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【结 构 式】

【分子编号】13423

【品名】1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate

【CA登记号】543-27-1

【 分 子 式 】C5H9ClO2

【 分 子 量 】136.57796

【元素组成】C 43.97% H 6.64% Cl 25.96% O 23.43%
与该中间体有关的原料药合成路线共 18 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5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18

合成路线1

该中间体在本合成路线中的序号：(A)

The condensation of 4-ethylpyridine-2-carboxylic acid (I) with methyl-6-amino-7-chloro-6,7,8-trideoxy-1-thio-L-threo-alpha-D-galacto-octopyranoside (II) by means of isobutyl chloroformate (A) and triethylamine in acetonitrile gives the corresponding amide (III), which is then hydrogenated with H2 over PtO2 in methanol - water - HCl.

参考文献 中间体
合成目标
【1】 Hillier, K.; Serradell, M.N.; Blancafort, P.; Castaner, J.; Pirlimycin hydrochloride. Drugs Fut 1983, 8, 4, 338.
【2】 Birkenmeyer, R.D. (Pharmacia Corp.); Novel antibiotics, their preparation and their use. BE 0886301 .
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) 13423 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate 543-27-1 C5H9ClO2 详情 详情
(I) 36053 4-ethyl-2-pyridinecarboxylic acid C8H9NO2 详情 详情
(II) 36054 (2R,3R,4S,5R,6R)-2-[(1S,2S)-1-amino-2-chloropropyl]-6-(methylsulfanyl)tetrahydro-2H-pyran-3,4,5-triol C9H18ClNO4S 详情 详情
(III) 36055 N-[(1S,2S)-2-chloro-1-[(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(methylsulfanyl)tetrahydro-2H-pyran-2-yl]propyl]-4-ethyl-2-pyridinecarboxamide C17H25ClN2O5S 详情 详情

合成路线2

该中间体在本合成路线中的序号：(A)

N2-tert-Butyloxycarbonyl-N5-benzyloxycarbonyl-L-arginine (I) is cyclized by treatment with isobutyloxycarbonyl chloride and N-methylmorpholine to the lactam (II). The tert-butyloxycarbonyl group is removed by hydrochloric acid to give the aminolactam (III), which is coupled with N-benzyloxycarbonyl-D-phenylalanyl-L-proline (IV) using, as in the first step, the mixed anhydride method. The resulting tripeptide lactam (V) is reduced with LiAlH4 to an aldehyde, present as the cyclic alpha-aminoalcohol (VI). Deblocking by hydrogenolysis gives RGH-2958. In solution the aldehyde group is either in the cyclic alpha-aminoalcohol form or is hydrated.

参考文献 中间体
合成目标
【1】 Rabloczky, Gy.; Bagdy, D.; Bajusz, S.; RGH-2958. Drugs Fut 1985, 10, 10, 829.
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) 13423 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate 543-27-1 C5H9ClO2 详情 详情
(B) 28928 4-methylmorpholine 109-02-4 C5H11NO 详情 详情
(I) 29740 N(5)-[[[(benzyloxy)carbonyl]amino](imino)methyl]-N(2)-(tert-butoxycarbonyl)ornithine 51219-18-2 C19H28N4O6 详情 详情
(II) 28933 tert-butyl 1-(amino[[(benzyloxy)carbonyl]imino]methyl)-2-oxo-3-piperidinylcarbamate C19H26N4O5 详情 详情
(III) 28929 benzyl (E)-amino(3-amino-2-oxo-1-piperidinyl)methylidenecarbamate C14H18N4O3 详情 详情
(IV) 29741 (2S)-1-((2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropanoyl)-2-pyrrolidinecarboxylic acid 7669-64-9 C22H24N2O5 详情 详情
(V) 29742 benzyl (E)-amino[3-([[(2S)-1-((2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropanoyl)pyrrolidinyl]carbonyl]amino)-2-oxo-1-piperidinyl]methylidenecarbamate C36H40N6O7 详情 详情
(VI) 29743 benzyl (E)-amino[3-([[(2S)-1-((2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropanoyl)pyrrolidinyl]carbonyl]amino)-2-hydroxy-1-piperidinyl]methylidenecarbamate C36H42N6O7 详情 详情

合成路线3

该中间体在本合成路线中的序号：(A)

The condensation of N(G)-nitro-N2-(tert-butoxy-carbonyl)-L-arginine (I) with ethyl 4-methylpiperidine-2-carboxylate (II) by means of isobutyl chloroformate (A) and triethylamine in THF gives ethyl 1-[N(G)-nitro-N2-(tert-butoxycarbonyl)-L-arginyl]-4-methylpiperidine-2-carboxylate (III), which is protected with HCl in ethyl acetate yielding ethyl 1-(N(G)-nitro-L-arginyl)-4-methylpiperidine-2-carboxylate (IV). The condensation of (IV) with 3-methylquinoline-8-sulfonyl chloride (V) by means of triethylamine in chloroform affords ethyl 1-(N(G)-nitro-N2-(3-methyl-8-quinolinylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate (VI), which is hydrolyzed with NaOH in ethanol-water giving 1-[N(G)-nitro-N2-(3-methyl-8-quinolinylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid (VII). Finally, this compound is deprotected and reduced by hydrogenation with H2 over Pd/C in ethanol.

参考文献 中间体
合成目标
【1】 Kikumoto, R.; Tamao, Y.; Onkubo, K.; Tezuka, T.; Tonomura, S.; Hihikata, A.; Okamoto, S. (Mitsubishi Chemical Corp.); N2-Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof. US 4201863 .
【2】 Kikumoto, R.; Tamao, Y.; Onkubo, K.; Tezuka, T.; Tonomura, S.; Hihikata, A.; Okamoto, S. (Mitsubishi Chemical Corp.); N2-Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof. EP 0008746; US 4258192 .
【3】 Castaner, J.; Grau, M.; Blancafort, P.; Serradell, M.N.; MD-805. Drugs Fut 1982, 7, 11, 810.
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) 13423 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate 543-27-1 C5H9ClO2 详情 详情
(I) 32085 N(G)-nitro-N2-(tert-butoxy-carbonyl)-L-arginine; Nalpha-(tert-butoxycarbonyl)-Nomega-nitro-L-arginine C11H21N5O6 详情 详情
(II) 32086 Ethyl (2R,4R)-4-methyl-2-piperidinecarboxylate C9H17NO2 详情 详情
(III) 32087 Ethyl 1-[N(G)-nitro-N2-(tert-butoxycarbonyl)-L-arginyl]-4-methylpiperidine-2-carboxylate; [Nalpha-(tert-butoxycarbonyl)-Nomega-nitro-L-arginyl]-4(R)-methylpiperidine-2(R)-carboxylic acid ethyl ester C20H36N6O7 详情 详情
(IV) 32088 1-(N-omega-nitro-L-arginyl)-4(R)-methylpiperidine-2(R)-carboxylic acid ethyl ester; Ethyl 1-(N(G)-nitro-L-arginyl)-4-methylpiperidine-2-carboxylate C15H28N6O5 详情 详情
(V) 32089 3-methylquinoline-8-suIfonyl chloride; 3-methyl-8-quinolinesulfonyl chloride C10H8ClNO2S 详情 详情
(VI) 32090 Ethyl 1-(N(G)-nitro-N2-(3-methyl-8-quinolinylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate; [Nalpha-(3-Methylquinolin-8-ylsulfonyl)-Nomega-nitro-L-arginyl]-4(R)-methylpiperidine-2(R)-carboxylic acid ethyl ester C25H35N7O7S 详情 详情
(VII) 32091 [Nalpha-(3-Methylquinolin-8-ylsulfonyl)-Nomega-nitro-L-arginyl]-4(R)-methylpiperidine-2(R)-carboxylic acid; 1-[N(G)-Nitro-N2-(3-methyl-8-quinolinylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid C23H31N7O7S 详情 详情

合成路线4

该中间体在本合成路线中的序号：(A)

N2-tert-Butoxycarbonyl-N6-benzyloxycarbonyl-L-arginine (I) is converted by treatment with isobutyl oxycarbonyl chloride (A) and N-methylmorpholine (B) to the lactam (II), and the tert-butoxycarbonyl group is cleaved off to give the aminolactam (III), which is coupled with N-tert-butoxycarbonyl-D-phenylalanyl-L-proline (IV) to the tripeptide (V) using the mixed anhydride method as in the first step. The lactam carbonyl is reduced with LiAlH4 to an aldehyde group present as the cyclic a aminoalcohol (VI). Removal of the benzyloxycarbonyl blocking group provides GYKI-14451. In solution the aldehyde group is either in the cyclic alpha-aminoalcohol form or is hydrated.

参考文献 中间体
合成目标
【1】 Voutilainen, S.; Valkonen, V.P.; Venho, B.; et al.; Magy Kem Lapja 1982, 27, 2, 358-365.
【2】 Bajusz, S.; Szell, E.; Barabas, E.; Bagdy, D. (Gedeon Richter Ltd.); D-Phenylalanyl-L-prolyl-L-arginine aldehyde sulfate and process for the preparation thereof. DE 3200812; FR 2497799; GB 2091270; JP 57181046; US 4399065; US 4478745 .
【3】 Nogradi, M.; GYKI-14451. Drugs Fut 1985, 10, 1, 23.
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) 13423 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate 543-27-1 C5H9ClO2 详情 详情
(B) 28928 4-methylmorpholine 109-02-4 C5H11NO 详情 详情
(I) 28927 tert-butyl 3-[(amino[[(benzyloxy)carbonyl]imino]methyl)amino]propylcarbamate C17H26N4O4 详情 详情
(II) 28933 tert-butyl 1-(amino[[(benzyloxy)carbonyl]imino]methyl)-2-oxo-3-piperidinylcarbamate C19H26N4O5 详情 详情
(III) 28929 benzyl (E)-amino(3-amino-2-oxo-1-piperidinyl)methylidenecarbamate C14H18N4O3 详情 详情
(IV) 28932 (2S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl]-2-pyrrolidinecarboxylic acid C19H26N2O5 详情 详情
(V) 28930 tert-butyl (1R)-2-[(2S)-2-([[1-(amino[[(benzyloxy)carbonyl]imino]methyl)-2-oxo-3-piperidinyl]amino]carbonyl)pyrrolidinyl]-1-benzyl-2-oxoethylcarbamate C33H42N6O7 详情 详情
(VI) 28931 tert-butyl (1R)-2-[(2S)-2-([[1-(amino[[(benzyloxy)carbonyl]imino]methyl)-2-hydroxy-3-piperidinyl]amino]carbonyl)pyrrolidinyl]-1-benzyl-2-oxoethylcarbamate C33H44N6O7 详情 详情

合成路线5

该中间体在本合成路线中的序号：(VI)

This compound can be obtained by two related ways: 1) The reaction of vinblastine (I) with anhydrous hydrazine in hot ethanol gives 4-deacetylvinblastine-23-acid hydrazide (II), which by reaction with HCl and NaNO2 in cool methanol - water is converted into the corresponding azide (III). Finally, this compound is condensed with L-tryptophan ethyl ester (IV) in dichloromethane. 2) The hydrolysis of vinblastine (I) with NaOH in refluxing ethanol gives 4-deacetylvinblastoic acid (V), which is condensed with L-tryptophan ethyl ester (IV) by means of isobutyl chloroformate (VI) and N-ethylmorpholine in DMF to afford the 4-O-(isobutoxycarbonyl) derivative (VII). Finally, this compound is partially hydrolyzed with KOH in ethanol.

参考文献 中间体
合成目标
【1】 Trouet, A.B.L.; Hannart, J.A.A.J.; Rao, K.S.B. (OmniChem); Vinblastin-23-oyl amino acid derivs. US 4639456 .
【2】 Hamashima, Y. (Shionogi & Co. Ltd.); 7-Carboxyalkenoylamido-3-cephem-4-carboxylic acid derivs.. EP 0136721; ES 8604602; ES 8605278; ES 8700222; GB 2154580; GB 2198727; JP 1985078987; JP 1985163884; JP 1985246388; US 4634697; US 4748170 .
【3】 Trouet, A.B.L.; Rao, K.S.B.; Hannart, J.A.A. (OmniChem); N-Vinblastinoyl-23) derivs. of amino acids and peptides, their preparation and their therapeutic application. EP 0041935 .
【4】 Atassi, G.; Rao, K.S.P.B.; Collard, M.-P.M.; Trouet, A.; Dejonghe, J.P.C.; Hannart, J.A.; Vinblastin-23-oyl amino acid derivatives: Chemistry, physicochemical data, toxicity, and antitumor activities against P388 and L1210 leukemias. J Med Chem 1985, 28, 8, 1079.
【5】 Castaner, J.; Prous, J.; Vintriptol Mesylate. Drugs Fut 1992, 17, 7, 569.
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) 10346 methyl (3aR,4R,5S,5aR,10bR,13aR)-4-(acetoxy)-3a-ethyl-9-[(13S,15S,17S)-17-ethyl-17-hydroxy-13-(methoxycarbonyl)-1,11-diazatetracyclo[13.3.1.0(4,12).0(5,10)]nonadeca-4(12),5,7,9-tetraen-13-yl]-5-hydroxy-8-methoxy-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate 446-86-6 C46H58N4O9 详情 详情
(II) 10347 methyl (13S,15S,17S)-13-[(3aR,4R,5S,5aR,10bR,13aR)-3a-ethyl-5-(hydrazinocarbonyl)-4,5-dihydroxy-8-methoxy-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazol-9-yl]-17-ethyl-17-hydroxy-1,11-diazatetracyclo[13.3.1.0(4,12).0(5,10)]nonadeca-4(12),5,7,9-tetraene-13-carboxylate C43H56N6O7 详情 详情
(III) 10348 1-([(3aR,4R,5S,5aR,10bR,13aR)-3a-Ethyl-9-[(13S,15S,17S)-17-ethyl-17-hydroxy-13-(methoxycarbonyl)-1,11-diazatetracyclo[13.3.1.0(4,12).0(5,10)]nonadeca-4(12),5,7,9-tetraen-13-yl]-4,5-dihydroxy-8-methoxy-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazol-5-yl]carbonyl)-1,2-triazadien-2-ium C43H53N7O7 详情 详情
(IV) 10349 ethyl (2S)-2-amino-3-(1H-indol-3-yl)propanoate C13H16N2O2 详情 详情
(V) 10350 (3aR,4R,5S,5aR,10bR,13aR)-3a-Ethyl-9-[(13S,15S,17S)-17-ethyl-17-hydroxy-13-(methoxycarbonyl)-1,11-diazatetracyclo[13.3.1.0(4,12).0(5,10)]nonadeca-4(12),5,7,9-tetraen-13-yl]-4,5-dihydroxy-8-methoxy-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylic acid C43H54N4O8 详情 详情
(VI) 13423 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate 543-27-1 C5H9ClO2 详情 详情
(VII) 10351 methyl (13S,15S,17S)-13-[(3aR,4R,5S,5aR,10bR,13aR)-5-([[(1S)-2-ethoxy-1-(1H-indol-3-ylmethyl)-2-oxoethyl]amino]carbonyl)-3a-ethyl-5-hydroxy-4-[(isobutoxycarbonyl)oxy]-8-methoxy-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazol-9-yl]-17-ethyl-17-hydroxy-1,11-diazatetracyclo[13.3.1.0(4,12).0(5,10)]nonadeca-4(12),5,7,9-tetraene-13-carboxylate C61H76N6O11 详情 详情

合成路线6

该中间体在本合成路线中的序号：(A)

Prepared by reacting 2-methoxy-5-methylsulfonylbenzoic acid (I) with isobutyl chloroformate (A) in dioxane to give the corresponding anhydride (II), which is finally condensed with N,N-diethylethylenediamine (B).

参考文献 中间体
合成目标
【1】 Bulteau, G.; Acher, J.; Process for preparing benzamides. CH 585699; DE 2327192; GB 1394563; JP 49085037 .
【2】 Neuman, M.; Prous, J.R.; Tiapride. Drugs Fut 1976, 1, 2, 88.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 12420 N-(2-Aminoethyl)-N,N-diethylamine; N,N-Diethylethylene-diamine; N(1),N(1)-Diethyl-1,2-ethanediamine 100-36-7 C6H16N2 详情 详情
(A) 13423 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate 543-27-1 C5H9ClO2 详情 详情
(I) 34068 2-methoxy-5-(methylsulfonyl)benzoic acid 50390-76-6 C9H10O5S 详情 详情
(II) 34069 　 C14H18O7S 详情 详情

合成路线7

该中间体在本合成路线中的序号：(V)

The reduction of L-pyroglutamic acid (I) with NaBH4 gives the chiral pyrrolidinone (II), which is cyclized with benzaldehyde (III) by means of Ts-OH in refluxing toluene to yield the N,O-acetal (IV). The reaction of (IV) with isobutyl chloroformate (V) and phenylselanyl chloride by means of LiHMDS in THF affords the selenoester (VI), which is treated directly with H2O2 in dichloromethane to provide the unsaturated bicyclic lactam (VII). The diastereoselective reaction of (VII) with lithium di(4-fuorophenyl)cuprate (VIII) gives the all-trans trisubstituted pyrrolidone (IX). The reduction of the carbonyl group (IX) with BH3 in THF that also causes the cleavage of the C-O bond of the oxazolidinone yields the pyrrolidine methanol derivative (X), which is submitted to ring expansion by treatment with MsCl, DCE and TEA to afford the expected trisubstituted 3-chloropiperidine (XI). The dechlorination of (XI) by means of Bu3SnH and AIBN in refluxing toluene provides the trans-1-benzyl-4-(4-fluorophenyl)piperidine-3-carboxylic acid isobutyl ester (XII), which is reduced with LiAlH4 in THF to furnish the carbinol (XIII). The reaction of (XIII) with Ms-Cl and TEA in dichloromethane gives the corresponding mesylate (XIV), which is condensed with 1,3-benzodioxol-5-ol (XV) by means of sodium isopropoxide in refluxing isopropanol to yield the aryl ether (XVI). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in methanol to afford the target trans-piperidine derivative.

参考文献 中间体
合成目标
【1】 Liu, L.T.; Hong, P.-C.; Huang, H.-L.; Chen, S.-F.; Wang, C.-L. J.; Wen, Y.-S.; ASsymetric syntheses of trans-3,4-disubstituted 2-piperidinones and piperidines. Tetrahedron Asymmetry 2001, 12, Suppl. 3, 419-26.
【2】 Cossy, J.; et al.; Ring expansion: Formal total synthesis of (-)-paroxetine. Tetrahedron Lett 2001, 42, 33, 5705.
【3】 Thottathil, J.K.; et al.; Conversion of L-pyroglutamic acid to 4-alkyl substituted L-prolines. The synthesis of trans-4-cyclohexyl L-proline. J Org Chem 1986, 51, 16, 3140.
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) 12085 (2R)-5-Oxotetrahydro-1H-pyrrole-2-carboxylic acid; 5-Oxo-D-proline; D-Pyroglutamic acid; (R)-(+)-2-Pyrrolidone-5-carboxylic acid 4042-36-8 C5H7NO3 详情 详情
(II) 56485 (5S)-5-(hydroxymethyl)-2-pyrrolidinone C5H9NO2 详情 详情
(III) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(IV) 38561 (3R,7aS)-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one 103201-79-2 C12H13NO2 详情 详情
(V) 13423 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate 543-27-1 C5H9ClO2 详情 详情
(VI) 56478 isobutyl (3R,7aS)-5-oxo-3-phenyl-6-(phenylselanyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazole-6-carboxylate C23H25NO4Se 详情 详情
(VII) 56479 isobutyl (3R,7aS)-5-oxo-3-phenyl-5,7a-dihydro-1H-pyrrolo[1,2-c][1,3]oxazole-6-carboxylate C17H19NO4 详情 详情
(VIII) 56475 　 C27H25CuF4Li 详情 详情
(IX) 56480 isobutyl (3R,6S,7R,7aS)-7-(4-fluorophenyl)-5-oxo-3-phenyltetrahydro-1H-pyrrolo[1,2-c][1,3]oxazole-6-carboxylate C23H24FNO4 详情 详情
(X) 56481 isobutyl (3S,4R,5S)-1-benzyl-4-(4-fluorophenyl)-5-(hydroxymethyl)-3-pyrrolidinecarboxylate C23H28FNO3 详情 详情
(XI) 56482 isobutyl (3S,4R,5R)-1-benzyl-5-chloro-4-(4-fluorophenyl)-3-piperidinecarboxylate C23H27ClFNO2 详情 详情
(XII) 56483 isobutyl (3S,4R)-1-benzyl-4-(4-fluorophenyl)-3-piperidinecarboxylate C23H28FNO2 详情 详情
(XIII) 44020 [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methanol C19H22FNO 详情 详情
(XIV) 56484 [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methyl methanesulfonate C20H24FNO3S 详情 详情
(XV) 10985 1,3-Benzodioxol-5-ol; Sesamol 533-31-3 C7H6O3 详情 详情
(XVI) 44022 (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-1-benzyl-4-(4-fluorophenyl)piperidine; 1,3-benzodioxol-5-yl [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methyl ether C26H26FNO3 详情 详情

合成路线8

该中间体在本合成路线中的序号：(A)

4,4'-Ethane-1,2-diylbis(piperazine-2,6-dione) in DMF is heated at 130 C for 10 min. Aqueous formaldehyde is then gradually added, and the mixture is heated at 130 C for 1.5 h. 4,4'-Ethane-1,2-diylbis[1-(hydroxymethyl)piperazine-2,6-dione] precipitates from the solution on cooling. It can be purified by recrystallization from dioxane. The hydroxymethyl compound (II) is then stirred with pyridine and chloroform at 10 C. Isobutoxycarbonyl chloride is gradually added, and the mixture is stirred for 6 h at room temperature. The resulting solution is diluted with chloroform. The combined solution is washed with water and then dried. Evaporation of the chloroform gives MST-16. It can be purified by recrystallization from ethylene glycol monomethyl ether.

参考文献 中间体
合成目标
【1】 Ruyun, J.; MST-16. Drugs Fut 1986, 11, 4, 267.
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) 13423 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate 543-27-1 C5H9ClO2 详情 详情
(I) 28033 4-[2-(3,5-dioxo-1-piperazinyl)ethyl]-2,6-piperazinedione C10H14N4O4 详情 详情
(II) 28034 1-(hydroxymethyl)-4-[2-[4-(hydroxymethyl)-3,5-dioxo-1-piperazinyl]ethyl]-2,6-piperazinedione C12H18N4O6 详情 详情

合成路线9

该中间体在本合成路线中的序号：(Vb)

The synthesis of 10-EDAM is as follows: 3-Methoxyallyl chloride (II) is prepared in situ by treatment of 1-methoxyallene (I) with an equivalent of HCl in ether at low temperature. The dianion of p-n-propylbenzoic acid is generated in THF at 0-5 C by lithium diisopropyl amide and subsequently alkylated with (II). The resulting 4-(p-carboxyphenyl)-1-methoxy-1-hexene (III) is brominated at pH 7-8 to give the alpha-bromoaldehyde acid (IV). Condensation with tetraaminopyrimidine in aqueous AcOH and subsequent in situ oxidation of the resultant dihydropteridine affords crystalline 10-ethyl-10-deaza-4-amino-4-desoxypteroic acid (V). Coupling of (V) with diethyl L-glutamate via the mixed anhydride method using isobutyl chloroformate affords the diethyl ester of 10-EDAM (VI). Following chromatographic purification on silica gel, the diester is saponified with 1N NaOH in methoxyethanol at room temperature to yield 10-EDAM.

参考文献 中间体
合成目标
【1】 DeGraw, J.I.; EDATREXATE. Drugs Fut 1989, 14, 9, 849.
【2】 Hoff, S.; Brandsma, L.; Acid catalyzed ring closure of 1-methoxy or 1-(methylthio)-1-(alpha or beta-hydroxyalkyl)allenes. Recl Trav Chim Pays-Bas 1969, 88, 845.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(Va) 11012 4-[1-[(2,4-Diamino-6-pteridinyl)methyl]propyl]benzoic acid C17H18N6O2 详情 详情
(Vb) 13423 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate 543-27-1 C5H9ClO2 详情 详情
(IIa) 19518 (E)-3-chloro-1-propenyl methyl ether; (E)-3-chloro-1-methoxy-1-propene C4H7ClO 详情 详情
(IIb) 19519 4-propylbenzoic acid 2438-05-3 C10H12O2 详情 详情
(IVa) 19521 4-(3-bromo-1-ethyl-4-oxobutyl)benzoic acid C13H15BrO3 详情 详情
(IVb) 19522 2,4,6-triamino-5-pyrimidinylamine; 2,4,5,6-pyrimidinetetramine 1004-74-6 C4H8N6 详情 详情
(Vc) 19525 diethyl 2-aminopentanedioate C9H17NO4 详情 详情
(I) 19517 methyl 1,2-propadienyl ether; 1-methoxyallene C4H6O 详情 详情
(III) 19520 4-[(E)-1-ethyl-4-methoxy-3-butenyl]benzoate C14H17O3 详情 详情
(VI) 19526 diethyl 2-[(4-[1-[(2,4-diamino-6-pteridinyl)methyl]propyl]benzoyl)amino]pentanedioate C26H33N7O5 详情 详情

合成路线10

该中间体在本合成路线中的序号：

The benzoylation of thiazolidine-4(R)-carboxylic acid (I) with benzoyl chloride (II) by means of NaOH in acetone water gives the corresponding N-benzoyl derivative (III), which is then condensed with alpha-(R)-methylbenzylamine (IV) by means of isobutyl chloroformate and triethylamine in dichloromethane.

参考文献 中间体
合成目标
【1】 Matsui, T.; Nagano, M.; KLitamura, K.; Shimizu, F. (Sankyo Co., Ltd.); Amino acid derivatives having anti-tumor activity and compositions containing them.. EP 0173441; ES 8703830; US 4904680 .
【2】 Castaner, J.; Prous, J.; RS-0481. Drugs Fut 1988, 13, 7, 627.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
13423 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate 543-27-1 C5H9ClO2 详情 详情
(I) 12899 L-(-)-Thiazolidine-4-carboxylic acid; (4R)-1,3-Thiazolidine-4-carboxylic acid; (R)-(-)-Thiazolidine-4-carboxylic acid 34592-47-7 C4H7NO2S 详情 详情
(II) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(III) 22557 (4R)-3-benzoyl-1,3-thiazolidine-4-carboxylic acid C11H11NO3S 详情 详情
(IV) 10039 (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine 3886-69-9 C8H11N 详情 详情

合成路线11

该中间体在本合成路线中的序号：(III)

The condensation of 4-(1-benzyloxy-N-methylformamido)butyric acid (I) with o-phenylenediamine (II) and isobutyl chloroformate (III) by means of triethylamine gives N-[3-[N-(2-aminophenyl)carbamoyl]propyl]-N-methylcarbamic acid benzyl ester (IV), which is cyclized by means of p-toluenesulfonic acid in refluxing toluene to the benzimidazole derivative (V). Hydrogenation of (V) with H2 over Pd/C in methanol affords 2-[3-(methylamino)propyl]benzimidazole (VI), which is condensed with the chiral p-toluenesulfonate (VII) by heating at 120 C to give the chiral tetrahydronaphthol (VIII). Finally, this alcohol is esterified with 2-methoxyacetyl chloride and ethyl diisopropylamine in chloroform.

参考文献 中间体
合成目标
【1】 Merlos, M.; Castaner, J.; Casa, A.; Graul, A.; Mibefradil Hydrochloride. Drugs Fut 1997, 22, 10, 1091.
【2】 Branca, Q.; Jaunin, R.; Marki, H.P.; Marti, F.; Ramuz, H. (F. Hoffmann-La Roche AG); Tetrahydronaphthalene derivs. and medicines containing them. EP 0268148; JP 1988139171; US 4808605 .
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) 13421 4-[[(Benzyloxy)carbonyl](methyl)amino]butyric acid C13H17NO4 详情 详情
(II) 12824 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine 95-54-5 C6H8N2 详情 详情
(III) 13423 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate 543-27-1 C5H9ClO2 详情 详情
(IV) 13424 benzyl 4-(2-aminoanilino)-4-oxobutyl(methyl)carbamate C19H23N3O3 详情 详情
(V) 13425 benzyl 3-(1H-benzimidazol-2-yl)propyl(methyl)carbamate C19H21N3O2 详情 详情
(VI) 13426 N-[3-(1H-Benzimidazol-2-yl)propyl]-N-methylamine; 3-(1H-Benzimidazol-2-yl)-N-methyl-1-propanamine C11H15N3 详情 详情
(VII) 13427 2-[(1S,2S)-6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydro-2-naphthalenyl]ethyl 4-methylbenzenesulfonate C22H27FO4S 详情 详情
(VIII) 13428 (1S,2S)-2-[2-[[3-(1H-Benzimidazol-2-yl)propyl](methyl)amino]ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydro-2-naphthalenol C26H34FN3O 详情 详情
(IX) 13429 2-Methoxyacetyl chloride; Methoxyacetyl chloride 38870-89-2 C3H5ClO2 详情 详情

合成路线12

该中间体在本合成路线中的序号：(XV)

The desired product is finally obtained by first formation of a mixed anhydride (XVI) by reaction of the cyclohexylphenyl glycolic acid (IV) with isobutylchloroformate (XV) in cyclohexane in the presence of Et3N, followed by treatment with 4-N,N-diethylamino butynol (XVII) (obtained on turn from reaction of propargyl alcohol (XVIII) with diethylamine (XIX) in the presence of paraformaldehyde and CuCl.

参考文献 中间体
合成目标
【1】 Senanayake, C.H.; Bakale, R.P.; Vandenbossche, C.P.; McConville, F.X.; Lopez, J.L. (Sepracor Inc.); Synthesis of optically active cyclohexylphenylglycolic acid and its esters. US 5973182; US 6140529; WO 0023414 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 51215 (2S)-2-cyclohexyl-2-hydroxy-2-phenylethanoic acid C14H18O3 详情 详情
(XV) 13423 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate 543-27-1 C5H9ClO2 详情 详情
(XVI) 51222 　 C19H26O5 详情 详情
(XVII) 51223 4-(diethylamino)-2-butyn-1-ol C8H15NO 详情 详情
(XVIII) 16664 Propargyl Alcohol; 2-propyn-1-ol 107-19-7 C3H4O 详情 详情
(XIX) 24486 Diethylamine; N,N-Diethylamine 109-89-7 C4H11N 详情 详情

合成路线13

该中间体在本合成路线中的序号：(II)

N-(tert-Butoxycarbonyl)-L-methionine (I) was converted to mixed anhydride (III) upon treatment with isobutyl chloroformate (II). Subsequent condensation of (III) with hydroxylamine gave hydroxamic acid (IV). Finally, the Boc group was cleared with trifluoroacetic acid in anisole to furnish the target methionine hydroxamate).

参考文献 中间体
合成目标
【1】 Lee, J.; Kang, M.K.; Chun, M.W.; Jo, Y.J.; Kwak, J.H.; Kim, S.; Methionine analogues as inhibitors of methionyl-tRNA synthetase. Bioorg Med Chem Lett 1998, 8, 24, 3511.
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) 17634 (2S)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butyric acid; N-alpha-t-BOC-L-methionine 2488-15-5 C10H19NO4S 详情 详情
(II) 13423 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate 543-27-1 C5H9ClO2 详情 详情
(III) 20090 N-(Tert-butoxycarbonyl)-L-methionine isobutoxycarbonyl anhydride C15H27NO6S 详情 详情
(IV) 20091 tert-butyl (1S)-1-[(hydroxyamino)carbonyl]-3-(methylsulfanyl)propylcarbamate C10H20N2O4S 详情 详情

合成路线14

该中间体在本合成路线中的序号：(XII)

The compound was also prepared by solution-phase synthesis. Treatment of O-tert-butyl-D-serine (XIII) with isobutyl chloroformate (XII) produced carbamate (XIV). Subsequent coupling of (XIV) with L-alanine tert-butyl ester (XV) by means of EDC and HOBt yielded the protected dipeptide (XVI). Deprotection of both tert-butyl groups of (XVI) with trifluoroacetic acid produced dipeptide (XVII), which was coupled to nitro-L-arginine ethyl aminal (XVIII) to furnish tripeptide (XIX). Hydrogenolysis of the nitro group of (XIX) over Pd/C gave (XX). The ethyl acetal of (XX) was finally hydrolyzed in 3M HCl to yield the title compound.

参考文献 中间体
合成目标
【1】 Cohen, C.R.; Weinhouse, M.I.; Roberts, C.; et al.; Synthesis and biological activity of transition-state urokinase inhibitors. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 090.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 13423 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate 543-27-1 C5H9ClO2 详情 详情
(XIII) 29383 (2R)-2-amino-3-(tert-butoxy)propionic acid C7H15NO3 详情 详情
(XIV) 29384 (2R)-3-(tert-butoxy)-2-[(isobutoxycarbonyl)amino]propionic acid C12H23NO5 详情 详情
(XV) 29385 tert-butyl (2S)-2-aminopropanoate C7H15NO2 详情 详情
(XVI) 29386 tert-butyl (2S)-2-([(2R)-3-(tert-butoxy)-2-[(isobutoxycarbonyl)amino]propanoyl]amino)propanoate C19H36N2O6 详情 详情
(XVII) 29387 (2S)-2-([(2R)-3-hydroxy-2-[(isobutoxycarbonyl)amino]propanoyl]amino)propionic acid C11H20N2O6 详情 详情
(XVIII) 29388 3(S)-Amino-2-ethoxy-N2-nitropiperidine-1-carboxamidine C8H17N5O3 详情 详情
(XIX) 29389 Isobutoxycarbinyl-D-seryl-L-alanine 1-[2-ethoxy-1-(N2-nitroamidino)piperidin-3(S)-ylamide C19H35N7O8 详情 详情
(XX) 29390 isobutyl (1R)-2-[[(1S)-2-([(3S)-1-[amino(imino)methyl]-2-ethoxypiperidinyl]amino)-1-methyl-2-oxoethyl]amino]-1-(hydroxymethyl)-2-oxoethylcarbamate C19H36N6O6 详情 详情

合成路线15

该中间体在本合成路线中的序号：(II)

The reaction of 3-fluoroaniline (I) with isobutyl chloroformate (II) by means of K2CO3 in dichloromethane/water gives the carbamate (III), which is brominated with 1,3-dibromo-5,5-dimethylhydantoin (DBDH) to yield the 4-bromo-3-fluorophenyl carbamate (IV). The condensation of (IV) with tetrahydrothiopyran-4-one (V) by means of EtMgBr and BuLi in THF affords the tertiary alcohol (VI), which is dehydrated by means of TFA in dichloromethane and oxidized with NaIO4 in methanol/water to provide the unsaturated sulfoxide (VII). The stereoselective reduction of (VII) by means of H2 over Pt/C in DMF gives the cis sulfoxide (VIII). The cyclization of the carbamate (VIII) with (S)-3-chloropropane-1,2-diol (IX) by means of Li t-amylate in DMF gives the oxazolidinone (X), whose free OH group is activated with 2,5-dichlorobenzenesulfonyl chloride (XI) and TEA in dichloromethane to yield the sulfonate (XII). The reaction of (XII) with NH4OH in methanol/acetonitrile affords the aminomethyl derivative (XIII), which is finally acylated with acetic anhydride (XIV) to provide the target sulfoxide.

参考文献 中间体
合成目标
【1】 Gage, J.R.; et al.; Stereodivergent synthesis of sulfoxide-containing oxazolidinone antibiotics. Tetrahedron Lett 2000, 41, 22, 4301.
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) 20697 3-fluoroaniline; 3-fluorophenylamine 372-19-0 C6H6FN 详情 详情
(II) 13423 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate 543-27-1 C5H9ClO2 详情 详情
(III) 49690 isobutyl 3-fluorophenylcarbamate C11H14FNO2 详情 详情
(IV) 49691 isobutyl 4-bromo-3-fluorophenylcarbamate C11H13BrFNO2 详情 详情
(V) 49692 Tetrahydrothiopyran-4-one; Tetrahydro-4H-thiopyran-4-one; 4-Oxothiane 1072-72-6 C5H8OS 详情 详情
(VI) 49693 isobutyl 3-fluoro-4-(4-hydroxytetrahydro-2H-thiopyran-4-yl)phenylcarbamate C16H22FNO3S 详情 详情
(VII) 49694 4-[2-fluoro-4-[(isobutoxycarbonyl)amino]phenyl]-3,6-dihydro-2H-thiopyranium-1-olate C16H20FNO3S 详情 详情
(VIII) 49695 4-[2-fluoro-4-[(isobutoxycarbonyl)amino]phenyl]tetrahydro-2H-thiopyranium-1-olate C16H22FNO3S 详情 详情
(IX) 49696 (S)-(+)-Alpha-Chlorohydrin; (S)-(+)-3-Chloro-1,2-propanediol; (S)-3-Chloro-1,2-propanediol 60827-45-4 C3H7ClO2 详情 详情
(X) 49697 4-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]tetrahydro-2H-thiopyranium-1-olate C15H18FNO4S 详情 详情
(XI) 49698 2,5-Dichlorobenzenesulfonic acid 88-42-6 C6H4Cl2O3S 详情 详情
(XII) 49699 4-[4-[(5R)-5-([[(2,5-dichlorophenyl)sulfonyl]oxy]methyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]tetrahydro-2H-thiopyranium-1-olate C21H20Cl2FNO6S2 详情 详情
(XIII) 49700 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]tetrahydro-2H-thiopyranium-1-olate C15H19FN2O3S 详情 详情
(XIV) 49701 Acetic anhydride; Acetyl oxide 108-24-7 C4H6O3 详情 详情

合成路线16

该中间体在本合成路线中的序号：(II)

The reaction of 3-fluoroaniline (I) with isobutyl chloroformate (II) by means of K2CO3 in dichloromethane/water gives the carbamate (III), which is brominated with 1,3-dibromo-5,5-dimethylhydantoin (DBDH) to yield the 4-bromo-3-fluorophenyl carbamate (IV). The condensation of (IV) with tetrahydrothiopyran-4-one (V) by means of EtMgBr and BuLi in THF affords the tertiary alcohol (VI), which is dehydroxylated by means of poly(methylhydrosiloxane) (PMHS), (Me3Si)2O and Ts-OH in toluene to provide the intermediate (VII). The stereoselective oxidation of (VII) to the trans sulfoxide (VIII) is performed by means of Ti(OiPr)4 and tert-butyl hydroperoxide in the presence of diisopropyl D-tartrate. The cyclization of the carbamate (VIII) with (S)-3-chloropropane-1,2-diol (IX) by means of Li t-amylate in DMF gives the oxazolidinone (X), whose free OH group is activated with 3-nitrobenzenesulfonyl chloride and TEA in dichloromethane to yield the sulfonate (XII). The reaction of (XII) with NH4OH in methanol/acetonitrile affords the aminomethyl derivative (XIII), which is finally acylated with propionic anhydride (XIV) to provide the target sulfoxide.

参考文献 中间体
合成目标
【1】 Gage, J.R.; et al.; Stereodivergent synthesis of sulfoxide-containing oxazolidinone antibiotics. Tetrahedron Lett 2000, 41, 22, 4301.
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) 20697 3-fluoroaniline; 3-fluorophenylamine 372-19-0 C6H6FN 详情 详情
(II) 13423 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate 543-27-1 C5H9ClO2 详情 详情
(III) 49690 isobutyl 3-fluorophenylcarbamate C11H14FNO2 详情 详情
(IV) 49691 isobutyl 4-bromo-3-fluorophenylcarbamate C11H13BrFNO2 详情 详情
(V) 49692 Tetrahydrothiopyran-4-one; Tetrahydro-4H-thiopyran-4-one; 4-Oxothiane 1072-72-6 C5H8OS 详情 详情
(VI) 49693 isobutyl 3-fluoro-4-(4-hydroxytetrahydro-2H-thiopyran-4-yl)phenylcarbamate C16H22FNO3S 详情 详情
(VII) 49702 isobutyl 3-fluoro-4-tetrahydro-2H-thiopyran-4-ylphenylcarbamate C16H22FNO2S 详情 详情
(VIII) 49706 4-[2-fluoro-4-[(isobutoxycarbonyl)amino]phenyl]tetrahydro-2H-thiopyranium-1-olate C16H22FNO3S 详情 详情
(IX) 49696 (S)-(+)-Alpha-Chlorohydrin; (S)-(+)-3-Chloro-1,2-propanediol; (S)-3-Chloro-1,2-propanediol 60827-45-4 C3H7ClO2 详情 详情
(X) 49707 4-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]tetrahydro-2H-thiopyranium-1-olate C15H18FNO4S 详情 详情
(XI) 49703 m-nitrobenzenesulfonic acid; 3-nitrobenzenesulfonic acid 98-47-5 C6H5NO5S 详情 详情
(XII) 49704 4-[2-fluoro-4-[(5R)-5-([[(3-nitrophenyl)sulfonyl]oxy]methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]tetrahydro-2H-thiopyranium-1-olate C21H21FN2O8S2 详情 详情
(XIII) 49705 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]tetrahydro-2H-thiopyranium-1-olate C15H19FN2O3S 详情 详情
(XIV) 49701 Acetic anhydride; Acetyl oxide 108-24-7 C4H6O3 详情 详情

合成路线17

该中间体在本合成路线中的序号：(V)

Racemic amine (I) can be resolved by the following alternative procedures: An alternative procedure to compound (VII) begins by condensating amine (II) with N-Boc-L-alanine (IV) in the presence of HOBt.H2O, DIEA and EDC in THF to yield the N-Boc-L-alaninamide derivative (IX) . Similarly, the hydrochloride of amine (II) reacts with N-Boc-L-alanine (IV) in the presence of HOBt.H2O, DIEA and EDC in THF . Intermediate (IX) is then deprotected with either HCl in EtOAc or 1,4-dioxane , or concentrated HCl , and the resulting amine (VII) is obtained as the free base or employed without isolation, respectively. Finally, either hydrochloride (VII) or the nonisolated species obtained from compound (IX) is condensed with 2(S)-hydroxy-3-methylbutyric acid (X) by means of HOBt.H2O, NMM and EDC.HCl in H2O to give semagacestat . Under related conditions, the free base of (VII) couples with acid (XI) in the presence of HOBt.H2O, DIEA and EDC in THF . Alternatively, silylation of 2(S)-hydroxy-3-methylbutyric acid (X) with HMDS in the presence of (NH4)2SO4 at reflux gives trimethylsilyl 3-methyl-2(S)-(trimethylsilyloxy) butanoate (XI), which is first reacted with (COCl)2 in the presence of DMF in CH2Cl2 and then with the mesylate salt (VIII) by means of NMM in CH2Cl2 .

参考文献 中间体
合成目标
【1】 Koenig, T.M., Nissen, J.S., Mitchell, D. (Eli Lilly and Company). Lactam compound. EP 1345955, JP 2005538031, WO 2002040508.
【2】 Audia, J.E., John, V., Latimer, L.H., Tung, J.S., Nissen, J.S., Thorsett, E.D., McDaniel, S.L. (Eli Lilly and Company; Elan Pharmaceuticals, Inc.). Lactam compound. JP 2004517090, WO 2002047671.
【3】 Koenig, T.M., Audia, J.E., Mitchell, D., Aikins, J.A., Buccilli, L.A., Engel,G.L., McDaniel, S.L. (Eli Lilly and Company). Lactam compound. CA 2425497, EP 1353910, JP 2004521084, WO 2002040451.
【4】 Audia, J.E., Diseroad, B.A., Varghese, J. et al. (Eli Lilly and Company).Lactam compound. US 2007299053, US 7468365.
【5】 Mitchell, D., Hay, L.A., Koenig, T.M., McDaniel, S., Nissen, J.S., Audia, J.E.Classical and dynamic resolution of 1-amino-3-methyl-1,3,4,5-tetrahydrobenzo[d]azepin-2-one. Tetrahedron Asymmetry 2005, 16(23): 3814-9.
【6】 Pu, Y.J., Vaid, R.K., Boini, S.K., Towsley, R.W., Doecke, C.W., Mitchell, D. A practical method for functionalized peptide or amide bond formation in aqueous-ethanol media with EDC as activator. Org Process Res Dev 2009, 13(2): 310-4.
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) 69307 1-amino-3-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one C11H14N2O 详情 详情
(II) 69308 1(S)-amino-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one C11H14N2O 详情 详情
(III) 69309 1(S)-amino-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one C11H14N2O 详情 详情
(IV) 26450 Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid 15761-38-3 C8H15NO4 详情 详情
(V) 13423 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate 543-27-1 C5H9ClO2 详情 详情
(VI) 69310 (S)-2-((tert-butoxycarbonyl)amino)propanoic (isobutyl carbonic) anhydride C13H23NO6 详情 详情
(VII) 69311 (S)-2-amino-N-((R)-3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)propanamide hydrochloride C14H19N3O2.HCl 详情 详情
(VIII) 69312 (S)-2-amino-N-((R)-3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)propanamide methanesulfonate C14H19N3O2.CH4O3S 详情 详情
(IX) 69313 tert-butyl ((S)-1-(((R)-3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl)amino)-1-oxopropan-2-yl)carbamate C19H27N3O4 详情 详情
(X) 69314 2(S)-hydroxy-3-methylbutyric acid C5H10O3 详情 详情
(XI) 69315 (S)-trimethylsilyl 3-methyl-2-((trimethylsilyl)oxy)butanoate C11H26O3Si2 详情 详情

合成路线18

该中间体在本合成路线中的序号：(XIII)

Bromination of 2-amino-5-methylpyrazine (X) with Br2 in CHCl3 affords the bromopyrazine (XI), which by subsequent bromide displacement by means of sodium methoxide in refluxing methanol gives the methoxypyrazine (XII). Then, the amino group of (XII) is protected by acylation with isobutyl chloroformate (XIII) in the presence of pyridine in CH2Cl2 to provide carbamate (XIV), which finally, after being pretreated with NaH, is sulfonylated with 2-chloropyridine-3-sulfonyl chloride (XV) in DMF. Compound (XV) is prepared from 3-amino-2-chloropyridine (XVI) by diazotization and subsequent treatment with sulfur dioxide in the presence of CuCl in AcOH .

参考文献 中间体
合成目标
【1】 Bradbury, R.H., Butlin, R.J., James, R. (AstraZeneca plc). N-Heteroarylpyridinesulfonamide derivatives and their use as endothelin antagonists. EP 0832082, JP 1999509175, US 6060475, US 6258817, WO 1996040681.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 69329 isobutyl (2-chloropyridin-3-yl)sulfonyl(3-methoxy-5-methyl-4,5-dihydropyrazin-2-yl)carbamate C16H21ClN4O5S 详情 详情
(X) 64109 5-methyl-2-pyrazinamine; 5-methyl-2-pyrazinylamine C5H7N3 详情 详情
(XI) 64110 3-bromo-5-methyl-2-pyrazinamine; 3-bromo-5-methyl-2-pyrazinylamine C5H6BrN3 详情 详情
(XII) 64111 5-methyl-3-(methyloxy)-2-pyrazinamine; 5-methyl-3-(methyloxy)-2-pyrazinylamine C6H9N3O 详情 详情
(XIII) 13423 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate 543-27-1 C5H9ClO2 详情 详情
(XIV) 64112 2-methylpropyl 5-methyl-3-(methyloxy)-2-pyrazinylcarbamate C11H17N3O3 详情 详情
(XV) 64113 2-chloro-3-pyridinesulfonyl chloride C5H3Cl2NO2S 详情 详情
(XVI) 11160 2-Chloro-3-pyridinamine; 2-Chloro-3-pyridinylamine; 3-Amino-2-chloropyridine; 2-Chloro-3-aminopyridine 6298-19-7 C5H5ClN2 详情 详情
Extended Information