环虫酰肼的合成

乙酰乙酸乙酯与甲醛缩合,然后脱羧得到2-甲基-4-氧-2-环己烯甲酸乙酯,在四乙基溴化铵催化下与1-溴-3-氯丙烷反应,得到5-甲基-7,8-2H-6-苯并二氢吡喃甲酸乙酯,再在硫粉的催化下脱氢得到5-甲基苯并二氢吡喃-6-甲酸乙酯,然后经水解、酰肼化得到关键中间体N-5-甲基苯并二氢吡喃-6-甲酰-N'-特丁基肼,最后与3,5-二甲基苯甲酰氯反应得到环虫酰肼,总收率23.3%。     

甲氧虫酰肼的合成

采用3-甲氧基-2-甲基苯甲酰氯与叔丁基肼反应生成单芳酰基特丁基肼中间体,再与3,5-二甲基苯甲酰氯反应制备甲氧虫酰肼。     

虫酰肼的合成

以叔丁基肼盐酸盐为起始原料,与对乙基苯甲酰氯反应合成N-(4-乙基苯甲酰基)-N'-叔丁基肼,反应收率97.9%。其再与3,5-二甲基苯甲酰氯反应合成虫酰肼,纯度大于96%,总收率大于86%。     

N,N'-双[β-(3,5-二叔丁基-4-羟基苯基)丙酰]肼的合成

N,N'-双[β-(3,5-二叔丁基-4-羟基苯基)丙酰]肼的制备先由β-(3,5-二叔丁基-4-羟基苯基)丙酸甲酯与水合肼按下列反应式合成β-(3,5-二叔丁基-4-羟基苯基)丙酰肼:     

GPR40激动剂的合成

以3-甲硫基丙醇(2)与对甲基苯磺酰氯(3)发生取代反应、氧化反应得3-(甲基磺酰基)丙基-4-甲基苯磺酸(5),再以间苯二酚(6)与4-氯乙酰乙酸乙酯(7)缩合成环、水解、成酯、氢化还原得6-羟基-苯并呋喃-3-乙酸甲酯(11),以4-溴-3,5-二甲基苯酚(12)与3-甲酰基苯硼酸(13)发生suzuki偶联得4'-羟基-2',6'-二甲基-[1,1'-联苯]-3-甲醛(14),再与(4)亲核取代、还原得3-(甲基磺酰基)丙基-4-甲基苯磺酸(16),(16)与(11)缩合,最终水解得到6-({2',6'-二甲基-4'-[3-(甲磺酰基)丙酰基]-联苯}甲氧基)-2,3-二氢苯并呋喃-3-乙酸(18)。     

(+)-5-氯-2,3-二氢-2-羟基-l-氧代-1H-茚-2-羧酸甲酯合成

采用以4-氯苯乙酰氯为起始原料,合成得到手性5-氯-2,3-二氢-2-羟基-1-氧-1H-茚-2-羧酸甲酯。实验重点研究了手性中间体5-氯-2,3-二氢-2-羟基-l-氧代-1 H-茚-2-羧酸甲酯不对称合成过程中氧化剂、催化剂、溶剂、温度等工艺条件对于ee值的影响,最终筛选出了最优的反应条件,收率达到64.15%,ee值达到92%。     

吲哒帕胺的合成研究

以4-氯-3-磺胺基苯甲酸和2,3-二氢-2-甲基-1H-吲哚为主要原料,经3步反应合成了降压药吲哒帕胺.4-氯-3-磺胺基苯甲酸与氯化亚砜反应得4-氯-3-磺胺基苯甲酰氯(Ⅰ),产率98.0%;2,3-二氢-2-甲基-1H-吲哚与亚硝酸反应得到N-亚硝基-2,3-二氢-2-甲基-1H-吲哚(Ⅱ),不用分离出Ⅱ,直接用钯/碳催化剂催化氢化得到N-氨基-2,3-二氢-2-甲基-1H-吲哚(Ⅲ),再进一步制成N-氨基-2,3-二氢-2-甲基-1H-吲哚盐酸盐(Ⅳ),产率92.0%;Ⅰ和Ⅳ反应得到目标产物吲哒帕胺(Ⅴ),产率92.5%,所得产品符合药典标准.     

艾氟康唑及其关键中间体合成工艺改进

为控制艾氟康唑及其中间体的合成产品质量,开发了以R-乳酸甲酯为原料,经吗啉胺化成4-[(R)-2-羟基丙酮基]吗啉,在羟基保护后与格氏试剂2,4-二氟苯基溴化镁反应得到(2R)-2',4'-二氟-2-(3,4,5,6-四氢-2H-吡喃-2-氧)-丙基苯基酮,之后采用"一锅法"得到化合物(2R,3R)-2-(2,4-二氟苯基)-1-(1H-1,2,4-三氮唑-1-基)-2,3-丁二醇,经甲磺酰化、成环氧、与4-亚甲基哌啶缩合,得产物艾氟康唑,HPLC纯度为99.5%,ee值为99.9%。     

1H-茚-3-酮-1-甲酸类化合物的合成研究

以3-氧代-2,3-二氢-1H-茚-1-甲酸类化合物为原料,经过液溴单溴代、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)脱溴化氢两步反应,合成2个1H-茚-3-酮-1-甲酸类化合物。并采用正交实验法,优化溴代反应的工艺条件,收率达97%,合成工艺具应用价值。     

2-(乙氧基甲基)-1H-茚-1-酮的合成

通过2,3-二氢-1H-茚-1-酮与原甲酸三乙酯反应,以78%的收率高效合成了化合物2-(乙氧基甲基)-1H-茚-1-酮。该化合物通过高分辨质谱(HRMS)以及核磁共振(1HNMR和13CNMR)进行了结构表征。     

新除草剂RZH-01-004的合成及除草活性

通过7-氯-5-氟4异氰酸酯基-2,2-二甲基-2,3-二氢-1-苯并呋喃和2-羟基-甲基-3-丁烯酸乙酯发生加成环化反应制得除草剂3-（7-氯-5-氟-2,2-二甲基-2,3-二氢-1-苯并呋喃-4-基）-5-（1-甲基亚乙基）-1,3-噁唑烷．2,4-二酮,收率70％,含量97.8％。产品结构用CIMS,HNMR进行了确定。室内生测结果表明,RZH-01-004苗后茎叶处理对大多数阔叶杂草有较高的除草活性。     

Bioconversion process for synthesis of tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate using liquid-core immobilized Saccharomyces cerevisiae CGMCC No 2233

Tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate was synthesized using asymmetric reduction of tert-butyl (S)-6-chloro-5-hydroxy-3-oxo-hexanoate with liquid-core immobilized Saccharomyces cerevisiae CGMCC No. 2233. The optimum conditions for preparation of the liquid-core immobilized cells were found to be 2% guar gum, 5% CaCl₂, 0.8% sodium alginate, capsule diameter 2mm, 0.3% chitosan (1.0×10⁵) solution, and 30 min for formation of the film of liquid-core immobilized cells. The optimum re-cultivation time was 32 h. The optimum reduction conditions were found to be pH 6.8–7.2, 160 r/min, and 30 °C. Conversion was found to reach 100% when initial concentration of substrate was less than 50 g/L. The diastereomeric excess of tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate exceeded 99%. The liquid-core immobilized cells retained their effectiveness even after 15 uses.     

沙奎那韦中间体合成工艺改进

治疗艾滋病的沙奎那韦的中间体———(3S,4 aS,8 aS)-2〔-(2R,3S)-3氨-基-2羟-基-4苯-基丁基〕-N-叔丁基-十氢异喹啉-3-羧酰胺(Ⅱ)是通过(2S,3S)-4氯--3羟-基-1苯-基丁烷-2氨-基甲酸苄酯(Ⅲ)和(3S,4 aS,8 aS)-N-叔丁基-十氢异喹啉-3-羧酰胺(Ⅴ)反应得到的。该文对工艺进行了如下改进:Ⅲ的环化和与Ⅴ的反应合并为“一锅煮”工艺,去除原有文献报道的柱层析过程,只需洗去氢氧化钾的分液操作,直接加入w(Pd)=10%的Pd/C催化剂,室温反应12 h即脱去保护基。反应完毕后,以乙腈重结晶即得到目标产物Ⅱ。改进后的工艺总产率达到87%,w(Ⅱ)=98.5%。该法原则上适用于多种H IV蛋白酶抑制剂的合成。     

Synthesis and bacteriostatic properties of acylarylureas and alkylarylureas

Fatty substituted ureas (RNHCONHR’) were prepared where R is an aliphatic acyl or alkyl group and R’ is a substituted phenyl group or a thiazole group. The benzene ring was generally substituted with chlorine, nitro, hydroxy, or a combination of these groups. The compounds were ineffective against gram-negative microorganisms but a number of samples inhibited the growth ofStaphylococcus aureus at 1 ppm. Bacteriostatic activity was generally observed where the acyl or alkyl group contained 6–10 carbon atoms and where R’ is 4-nitrophenyl, 4-chloro-3-nitrophenyl or a thiazole group derived from 2-amino-5-nitrothiazole. Scattered activity at 1 ppm was observed where R’ is 3-nitrophenyl, 2,4- and 3,5-dichlorophenyl, 2-hydroxy-5-chlorophenyl, 2-hydroxy-5-nitrophenyl, 3-nitro-4-hydroxyphenyl, 3,5-dinitrophenyl and 2-nitro-4-chlorophenyl. The alkylureas appear to be more active than the acylureas.     

4-苄基-2-[(R)-1-[3,5-二(三氟甲基)苯基]乙氧基]吗啉-3-酮的不对称转化的动态动力学拆分

以4-苄基-2-羟基吗啉-3-酮为原料,经两步反应制备得到一对非对映异构体4-苄基-2-[(R)-1-[3,5-二(三氟甲基)苯基]乙氧基]吗啉-3-酮,然后以叔丁醇钾为碱环境,利用不对称转化的动态动力学拆分,转化为手性纯(R)-4-苄基-2-[(R)-1-[3,5-二(三氟甲基)苯基]乙氧基]吗啉-3-酮。转化后手性产物与非对映异构体的比例为96∶4,在工业化制备神经激肽-1(NK-1)受体阻滞剂阿瑞吡坦过程中有较好的应用价值。     

Syntheses of deep coloured aminonaphthoquinonoid dyes. Reaction of dichloronaphthazarins with 2-aminobenzenethiol and related compounds

The reaction of 2,3-dichloronaphthazarin 1a with potassium 2-amino-benzenethiolate gives the ring-closure product 10,11-dithia-5H,16H-5, 16-diazadinaphtho[2,3a],[2,3c]-1,4-naphthoquinone 9 in 86.2% yield together with small amounts of 5-hydroxy-6-chloro-7-thia-12H-12-azanaphtho[2,3a]-1,4-naphthoquinone 8. Dye 9 is green in colour and absorbs infrared light at 727 nm. Oxidation of 9 by hydrogen peroxide gives 10,11-dithia-5H,16H-5,16-diazadinaphtho[2,3a],[2,3c]-1,4-naphtho-quinone-10,11-dioxide 14 which absorbs infrared light at 827nm. The reaction of 1a with 2-aminoethanethiol gives 5-hydroxy-6-chloro-7-thia-10-aza-8, 9,10-trihydrobenzo[2,3a]-1,4-naphthoquinone 4 and 2,3-di-chloro-5-hydroxy-7-thia-10-aza-8, 9,10-trihydrobenzo[2,3a]-1,4-naphtho-quinone 5 in yields of 14.2 % and 3.2 %, respectively.     

4-氨基-7-氯-5-氟-2,3-二氢-2-甲基苯并呋喃的合成研究

4-氨基-7-氯-5-氟-2,3-二氢-2-甲基苯并呋喃是合成除草剂的中间体。它通过以下途径制得:4-氯-2-氟-5-羟基-苯基氨基羧酸乙酯经醚化、水解、转位、闭环制得产品,总收率为21.7%,产品结构经核磁共振氢谱确认。     

Oxidation of the α-tocopherol model compound 2,2,5,7,8-pentamethyl-6-chromanol in the presence of alcohols

Oxidation of the vitamin E model compound, 2,2,5,7,8-pentamethyl-6-chromanol (1b) byt-butyl hydroperoxide in chloroform has been studied in the presence of ethanol, heptanol and cholesterol. In the absence of an alcohol, the major products were the spirodimer (13b) and spirotrimer (14b) of 1b, together with 1H,2,3-dihydro-3,3,5,6,9,10,11a(R)-heptamethyl-7a(S)-(3-hydroxy-3-methylbutyl)-pyrano[2,3-a] xanthene 8(7aH), 11(11aH) dione (6b). In the presence of ethanol, heptanol and cholesterol, the major products were 5-ethoxymethyl-2,2,7,8-tetramethyl-6-chromanol (16b), 5-heptoxymethyl-2,2,7,8-tetramethyl-6-chromanol (17) and 5-cholesteroxymethyl-2,2,7,8-tetramethyl-6-chromanol (18). However, when water was present in a homogeneous reaction, the most rapidly formed product was 2-(3-hydroxy-3-methylbutyl)-3,5,6-trimethyl-1,4-benzoquinone (5b). Compounds 13b, 14b, 16b, 17 and 18 are formedvia a quinone methide intermediate, and compound 5b is formedvia a phenoxylium ion. The phenoxylium species appears to be the preferred intermediate when water is present, whereas the quinone methide species is prefered in the absence of water.     

平行-连续法合成沙奎那韦

采用平行-连续法合成了H IV蛋白酶抑制剂沙奎那韦。在中间体(S)-4-氨基-4-氧代-2-(喹啉-2-羧酰胺基)丁酸的合成中,由喹哪啶-2-羧酸与亚硫酰氯反应得其酰氯作为活化剂,最佳反应条件为:回流8 h,收率95.0%;采用水介质合成了(S)-4-氨基-4-氧代-2-(喹啉-2-羧酰胺基)丁酸,收率82.0%。在硅胶存在下,(S)-1-〔(S)-2-环氧乙烷〕-2-苯基乙基氨基甲酸苄酯和(3S,4aS,8aS〕-N-叔丁基-十氢异喹啉-3-羧酰胺室温反应72 h,得(2S,3R)-4-〔(3S,4aS,8aS)-3-(叔丁氨甲酰基)-十氢异喹啉〕-3-羟基-1-苯基丁基-2-氨基甲酸苄酯,不经提纯,加入Pd/C〔w(Pd)=10%〕催化剂室温下与H2反应12 h脱去保护基,反应完毕后以乙腈重结晶即得另一中间体(3S,4aS,8aS)-2-〔(2R,3S)-3-氨基-2-羟基-4-苯基丁基〕-N-叔丁基-十氢异喹啉-3-羧酰胺,收率87.0%;两个中间体连接时,使用便宜、常见的N-羟基琥珀酰亚胺,收率82.0%。     

氯虫苯甲酰胺的合成

以顺丁烯二酸酐、2,3-二氯吡啶为起始原料经8步反应合成中间体3-溴-1-(3-氯吡啶-2-吡啶基)-1H-吡唑-5-甲酸(9);以2-氨基-3-甲基苯甲酸为原料经1步反应合成中间体5-氯-2-氨基-3-甲基苯甲酸(10).中间体9与10反应生成氯虫苯甲酰胺.目标化合物经1H NMR确证.反应总收率36.3%(以2,3-二氯吡啶计),产品含量(HPLC)不小于95%.