 26758001a). This alcohol is oxidized to aldehyde with NMMO and tetrapropylammonium perruthenate (TPAP), and further oxidized to carboxylic acid (XVIII) with KMnO4 and tetrabutylammonium bromide (TBAB). Coupling of (XVIII) with aminoamide (XIX) by means of diethyl cyanophosphonate and TEA gives (XX). Finally, acid hydrolysis of the oxazolidine ring and Boc protecting groups of (XX) furnishes the corresponding amino alcohol, which is finally converted to the hemifumarate salt (1, 2) (Scheme 26758001b). b) The intermediate g-butyrolactone (XXVIII) has been obtained as follows: Allylation of the imidazolidinone intermediate (V) with allyl bromide (XXI) and LiHMDS in THF gives the chiral intermediate (XXII), which by dihydroxylation and cleavage of the chiral auxiliary with OsO4 and NMMO in tert-butanol/acetone/water yields the lactone alcohol (XXIII). Oxidation of (XXIII) with NaIO4 and RuCl3 in CCl4/acetonitrile/water affords the carboxylic acid (XXIV), which by treatment with (COCl)2 in toluene provides the acyl chloride (XXV). Esterification of (XXV) with benzyl alcohol gives the corresponding benzyl ester as a diastereomeric mixture, from which the desired isomer (XXVI) is separated by flash chromatography. Hydrogenolysis of the benzyl ester (XXVI) with H2 over Pd/C in ethyl acetate yields the carboxylic acid (XXVII), which is treated with oxalyl chloride in toluene to afford the desired g-butyrolactone intermediate (XXVIII) (3) (Scheme 26758001c). The reduction of the chiral propionic acid (VII) with NaBH4 in THF gives the primary alcohol (XXIX), which by reaction with SOCl2 and pyridine in CHCl3 yields the chloride (XXX). Condensation of (XXX) with the butyrolactone intermediate (XXVII) by means of Mg and dibromoethane affords the ketonic adduct (XXXI). Reduction of the exocyclic carbonyl group of (XXXI) with NaBH4 in THF/ methanol provides a 3:1 diastereomeric mixture of the desired chiral alcohol (XXXII) and its OH-epimer (XXXIII) that are separated by flash chromatography. Reaction of (XXXII) with MsCl and TEA, followed by treatment with NaN3, affords the azido derivative (XXXIV), which is condensed with 4-amino-3,3-dimethylbutyramide (XIX) by means of 2-hydroxypyridine and TEA to provide the adduct (XXXV). Finally, the azido group of (XXXV) is reduced with H2 over Pd/ in methanol to yield the target amino alcohol (3) (Scheme 26758001d). An extensive study on the stereoselective reduction of the ketonic adduct (XXXI) has been performed. No better diastereoselectivity than 3:1 has been obtained for the synthesis of the chiral alcohol (XXXII). However, excellent diastereoselectivity (97:3) has been obtained for the synthesis of its OH-epimer, alcohol (XXXIII), with K-selectride in THF, which could potentially provide access to the target amino alcohol via a double inversion protocol. c) Alternatively, the chiral phenylpropyl chloride (XXX) can also be prepared as follows: Reduction of the cinnamic acid (XXXVI) with H2 over Pd/C in ethyl acetate gives the phenylpropionic acid (XXXVII), which is treated with oxalyl chloride to yield the acyl chloride (XXXVIII). Condensation of (XXXVIII) with (+)-pseudoephedrine (XXXIX) by means of NaOH in toluene/water affords the chiral amide (XL), which is enantioselectively alkylated with 2-iodopropane (XLI) by means of LDA in THF to provide the adduct (XLII). Reduction of the amide group of (XLII) with BH3/NH3 in THF gives the already reported primary alcohol (XXIX), which is finally treated with POCl3 in hot toluene to afford the phenylpropyl chloride intermediate (XXX) (4) (Scheme 26758001e). d) The chiral azido intermediate (XXXIV) can also be obtained as follows: Reaction of (+)-pseudoephedrine isovaleramide (XLIII) with allyl bromide (XXI) by means of LDA in THF gives the pentenoyl amide (XLIV), which is treated with NBS in DME/water to yield the spiro compound (XLV). Hydrolysis of the bromomethyl group of (XLV) with tetrabutylammonium acetate and K2CO3 affords the carbinol (XLVI), which is oxidized to aldehyde (XLVII) with SO3/pyridine and TEA in DMSO/dichloro-methane. Condensation of (XLVII) with the propyl chloride intermediate (XXX) by means of Mg, dibromoethane and CeCl3 in refluxing THF provides the already reported chiral hydroxylactone (XXXII), which is treated first with 4-bromobenzenesulfonyl chloride and then with NaN3 to give the desired azido derivative (XXXIV) (4) (Scheme 26758001f). e) Alternatively, the chiral azido intermediate (XXXIV) can also be synthesized as follows: Alkylation of oxazolidinone (V) with 1-chloro-3-iodopropene (XLVIII) by means of LiHMDS in THF gives compound (XLIX), which is condensed with the magnesium derivative of the phenylpropyl chloride (XXX) to yield, after working up, amide (L). Bromination of (L) with NBS and phosphoric acid affords the bromolactone (LI), which by treatment with NaN3 in tripropylene glycol/water provides the azido derivative (XXXIV) (5) (Scheme 26758001g). f) Alternatively, the spiro aldehyde (XLVII) is treated with N-benzylhydroxylamine in dichloromethane to give nitrone (LII), which is submitted to a Grignard reaction with the magnesium derivative of intermediate (XXX) in THF to afford the adduct (LIII) as a mixture of epimers at the amino group. Simultaneous N-dehydroxylation and cleavage of the spiro function of (LIII) by means of Zn, Cu(OAc)2 in AcOH/water gives lactone (LIV), which is condensed with 3-amino-2,2-dimethylpropionamide (XIX) by means of TEA and 2-hydroxypyridine giving the adduct (LV). Finally, the benzylamino group of (LV) is removed with H2 over Pd/C in methanol to yield a mixture of two epimers at the amino group, from which aliskiren is separated (6) (Scheme 26758001h). Manufacturers Novartis Pharma AG (CH); licensed to Speedel Pharma AG (CH). References 1. Gschke, R., Maibaum, J.K., Schilling, W., Stutz, S., Rigollier, P, Yamaguchi, Y., Cohen, N.C., Herold, P. (Novartis AG). d-Amino-g-hydroxy-w-aryl alkanoic acid amides with enzyme especially renin inhibiting activities. EP 0678500, EP 0678503, JP 1996053434, JP 1996081430, US 5559111, US 5627182, US 5646143. 2. Wood, J., Yamaguchi, Y. Rigollier, P., Goeschke, R., Stutz, S., Maibaum, J. Structural modification of the P2' position of 2,7-dialkyl substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octane-carboxamides: Discovery of a potent non-peptide renin inhibitor active after once daily dosing in marmosets. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.230. 3. Reger, H., Stutz, S., Gschke, R., Spindler, F., Maibaum, J. A convergent synthesis approach towards CGP60536B, a non-peptide orally potent renin inhibitor, via an enantiomerically pure ketolactone intermediate. Tetrahedron Lett. 2000, 41: 10085-9. 4. Sandham, D.A., Taylor, R.J., Carey, J.S., Fssler, A. A convergent synthesis of the renin inhibitor CGP60536B. Tetrahedron Lett 2000, 41: 10091-4. 5. Herold, P., Stutz, S., Indolese, A. (Speedel Pharma Inc.). Production of N-substd. 2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoylamides. WO 0109079, WO 0109083. 6. Dondoni, A., De Lathauwer, G., Perrone, D. A convergent synthesis of the renin inhibitor SPP-100 using a nitrone intermediate. Tetrahedron Lett 2001, 42: 4819-23.
  • 〖来源〗Drugs Fut
  • 〖合成路线〗
  • 〖标题〗Aliskiren Fumarate
  • 〖合成方法〗Alternatively, the chiral azido intermediate (XXXIV) can also be synthesized as follows: Alkylation of oxazolidinone (V) with 1-chloro-3-iodopropene (XLVIII) by means of LiHMDS in THF gives compound (XLIX), which is condensed with the magnesium derivative of the phenylpropyl chloride (XXX) to yield, after working up, amide (L). Bromination of (L) with NBS and phosphoric acid affords the bromolactone (LI), which by treatment with NaN3 in tripropylene glycol/water provides the azido derivative (XXXIV).
  • 〖作者〗Mealy, N.E.; Castaer, R.M.; Silvestre, J.S.; Castaer, J.
  • 〖参考〗Mealy, N.E.; Castaer, R.M.; Silvestre, J.S.; Castaer, J.; Aliskiren Fumarate. Drugs Fut 2001, 26, 12, 1139
  • 〖出处〗Drugs Fut2001,26,(12):1139
  • 〖备注〗Synthesis of Aliskiren Fumarate (EN:267580): Aliskiren can be obtained by several different ways: a) Alkylation of 3-hydroxy-4-methoxybenzyl alcohol (I) with 1-bromo-3-methoxypropane (II) gives ether (III). Subsequent conversion of benzyl alcohol (III) into bromide (IV) is carried out using bromotrimetylsilane. The chiral isovaleryloxazolidinone (V) is alkylated with bromide (IV) by means of LiHMDS to afford (VI), which is hydrolyzed to the (S)-2-aryl-2-isopropylpropionic acid (VII) by means of lithium peroxide. The reduction of acid (VII) to the corresponding alcohol with NaBH4/I2 reagent, followed by treatment with PPh3 and NBS, provides bromide (VIII). Alkylation of the chiral dimethoxydihydropyrazin (IX) with bromide (VIII) produces (X). Further hydrolysis of the pyrazine ring of (X) with HCl, followed by Boc protection of the resulting (S,S)-amino ester, yields compound (XI). Reduction of the ester group of (XI) with DIBAL gives aldehyde (XII). This compound is condensed with the Grignard reagent (XIII) to afford the diastereomeric mixture of amino alcohols (XIV). Treatment of mixture (XIV) with 2,2-dimethoxypropane (XV) and TsOH produces a mixture of oxazolidines, from which the required (S,S,S)-isomer (XVI) is isolated by flash chromatography. Hydrogenolitic deprotection of the benzyl ether of (XVI) gives alcohol (XVII) (Scheme 26758001a). This alcohol is oxidized to aldehyde with NMMO and tetrapropylammonium perruthenate (TPAP), and further oxidized to carboxylic acid (XVIII) with KMnO4 and tetrabutylammonium bromide (TBAB). Coupling of (XVIII) with aminoamide (XIX) by means of diethyl cyanophosphonate and TEA gives (XX). Finally, acid hydrolysis of the oxazolidine ring and Boc protecting groups of (XX) furnishes the corresponding amino alcohol, which is finally converted to the hemifumarate salt (1, 2) (Scheme 26758001b). b) The intermediate g-butyrolactone (XXVIII) has been obtained as follows: Allylation of the imidazolidinone intermediate (V) with allyl bromide (XXI) and LiHMDS in THF gives the chiral intermediate (XXII), which by dihydroxylation and cleavage of the chiral auxiliary with OsO4 and NMMO in tert-butanol/acetone/water yields the lactone alcohol (XXIII). Oxidation of (XXIII) with NaIO4 and RuCl3 in CCl4/acetonitrile/water affords the carboxylic acid (XXIV), which by treatment with (COCl)2 in toluene provides the acyl chloride (XXV). Esterification of (XXV) with benzyl alcohol gives the corresponding benzyl ester as a diastereomeric mixture, from which the desired isomer (XXVI) is separated by flash chromatography. Hydrogenolysis of the benzyl ester (XXVI) with H2 over Pd/C in ethyl acetate yields the carboxylic acid (XXVII), which is treated with oxalyl chloride in toluene to afford the desired g-butyrolactone intermediate (XXVIII) (3) (Scheme 26758001c). The reduction of the chiral propionic acid (VII) with NaBH4 in THF gives the primary alcohol (XXIX), which by reaction with SOCl2 and pyridine in CHCl3 yields the chloride (XXX). Condensation of (XXX) with the butyrolactone intermediate (XXVII) by means of Mg and dibromoethane affords the ketonic adduct (XXXI). Reduction of the exocyclic carbonyl group of (XXXI) with NaBH4 in THF/ methanol provides a 3:1 diastereomeric mixture of the desired chiral alcohol (XXXII) and its OH-epimer (XXXIII) that are separated by flash chromatography. Reaction of (XXXII) with MsCl and TEA, followed by treatment with NaN3, affords the azido derivative (XXXIV), which is condensed with 4-amino-3,3-dimethylbutyramide (XIX) by means of 2-hydroxypyridine and TEA to provide the adduct (XXXV). Finally, the azido group of (XXXV) is reduced with H2 over Pd/ in methanol to yield the target amino alcohol (3) (Scheme 26758001d). An extensive study on the stereoselective reduction of the ketonic adduct (XXXI) has been performed. No better diastereoselectivity than 3:1 has been obtained for the synthesis of the chiral alcohol (XXXII). However, excellent diastereoselectivity (97:3) has been obtained for the synthesis of its OH-epimer, alcohol (XXXIII), with K-selectride in THF, which could potentially provide access to the target amino alcohol via a double inversion protocol. c) Alternatively, the chiral phenylpropyl chloride (XXX) can also be prepared as follows: Reduction of the cinnamic acid (XXXVI) with H2 over Pd/C in ethyl acetate gives the phenylpropionic acid (XXXVII), which is treated with oxalyl chloride to yield the acyl chloride (XXXVIII). Condensation of (XXXVIII) with (+)-pseudoephedrine (XXXIX) by means of NaOH in toluene/water affords the chiral amide (XL), which is enantioselectively alkylated with 2-iodopropane (XLI) by means of LDA in THF to provide the adduct (XLII). Reduction of the amide group of (XLII) with BH3/NH3 in THF gives the already reported primary alcohol (XXIX), which is finally treated with POCl3 in hot toluene to afford the phenylpropyl chloride intermediate (XXX) (4) (Scheme 26758001e). d) The chiral azido intermediate (XXXIV) can also be obtained as follows: Reaction of (+)-pseudoephedrine isovaleramide (XLIII) with allyl bromide (XXI) by means of LDA in THF gives the pentenoyl amide (XLIV), which is treated with NBS in DME/water to yield the spiro compound (XLV). Hydrolysis of the bromomethyl group of (XLV) with tetrabutylammonium acetate and K2CO3 affords the carbinol (XLVI), which is oxidized to aldehyde (XLVII) with SO3/pyridine and TEA in DMSO/dichloro-methane. Condensation of (XLVII) with the propyl chloride intermediate (XXX) by means of Mg, dibromoethane and CeCl3 in refluxing THF provides the already reported chiral hydroxylactone (XXXII), which is treated first with 4-bromobenzenesulfonyl chloride and then with NaN3 to give the desired azido derivative (XXXIV) (4) (Scheme 26758001f). e) Alternatively, the chiral azido intermediate (XXXIV) can also be synthesized as follows: Alkylation of oxazolidinone (V) with 1-chloro-3-iodopropene (XLVIII) by means of LiHMDS in THF gives compound (XLIX), which is condensed with the magnesium derivative of the phenylpropyl chloride (XXX) to yield, after working up, amide (L). Bromination of (L) with NBS and phosphoric acid affords the bromolactone (LI), which by treatment with NaN3 in tripropylene glycol/water provides the azido derivative (XXXIV) (5) (Scheme 26758001g). f) Alternatively, the spiro aldehyde (XLVII) is treated with N-benzylhydroxylamine in dichloromethane to give nitrone (LII), which is submitted to a Grignard reaction with the magnesium derivative of intermediate (XXX) in THF to afford the adduct (LIII) as a mixture of epimers at the amino group. Simultaneous N-dehydroxylation and cleavage of the spiro function of (LIII) by means of Zn, Cu(OAc)2 in AcOH/water gives lactone (LIV), which is condensed with 3-amino-2,2-dimethylpropionamide (XIX) by means of TEA and 2-hydroxypyridine giving the adduct (LV). Finally, the benzylamino group of (LV) is removed with H2 over Pd/C in methanol to yield a mixture of two epimers at the amino group, from which aliskiren is separated (6) (Scheme 26758001h). Manufacturers Novartis Pharma AG (CH); licensed to Speedel Pharma AG (CH). References 1. Gschke, R., Maibaum, J.K., Schilling, W., Stutz, S., Rigollier, P, Yamaguchi, Y., Cohen, N.C., Herold, P. (Novartis AG). d-Amino-g-hydroxy-w-aryl alkanoic acid amides with enzyme especially renin inhibiting activities. EP 0678500, EP 0678503, JP 1996053434, JP 1996081430, US 5559111, US 5627182, US 5646143. 2. Wood, J., Yamaguchi, Y. Rigollier, P., Goeschke, R., Stutz, S., Maibaum, J. Structural modification of the P2' position of 2,7-dialkyl substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octane-carboxamides: Discovery of a potent non-peptide renin inhibitor active after once daily dosing in marmosets. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.230. 3. Reger, H., Stutz, S., Gschke, R., Spindler, F., Maibaum, J. A convergent synthesis approach towards CGP60536B, a non-peptide orally potent renin inhibitor, via an enantiomerically pure ketolactone intermediate. Tetrahedron Lett. 2000, 41: 10085-9. 4. Sandham, D.A., Taylor, R.J., Carey, J.S., Fssler, A. A convergent synthesis of the renin inhibitor CGP60536B. Tetrahedron Lett 2000, 41: 10091-4. 5. Herold, P., Stutz, S., Indolese, A. (Speedel Pharma Inc.). Production of N-substd. 2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoylamides. WO 0109079, WO 0109083. 6. Dondoni, A., De Lathauwer, G., Perrone, D. A convergent synthesis of the renin inhibitor SPP-100 using a nitrone intermediate. Tetrahedron Lett 2001, 42: 4819-23.
  • 〖来源〗Tetrahedron Lett
  • 〖合成路线〗
  • 〖标题〗A convergent synthesis of the renin inhibitor SPP-100 using a nitrone intermediate
  • 〖合成方法〗Alternatively, the spiro aldehyde (XLVII) is treated with N-benzylhydroxylamine in dichloromethane to give nitrone (LII), which is submitted to a Grignard reaction with the magnesium derivative of intermediate (XXX) in THF to afford the adduct (LIII) as a mixture of epimers at the amino group. Simultaneous N-dehydroxylation and cleavage of the spiro function of (LIII) by means of Zn, Cu(OAc)2 in AcOH/water gives lactone (LIV), which is condensed with 3-amino-2,2-dimethylpropionamide (XIX) by means of TEA and 2-hydroxypyridine giving the adduct (LV). Finally, the benzylamino group of (LV) is removed with H2 over Pd/C in methanol to yield a mixture of two epimers at the amino group, from which aliskiren is separated.
  • 〖作者〗De Lathauwer, G.; Perrone, D.; Dondoni, A.
  • 〖参考〗De Lathauwer, G.; Perrone, D.; Dondoni, A.; A convergent synthesis of the renin inhibitor SPP-100 using a nitrone intermediate. Tetrahedron Lett 2001, 42, 29, 4819
  • 〖出处〗Tetrahedron Lett2001,42,(29):4819
  • 〖备注〗
  • 〖来源〗Drugs Fut
  • 〖合成路线〗
  • 〖标题〗Aliskiren Fumarate
  • 〖合成方法〗Alternatively, the spiro aldehyde (XLVII) is treated with N-benzylhydroxylamine in dichloromethane to give nitrone (LII), which is submitted to a Grignard reaction with the magnesium derivative of intermediate (XXX) in THF to afford the adduct (LIII) as a mixture of epimers at the amino group. Simultaneous N-dehydroxylation and cleavage of the spiro function of (LIII) by means of Zn, Cu(OAc)2 in AcOH/water gives lactone (LIV), which is condensed with 3-amino-2,2-dimethylpropionamide (XIX) by means of TEA and 2-hydroxypyridine giving the adduct (LV). Finally, the benzylamino group of (LV) is removed with H2 over Pd/C in methanol to yield a mixture of two epimers at the amino group, from which aliskiren is separated.
  • 〖作者〗Mealy, N.E.; Castaer, R.M.; Silvestre, J.S.; Castaer, J.
  • 〖参考〗Mealy, N.E.; Castaer, R.M.; Silvestre, J.S.; Castaer, J.; Aliskiren Fumarate. Drugs Fut 2001, 26, 12, 1139
  • 〖出处〗Drugs Fut2001,26,(12):1139
  • 〖备注〗Synthesis of Aliskiren Fumarate (EN:267580): Aliskiren can be obtained by several different ways: a) Alkylation of 3-hydroxy-4-methoxybenzyl alcohol (I) with 1-bromo-3-methoxypropane (II) gives ether (III). Subsequent conversion of benzyl alcohol (III) into bromide (IV) is carried out using bromotrimetylsilane. The chiral isovaleryloxazolidinone (V) is alkylated with bromide (IV) by means of LiHMDS to afford (VI), which is hydrolyzed to the (S)-2-aryl-2-isopropylpropionic acid (VII) by means of lithium peroxide. The reduction of acid (VII) to the corresponding alcohol with NaBH4/I2 reagent, followed by treatment with PPh3 and NBS, provides bromide (VIII). Alkylation of the chiral dimethoxydihydropyrazin (IX) with bromide (VIII) produces (X). Further hydrolysis of the pyrazine ring of (X) with HCl, followed by Boc protection of the resulting (S,S)-amino ester, yields compound (XI). Reduction of the ester group of (XI) with DIBAL gives aldehyde (XII). This compound is condensed with the Grignard reagent (XIII) to afford the diastereomeric mixture of amino alcohols (XIV). Treatment of mixture (XIV) with 2,2-dimethoxypropane (XV) and TsOH produces a mixture of oxazolidines, from which the required (S,S,S)-isomer (XVI) is isolated by flash chromatography. Hydrogenolitic deprotection of the benzyl ether of (XVI) gives alcohol (XVII) (Scheme 26758001a). This alcohol is oxidized to aldehyde with NMMO and tetrapropylammonium perruthenate (TPAP), and further oxidized to carboxylic acid (XVIII) with KMnO4 and tetrabutylammonium bromide (TBAB). Coupling of (XVIII) with aminoamide (XIX) by means of diethyl cyanophosphonate and TEA gives (XX). Finally, acid hydrolysis of the oxazolidine ring and Boc protecting groups of (XX) furnishes the corresponding amino alcohol, which is finally converted to the hemifumarate salt (1, 2) (Scheme 26758001b). b) The intermediate g-butyrolactone (XXVIII) has been obtained as follows: Allylation of the imidazolidinone intermediate (V) with allyl bromide (XXI) and LiHMDS in THF gives the chiral intermediate (XXII), which by dihydroxylation and cleavage of the chiral auxiliary with OsO4 and NMMO in tert-butanol/acetone/water yields the lactone alcohol (XXIII). Oxidation of (XXIII) with NaIO4 and RuCl3 in CCl4/acetonitrile/water affords the carboxylic acid (XXIV), which by treatment with (COCl)2 in toluene provides the acyl chloride (XXV). Esterification of (XXV) with benzyl alcohol gives the corresponding benzyl ester as a diastereomeric mixture, from which the desired isomer (XXVI) is separated by flash chromatography. Hydrogenolysis of the benzyl ester (XXVI) with H2 over Pd/C in ethyl acetate yields the carboxylic acid (XXVII), which is treated with oxalyl chloride in toluene to afford the desired g-butyrolactone intermediate (XXVIII) (3) (Scheme 26758001c). The reduction of the chiral propionic acid (VII) with NaBH4 in THF gives the primary alcohol (XXIX), which by reaction with SOCl2 and pyridine in CHCl3 yields the chloride (XXX). Condensation of (XXX) with the butyrolactone intermediate (XXVII) by means of Mg and dibromoethane affords the ketonic adduct (XXXI). Reduction of the exocyclic carbonyl group of (XXXI) with NaBH4 in THF/ methanol provides a 3:1 diastereomeric mixture of the desired chiral alcohol (XXXII) and its OH-epimer (XXXIII) that are separated by flash chromatography. Reaction of (XXXII) with MsCl and TEA, followed by treatment with NaN3, affords the azido derivative (XXXIV), which is condensed with 4-amino-3,3-dimethylbutyramide (XIX) by means of 2-hydroxypyridine and TEA to provide the adduct (XXXV). Finally, the azido group of (XXXV) is reduced with H2 over Pd/ in methanol to yield the target amino alcohol (3) (Scheme 26758001d). An extensive study on the stereoselective reduction of the ketonic adduct (XXXI) has been performed. No better diastereoselectivity than 3:1 has been obtained for the synthesis of the chiral alcohol (XXXII). However, excellent diastereoselectivity (97:3) has been obtained for the synthesis of its OH-epimer, alcohol (XXXIII), with K-selectride in THF, which could potentially provide access to the target amino alcohol via a double inversion protocol. c) Alternatively, the chiral phenylpropyl chloride (XXX) can also be prepared as follows: Reduction of the cinnamic acid (XXXVI) with H2 over Pd/C in ethyl acetate gives the phenylpropionic acid (XXXVII), which is treated with oxalyl chloride to yield the acyl chloride (XXXVIII). Condensation of (XXXVIII) with (+)-pseudoephedrine (XXXIX) by means of NaOH in toluene/water affords the chiral amide (XL), which is enantioselectively alkylated with 2-iodopropane (XLI) by means of LDA in THF to provide the adduct (XLII). Reduction of the amide group of (XLII) with BH3/NH3 in THF gives the already reported primary alcohol (XXIX), which is finally treated with POCl3 in hot toluene to afford the phenylpropyl chloride intermediate (XXX) (4) (Scheme 26758001e). d) The chiral azido intermediate (XXXIV) can also be obtained as follows: Reaction of (+)-pseudoephedrine isovaleramide (XLIII) with allyl bromide (XXI) by means of LDA in THF gives the pentenoyl amide (XLIV), which is treated with NBS in DME/water to yield the spiro compound (XLV). Hydrolysis of the bromomethyl group of (XLV) with tetrabutylammonium acetate and K2CO3 affords the carbinol (XLVI), which is oxidized to aldehyde (XLVII) with SO3/pyridine and TEA in DMSO/dichloro-methane. Condensation of (XLVII) with the propyl chloride intermediate (XXX) by means of Mg, dibromoethane and CeCl3 in refluxing THF provides the already reported chiral hydroxylactone (XXXII), which is treated first with 4-bromobenzenesulfonyl chloride and then with NaN3 to give the desired azido derivative (XXXIV) (4) (Scheme 26758001f). e) Alternatively, the chiral azido intermediate (XXXIV) can also be synthesized as follows: Alkylation of oxazolidinone (V) with 1-chloro-3-iodopropene (XLVIII) by means of LiHMDS in THF gives compound (XLIX), which is condensed with the magnesium derivative of the phenylpropyl chloride (XXX) to yield, after working up, amide (L). Bromination of (L) with NBS and phosphoric acid affords the bromolactone (LI), which by treatment with NaN3 in tripropylene glycol/water provides the azido derivative (XXXIV) (5) (Scheme 26758001g). f) Alternatively, the spiro aldehyde (XLVII) is treated with N-benzylhydroxylamine in dichloromethane to give nitrone (LII), which is submitted to a Grignard reaction with the magnesium derivative of intermediate (XXX) in THF to afford the adduct (LIII) as a mixture of epimers at the amino group. Simultaneous N-dehydroxylation and cleavage of the spiro function of (LIII) by means of Zn, Cu(OAc)2 in AcOH/water gives lactone (LIV), which is condensed with 3-amino-2,2-dimethylpropionamide (XIX) by means of TEA and 2-hydroxypyridine giving the adduct (LV). Finally, the benzylamino group of (LV) is removed with H2 over Pd/C in methanol to yield a mixture of two epimers at the amino group, from which aliskiren is separated (6) (Scheme 26758001h). Manufacturers Novartis Pharma AG (CH); licensed to Speedel Pharma AG (CH). References 1. Gschke, R., Maibaum, J.K., Schilling, W., Stutz, S., Rigollier, P, Yamaguchi, Y., Cohen, N.C., Herold, P. (Novartis AG). d-Amino-g-hydroxy-w-aryl alkanoic acid amides with enzyme especially renin inhibiting activities. EP 0678500, EP 0678503, JP 1996053434, JP 1996081430, US 5559111, US 5627182, US 5646143. 2. Wood, J., Yamaguchi, Y. Rigollier, P., Goeschke, R., Stutz, S., Maibaum, J. Structural modification of the P2' position of 2,7-dialkyl substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octane-carboxamides: Discovery of a potent non-peptide renin inhibitor active after once daily dosing in marmosets. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.230. 3. Reger, H., Stutz, S., Gschke, R., Spindler, F., Maibaum, J. A convergent synthesis approach towards CGP60536B, a non-peptide orally potent renin inhibitor, via an enantiomerically pure ketolactone intermediate. Tetrahedron Lett. 2000, 41: 10085-9. 4. Sandham, D.A., Taylor, R.J., Carey, J.S., Fssler, A. A convergent synthesis of the renin inhibitor CGP60536B. Tetrahedron Lett 2000, 41: 10091-4. 5. Herold, P., Stutz, S., Indolese, A. (Speedel Pharma Inc.). Production of N-substd. 2,7-dialkyl-4-hydroxy-5-amino-8-aryl-octanoylamides. WO 0109079, WO 0109083. 6. Dondoni, A., De Lathauwer, G., Perrone, D. A convergent synthesis of the renin inhibitor SPP-100 using a nitrone intermediate. Tetrahedron Lett 2001, 42: 4819-23.
  • 〖来源〗EP 0678500; EP 0678503; JP 1996053434; JP 1996081430; US 5559111; US 5627182; US 5646143
  • 〖合成路线〗
  • 〖标题〗Delta-amino-gamma-hydroxy-omega-aryl alkanoic acid amides with enzyme especially renin inhibiting activities
  • 〖合成方法〗Alkylation of 3-hydroxy-4-methoxybenzyl alcohol (I) with 1-bromo-3-methoxypropane (II) gives ether (III). Subsequent conversion of benzyl alcohol (III) into bromide (IV) is carried out using bromotrimetylsilane. The chiral isovaleryloxazolidinone (V) is alkylated with bromide (IV) by means of LiHMDS to afford (VI), which is hydrolyzed to the (S)-2-aryl-2-isopropylpropionic acid (VII) by means of lithium peroxide. The reduction of acid (VII) to the corresponding alcohol with NaBH4/I2 reagent, followed by treatment with PPh3 and NBS, provides bromide (VIII). Alkylation of the chiral dimethoxydihydropyrazin (IX) with bromide (VIII) produces (X). Further hydrolysis of the pyrazine ring of (X) with HCl, followed by Boc protection of the resulting (S,S)-amino ester, yields compound (XI). Reduction of the ester group of (XI) with DIBAL gives aldehyde (XII). This compound is condensed with the Grignard reagent (XIII) to afford the diastereomeric mixture of amino alcohols (XIV). Treatment of mixture (XIV) with 2,2-dimethoxypropane (XV) and TsOH produces a mixture of oxazolidines, from which the required (S,S,S)-isomer (XVI) is isolated by flash chromatography. Hydrogenolitic deprotection of the benzyl ether of (XVI) gives alcohol (XVII).
  • 〖作者〗Gschke, R.; Maibaum, J.K.; Schilling, W.; Stutz, S.; Rigollier, P.; Yamaguchi, Y.; Cohen, N.C.; Herold, P. (Novartis AG)
  • 〖参考〗Gschke, R.; Maibaum, J.K.; Schilling, W.; Stutz, S.; Rigollier, P.; Yamaguchi, Y.; Cohen, N.C.; Herold, P. (Novartis AG); Delta-amino-gamma-hydroxy-omega-aryl alkanoic acid amides with enzyme especially renin inhibiting activities. EP 0678500; EP 0678503;ww.chemdrug.com/extend/view.php?i??=耀?ul class="old_db">li>spa
  • 〖出处〗EP 0678500; EP 0678503; JP 1996053434; JP 1996081430; US 5559111; US 5627182; US 5646143,,():
  • 〖备注〗Alkylation of 3-hydroxy-4-methoxybenzyl alcohol (I) with 1-bromo-3-methoxypropane (II) gave ether (III). Subsequent conversion of the benzyl alcohol (III) into bromide (IV) was effected using bromotrimethylsilane. The chiral isovaleryloxazolidinone (V) was alkylated with bromide (IV) in the presence of lithium hexamethyldisilazide to afford (VI), which was hydrolyzed to the (S)-3-aryl-2-isopropylpropionic acid (VII) by means of lithium peroxide. Reduction of (VII) to alcohol with NaBH4 - I2 reagent, followed by treatment with triphenylphosphine and N-bromosuccinimide provided bromide (VIII). Alkylation of chiral dimethoxydihydropyrazin (IX) wwith bromide (VIII) produced (X). Further hydrolysis of the pyrazine ring of (X) with HCl, followed by Boc protection of the resulting (S,S)-aminoester yielded (XI). Reduction of the ester group of (XI) with DIBAL gave aldehyde (XII) (1). This was condensed with Grignard reagent (XIII) to afford the diastereomeric mixture of aminoalcohols (XIV). (Scheme 26758001a) Treatment of (XIV) with 2,2-dimethoxypropane and p-toluenesulfonic acid produced a mixture of oxazolidines, from which the required (S,S,S)-isomer (XV) was isolated by flash chromatography. Hydrogenolytic deprotection of the benzyl ether of (XV) gave alcohol (XVI). This was oxidized to aldehyde with N-methylmorpholine-N-oxide and tetrapropylammonium perruthenate, and further oxidized to carboxylic acid (XVII) with KMnO4 and tetrabutylammonium bromide. Coupling of (XVII) with aminoamide (XVIII) by means of diethyl cyanophosphonate gave (XIX). Finally, acid hydrolysis of the oxazolidine and Boc protecting groups of (XIX) furnished the corresponding aminoalcohol, which was finally converted to the hemifumarate salt. (Scheme 26758001b)
  • 〖来源〗EP 0678500; EP 0678503; JP 1996053434; JP 1996081430; US 5559111; US 5627182; US 5646143
  • 〖合成路线〗
  • 〖标题〗Delta-amino-gamma-hydroxy-omega-aryl alkanoic acid amides with enzyme especially renin inhibiting activities
  • 〖合成方法〗This alcohol is oxidized to aldehyde with NMMO and tetrapropylammonium perruthenate (TPAP), and further oxidized to carboxylic acid (XVIII) with KMnO4 and tetrabutylammonium bromide (TBAB). Coupling of (XVIII) with aminoamide (XIX) by means of diethyl cyanophosphonate and TEA gives (XX). Finally, acid hydrolysis of the oxazolidine ring and Boc protecting groups of (XX) furnishes the corresponding amino alcohol, which is finally converted to the hemifumarate salt.
  • 〖作者〗Gschke, R.; Maibaum, J.K.; Schilling, W.; Stutz, S.; Rigollier, P.; Yamaguchi, Y.; Cohen, N.C.; Herold, P. (Novartis AG)
  • 〖参考〗Gschke, R.; Maibaum, J.K.; Schilling, W.; Stutz, S.; Rigollier, P.; Yamaguchi, Y.; Cohen, N.C.; Herold, P. (Novartis AG); Delta-amino-gamma-hydroxy-omega-aryl alkanoic acid amides with enzyme especially renin inhibiting activities. EP 0678500; EP 0678503;ww.chemdrug.com/extend/view.php?i??=耀?ul class="old_db">li>spa
  • 〖出处〗EP 0678500; EP 0678503; JP 1996053434; JP 1996081430; US 5559111; US 5627182; US 5646143,,():
  • 〖备注〗Alkylation of 3-hydroxy-4-methoxybenzyl alcohol (I) with 1-bromo-3-methoxypropane (II) gave ether (III). Subsequent conversion of the benzyl alcohol (III) into bromide (IV) was effected using bromotrimethylsilane. The chiral isovaleryloxazolidinone (V) was alkylated with bromide (IV) in the presence of lithium hexamethyldisilazide to afford (VI), which was hydrolyzed to the (S)-3-aryl-2-isopropylpropionic acid (VII) by means of lithium peroxide. Reduction of (VII) to alcohol with NaBH4 - I2 reagent, followed by treatment with triphenylphosphine and N-bromosuccinimide provided bromide (VIII). Alkylation of chiral dimethoxydihydropyrazin (IX) wwith bromide (VIII) produced (X). Further hydrolysis of the pyrazine ring of (X) with HCl, followed by Boc protection of the resulting (S,S)-aminoester yielded (XI). Reduction of the ester group of (XI) with DIBAL gave aldehyde (XII) (1). This was condensed with Grignard reagent (XIII) to afford the diastereomeric mixture of aminoalcohols (XIV). (Scheme 26758001a) Treatment of (XIV) with 2,2-dimethoxypropane and p-toluenesulfonic acid produced a mixture of oxazolidines, from which the required (S,S,S)-isomer (XV) was isolated by flash chromatography. Hydrogenolytic deprotection of the benzyl ether of (XV) gave alcohol (XVI). This was oxidized to aldehyde with N-methylmorpholine-N-oxide and tetrapropylammonium perruthenate, and further oxidized to carboxylic acid (XVII) with KMnO4 and tetrabutylammonium bromide. Coupling of (XVII) with aminoamide (XVIII) by means of diethyl cyanophosphonate gave (XIX). Finally, acid hydrolysis of the oxazolidine and Boc protecting groups of (XIX) furnished the corresponding aminoalcohol, which was finally converted to the hemifumarate salt. (Scheme 26758001b)
  • 〖来源〗WO 0109079; WO 0109083
  • 〖合成路线〗
  • 〖标题〗2-Alkyl-5-halogen-pent-4-ene carboxylic acids and their production
  • 〖合成方法〗Alternatively, the chiral azido intermediate (XXXIV) can also be synthesized as follows: Alkylation of oxazolidinone (V) with 1-chloro-3-iodopropene (XLVIII) by means of LiHMDS in THF gives compound (XLIX), which is condensed with the magnesium derivative of the phenylpropyl chloride (XXX) to yield, after working up, amide (L). Bromination of (L) with NBS and phosphoric acid affords the bromolactone (LI), which by treatment with NaN3 in tripropylene glycol/water provides the azido derivative (XXXIV).
  • 〖作者〗Stutz, S.; Herold, P. (Speedel Pharma Inc.)
  • 〖参考〗Stutz, S.; Herold, P. (Speedel Pharma Inc.); 2-Alkyl-5-halogen-pent-4-ene carboxylic acids and their production. WO 0109079; WO 0109083
  • 〖出处〗WO 0109079; WO 0109083,,():
  • 〖备注〗
  • 〖来源〗WO 0208172
  • 〖合成路线〗
  • 〖标题〗Process for the preparation of substd. octanoyl amides
  • 〖合成方法〗The condensation of ethyl isovalerate (I) with 1,3-dichloropropene (II) by means of BuLi and DIA in THF gives 5-chloro-2-isopropyl-4-pentenoic acid ethyl ester (III), which is hydrolyzed with NaOH in ethanol to yield the corresponding racemic acid (IV). The optical resolution of (IV) is carried out by means of cinchonidine and TEA in THF to afford 5-chloro-2(S)-isopropyl-4-pentenoic acid (V), which can also be obtained by asymmetric synthesis as follows: Condensation of 4(S)-benzyl-3-(3-methylbutyryl)oxazolidin-2-one (VI) with 3-iodo-1-propenyl chloride (VII) by means of LiHMDS in THF gives 4(S)-benzyl-3-(2(S)-isopropyl-3-methylbutyryl)oxazolidin-2-one (VIII), which is hydrolyzed with LiOH in THF/water to afford the chiral pentanoic acid (V). The reaction of (V) with oxalyl chloride in toluene gives the corresponding acyl chloride (IX), which is treated with dimethylamine and pyridine in dichloromethane to yield the dimethylamide (X). The condensation of (X) with the chiral chloro derivative (XI) (obtained by reaction of the corresponding alcohol (XII) with CCl4 and trioctylphosphine) by means of Mg and 1,2-dibromoethane in THF affords the octenamide (XIII). The cyclization of (XIII) by means of phosphoric acid and simultaneous bromination with NBS in THF provides the chiral bromolactone (XIV), which is opened by means of dimethylamine and Et2AlCl in dichloromethane to give the chiral 5-bromo-4-hydroxy-2,7-diisopropyloctanamide (XV). The reaction of (XV) with acetic anhydride and pyridine in dichloromethane yields the acetoxy derivative (XVI), which is treated with LiN3 to afford the 5(S)-azido derivative (XVII).
  • 〖作者〗Herold, P.; Stutz, S. (Speedel Pharma Inc.)
  • 〖参考〗Herold, P.; Stutz, S. (Speedel Pharma Inc.); Process for the preparation of substd. octanoyl amides. WO 0208172
  • 〖出处〗WO 0208172,,():
  • 〖备注〗
  • 〖来源〗WO 0208172
  • 〖合成路线〗
  • 〖标题〗Process for the preparation of substd. octanoyl amides
  • 〖合成方法〗The cyclization of (XVII) by means of TsOH in refluxing methanol gives the chiral lactone (XVIII), which is condensed with 3-amino-2,2-dimethylpropionamide (XIX) by means of TEA and 2-hydroxypyridine at 90 C to yield the corresponding amide (XX). Finally, the azido group of (XX) is reduced with H2 over Pd/C in tert-butyl methyl ether to afford the target Aliskiren.
  • 〖作者〗Herold, P.; Stutz, S. (Speedel Pharma Inc.)
  • 〖参考〗Herold, P.; Stutz, S. (Speedel Pharma Inc.); Process for the preparation of substd. octanoyl amides. WO 0208172
  • 〖出处〗WO 0208172,,():
  • 〖备注〗
  • 〖来源〗WO 0202508
  • 〖合成路线〗
  • 〖标题〗Process for the preparation of substd. octanoyl amides
  • 〖合成方法〗The condensation of the chiral chloro derivative (I) with 5-chloro-[2(S)-isopropyl]-4-pentanoic acid methyl ester (II) by means of Mg and dibromoethane in THF gives the chiral octenoic ester (III) which is converted to the corresponding acid (IV) by means of LiOH in THF/methanol/water. The reaction of (IV) with NBS in dichloromethane yields the bromolactone (V), which is treated with LiOH in isopropanol to yield the epoxide (VI). This compound, without isolation, is treated with HCl in the same solvent to afford the chiral hydroxylactone (VII). The reaction of the OH group of (VII) with MsCl and pyridine in toluene provides the mesylate (VIII), which is treated with NaN3 in hot 1,3-dimethylperhydropyrimidin-2-one to give the azido derivative (IX). The condensation of (IX) with 3-amino-2,2-dimethylpropionamide (X) by means of 2-hydroxypyridine in hot TEA yields the carboxamide (XI). Finally, the azido group of (XI) is reduced with H2 over Pd/C in tert-butyl methyl ether to provide the target Aliskiren.
  • 〖作者〗Herold, P.; Stutz, S.; Spindler, F. (Speedel Pharma Inc.)
  • 〖参考〗Herold, P.; Stutz, S.; Spindler, F. (Speedel Pharma Inc.); Process for the preparation of substd. octanoyl amides. WO 0202508
  • 〖出处〗WO 0202508,,():
  • 〖备注〗
  • 〖来源〗WO 0202487
  • 〖合成路线〗
  • 〖标题〗Process for the preparation of (R)-2-alkyl-3-phenyl-1-propanols
  • 〖合成方法〗The condensation of benzaldehyde (I) with ethyl isovalerate (II) by means of hexyl lithium and DIA in THF gives the hydroxyester (III), which is acylated with Ac2O and DMAP in THF to yield the acetoxy derivative (IV). The elimination reaction in (IV) by means of t-BuOK in THF affords the unsaturated ester (V), which is reduced with diisobutylaluminum hydride in toluene to provide the unsaturated alcohol (VI). Finally, this compound is enantioselectively reduced with H2 over a chiral biphenylyl diphenylphosphine catalyst and a [Rh(norbornadiene)Cl]2 catalyst in toluene to give the target intermediate 2(R)-isopropyl-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]-1-propanol (VII). (see scheme 26758001d, intermediate (XXIX)).
  • 〖作者〗Herold, P.; Stutz, S.; Spindler, F. (Speedel Pharma Inc.)
  • 〖参考〗Herold, P.; Stutz, S.; Spindler, F. (Speedel Pharma Inc.); Process for the preparation of (R)-2-alkyl-3-phenyl-1-propanols. WO 0202487
  • 〖出处〗WO 0202487,,():
  • 〖备注〗
  • 〖来源〗WO 0202500
  • 〖合成路线〗
  • 〖标题〗Preparation of (R)-2-alkyl-3-phenylpropionic acids
  • 〖合成方法〗The condensation of benzaldehyde (I) with ethyl isovalerate (II) by means of hexyl lithium and DIA in THF gives the hydroxyester (III), which is acylated with Ac2O and DMAP in THF to yield the acetoxy derivate (IV). The elimination reaction in (IV) by means of t-BuOK in THF affords the unsaturated ester (V), which is hydrolyzed with KOH in ethanol to provide the unsaturated free acid (VI). Finally, this compound is enantioselectively reduced with H2 over several chiral Rh catalysts {[Rh(NBD)2BF4, [Rh(NBD)(OCOCF3)2], [Rh(NBD)Cl2], etc} to give the target intermediate 2(R)-isopropyl-3-[4-methoxy-3-(3-methoxypropoxy)phenyl]propionic acid (VII). (see scheme 26758001a, intermediate (VII)).
  • 〖作者〗Herold, P.; Stutz, S. (Speedel Pharma Inc.)
  • 〖参考〗Herold, P.; Stutz, S. (Speedel Pharma Inc.); Preparation of (R)-2-alkyl-3-phenylpropionic acids. WO 0202500
  • 〖出处〗WO 0202500,,():
  • 〖备注〗
 
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  • (1) Aliskiren fumarate, CGP-60536(free base), SPP-100B, SPP-100(
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