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17016-83-0,C6H11NO2,129.1601,(4S)-4-Isopropyl-1,3-oxazolidin

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摘 要:17016-83-0,C6H11NO2,129.1601,(4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone
  • 【化学名】(4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone
  • 【CAS登记号】17016-83-0
  • 【结构式】17016-83-0,C6H11NO2,129.1601,(4S)-4-Isopropyl-1,3-oxazolidin--药物合成数据库
  • 【分子式】C6H11NO2
  • 【分子量】129.1601
  • 【来源】ABCR GmbH & Co.; Acros Organics; Aldrich; Alfa Aesar; Daiso Co., Ltd.; Davos Chemical Corporation; Fluka; George Uhe Company, Inc.; Indofine Chemical Company, Inc.; Lancaster Synthesis Inc.; NSC Technologies; Omega Chemical Co., Inc.; SynChem, Inc.; TCI
  • 【合成情况】 
  • 〖目标产物〗PS-5
  • 〖合成路线〗
  • 〖合成方法〗A new and stereoselective synthesis of (3R-trans)-3-ethyl-1-(tert-butyldimethylsilyl)-4-[2-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (XVII), a key intermediate in the synthesis of PS-5 has been developed: The oxidation of 3-benzyloxy-1-propanol (I) with oxalyl chloride in DMSO gives the corresponding aldehyde (II), which is condensed with the phosphonate (III) by means of NaH yielding a mixture of the (Z)- and (E)-isomers of 5-benzyloxy-2-ethyl-2-pentenoic acid ethyl ester (IV) and (V). The undesired (Z)-isomer (IV) is isomerized by treating the mixture with diphenyldisulfide in refluxing THF. The hydrolysis of (V) with LiOH in THF/methanol/water gives the expected free acid (VI), which is treated with SOCl2 in refluxing benzene to afford the acid chloride (VII). The condensation of (VII) with the chiral oxazolidinone (VIII) by means of butyllithium in THF gives the acylated compound (IX), which is treated with benzenethiol and butyllithium in THF to give the addition compound (X) that is purified by medium pressure column chromatography to eliminate the undesired diastereomer. The elimination of the oxazolidinone group of (X) by reaction with trimethylaluminum, benzylthiol and butyllithium in THF yields the thioester (XI), which is treated with silver trfluoroacetate and water to afford the corresponding free acid (XII). The reaction of (XII) with methoxyamine and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDPC) in water affords the methoxyamide (XIII), which is methylated by means of methyl iodide and silver perchlorate to give the sulfonium salt (XIV). The cyclization of (XIV) by means of K2CO3 yields the azetidinone (XV), which is debenzylated by means of calcium in liquid ammonia affording (3R-trans)-3-ethyl-4-(2-hydrxyethyl)azetidin-2-one (XVI). Finally, this compound is silylated with tert-butyldimethylsilyl (TBDMS) trifluoromethanesulfonate affording (3R-trans)-3-ethyl-1-(tert-butyldimethylsilyl)-4-[2-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (XVII), the desired target key intermediate in the synthesis of PS-5.
  • 〖参考〗Fujiwara,Y.; Ninomiya, I.; Miyata, O.; Naito, T.; Efficient stereoselective route to beta-lactams and their application to the stereoselective synthesis of a key intermediate for carbapenem antibiotic (+)-PS-5. J Chem Soc - Perkins Trans I 1998, 14, 14, 2d/S
  • 〖目标产物〗ES-6864
  • 〖合成路线〗
  • 〖合成方法〗The starting product (I) is obtained as follows: The acylation of 4(S)-isopropyloxazolidin-2-one (IV) with 3-(1-naphthyl)propionyl chloride (III) by means of butyllithium in THF-hexane yields 4(S)-isopropyl-3-[3-(1-naphthyl)propionyl]oxazolidin-2-one (V), which is condensed with benzyl bromoacetate (VI) by means of lithium diisopropylamide in THF to afford 3-[3-(benzyloxycarbonyl)-2(R)-(1-naphthylmethyl)propionyl]-4(S)-isoprop yloxazolidin-2-one (VII). The hydrogenolysis of (VII) with H2 over Pd/C in ethanol gives the carboxylic acid (VIII), which is condensed with morpholine (IX) by means of triethylamine and diethylphosphoryl cyanide in THF yielding 4(S)-isopropyl-3-[3-(morpholinocarbonyl)-2(R)-(1-naphthylmethyl)propion yl]oxazolidin-2-one (X). Finally, this compound is hydrolyzed with LiOH in THF - water to afford the acid (I).
  • 〖参考〗Nishi, T.; Nagahori, H.; Saito, F.; et al.; Syntheses and biological activities of renin inhibitors containing statine analogues. Chem Pharm Bull 1990, 38, 1, 103-9
  • 〖目标产物〗Sch-51048
  • 〖合成路线〗
  • 〖合成方法〗The reaction of allyl alcohol (I) with triethyl orthoacetate at 120 C gives the 4-pentenoic ester (II), which is hydrolyzed with KOH to the corresponding free acid (III). The reaction of (III) with (COCl)2 yields the acyl chloride (IV), which is condensed with 4(S)-isopropyloxazolidin-2-one (V) (a chiral auxiliary), by means of BuLi to afford the chiral imide (VI). The diastereoselective alkylation of (VI) with benzyloxymethyl chloride (VII) by means of TiCl4 and TEA in dichloromethane provides the alkylated compound (VIII) with a diastereoselectivity of 70/30% and combined yields of 84%. The reductive elimination of the chiral auxiliary in (VIII) by means of LiAlH4 gives the alcohol (IX), which is treated with Ac2O to yield the acetate (X). The cyclization of (X) by means of I2 and pyridine in acetonitrile affords the chiral tetrahydrofuran (XI)????XI)a, which is condensed with the sodium salt of 1,2,4-triazole (XII) in hot DMF to provide the adduct (XIII). The debenzylation of (XIII) with H2 over Pd/C gives the alcohol (XIV), which is finally treated with Ts-Cl and pyridine to give rise to the target intermediate tosylate (XV) (see scheme no. 20027601a, intermediate no. (II))
  • 〖参考〗Saksena, A.K.; Girijavallabhan, V.M.; Wang, H.Y.; Liu, Y.T.; Pike, R.E.; Ganguly, A.K.; Concise asymmetric routes to 2,2,4-trisubstituted tetrahydrofurans via chiral titanium imide enolates: Key intermediates towards synthesis of highly active azole antifd/SYNTHESIS/SYN/14/14415701b.gif'??缙???i/>/a>/li>?[?i?`鹰h?c'/
  • 〖目标产物〗Atrasentan, A-147627, (+)-A-127722, ABT-627
  • 〖合成路线〗
  • 〖合成方法〗Reaction of 2-(1,3-dioxol-5-yl)acetic acid (XXI) with pivaloyl chloride and TEA gives the corresponding anhydride (XXII), which is condensed with the chiral oxazolidinone (XXIII) by means of n-BuLi in THF to yield the amide (XXIV). Condensation of (XXIV) with 2-bromoacetic acid tert-butyl ester (XXV) by means of NaHMDS in THF affords the adduct (XXVI). Elimination of the chiral auxiliary of (XXVI) by means of LiOOH in THF/water provides the chiral succinic acid hemiester (XXVII) (93% ee), which is selectively reduced with BH3THF complex to give the 4-hydroxysuccinate (XXVIII). Reaction of succinate (XXVIII) with 4-chlorophenylsulfonyl chloride, TEA and DMAP in dichloromethane yields the sulfonate (XXIX), which is condensed with 4-methoxybenzaldoxime (XXX) by means of Cs2CO3 in hot acetonitrile to afford the oxime ether (XXXI). Transesterification of the tert-butyl ester of (XXXI) with trimethyl orthoformate and p-toluenesulfonic acid in hot methanol provides the methyl ester (XXXII), which is cyclized by means of trimethylsilyl triflate and tributylamine in dichloroethane to afford a 9:1 diastereomeric mixture of perhydro-1,2-oxazines (XXXIII) and (XXXIV) which is easily separated. The reductive N-O-bond cleavage of the major oxazine diastereomer (XXXIII) by means of Zn/HOAc or H2 over Pd/C gives the trisubstituted 4-aminobutanol (XXXV), which is cyclized by means of CBr4, PPh3 and TEA to yield chiral pyrrolidine (XXXVI) (4). Finally, pyrrolidine (XXXVI) is alkylated with N,N-dibutyl-2-bromoacetamide (XIII) followed by ester hydrolysis as before.
  • 〖参考〗Winn, M.; et al.; 2,4-Diarylpyrrolidine-3-carboxylic acids-potent ETA selective endothelin receptor antagonists. 1. Discovery of A-127722. J Med Chem 1996, 39, 5, 1039
  • 〖目标产物〗Atrasentan, A-147627, (+)-A-127722, ABT-627
  • 〖合成路线〗
  • 〖合成方法〗Reaction of 2-(1,3-dioxol-5-yl)acetic acid (XXI) with pivaloyl chloride and TEA gives the corresponding anhydride (XXII), which is condensed with the chiral oxazolidinone (XXIII) by means of n-BuLi in THF to yield the amide (XXIV). Condensation of (XXIV) with 2-bromoacetic acid tert-butyl ester (XXV) by means of NaHMDS in THF affords the adduct (XXVI). Elimination of the chiral auxiliary of (XXVI) by means of LiOOH in THF/water provides the chiral succinic acid hemiester (XXVII) (93% ee), which is selectively reduced with BH3THF complex to give the 4-hydroxysuccinate (XXVIII). Reaction of succinate (XXVIII) with 4-chlorophenylsulfonyl chloride, TEA and DMAP in dichloromethane yields the sulfonate (XXIX), which is condensed with 4-methoxybenzaldoxime (XXX) by means of Cs2CO3 in hot acetonitrile to afford the oxime ether (XXXI). Transesterification of the tert-butyl ester of (XXXI) with trimethyl orthoformate and p-toluenesulfonic acid in hot methanol provides the methyl ester (XXXII), which is cyclized by means of trimethylsilyl triflate and tributylamine in dichloroethane to afford a 9:1 diastereomeric mixture of perhydro-1,2-oxazines (XXXIII) and (XXXIV) which is easily separated. The reductive N-O-bond cleavage of the major oxazine diastereomer (XXXIII) by means of Zn/HOAc or H2 over Pd/C gives the trisubstituted 4-aminobutanol (XXXV), which is cyclized by means of CBr4, PPh3 and TEA to yield chiral pyrrolidine (XXXVI) (4). Finally, pyrrolidine (XXXVI) is alkylated with N,N-dibutyl-2-bromoacetamide (XIII) followed by ester hydrolysis as before.
  • 〖参考〗Leeson, P.; Castaer, R.M.; Sorbera, L.A.; Castaer, J.; Atrasentan. Drugs Fut 2001, 26, 10, 939
  • 〖目标产物〗Atrasentan, A-147627, (+)-A-127722, ABT-627
  • 〖合成路线〗
  • 〖合成方法〗Reaction of 2-(1,3-dioxol-5-yl)acetic acid (XXI) with pivaloyl chloride and TEA gives the corresponding anhydride (XXII), which is condensed with the chiral oxazolidinone (XXIII) by means of n-BuLi in THF to yield the amide (XXIV). Condensation of (XXIV) with 2-bromoacetic acid tert-butyl ester (XXV) by means of NaHMDS in THF affords the adduct (XXVI). Elimination of the chiral auxiliary of (XXVI) by means of LiOOH in THF/water provides the chiral succinic acid hemiester (XXVII) (93% ee), which is selectively reduced with BH3THF complex to give the 4-hydroxysuccinate (XXVIII). Reaction of succinate (XXVIII) with 4-chlorophenylsulfonyl chloride, TEA and DMAP in dichloromethane yields the sulfonate (XXIX), which is condensed with 4-methoxybenzaldoxime (XXX) by means of Cs2CO3 in hot acetonitrile to afford the oxime ether (XXXI). Transesterification of the tert-butyl ester of (XXXI) with trimethyl orthoformate and p-toluenesulfonic acid in hot methanol provides the methyl ester (XXXII), which is cyclized by means of trimethylsilyl triflate and tributylamine in dichloroethane to afford a 9:1 diastereomeric mixture of perhydro-1,2-oxazines (XXXIII) and (XXXIV) which is easily separated. The reductive N-O-bond cleavage of the major oxazine diastereomer (XXXIII) by means of Zn/HOAc or H2 over Pd/C gives the trisubstituted 4-aminobutanol (XXXV), which is cyclized by means of CBr4, PPh3 and TEA to yield chiral pyrrolidine (XXXVI) (4). Finally, pyrrolidine (XXXVI) is alkylated with N,N-dibutyl-2-bromoacetamide (XIII) followed by ester hydrolysis as before.
  • 〖参考〗McLaughlin, M.A.; Wittenberger, S.J.; Preparation of endothelin antagonist ABT-627. Tetrahedron Lett 1999, 40, 7175
  • 〖目标产物〗R-94138
  • 〖合成路线〗
  • 〖合成方法〗Acylation of the chiral oxazolidinone (I) with undecanoyl chloride furnished the N-acyl oxazolidinone (II). The lithium enolate of (II) was diastereoselectively alkylated with tert-butyl bromoacetate (III) producing (IV) as the major isomer. Then, removal of the chiral auxiliary of (IV) with lithium benzyloxide yielded benzyl ester (V). Acidic cleavage of the tert-butyl ester group of (V) provided carboxylic acid (VI), which was subsequently converted to the trichloroethyl ester (VII) via formation of the corresponding acid chloride, followed by treatment with trichloroethanol. After removal of the benzyl ester group of (VII) by hydrogenolysis, chlorination by means of oxalyl chloride gave acid chloride (VIII). This was then coupled with the protected (S)-perhydropyrazine-3-carboxylic acid (IX) to afford amide (X).
  • 〖参考〗Tamaki, K.; et al.; Synthesis and structure-activity relationships of gelatinase inhibitors derived from Matlystatins. Chem Pharm Bull 1995, 43, 11, 1883
  • 〖目标产物〗BILD-1633-SE
  • 〖合成路线〗
  • 〖合成方法〗The intermediate cyclopentanecarboxylic ester (XII) has been obtained as follows: The reaction of 2-oxaspiro[4.4]nonane-1,3-dione (XXVI) with the chiral auxiliary 4(S)-isopropyloxazolidin-2-one (XXVII) by means of BuLi in THF gives the addition product (XXVIII), which is protected as the benzyl ester (XXIX) with benzylbromide and DBU. The regioselective azidation of (XXIX) with 2,4,6-triisopropylbenzenesulfonyl azide and potassium bis(trimethylsilyl)amide affords the (S)-azide (XXX), which is treated with H2O2 in THF/water to eliminate chiral auxiliary and providing 2(S)-azido-2-[1-(benzyloxycarbonyl)cyclopentyl]acetic acid (XXXI). Condensation of (XXXI) with 1(R)-ethyl-2,2-dimethylpropylamine (XXXII) by means of HBTU in dichloromethane gives the corresponding amide (XXXIII), which is finally reduced at the azido group with SnCl2 in methanol to afford the target intermediate (XII). The intermediate 1(R)-ethyl-2,2-dimethylpropylamine (XXXII) has been obtained as follows: The reaction of 2,2-dimethyl-3-pentanone (XXXIV) with the chiral auxiliary 1(R)-phenylethylamine (XXXV) by means of TiCl4 in benzene gives N-(1(R)-ethyl-2,2-dimethylpropyl)-N-(1(R)-phenylethyl)amine (XXXVI), which is then hydrogenated with H2 over Pd/C in methanol to eliminate the chiral auxiliary and obtain the target amine (XXXII).
  • 〖参考〗Gauthier, J.-A.; Moss, N. (Bio-Mega, Inc.; Boehringer Ingelheim GmbH); Herpes ribonucleotide reductase inhibitors. EP 0837845; JP 1999508246; US 5672586; WO 9700855
  • 〖目标产物〗BILD-1633-SE
  • 〖合成路线〗
  • 〖合成方法〗The intermediate 3-cyclohexyl-2(R)-methylpropionyl chloride (XVIII) has been obtained as follows: The reaction of 4(S)-isopropyloxazolidin-2-one (XIX) with propionyl chloride (XX) by means of BuLi in THF gives 4(S)-isopropyl-3-propionyloxazolidin-2-one (XXI), which is condensed with benzyl bromide (XXII) by means of LHMDS in THF yielding 4(S)-isopropyl-3-(2(R)-methyl-3-phenylpropionyl)oxazolidin-2-one (XXIII). The oxidative cleavage of (XXIII) with H2O2 in THF/water affords 2(R)-methyl-3-phenylpropionic acid (XXIV), which is hydrogenated with H2 over alumina providing 3-cyclohexyl-2(R)-methylpropionic acid (XXV). Finally, this compound is treated with oxalyl chloride in DMF to afford the desired intermediate 3-cyclohexyl-2(R)-methylpropionyl chloride (XVIII).
  • 〖参考〗Gauthier, J.-A.; Moss, N. (Bio-Mega, Inc.; Boehringer Ingelheim GmbH); Herpes ribonucleotide reductase inhibitors. EP 0837845; JP 1999508246; US 5672586; WO 9700855
  • 〖目标产物〗
  • 〖合成路线〗
  • 〖合成方法〗The intermediate (S)-1-(4-isopropylphenyl)ethylamine (VII) was prepared as shown in Scheme 1. Condensation of (4-isopropylphenyl)acetyl chloride (I) with the lithium salt of (S)-4-isopropyl-2-oxazolidinone (II) produced the chiral N-acyl oxazolidinone (III). Diastereoselective alkylation of (III) with MeI in the presence of lithium hexamethyldisilazide provided (IV). Removal of the chiral auxiliary of (IV) was accomplished by treatment with lithium hydroperoxide to afford the (S)-arylpropionic acid (V). Subsequent Curtius rearrangement of (V) using diphenyl phosphoryl azide, followed by treatment of the intermediate isocyanate with benzyl alcohol, furnished the benzyl carbamate (VI). Then, catalytic hydrogenation of (VI) over Pd/C yielded the target amine (VII).
  • 〖参考〗Llins-Brunet, M.; et al.; Phosphotyrosine-containing dipeptides as high-affinity ligands for the p56lck SH2 domain. J Med Chem 1999, 42, 4, 722
  • 〖目标产物〗SPA-110(trifluoroacetate salt), HTI-286
  • 〖合成路线〗
  • 〖合成方法〗The amino acid building block (XI) was prepared as follows. Friedel-Crafts condensation of dimethylacrylic acid (I) with benzene in the presence of AlCl3 afforded 3-methyl-3-phenylbutanoic acid (II). After activation of acid (II) as the mixed anhydride (IV) by treatment with pivaloyl chloride (III) and Et3N, coupling with the lithium salt of (S)-4-isopropyl-2-oxazolidinone (V) furnished the chiral N-acyl oxazolidinone (VI). Diastereoselective introduction of an azido group into the lithium enolate of (VI) by means of 2,4,6-triisopropylbenzenesulfonyl azide led to the (S,S)-azido compound (VII). Catalytic hydrogenation of azide (VII) in the presence of Boc2O provided the Boc-protected amine (VIII). The chiral auxiliary of (VIII) was removed by hydrolysis with lithium hydroperoxide, and the resultant carboxylic acid was further converted to the methyl ester (IX) upon treatment with an ethereal solution of diazomethane. The N-methyl derivative (X) was then prepared by alkylation of the tert-butyl carbamate (IX) with iodomethane in the presence of NaH. Basic hydrolysis of ester (X) provided the target N-Boc amino acid (XI).
  • 〖参考〗Roberge, M.; Andersen, R.; Pers, E.; Nieman, J.; Coleman, J. (University of British Columbia); Hemiasterlin analogs. WO 9932509
  • 〖目标产物〗
  • 〖合成路线〗
  • 〖合成方法〗Acylation of Evans oxazolidinone (II) with heptanoyl chloride (I) provides the chiral adduct (III). The lithium enolate of (III) is then diastereoselectively alkylated with tert-butyl bromoacetate (IV) to afford the succinate derivative (V). Removal of the chiral auxiliary group of (V) with lithium peroxide furnishes the carboxylic acid (VI), which is further activated as the succinimidyl ester (VII) upon treatment with N-hydroxysuccinimide and DCC. The activated ester (VII) is then condensed with L-valine (VIII), producing amide (IX). Subsequent coupling of (IX) with N-aminoproline methyl ester (X) leads to hydrazide (XI). After acidic tert-butyl ester cleavage in (XI), the resultant carboxylic acid (XII) is condensed with hydroxylamine to yield the desired hydroxamic acid.
  • 〖参考〗Borella, C.; et al.; Asymmetric solid phase and solution parallel synthesis and antitumor properties of actinonin analogs. Proc Am Assoc Cancer Res 2002, 43
 
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