合成3,4-二氟苯基异硫氰酸酯的绿色工艺

目的开发出一条新的环保工艺代替文献报导的卡卢扎反应,制备3,4-二氟苯基异硫氰酸酯。方法3,4-二氟苯胺与二硫化碳在氢氧化钠水溶液中反应1 h,制得新的中间体N,N-二（3,4-二氟苯基）硫脲,后者在醋酐中加热分解得到1分子的目标物和1分子3,4-二氟苯基乙酰胺,副产物可以回收再使用。结果得到3,4-二氟苯基异硫氰酸酯,收率为40%。结论新工艺无需使用氯甲酸乙酯,避免了原工艺长时间的低温控制。     

3,6-二甲氧基-2,5-二氢吡嗪-2-羧酸乙酯的合成

用苄氧羰基氨基乙酸在N-甲基吗啉的催化下与氯甲酸异丁酯反应后,无需分离直接与氨基丙二酸二乙酯盐酸盐反应得到(2-苄氧羰基氨基乙酰胺基)丙二酸二乙酯,经Pd/C催化氢解、环合后在二氯甲烷中与Me3OBF4反应制得α-取代丝氨酸的合成中间体3,6-二甲氧基-2,5-二氢吡嗪-2-羧酸乙酯,总收率35.1%.     

氟哌酸中间体—3-氯-4-氟苯胺亚甲基丙二酸二乙酯的合成工艺改进

3-氯-4-氟苯胺在适当的Lewis酸存在下,与原甲酸三乙酯及丙二酸二乙酯缩合,一步制得了3-氯-4-氟苯胺亚甲基丙二酸二乙酯(Ⅲ),反应收率几乎为100％,本方法可在氟哌酸的生产巾完全代替乙氧_亚甲基丙二酸二乙酯工艺。     

3-氯-4-氟苯胺基亚甲丙二酸二乙酯制备的改进

3-氯-4-氟苯胺在 Lewis 酸存在下直接同原甲酸三乙酯、丙二酸二乙酯反应,除得到60～70%收率的主产物3-氯-4-氟苯胺基亚甲丙二酸二乙酯(1)外,还分离到三个产物,经 IR、MS、~1HNMR 及元素分析,证明其结构分别是甲脒3的盐酸盐、4和5。可用本法代替原用乙氧亚甲丙二酸二乙酯制备1的工艺。     

3-二氟甲氧基-2,4,5-三氟苯甲酸的合成

3-羟基-2,4,5-三氟苯甲酸酯化后在溴化四丁铵参与下与二氟氯甲烷进行醚化反应得到3-二氟甲氧基-2,4,5-三氟苯甲酸乙酯,再经水解得到氟喹诺酮类抗菌剂的中间体3-二氟甲氧基-2,4,5-三氟苯甲酸,总收率74%.     

硫酸二乙酯作乙基化剂制备-7氯-1-乙基-6-氟1,4-二氢-4-氧喹啉-3-羧酸的工艺改进

本文采用硫酸二乙酯与7-氯-6-氟-4-羟基喹啉-3-羧酸乙酯反应,然后用氢氧化钠液水解得7-氯-1-乙基-6-氟-1,4-二氢-4-氧喹啉-3-羧酸。其总收率为80％,此法降低了原料成本,简化了工艺,适合工业生产。     

罗氟司特中间体3-环丙基甲氧基-4-二氟甲氧基苯甲醛的合成

目的研究罗氟司特中间体的合成。方法 3,4-二羟基苯甲醛依次与Boc酸酐和氯甲基环丙烷反应后得3-环丙基甲氧基-4-O-Boc-苯甲醛,脱掉Boc后再与二氟一氯甲烷醚化制得罗氟司特中间体3-环丙基甲氧基-4-二氟甲氧基苯甲醛。结果总收率约62%。结论本合成路线操作简单,成本低,有利于大规模制备。     

罗氟司特的合成

3,4-二羟基苯甲醛与二氟一氯甲烷醚化得到3-羟基-4-二氟甲氧基苯甲醛,与氯甲基环丙烷醚化得到3-环丙基甲氧基-4-二氟甲氧基苯甲醛,再经氧化、氯代后与4-氨基-3,5-二氯吡啶反应,制得慢性阻塞性肺病治疗药罗氟司特,总收率约23％.     

2-(3-氰基-4-羟基)苯基-4-甲基-5-噻唑甲酸乙酯的合成

目的优化非布司他关键中间体2-(3-氰基-4-羟基)苯基-4-甲基-5-噻唑甲酸乙酯(4)的合成方法。方法采用"一勺烩"方法,以4-羟基苯甲腈为起始原料,首先与硫氢化钠和无水氯化镁在N,N-二甲基甲酰胺中反应,所得中间体不经分离,直接加入2-氯乙酰乙酸乙酯进行环合反应,得到2-(4-羟基)苯基-4-甲基-5-噻唑甲酸乙酯(2);然后通过六亚甲基四胺/三氟乙酸进行Duff反应,得到2-(3-甲酰基-4-羟基)苯基-4-甲基-5-噻唑甲酸乙酯(3);再经盐酸羟胺/甲酸/甲酸钠体系脱水得到目标化合物。结果经四步反应合成非布司他关键中间体4,总收率为22.6%,其结构经核磁共振氢谱、质谱确证。结论改进后的工艺终产品无需柱色谱纯化,适合工业化生产。     

利奈唑胺的合成

(S)-环氧氯丙烷(2)用叠氮钠开环得到(S)-1-叠氮基-3-氯-2-丙醇(3);另用3,4-二氟硝基苯(4)经与吗啉反应后以铁粉还原硝基,再与氯甲酸乙酯反应得到N-[3-氟-4- (4-吗啉基)苯基]氨基甲酸乙酯(7).3和7经环合反应制得(S)-3-[3-氟-4- (4-吗啉基)苯基]-5-叠氮甲基-1,3-噁唑烷-2-酮后,再经水合肼还原、氨基乙酰化得到抗菌剂利奈唑胺,总收率约40％(以4计).     

6-氨基-3,4-二氢-2(1H)-喹啉酮的合成

苯胺用3-氯丙酰氯酰化得到N-苯基-3-氯丙酰胺,在AlCl3作用下闭环得到3,4-二氢-2(1H)-喹啉酮后,经HNO3/H2SO4硝化、Pd-C/H2还原反应得到6-氨基-3,4-二氢-2(1H)-喹啉酮,总收率79%(按实际反应的苯胺计).     

法西多曲的合成

参照已知方法制得的2-乙氧羰基-3-(3,4-亚甲二氧基)苯基丙酸钾(6),用KBH_4/ZnCl_2选择性还原得2-羟甲基-3-(3,4-亚甲二氧基)苯基丙酸(7),再经葡辛胺拆分、双氯化得到的(R)-2-氯甲基-3-(3,4-亚甲二氧基)苯丙酰氯(8)与L-丙氨酸苄酯缩合后得N-[(2S)-2-氯甲基-3-(3,4-亚甲二氧基)苯丙酰基]-L-丙氨酸苄酯(9),与硫代乙酸钾反应得法西多曲,总收率约16%(以胡椒醛计)。其中2个中间体(8和9)为未见文献报道的新化合物。     

丁苯那嗪的合成工艺优化

5-甲基-2-己酮(2)、二甲胺盐酸盐和多聚甲醛在95%乙醇中反应得3-[(二甲胺基)甲基]-5-甲基-2-己酮(3),后处理时使用对甲苯磺酸一水合物与3的同分异构体1-二甲胺基-6-甲基庚烷-3-酮(6)成盐,将3中6的含量降低至3.73%。3和碘甲烷在乙酸乙酯中反应得(2-乙酰基-4-甲基戊基)三甲基碘化铵(4)。4和6,7-二甲氧基-3,4-二氢异喹啉盐酸盐(5)在碳酸钾作用下反应得丁苯那嗪(1)粗品,再经乙醇和甲醇重结晶得1纯品,纯度100%。该3步反应路线中每步的反应时间均缩短,总收率21%(以2计)。     

S-(-)-泮托拉唑钠的合成研究

目的改进S-(-)-泮托拉唑钠的合成方法。方法使用5-二氟甲氧基-[[(3,4-二甲氧基-2-吡啶基)甲基]硫基]-1 H-苯并咪唑与过氧化羟基异丙苯反应制得S-(-)-泮托拉唑,再与氢氧化钠反应合成产品S-(-)-泮托拉唑钠。结果与结论通过该法得到了目标产物S-(-)-泮托拉唑钠,且该法操作简单。     

Cardioselectivity of beta-adrenoceptor blocking agents 1. 1-[(4-Hydroxyphenethyl)amino]-3-(aryloxy)propan-2-ols.

A series of 1-[(4-hydroxyphenethyl)amino]-3-(aryloxy)propan-2-ols was synthesized together with several 1-[(3,4-dimethoxyphenethyl)amino]-3-(aryloxy)propan-2-ols. Their affinity to beta 1- and beta-2-adrenoceptors was determined and compared with the affinity of known beta-blockers. We were able to confirm the substantial cardioselectivity of 1-(3,4-dimethoxyphenethyl)-3-[(4-substituted aryl)oxy]propan-2-ols when compared to those with a 1-(4-hydroxyphenethyl) group. An increase in the size of the 4 substitutent of the 3-(aryloxy) moiety to caproamido leads to a substantially higher affinity for the beta 1--adrenoceptor of rat ventricular muscle in the presence of the 3,4-dimethoxyphenethyl than in the presence of the 4-hydroxyphenethyl or isopropyl group; this combination also gave the highest cardioselectivity.     

Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. II. Synthesis of new series of 1- or 2-substituted 4H-s-triazolo[3,4-c]-1,4-benzothiazines and related compounds with potential CNS activity

New series of 1- or 2-substituted 4H-s-triazolo[3,4-c]-1,4-benzothiazines have been prepared. The 1-substituted products were obtained starting from 3-hydrazino-2H-1,4-benzothiazine derivatives (III) by treatment with chloroacethyl chloride followed by cyclization of the resulting chloroacethylderivatives into the chloromethyltriazolobenzothiazines (IV a-e), which were then reacted with the appropriate amines to give the desired compounds (V a-n). Other 1-substituted compounds were prepared by ring closure of (III) with cyanogen bromide, affording 1-amino-4H-s-triazolo [3,4-c]-1,4-benzothiazines (XI a-e). The 2-substituted compounds (VIII) were prepared from 2,4-dihydro-1H-s-triazolo [3,4-c]-1,4-benzothiazin-1-ones (VII), synthesized from (I) by reaction with ethyl carbazate. The aminoalkyl side chain was introduced into (VII) in two steps: first by treatment with 1-bromo-3-chloropropane, then by refluxing the resulting product with the appropriate amine. Some 4H-tetrazolo[5,1-c]-1,4-benzothiazines (XII) were also synthesized from (III). Preliminary pharmacological data on the CNS activity of the synthesized tricyclic compounds are reported.     

Synthesis, X-ray structure, and pharmacological activity of some 6,6-disubstituted chromeno[4,3-b]- and chromeno- [3,4-c]-quinolines

Some chromeno[4,3-b]quinolines 4a-i were obtained from beta-chloro carboxyaldehydes 3a-c with different aniline derivatives namely, aniline, 4-fluoroaniline, and 2-aminophenol. Surprisingly, 3a-c reacted with 2-aminothiophenol and afforded the chromeno[3,4-c]quinoline derivatives 5a-c. Single-crystal X-ray diffraction studies of 4e and 5b provided good support for the established structure. Compounds 4b and 5b showed significant anti-inflammatory and ulcerogenic score activities compared to that of indomethacin.     

2-二乙胺基甲基咪唑的合成

咪唑和苯甲酰氯经酰化、成盐、催化氢化还原和水解反应制得咪唑-2-甲醛,再在硼氢化钠作用下,与二乙胺发生还原胺化反应制得2-二乙胺基甲基咪唑,总收率为40%。     

Pseudopolymorphism of NO-SPA, 1-(3,4-diethoxy-benzyl)-6,7-diethoxy-3,4-dihydro-isoquinoli ne hydrochloride]

The spasmolytic agent No-Spa, 1-(3,4-diethoxybenzyl)-6,7-diethoxy-3,4-dihydroisoquinoli ne hydrochloride (1) is a synthetic analogue of the naturally occurring alkaloid papaverine. (1) is prone to form stoichiometric crystalline solvates with a number of solvents causing technological and stability problem. Present paper describes the X-ray structure determination of the hemiethanol, hemibenzene and hemihydrochloride structures being the most important and interesting from both practical and theoretical point of view. The solvate formation is facilitated by the presence of the flexible ethoxy group encapsulating the solvent and by the quasi perpendicular position of the isoquinoline and phenyl group.