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【结 构 式】 
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【分子编号】22277 【品名】Cyclopropyl bromide; 1-(Bromomethyl)cyclopropane 【CA登记号】7051-34-5 |
【 分 子 式 】C4H7Br 【 分 子 量 】135.00358 【元素组成】C 35.59% H 5.23% Br 59.19% |
合成路线1
该中间体在本合成路线中的序号：(A)The condensation of ethyl p-hydroxyphenylacetate (I) with benzyl chloride (II) by means of sodium ethoxide in refluxing ethanol gives ethyl p-(benzyloxy)phenylacetate (III), which is reduced with LiAlH4 in THF to 2-(p-benzyloxyphenyl)ethanol (IV). The etherification of (IV) with cyclopropyl bromide (A) by means of NaH in hot DMF affords 4-(cyclopropylmethoxyethyl)-1-benzyloxybenzene (V), which is debenzylated by hydrogenation with H2 and Pd/C in methanol giving rise to p-(cyclopropylmethoxyethyl)phenol (VI). The condensation of (VI) with epichlorohydrin (B) by means of NaOH in water yields 1-[p-(cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane (VII), which is treated with isopropylamine (C) and finally with HCl in ether.
| 【1】 Manoury, P.M.J.; et al. (Sanofi-Synthelabo ); Phenol ethers. DE 2649605; FR 2330383; GB 1515978; JP 52085146; US 4252984 . |
| 【2】 Hillier, K.; Castaner, J.; Serradell, M.N.; Blancafort, P.; Betaxolol hydrochloride. Drugs Fut 1979, 4, 12, 867. |
| 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) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (A) | 22277 | Cyclopropyl bromide; 1-(Bromomethyl)cyclopropane | 7051-34-5 | C4H7Br | 详情 | 详情 |
| (I) | 24994 | Ethyl 2-(4-hydroxyphenyl)acetate | 17138-28-2 | C10H12O3 | 详情 | 详情 |
| (II) | 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 |
| (III) | 28637 | Ethyl 2-[4-(benzyloxy)phenyl]acetate; p-(Benzyloxy)phenylacetate | C17H18O3 | 详情 | 详情 | |
| (IV) | 33328 | 2-(p-Benzyloxyphenyl)ethanol; 2-[4-(Benzyloxy)phenyl]-1-ethanol | C15H16O2 | 详情 | 详情 | |
| (V) | 33329 | 4-(Cyclopropylmethoxyethyl)-1-benzyloxybenzene; 1-(Benzyloxy)-4-[2-(cyclopropylmethoxy)ethyl]benzene; Benzyl 4-[2-(cyclopropylmethoxy)ethyl]phenyl ether | C19H22O2 | 详情 | 详情 | |
| (VI) | 33330 | 4-[2-(Cyclopropylmethoxy)ethyl]phenol; p-(Cyclopropylmethoxyethyl)phenol | C12H16O2 | 详情 | 详情 | |
| (VII) | 33331 | 2-([4-[2-(Cyclopropylmethoxy)ethyl]phenoxy]methyl)oxirane; 1-[p-(Cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane; 4-[2-(Cyclopropylmethoxy)ethyl]phenyl 2-oxiranylmethyl ether | C15H20O3 | 详情 | 详情 | |
| (C) | 23933 | 2-Propanamine; Isopropylamine | 75-31-0 | C3H9N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(Ib)The reaction of cyclopropylmethyl chloride or cyclopropylmethyl bromide (Ia-b) with piperazine (II) by means of Na2CO3 in anhydrous DMF gives N,N-dicyclopropylmethylpiperazine.
| 【1】 Robba, M.F.; Aurousseau, M.E. (Laboratoire Innothera SA); Cyclopropylmethyl piperazines, the process for preparing the same and their use in therapeutics. CA 1171085; EP 81401516; FR 8021527; JP 163681; US 4474783 . |
| 【2】 Leclerc, G.; INO-2628 CZ. Drugs Fut 1985, 10, 11, 907. |
合成路线3
该中间体在本合成路线中的序号：(C)This compound can be obtained in two related ways: 1) The reaction of codeinon (I) with ethyllithium and CuI in ether gives 4,5alpha-epoxy-8beta-ethyl-3-methoxy-17-methylmorphinan-6-one (II), which by treatment with cyanogen bromide and K2CO3 in CHCl3 is converted into 17-cyano-4,5alpha-epoxy-8beta-ethyl-3-methoxymorphinan-6-one (III). Elimination of the cyano group of (III) by treatment with refluxing aqueous 2N HCl yields 4,5alpha-epoxy-8beta-ethyl-3-methoxymorphinan-6-one (IV), which is finally alkylated with cyclopropylmethyl bromide (C) and NaHCO3 in DMF at 100 C. 2) The reaction of codeinon (I) with vinyl bromide (A), tert-butyllithium and CuI in ether gives 4,5alpha-epoxy-3-methoxy-17-methyl-8beta-vinylmorphinanone (V), which is reduced with H2, Pd/C in ethanol to yield (II).
| 【1】 Kotick, M.P.; DE 2900918 . |
| 【2】 Hillier, K.; Castaner, J.; Codorphone Hydrochloride. Drugs Fut 1981, 6, 12, 766. |
| 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) | 28790 | 1-bromoethylene | 593-60-2 | C2H3Br | 详情 | 详情 |
| (B) | 37473 | Ethyl lithium; Ethyllithium | 811-49-4 | C2H5Li | 详情 | 详情 |
| (I) | 37472 | (1S,5R,13R,17R)-10-methoxy-4-methyl-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10,15-tetraen-14-one | C18H19NO3 | 详情 | 详情 | |
| (II) | 37474 | (1S,5R,13R,16S,17R)-16-ethyl-10-methoxy-4-methyl-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-trien-14-one | C20H25NO3 | 详情 | 详情 | |
| (III) | 37475 | (1S,5R,13R,16S,17R)-4-cyano-16-ethyl-10-methoxy-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-trien-14-one | C20H22N2O3 | 详情 | 详情 | |
| (IV) | 37476 | (1S,5R,13R,16S,17R)-16-ethyl-10-methoxy-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-trien-14-one | C19H23NO3 | 详情 | 详情 | |
| (V) | 37477 | (1S,5R,13R,16R,17R)-10-methoxy-4-methyl-16-vinyl-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-trien-14-one | C20H23NO3 | 详情 | 详情 | |
| (C) | 22277 | Cyclopropyl bromide; 1-(Bromomethyl)cyclopropane | 7051-34-5 | C4H7Br | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(C)Compound can be prepared in two different ways both starting from 14-hydroxydihydronormorphinone (I): 1) By reaction of (I) with cyclopropylmethyl bromide (C) in DMF at 70 C. 2) Product (I) is ketalized with ethylene glycol (A) by means of p-toluenesulfonic acid giving the cyclic ketal (II), m.p. 311-3 C; this in turn, is treated with cyclopropyl carbonyl chloride (B) in a mixture of methylene chloride and triethylamine yielding the N,O-dicyclopropylcarbonyl derivative (III), mp 219-20 C. Compound (III) is reduced with LiAlH4, in refluxing THF yielding the ethylene ketal of naltrexone (IV), m.p. 221-2 C, which is finally hydrolyzed with aqueous HCl at 100 C.
| 【1】 Blumberg, H.; et al.; 14-Hydroxydihydronormorphinone derivatives. US 3332950 . |
| 【2】 Blumberg, H.; et al.; Verfahren zur Herstellung von N-substituierten 14-Hydroxydidronormorphinen. CH 493522; DE 1670616; DE 1795707; GB 1119270 . |
| 【3】 Derives de 14-hydroxydihydronormorphinones. FR 6358M . |
| 【4】 Castaner, J.; Roberts, P.J.; Naltrexone. Drugs Fut 1977, 2, 1, 45. |
| 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) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (B) | 14061 | Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride | 4023-34-1 | C4H5ClO | 详情 | 详情 |
| (I) | 33610 | (1S,5R,13R,17R)-10,17-dihydroxy-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-trien-14-one | C16H17NO4 | 详情 | 详情 | |
| (II) | 33611 | C18H21NO5 | 详情 | 详情 | ||
| (III) | 33612 | C26H29NO7 | 详情 | 详情 | ||
| (IV) | 33613 | C22H27NO5 | 详情 | 详情 | ||
| (C) | 22277 | Cyclopropyl bromide; 1-(Bromomethyl)cyclopropane | 7051-34-5 | C4H7Br | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)By quaternization of scopolamine base (I) with cyclopropylmethyl bromide (II) in refluxing acetonitrile.
| 【1】 Casadio, S.; Donetti, A.; Certain N-substituted Scopolammonium compounds. DE 2316728; FR 2187333; GB 1413484; JP 49014615; US 3853886 . |
| 【2】 de Angelis, L.; Castaner, J.; DA-3177. Drugs Fut 1978, 3, 7, 509. |
合成路线6
该中间体在本合成路线中的序号：(A)The reaction of o-fluorophenylpyruvate (I) with p-chlorophenylhydrazine (X) in refluxing ethanol gives ethyl o-fluorophenylpyruvate p-chlorophenylhydrazone (XI), which is cyclized by treatment with dry HCl in refluxing ethanol yielding ethyl 3-(2-fluorophenyl)-5-chloroindole-2-carboxylate (XII). The N-alkylation of (XII) with cyclopropylmethyl bromide (A) by means of KOH in refluxing acetone affords compound (IV) of the preceding sequence.
| 【1】 Yamamoto, H.; et al. (Sumitomo Chemical Co., Ltd.); Process for producing benzodiazepine derivatives. US 3632574 . |
| 【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; KB-509. Drugs Fut 1979, 4, 10, 720. |
| 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) | 22277 | Cyclopropyl bromide; 1-(Bromomethyl)cyclopropane | 7051-34-5 | C4H7Br | 详情 | 详情 |
| (I) | 33337 | ethyl 3-(2-fluorophenyl)-2-oxopropanoate | C11H11FO3 | 详情 | 详情 | |
| (IV) | 33339 | ethyl 5-chloro-1-(cyclopropylmethyl)-3-(2-fluorophenyl)-1H-indole-2-carboxylate | C21H19ClFNO2 | 详情 | 详情 | |
| (X) | 33345 | 1-(4-chlorophenyl)hydrazine; 4-Chlorophenylhydrazine | 1073-70-7 | C6H7ClN2 | 详情 | 详情 |
| (XI) | 33346 | ethyl 2-[(E)-2-(4-chlorophenyl)hydrazono]-3-(2-fluorophenyl)propanoate | C17H16ClFN2O2 | 详情 | 详情 | |
| (XII) | 33347 | ethyl 5-chloro-3-(2-fluorophenyl)-1H-indole-2-carboxylate | C17H13ClFNO2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(A)The hydrolysis of 3-(2-fluorophenyl)-5-chloroindole-2-carboxylate (XII) with KOH in refluxing ethanol affords the corresponding free acid (XVI), which by treatment with refluxing SOCl2 is converted into the acyl chloride (XVII). The reaction of (XVII) with NH3 in ether yields the amide (XVIII), which by N-alkylation with cyclopropylmethyl bromide (A) by means of NaH in DMF gives rise to the alkylated amide (VII) already obtained.
| 【1】 Yamamoto, H.; et al.; ZA 6806061 . |
| 【2】 Yamamoto, H.; et al. (Sumitomo Chemical Co., Ltd.); Process for producing benzodiazepine derivatives. US 3632574 . |
| 【3】 Blancafort, P.; Serradell, M.N.; Castaner, J.; KB-509. Drugs Fut 1979, 4, 10, 720. |
| 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) | 22277 | Cyclopropyl bromide; 1-(Bromomethyl)cyclopropane | 7051-34-5 | C4H7Br | 详情 | 详情 |
| (VII) | 33342 | 5-chloro-1-(cyclopropylmethyl)-3-(2-fluorophenyl)-1H-indole-2-carboxamide | C19H16ClFN2O | 详情 | 详情 | |
| (XII) | 33347 | ethyl 5-chloro-3-(2-fluorophenyl)-1H-indole-2-carboxylate | C17H13ClFNO2 | 详情 | 详情 | |
| (XVI) | 33350 | 5-chloro-3-(2-fluorophenyl)-1H-indole-2-carboxylic acid | C15H9ClFNO2 | 详情 | 详情 | |
| (XVII) | 33351 | 5-chloro-3-(2-fluorophenyl)-1H-indole-2-carbonyl chloride | C15H8Cl2FNO | 详情 | 详情 | |
| (XVIII) | 33352 | 5-chloro-3-(2-fluorophenyl)-1H-indole-2-carboxamide | C15H10ClFN2O | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(A)The dehydration of the amide (XVIII) with refluxing POCl3 gives the corresponding nitrile (XIX), which by reduction with LiAlH4 in ether is converted into the 2-aminomethyl derivative (XX). The treatment of (XX) with CrO3 in acetic acid yields 5-(2-fluorophenyl)-7chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXI) (1,10), which is finally N-alkylated with cyclopropylmethy bromide (A) by means of phenyllithium in THF.
| 【1】 Yamamoto, H.; et al.; ZA 6806061 . |
| 【2】 Okamoto, T.; et al.; Process for producing 1-substituted benzodiazepine derivatives. DE 2151540; FR 2110017; GB 1338106; NL 7114202; US 3832344 . |
| 【3】 Yamamoto, H.; et al. (Sumitomo Chemical Co., Ltd.); Process for producing benzodiazepine derivatives. US 3632574 . |
| 【4】 Blancafort, P.; Serradell, M.N.; Castaner, J.; KB-509. Drugs Fut 1979, 4, 10, 720. |
| 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) | 22277 | Cyclopropyl bromide; 1-(Bromomethyl)cyclopropane | 7051-34-5 | C4H7Br | 详情 | 详情 |
| (XVIII) | 33352 | 5-chloro-3-(2-fluorophenyl)-1H-indole-2-carboxamide | C15H10ClFN2O | 详情 | 详情 | |
| (XIX) | 33353 | 5-chloro-3-(2-fluorophenyl)-1H-indole-2-carbonitrile | C15H8ClFN2 | 详情 | 详情 | |
| (XX) | 33354 | [5-chloro-3-(2-fluorophenyl)-1H-indol-2-yl]methanamine; [5-chloro-3-(2-fluorophenyl)-1H-indol-2-yl]methylamine | C15H12ClFN2 | 详情 | 详情 | |
| (XXI) | 33355 | 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one | 2886-65-9 | C15H10ClFN2O | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(III)Cyclization of hydroxyfuranone (I) with hydrazine in refluxing EtOH produced the pyridazinone (II), which was subsequently alkylated with cyclopropylmethyl bromide (III) in the presence of NaOH to afford the title compound.
| 【1】 Therien, M.; Li, C.S.; Lau, C.K.; Prasit, P.; Gauthier, J.Y. (Merck Frosst Canada Inc.); Pyridazinones as inhibitors of cyclooxygenase-2. EP 0975604; US 6004960; WO 9841511 . |
| 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) | 22275 | 3-(4-fluorophenyl)-5-hydroxy-4-[4-(methylsulfonyl)phenyl]-2(5H)-furanone | C17H13FO5S | 详情 | 详情 | |
| (II) | 22276 | 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone | C17H13FN2O3S | 详情 | 详情 | |
| (III) | 22277 | Cyclopropyl bromide; 1-(Bromomethyl)cyclopropane | 7051-34-5 | C4H7Br | 详情 | 详情 |