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【结 构 式】 
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【分子编号】24677 【品名】1,3-benzothiazol-2-ylhydrosulfide 【CA登记号】149-30-4 |
【 分 子 式 】C7H5NS2 【 分 子 量 】167.25544 【元素组成】C 50.27% H 3.01% N 8.37% S 38.34% |
合成路线1
该中间体在本合成路线中的序号：(I)Condensation of 2-mercaptobenzothiazole (I) with isonicotinic acid hydrazide (INH) (II) in the presence of formaldehyde affords H-15 in 80% yield.
| 【1】 Odlerova, Z.; Holbova, E.; Benzothiazole compounds. XVI. Preparation aand antimycobacterial activity of N',N'-bis))2-thioxo-3-benzothiazolinyl)methyl)hydrazides. ChemZvesti 1989, 34, 399. |
| 【2】 Shaefer, H.; et al. (Byk Gulden Lomberg Chemische Fabrik GmbH); Alkylsubstituierte piperidin-N-oxide, verfahren zu ihrer herstellung. Ihre verwendung und sie enthaltende Arzneimittel. DE 2825322 . |
| 【3】 Radi, S.; H-15. Drugs Fut 1986, 11, 9, 743. |
合成路线2
该中间体在本合成路线中的序号：(XXXI)The oxidation of (XXV) with DMP in dichloromethane gives the aldehyde (XXVII), which is condensed with phosphorane (XXVIII) in refluxing toluene to yield aldehyde (XXIX). The reduction of (XXIX) with Zn(BH4)2 in ethyl ether affords alcohol (XXX), which is condensed with 2-sulfanylbenzothiazole (XXXI) by means of Bu3P and TMAD in benzene providing the thioether (XXXII). The oxidation of (XXXII) with Mo7O24(NH4)6 and H2O2 in ethanol gives the sulfone (XXXIII), which is condensed with the aldehyde (XXXIV) by means of LHMDS in THF to yield intermediate (XXXV). The selective monodesilylation of (XXXV) with PPTS in chloroform/methanol, followed by oxidation with DMP, affords the aldehyde (XXXVI).
| 【1】 Shimizu, T.; et al.; Total synthesis of reveromycin A. Org Lett 2000, 2, 14, 2153. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXV) | 42472 | 1-allyl 4-[(2S,3R,6S,8R,9S)-2-[(1E,3E)-5-(allyloxy)-3-methyl-5-oxo-1,3-pentadienyl]-3-butyl-8-(2-hydroxyethyl)-9-methyl-1,7-dioxaspiro[5.5]undec-3-yl] succinate | C32H48O9 | 详情 | 详情 | |
| (XXVII) | 42474 | 1-allyl 4-[(2S,3R,6S,8R,9S)-2-[(1E,3E)-5-(allyloxy)-3-methyl-5-oxo-1,3-pentadienyl]-3-butyl-9-methyl-8-(2-oxoethyl)-1,7-dioxaspiro[5.5]undec-3-yl] succinate | C32H46O9 | 详情 | 详情 | |
| (XXVIII) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (XXIX) | 42475 | 1-allyl 4-[(2S,3R,6S,8R,9S)-2-[(1E,3E)-5-(allyloxy)-3-methyl-5-oxo-1,3-pentadienyl]-3-butyl-9-methyl-8-[(E)-3-methyl-4-oxo-2-butenyl]-1,7-dioxaspiro[5.5]undec-3-yl] succinate | C35H50O9 | 详情 | 详情 | |
| (XXX) | 42476 | 1-allyl 4-[(2S,3R,6S,8R,9S)-2-[(1E,3E)-5-(allyloxy)-3-methyl-5-oxo-1,3-pentadienyl]-3-butyl-8-[(E)-4-hydroxy-3-methyl-2-butenyl]-9-methyl-1,7-dioxaspiro[5.5]undec-3-yl] succinate | C35H52O9 | 详情 | 详情 | |
| (XXXI) | 24677 | 1,3-benzothiazol-2-ylhydrosulfide | 149-30-4 | C7H5NS2 | 详情 | 详情 |
| (XXXII) | 42477 | 1-allyl 4-[(2S,3R,6S,8R,9S)-2-[(1E,3E)-5-(allyloxy)-3-methyl-5-oxo-1,3-pentadienyl]-8-[(E)-4-(1,3-benzothiazol-2-ylsulfanyl)-3-methyl-2-butenyl]-3-butyl-9-methyl-1,7-dioxaspiro[5.5]undec-3-yl] succinate | C42H55NO8S2 | 详情 | 详情 | |
| (XXXIII) | 42478 | 1-allyl 4-[(2S,3R,6S,8R,9S)-2-[(1E,3E)-5-(allyloxy)-3-methyl-5-oxo-1,3-pentadienyl]-8-[(E)-4-(1,3-benzothiazol-2-ylsulfonyl)-3-methyl-2-butenyl]-3-butyl-9-methyl-1,7-dioxaspiro[5.5]undec-3-yl] succinate | C42H55NO10S2 | 详情 | 详情 | |
| (XXXIV) | 42479 | (2R,3S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-[(triethylsilyl)oxy]butanal | C17H38O3Si2 | 详情 | 详情 | |
| (XXXV) | 42480 | 1-allyl 4-((2S,3R,6S,8R,9S)-2-[(1E,3E)-5-(allyloxy)-3-methyl-5-oxo-1,3-pentadienyl]-3-butyl-8-[(2E,4E,6S,7S)-6-[[tert-butyl(dimethyl)silyl]oxy]-3,7-dimethyl-8-[(triethylsilyl)oxy]-2,4-octadienyl]-9-methyl-1,7-dioxaspiro[5.5]undec-3-yl) succinate | C52H88O10Si2 | 详情 | 详情 | |
| (XXXVI) | 42481 | 1-allyl 4-[(2S,3R,6S,8R,9S)-2-[(1E,3E)-5-(allyloxy)-3-methyl-5-oxo-1,3-pentadienyl]-3-butyl-8-((2E,4E,6S,7R)-6-[[tert-butyl(dimethyl)silyl]oxy]-3,7-dimethyl-8-oxo-2,4-octadienyl)-9-methyl-1,7-dioxaspiro[5.5]undec-3-yl] succinate | C46H72O10Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)Protection of D-alaninol (I) with di-tert-butyl dicarbonate gave rise to carbamate (II). Subsequent Mitsunobu coupling of (II) with 2-mercaptobenzothiazole (III) furnished thioether (IV), which was deprotected with HCl in EtOAc. The resulting amine (V) was condensed with dichloropurine (VI) to afford the chloroadenosine derivative (VII). Finally, cleavage of the acetate esters of (VII) was achieved by treatment with NaOMe in MeOH.
| 【1】 Lau, J.; Judge, M.E.; Sheardown, M.J.; Petersen, H.; Shalmi, M.; Knutsen, L.J.S.; Hansen, A.J.; Thomsen, C.; Weis, J.U.; N-substituted adenosines as novel neuroprotective A1 agonists with diminished hypotensive effects. J Med Chem 1999, 42, 18, 3463. |
| 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) | 21414 | (2R)-2-Amino-1-propanol; D-Alaninol; D-(-)-Alaninol | 35320-23-1 | C3H9NO | 详情 | 详情 |
| (II) | 31758 | tert-butyl (1R)-2-hydroxy-1-methylethylcarbamate | C8H17NO3 | 详情 | 详情 | |
| (III) | 24677 | 1,3-benzothiazol-2-ylhydrosulfide | 149-30-4 | C7H5NS2 | 详情 | 详情 |
| (IV) | 31759 | tert-butyl (1R)-2-(1,3-benzothiazol-2-ylsulfanyl)-1-methylethylcarbamate | C15H20N2O2S2 | 详情 | 详情 | |
| (V) | 31760 | (2R)-1-(1,3-benzothiazol-2-ylsulfanyl)-2-propanamine; (1R)-2-(1,3-benzothiazol-2-ylsulfanyl)-1-methylethylamine | C10H12N2S2 | 详情 | 详情 | |
| (VI) | 25228 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(2,6-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C16H16Cl2N4O7 | 详情 | 详情 | |
| (VII) | 31761 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-[[(1R)-2-(1,3-benzothiazol-2-ylsulfanyl)-1-methylethyl]amino]-2-chloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C26H27ClN6O7S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(A)1) Treatment of 6-azopenicillanate (I) with boron trifluoroetherate in a mixture of methanol and methylene chloride gives 6alpha-methoxy penicillanate (II), which on oxidation with peracetic acid gives the corresponding 1beta-oxide (III). Ring opening of the oxide (III) by heating with 2-mercaptohenzothiazole in toluene gives the intermediate (IV), which on cyclization with bromine in methylene chloride gives 2beta-bromomethyl penicillanate (V). Rearrangement of (V) with pyridine in dimethyl sulfoxide gives the cephem intermediate (VI). The sulfone derivative (VII) is obtained by oxidizing (VI) with peracetic acid in methylene chloride. Introduction of the double bound at C-2 position of the sulfone (VII) is achieved by heating with dimethylamine hydrochloride in a mixture of tert-BuOH methylene chloride and formaldehyde. Reaction of the intermediate (VIII) with diazo cyclopentane, generated in situ by treatment of cyclopentyl hydrazono with silver (I) oxide, gives 2,2,2-tricholoroethyl-7alpha-methoxy-2-spiro-(2'-spirocyclopentyl)cyclopropyl-3-methyl-3-cephem-4-carboxylate-1,1-dioxide (IX). Removal of the trichloroethyl group by treatment with Zn/glacial acetic acid gives the corresponding acid (X). Reaction of the acid (X) with oxalyl chloride in methylene chloride gives the acid chloride (XI), which is condensed with 4-(1-butoxycarbonylmethyl)piperazine to afford the product (XII). Deprotection of the tert-butyl group with formic acid gives the free acid (XIII). Finally, this compound is converted into the sodium salt (XIV) of Syn-1390 by treatment with sodium carbonate in water.
| 【1】 Maiti, S.N.; Woods, D.E.; Cantin, A.M.; 2-Spirocyclopropyl cephem sulfones: Human neutrophil elastase inhibitors Syn-1390 and Syn-1396. Drugs Fut 1998, 23, 6, 635. |
| 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) | 24677 | 1,3-benzothiazol-2-ylhydrosulfide | 149-30-4 | C7H5NS2 | 详情 | 详情 |
| (B) | 25055 | cyclopentanone hydrazone | C5H10N2 | 详情 | 详情 | |
| (I) | 27608 | 6-Diazo-2,2-dimethylpenam-3(R)-carboxylic acid 2,2,2-trichlloroethyl ester | C10H10Cl3N3O3S | 详情 | 详情 | |
| (II) | 27609 | 2,2,2-trichloroethyl (2S,6S)-6-methoxy-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C11H14Cl3NO4S | 详情 | 详情 | |
| (III) | 27610 | 2,2,2-trichloroethyl (2S,6S)-6-methoxy-3,3-dimethyl-4,7-dioxo-4lambda(4)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C11H14Cl3NO5S | 详情 | 详情 | |
| (IV) | 27611 | 2,2,2-trichloroethyl (2R)-2-[(3S)-2-(1,3-benzothiazol-2-yldisulfanyl)-3-methoxy-4-oxoazetidinyl]-3-methyl-3-butenoate | C18H17Cl3N2O4S3 | 详情 | 详情 | |
| (V) | 27612 | 2,2,2-trichloroethyl (2S,3R,6S)-3-(bromomethyl)-6-methoxy-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C11H13BrCl3NO4S | 详情 | 详情 | |
| (VI) | 27613 | 2,2,2-trichloroethyl (7S)-7-methoxy-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C11H12Cl3NO4S | 详情 | 详情 | |
| (VII) | 27614 | 2,2,2-trichloroethyl (7S)-7-methoxy-3-methyl-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C11H12Cl3NO6S | 详情 | 详情 | |
| (VIII) | 27615 | 2,2,2-trichloroethyl (7S)-7-methoxy-3-methyl-4-methylene-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C12H12Cl3NO6S | 详情 | 详情 | |
| (IX) | 27616 | 7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-ene]-2''-carboxylic acid 2,2,2-trichloroethyl ester S,S-dioxide | C17H20Cl3NO6S | 详情 | 详情 | |
| (X) | 27617 | 7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-ene]-2''-carboxylic acid S,S-dioxide | C15H19NO6S | 详情 | 详情 | |
| (XI) | 27618 | 7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-ene]-2''-carbonyl chloride S,S-dioxide | C15H18ClNO5S | 详情 | 详情 | |
| (XII) | 27619 | 2-[4-[7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-en]-2''-ylcarbonyl]piperazin-1-yl]acetic acid tert-butyl ester S,S-dioxide | C25H37N3O7S | 详情 | 详情 | |
| (XIII) | 27620 | 2-[4-[7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-en]-2''-ylcarbonyl]piperazin-1-yl]acetic acid S,S-dioxide | C21H29N3O7S | 详情 | 详情 | |
| (C) | 25056 | tert-butyl 2-(1-piperazinyl)acetate | C10H20N2O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(A)1) Treatment of 6-azopenicillanate (I) with boron trifluoroetherate in a mixture of methanol and methylene chloride gives 6alpha-methoxy penicillanate (II), which on oxidation with peracetic acid gives the corresponding 1beta-oxide (III). Ring opening of the oxide (III) by heating with 2-mercaptohenzothiazole in toluene gives the intermediate (IV), which on cyclization with bromine in methylene chloride gives 2beta-bromomethyl penicillanate (V). Rearrangement of (V) with pyridine in dimethyl sulfoxide gives the cephem intermediate (VI). The sulfone derivative (VII) is obtained by oxidizing (VI) with peracetic acid in methylene chloride. Introduction of the double bound at C-2 position of the sulfone (VII) is achieved by heating with dimethylamine hydrochloride in a mixture of tert-BuOH methylene chloride and formaldehyde. Reaction of the intermediate (VIII) with diazo cyclopentane, generated in situ by treatment of cyclopentyl hydrazono with silver (I) oxide, gives 2,2,2-tricholoroethyl-7alpha-methoxy-2-spiro-(2'-spirocyclopentyl)cyclopropyl-3-methyl-3-cephem-4-carboxylate-1,1-dioxide (IX). Removal of the trichloroethyl group by treatment with Zn/glacial acetic acid gives the corresponding acid (X). Reaction of the acid (X) with oxalyl chloride followed by treatment with 4-tert-butoxycarbonyl piperidine in methylene chloride gives the intermediate (XV). Hydrolysis of the tert-butyl ester with formic acid gives the free acid (XVI). Treatment with sodium carbonate in water gives the corresponding sodium salt of Syn-1396 (XVII).
| 【1】 Maiti, S.N.; Woods, D.E.; Cantin, A.M.; 2-Spirocyclopropyl cephem sulfones: Human neutrophil elastase inhibitors Syn-1390 and Syn-1396. Drugs Fut 1998, 23, 6, 635. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 | |
| (A) | 24677 | 1,3-benzothiazol-2-ylhydrosulfide | 149-30-4 | C7H5NS2 | 详情 | 详情 |
| (B) | 25055 | cyclopentanone hydrazone | C5H10N2 | 详情 | 详情 | |
| (I) | 27608 | 6-Diazo-2,2-dimethylpenam-3(R)-carboxylic acid 2,2,2-trichlloroethyl ester | C10H10Cl3N3O3S | 详情 | 详情 | |
| (II) | 27609 | 2,2,2-trichloroethyl (2S,6S)-6-methoxy-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C11H14Cl3NO4S | 详情 | 详情 | |
| (III) | 27610 | 2,2,2-trichloroethyl (2S,6S)-6-methoxy-3,3-dimethyl-4,7-dioxo-4lambda(4)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C11H14Cl3NO5S | 详情 | 详情 | |
| (IV) | 27611 | 2,2,2-trichloroethyl (2R)-2-[(3S)-2-(1,3-benzothiazol-2-yldisulfanyl)-3-methoxy-4-oxoazetidinyl]-3-methyl-3-butenoate | C18H17Cl3N2O4S3 | 详情 | 详情 | |
| (V) | 27612 | 2,2,2-trichloroethyl (2S,3R,6S)-3-(bromomethyl)-6-methoxy-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C11H13BrCl3NO4S | 详情 | 详情 | |
| (VI) | 27613 | 2,2,2-trichloroethyl (7S)-7-methoxy-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C11H12Cl3NO4S | 详情 | 详情 | |
| (VII) | 27614 | 2,2,2-trichloroethyl (7S)-7-methoxy-3-methyl-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C11H12Cl3NO6S | 详情 | 详情 | |
| (VIII) | 27615 | 2,2,2-trichloroethyl (7S)-7-methoxy-3-methyl-4-methylene-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C12H12Cl3NO6S | 详情 | 详情 | |
| (IX) | 27616 | 7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-ene]-2''-carboxylic acid 2,2,2-trichloroethyl ester S,S-dioxide | C17H20Cl3NO6S | 详情 | 详情 | |
| (X) | 27617 | 7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-ene]-2''-carboxylic acid S,S-dioxide | C15H19NO6S | 详情 | 详情 | |
| (XV) | 27627 | 4-[7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-en]-2''-ylcarbonyl]piperazine-1-carboxylic acid tert-butyl ester S,S-dioxide | C24H35N3O7S | 详情 | 详情 | |
| (XVI) | 27628 | 4-[7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-en]-2''-ylcarbonyl]piperazine-1-carboxylic acid S,S-dioxide | C20H27N3O7S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)6-Aminopenicillanic acid benzhydryl ester (I) was protected as the carbamate (II) using allyl chloroformate. Subsequent oxidation of (II) with m-chloroperbenzoic acid provided sulfoxide (III). Opening of the thiazolidine ring of (III) by means of 2-mercaptobenzothiazole (IV) produced disulfide (V), which was further cyclized in the presence of arylacetic acid (VI) and silver acetate to furnish a 4:1 mixture of penicillanic ester (VII) and the cephalosporanic analogue (VIII). Deprotection of the required isomer (VII) employing Pd(PPh3)4 and Bu3SnH afforded amine (IX). Diazotization of (IX) with isopropyl nitrite, followed by treatment with propylene oxide and Rh2(OAc)4 gave rise to oxolactam (X). Wittig reaction of (X) with the ylide resulting from phosphonium salt (XI) and NaNH2 provided the (pyridylmethylene) derivative (XII). Finally, oxidation to the corresponding sulfone and cleavage of the protecting groups provided the title compound.
| 【1】 Buynak, J.D.; et al.; New beta-lactamase inhibitors of the class A and class C enzymes. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 194. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 | |
| (I) | 35142 | benzhydryl (2S,5R,6R)-6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C21H22N2O3S | 详情 | 详情 | |
| (II) | 35143 | benzhydryl (2S,5R,6R)-6-[[(allyloxy)carbonyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C25H26N2O5S | 详情 | 详情 | |
| (III) | 35144 | benzhydryl (2S,5R,6R)-6-[[(allyloxy)carbonyl]amino]-3,3-dimethyl-4,7-dioxo-4lambda(4)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C25H26N2O6S | 详情 | 详情 | |
| (IV) | 24677 | 1,3-benzothiazol-2-ylhydrosulfide | 149-30-4 | C7H5NS2 | 详情 | 详情 |
| (V) | 35145 | benzhydryl (2R)-2-[(2R,3R)-3-[[(allyloxy)carbonyl]amino]-2-(1,3-benzothiazol-2-yldisulfanyl)-4-oxoazetidinyl]-3-methyl-3-butenoate | C32H29N3O5S3 | 详情 | 详情 | |
| (VI) | 35146 | 2-[3,4-di(tert-butoxy)phenyl]acetic acid | C16H24O4 | 详情 | 详情 | |
| (VII) | 35147 | benzhydryl (2S,3R,5R,6R)-6-[[(allyloxy)carbonyl]amino]-3-[([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)methyl]-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C41H48N2O9S | 详情 | 详情 | |
| (VIII) | 35148 | benzhydryl (2R,3S,7R)-7-[[(allyloxy)carbonyl]amino]-3-([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]octane-2-carboxylate | C41H48N2O9S | 详情 | 详情 | |
| (IX) | 35149 | benzhydryl (2S,3R,5R,6R)-6-amino-3-[([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)methyl]-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C37H44N2O7S | 详情 | 详情 | |
| (X) | 35150 | benzhydryl (2S,3R,5R)-3-[([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)methyl]-3-methyl-6,7-dioxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C37H41NO8S | 详情 | 详情 | |
| (XI) | 35151 | triphenyl(2-pyridinylmethyl)phosphonium chloride; 2-picolyl triphenylphosphonium chloride | 73870-25-4 | C24H21ClNP | 详情 | 详情 |
| (XII) | 35152 | benzhydryl (2S,3R,5R)-3-[([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)methyl]-3-methyl-7-oxo-6-[(Z)-2-pyridinylmethylidene]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C43H46N2O7S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)The reaction of N-(benzyloxycarbonyl)-L-serine methyl ester (I) with 2-mercaptobenzothiazole (II) by means of DIAD and PPh3 in THF gives the thioether (III), which is reduced with NaBH4 and CaCl2 in THF to yield the alcohol (IV). The cyclization of (IV) with 2,2-dimethoxypropane (V) by means of TsOH in dichloromethane affords the oxazolidine (VI), which is oxidized at the thioether group by means of Mo7O24(NH4)6 and H2O2 in ethanol to provide the sulfone (VII). The condensation of (VII) with 7-iodoisatin (VIII) employing LiHMDS and DMPU in THF gives the adduct (IX), which is condensed with the boronic ester (X) -obtained by reaction of the tyrosine derivative (XI) with bis(pinacolato)diboron, KOH and Pd(dppf)Cl2 in hot DMSO- by means of K2CO3 and Pd(dppf)Cl2 in aqueous DME to yield the coupled product (XII). The hydrolysis of the ester group of (XII) with LiOH, followed by condensation with asparagine benzyl ester (XIII) by means of HOAT, EDC and NMM in dichloromethane affords the amide (XIV). This is oxidized at its exocyclic double bond by means of OsO4 and pyridine in THF/methanol to provide the diol (XV).
| 【1】 Albrecht, B.K.; Williams, R.M.; A concise formal total synthesis of TMC-95A/B proteasome inhibitors. Org Lett 2003, 5, 2, 197. |
| 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) | 51660 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxypropanoate | C12H15NO5 | 详情 | 详情 | |
| (II) | 24677 | 1,3-benzothiazol-2-ylhydrosulfide | 149-30-4 | C7H5NS2 | 详情 | 详情 |
| (III) | 61814 | methyl (2R)-3-(1,3-benzothiazol-2-ylsulfanyl)-2-{[(benzyloxy)carbonyl]amino}propanoate | C19H18N2O4S2 | 详情 | 详情 | |
| (IV) | 61815 | benzyl (1R)-2-(1,3-benzothiazol-2-ylsulfanyl)-1-(hydroxymethyl)ethylcarbamate | C18H18N2O3S2 | 详情 | 详情 | |
| (V) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (VI) | 61816 | benzyl (4S)-4-[2-(1,3-benzothiazol-2-ylsulfanyl)ethyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C22H24N2O3S2 | 详情 | 详情 | |
| (VII) | 61817 | benzyl (4S)-4-[2-(1,3-benzothiazol-2-ylsulfonyl)ethyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C22H24N2O5S2 | 详情 | 详情 | |
| (VIII) | 61824 | 7-iodo-1H-indole-2,3-dione | C8H4INO2 | 详情 | 详情 | |
| (IX) | 61818 | benzyl (4S)-4-[(7-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C22H21IN2O4 | 详情 | 详情 | |
| (X) | 61820 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(methoxymethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate | C23H36BNO8 | 详情 | 详情 | |
| (XI) | 61819 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-iodo-4-(methoxymethoxy)phenyl]propanoate | C17H24INO6 | 详情 | 详情 | |
| (XII) | 61821 | benzyl (4S)-4-({7-[5-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl}-2-(methoxymethoxy)phenyl]-2-oxo-1,2-dihydro-3H-indol-3-ylidene}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C39H45N3O10 | 详情 | 详情 | |
| (XIII) | 61825 | benzyl (2S)-2,4-diamino-4-oxobutanoate | C11H14N2O3 | 详情 | 详情 | |
| (XIV) | 61822 | benzyl (4S)-4-({7-[5-{(2S)-3-({(1S)-3-amino-1-[(benzyloxy)carbonyl]-3-oxopropyl}amino)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}-2-(methoxymethoxy)phenyl]-2-oxo-1,2-dihydro-3H-indol-3-ylidene}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C49H55N5O12 | 详情 | 详情 | |
| (XV) | 61823 | benzyl (4R)-4-[(R)-{(3S)-7-[5-{(2S)-3-({(1S)-3-amino-1-[(benzyloxy)carbonyl]-3-oxopropyl}amino)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}-2-(methoxymethoxy)phenyl]-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl}(hydroxy)methyl]-2,2-dimethyl-1,3-oxazoli | C49H57N5O14 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(V)4-Hydroxy-6-methyl-3-nitropyridone (I) is chlorinated to (II) by treatment with POCl3 in the presence of benzyltriethylammonium chloride. Alkylation of pyridone (II) with ethyl bromoacetate (III) and NaH leads to the pyridoneacetate (IV) (1). Displacement of the chloride group of (IV) with 2-mercaptobenzothiazole (V) affords the thioether (VI). After reduction of the nitro group of (VI) by catalytic hydrogenation, the resultant amine (VII) is protected as the di-Boc derivative (VIII) with di-tert-butyl dicarbonate and DMAP. Oxidation of the thioether (VIII) with KmnO4 gives the sulfone (IX), which is submitted to reductive cleavage with Zn/AcOH. Finally chlorination of the intermediate zinc sulfinate with NCS furnishes the sulfonyl chloride (X) (1,2).
| 【1】 Sanderson, P.E.J.; Cutrona, K.J.; Savage, K.L.; Naylor-Olsen, A.M.; Bickel, D.J.; Bohn, D.L.; Clayton, F.C.; Krueger, J.A.; Lewis, S.D.; Lucas, B.J.; Lyle, E.A.; Wallace, A.A.; Welsh, D.C.; Yan, Y.; 3-Amino-4-sulfonylpyridinone acetamide and related pyridothiadiazine thrombin inhibitors. Bioorg Med Chem Lett 2003, 13, 8, 1441. |
| 【2】 Sanderson, P.E.; Cutrona, K. (Merck & Co., Inc.); Thrombin inhibitors. EP 1117660; JP 2002525370; US 6117888; WO 0018762 . |
| 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) | 23337 | 4-hydroxy-6-methyl-3-nitro-2(1H)-pyridinone | 4966-90-9 | C6H6N2O4 | 详情 | 详情 |
| (II) | 23339 | 4-chloro-6-methyl-3-nitro-2(1H)-pyridinone | C6H5ClN2O3 | 详情 | 详情 | |
| (III) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (IV) | 64710 | ethyl 2-[4-chloro-6-methyl-3-nitro-2-oxo-1(2H)-pyridinyl]acetate | C10H11ClN2O5 | 详情 | 详情 | |
| (V) | 24677 | 1,3-benzothiazol-2-ylhydrosulfide | 149-30-4 | C7H5NS2 | 详情 | 详情 |
| (VI) | 64711 | ethyl 2-[4-(1,3-benzothiazol-2-ylsulfanyl)-6-methyl-3-nitro-2-oxo-1(2H)-pyridinyl]acetate | C17H15N3O5S2 | 详情 | 详情 | |
| (VII) | 64712 | ethyl 2-[3-amino-4-(1,3-benzothiazol-2-ylsulfanyl)-6-methyl-2-oxo-1(2H)-pyridinyl]acetate | C17H17N3O3S2 | 详情 | 详情 | |
| (VIII) | 64713 | ethyl 2-[4-(1,3-benzothiazol-2-ylsulfanyl)-3-[bis(tert-butoxycarbonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetate | C27H33N3O7S2 | 详情 | 详情 | |
| (IX) | 64714 | ethyl 2-[4-(1,3-benzothiazol-2-ylsulfonyl)-3-[bis(tert-butoxycarbonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetate | C27H33N3O9S2 | 详情 | 详情 | |
| (X) | 64715 | ethyl 2-[3-[bis(tert-butoxycarbonyl)amino]-4-(chlorosulfonyl)-6-methyl-2-oxo-1(2H)-pyridinyl]acetate | C20H29ClN2O9S | 详情 | 详情 |