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【结 构 式】 
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【分子编号】14330 【品名】tert-Butyl cyanoacetate; tert-butyl 2-cyanoacetate 【CA登记号】1116-98-9 |
【 分 子 式 】C7H11NO2 【 分 子 量 】141.16988 【元素组成】C 59.56% H 7.85% N 9.92% O 22.67% |
合成路线1
该中间体在本合成路线中的序号：(I)Reaction of tert-butyl cyanoacetate (I) with ethyl mercaptoacetate (II) in the presence of potassium carbonate, followed by N-methylation and ester cleavage affords the intermediate carboxylic acid (III). This compound, by POCl3 in dimethylformamide or by Br2/TPP, is converted to the corresponding acid halogenide (IV), which is finally condensed with 2-chloro-6-methylaniline (V).
| 【1】 Bartoszyk, G.; Hartenstein, J.; Herrmann, M.; Fritschi, E.; Satzinger, G. (Godecke AG); 4-Oxothiazolidin-2-ylideneacetamide derivatives as CNS agents. DE 3317000; EP 0124911; US 4563471 . |
| 【2】 Satzinger, G.; Ralitoline. Drugs Fut 1985, 10, 11, 920. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IVa) | 29787 | 2-(3-methyl-4-oxo-1,3-thiazolidin-2-ylidene)acetyl chloride | C6H6ClNO2S | 详情 | 详情 | |
| (IVb) | 29788 | 2-(3-methyl-4-oxo-1,3-thiazolidin-2-ylidene)acetyl bromide | C6H6BrNO2S | 详情 | 详情 | |
| (I) | 14330 | tert-Butyl cyanoacetate; tert-butyl 2-cyanoacetate | 1116-98-9 | C7H11NO2 | 详情 | 详情 |
| (II) | 23995 | ethyl 2-sulfanylacetate | 2713-34-0 | C4H8O2S | 详情 | 详情 |
| (III) | 29786 | 2-(3-methyl-4-oxo-1,3-thiazolidin-2-ylidene)acetic acid | C6H7NO3S | 详情 | 详情 | |
| (V) | 29789 | 2-chloro-6-methylphenylamine; 2-chloro-6-methylaniline | 87-63-8 | C7H8ClN | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)A new synthesis of T-3761 has been described: The esterification of 2,3,4,5-tetrafluorobenzoic acid (I) with ethyl bromide and K2CO3 in DMSO gives the corresponding ethyl ester (II), which is condensed with tert-butyl cyanoacetate (III) by means of K2CO3, yielding 4-(cyanomethyl)-2,3,5-trifluorobenzoic acid ethyl ester (V) through the intermediate (IV). The cyclopropanation of (V) with 1,2-dibromoethane and benzyltriethylammonium chloride and NaOH in water/dichloromethane affords 4-(1-cyanocyclopropyl)-2,3,5-trifluorobenzoic acid, which by treatment with H2O2 and NaOH is converted to 4-(1-carbamoylcyclopropyl)-2,3,5-trifluorobenzoic acid (VII). Degradation of amide (VII) with Cl2 and NaOH gives the corresponding 4-aminocyclopropyl derivative (VIII), which is acetylated with acetic anhydride to the acetamide (IX). The reaction of (IX) with SOCl2 yields the acid chloride (X), which is condensed with malonic acid monoethyl ester potassium salt (XI) by means of triethylamine to afford 2-[4-(1-acetamidocyclopropyl)-2,3,5-trifluorobenzoyl]acetic acid ethyl ester (XII). The consecutive reaction of (XII) first with dimethylformamide dimethylacetal (XIII) in acetic acid and then with 2(S)-aminopropanol (XIV) gives the benzoylacrylic intermediate (XV), which, without isolation, is treated with K2CO3 in DMSO at 100 C to afford the ethyl ester of the acetylated T-3761 (XVI). Finally, this compound is deprotected by successive treatment first with ethanolic NaOH and then with hot 6N HCl.
| 【1】 Iino, F.; Momonoi, K.; Hayashi, K.; Todo, Y.; Kuroda, H.; Takagi, H.; Narita, H.; Takata, M.; Practical synthesis of T-3761, (S)-10-(1-aminocyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid. Chem Pharm Bull 1994, 42, 12, 2629. |
| 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) | 14328 | 2,3,4,5-tetrafluorobenzoic acid | 1201-31-6 | C7H2F4O2 | 详情 | 详情 |
| (II) | 14313 | diethyl (2S)-2-[(4-[2-[(6R)-2-(acetamido)-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl)amino]pentanedioate | C27H35N5O7 | 详情 | 详情 | |
| (III) | 14330 | tert-Butyl cyanoacetate; tert-butyl 2-cyanoacetate | 1116-98-9 | C7H11NO2 | 详情 | 详情 |
| (IV) | 14331 | ethyl 4-[2-(tert-butoxy)-1-cyano-2-oxoethyl]-2,3,5-trifluorobenzoate | C16H16F3NO4 | 详情 | 详情 | |
| (V) | 14332 | ethyl 4-(cyanomethyl)-2,3,5-trifluorobenzoate | C11H8F3NO2 | 详情 | 详情 | |
| (VI) | 14333 | ethyl 4-(1-cyanocyclopropyl)-2,3,5-trifluorobenzoate | C13H10F3NO2 | 详情 | 详情 | |
| (VII) | 14334 | 4-[1-(aminocarbonyl)cyclopropyl]-2,3,5-trifluorobenzoic acid | C11H8F3NO3 | 详情 | 详情 | |
| (VIII) | 14335 | 4-(1-aminocyclopropyl)-2,3,5-trifluorobenzoic acid | C10H8F3NO2 | 详情 | 详情 | |
| (IX) | 14336 | 4-[1-(acetamido)cyclopropyl]-2,3,5-trifluorobenzoic acid | C12H10F3NO3 | 详情 | 详情 | |
| (X) | 14337 | 4-[1-(acetamido)cyclopropyl]-2,3,5-trifluorobenzoyl chloride | C12H9ClF3NO2 | 详情 | 详情 | |
| (XI) | 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 |
| (XII) | 14339 | ethyl 3-[4-[1-(acetamido)cyclopropyl]-2,3,5-trifluorophenyl]-3-oxopropanoate | C16H16F3NO4 | 详情 | 详情 | |
| (XIII) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (XIV) | 14341 | L-Alaninol; (2S)-2-Amino-1-propanol; L-(+)-Alaninol | 2749-11-3 | C3H9NO | 详情 | 详情 |
| (XV) | 14342 | ethyl (E)-2-[4-[1-(acetamido)cyclopropyl]-2,3,5-trifluorobenzoyl]-3-[[(1S)-2-hydroxy-1-methylethyl]amino]-2-propenoate | C20H23F3N2O5 | 详情 | 详情 | |
| (XVI) | 14343 | ethyl (3S)-10-[1-(acetamido)cyclopropyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate | C20H21FN2O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The condensation of 2(S)-(2-fluorobiphenyl-4-yl)propionic acid (I) with tert-butyl cyanacetate (II) by means of lithium amide in THF gives lithium enolate (III), which is cyclized with hydroxylamine in aqueous DMF to yield the 5-aminoisoxazole (IV). Finally, this compound is condensed with morpholine-4-carbonitrile by means of lithium amide in toluene/tert-butanol to afford the target amidine.
| 【1】 Nakatsuka, M.; et al.; Novel disease modifying anti-rheumatic agents (DMARDs): Syntheses and SAR of 5-guanidinoisoxazoles. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 269. |
| 【2】 Ueno, Y.; Okada, S.; Nakatsuka, M.; Nishikaku, F. (Sumitomo Pharmaceuticals Co., Ltd.); Isoxazole derivs.. EP 0979226; JP 1999240873; US 6100260; WO 9847880 . |
| 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) | 52007 | (2S)-2-(2-fluoro[1,1'-biphenyl]-4-yl)propionic acid | C15H13FO2 | 详情 | 详情 | |
| (II) | 14330 | tert-Butyl cyanoacetate; tert-butyl 2-cyanoacetate | 1116-98-9 | C7H11NO2 | 详情 | 详情 |
| (III) | 52008 | C22H21FLiNO3 | 详情 | 详情 | ||
| (IV) | 52009 | 3-[(1S)-1-(2-fluoro[1,1'-biphenyl]-4-yl)ethyl]-5-isoxazolamine; 3-[(1S)-1-(2-fluoro[1,1'-biphenyl]-4-yl)ethyl]-5-isoxazolylamine | C17H15FN2O | 详情 | 详情 | |
| (V) | 52010 | 4-Morpholinecarbonitrile; Morpholine-4-carbonitrile; N-Cyanomorpholine | 1530-89-8 | C5H8N2O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XI)Condensation between (S)-alpha-methylbenzylamine (I) and ethyl glyoxylate (II) afforded imine (III), which was subjected to hetero-Diels-Alder cycloaddition with 2-(trimethylsilyloxy)-1,3-butadiene (IV) producing piperidinecarboxylate (V) as the major diastereoisomer. Ketalization of (V) with triethyl orthoformate gave the corresponding the diethyl acetal (VI). The ester group of (VI) was then reduced to alcohol (VII) employing LiAlH4. Mitsunobu condensation of alcohol (VII) with phthalimide (VIII) gave (IX) which, followed by acidic ketal hydrolysis, furnished (X). Condensation of piperidinone (X) with t-butyl cyanoacetate (XI) in the presence of sulfur and morpholine gave rise to two regioisomeric thienopyridine derivatives (XII) and (XIII), which were separated by column chromatography.
| 【1】 Lau, J.; Andersen, H.S.; Newman, M.J.; Hansen, T.K.; Olsen, O.H.; Bakir, F.; Holsworth, D.D.; Axe, F.U.; Ge, Y.; Uyeda, R.T.; Judge, L.M.; Moeller, N.P.H.; Shapira, B.Z. (Novo Nordisk A/S; Ontogen Corp.); Modulators of protein tyrosine phosphatases (PTPases). WO 0204459 . |
| 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) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (II) | 48591 | Ethyl glyoxylate; Ethyl oxoacetate; Glyoxylic acid ethyl ester | 924-44-7 | C4H6O3 | 详情 | 详情 |
| (III) | 58785 | ethyl 2-{[(1S)-1-phenylethyl]imino}acetate | C12H15NO2 | 详情 | 详情 | |
| (IV) | 18557 | 1-methylene-2-propenyl trimethylsilyl ether; trimethyl[(1-methylene-2-propenyl)oxy]silane | 38053-91-7 | C7H14OSi | 详情 | 详情 |
| (V) | 58786 | ethyl (2R)-4-oxo-1-[(1S)-1-phenylethyl]-2-piperidinecarboxylate | C16H21NO3 | 详情 | 详情 | |
| (VI) | 58787 | ethyl (2R)-4,4-diethoxy-1-[(1S)-1-phenylethyl]-2-piperidinecarboxylate | C20H31NO4 | 详情 | 详情 | |
| (VII) | 58788 | {(2R)-4,4-diethoxy-1-[(1S)-1-phenylethyl]piperidinyl}methanol | C18H29NO3 | 详情 | 详情 | |
| (VIII) | 12376 | Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione | 85-41-6 | C8H5NO2 | 详情 | 详情 |
| (IX) | 58789 | 2-({(2R)-4,4-diethoxy-1-[(1S)-1-phenylethyl]piperidinyl}methyl)-1H-isoindole-1,3(2H)-dione | C26H32N2O4 | 详情 | 详情 | |
| (X) | 58790 | 2-({(2R)-4-oxo-1-[(1S)-1-phenylethyl]piperidinyl}methyl)-1H-isoindole-1,3(2H)-dione | C22H22N2O3 | 详情 | 详情 | |
| (XI) | 14330 | tert-Butyl cyanoacetate; tert-butyl 2-cyanoacetate | 1116-98-9 | C7H11NO2 | 详情 | 详情 |
| (XII) | 58791 | tert-butyl (7S)-2-amino-7-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-6-[(1S)-1-phenylethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate | C29H31N3O4S | 详情 | 详情 | |
| (XIII) | 58792 | tert-butyl (5R)-2-amino-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-6-[(1S)-1-phenylethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate | C29H31N3O4S | 详情 | 详情 |