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【结 构 式】 
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【分子编号】21178 【品名】isopropenyl acetate 【CA登记号】108-22-5 |
【 分 子 式 】C5H8O2 【 分 子 量 】100.11732 【元素组成】C 59.98% H 8.05% O 31.96% |
合成路线1
该中间体在本合成路线中的序号：(A)The enol acylation of 5alpha-androst-2-en-17-one (I) with isopropenyl acetate (A) using H2SO4 as catalyst gives 17-acetoxyandrost-2,16-diene (II), which is epoxidized by treatment with m-chloroperbenzoic acid in ether yielding 2alpha,3alpha:16alpha,17alpha-diepoxy-17beta-acetoxy-5alpha-androstane (III). The hydrolytic rearrangement of (III) with KOH affords 2alpha,3alpha-epoxy-5alpha-androstan-17beta-ol-16-one (IV), which is condensed with refluxing aqueous piperidine (B) to give 2beta,16beta-dipiperidino-5alpha-androstan-3alpha-ol-17-one (V). The reduction of (V) with NaBH4 in methylene chloride - methanol yields 2beta,16beta-dipiperidino-5alpha-androstan-3alpha,17beta-diol (VI), which is acetylated by reaction with acetyl chloride as usual to afford the corresponding diacetate (VII). Finally, this compound is quaternized by reaction with methyl bromide in ether.
| 【1】 Buckett, W.R.; et al.; Pancuronium bromide and other steroidal neuromuscular blocking agents containing acetylcholine fragments. J Med Chem 1973, 16, 10, 1116-24. |
| 【2】 Serradell, M.N.; Castaner, J.; Blancafort, P.; Hillier, K.; ORG-NC-45. Drugs Fut 1981, 6, 5, 287. |
| 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) | 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 |
| (A) | 21178 | isopropenyl acetate | 108-22-5 | C5H8O2 | 详情 | 详情 |
| (I) | 32178 | (5S,8R,9S,10S,13S,14S)-10,13-dimethyl-1,4,5,6,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C19H28O | 详情 | 详情 | |
| (II) | 32179 | (5S,8R,9S,10S,13S,14S)-10,13-dimethyl-4,5,6,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate | C21H30O2 | 详情 | 详情 | |
| (III) | 32180 | (1aS,2aS,2bS,4aS,5aR,6aS,6bR,8aS,9aS)-2a,4a-dimethylhexadecahydro-4bH-oxireno[2'',3'':4',5']cyclopenta[1',2':7,8]phenanthro[2,3-b]oxiren-4-yl acetate | C21H30O4 | 详情 | 详情 | |
| (IV) | 32181 | (1R,3aS,3bR,5aS,6aS,7aS,8aS,8bS,10aS)-1-hydroxy-8a,10a-dimethylhexadecahydro-2H-cyclopenta[7,8]phenanthro[2,3-b]oxiren-2-one | C19H28O3 | 详情 | 详情 | |
| (V) | 16465 | (2S,3S,5S,8R,9S,10S,13S,14S,16S)-3-hydroxy-10,13-dimethyl-2,16-di(1-piperidinyl)hexadecahydro-17H-cyclopenta[a]phenanthren-17-one | C29H48N2O2 | 详情 | 详情 | |
| (VI) | 32182 | (2S,3S,5S,8R,9S,10S,13S,14S,16S,17R)-10,13-dimethyl-2,16-di(1-piperidinyl)hexadecahydro-1H-cyclopenta[a]phenanthrene-3,17-diol | C29H50N2O2 | 详情 | 详情 | |
| (VII) | 32183 | (2S,3S,5S,8R,9S,10S,13S,14S,16S,17R)-17-(acetoxy)-10,13-dimethyl-2,16-di(1-piperidinyl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C33H54N2O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The reaction of 5alpha-androst-2-ene-17-one (I) with isopropenyl acetate (II) by means of H2SO4 as catalyst gives 17beta-acetoxy-5alpha-androsta-2,16-diene (III), which is epoxidized by means of perbenzoic acid (A) in benezene yielding 2alpha, 3alpha:16alpha,17alpha-diepoxy-17beta-acetoxy-5alpha-androstane (IV). The reaction of (IV) with N-methylpiperazine (V) in refluxing water affords 2beta,16beta-bis(4-methyl-1-piperazino)-3alpha-hydroxy-5alpha-androstane-17-one (VI), which is reduced with NaBH4 in THF methanol to give 2,16-bis(4-methyl-1-piperazino)-3alpha,17beta-dihydroxy-5alpha-androstane (VII). The acetylation of (VII) with acetic anhydride by means of ZnCl2 in acetic acid yields 2beta,16beta-bis(4-methyl-1-piperazino)-3alpha, 17beta-diacetoxy-5alpha-androstane (VIII), which is finally treated with methyl bromide in acetone.
| 【1】 US 312398 . |
| 【2】 Tuba, Z.; et al.; GB 1398050 . |
| 【3】 Blancafort, P.; Castaner, J.; Serradell, M.N.; Hopkins, S.J.; Pipecuronium bromide. Drugs Fut 1980, 5, 12, 621. |
| 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) | 39215 | benzenecarboperoxoic acid | 93-59-4 | C7H6O3 | 详情 | 详情 |
| (I) | 32178 | (5S,8R,9S,10S,13S,14S)-10,13-dimethyl-1,4,5,6,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C19H28O | 详情 | 详情 | |
| (II) | 21178 | isopropenyl acetate | 108-22-5 | C5H8O2 | 详情 | 详情 |
| (III) | 32179 | (5S,8R,9S,10S,13S,14S)-10,13-dimethyl-4,5,6,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate | C21H30O2 | 详情 | 详情 | |
| (IV) | 13647 | (1aR,2aS,2bS,4aS,5aR,6aS,6bR,8aS,9aS)-2a,4a-dimethylhexadecahydro-4bH-oxireno[2'',3'':4',5']cyclopenta[1',2':7,8]phenanthro[2,3-b]oxiren-4-yl acetate | C21H30O4 | 详情 | 详情 | |
| (V) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (VI) | 39216 | (2S,3S,5S,8R,9S,10S,13S,14S,16S)-3-hydroxy-10,13-dimethyl-2,16-bis(4-methyl-1-piperazinyl)hexadecahydro-17H-cyclopenta[a]phenanthren-17-one | C29H50N4O2 | 详情 | 详情 | |
| (VII) | 39217 | (2S,3S,5S,8R,9S,10S,13S,14S,16S,17R)-10,13-dimethyl-2,16-bis(4-methyl-1-piperazinyl)hexadecahydro-1H-cyclopenta[a]phenanthrene-3,17-diol | C29H52N4O2 | 详情 | 详情 | |
| (VIII) | 39218 | (2S,3S,5S,8R,9S,10S,13S,14S,16S,17R)-17-(acetoxy)-10,13-dimethyl-2,16-bis(4-methyl-1-piperazinyl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C33H56N4O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)Similarly, thiazepinone (I) was transesterified with isopropenyl acetate (V) to afford acetate ester (IV). Subsequent alkylation of the lactam N of (IV) with 2-(dimethylamino)ethyl mesylate (VI) in the presence of K2CO3 furnished diltiazem. Similarly, thiazepinone (I) was transesterified with isopropenyl acetate (V) to afford acetate ester (IV). Subsequent alkylation of the lactam N of (IV) with 2-(dimethylamino)ethyl mesylate (VI) in the presence of K2CO3 furnished diltiazem.
| 【1】 Harsanyi, K.; Gizur, T.; Demeter, A.; Aracs, Z.; Felmeri, J.; Berki, K.; Trischeler, F.; Vincze, Z. (Gedeon Richter Ltd.); Process for the preparation of benzothiazepin-4(5H)-one derivs.. ES 2001146; JP 1987108872 . |
| 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) | 62436 | (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C16H15NO3S | 详情 | 详情 | |
| (III) | 62488 | (2S,3S)-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C20H24N2O3S | 详情 | 详情 | |
| (IV) | 62490 | (2S,3S)-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl acetate | C18H17NO4S | 详情 | 详情 | |
| (V) | 21178 | isopropenyl acetate | 108-22-5 | C5H8O2 | 详情 | 详情 |
| (VI) | 62491 | ethyl 3-chloro-3-(3-pyridinyl)propyl(methyl)carbamate | C12H17ClN2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXIII)An alternative procedure for the chiral hydroxy sulfoxide (XIX) involved a lipase-catalyzed kinetic resolution. Transesterification of racemic hydroxy sulfoxide (XXII) with isopropenyl acetate (XXIII) catalyzed by lipase AL yielded the acetate ester of the required (S)-isomer (XXIV), along with the unreacted (R)-alcohol (XXV). Separation was achieved upon treatment with phthalic anhydride (XXVI) in the presence of DMAP and pyridine to produce the phthalic acid derivative (XXVII) of the unreacted alcohol, which could be separated from the desired acetate ester (XXIV) by means of selective extraction. The target enantiomerically pure (S)-hydroxy sulfoxide intermediate (XIX) was then obtained by methanolysis of the acetate ester (XXIV) with K2CO3, followed by two recrystallizations from EtOAc. The corresponding (R)-alcohol was recovered by NaOH hydrolysis of the phthalate ester (XXVII), and was completely racemized by treatment with aqueous HCl.
| 【1】 Morita, S.; et al.; Synthesis of a key intermediate, (S)-2-[(3-hydroxypropyl)sulfinyl]-1-(o-tolyl)imidazole, for the antiplatelet aggregation inhibitor, OPC-29030 via lipase-catalyzed enantioselective transesterification. Tetrahedron Asymmetry 1997, 8, 22, 3707. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIX) | 30240 | 3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfinyl]-1-propanol | C13H16N2O2S | 详情 | 详情 | |
| (XXII) | 30245 | 3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfinyl]-1-propanol | C13H16N2O2S | 详情 | 详情 | |
| (XXIII) | 21178 | isopropenyl acetate | 108-22-5 | C5H8O2 | 详情 | 详情 |
| (XXIV) | 30243 | 3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfinyl]propyl acetate | C15H18N2O3S | 详情 | 详情 | |
| (XXV) | 30246 | 3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfinyl]-1-propanol | C13H16N2O2S | 详情 | 详情 | |
| (XXVI) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (XXVII) | 30244 | 2-[(3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfinyl]propoxy)carbonyl]benzoic acid | C21H20N2O5S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XXIV)2) The chiral intermediate (X) has been obtained by two different ways: a) The Knovenagel condensation of dimethyl malonate (XVII) with 3-nitrobenzaldehyde (XVIII) gives the corresponding benzylidenemalonate (XIX), which is alkylated with diethyl zinc and CuBr in DMSO yielding 2-[1-(3-nitrophenyl)propyl]malonic acid dimethyl ester (XX). The partial decarboxylation of (XX) with 6N HCl affords racemic 3-(3-nitrophenyl)pentanoic acid (XXI), which is esterified with methanol/HCl to the racemic methyl ester (XXII). Finally, this racemate is resolved by chromatography over a chiral (R,R)Whelk-O1 column giving the desired intermediate (X). b) The regioselective acetylation of 1-(3-nitrophenyl)-1-propanol (XXIII) with isopropenyl acetate (XXIV) catalyzed by Amano P30 lipase gives a mixture of the (S)-acetate (XXV) and unreacted (R)-alcohol (XXVI). After separation, (XXVI) was mesylated with mesyl chloride as usual yielding mesylate (XXVII), which was condensed with the sodium salt of diethyl malonate (XXVIII) affording the chiral malonic ester (XXIX). Partial decarboxylation of (XXIX) with 6N HCl gives the chiral pentanoic acid (XXX), which is finally esterified to the desired intermediate (X) with methanol/HCl.
| 【1】 Fors, K.S.; et al.; A convergent, scalable synthesis of HIV protease inhibitor PNU-140690. J Org Chem 1998, 63, 21, 7348. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 21164 | methyl (3S)-3-(3-nitrophenyl)pentanoate | C12H15NO4 | 详情 | 详情 | |
| (XVII) | 19373 | dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester | 108-59-8 | C5H8O4 | 详情 | 详情 |
| (XVIII) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (XIX) | 21173 | dimethyl 2-(3-nitrobenzylidene)malonate | C12H11NO6 | 详情 | 详情 | |
| (XX) | 21174 | dimethyl 2-[1-(3-nitrophenyl)propyl]malonate | C14H17NO6 | 详情 | 详情 | |
| (XXI) | 21175 | 3-(3-nitrophenyl)pentanoic acid | C11H13NO4 | 详情 | 详情 | |
| (XXII) | 21176 | methyl 3-(3-nitrophenyl)pentanoate | C12H15NO4 | 详情 | 详情 | |
| (XXIII) | 21177 | 1-(3-nitrophenyl)-1-propanol | C9H11NO3 | 详情 | 详情 | |
| (XXIV) | 21178 | isopropenyl acetate | 108-22-5 | C5H8O2 | 详情 | 详情 |
| (XXV) | 21179 | (1S)-1-(3-nitrophenyl)propyl acetate | C11H13NO4 | 详情 | 详情 | |
| (XXVI) | 21180 | (1R)-1-(3-nitrophenyl)-1-propanol | C9H11NO3 | 详情 | 详情 | |
| (XXVII) | 21181 | (1R)-1-(3-nitrophenyl)propyl methanesulfonate | C10H13NO5S | 详情 | 详情 | |
| (XXVIII) | 21182 | Diethyl malonate sodium salt | C7H11NaO4 | 详情 | 详情 | |
| (XXIX) | 21183 | diethyl 2-[(1S)-1-(3-nitrophenyl)propyl]malonate | C16H21NO6 | 详情 | 详情 | |
| (XXX) | 21184 | (3S)-3-(3-nitrophenyl)pentanoic acid | C11H13NO4 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XVII)Intermediates (II) and (IV) are prepared as follows. Alkylation of the sodium enolate of methyl 3-bromophenylacetate (VII) with 4-chlorobenzyl bromide (VIII) in cold THF followed by methyl ester hydrolysis with LiOH in aqueous acetonitrile affords 2-(m-bromophenyl)-3-(p-chlorophenyl)propionic acid (IX), which is converted to the corresponding Weinreb amide (X) by chlorination with oxalyl chloride and subsequent treatment with N,O-dimethylhydroxylamine. Addition of methylmagnesium bromide to the methoxyamide (X) gives the 3,4-diaryl-2-butanone (XI), which is then reduced using NaBH4 or LiBH(s-Bu)3 (L-selectride) to provide alcohol (XIIa) as the major diastereoisomer. After conversion of alcohol (XIIa) to the corresponding mesylate, displacement with NaN3 in hot DMF leads to azide (XIII), which is reduced by catalytic hydrogenation in the presence of PtO2 and Boc2O to afford the Boc-protected amine (XIV). Then, palladium-catalyzed substitution of the aryl bromide (XIV) with zinc cyanide yields the nitrile (XV), which is deprotected to (IIa) using HCl in EtOAc (2, 3). Similarly, coupling between 3-bromobenzonitrile (XVI) and isopropenyl acetate (XVII) in the presence of Pd2(dba)3 and 2-(dicyclohexylphosphino)-2’-(dimethylamino)biphenyl (DCPDMAB) gives 1-(m-cyanophenyl)acetone (XVIII), which is alkylated with 3-chlorobenzyl chloride (XIX) in the presence of cesium hydroxide and tetrabutylammonium iodide to yield the diarylbutanone (XX). Reduction of ketone (XX) with lithium tri(sec-butyl)borohydride produces alcohol (XXI), which is converted to the Boc-protected amine (XV) by mesylation followed by displacement with NaN3, and then reduction of the resulting azide (XXII) by catalytic hydrogenation in the presence of PtO2 and Boc2O (1). The ketonitrile (XX) is alternatively produced by palladium-catalyzed cyanuration of aryl bromide (XI) with either zinc cyanide or potassium ferrocyanide. The intermediate enol tosylate (IV) can be obtained by treatment of (XX) with sodium tert-butoxide and p-toluenesulfonic anhydride (5, 6). Preparation of the enantiomerically pure amine (IIb) can be accomplished by resolution at the stage of the diarylpropionic acid (IX) or, in a more efficient method, by dynamic kinetic resolution of (XI) via stereoselective hydrogenation to (XIIb) in the presence of the chiral Ru catalyst [(S)-xyl-BINAP]-[(S)-DAIPEN]RuCl2 and excess potassium tert-butoxide (4). Scheme 2.
| 【1】 Hagmann, W.K., Lin, L.S., Shah, S.K. et al. (Merck & Co., Inc.). Substituted amides. CA 2478183, EP 1496838, JP 2005519958, JP 2006257090, US 2004058820, US 6972295, WO 03077847. |
| 【2】 Hagmann, W.K., Lin, L.S., Shah, S.K. et al. (Merck & Co., Inc.). Substituted amides active at the cannabinoid-1 receptor. WO 2004048317. |
| 【3】 Lin, L.S., Lanza, T.J. Jr., Jewell, J.P. et al. Discovery of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity. J Med Chem 2006, 49(26): 7584-7. |
| 【4】 Chen, C., Frey, L.F., Shultz, S. et al. Catalytic, enantioselective synthesis of taranabant, a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity. Org Proc Res Devel 2007, 11(3): 616-23. |
| 【5】 Campos, K.R., Klapars, A., McWilliams, J.C. et al. (Merck & Co., Inc.). Formation of tetra-substituted enamides and stereoselective reduction thereof. WO 2006017045. |
| 【6】 Weissman, S.A. (Merck & Co., Inc.). Cyanation of aromatic halides. US 2006106223. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIIa) | 65595 | C16H16BrClO | 详情 | 详情 | ||
| (XIIb) | 65596 | C16H16BrClO | 详情 | 详情 | ||
| (Iia) | 65586 | 3-[(1RS,2RS)-2-Amino-1-[(4-Chlorophenyl)Methyl]Propyl]Benzonitrile | C17H17ClN2 | 详情 | 详情 | |
| (Iib) | 65587 | 3-[(1S,2S)-2-Amino-1-[(4-Chlorophenyl)Methyl]Propyl]Benzonitrile | 732982-66-0 | C17H17ClN2 | 详情 | 详情 |
| (IV) | 65582 | (R )-(-)-4-Penten-2-ol | 64584-92-5 | C5H10O | 详情 | 详情 |
| (VII) | 50901 | methyl 2-(3-bromophenyl)acetate | 150529-73-0 | C9H9BrO2 | 详情 | 详情 |
| (VIII) | 16481 | 1-(bromomethyl)-4-chlorobenzene | 622-95-7 | C7H6BrCl | 详情 | 详情 |
| (IX) | 65592 | C15H12BrClO2 | 详情 | 详情 | ||
| (X) | 65593 | C17H17BrClNO2 | 详情 | 详情 | ||
| (XI) | 65594 | 3-(3-Bromophenyl)-4-(4-Chlorophenyl)Butan-2-One | 848310-98-5 | C16H14BrClO | 详情 | 详情 |
| (XIII) | 65597 | C16H15BrClN3 | 详情 | 详情 | ||
| (XIV) | 65598 | C21H25BrClNO2 | 详情 | 详情 | ||
| (XV) | 65599 | C22H25ClN2O2 | 详情 | 详情 | ||
| (XVI) | 26573 | 3-bromobenzonitrile | 6952-59-6 | C7H4BrN | 详情 | 详情 |
| (XVII) | 21178 | isopropenyl acetate | 108-22-5 | C5H8O2 | 详情 | 详情 |
| (XVIII) | 65600 | (3-Cyanophenyl)Acetone | C10H9NO | 详情 | 详情 | |
| (XIX) | 10356 | 1-Chloro-4-(chloromethyl)benzene; 4-Chlorobenzyl chloride | 104-83-6 | C7H6Cl2 | 详情 | 详情 |
| (XX) | 65601 | C17H14ClNO | 详情 | 详情 | ||
| (XXI) | 65602 | C17H16ClNO | 详情 | 详情 | ||
| (XXII) | 65603 | C17H15ClN4 | 详情 | 详情 |