(3S)-3-(叔丁氧羰基氨基)-4-氧代丁酸甲酯的合成

L-门冬氨酸在氯化亚砜作用下选择性甲酯化生成L-门冬氨酸-4-甲酯盐酸盐,经二碳酸二叔丁酯保护氨基、与氯甲酸乙酯成混酐后经硼氢化钠还原得到(3S)-3-(叔丁氧羰基氨基)-4-羟基丁酸甲酯,最后经NaClO/TEMPO氧化得到西他列汀重要手性中间体(3S)-3-(叔丁氧羰基氨基)-4-氧代丁酸甲酯,总收率约41%。     

他汀类药物中间体(S)-4-氯-3-羟基丁酸乙酯生物催化合成的研究进展

(S)-4-氯-3-羟基丁酸乙酯[(S)-CHBE]是羟甲戊二酰辅酶A还原酶抑制剂即他汀类药物的关键手性中间体。本文综述生物催化合成(S)-CHBE的研究进展。     

(S)-3-羟基四氢呋喃的合成工艺优化

对(S)-3-羟基四氢呋喃(1)的产业化合成工艺进行了改进。在乙醇溶剂中，起始原料(S)-4-氯-3-羟基丁酸乙酯(2)经硼氢化钠还原得到(S)-4-氯-1,3-丁二醇(3)。反应完毕后，淬灭反应，过滤后蒸除溶剂，直接投入下一步反应，以水为溶剂加热环合，后处理采用连续萃取的方式，再经减压蒸馏分离、纯化得1，总收率76.2%，纯度99.8%,ee值大于99.8%。改进后的工艺成本低、生产过程安全，适合工业化生产。     

(R,S)-N-(1-乙氧羰基)-3-苯丙基-L-丙氨酸的合成

(S)-苹果酸经羟基保护并脱水得(S)-2-乙酰氧基丁二酸酐,经傅-克酰化反应、钯炭催化还原后成乙酯得(S)-2-羟基-4-苯丁酸乙酯,与三氟甲磺酸酐成酯后,与L-丙氨酸苄酯发生取代反应,最后氢化脱苄制得(R,S)-N-(1-乙氧羰基)-3-苯丙基-L-丙氨酸,总收率约30％.     

两步法合成(S)-1-(2-氯乙酰基)-2-腈基吡咯烷的工艺研究

目的 研究(S)-1-(2-氯乙酰基)-2-腈基吡咯烷的合成工艺.方法 L-脯氨酸与氯乙酰氯通过N-乙酰化得到(S)-1-(2-氯乙酰基)-2-吡咯烷甲酸,然后加入脲素和氨基磺酸实行分段保温反应得到产物(S)-1-(2-氯乙酰基)-2-腈基吡咯烷.结果 此路线所得产品收率为75.5％.结论 此工艺路线条件温和、操作简便、原料价廉易得.     

3-(S)-(1-氨甲酰基-1,1-二苯甲基)吡咯烷的合成

反式-4-羟基-L-脯氨酸经脱羧、N-Boc保护和氯代反应制得N-Boc-3-(S)-氯吡咯烷,在叔丁醇钾作用下与二苯乙腈缩合得N-Boc-3-(S)-(1-氰基-1,1-二苯甲基)毗咯烷,再经水解、脱保护、经L-(+)-酒石酸处理后碱化制得氢溴酸达非那新中间体3-(S)-(1-氨甲酰基-1,1-二苯基甲基)吡咯烷,总收率约14%.     

(S-2-乙氧基-3-(4-羟基苯基)丙酸乙酯的合成

L-酪氨酸经O-苄基化和重氮化反应制得（S）-2-羟基-3-（4-苄氧苯基）丙酸，再进行O-乙基化及乙酯化得到（S）-2-乙氧基-3-（4-苄氧苯基）丙酸乙酯，续经催化氢化脱苄基得到手性中间体（S）-2-乙氧基-3-（4-羟基苯基）丙酸乙酯，总收率19％，ee值98．5％。     

4-(1-羟基-1-甲基乙基)-2-丙基-1H-咪唑-5-羧酸乙酯的合成

2-甲基-2-羟基丙腈(2)经三甲基硅基(TMS)保护后,经Blaise反应并脱三甲基硅烷基保护,在亚硝酸钠和乙酸作用下肟化和Pd/C催化还原得到2-氨基-4-羟基-4-甲基-3-氧代戊酸乙酯三氟乙酸盐,再与丁酰亚氨酸甲酯盐酸盐环合得到奥美沙坦酯关键中间体4-(1-羟基-1-甲基乙基)-2-丙基-1H-咪唑-5-羧酸乙酯,总收率约40%。     

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。     

3-(S)-(-)-(1-氨甲酰基-1,1-二苯甲基)吡咯烷酒石酸盐的制备

以L-苹果酸(2)为原料,经与苄胺缩合、还原、氢解脱苄、磺酰化、烷基化、脱保护基、水解后成盐制得氢溴酸达非那新关键中间体3-(S)-(-)-(1-氨甲酰基-1,1-二苯甲基)吡咯烷酒石酸盐,总收率约22%(以2计).     

(R)-(-)-1-(2-萘基)-2-N-甲基氨基乙醇的合成

目的研究拟β-肾上腺素(R)-(-)-1-(2-萘基)-2-N-甲基氨基乙醇(1)的合成方法.方法以β-萘乙烯(2)为原料,通过烯烃的Sharpless不对称双羟化、环化、选择性开环、催化氢化、甲酰化、还原等6步反应制备目标产物.结果与结论设计的合成路线以β-萘乙烯计,6步反应总收率为39.3%,ee值高达97%～99%,合成路线易行.目标产物的结构经质谱、红外光谱、1H-NMR和13C-NMR确证.     

(S)-(-)-氨磺必利-D-(-)-酒石酸盐的合成

目的研究（S）-（-）-氨磺必利-D-（-）-酒石酸盐的制备方法。方法以4-氨基-2-甲氧基-5-巯基苯甲酸为原料,经乙基化、氧化得4-氨基-2-甲氧基-5-乙基磺酰基苯甲酸（4）,另由1-乙基-2-氨甲基吡咯烷经D-（-）-酒石酸拆分得S-（-）-1-乙基-2-氨甲基吡咯烷（6）,4与6缩合制得S-（-）-氨磺必利（7）,再与D-（-）-酒石酸成盐制得目标物S-（-）-氨磺必利-D-（-）-酒石酸盐（1）。总收率达25%（以4-氨基-2-甲氧基-5-巯基苯甲酸计算）。结果所得产物经元素分析,红外光谱、核磁共振谱及质谱确证了结构。结论本方法原料易得,反应条件温和,产品质量易控制。     

3-(R)-(碱基)-4-(S)-羟基-5-(R)-羟亚甲基四氢呋喃的合成及抗肿瘤活性

目的：研究一系列３（Ｒ）单脱氧异核苷的合成和抗肿瘤活性。方法和结果：由Ｌ木糖出发,合成了环氧化物５（Ｒ）二甲氧甲基３（Ｓ）,４（Ｓ）环氧四氢呋喃４;在碱性条件下,利用嘌呤的Ｎ９位或嘧啶的Ｎ１位对环氧化物进行亲核进攻,得到一系列３（Ｒ）单脱氧异核苷５ａｄ和６ａｄ;并进行了体外抗肿瘤活性筛选。结论：其中３（Ｒ）单脱氧异核苷５ａｄ为首次报道;同已报道的３（Ｓ）单脱氧异核苷合成方法相比,路线缩短,收率提高。在体外抗肿瘤和端粒酶抑制活性筛选中,只有化合物６ａ显示了对ＢＩＵ细胞较弱的抑制活性,其余均未显示有意义的抗肿瘤活性和端粒酶抑制活性。     

Synthesis of (R)-(-)- and (S)-(+)-4-fluorodeprenyl and (R)-(-)- and (S)-(+)-[N-11C-methyl]-4-fluorodeprenyl and positron emission tomography studies in baboon brain

(R)-(-)- and (S)-(+)-alpha-methyl-beta-4-(fluorophenyl)-N-methyl-N- propynylethylamine [R)-(-)- and (S)-(+)-4-fluorodeprenyl) were synthesized via the reaction of 4-fluorobenzaldehyde with nitroethane followed by reduction with lithium aluminum hydride to produce racemic 4-fluoroamphetamine, which was resolved by recrystallization with L- or D-N-acetylleucine to yield (R)-(-)-4-fluoroamphetamine or (S)-(+)-4-fluoroamphetamine in greater than 96% enantiomeric excesses and in yields of 42 and 39%, respectively. Alkylation with propargyl bromide gave (R)-(-)- or (S)-(+)-4-fluoronordeprenyl which was reductively methylated (Borch conditions) to produce (R)-(-)- or (S)-(+)-4-fluorodeprenyl. Alkylation of (R)-(-)- or (S)-(+)-4-fluoronordeprenyl with carbon-11 labeled methyl iodide gave (R)-(-)- or (S)-(+)-[N-11C-methyl]-4-fluorodeprenyl in a radiochemical yield of 30-40%. Comparative PET studies of the two labeled enantiomers in baboons showed a significantly lower retention of radioactivity in the striatum for the (S)-(+) enantiomer relative to the (R)-(-) enantiomer.     

2-(2-(3-(2-(7-氯-2-喹啉基)乙烯基)苯基)-3-氧代丙基)苯基丙醇的合成工艺

目的对2-(2-(3-(2-(7-氯-2-喹啉基)乙烯基)苯基-3-氧代丙基)苯基)丙醇的合成工艺进行研究。方法以间氰基苯甲醛和邻甲基苯乙酮分别作为起始原料,经过缩合、格氏反应、羟基保护、羟甲基反应、卤化反应,缩合得到最终目标产物。结果总收率为质量分数47.5%。结论该工艺原料易得,降低了制备成本、简化了反应操作条件、提高了产率,更适合工业化生产。     

左旋泮托拉唑钠的合成

5-二氟甲氧基-2-[[(3,4-二甲氧基-2-吡啶基)甲基]硫基]-1H-苯并咪唑在由D-(-)-酒石酸二乙酯-四异丙醇钛-水(2∶1∶0.5)制成的手性络合物和N,N-二异丙基乙胺(DIPEA)作用下,经过氧化羟基异丙苯不对称氧化,再用乙腈重结晶制得左旋泮托拉唑,在乙酸乙酯中经氢氧化钠溶液成盐后冷却析晶,即可制得高纯度左旋泮托拉唑钠,总收率约70%,纯度99.9%。     

Synthesis and antimicrobial activity of some 1-(2,4-dinitrophenyl)-3-(3-nitrophenyl)-5-(4-substituted phenyl)-4-bromo-2-pyrazolines and 1-(2,4-dinitrophenyl)-3-(3-nitrophenyl)-5-(4-substituted phenyl)-2-pyrazolin-4-ones

A series of 1-(2,4-dinitrophenyl)-3-(3-nitrophenyl)-5-(4-substituted phenyl)-2-pyrazolin-4-ones (4a-e) have been synthesized by the oxidation of 1-(2,4-dinitrophenyl)-3-(3-nitrophenyl)-5-(4-substituted phenyl)-4-bromo-2-pyrazolines (3a-e) with dimethylsulfoxide. The structure has been established on the basis of spectral data (IR,1H NMR). The synthesized compounds have been screened in vitro for their possible antimicrobial activity.     

Synthesis and antirhinovirus activity of 6-(dimethylamino)-2-(trifluoromethyl)-9-(substituted benzyl)-9H-purines

A series of 6-(dimethylamino)-2-(trifluoromethyl)-9-(substituted benzyl)purines was synthesized and tested for antirhinovirus activity. Most of the compounds were synthesized by alkylation of 6-chloro-2-(trifluoromethyl)-9H-purine with the appropriate benzyl halide followed by displacement of the chloro group with dimethylamine. Alternatively, 6-(dimethylamino)-2-(trifluoromethyl)purine was alkylated with the appropriate benzyl halide. Although several different aryl substituents provided compounds with IC50's = 0.03 microM against rhinovirus serotype 1B, no congener was significantly more active than the parent 2. Twenty-three compounds were tested against 18 other serotypes, but none exhibited a uniform profile of activity.     

8-chloro-(S)- and -(R)-10-((S)-and -(R)-3'-methylethylaminopyrrolidino)- 10,11-dihydrodibenzo(b,f)thiepins. Synthesis and pharmacological studies.

The synthesis for 8-chloro-(S)- and -(R)-10-[(S)- and -(R)-3'-methylethylaminopyrrolidino]-10,11-dihydrodibenzo[b,f]thiepins is presented. The absolute configuration at position 3' of the aminopyrrolidino side chain is known from synthesis and corresponds to the asymmetric carbon atom in (S)- or (R)-aspartic acid. The absolute configuration at C-10 of the dihydrodibenzo[b,f]thiepin ring system was deduced from ORD-CD analysis coupled with degradation of partially resolved (+)-8-chloro-10-amino-10,11-dihydrodibenzo[b,f]thiepin to (+)-(S)-1,2-diphenylethylamine. The four isomers were studied in mice for their ability to block conditioned avoidance responding, antagonize oxotremorine, and act as analgetics and anticonvulsants. These compounds were found to be nonselective antagonists of histamine, acetylcholine, and BaCl2 in vitro. The compounds exerted effects similar to those of chlorpromazine. Stereoselective differences in activity between diastereoisomers, rather than between enantiomorphs, were generally observed.