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【结 构 式】

【药物名称】SNAP-6383, L-771688

【化学名称】4(S)-(3,4-Difluorophenyl)-6-(methoxymethyl)-2-oxo-3-[3-[4-(2-pyridinyl)piperidin-1-yl]propylcarbamoyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester

【CA登记号】200050-59-5, 200051-19-0 (diHCl)

【 分 子 式 】C28H33F2N5O5

【 分 子 量 】557.60251

【开发单位】Merck & Co. (Originator), Synaptic (Originator)

【药理作用】Benign Prostatic Hyperplasia Therapy, RENAL-UROLOGIC DRUGS, alpha1A-Adrenoceptor Antagonists

合成路线1合成路线2合成路线3合成路线4合成路线5

合成路线1

Condensation of 2-pyridylacetonitrile (I) with N,N-bis-(2-chloroethyl)benzylamine (II) under phase-transfer conditions produced the pyridylpiperidine (III). The cyano group of (III) was hydrolyzed to carboxamide (IV) with concentrated sulfuric acid and then decarboxylated to (V) by treatment with methanolic HCl. Subsequent hydrogenolysis of the N-benzyl group of (V) afforded piperidine (VI). N-Boc-3-bromopropylamine (VIII) was prepared by treatment of 3-bromopropylamine (VII) with di-tert-butyl dicarbonate. Alkylation of piperidine (VI) with bromide (VIII) gave adduct (IX). The N-Boc protecting group of (IX) was then removed by treatment with trifluoroacetic acid to yield intermediate aine (X).

参考文献 中间体
【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 .
【2】 Lagu, B.; Nagarathnam, D.; Marzabadi, M.R.; Wong, W.C.; Gluchowski, C. (Synaptic Pharmaceutical Corp.); Dihydropyrimidines and uses thereof. WO 9851311 .
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) 36179 2-(2-pyridinyl)acetonitrile C7H6N2 详情 详情
(II) 23122 N-benzyl-2-chloro-N-(2-chloroethyl)-1-ethanamine; N-Benzylbis(2-chloroethyl)amine 10429-82-0 C11H15Cl2N 详情 详情
(III) 48382 1-benzyl-4-(2-pyridinyl)-4-piperidinecarbonitrile C18H19N3 详情 详情
(IV) 48383 1-benzyl-4-(2-pyridinyl)-4-piperidinecarboxamide C18H21N3O 详情 详情
(V) 48384 1-benzyl-4-(2-pyridinyl)piperidine C17H20N2 详情 详情
(VI) 48385 2-(4-piperidinyl)pyridine C10H14N2 详情 详情
(VII) 25449 3-bromo-1-propanamine; 3-bromopropylamine 18370-81-5 C3H8BrN 详情 详情
(VIII) 37752 tert-butyl 3-bromopropylcarbamate C8H16BrNO2 详情 详情
(IX) 48386 tert-butyl 3-[4-(2-pyridinyl)-1-piperidinyl]propylcarbamate C18H29N3O2 详情 详情
(X) 48387 3-[4-(2-pyridinyl)-1-piperidinyl]propylamine; 3-[4-(2-pyridinyl)-1-piperidinyl]-1-propanamine C13H21N3 详情 详情

合成路线2

In an alternative method, 2,4'-dipyridyl (XI) was alkylated with 3-bromopropylamine hydrobromide (VII) in hot DMF to provide the pyridinium salt (XII). Reduction of (XII) with NaBH4 gave the tetrahydropyridine (XIII), which was further hydrogenated in the presence of Pearlman's catalyst to yield the intermediate pyridylpiperidine (X).

参考文献 中间体
【1】 O'Malley, S.S.; Chen, T.-B.; Chang, R.S.L.; et al.; In vitro studies on L-771,688 (SNAP 6383), a new potent and selective alpha1A-adrenoceptor antagonist. Eur J Pharmacol 2000, 409, 3, 301.
【2】 Ikemoto, N.; Taylor, C.S.; Sidler, D.R.; Chartrain, M.; Bills, G.F.; Roberge, C.M.; Li, W.; Larsen, R.D. (Merck & Co., Inc.); alpha 1a Adrenergic receptor antagonist. WO 9907695 .
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) 48387 3-[4-(2-pyridinyl)-1-piperidinyl]propylamine; 3-[4-(2-pyridinyl)-1-piperidinyl]-1-propanamine C13H21N3 详情 详情
(XI) 36311 2,4'-Dipyridyl 581-47-5 C10H8N2 详情 详情
(XII) 25449 3-bromo-1-propanamine; 3-bromopropylamine 18370-81-5 C3H8BrN 详情 详情
(XIII) 48388 1-(3-aminopropyl)-4-(2-pyridinyl)pyridinium bromide C13H16BrN3 详情 详情
(XIV) 48389 3-[4-(2-pyridinyl)-3,6-dihydro-1(2H)-pyridinyl]-1-propanamine; 3-[4-(2-pyridinyl)-3,6-dihydro-1(2H)-pyridinyl]propylamine C13H19N3 详情 详情

合成路线3

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.

参考文献 中间体
【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

合成路线4

Coupling of (XXV) with the intermediate amine (X) gave urea (XXVI). The methoxydihydropyrimidine ring (XXVI) was hydrolyzed to the tetrahydropyrimidinone (XXVII) by treatment with HCl, and the cyanoethyl ester group was further removed using NaOH in aqueous acetone. The resultant carboxylic acid (XXVIII) was finally esterified with methanol by using EDC and DMAP as the coupling reagents.

参考文献 中间体
【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 .
【2】 Lagu, B.; Nagarathnam, D.; Marzabadi, M.R.; Wong, W.C.; Gluchowski, C. (Synaptic Pharmaceutical Corp.); Dihydropyrimidines and uses thereof. WO 9851311 .
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) 48387 3-[4-(2-pyridinyl)-1-piperidinyl]propylamine; 3-[4-(2-pyridinyl)-1-piperidinyl]-1-propanamine C13H21N3 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
(XXVI) 48397 2-cyanoethyl (6S)-6-(3,4-difluorophenyl)-2-methoxy-4-(methoxymethyl)-1-[([3-[4-(2-pyridinyl)-1-piperidinyl]propyl]amino)carbonyl]-1,6-dihydro-5-pyrimidinecarboxylate C31H36F2N6O5 详情 详情
(XXVII) 48398 2-cyanoethyl (4S)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-3-[([3-[4-(2-pyridinyl)-1-piperidinyl]propyl]amino)carbonyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate C30H34F2N6O5 详情 详情
(XXVIII) 48399 (4S)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-3-[([3-[4-(2-pyridinyl)-1-piperidinyl]propyl]amino)carbonyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid C27H31F2N5O5 详情 详情

合成路线5

In a related synthetic method, condensation between 4-methoxyacetoacetate (XIV), 3,4-difluorobenzaldehyde (XVII) and urea (XXIX) in the presence of copper acetate and boron trifluoride etherate furnished the racemic pyrimidinone (XXX). Enzymatic resolution of (XXX) by incubation with subtilisin yielded a separable mixture of the (R)-acid (XXXII) and the unreacted (S)-ester (XXXI). Alternatively, the (S)-enantiomer (XXXI) was isolated by chiral preparative HPLC. Pyrimidinone (XXXI) was activated by conversion to either aryl carbamate (XXXIII) using 4-nitrophenyl chloroformate or to imidazolide (XXXIV) with carbonyl diimidazole. Finally, coupling of the intermediate amine (X) with either the carbamate (XXXIII) or the imidazolide (XXXIV) furnished the title compound.

参考文献 中间体
【1】 O'Malley, S.S.; Chen, T.-B.; Chang, R.S.L.; et al.; In vitro studies on L-771,688 (SNAP 6383), a new potent and selective alpha1A-adrenoceptor antagonist. Eur J Pharmacol 2000, 409, 3, 301.
【2】 Broten, T.P.; Nichtberger, S.A.; Siegl, P.K.S. (Merck & Co., Inc.); Combination therapy for the treatment of benign prostatic hyperplasia. WO 9948530 .
【3】 Evans, B.; Dunn, M.; Lagu, B.; Kari, H.P.; Nagarathnam, D.; Vyas, K.P.; Cui, D.; Davis, M.R.; Zhang, K. (Merck & Co., Inc.; Synaptic Pharmaceutical Corp.); Dihydropyrimidines and uses thereof. WO 0037026 .
【4】 Ikemoto, N.; Taylor, C.S.; Sidler, D.R.; Chartrain, M.; Bills, G.F.; Roberge, C.M.; Li, W.; Larsen, R.D. (Merck & Co., Inc.); alpha 1a Adrenergic receptor antagonist. WO 9907695 .
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) 48387 3-[4-(2-pyridinyl)-1-piperidinyl]propylamine; 3-[4-(2-pyridinyl)-1-piperidinyl]-1-propanamine C13H21N3 详情 详情
(XIV) 26655 methyl 4-methoxy-3-oxobutanoate;Methyl 4-methoxyacetoacetate;Methyl 4-methoxy-3-oxo-butanoate 41051-15-4 C6H10O4 详情 详情
(XVII) 26654 3,4-difluorobenzaldehyde 34036-07-2 C7H4F2O 详情 详情
(XXIX) 19310 urea 57-13-6 CH4N2O 详情 详情
(XXX) 39303 methyl 4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate C14H14F2N2O4 详情 详情
(XXXI) 48402 methyl (4S)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate C14H14F2N2O4 详情 详情
(XXXII) 39304 methyl (4R)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate C14H14F2N2O4 详情 详情
(XXXIII) 48400 5-methyl 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate C21H17F2N3O8 详情 详情
(XXXIV) 48401 methyl (4S)-4-(3,4-difluorophenyl)-3-(1H-imidazol-1-ylcarbonyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate C18H16F2N4O5 详情 详情
Extended Information
Drug NewChemical Entity Original Patent(1)