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【结 构 式】 
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【分子编号】23995 【品名】ethyl 2-sulfanylacetate 【CA登记号】2713-34-0 |
【 分 子 式 】C4H8O2S 【 分 子 量 】120.17232 【元素组成】C 39.98% H 6.71% O 26.63% S 26.68% |
合成路线1
该中间体在本合成路线中的序号：(II)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：(II)This compound can be prepared by the route shown in scheme: Reaction of chlorodifluoromethane (Freon 22) with ethyl thioglycolate (II) in the presence of ethanolic sodium ethoxide gives ethyl 2-(difluoro-methylthio)acetate (III), which is hydrolyzed with aqueous potassium hydroxide to yield 2-(difluoromethylthio)acetic acid (IV). Substitution of diphenylmethyl-7alpha-benzamido-3-chloromethyl-1-oxa-3-cephem-4-carboxylate (V), an important intermediate for production of latamoxef, with 1-(2-hydroxyethyl)-1H-tetrazole-5-thiol (VI) in the presence of sodium methoxide, followed by protection of the hydroxyl group by means of p-methylbenzyl chlorocarbonate (VII) and pyridine, gives diphenylmethyl 7alpha-benzamido-3-[[1-[2-(p-methylbenzyloxycarbonyloxy)ethyl-1H-tetrazol-5-yl]thiomethyl]-1-oxa-3-cephem-4-carboxylate (VIII). Methoxylation of (VIII) with tert-butylhypochlorite and lithium methoxide, followed by the conventional side-chain cleavage with phosphorus pentachloride pyridine methanol, affords diphenylmethyl 7beta-amino-7alpha-methoxy-3-[[1-[2-(p-methylbenzyloxycarbonyloxy)ethyl]-1H-tetrazol-5-yl]thiomethyl]-1-oxa-3-cephem-4-carboxylate (X). This amine (IX) is condensed with the acid (IV) by means of phosphoryl chloride and pyridine fo yield diphenyl-methyl 7beta[2-(dfluoromelhylthio)acetamido]-7alpha-methoxy-3-[[1-[2-(p-methylbenzyloxycarbonyloxy)ethyl]-1H-tetrazol-5 yl)thiomethyl]-1-oxa-3-cephem 4-carboxylate (X), which undergoes deprotection with stannic chloride and anisole, neutralization with aqueous sodium bicarbonate and lyophilization giving the sodium salt (XI).
| 【1】 Tsuji, T.; et al.; Synthesis and antibacterial activity of 6315-S, a new member of the oxacephem antibiotic. J Antibiot 1984, 38, 4, 466. |
| 【2】 Castaner, J.; Serradell, M.N.; Flomoxef sodium. Drugs Fut 1986, 11, 6, 452. |
| 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) | 23985 | Chlorodifluoromethane; Chloro(difluoro)methane | 75-45-6 | CHClF2 | 详情 | 详情 |
| (II) | 23995 | ethyl 2-sulfanylacetate | 2713-34-0 | C4H8O2S | 详情 | 详情 |
| (III) | 23994 | ethyl 2-[(difluoromethyl)sulfanyl]acetate | C5H8F2O2S | 详情 | 详情 | |
| (IV) | 23986 | 2-[(difluoromethyl)sulfanyl]acetic acid | C3H4F2O2S | 详情 | 详情 | |
| (V) | 23987 | benzhydryl (7R)-7-(benzoylamino)-3-(chloromethyl)-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C28H23ClN2O5 | 详情 | 详情 | |
| (VI) | 23988 | 2-(5-sulfanyl-1H-1,2,3,4-tetraazol-1-yl)-1-ethanol | C3H6N4OS | 详情 | 详情 | |
| (VII) | 23989 | 1-[[(chlorocarbonyl)oxy]methyl]-4-methylbenzene | C9H9ClO2 | 详情 | 详情 | |
| (VIII) | 23990 | benzhydryl (7R)-7-(benzoylamino)-3-[([1-[2-([[(3-methylbenzyl)oxy]carbonyl]oxy)ethyl]-1H-1,2,3,4-tetraazol-5-yl]sulfanyl)methyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C40H36N6O8S | 详情 | 详情 | |
| (IX) | 23991 | benzhydryl (7R)-7-amino-7-methoxy-3-[([1-[2-([[(3-methylbenzyl)oxy]carbonyl]oxy)ethyl]-1H-1,2,3,4-tetraazol-5-yl]sulfanyl)methyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C34H34N6O8S | 详情 | 详情 | |
| (X) | 23992 | benzhydryl (7R)-7-([2-[(difluoromethyl)sulfanyl]acetyl]amino)-3-[[(1-[2-[(ethoxycarbonyl)oxy]ethyl]-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C31H32F2N6O9S2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The reaction of ethyl 2-sulfanylacetate (I) with 2-bromoacetonitrile (II) by means of NaOEt in ethanol gives ethyl 2-(cyanomethylsulfanyl)acetate (III), which is cyclized with diethyl oxalate (IV) by means of NaOEt in ethanol yielding 5-cyano-3,4-dihydroxythiophene-2-carboxylic acid ethyl ester (V). The protection of the hydroxyl groups of (V) with 2-methoxyethoxymethyl chloride (Mem-Cl) and DIEA in dichloromethane affords the protected thiophene (VI), which is reduced with (t-BuO)2AlH in THF providing the carbinol (VII). The oxidation of (VII) with MnO2 in dichloromethane yields the carbaldehyde (VIII), which is condensed with malonodinitrile (IX) by means of piperidine in dioxane giving the alkylidenemalonodinitrile (X). The epoxidation of (X) with tert-butyl hydroperoxide and TEA in dioxane yields the epoxide (XI), which is treated with HCl in THF to afford 2-chloro-2-[5-cyano-3,4-bis(2-methoxyethoxymethoxy) thiophen-2-yl]acetic acid (XII). The esterification of (XII) with diphenyldiazomethane affords the corresponding diphenylmethyl ester (XIII), which is condensed with N-hydroxyphthalimide (XIV) and NaHCO3 in dichloromethane providing the adduct (XV). The cleavage of the phthalimido group of (XV) with hydrazine in methanol gives 2-(aminooxy)-2-[5-cyano-3,4-bis(2-methoxyethoxymethoxy)thiophen-2-yl]acetic acid diphenylmethyl ester (XVI), which is condensed with 2-oxo-2-[2-(tritylamino)thiazol-4-yl]acetic acid (XVII) yielding the corresponding alcoxyimino derivative (XVIII).
| 【1】 Aszodi, J.; Dini, C.; Fauveau, P. (Aventis Pharma SA); Cephalosporins having in position 7 as substd. axymino radical, intermediates, processes for their preparation and their use as medicaments. CA 2111164; EP 0628562; JP 1994345776 . |
| 【2】 Dini, C.; Aszodi, J.; Synthesis of a dihydroxythiophene analogue of catechosporines. Bioorg Med Chem Lett 2000, 10, 4, 349. |
| 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) | 23995 | ethyl 2-sulfanylacetate | 2713-34-0 | C4H8O2S | 详情 | 详情 |
| (II) | 31883 | 2-bromoacetonitrile | 590-17-0 | C2H2BrN | 详情 | 详情 |
| (III) | 35506 | ethyl 2-[(cyanomethyl)sulfanyl]acetate | C6H9NO2S | 详情 | 详情 | |
| (IV) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (V) | 35507 | ethyl 5-cyano-3,4-dihydroxy-2-thiophenecarboxylate | C8H7NO4S | 详情 | 详情 | |
| (VI) | 35508 | ethyl 5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thiophenecarboxylate | C16H23NO8S | 详情 | 详情 | |
| (VII) | 35509 | 5-(hydroxymethyl)-3,4-bis[(2-methoxyethoxy)methoxy]-2-thiophenecarbonitrile | C14H21NO7S | 详情 | 详情 | |
| (VIII) | 35510 | 5-formyl-3,4-bis[(2-methoxyethoxy)methoxy]-2-thiophenecarbonitrile | C14H19NO7S | 详情 | 详情 | |
| (X) | 35511 | 2-([5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]methylene)malononitrile | C17H19N3O6S | 详情 | 详情 | |
| (XI) | 35512 | 3-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]-2,2-oxiranedicarbonitrile | C17H19N3O7S | 详情 | 详情 | |
| (XII) | 35513 | 2-chloro-2-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]acetic acid | C15H20ClNO8S | 详情 | 详情 | |
| (XIII) | 35514 | benzhydryl 2-chloro-2-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]acetate | C28H30ClNO8S | 详情 | 详情 | |
| (XIV) | 13505 | N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione | 524-38-9 | C8H5NO3 | 详情 | 详情 |
| (XV) | 35515 | benzhydryl 2-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]acetate | C36H34N2O11S | 详情 | 详情 | |
| (XVI) | 35516 | benzhydryl 2-(aminooxy)-2-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]acetate | C28H32N2O9S | 详情 | 详情 | |
| (XVII) | 23008 | 2-oxo-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid | C24H18N2O3S | 详情 | 详情 | |
| (XVIII) | 35517 | 2-[(2-(benzhydryloxy)-1-[5-cyano-3,4-bis[(2-methoxyethoxy)methoxy]-2-thienyl]-2-oxoethoxy)imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid | C52H48N4O11S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)Condensation of (4-methoxyphenyl)acetic acid (I) with anisole (II) in hot PPA produced ketone (III). Subsequent treatment of (III) with the Vilsmeier reagent afforded chloroaldehyde (IV). The required thiophene (VI) was then obtained by cyclization with ethyl mercaptoacetate (V) in the presence of NaOEt. After basic hydrolysis of the ester group of (VI), the resulting acid (VII) was decarboxylated by means of copper in quinoline at 180 C, yielding thiophene (VIII). Stannic chloride-promoted Friedel-Crafts acylation of (VIII) with 3-(methoxycarbonyl)propionyl chloride (IX) gave ketoester (X). The keto group of (X) was further reduced employing triethylsilane in trifluoroacetic acid to afford (XI). Hydrolysis of the methyl ester of (XI), followed by treatment with oxalyl chloride furnished acid chloride (XII). The title hydroxamic acid was then obtained by coupling of (XII) with O-(tert-butyldimethylsilyl)-N-methylhydroxylamine and subsequent acid-catalyzed desilylation.
| 【1】 Wierzbicki, M.; Sauveur, F.; Bonnet, J.; Tordjman, C. (ADIR et Cie.); Thiophene cpds., process for their preparation and pharmaceutical compsns. containing them. EP 0728755; FR 2730996; JP 1996253470 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40600 | tert-butyl(dimethyl)[(methylamino)oxy]silane; O-[tert-butyl(dimethyl)silyl]-N-methylhydroxylamine | C7H19NOSi | 详情 | 详情 | ||
| (I) | 34793 | 2-(4-methoxyphenyl)acetic acid; p-Methoxyphenyl formate; Homoanisic acid; p-Methyl benzyl formate; 4-methoxyphenylacetic acid; 4-methoxybenzeneacetic acid; p-methoxyphenylacetic acid | 104-01-8 | C9H10O3 | 详情 | 详情 |
| (II) | 23767 | Methoxybenzene; Methyl phenyl ether; Anisole | 100-66-3 | C7H8O | 详情 | 详情 |
| (III) | 22991 | 1,2-bis(4-methoxyphenyl)-1-ethanone | 120-44-5 | C16H16O3 | 详情 | 详情 |
| (IV) | 34794 | (E)-3-chloro-2,3-bis(4-methoxyphenyl)-2-propenal | C17H15ClO3 | 详情 | 详情 | |
| (V) | 23995 | ethyl 2-sulfanylacetate | 2713-34-0 | C4H8O2S | 详情 | 详情 |
| (VI) | 34795 | ethyl 4,5-bis(4-methoxyphenyl)-2-thiophenecarboxylate | C21H20O4S | 详情 | 详情 | |
| (VII) | 34796 | 4,5-bis(4-methoxyphenyl)-2-thiophenecarboxylic acid | C19H16O4S | 详情 | 详情 | |
| (VIII) | 34797 | 2,3-bis(4-methoxyphenyl)thiophene; 4-[2-(4-methoxyphenyl)-3-thienyl]phenyl methyl ether | C18H16O2S | 详情 | 详情 | |
| (IX) | 18060 | 4-Chloro-4-oxobutyric acid methyl ester; 3-Carbomethosypropionyl chloride; Methyl 4-chloro-4-oxobutanoate | 1490-25-1 | C5H7ClO3 | 详情 | 详情 |
| (X) | 34798 | methyl 4-[4,5-bis(4-methoxyphenyl)-2-thienyl]-4-oxobutanoate | C23H22O5S | 详情 | 详情 | |
| (XI) | 34799 | methyl 4-[4,5-bis(4-methoxyphenyl)-2-thienyl]butanoate | C23H24O4S | 详情 | 详情 | |
| (XII) | 34800 | 4-[4,5-bis(4-methoxyphenyl)-2-thienyl]butanoyl chloride | C22H21ClO3S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XVI)Treatment of carboxylic acid (I) with MeOH and H2SO4 yields methyl ester (II), which is then converted into cyano derivative (III) by reaction with LiCN in DMF and AcOH. Hydrolysis of (III) with aqueous KOH in EtOH provides dicarboxylic acid (IV), which is cyclized by means of Ac2O to give the dicarboxylic anhydride (V). Alternatively, (V) can be obtained by condensation of ester (VI) with diethyl oxalate (A) in Et2O in the presence of t-BuOK to afford (VII), which is cyclized with H2SO4 and submitted to catalytic hydrogenation over Pd/C. Condensation of anhydride (V) with (S)-alpha-methylbenzylamine yields a mixture of imides, from which (3aR,9bR)-(IX) is obtained by crystallization. Reduction of (3aR,9bR)-(IX) with BH3·THF followed by hydrogenation over Pd/C affords isoindole derivative (X), which is then alkylated with chloroacetonitrile (XI) in acetonitrile in the presence of DIEA and reduced with LiAlH4 to give the primary amine (XII). Treatment of (XIII) with POCl3 and Et3N yields 2-chloro-3-cyanopyrazine (XIV), which is oxidized to provide (XV) by means of K2S2O8 in H2SO4. Treatment of N-oxide (XV) with ethyl thioglycolate (XVI) and NaOEt in DMF affords pyrazinothiophene (XVII), which is then chlorinated with POCl3 to give (XVIII). Finally, reaction of amine (XII) with (XVIII) and triphosgene in toluene and Et3N affords the desired product.
| 【1】 Meyer, M.D.; Altenbach, R.J.; Basha, F.Z.; Carroll, W.A.; Drizin, I.; Kerwin, J.F. Jr.; Lebold, S.A.; Lee, E.L.; Elmore, S.W.; Sippy, K.B.; Tietje, K.R.; Wendt, M.D.; Yamamoto, D.M. (Abbott Laboratories Inc.); Tricyclic substd. hexahydrobenz[e]isoindole alpha-1 adrenergic antagonists. EP 0808318; US 5597823; WO 9622992 . |
| 【2】 Basha, F.Z.; Meyer, M.D.; Altenbach, R.J.; et al.; Structure-activity studies for a novel series of tricycic substituted hexahydrobenz[e]isoindole alpha1A adrenoceptor antagonists as potential agents for the symptomatic treatment of bening prostatic hyperplasia (BPH). J Med Chem 2000, 43, 8, 1586. |
| 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) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (I) | 42524 | 5-methoxy-3,4-dihydro-1-naphthalenecarboxylic acid | C12H12O3 | 详情 | 详情 | |
| (II) | 42525 | methyl 5-methoxy-3,4-dihydro-1-naphthalenecarboxylate | C13H14O3 | 详情 | 详情 | |
| (III) | 42526 | methyl 2-cyano-5-methoxy-1,2,3,4-tetrahydro-1-naphthalenecarboxylate | C14H15NO3 | 详情 | 详情 | |
| (IV) | 42527 | 5-methoxy-1,2,3,4-tetrahydro-1,2-naphthalenedicarboxylic acid | C13H14O5 | 详情 | 详情 | |
| (V) | 42528 | (3aR,9bR)-6-methoxy-3a,4,5,9b-tetrahydronaphtho[1,2-c]furan-1,3-dione | C13H12O4 | 详情 | 详情 | |
| (VI) | 42529 | ethyl 4-(2-methoxyphenyl)butanoate | C13H18O3 | 详情 | 详情 | |
| (VII) | 42530 | diethyl 2-(2-methoxyphenethyl)-3-oxosuccinate | C17H22O6 | 详情 | 详情 | |
| (VIII) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (IX) | 42531 | (3aR,9bR)-6-methoxy-2-[(1S)-1-phenylethyl]-3a,4,5,9b-tetrahydro-1H-benzo[e]isoindole-1,3(2H)-dione | C21H21NO3 | 详情 | 详情 | |
| (X) | 42532 | (3aR,9bR)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindol-6-yl methyl ether; (3aR,9bR)-6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole | C13H17NO | 详情 | 详情 | |
| (XI) | 14443 | 2-chloroacetonitrile; chloroacetonitrile | 107-14-2 | C2H2ClN | 详情 | 详情 |
| (XII) | 42533 | (3aR,9bR)-2-(2-aminoethyl)-6-methoxy-3a,4,5,9b-tetrahydro-1H-benzo[e]isoindole-1,3(2H)-dione | C15H18N2O3 | 详情 | 详情 | |
| (XIII) | 42534 | 3-hydroxy-2-pyrazinecarboxamide | 55321-99-8 | C5H5N3O2 | 详情 | 详情 |
| (XIV) | 42535 | 3-chloro-2-pyrazinecarbonitrile | 55557-52-3 | C5H2ClN3 | 详情 | 详情 |
| (XV) | 42536 | 3-chloro-2-cyanopyrazin-1-ium-1-olate | C5H2ClN3O | 详情 | 详情 | |
| (XVI) | 23995 | ethyl 2-sulfanylacetate | 2713-34-0 | C4H8O2S | 详情 | 详情 |
| (XVII) | 42537 | 7-amino-6-(ethoxycarbonyl)thieno[2,3-b]pyrazin-1-ium-1-olate | C9H9N3O3S | 详情 | 详情 | |
| (XVIII) | 42538 | ethyl 7-amino-2-chlorothieno[2,3-b]pyrazine-6-carboxylate | C9H8ClN3O2S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VI)Opening of the (S,S)-epoxide (I) with the silylmethyl Grignard reagent (II) in the presence of CuI, followed by oxidative cleavage of the silyl alcohol (III) with H2O2 gave diol (IV). Then, selective protection of the primary hydroxyl group of (IV) with tert-butyldimethylsilyl chloride, followed by condensation with methanesulfonyl chloride, afforded mesylate (V). Subsequent alkylation of the sodium salt of ethyl mercaptoacetate (VI) gave thioether (VII). Desilylation of (VII) with tetrabutylammonium fluoride, followed by mesylation provided sulfonate (VIII). Subsequent intramolecular ring closure of (VIII) using NaH in DMF produced the tetrahydrothiophene (IX) as a 2:3 mixture of stereoisomers. Hydrolysis of the ethyl ester of (IX) with LiOH gave carboxylic acid (X), which was submitted to a modified Hunsdiecker reaction with Pb(OAc)4 to furnish the 1-O-acetate (XI) as a 1:1 anomeric mixture.
| 【1】 Upcroft, P.; Campbell, R.W.; Benakli, K.; Upcroft, J.A.; Vanelle, P.; Efficacy of new 5-nitroimidazoles against metronidazole-susceptible and -resistant Giardia, Trichomonas, and Entamoeba spp. Antimicrob Agents Chemother 1999, 43, 1, 73. |
| 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) | 25266 | benzyl [(2S,3S)-3-[(benzyloxy)methyl]oxiranyl]methyl ether; (2S,3S)-2,3-bis[(benzyloxy)methyl]oxirane | C18H20O3 | 详情 | 详情 | |
| (III) | 25267 | (2R,3R)-1,4-bis(benzyloxy)-3-[[isopropoxy(dimethyl)silyl]methyl]-2-butanol | C24H36O4Si | 详情 | 详情 | |
| (IV) | 25268 | (2R,3R)-4-(benzyloxy)-2-[(benzyloxy)methyl]-1,3-butanediol | C19H24O4 | 详情 | 详情 | |
| (V) | 25269 | (1R,2S)-3-(benzyloxy)-1-[(benzyloxy)methyl]-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)propyl methanesulfonate | C26H40O6SSi | 详情 | 详情 | |
| (VI) | 23995 | ethyl 2-sulfanylacetate | 2713-34-0 | C4H8O2S | 详情 | 详情 |
| (VII) | 25270 | ethyl 2-[[(1S,2S)-3-(benzyloxy)-1-[(benzyloxy)methyl]-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)propyl]sulfanyl]acetate | C29H44O5SSi | 详情 | 详情 | |
| (VIII) | 25271 | ethyl 2-[((1S,2S)-3-(benzyloxy)-1-[(benzyloxy)methyl]-2-[[(methylsulfonyl)oxy]methyl]propyl)sulfanyl]acetate | C24H32O7S2 | 详情 | 详情 | |
| (IX) | 25272 | ethyl (4R,5S)-4,5-bis[(benzyloxy)methyl]tetrahydro-2-thiophenecarboxylate | C23H28O4S | 详情 | 详情 | |
| (X) | 25273 | (4R,5S)-4,5-bis[(benzyloxy)methyl]tetrahydro-2-thiophenecarboxylic acid | C21H24O4S | 详情 | 详情 | |
| (XI) | 25274 | (4R,5S)-4,5-bis[(benzyloxy)methyl]tetrahydro-2-thiophenyl acetate | C22H26O4S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VI)The condensation between 3-methoxybenzaldehyde (I), S-methylisothiourea (II) and ethyl cyanoacetate (III) in the presence of K2CO3 in hot EtOH leads to pyrimidine (IV). Subsequent chlorination of (IV) by means of POCl3 and dimethylaniline furnishes the 6-chloropyrimidine (V). Reaction of (V) with ethyl mercaptoacetate (VI) and potassium tert-butoxide gives rise to the thienopyrimidine (VII). The ethyl ester group of (VII) is then hydrolyzed to the carboxylic acid (VIII) employing LiOH. Finally, coupling of acid (VIII) with tert-butylamine by means of TBTU produces the target N-tert-butyl amide
| 【1】 Adang, A.E.P.; Gerritsma, G.G.; Van Straten, N.C.R. (Akzo Nobel N.V.); Bicyclic heteroaromatic cpds. useful as LH agonists. EP 1171443; JP 2002541259; US 6569863; WO 0061586 . |
| 【2】 Timmers, C.M.; Karstens, W.F.J. (Akzo Nobel N.V.); Bicyclic heteroaromatic cpds.. WO 0224703 . |
| 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) | 20589 | 3-methoxybenzaldehyde; m-Anisaldehyde | 591-31-1 | C8H8O2 | 详情 | 详情 |
| (II) | 10272 | [[Amino(imino)methyl]sulfanyl]methane | 2986-19-8 | C2H6N2S | 详情 | 详情 |
| (III) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (IV) | 60410 | 4-hydroxy-6-(3-methoxyphenyl)-2-(methylsulfanyl)-5-pyrimidinecarbonitrile | C13H11N3O2S | 详情 | 详情 | |
| (V) | 60411 | 4-chloro-6-(3-methoxyphenyl)-2-(methylsulfanyl)-5-pyrimidinecarbonitrile | C13H10ClN3OS | 详情 | 详情 | |
| (VI) | 23995 | ethyl 2-sulfanylacetate | 2713-34-0 | C4H8O2S | 详情 | 详情 |
| (VII) | 60412 | ethyl 5-amino-4-(3-methoxyphenyl)-2-(methylsulfanyl)thieno[2,3-d]pyrimidine-6-carboxylate | C17H17N3O3S2 | 详情 | 详情 | |
| (VIII) | 60413 | 5-amino-4-(3-methoxyphenyl)-2-(methylsulfanyl)thieno[2,3-d]pyrimidine-6-carboxylic acid | C15H13N3O3S2 | 详情 | 详情 |