methyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】11905

【品名】methyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate

【CA登记号】

【分子式】C₁₁H₁₂O₄

【分子量】208.21388

【元素组成】C 63.45% H 5.81% O 30.74%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(II)

A new synthesis of TA-3090 has been published: The cyclization of 2-amino-5-chlorothiophenol (I) with trans-2,3-epoxy-3-(4-methoxyphenyl)propanoic acid methyl ester (II) by heating at 160 C gives cis-8-chloro-3-hydroxy-2-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1,5-benzo thiazepin-4-one (III), which is submitted to optical resolution with (S)-1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyl chloride. The (2S-cis)-isomer of (III) is then condensed with 2-(dimethylamino)ethyl chloride (IV) by means of K2CO3 in refluxing acetone - water, yielding (2S-cis)-8-chloro-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphen yl-2,3,4,5-tetrahydro-1,5-benzothiazepin-4-one (V). Finally, this compound is acetylated with acetic anhydride in refluxing pyridine and converted into the maleate salt.

参考文献中间体

合成目标

【1】 Inoue, H.; Konda, M.; Hashiyama, T.; et al.; Synthesis of halogen-substituted 1,5-benzothiazepine derivatives and their vasodilating and hypotensive activities. J Med Chem 1991, 34, 2, 675-87.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	11904	2-Amino-5-chlorobenzenethiol; 2-Amino-5-chlorophenylhydrosulfide		C₆H₆ClNS	详情	详情
(II)	11905	methyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate		C₁₁H₁₂O₄	详情	详情
(III)	11906	(2S,3S)-8-Chloro-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one		C₁₆H₁₄ClNO₃S	详情	详情
(IV)	11907	Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine	107-99-3	C₄H₁₀ClN	详情	详情
(V)	11908	(2S,3S)-8-Chloro-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one		C₂₀H₂₃ClN₂O₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XII)

In a further process, the racemic trans glycidic ester (XII), prepared by Darzen's condensation between anisaldehyde (X) and methyl chloroacetate (XI), was resolved by enantioselective enzymatic hydrolysis, using several different enzymes and reaction conditions to produce the undesired (2S,3R) acid (XIII), while leaving intact the required (2R,3S)-glycidic ester (XIV) (4-7). Opening of the chiral epoxide (XIV) with 2-aminobenzenethiol (VII) proceeded with retention of the configuration, producing methyl (2S,3S)-2-hydroxy-3-(2-aminophenylsulfanyl)-3-(4-methoxyphenyl)propionate (XV) (8). Alternatively, the (S,S)-amino ester (XV) was obtained by resolution with tartaric acid of the racemic three-adduct resulting from epoxide (XII) and 2-aminobenzenethiol (VII) (9). Cyclization of amino ester (XV) in refluxing xylene in the presence of p-toluenesulfonic acid afforded the target lactam (VIII) (9). The cyclization of (XV) to lactam (VIII) was also accomplished by means of trichloroacetic acid or under basic conditions

参考文献中间体

合成目标

【1】 Bhushan, L.B.; Jayachandran, B.E.; Bhushan, L.V.; Thottappillil, R. (Council of Scientific and Industrial Research); Process for preparing diltiazem. US 5869697 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	25182	2-aminobenzenethiol	137-07-5	C₆H₇NS	详情	详情
(VIII)	62436	(2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one		C₁₆H₁₅NO₃S	详情	详情
(X)	27251	4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde	123-11-5	C₈H₈O₂	详情	详情
(XI)	10257	methyl 2-chloroacetate; methyl chloroacetate	96-34-4	C₃H₅ClO₂	详情	详情
(XII)	11905	methyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate		C₁₁H₁₂O₄	详情	详情
(XIII)	62438	(2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylic acid		C₁₀H₁₀O₄	详情	详情
(XIV)	62435	ethyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate		C₁₂H₁₄O₄	详情	详情
(XV)	62439	methyl (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-hydroxy-3-(4-methoxyphenyl)propanoate		C₁₇H₁₉NO₄S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XII)

In a variation of the preceding methods, the chiral glycidic amide (XLVII) was used as the synthetic precursor. Amide (XLVII) was either prepared by treatment of the chiral glycidic ester (VI) with ammonia, or by enzymatic resolution of (XII), followed by amidation. Iron-catalyzed addition of 2-aminothiophenol (VII) to the glycidamide (XLVII) in refluxing chlorobenzene yielded the desired threo adduct (XLVIII) as the major isomer. Cyclization of amino amide (XLVIII) under acidic conditions furnished thiazepinone (VIII)

参考文献中间体

合成目标

【1】 Yamada, S.; Tsujioka, I.; Shibatini, T.; Yoshioka, R.; Efficient alterative synthetic route to diltiazem via (2R,3S)-3-(4-methoxyphenyl)glycidamide. Chem Pharm Bull 1999, 47, 2, 146.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	62435	ethyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate		C₁₂H₁₄O₄	详情	详情
(VII)	25182	2-aminobenzenethiol	137-07-5	C₆H₇NS	详情	详情
(VIII)	62436	(2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one		C₁₆H₁₅NO₃S	详情	详情
(XII)	11905	methyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate		C₁₁H₁₂O₄	详情	详情
(XLVII)	62463	(2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxamide		C₁₀H₁₁NO₃	详情	详情
(XLVIII)	62464	(2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-hydroxy-3-(4-methoxyphenyl)propanamide		C₁₆H₁₈N₂O₃S	详情	详情

合成路线4

该中间体在本合成路线中的序号：(IX)

Several related procedures utilize racemic intermediates that are resolved in more advanced synthetic steps. The racemic trans-glycidic ester (IX) was prepared by Darzen's condensation between anisaldehyde (VII) and methyl chloroacetate (VIII). Opening of the epoxide group of (IX) with 2-aminothiophenol (X) in hot chlorobenzene in the presence of FeCl3 gave rise to the racemic threo adduct (XI) which, without isolation, was cyclized to the cis-lactam (XII) by addition of methanesulfonic acid and then heating to reflux. Alkylation of the lactam N of (XII) with 2-(dimethylamino)ethyl chloride (II) led to the racemic precursor (XIII). Resolution of (XIII) to provide the (S,S)-isomer (VII) was then accomplished by preferential crystallization of supersaturated solutions of several sulfonate salts of (XIII) upon seeding with the desired enantiomer. Racemic diltiazem (XIV), obtained by acetylation of (XIII), has been resolved via formation of the corresponding diastereoisomeric salts with (S)-naproxen

参考文献中间体

合成目标

【1】 Gizur, T.; Harsanyi, K.; Fogassy, E.; Studies of the resolution of racemates in the synthesis of diltiazem. J Prakt Chem Chem-Ztg 1994, 336, 7, 628.
【2】 Yamada, S.; Yoshioka, R.; Shibatani, T.; Optical resolution of a 1,5-benzothiazepine derivative,a synthetic intermediate of diltiazem, by preferential crystallization and diastereomeric salt formation. Chem Pharm Bull 1997, 45, 12, 1922.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	11907	Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine	107-99-3	C₄H₁₀ClN	详情	详情
(VII)	27251	4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde	123-11-5	C₈H₈O₂	详情	详情
(VII)	62488	(2S,3S)-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one		C₂₀H₂₄N₂O₃S	详情	详情
(VIII)	10257	methyl 2-chloroacetate; methyl chloroacetate	96-34-4	C₃H₅ClO₂	详情	详情
(IX)	11905	methyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate		C₁₁H₁₂O₄	详情	详情
(X)	25182	2-aminobenzenethiol	137-07-5	C₆H₇NS	详情	详情
(XI)	62439	methyl (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-hydroxy-3-(4-methoxyphenyl)propanoate		C₁₇H₁₉NO₄S	详情	详情
(XII)	62436	(2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one		C₁₆H₁₅NO₃S	详情	详情
(XIII)	62487	5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one		C₂₀H₂₄N₂O₃S	详情	详情
(XIV)	62489	5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl acetate		C₂₂H₂₆N₂O₄S	详情	详情

Extended Information