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【结 构 式】 
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【分子编号】11191 【品名】2-Chloropyrimidine 【CA登记号】1722-12-9 |
【 分 子 式 】C4H3ClN2 【 分 子 量 】114.534 【元素组成】C 41.95% H 2.64% Cl 30.95% N 24.46% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of piperazine (I) with [14C]-labeled 2-chloropyrimidine (II) in refluxing ethanol gives the labeled 1-(2-pyrimidinyl)piperazine (III), which is then condensed with the N-(4-bromobutyl)imide (IV) by means of K2CO3 and KI as before, affording SM-3997 labeled at the pyrimidine ring.
| 【1】 Kanamaru, H.; Nishioka, K.; 14C-labeling of a novel anxiolytic agent tandospirone. J Label Compd Radiopharm 1992, 31, 6, 427. |
| 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) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (II) | 11191 | 2-Chloropyrimidine | 1722-12-9 | C4H3ClN2 | 详情 | 详情 |
| (II) | 45056 | 2-chloropyrimidine | C4H3ClN2 | 详情 | 详情 | |
| (III) | 11175 | 2-(1-Piperazinyl)pyrimidine; 2-Piperazinopyrimidine; N-(Pyrimidinyl)piperazine | 20980-22-7 | C8H12N4 | 详情 | 详情 |
| (III) | 45057 | 2-(1-piperazinyl)pyrimidine | C8H12N4 | 详情 | 详情 | |
| (IV) | 11174 | (1R,2S,6R,7S)-4-(4-Bromobutyl)-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C13H18BrNO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)The esterification of pyridine-2,5-dicarboxylic acid (I) with thionyl chloride/methanol gives the corresponding dimethyl ester (II), which is hydrogenated with H2 over PtO2 in acetic acid yielding piperidine-2,5-dicarboxylic acid dimethyl ester (III), as a mixture of the cis- and trans-isomers. The condensation of (III) with 2-chloroacetonitrile (IV) by means of Na2CO3 in refluxing isobutyl methyl ketone affords the expected 1-(cyanomethyl) derivative (V), which is cyclized by hydrogenation with H2 over RaNi in methanol/ethyl acetate giving racemic cis-1-oxo-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylic acid methyl ester (VI). The reduction of (VI) with LiAlH4 in refluxing THF yields the corresponding hydroxymethyl derivative (VII), which is condensed with 2-chloropyrimidine by means of Na2CO3 in refluxing water affording racemic cis-7-(hydroxymethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (IX). The reaction of (IX) with methanesulfonyl chloride and triethylamine gives the expected mesylate (X), which is treated with sodium azide in DMF to afford the corresponding azido derivative (XI). The reaction of (XI) with hydrazine in refluxing ethanol gives the racemic cis-7-(aminomethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (XII), which is submitted to optical resolution by formation of the corresponding salt with (-)-mandelic acid, separation of the diastereomers by crystallization, and decomposition of the desired salt with NaOH to yield (7R,9aS)-7-(aminomethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (XIII). Finally, this compound is condensed with succinic anhydride (XIV) in refluxing xylene.
| 【1】 Castaner, J.; Graul, J.; Silvestre, J.S.; Sunepitron Hydrochloride. Drugs Fut 1998, 23, 2, 161. |
| 【2】 Desai, K.A.; Bright, G.M. (Pfizer Inc.); Bis-aza-bicyclic anxiolytic agents and antidepressants. EP 0380217; JP 1990233681; US 5122525; WO 9008144; WO 9008148 . |
| 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) | 14440 | 2,5-pyridinedicarboxylic acid | 100-26-5 | C7H5NO4 | 详情 | 详情 |
| (II) | 14441 | dimethyl 2,5-pyridinedicarboxylate | 881-86-7 | C9H9NO4 | 详情 | 详情 |
| (III) | 14442 | dimethyl 2,5-piperidinedicarboxylate | C9H15NO4 | 详情 | 详情 | |
| (IV) | 14443 | 2-chloroacetonitrile; chloroacetonitrile | 107-14-2 | C2H2ClN | 详情 | 详情 |
| (V) | 14444 | dimethyl 1-(cyanomethyl)-2,5-piperidinedicarboxylate | C11H16N2O4 | 详情 | 详情 | |
| (VI) | 14445 | methyl (7S,9aS)-1-oxooctahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylate | C10H16N2O3 | 详情 | 详情 | |
| (VII) | 14446 | (7S,9aS)octahydro-2H-pyrido[1,2-a]pyrazin-7-ylmethanol | C9H18N2O | 详情 | 详情 | |
| (VIII) | 11191 | 2-Chloropyrimidine | 1722-12-9 | C4H3ClN2 | 详情 | 详情 |
| (IX) | 14448 | [(7S,9aS)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methanol | C13H20N4O | 详情 | 详情 | |
| (X) | 14449 | [(7S,9aS)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methyl methanesulfonate | C14H22N4O3S | 详情 | 详情 | |
| (XI) | 14450 | [(7S,9aS)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methyl azide; (7S,9aS)-7-(azidomethyl)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazine | C13H19N7 | 详情 | 详情 | |
| (XII) | 63830 | [(7S,9aS)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methylamine; [(7S,9aS)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methanamine | C13H21N5 | 详情 | 详情 | |
| (XIII) | 14451 | [(7R,9aS)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methylamine; [(7R,9aS)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methanamine | C13H21N5 | 详情 | 详情 | |
| (XIV) | 11291 | Dihydro-2,5-furandione; Succinic anhydride | 108-30-5 | C4H4O3 | 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 conversion of 2-chloropyrimidine (I) to pyrimidine-2-carboxamidine (III) is performed by known methods through the intermediate pyrimidine-2-carbonitrile (II). The cyclization of (III) with 2-(2-methoxyphenoxy)malonic acid diethyl ester (IV) -prepared by condensation of 2-chloromalonic acid diethyl ester (V) with guaiacol (VI)- yields the bipyrimidinedione (VII). This compound is treated with refluxing POCl3 to afford the dichlorobipyrimidine (VIII). The chlorine monosubstitution in (VIII) with 4-tert-butylphenylsulfonamide (IX), K2CO3 and tetrabutylammonium bromide (TBAB) in toluene provides the substituted sulfonamide (X), which is submitted to a second chlorine substitution with ethyleneglycol mono-tert-butyl ether (XI) by means of NaOH in hot toluene to give the tert-butyl-intermediate (XII). Finally, this compound is deprotected by reaction with formic acid yielding the formate ester (XIII), which is hydrolyzed with NaOH in ethanol/water, and submitted to crystallization in refluxing ethanol/water to afford the target bosentan.
| 【1】 Harrington, P.J.; Khatri, H.N.; DeHoff, B.S.; Guinn, M.R.; Boehler, M.A.; Glaser, K.A.; Research and development of a second-generation process for bosentan, and endothelin receptor antagonist. Org. Proc. Res. & Develop. 2002, 6, 2, 120. |
| 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) | 11191 | 2-Chloropyrimidine | 1722-12-9 | C4H3ClN2 | 详情 | 详情 |
| (II) | 61568 | 2-Pyrimidinecarbonitrile; 2-Cyanopyrimidine | 14080-23-0 | C5H3N3 | 详情 | 详情 |
| (III) | 50368 | 2-pyrimidinecarboximidamide | C5H6N4 | 详情 | 详情 | |
| (IV) | 61569 | dimethyl 2-(2-methoxyphenoxy)malonate | C12H14O6 | 详情 | 详情 | |
| (V) | 59503 | dimethyl chloromalonate | 28868-76-0 | C5H7ClO4 | 详情 | 详情 |
| (VI) | 13182 | Guaiacol; 2-Methoxyphenol | 90-05-1 | C7H8O2 | 详情 | 详情 |
| (VII) | 50370 | 5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4,6(1H,5H)-pyrimidinedione | C15H12N4O4 | 详情 | 详情 | |
| (VIII) | 41585 | C15H10Cl2N4O2 | 详情 | 详情 | ||
| (IX) | 50371 | 4-(tert-Butyl)benzenesulphonamide | C10H15NO2S | 详情 | 详情 | |
| (X) | 50372 | C25H24ClN5O4S | 详情 | 详情 | ||
| (XI) | 50373 | 2-tert-Butoxyethanol; Ethylene glycol mono-tert-butyl ester | 7580-85-0 | C6H14O2 | 详情 | 详情 |
| (XII) | 50374 | C31H37N5O6S | 详情 | 详情 | ||
| (XIII) | 50375 | C28H29N5O7S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The reaction of 2-chloropyrimidine (I) with NaOMe in methanol gives 2-methoxypyrimidine (II), which is iodinated with N-iodosuccinimide (NIS) and trifluoroacetic anhydride in refluxing THF to yield 5-iodo-2-methoxypyrimidine (III). The condensation of (III) with methyl acrylate (IV) by means of Pd(OAc)2, K2CO3 and Bu4NCl at 120 C affords 3-(2-methoxypyrimidin-5-yl)acrylic acid methyl ester (V), which is hydrolyzed with KOH in methanol to provide the free acid (VI). The esterification of (VI) with p-nitrophenol (VII) by means of DCC and DMAP in dichloromethane gives the activate ester (VIII). The condensation of (VIII) with the tetracyclic ketone (IX) (obtained by treatment of the dimeric ketonic compound (X) with NaOMe in methanol) affords the adduct (XI), which is treated with HBr in acetonitrile to open the cyclopropane ring and provide the bromomethyl compound (XII). The aromatization of (XII) with p-nitrophenyl chloroformate (XIII) and TEA in dichloromethane affords the activated carbonate ester (XIV), which is finally treated with 1-methylpiperazine (XV) to furnish the target carbamate.
| 【1】 Nagamura, S.; et al.; Synthesis and antitumor activity of duocarmycin derivatives: Modification of affinity moiety to DNA minor groove. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 206. |
| 【2】 Saito, H.; Nagamura, S.; Amishiro, N.; Kobayashi, E.; Gomi, K.; New water-soluble duocarmycin derivatives: Synthesis and antitumor activity of A-ring pyrrole compounds bearing beta-heteroarylacryloyl groups. J Med Chem 1999, 42, 4, 669. |
| 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) | 11191 | 2-Chloropyrimidine | 1722-12-9 | C4H3ClN2 | 详情 | 详情 |
| (II) | 38398 | methyl 2-pyrimidinyl ether; 2-methoxypyrimidine | C5H6N2O | 详情 | 详情 | |
| (III) | 38394 | 5-iodo-2-methoxypyrimidine; 5-iodo-2-pyrimidinyl methyl ether | C5H5IN2O | 详情 | 详情 | |
| (IV) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (V) | 38395 | methyl (E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoate | C9H10N2O3 | 详情 | 详情 | |
| (VI) | 38396 | (E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoic acid | C8H8N2O3 | 详情 | 详情 | |
| (VII) | 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 |
| (VIII) | 38397 | 4-nitrophenyl (E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoate | C14H11N3O5 | 详情 | 详情 | |
| (IX) | 38365 | methyl (3bR,4aS)-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C14H14N2O3 | 详情 | 详情 | |
| (X) | 38366 | methyl (2R,3bR,4aS)-2-methyl-3,8-dioxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,4,4a,5,6,8-octahydrocyclopropa[c]pyrrolo[3,2-e]indole-2-carboxylate | C26H25N3O8 | 详情 | 详情 | |
| (XI) | 38399 | methyl (3bR,4aS)-6-[(E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoyl]-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C22H20N4O5 | 详情 | 详情 | |
| (XII) | 38400 | methyl (8S)-8-(bromomethyl)-6-[(E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoyl]-2-methyl-4-oxo-3,4,6,7,8,8a-hexahydropyrrolo[3,2-e]indole-1-carboxylate | C22H21BrN4O5 | 详情 | 详情 | |
| (XIII) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (XIV) | 38401 | methyl (8S)-8-(bromomethyl)-6-[(E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoyl]-2-methyl-4-[[(4-nitrophenoxy)carbonyl]oxy]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C29H24BrN5O9 | 详情 | 详情 | |
| (XV) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The reaction of 2-chloropyrimidine (I) with NaOMe in methanol gives 2-methoxypyrimidine (II), which is iodinated with N-iodosuccinimide (NIS) and trifluoroacetic anhydride in refluxing THF to yield 5-iodo-2-methoxypyrimidine (III). The condensation of (III) with methyl acrylate (IV) by means of Pd(OAc)2, K2CO3 and Bu4NCl at 120 C affords 3-(2-methoxypyrimidin-5-yl)acrylic acid methyl ester (V), which is hydrolyzed with KOH in methanol to provide the free acid (VI). The esterification of (VI) with p-nitrophenol (VII) by means of DCC and DMAP in dichloromethane gives the activate ester (VIII). Finally, the condensation of (VIII) with the tetracyclic ketone (IX) (obtained by treatment of the dimeric ketonic compound (X) with NaOMe in methanol) affords the target compound.
| 【1】 Saito, H.; Nagamura, S.; Amishiro, N.; Kobayashi, E.; Gomi, K.; New water-soluble duocarmycin derivatives: Synthesis and antitumor activity of A-ring pyrrole compounds bearing beta-heteroarylacryloyl groups. J Med Chem 1999, 42, 4, 669. |
| 【2】 Nagamura, S.; et al.; Synthesis and antitumor activity of duocarmycin derivatives: Modification of affinity moiety to DNA minor groove. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 206. |
| 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) | 11191 | 2-Chloropyrimidine | 1722-12-9 | C4H3ClN2 | 详情 | 详情 |
| (II) | 38398 | methyl 2-pyrimidinyl ether; 2-methoxypyrimidine | C5H6N2O | 详情 | 详情 | |
| (III) | 38394 | 5-iodo-2-methoxypyrimidine; 5-iodo-2-pyrimidinyl methyl ether | C5H5IN2O | 详情 | 详情 | |
| (IV) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (V) | 38395 | methyl (E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoate | C9H10N2O3 | 详情 | 详情 | |
| (VI) | 38396 | (E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoic acid | C8H8N2O3 | 详情 | 详情 | |
| (VII) | 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 |
| (VIII) | 38397 | 4-nitrophenyl (E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoate | C14H11N3O5 | 详情 | 详情 | |
| (IX) | 38365 | methyl (3bR,4aS)-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C14H14N2O3 | 详情 | 详情 | |
| (X) | 38366 | methyl (2R,3bR,4aS)-2-methyl-3,8-dioxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,4,4a,5,6,8-octahydrocyclopropa[c]pyrrolo[3,2-e]indole-2-carboxylate | C26H25N3O8 | 详情 | 详情 |