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【结 构 式】 
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【分子编号】33553 【品名】2-methylacryloyl chloride 【CA登记号】920-46-7 |
【 分 子 式 】C4H5ClO 【 分 子 量 】104.5358 【元素组成】C 45.96% H 4.82% Cl 33.91% O 15.31% |
合成路线1
该中间体在本合成路线中的序号：(V)This compound can be obtained by several related ways: 1) The hydrolysis of ethyl indoline 2 carboxylate (I) with KOH in aqueous DMSO gives indoline 2-carboxylic acid (II), which is acylated with 3-(benzoylthio)-2-methylpropanoyl chloride (III) in methylene chloride yielding 1-[3-(benzoylthio)-2-methyl-1-oxopropyl]indoline-2-carboxylic acid (IV). Finally, this compound is debenzoylated by treatment with 2-methoxyethylamine (A). 2) The acylation of (I) with methacryloyl chloride (V) by means of triethylamine in ether yields ethyl 1-methacryloylindoline-2-carboxylate (VI), which is hydrolyzed with KOH in aqueous DMSO affording 1-methacryloylindoline-2-carboxylic acid (VII). Finally, this compound is treated with thiobenzoic acid (VIII) and 4-dimethylaminopyridine in acetone to give (IV), previously synthesized. 3) The acylation of acid (II) with (V) as before also gives (VII).
| 【1】 Kim, D.H.; et al.; Mercaptopropanoyl)indoline-2-carboxylic acids and related compounds as potent angiotensin converting enzyme inhibitors and antihypertensive agents. J Med Chem 1983, 26, 3, 394-403. |
| 【2】 Serradell, M.N.; Castaner, J.; Blancafort, P.; WY-44221. Drugs Fut 1983, 8, 11, 953. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 34675 | 2-methoxyethylamine; 2-methoxy-1-ethanamine | 109-85-3 | C3H9NO | 详情 | 详情 |
| (I) | 34308 | ethyl (2S)-2,3-dihydro-1H-indole-2-carboxylate | C11H13NO2 | 详情 | 详情 | |
| (II) | 34307 | (2S)-2,3-dihydro-1H-indole-2-carboxylic acid | C9H9NO2 | 详情 | 详情 | |
| (III) | 34309 | S-[(2S)-3-chloro-2-methyl-3-oxopropyl] benzenecarbothioate | C11H11ClO2S | 详情 | 详情 | |
| (IV) | 36214 | (2S)-1-[(2R)-3-(benzoylsulfanyl)-2-methylpropanoyl]-2,3-dihydro-1H-indole-2-carboxylic acid | C20H19NO4S | 详情 | 详情 | |
| (V) | 33553 | 2-methylacryloyl chloride | 920-46-7 | C4H5ClO | 详情 | 详情 |
| (VI) | 36211 | ethyl (2S)-1-methacryloyl-2,3-dihydro-1H-indole-2-carboxylate | C15H17NO3 | 详情 | 详情 | |
| (VII) | 36212 | (2S)-1-methacryloyl-2,3-dihydro-1H-indole-2-carboxylic acid | C13H13NO3 | 详情 | 详情 | |
| (VIII) | 36213 | benzenecarbothioic S-acid | 98-91-9 | C7H6OS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)It is prepared by hydrolysis with ammonia in methanol of N-(3-acetylthio-2-methylpropanoyl)-L-proline (I). Compound (I) can be obtained in three different ways: 1) The reaction of L-proline tert-butyl ester (II) with 3-acetylthio-2-methyl-propanoic acid (III) by means of dicyclohexylcarbodiimide in CH2Cl2 gives N-(3-acetylthio-2-methylpropanoyl)-L-proline tert-butyl ester (IV), which is hydrolyzed with trifluoroacetic acid in anisole. 2) By condensation of L-proline (V) with 3-acetylthio-2-methylpropanoyl chloride (VI) (prepared from the corresponding acid (III) with SOCl2) by means of NaOH in water. 3) The condensation of L-proline (V) with methacryloyl chloride (VII) by means of NaHCO3 in water yields N-methacryloyl-L-proline (VIII), which is then treated with thiolacetic acid (A) and azobisisobutyronitrile. The acid (III) is obtained by addition of thiolacetic acid (IX) to methacrylic acid (X) at 100 C.
| 【1】 Cushman, D.W.; Ondetti, M.A.; Azetidine-2-carboxylic acid derivatives. BE 0851361; DD 283999; JP 58189113; JP 58189158; US 4046889; US 4154840 . |
| 【2】 Roberts, P.J.; Castaner, J.; Captopril. Drugs Fut 1978, 3, 11, 795. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 33555 | Thiolacetic acid; Thioacetic acid; ethanethioic O-acid; Ethanethioic acid | 507-09-5 | C2H4OS | 详情 | 详情 |
| (I) | 33552 | (2S)-1-[(2S)-3-(acetylsulfanyl)-2-methylpropanoyl]-2-pyrrolidinecarboxylic acid | 65167-28-4 | C11H17NO4S | 详情 | 详情 |
| (II) | 19832 | tert-butyl (2S)-2-pyrrolidinecarboxylate | C9H17NO2 | 详情 | 详情 | |
| (III) | 33556 | 3-(acetylsulfanyl)-2-methylpropionic acid | C6H10O3S | 详情 | 详情 | |
| (IV) | 33551 | tert-butyl (2S)-1-[(2S)-3-(acetylsulfanyl)-2-methylpropanoyl]-2-pyrrolidinecarboxylate | C15H25NO4S | 详情 | 详情 | |
| (V) | 16731 | L-proline | 147-85-3 | C5H9NO2 | 详情 | 详情 |
| (VI) | 33557 | S-(3-chloro-2-methyl-3-oxopropyl) ethanethioate | C6H9ClO2S | 详情 | 详情 | |
| (VII) | 33553 | 2-methylacryloyl chloride | 920-46-7 | C4H5ClO | 详情 | 详情 |
| (VIII) | 33554 | (2S)-1-methacryloyl-2-pyrrolidinecarboxylic acid | C9H13NO3 | 详情 | 详情 | |
| (IX) | 12893 | Ethanethioic S-acid | C2H4OS | 详情 | 详情 | |
| (X) | 33550 | 2-methylacrylic acid | 79-41-4 | C4H6O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Coupling of methacryloyl chloride (I) with substituted aniline (II) in dimethylacetamide yields amide (III), which is then converted into the epoxy derivative (IV) by oxidation with m-chloroperbenzoic acid (mCPBA) and 4-methyl-2,6-di-tert-butylphenol (A) in refluxing 1,1,1-trichloroethane. Condensation of (IV) with thiol (V) by means of NaH in THF provides fluorophenylthio derivative (VI), which is finally oxidized with mCPBA in CH2Cl2 to furnish the desired compound trichloroethane.
| 【1】 Tucker, H. (AstraZeneca plc); Amide derivs.. EP 0100172; JP 1990131462; US 4636505 . |
| 【2】 Crook, J.W.; Tucker, H.; Chesterson, G.J.; Nonsteroidal antiandrogens. Synthesis and structure-activity relationships of 3-substituted derivatives of 2-hydroxypropionanilides. J Med Chem 1988, 31, 5, 954. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 48072 | 2,6-di(tert-butyl)-4-methylphenol | 128-37-0 | C15H24O | 详情 | 详情 |
| (I) | 33553 | 2-methylacryloyl chloride | 920-46-7 | C4H5ClO | 详情 | 详情 |
| (II) | 18743 | 4-amino-2-(trifluoromethyl)benzonitrile；5-Amino-2-cyanobenzotrifluoride | 654-70-6 | C8H5F3N2 | 详情 | 详情 |
| (III) | 48071 | N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methylacrylamide | C12H9F3N2O | 详情 | 详情 | |
| (IV) | 48074 | N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyl-2-oxiranecarboxamide | C12H9F3N2O2 | 详情 | 详情 | |
| (V) | 22971 | 4-fluorobenzenethiol; 4-fluorophenylhydrosulfide; 4-Fluorothiophenol | 371-42-6 | C6H5FS | 详情 | 详情 |
| (VI) | 48073 | N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfanyl]-2-hydroxy-2-methylpropanamide | C18H14F4N2O2S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Coupling of the chiral auxiliary (R)-proline (I) with methacryloyl chloride (II) under Schotten-Baumann conditions provided amide (III). This was converted to bromolactone (IV) by asymmetric bromolactonization in the presence of N-bromosuccinimide. Subsequent acid hydrolysis yielded the chiral (R)-bromoacid (V), that was converted to acid chloride (VI) and then coupled with 4-amino-2-trifluoromethylbenzonitrile (VII) in DMA at low temperature to afford anilide (VIII). Coupling with 4-aminothiophenol (IX) using NaH in THF produced sulfide (X). Finally, conversion of the aniline precursor (X) to the target isothiocyanate was achieved by reaction with thiophosgene in the presence of NaHCO3.
| 【1】 Mukherjee, A.; et al.; Affinity labeling of the androgen receptor with nosteroidal chemoaffinity ligands. Biochem Pharmacol 1999, 58, 8, 1259. |
| 【2】 Dalton, J.T.; Miller, D.D.; Kirkovsky, L.; Mukherjee, A.; Yin, D.; Chiral nonsteroidal affinity ligands for the androgen receptor. 1. Bicalutamide analogues bearing electrophilic groups in the B aromatic ring. J Med Chem 2000, 43, 4, 581. |
| 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) | 28284 | D-proline | 344-25-2 | C5H9NO2 | 详情 | 详情 |
| (II) | 33553 | 2-methylacryloyl chloride | 920-46-7 | C4H5ClO | 详情 | 详情 |
| (III) | 40972 | (2R)-1-methacryloyl-2-pyrrolidinecarboxylic acid | C9H13NO3 | 详情 | 详情 | |
| (IV) | 40967 | (3R,8aR)-3-(bromomethyl)-3-methyltetrahydro-1H-pyrrolo[2,1-c][1,4]oxazine-1,4(3H)-dione | C9H12BrNO3 | 详情 | 详情 | |
| (V) | 40968 | (2R)-3-bromo-2-hydroxy-2-methylpropionic acid | C4H7BrO3 | 详情 | 详情 | |
| (VI) | 40969 | (2R)-3-bromo-2-hydroxy-2-methylpropanoyl chloride | C4H6BrClO2 | 详情 | 详情 | |
| (VII) | 18743 | 4-amino-2-(trifluoromethyl)benzonitrile；5-Amino-2-cyanobenzotrifluoride | 654-70-6 | C8H5F3N2 | 详情 | 详情 |
| (VIII) | 40970 | (2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide | C12H10BrF3N2O2 | 详情 | 详情 | |
| (IX) | 16490 | 4-aminophenylhydrosulfide; 4-aminothiophenol; 4-aminobenzenethiol | 1193-02-8 | C6H7NS | 详情 | 详情 |
| (X) | 40971 | (2R)-3-[(4-aminophenyl)sulfanyl]-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide | C18H16F3N3O2S | 详情 | 详情 |