硫酸氢氯吡格雷中有关物质的合成

为了对硫酸氢氯吡格雷产品质量进行控制,分别合成了美国药典31版所载硫酸氢氯吡格雷的3种有关物质--(+)-(S)-α-(2-氯苯基)-6,7-二氢噻吩并[3,2-c]吡啶基-5(4H)-乙酸盐酸盐(A)、α-(2-氯苯基)-4,5-二氢噻吩并[2,3-c]吡啶基-6(7H)-乙酸甲酯盐酸盐(B)、(-)-(R)-α.(2-氯苯基)-6,7-二氢噻吩并[3,2-c]吡啶基-5(4H)-乙酸甲酯硫酸氢盐(C),并经TR、~1HNMR、MS等确证结构.     

氯吡格雷硫酸氢盐的合成

(R)-邻氯扁桃酸经甲酯化、苯磺酰化得到(R)-2-苯磺酰氧基-2-(2-氯苯基)乙酸甲酯,再与4,5,6,7.四氢噻吩并-[3,2-c]吡啶盐酸盐经亲核取代反应制得氯吡格雷硫酸氢盐,总收率约83%.     

（＋）-生物素的合成

(3aS,4S,6aR)-1,3-二苄基-6-(3-甲氧基丙基)四氢噻吩并[3,4-d]咪唑-2-酮在甲酸中和浓盐酸反应制得(3aR,8aS,8bS)-1,3-二苄基-2-氧代十氢咪唑并[4,5-c]噻吩并[1,2-α]氯化锍鎓盐,再经缩合开环、水解后脱羧得剑(+)-生物素,总收率73%.     

普拉格雷的合成

环丙基-2-氟苄基酮经氯代得到2-氯-1-环丙基-2-(2-氟苯基)乙酮,然后与5,6,7,7-四氢噻吩并[3,2-c]吡啶-2(4H)-酮对甲苯磺酸盐进行偶联反应制得5-(-环丙羰基-2-氟苄基)-2-氧代-4,5,6,7-四氢噻吩并[3,2-c]吡啶,最后经乙酰化反应制得普拉格雷,总收率46%。     

新型的ADP受体拮抗剂——硫酸氢氯吡格雷

硫酸氢氯吡格雷片(PLAVIX,波立维),化学结构为甲基(+)-(S)-α(2-氯苯基)-6,7-二氢噻吩[3,2-c]吡啶-5(4H)-乙酸甲酯硫酸盐(1:1),是ADP诱导的血小板聚集抑制剂,它是通过直接抑制二磷酸腺苷与其受体结合以及继发ADP(二磷酸腺苷)介导的糖蛋白GPⅡb/Ⅲa复合物活化而起作用的.     

氯维地平的合成

2,3-二氯苯甲醛、乙酰乙酸甲酯和浓氨水经闭环缩合、选择性水解得4-(2,3-二氯苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸单甲酯,再与正丁酸氯甲酯反应制得抗高血压药氯维地平,总收率约44%.     

丁酸氯维地平的合成工艺

摘 要：目的 研究适合工业化生产的丁酸氯维地平合成方法。方法 采用2,3-二氯苯甲醛、β-氨基巴豆酸甲酯与乙酰乙酸乙酯环化缩合,选择性水解得到4-(2,3-二氯苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸单甲酯钾盐,再同丁酸氯甲酯反应得到丁酸氯维地平。结果 该合成工艺的丁酸氯维地平总收率为48%。结论 该工艺稳定,操作简单,适合工业化生产丁酸氯维地平。     

超声-水解酶法合成丁酸氯维地平

2,3-二氯苯甲醛、乙酸铵和乙酰乙酸甲酯在超声作用下缩合成二氢吡啶环,再用羧酸酯酶进行选择性水解得4-(2,3-二氯苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸单甲酯,最后与正丁酸氯甲酯缩合制得抗高血压药丁酸氯维地平,总收率约57％.     

氯维地平的合成

3-羟基丙腈和双乙烯酮在三乙胺作用下制得乙酰乙酸(2-氰基乙基)酯(2),再与2,3-二氯苯甲醛和3-氨基巴豆酸甲酯经Hantzsch缩合闭环,接着用硫化钠在常温下选择性水解得4-(2,3-二氯苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸单甲酯,最后与正丁酸氯甲酯反应即得抗高血压药氯维地平,总收率约59%(以2计)。     

普拉格雷的合成

目的合成普拉格雷。方法邻氟苯乙酸钠和格氏试剂反应生成伊万诺夫试剂,然后和环丙基甲酸甲酯反应得到环丙基-2-氟苄基酮,经无溶剂溴化反应得到α-环丙羰基-2-氟苄基溴,再与5,6,7,7a-四氢噻吩并[3,2-c]吡啶-2(4H)-酮缩合、乙酰化得到普拉格雷。结果该方法普拉格雷的总收率为35%。结论此工艺收率高、成本低、易于工业化。     

Synthesis of pyrimido[5,4-c]quinolines and related quinolines as potential antimalarials.

3-Ethylaminomethyl-2-methyl-4(1H)-quinolone (1a) and its 6-CH3, 6-OCH3, and 7-Cl derivatives were prepared by means of the Mannich reaction. Conversion to the 4-chloro derivatives and condensation with 3-chloroaniline gave the corresponding 4-(3-chloroanilino) derivatives. Cyclization of 4-(3-chloroanilino)-2,6-dimethyl-3-ethyl-aminomethylquinoline (3a) and its 6-OCH3 derivative with paraformaldehyde gave 1-(3-chlorophenyl)-3,9-dimethyl-3-ethyltetrahydropyrimido[5,4-c]quinoline (4a) and the 9-OCH3 derivative 4b. Treatment of 4b with benzaldehyde gave 1-(3-chlorophenyl)-3-ethyl-9-methoxy-5-styryltetrahydropyrimido[5,4-c]quinoline (5). 3-Benzylaminomethyl-6-methoxy-2-methyl-4(1H)-quinolone (1e) and 3,3'-(1,3-benzyliminodimethylene)di[2-methyl-4(1H)-quinolone] (6b) were also synthesized. The compounds were inactive as antimalarials.     

Synthesis and anxiolytic activity of 1-phenyl-2-(4-aryl-1,3,4,5-tetrahydropyrido[2,3-b][1 ,4]diazepin-2-ylidene)-ethanone

A two-step, general synthesis of 1-phenyl-2-(4-aryl-1,3,4,5-tetrahydropyrido[2,3-b][1,4]diazepin-2-ylidene)-ethanones 3-9 is presented. This synthesis employs a condensation of 2,3-diaminopyridine with benzoylacetone followed by a basic-activated cyclization reaction with substituted benzaldehydes for final closure of the seven-membered ring. Molecular diversity is fixed by appropriate aldehydes: 2-chloro-, 4-chloro-, 2-bromo-, 4-bromo-, 4-fluoro-, 4-trifluoro- and 3-bromo-4,5-dimethoxybenzaldehyde. Compounds 4, 6, 8, 9 and 10 were examined for their anxiolytic activity. The most active was the compound with the chlorophenyl substituent i.e. 1-phenyl-2-{4-(4-chlorophenyl)-1,3,4,5-tetrahydropyrido[2,3-b][1,4]diazepin-2-ylidene}-ethanone (4).     

Synthesis, evaluation and structure-activity relationships of 5-alkyl-2,3-dihydroimidazo[1,2-c] quinazoline, 2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-thiones and their oxo-analogues as new potential bronchodilators

With an aim to obtain potent bronchodilators, two series of 5-alkyl-2,3-dihydroimidazo[1,2-c]quinazolines (Va-1), 2,3-dihydroimidazo[1,2-c]quinazolin-5-(6H)-thiones (VIIIa-d) and their oxo-analogues (IXa-d) have been designed. The compounds Va-1 were synthesized by two alternative routes. The former (Method A) based on the dehydrocyclization of 4-(1-hydroxyethyl)-aminoquinazoline (IV) and the latter (Method B) involves the usage of 2-aminobenzonitrile (VI) which on reaction with ethylenediamine leads to the formation of the key intermediate 2-(2-aminophenyl)-4,5-dihydro-1H-imidazoles (VII). Finally the intermediate VII on condensation with different acidanhydrides yielded the title compound V. In general method-A resulted the compound V in quantitatively higher yields. 2,3-Dihydroimidazo[1,2-c]quinazolin-5 (6H)-thiones (VIII) were obtained by condensing VII with carbon disulfide and a further oxidation of VIII gave their corresponding oxo-analogues (IX). The title compounds V, VIII and IX were evaluated for their bronchodilator activity using in vitro and in vivo (standard animal models) methods. All the test compounds exhibited bronchodilatory activity. The structure activity relationship studies indicated good correlation between the nature of the substituent and bronchodilatory activity. In the 5-alkyl substituted compounds V, a longer alkyl chain showed higher bronchodilatory activity. Compounds VIII and IX were found to be less potent and replacement of sulphur with oxygen showed no significant effect on the biological activity. The presence of halogens altered the biological activity in both the series. Among the compounds tested, 9-lodo-5-(n-propyl)-2,3-dihydroimidazo[1,2-c]quinazoline (VI) was found to be the most potent (percentage protection = 87.1%; relative activity = 1.1 compared to the standard aminophylline).     

Synthesis of New 6-{[ω-(Dialkylamino(heterocyclyl)alkyl]thio}-3-R-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones and Evaluation of their Anticancer and Antimicrobial Activities

Several novel 6-thio-3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazoline-based compounds containing an ω-(dialkylamino(heterocyclyl)]alkyl fragment were synthesized to examine their anticancer activity. Some of the 6-{[ω-(hetero-cyclyl)alkyl]thio}-3-R-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones (3.1-3.10) were obtained by the nucleophilic substitution of 6-[ω-halogenalkyl]thio-3-R-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones (2.1-2.8) with azaheterocycles. Alternatively, compounds 3.1-3.22 were synthesized by alkylation of 3-R-6-thio-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones potassium salts (1.1-1.4) with (2-chloroethyl)-N,N-dialkylamine hydrochlorides or 1-(2-chloroethyl)heterocycle hydrochlorides. The structures of compounds were elucidated by (1)H, (13)C NMR, LC-MS and EI-MS analysis. Then anticancer and antibacterial, bioluminescence inhibition of Photobacterium leiognathi Sh1 activities of the substances were tested in vitro. It was found that compound 3.18 possessed a wide range of anticancer activity against 27 cell lines of cancer: non-small cell lung, colon, CNS, ovarian, renal, prostate, breast, melanoma and leukemia (log GI(50) < -5.65). The "structure-activity" relationship was discussed. COMPARE analysis for synthesized anticancer active compounds was performed.     

Synthesis of new pyrido[4',3':4,5]thieno[2,3-d]-1,2,4-triazolo[3,4-c]pyrimidines and a 5,6-dihydro-1,2,4-triazolo[4",3":1',2']pyrido[4',3':4,5]thieno [2,3-d]-pyrimidine ring system

A series of substituted pyrido[4',3':4,5]thieno[2,3-d]-1,2,4-triazolo[3,4-c]pyrimidines 4-6, 8, pyrido[4',3':4,5]thieno[2,3-d]-1,2,4-triazolo[3,4-c]pyrimidines 11-13 and 5,6-dihydro-1,2,4-triazolo[4",3":1',2']pyrido[4',3':4,5]thieno[2,3-d] pyrimidines 16-19 have been synthesized from 3, 10 and 15 through the reaction with orthoesters and carbon disulphide, respectively.     

Synthesis and anticancer activity of isatin-based pyrazolines and thiazolidines conjugates

The synthesis and antitumor activity screening of novel isatin based conjugates with thiazolidine and pyrazoline moieties were performed. Reaction of 3,5-diaryl-4,5-dihydropyrazoles with chloroacetyl chloride yielded starting 2-chloro-1-(3,5-diaryl-4,5-dihydropyrazol-1-yl)-ethanones which were utilized in alkylation of isatin and 5-bromoisatin. Thus, corresponding 1-[2-(3,5-diaryl-4,5-dihydropyrazol-1-yl)-2-oxoethyl]-1H-indole-2,3-diones (1a-1d) have been obtained. The compounds 1a-1d have been used in Knoevenagel condensation with 4-thiazolidinones for obtaining a series of 5-ylidenederivatives 2a-2f and 3a-3d. The synthesized compounds were tested for their anticancer activity in NCI60 cell lines. Among the tested compounds, 5-bromo-1-{2-[5-(4-chlorophenyl)-3-(4-methoxyphenyl)-4,5-dihydropyrazol-1-yl]-2-oxoethyl}-1H-indole-2,3-dione (1d) was found to be the most active candidate with selective influence on leukemia subpanel tumor cell lines with GI(50) values range of 0.69-3.35 μM.     

Synthesis, isomerization, and antimicrobial evaluation of some pyrazolopyranotriazolopyrimidine derivatives

6-Amino-5-imino-pyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidine derivative 4 and pyrazolo-[4',3':5,6]pyrano[2,3-d]pyrimidin-5-ylhydrazine derivative 5 were prepared starting from 6-amino-3-methyl-4-(p-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile 1. The synthesis and structure characterization of 9,11-dihydropyrazolo[4',3':5,6]pyrano[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives 7 and 9 and their isomerization to 9,11-dihydropyrazolo[4',3':5,6]pyrano[3,2-e] [1,2,4]triazolo[1,5-c]pyrimidine derivatives 6 and 8, respectively, under different suitable reaction conditions are reported. Moreover, the synthesis of 9,11-dihydropyrazolo[4',3':5,6]pyrano[3,2-e] tetrazolo[1,5-c]pyrimidine derivative 14 and N(9)-acyclic nucleoside 15 are described. Some of the prepared products showed potent antimicrobial activity.     

Antiplasmodial and antioxidant isofuranonaphthoquinones from the roots of Bulbine capitata.

The roots of B. capitata yielded the new compounds 5,8-dihydroxy-1-tigloylmethylnaphtho[2,3-c]furan-4,9-dione, 1-acetoxymethyl-8-hydroxynaphtho[2,3-c]furan-4,9-dione, and 1-acetoxymethyl-5,8-dihydroxynaphtho[2,3-c]furan-4,9-dione, in addition to the known compounds chrysophanol, 10,10'-chrysophanol bianthrone, 8-hydroxy-1-methylnaphtho[2,3-c]furan-4,9-dione, 5,8-dihydroxy-1-methylnaphtho[2,3-c]furan-4,9-dione, 5,8-dihydroxy-1-hydroxymethylnaphtho[2,3-c]furan-4,9-dione, and 8-hydroxy-5-methoxy-1-methylnaphtho[2,3-c]furan-4,9-dione, or 5-hydroxy-8-methoxy-1-methylnaphtho[2,3-c]furan-4,9-dione. The new as well as the known isofuranonaphthoquinones showed antioxidant and weak antiplasmodial activities.     

Studies on the synthesis of condensed pyridazine derivatives. II. Synthesis and anxiolytic activities of 2-aryl-4,4a,5,6-tetrahydropyridazino[4,3-c]quinolin-3(2H)-ones, 2-aryl-4a,5-dihydro-2H-(1)benzothiopyrano[4,3-c]pyridazin-3(4H)-ones, and related compounds

A series of 2-aryl-4,4a,5,6-tetrahydropyridazino[4,3-c]quinolin-3(2H)- ones, 2-aryl-4a,5-dihydro-2H-(1)benzothiopyrano[4,3-c]pyridazin-3( 4H)-ones, and related compounds were synthesized and tested for their ability to displace [3H]diazepam from rat brain membranes in vitro, and to prevent bicuculline-induced convulsions in mice in vivo. Among them, 2-(4-chlorophenyl)-4a,5-dihydro-2H-(1)benzothiopyrano[4,3-c]pyr idazin-3(4H)- one (16b) showed remarkable activities both in vitro (Ki 48 nM) and in vivo (ED50 12.4 mg/kg, p.o.). The trans sulfoxide (19a) of 16b exhibited anxioselective pharmacological activities. Compound 19a was equipotent with diazepam in the anticonflict assay (Vogel type, rat, MED 10 mg/kg, p.o.) while exhibiting reduced muscle relaxation (rotarod test) and narcotic potentiation. The structure-activity relationships are discussed.