|
【结 构 式】 
|
【分子编号】14029 【品名】Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile 【CA登记号】109-78-4 |
【 分 子 式 】C3H5NO 【 分 子 量 】71.07884 【元素组成】C 50.69% H 7.09% N 19.71% O 22.51% |
合成路线1
该中间体在本合成路线中的序号：(V)The two enantiomers of amlodipine have been obtained as follows: The reaction of 2-azidoethanol (I) with chloroacetic acid (II) by means of NaH in THF gives 2-(2-azidoethoxy)acetic acid (III), which is condensed with Meldrum's acid (IV) and 3-hydroxypropionitrile (V) in dichloromethane to yield the 2-cyanoethyl acetoacetate (VI). The cyclization of (VI) with 2-chlorobenzaldehyde (VII) and methyl 3-aminocrotonate (VIII) in refluxing ethanol affords the dihydropyridine (IX), which is selectively hydrolyzed at the 2-cyanoethylester with NaOH to give the dihydropyridine monocarboxylic acid (X). The esterification of (X) with (S)-2-methoxy-2-phenylethanol (XI) by means of CDI in dichloromethane provides the ester (XII) as a diastereomeric mixture, which is separated by chromatography to furnish diastereomers (XXI A) and (XII B). The selective ethanolysis of (XII A) and (XII B) with sodium ethoxide in refluxing ethanol/diglyme gives enantiomers (+)-(XIII) and (-)-(XIII), which are finally reduced with H2 over Pd/CaCO3 in ethanol to afford the (-)- and (+)-isomers, respectively, of the target compound.
| 【1】 Arrowsmith, J.E.; et al.; Long-acting dihydropyridine calcium antagonists. 1. 2-Alkoxymethyl derivatives incorporating basic substituents. J Med Chem 1986, 29, 9, 1696. |
| 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) | 24111 | 2-azido-1-ethanol | C2H5N3O | 详情 | 详情 | |
| (II) | 11847 | 2-Chloroacetic acid; Chloroacetic Acid | 79-11-8 | C2H3ClO2 | 详情 | 详情 |
| (III) | 48263 | 2-(2-azidoethoxy)acetic acid | C4H7N3O3 | 详情 | 详情 | |
| (IV) | 14738 | Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester | 2033-24-1 | C6H8O4 | 详情 | 详情 |
| (V) | 14029 | Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile | 109-78-4 | C3H5NO | 详情 | 详情 |
| (VI) | 48264 | 2-cyanoethyl 4-(2-azidoethoxy)-3-oxobutanoate | C9H12N4O4 | 详情 | 详情 | |
| (VII) | 24114 | 2-chlorobenzaldehyde | 89-98-5 | C7H5ClO | 详情 | 详情 |
| (VIII) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (IX) | 48265 | 3-(2-cyanoethyl) 5-methyl 2-[(2-azidoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C21H22ClN5O5 | 详情 | 详情 | |
| (X) | 48266 | 2-[(2-azidoethoxy)methyl]-4-(2-chlorophenyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydro-3-pyridinecarboxylic acid | C18H19ClN4O5 | 详情 | 详情 | |
| (XI) | 48267 | (2S)-2-methoxy-2-phenyl-1-ethanol | 66051-01-2 | C9H12O2 | 详情 | 详情 |
| (XII) | 48268 | 3-[(2S)-2-methoxy-2-phenylethyl] 5-methyl 2-[(2-azidoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C27H29ClN4O6 | 详情 | 详情 | |
| (XIII) | 24115 | 3-ethyl 5-methyl 2-[(2-azidoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C20H23ClN4O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)Reaction of 2-(4-aminophenyl)ethanol (I) with bis(2-chloroethyl)amine hydrochloride (II) in butanol gives 2-[4-(1-piperazinyl)phenyl]ethanol (III), which is alkylated with diphenylbromomethane (IV) and potassium carbonate in dimethyl formamide to afford 2-[4-[4-(diphenylmethyl)-1-piperazinyl]phenyl]ethanol (V). Treatment of (V) with diketene (VI) in the presence of 4-dimethylaminopyridine in tetrahydrofuran yields 2-[4-[4-(diphenylmethyl)-1-piperazinyl]phenyl]ethyl acetoacetate (VII), which is finally condensed with 3-nitrobenzaldehyde (VIII) and methyl 3-aminocrotonate (IX) in isopropanol (1-5). This last condensation can be performed in two steps by reaction of compound (VII) with compound (VIII) in the presence of piperidine and acetic acid in benzene to give 2-[4-[4-(diphenylmethyl)-1-piperazinyl]phenyl]ethyl 2-(3-nitrobenzylidene)acetoacetate (X), which is finally treated with (IX) in isopropanol. An alternative procedure involves condensation of 3-nitrobenzaldehyde (VIII), diketene (VI), methyl 3-aminocrotonate (IX) and 3-hydroxypropionitrile (XI) in isopropanol to give 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 2-cyanoethyl ethyl diester (XII), which is hydrolyzed with sodium hydroxide to 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester (XIII). Compound (XIII) is finally esterified with compound (V) in a mixture of dimethylformamide and chloroform.
| 【1】 Ashimori, A.; Ono, T.; Inoue, Y.; Fukaya, C. (Welfide Corporation); Dihydropyridine derivs. and pharmaceutical compsns. Thereof. EP 0257616; JP 1988099042; JP 1988225356; US 4886819 . |
| 【2】 (Welfide Corporation); Use of dihydropyridines in cardiotonic pharmaceutical compsns. EP 0109039; US 4543354 . |
| 【3】 Kido, H.; Uchida, T.; Fukaya, C.; Yokoyama, K.; Uchida, Y. (Welfide Corporation); Dihydropyridine derivs. for the treatment of angiospasm. EP 0379737; JP 1990180826 . |
| 【4】 Ono, T.; Ashimori, A.; Inoue, Y.; Novel 1,4-dihydropyridine calcium antagonists. II. Synthesis and antihypertensive activity of 3-[4-(substituted amino)phenylalkyl]ester derivatives. Chem Pharm Bull 1991, 39, 1, 91-9. |
| 【5】 Ohe, K.; Tanaka, M.; Yokoyama, K.; Uchida, T.; Fukaya, C.; Watanabe, M.; Ohtaki, Y.; Ashimori, A.; Kagitani, M.; Synthesis and pharmacological effects of optically active 2-[4-(4-benzhydryl-1-piperazinyl)phenyl]ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicrboxylate hydrochloride. Chem Pharm Bull 1991, 39, 1, 108-11. |
| 【6】 Castaner, J.; Mealy, N.; Prous, J.; AE0047. Drugs Fut 1994, 19, 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 |
|---|---|---|---|---|---|---|
| (I) | 14019 | p-Aminophenylethanol; 2-(4-Aminophenyl)-1-ethanol | 104-10-9 | C8H11NO | 详情 | 详情 |
| (II) | 14020 | N,N-Bis(2-chloroethyl)amine hydrochloride; 2-Chloro-N-(2-chloroethyl)-1-ethanamine hydrochloride | C4H10Cl3N | 详情 | 详情 | |
| (III) | 14021 | 2-(4-Piperazinophenyl)-1-ethanol | C12H18N2O | 详情 | 详情 | |
| (IV) | 12079 | Bromodiphenylmethane; 1-[Bromo(phenyl)methyl]benzene; Benzhydrylbromide | 776-74-9 | C13H11Br | 详情 | 详情 |
| (V) | 14023 | 2-[4-(4-Benzhydrylpiperazino)phenyl]-1-ethanol | C25H28N2O | 详情 | 详情 | |
| (VI) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
| (VII) | 14025 | 4-(4-benzhydrylpiperazino)phenethyl 3-oxobutanoate | C29H32N2O3 | 详情 | 详情 | |
| (VIII) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (IX) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (X) | 14028 | 4-(4-benzhydryl-1-piperazinyl)phenethyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate | C36H35N3O5 | 详情 | 详情 | |
| (XI) | 14029 | Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile | 109-78-4 | C3H5NO | 详情 | 详情 |
| (XII) | 14030 | 3-(2-cyanoethyl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C19H19N3O6 | 详情 | 详情 | |
| (XIII) | 13950 | 5-(Methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C16H16N2O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIV)A synthesis of S-12968 has been published: The cyclization of 4-[2-(2-phthalimidoethoxy)ethoxy]-3-oxobutyric acid ethyl ester (I) with 2-(2,3-dichlorobenzylidene)-3-oxobutyric acid 2-cyanoethyl ester (II) and ammonium formate in hot ethanol gives the protected racemic 1,4-dihydropyridine (III), which is submitted to a chiral preparative HPLC to obtain the (R)-(-)-enantiomer (IV). The deprotection of (IV) with aqueous methylamine affords (S)-(-)-2-[2-(2-aminoethoxy)ethoxymethyl]-4-(2,3-dichlorophenyl)-1,4-di hydropyridine-3,5-dicarboxylic acid 3-monoethyl ester (V). Finally, this compound is methylated with diazomethane in ethyl ether/methanol. The starting compound, the dichlorobenzylidene derivative (II) has been obtained as follows: The condensation of Meldrum's acid (X) with acetic acid (XII) by means of CDI and pyridine as before gives 5-acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione (XIII), which is submitted to ring opening with 3-hydroxypropionitrile (XIV) in refluxing toluene yielding 2-cyanoethyl acetoacetate (XV). Finally, the condensation of (XV) with 2,3-dichlorobenzaldehyde (XVI) by means of piperidine and hexanoic acid in refluxing benzene affords the dichlorobenzylidene derivative (II) used as the second starting compound.
| 【1】 Dolle, F.; et al.; Highly efficient synthesis of [11C]S12968 and [11C]S12967, for the in vivo imaging of the cardiac calcium channels using PET. J Label Compd Radiopharm 2001, 44, 7, 481. |
| 【2】 Crouzel, C.; Duval, R.; Hinnen, F.; Fuseau, C.; Dollé, F.; Valette, H.; Péglion, J.-L.; Synthesis of two optically active calcium channel antagonists labelled with carbon-11 for in vivo cardiac PET imaging. Bioorg Med Chem 1997, 5, 4, 749. |
| 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) | 14743 | ethyl 4-[2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]-3-oxobutanoate | C18H21NO7 | 详情 | 详情 | |
| (II) | 14744 | 2-cyanoethyl (Z)-2-acetyl-3-(2,3-dichlorophenyl)-2-propenoate | C14H11Cl2NO3 | 详情 | 详情 | |
| (III) | 14745 | 5-(2-cyanoethyl) 3-ethyl 4-(2,3-dichlorophenyl)-2-([2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]methyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C32H31Cl2N3O8 | 详情 | 详情 | |
| (IV) | 14746 | 5-(2-cyanoethyl) 3-ethyl (4S)-4-(2,3-dichlorophenyl)-2-([2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]ethoxy]methyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C32H31Cl2N3O8 | 详情 | 详情 | |
| (V) | 14747 | (4R)-6-[[2-(2-aminoethoxy)ethoxy]methyl]-4-(2,3-dichlorophenyl)-5-(ethoxycarbonyl)-2-methyl-1,4-dihydro-3-pyridinecarboxylic acid | C21H26Cl2N2O6 | 详情 | 详情 | |
| (X) | 14738 | Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester | 2033-24-1 | C6H8O4 | 详情 | 详情 |
| (XIII) | 12273 | 5-Acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione | C8H10O5 | 详情 | 详情 | |
| (XIV) | 14029 | Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile | 109-78-4 | C3H5NO | 详情 | 详情 |
| (XV) | 13993 | 2-cyanoethyl 3-oxobutanoate | C7H9NO3 | 详情 | 详情 | |
| (XVI) | 14742 | 2,3-dichlorobenzaldehyde | 6334-18-5 | C7H4Cl2O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXV)Condensation of 3-methoxyandrosta-3,5,9(11)-trien-17-one (XI) with 3-hydroxypropionitrile (XXV) by means of LDA in THF provides 17a-(1-cyano-2- hydroxyethyl)-17b-hydroxyandrosta-4,9(11)-dien-3-one (XXVI), which is selectively monoacetylated by means of Ac2O in pyridine to yield monoacetate (XXVII). Dehydration of (XXVII) by means of SOCl2 in pyridine gives 20-cyano-21-acetoxypregna-4,9(11),17(20)-trien-3-one (XXVIII), which is treated with ethylene glycol, trimethyl orthoformate and TsOH in dichloromethane to afford the ethylene ketal (XXIX). Finally, compound (XXIX) is oxidized with KMnO4 in acetone/ethylene glycol and treated with NaHSO3 and HCOOH.
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; Bayes, M.; Anecortave Acetate. Drugs Fut 2002, 27, 11, 1039. |
| 【2】 Walker, J.A. (Pharmacia Corp.); Corticosteroids from 17-keto steroids via 20-cyano-DELTA17(20)-pregnanes. US 4600538 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 | |
| (XI) | 18040 | (8S,10R,13S,14S)-3-methoxy-10,13-dimethyl-1,2,7,8,10,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one | C20H26O2 | 详情 | 详情 | |
| (XXV) | 14029 | Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile | 109-78-4 | C3H5NO | 详情 | 详情 |
| (XXVI) | 56615 | 3-hydroxy-2-[(8S,10R,13S,14S,17R)-17-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,10,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]propanenitrile | C22H29NO3 | 详情 | 详情 | |
| (XXVII) | 56616 | 2-cyano-2-[(8S,10R,13S,14S,17R)-17-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,10,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]ethyl acetate | C24H31NO4 | 详情 | 详情 | |
| (XXVIII) | 56617 | 2-cyano-2-[(8S,10R,13S,14S)-10,13-dimethyl-3-oxo-1,2,3,6,7,8,10,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-ylidene]ethyl acetate | C24H29NO3 | 详情 | 详情 | |
| (XXIX) | 56618 | C26H33NO4 | 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 protection of the OH group of 2-hydroxyacetonitrile (I) with TBDMS-Cl and imidazole in THF gives the silyl ether (II), which is treated with pentylmagnesium bromide (III) in ethyl ether yielding the protected 1-hydroxyoctan-3-one (IV), which is deprotected with HCl in methanol/water affording the corresponding hydroxyketone (V). Finally, this compound is treated with hydroxylamine-O-sulfonic acid in liquid ammonia.
| 【1】 Forman, S.A.; Miller, K.W.; Olsen, R.W.; Kloczewiak, M.A.; Addona, G.H.; Husain, S.S.; Cohen, J.B.; Pratt, M.B.; Synthesis and properties of 3-(2-hydroxyethyl)-3-N-pentyldiazirine, a photoactivable general anesthetic. J Med Chem 1999, 42, 17, 3300. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40596 | (aminooxy)(hydroxy)dioxo-lambda(6)-sulfane | 2950-43-8 | H3NO4S | 详情 | 详情 | |
| (I) | 14029 | Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile | 109-78-4 | C3H5NO | 详情 | 详情 |
| (II) | 31870 | 3-[[tert-butyl(dimethyl)silyl]oxy]propanenitrile | C9H19NOSi | 详情 | 详情 | |
| (III) | 31871 | bromo(pentyl)magnesium | 693-25-4 | C5H11BrMg | 详情 | 详情 |
| (IV) | 31872 | 1-[[tert-butyl(dimethyl)silyl]oxy]-3-octanone | C14H30O2Si | 详情 | 详情 | |
| (V) | 31873 | 1-hydroxy-3-octanone | C8H16O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XV)Methyl 4-methoxyacetoacetate (XIV) was transesterified with 3-hydroxypropionitrile (XV) at 180 C to yield the 2-cyanoethyl ester (XVI). Subsequent condensation between 3,4-difluorobenzaldehyde (XVII) and ketoester (XVI) in the presence of piperidine acetate furnished the benzylidene derivative (XVIII), which was cyclized with O-methylisourea hemisulfate (XIX) to produce the racemic pyrimidine (XX). Resolution of (XX) was achieved via conversion to the 4-nitrophenyl carbamate (XXI), which was then condensed with (R)-1-phenylethylamine (XXII) to afford a separable mixture of diastereoisomeric amides. The desired isomer (XXIII) was treated with DBU in hot toluene to give the (+)-pyrimidine (XXIV). This was again converted to the corresponding 4-nitrophenyl carbamate (XXV) by reaction with 4-nitrophenyl chloroformate and DMAP.
| 【1】 Wong, W.C.; Lagu, B.; Nagarathnam, D.; Marzabadi, M.R.; Gluchowski, C. (Synaptic Pharmaceutical Corp.); Dihydropyrimidines and uses thereof. EP 1021185; JP 2000506904; WO 9742956 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 26655 | methyl 4-methoxy-3-oxobutanoate;Methyl 4-methoxyacetoacetate;Methyl 4-methoxy-3-oxo-butanoate | 41051-15-4 | C6H10O4 | 详情 | 详情 |
| (XV) | 14029 | Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile | 109-78-4 | C3H5NO | 详情 | 详情 |
| (XVI) | 48390 | 2-cyanoethyl 4-methoxy-3-oxobutanoate | C8H11NO4 | 详情 | 详情 | |
| (XVII) | 26654 | 3,4-difluorobenzaldehyde | 34036-07-2 | C7H4F2O | 详情 | 详情 |
| (XVIII) | 48391 | 2-cyanoethyl (Z)-3-(3,4-difluorophenyl)-2-(2-methoxyacetyl)-2-propenoate | C15H13F2NO4 | 详情 | 详情 | |
| (XIX) | 26657 | O-methyl isourea; [Amino(imino)methoxy]methane | 52328-05-9 | C2H6N2O | 详情 | 详情 |
| (XX) | 48392 | 2-cyanoethyl 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,6-dihydro-5-pyrimidinecarboxylate | C17H17F2N3O4 | 详情 | 详情 | |
| (XXI) | 48393 | 5-(2-cyanoethyl) 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,5(6H)-pyrimidinedicarboxylate | C24H20F2N4O8 | 详情 | 详情 | |
| (XXII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XXIII) | 48394 | 2-cyanoethyl (6S)-6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1-([[(1R)-1-phenylethyl]amino]carbonyl)-1,6-dihydro-5-pyrimidinecarboxylate | C26H26F2N4O5 | 详情 | 详情 | |
| (XXIV) | 48395 | 2-cyanoethyl (6S)-6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,6-dihydro-5-pyrimidinecarboxylate | C17H17F2N3O4 | 详情 | 详情 | |
| (XXV) | 48396 | 5-(2-cyanoethyl) 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1,5(6H)-pyrimidinedicarboxylate | C24H20F2N4O8 | 详情 | 详情 |