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【结 构 式】 
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【分子编号】17220 【品名】cyclohexanecarbonyl chloride; Cyclohexanecarboxylic acid chloride 【CA登记号】2719-27-9 |
【 分 子 式 】C7H11ClO 【 分 子 量 】146.61644 【元素组成】C 57.34% H 7.56% Cl 24.18% O 10.91% |
合成路线1
该中间体在本合成路线中的序号：(VII)For [14C]-labelling of alifedrine, the following reaction sequence has been used: In the first step Friedel-Crafts'-like acylation of ethylene (A) with cyclohexanoyl chloride (VII) in the presence of aluminum chloride yields beta-chloroethylcyclohexyl ketone (VIII), which reacts with (I) to give alifedrine hydrochloride. Alifedrine has also been synthesized by catalytic hydrogenation of (V) with 1-norephedrine (I) in the presence of hydrochloric acid and paraformaldehyde.
| 【1】 Engel, J.; et al.; Novel cycloaliphatic enamines. DE 3213371 . |
| 【2】 Engel, J.; et al.; Cycloaliphatic ketoamines. DE 2919495; FR 2426040; GB 2023575; JP 54151950; US 4542159 . |
| 【3】 Klingler, K.G.; Engel, J.; Bickel, E.; Syntheses of 14C-1-erythro-norephedrine and its N-substitution products 14C-oxyfedrine and 14C-D 13,625. Arzneim-Forsch Drug Res 1983, 33, 9, 1213. |
| 【4】 Bahre, M.; Thiemer, K.; Engel, J.; Breuel, H.P.; Stroman, F.; Kleemann, A.; Alifedrine. Drugs Fut 1984, 9, 10, 727. |
| 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) | 34264 | 2-amino-1-phenyl-1-propanol | C9H13NO | 详情 | 详情 | |
| (V) | 34263 | 1-cyclohexyl-1-ethanone | 823-76-7 | C8H14O | 详情 | 详情 |
| (VII) | 17220 | cyclohexanecarbonyl chloride; Cyclohexanecarboxylic acid chloride | 2719-27-9 | C7H11ClO | 详情 | 详情 |
| (VIII) | 34265 | 3-chloro-1-cyclohexyl-1-propanone | C9H15ClO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)Alifedrine hydrochloride can be synthesized by condensation of acetylcyclohexane with the bisoxazolidine (IV), which is obtained by reaction of (I) with paraformaldehyde in aqueous solution. Finally, alifedrine can be obtained by condensation of 3-oxo-3-cyclohexylpropanal (X) and norephedrine (I) under reducing conditions (VI).
| 【1】 Engel, J.; et al.; Cycloaliphatic ketoamines. DE 3043350 . |
| 【2】 Tromer, H.G.; Sheldrick, W.S.; Engel, J.; Chem Ztg 1982, 106, Suppl. 1, 427. |
| 【3】 Bahre, M.; Thiemer, K.; Engel, J.; Breuel, H.P.; Stroman, F.; Kleemann, A.; Alifedrine. Drugs Fut 1984, 9, 10, 727. |
| 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) | 34264 | 2-amino-1-phenyl-1-propanol | C9H13NO | 详情 | 详情 | |
| (IV) | 34266 | (E)-1-cyclohexyl-3-[(2-hydroxy-1-methyl-2-phenylethyl)amino]-2-propen-1-one | C18H25NO2 | 详情 | 详情 | |
| (VII) | 17220 | cyclohexanecarbonyl chloride; Cyclohexanecarboxylic acid chloride | 2719-27-9 | C7H11ClO | 详情 | 详情 |
| (IX) | 34267 | (E)-3-chloro-1-cyclohexyl-2-propen-1-one | C9H13ClO | 详情 | 详情 | |
| (X) | 34268 | 3-cyclohexyl-3-oxopropanal | C9H14O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)Nucleophilic displacement of 2-chloro-5-(trifluoromethyl)pyridine (I) with ethanesulfonamide (II) in the presence of K2CO3 in hot DMSO afforded the N-pyridyl sulfonamide (III). Subsequent nitration of (III) with fuming nitric acid in HOAc gave the 3-nitro derivative (IV). Preparation of this intermediate was also reported by displacement of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (V) with the sodium salt of ethanesulfonamide (II). Subsequent reduction of the nitro group of (IV) to the corresponding 3-aminopyridine (VI) was carried out by means of catalytic hydrogenation, iron in HOAc, or sodium hydrosulfite as the reducing agents. Amine (VI) was coupled either with cyclohexanecarbonyl chloride (VII) or with cyclohexanecarboxylic acid (VIII) in the presence of EDC to produce the cyclohexanecarboxamide (IX). The acidic sulfonamide NH group of (IX) was finally converted to the sodium salt by treatment with NaOH.
| 【1】 Kimura, H.; et al.; Synthesis and antipancreatitis activities of novel N-(2-sulfonylamino-5-trifluoromethyl-3-pyridyl)carboxamide derivatives as phospholipase A2 inhibitors. Chem Pharm Bull 1995, 43, 10, 1696. |
| 【2】 Haga, T.; Sugi, H.; Shigehara, I.; Odawara, S.; Yotsuya, S.; Kimura, H.; Yamamoto, K. (Ishihara Sangyo Kaisha, Ltd.); Diaminotrifluoromethylpyridine derivs., process for their production and phospholipase A2 inhibitor containing them. EP 0465913; JP 1993170742; JP 1994247934; JP 1994263735; US 5229403; US 5260320; US 5348967; US 5492908 . |
| 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) | 59113 | 2-Chloro-5-(trifluoromethyl)pyridine; 5-Trifluoromethyl-2-chloropyridine | 52334-81-3 | C6H3ClF3N | 详情 | 详情 |
| (II) | 59114 | 1-ethanesulfonamide | C2H7NO2S | 详情 | 详情 | |
| (III) | 59115 | N-[5-(trifluoromethyl)-2-pyridinyl]-1-ethanesulfonamide | C8H9F3N2O2S | 详情 | 详情 | |
| (IV) | 59116 | N-[3-nitro-5-(trifluoromethyl)-2-pyridinyl]-1-ethanesulfonamide | C8H8F3N3O4S | 详情 | 详情 | |
| (V) | 59117 | 2-chloro-3-nitro-5-(trifluoromethyl)pyridine | C6H2ClF3N2O2 | 详情 | 详情 | |
| (VI) | 59118 | N-[3-amino-5-(trifluoromethyl)-2-pyridinyl]-1-ethanesulfonamide | C8H10F3N3O2S | 详情 | 详情 | |
| (VII) | 17220 | cyclohexanecarbonyl chloride; Cyclohexanecarboxylic acid chloride | 2719-27-9 | C7H11ClO | 详情 | 详情 |
| (VIII) | 44803 | cyclohexanecarboxylic acid | 98-89-5 | C7H12O2 | 详情 | 详情 |
| (IX) | 59119 | N-[2-[(ethylsulfonyl)amino]-5-(trifluoromethyl)-3-pyridinyl]cyclohexanecarboxamide | C15H20F3N3O3S | 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 condensation of cyclohexanecarbonyl chloride (I) with 3-fluorobenzyl bromide (II) by means of tetrakis(triphenylphosphine)palladium and Zn in dimethoxyethane gives the ethanone (III), which is treated with lead tetraacetate in acetic acid, yielding the alpha-acetoxyethanone (IV). The cyclization of (IV) with ammonium acetate in refluxing acetic acid affords the oxazole derivative (V), which is treated with chlorosulfonic acid at 100 C, yielding the 4-chlorosulfonyl derivative (VI). Finally, this compound is amidated with ammonia in THF/water.
| 【1】 Hashimoto, H.; et al.; 4-(4-Cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamides as selective cyclooxygenase-2 inhibitors: Enhancement of the selectivity by introduction of a fluorine atom and identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522. J Med Chem 2002, 45, 7, 1511. |
| 【2】 Silvestre, J.S.; Leeson, P.A.; Castañer, J.; JTE-522. Drugs Fut 1998, 23, 6, 598. |
| 【3】 Haruta, J.; Hashimoto, H.; Matsushita, M. (Japan Tobacco Inc.); Heteroaromatic oxazole cpds. and use thereof. EP 0745596; EP 0826676; JP 1996325249; JP 1997052882; US 5994381; WO 9619462; WO 9619463 . |
| 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) | 17220 | cyclohexanecarbonyl chloride; Cyclohexanecarboxylic acid chloride | 2719-27-9 | C7H11ClO | 详情 | 详情 |
| (II) | 17221 | 3-Fluorobenzyl bromide; 1-(bromomethyl)-3-fluorobenzene | 456-41-7 | C7H6BrF | 详情 | 详情 |
| (III) | 17222 | 1-cyclohexyl-2-(3-fluorophenyl)-1-ethanone | C14H17FO | 详情 | 详情 | |
| (IV) | 17223 | 2-cyclohexyl-1-(3-fluorophenyl)-2-oxoethyl acetate | C16H19FO3 | 详情 | 详情 | |
| (V) | 17224 | 5-(3-fluorophenyl)-2-methyl-4-phenyl-1,3-oxazole | C16H12FNO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)The condensation of 1-(2-aminoethyl)-4-(2-methoxyphenyl)piperazine (I) with 2-chloronitrobenzene (II) by means of K2CO3 in refluxing butanol gives 1-(2-methoxyphenyl)-4-[2-(2-nitrophenylamino)ethyl]piperazine (III), which is finally condensed with cyclohexylcarbonyl chloride (IV) by means of TEA in dichloroethane to afford the target amide.
| 【1】 Leonardi, A.; Motta, G.; Testa, R.; Riva, C. (Recordati Industria Chimica e Farmaceutica SpA); 1-(N-Phenylaminoalkyl)-piperazine derivs. substd. at position 2 of the phenyl ring. EP 1000047; JP 2001512112; US 6399614; WO 9906384 . |
| 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) | 53508 | 2-[4-(2-methoxyphenyl)-1-piperazinyl]-1-ethanamine; 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethylamine | n/a | C13H21N3O | 详情 | 详情 |
| (II) | 15248 | 1-chloro-2-nitrobenzene | 88-73-3 | C6H4ClNO2 | 详情 | 详情 |
| (III) | 53509 | N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-nitrophenyl)amine; N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-2-nitroaniline | n/a | C19H24N4O3 | 详情 | 详情 |
| (IV) | 17220 | cyclohexanecarbonyl chloride; Cyclohexanecarboxylic acid chloride | 2719-27-9 | C7H11ClO | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XI)Cyclization of (5R)-5-hydroxy-L-lysine (VIII) by means of EDC and HOBt afforded the caprolactam (IX). The amino group of (IX) was then protected as the N-Boc derivative (X) by treatment with Boc2O. Hydroxyl group acylation in (X) with cyclohexanecarbonyl chloride (XI) produced ester (XII). The Boc protecting group of (XII) was then removed by treatment with trifluoroacetic acid, yielding the aminocaprolactam (XIII). Coupling of amine (XIII) with lactone (VII) in refluxing isopropanol produced amide (XIV). The title compound was then obtained by acidic hydrolysis of the remaining acetonide function of (XIV).
| 【1】 Kinder, F.R. Jr.; Versace, R.W.; Bair, K.W.; et al.; Synthesis and antitumor activity of ester-modified analogues of bengamide B. J Med Chem 2001, 44, 22, 3692. |
| 【2】 Bair, K.W.; Kinder, F.R. Jr.; Jagoe, C.T. (Novartis AG); Certain substd. caprolactams, pharmaceutical compsns. containing them and their use in treating tumors. EP 1131297; WO 0029382 . |
| 【3】 Bair, K.W.; Wattanasin, S.; Versace, R.W.; Kinder, F.R. Jr.; Jagoe, C.T. (Novartis AG); Certain substd. caprolactams, pharmaceutical compsns. containing them and a process for their preparation. US 6239127 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 54665 | (4R,4aR,7R,7aS)-4-[(E)-3,3-dimethyl-1-butenyl]-7-methoxy-2,2-dimethyltetrahydro-6H-furo[3,2-d][1,3]dioxin-6-one | C15H24O5 | 详情 | 详情 | |
| (VIII) | 47774 | (2S,5R)-2,6-diamino-5-hydroxyhexanoic acid | C6H14N2O3 | 详情 | 详情 | |
| (IX) | 47775 | (3S,6R)-3-amino-6-hydroxy-2-azepanone | C6H12N2O2 | 详情 | 详情 | |
| (X) | 47776 | tert-butyl (3S,6R)-6-hydroxy-2-oxoazepanylcarbamate | C11H20N2O4 | 详情 | 详情 | |
| (XI) | 17220 | cyclohexanecarbonyl chloride; Cyclohexanecarboxylic acid chloride | 2719-27-9 | C7H11ClO | 详情 | 详情 |
| (XII) | 54666 | (3R,6S)-6-[(tert-butoxycarbonyl)amino]-7-oxoazepanyl cyclohexanecarboxylate | C18H30N2O5 | 详情 | 详情 | |
| (XIII) | 54667 | (3R,6S)-6-amino-7-oxoazepanyl cyclohexanecarboxylate | C13H22N2O3 | 详情 | 详情 | |
| (XIV) | 54668 | (3R,6S)-6-[((2R)-2-{(4R,5R,6R)-6-[(E)-3,3-dimethyl-1-butenyl]-5-hydroxy-2,2-dimethyl-1,3-dioxan-4-yl}-2-methoxyethanoyl)amino]-7-oxoazepanyl cyclohexanecarboxylate | C28H46N2O8 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IV)Coupling of piperazine (I) with chloro derivative (II) by means of K2CO3 and KI in acetone affords protected compound (III), which is then condensed with acid chloride (IV) by means of n-BuLi in THF to yield amide (V). Deprotection of (V) by hydrogenation over Pd/C in EtOH provides (VI), which is finally cyclized by treatment with POCl3 in DMF. Alternatively, the synthesis of the target product can be achieved by an analogous route: Acylation of amine (VII) with acid chloride (IV) by means of K2CO3 in CH2Cl2 provides amide (VIII), which is then cyclized by heating with POCl3 in DMF/benzene to give oxazole (IX). Finally, (IX) is condensed with piperazine (I) by means of K2CO3 and KI in acetone.
| 【1】 Schechter, L.E.; Smith, D.L.; Nelson, F.C.; Greenblatt, L.P.; Kelly, M.G.; Novel trisubstituted oxazole derivatives as 5-HT1A receptor ligands. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 117. |
| 【2】 Kelly, M.G.; Greenblatt, L.P.; Nelson, F.C. (American Home Products Corp.); Trisubstd. oxazole derivs. as serotonin ligands. US 6242448 . |
| 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) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
| (II) | 37926 | benzyl (1S)-1-benzyl-3-chloro-2-oxopropylcarbamate | 26049-94-5 | C18H18ClNO3 | 详情 | 详情 |
| (III) | 46228 | benzyl 1-benzyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-oxopropylcarbamate | C29H33N3O4 | 详情 | 详情 | |
| (IV) | 17220 | cyclohexanecarbonyl chloride; Cyclohexanecarboxylic acid chloride | 2719-27-9 | C7H11ClO | 详情 | 详情 |
| (V) | 46229 | benzyl 1-benzyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-oxopropyl(cyclohexylcarbonyl)carbamate | C36H43N3O5 | 详情 | 详情 | |
| (VI) | 46230 | N-[1-benzyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-oxopropyl]cyclohexanecarboxamide | C28H37N3O3 | 详情 | 详情 | |
| (VII) | 46231 | 3-amino-1-chloro-4-phenyl-2-butanone | C10H12ClNO | 详情 | 详情 | |
| (VIII) | 46232 | N-(1-benzyl-3-chloro-2-oxopropyl)cyclohexanecarboxamide | C17H22ClNO2 | 详情 | 详情 | |
| (IX) | 46233 | 4-benzyl-5-(chloromethyl)-2-cyclohexyl-1,3-oxazole | C17H20ClNO | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VI)The acylation of N-[4-(4-aminophenyl)-2-thiazolyl]carbamic acid tert-butyl ester (I) with bromoacetyl bromide (II) gives the bromoacetamide (III), which is then condensed with 4-pyridylmethylamine (IV) to yield the glycinamide derivative (V). The acylation of (V) with cyclohexanecarbonyl chloride affords the protected precursor (VI), which is finally deprotected to provide the target BILS 103 BS.
| 【1】 Crute, J.J.; et al.; Herpes simplex virus helicase-primase inhibitors are active in animal models of human disease. Nat Med 2002, 8, 4, 386. |
| 【2】 Hargrave, K.D.; Simoneau, B.; Faucher, A.-M.; Thavonekham, B.; Grygon, C.A.; Crute, J.J. (Boehringer Ingelheim (Canada) Ltd.; Boehringer Ingelheim Pharmaceuticals Inc.); Phenyl thiazole derivs. with anti-herpes virus properties. EP 0871619; JP 2000502702; US 6057451; WO 9724343 . |
| 【3】 Hargrave, K.D.; Simoneau, B.; Faucher, A.-M.; Crute, J.J.; Thavonekham, B.; Grygon, C. (Boehringer Ingelheim (Canada) Ltd.; Boehringer Ingelheim Pharmaceuticals Inc.); Antiherpes virus cpds. and methods for their preparation and use. US 6288091 . |
| 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) | 54066 | tert-butyl 4-(4-aminophenyl)-1,3-thiazol-2-ylcarbamate | n/a | C14H17N3O2S | 详情 | 详情 |
| (II) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (III) | 54067 | tert-butyl 4-{4-[(2-bromoacetyl)amino]phenyl}-1,3-thiazol-2-ylcarbamate | n/a | C16H18BrN3O3S | 详情 | 详情 |
| (IV) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (V) | 54068 | tert-butyl 4-{4-[(2-{[(1S)-1-phenylethyl]amino}acetyl)amino]phenyl}-1,3-thiazol-2-ylcarbamate | n/a | C24H28N4O3S | 详情 | 详情 |
| (VI) | 17220 | cyclohexanecarbonyl chloride; Cyclohexanecarboxylic acid chloride | 2719-27-9 | C7H11ClO | 详情 | 详情 |
| (VII) | 54070 | tert-butyl 4-[4-({2-[(cyclohexylcarbonyl)(4-pyridinylmethyl)amino]acetyl}amino)phenyl]-1,3-thiazol-2-ylcarbamate | n/a | C29H35N5O4S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(V)Treatment of dexamethasone (I) with trimethyl orthocyclopropanecarboxylate (II) in the presence of p-toluenesulfonic acid gives the mixed orthoester (III), which, upon acidic hydrolysis with oxalic acid leads to the C-17 cyclopropanecarboxylate ester (IV). Subsequent esterification of (IV) with cyclohexanecarbonyl chloride (V) furnishes the desired dexamethasone diester.
| 【1】 Komoto, T.; Okawa, J.; Ogawa, Y.; Sato, S.; Taido, N.; Kuraishi, T. (SSP Co., Ltd.); Novel steroid derivs.. EP 0393658; JP 1990279694; US 5063222 . |
| 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) | 40461 | (8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-17-glycoloyl-11,17-dihydroxy-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C22H29FO5 | 详情 | 详情 | |
| (II) | 63235 | 1-(trimethoxymethyl)cyclopropane; cyclopropyl(dimethoxy)methyl methyl ether | C7H14O3 | 详情 | 详情 | |
| (III) | 63236 | C27H35FO6 | 详情 | 详情 | ||
| (IV) | 63237 | (8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-17-glycoloyl-11-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl cyclopropanecarboxylate | C26H33FO6 | 详情 | 详情 | |
| (V) | 17220 | cyclohexanecarbonyl chloride; Cyclohexanecarboxylic acid chloride | 2719-27-9 | C7H11ClO | 详情 | 详情 |