2-氯甲基-3，4-二甲氧基吡啶盐酸盐的制备

2-氯甲基 - 3,4-二甲氧基吡啶盐酸盐 (1 )是制备质子泵抑制剂泮托拉唑的重要中间体。文献 [1,2 ]以3-羟基 - 2 -甲基吡啶为起始原料 ,经氧化、硝化、醚化制得 6,再经乙酸化、水解、氯化制得 1。文献 [3] 报道以 3-甲氧基 - 2 -甲基 - 4-吡啶酮 (3)为起始原料 ,经氯化、氧化、醚化制得 6再制得 1。由于 3-羟基 - 2 -甲基吡啶没有国产品 ,而以国产麦芽酚 (2 -甲基 - 3-羟基 -γ-吡喃酮 ,2 )通过两步反应可制得 3。因此 ,参照文献[1～ 3] ,并对其工艺进行改进 ,制备了 1。文献[4 ] 报道3的制备是在 Ag2 O存在以下以 CH3I醚化 ,本文改用硫酸二…     

5—硝基香兰酸的合成

5-硝基香兰酸 ( 1 ) ,化学名 3-甲氧基 - 4-羟基 - 5-硝基苯甲酸 ,可用于 3,5-二取代儿茶酚类儿茶酚 -O-甲基转移酶 ( COMT)抑制剂的合成[1] ,或用于合成利福霉素类抗生素 ( 3-羟基利福霉素 ,3-羟基甲氧基利福霉素等 )生物合成时必要的前体物质 [2 ] 。以香兰素 ( 2 )为原料 ,主要有两种制备方法 :一是先氧化再硝化 ,收率分别为 92 .3%和 65% [3 ] ;也可先硝化再氧化制得 ,收率分别为 70 .0 4 %和 46.1 % [2 ] 。方法一中 ,氧化得到的香兰酸需在碱性条件下经 Na NO3硝化、酸化、水重结晶制得粗产物 ,以石油醚提取副产物 ,剩余物再经碱化…     

奥美拉唑产品中二种杂质的制备

为对奥美拉唑产品中的杂质进行定量控制,以2-巯基-5-甲氧基-IH-苯并咪唑和2-氯甲基-3,5-二甲基-4-甲氧基吡啶经缩合、氧化制得2个奥美拉唑杂质--5-甲氧基-2-[(4-甲氧基-3,5-二甲基吡啶-2-基)甲磺酰基]-1H-苯并咪唑和5-甲氧基-2-[(4-甲氧基-3,5-二甲基吡啶-2-基-1-氧化物)甲磺酰基]-1H-苯并咪唑,并经核磁共振和质谱确证结构.     

奥美拉唑杂质的合成

目的研究奥美拉唑杂质:2-[(5-甲氧基-1 H-苯并咪唑-2-亚磺酰基)甲基]-3,5-二甲基-4-羟基吡啶的合成方法。方法以2-氯甲基-4-甲氧基-3,5-二甲基吡啶盐酸盐(CMML)为原料,通过脱甲基、缩合、氧化三步反应制得2-[(5-甲氧基-1 H-苯并咪唑-2-亚磺酰基)甲基]-3,5]二甲基-4-羟基吡啶。结果合成的目标化合物经核磁共振氢谱、核磁共振碳谱及质谱确证。结论该合成通过三步得到目标化合物,收率约为23%。     

埃索美拉唑镁的合成

2-羟甲基-3,5-二甲基-4-硝基吡啶经氯化亚砜氯化后得2-氯甲基-3,5-二甲基-4-硝基吡啶盐酸盐(3),3与5-甲氧基-2-巯基苯并咪唑缩合得5-甲氧基-2[(3,5-二甲基-4-硝基-2-吡啶基)甲硫基]-1H苯并咪唑(4),4经不对称氧化得5-甲氧基-2-[[(3,5-二甲基-4-硝基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑(5),5再通过甲氧基化后得埃索美拉唑钠(6),最后6与氯化镁反应得埃索美拉唑镁,总收率约73.6％(以2-羟甲基-3,5-二甲基-4-硝基吡啶计).     

(2R,3S)-2-[(R)-1-[3,5-二(三氟甲基)苯基]乙氧基]-3-(4-氟苯基)吗啉盐酸盐的合成

对甲氧基苯甲醛(3)和2-氨基乙醇进行还原胺化反应得2-(4-甲氧基苄胺基)乙醇(4),4和乙醛酸经成环反应得2-羟基-4-对甲氧基苄基吗啉-3-酮(5),5和三氟乙酐反应得6后与(R)-1-[3,5-二(三氟甲基)苯基]乙醇(7)缩合,再经结晶诱导不对称转化、格氏反应、氢化脱保护及成盐反应制得阿瑞吡坦关键中间体(2R,3S)-2-[(R)-1-[3,5-二(三氟甲基)苯基]乙氧基]-3-(4-氟苯基)吗啉盐酸盐,总收率约18%(以3计)。     

多巴胺受体阻断剂左旋舒必利(Levosulpride)

本品为一多巴胺受体阻滞剂,临床上可用作镇吐剂、抗胃肠功能紊乱药、抗精神病药。合成左旋脯氨酸转化成相应的左旋乙酰脯氨酸后经还原、氯化、氨化得到左旋N-乙基-2-氨甲吡咯烷,再用2-甲氧基-5-氨磺酰苯甲酸酯处理得N-(1-乙基-2-吡咯甲烷)-2-甲氧基-5-氨磺酰苯甲胺而制得左     

多沙唑嗪、特拉唑嗪及哌唑嗪的高效合成

用4-氨基-2-氯-6,7-二甲氧基喹唑啉与无水哌嗪反应制得4-氨基-2-哌嗪基-6,7-二甲氧基喹唑啉(2).另用2-氯-4,6-二甲氧基-1,3,5-三嗪(3)和4-甲基吗啉(4)反应后加入相应的羧酸,制得的中间体7再与2反应分别制得多沙唑嗪(1a)、特拉唑嗪(1b)和哌唑嗪(1c),总收率分别为82.3％、88.0％和86.4％(以3计).     

盐酸多奈哌齐的合成

4-哌啶甲酸甲酯经N-苄基取代、KBH4/ZnCl2还原、Swern氧化得到1-苄基-4-哌啶甲醛(5);3-(3,4-二甲氧基苯基)丙烯酸经催化氢化、闭环生成5,6-二甲氧基-1-茚酮(8).5和8再经Aldol缩合、催化氢化、成盐制得盐酸多奈哌齐,总收率33%(以4-哌啶甲酸甲酯计).     

盐酸特拉唑嗪杂质的合成

目的为了加强对α受体阻滞剂类抗高血压药盐酸特拉唑嗪原料药的质量控制,合成了盐酸特拉唑嗪的3个特定杂质。方法以盐酸特拉唑嗪为原料,经重氮化、水解反应制得1-(4-羟基-6,7-二甲氧基-2-喹唑啉基)-4-[(四氢呋喃基)碳酰基]-哌嗪(杂质B);以盐酸特拉唑嗪为起始原料,经水解制得1-(4-氨基-6,7-二甲氧基-2-喹唑啉基)哌嗪二盐酸盐(杂质C);以2-氯-4-氨基-6,7-二甲氧基喹唑啉为起始原料,经N-取代反应制得1,4-二(4-氨基-6,7-二甲氧基-2-喹唑啉基)哌嗪二盐酸盐(杂质E)。结果与结论合成的3种杂质的结构经1H-NMR、MS确证,纯度相当或优于美国药典杂质对照品,可以作为盐酸特拉唑嗪原料药质量控制的杂质对照品。     

(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。     

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.     

Genotoxic Properties of (E)-5-(2-Bromovinyl)-2'-deoxyuridine (BVDU)

(E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) is a 5-substituted2'-deoxyuridine antiviral compound that inhibits thymidylatesynthetase. The selectivity of BVDU for virus-infected cellshas been attributed to phosphorylation of BVDU by a virus-inducedthymidine kinase. Since the closely related compounds 5-bromo-2'-deoxyuridineand 5-iodo-2'-deoxyuridine are in vitro and in vivo mutagens,BVDU was tested for genotoxic activity in bacterial and mammaliancell mutation assays as well as in assays measuring DNA damage/repairand clastogenic activity. Mutation assays with BVDU at concentrationsranging from 10 to 5000 µg/plate using Salmonella typhimuriumstrains TA1535, TA1537, TA1538, TA98, and TA100 were negative,both with and without S9 activation. BVDU was also negativein the in vitro rat hepatocyte unscheduled DNA synthesis assayat concentrations of 750 and 1000 µg/ml. In contrast,BVDU was positive in the L5178Y TK^± mouse lymphoma mutationassay without S9 activation at five concentrations ranging from500 to 2000 µg/ml. A Chinese hamster ovary cell (CHO)/hypoxanthineguanine phosphoribosyl transferase gene mutation assay conductedwithout S9 over similar concentrations was negative. However,micronucleus induction by BVDU was detected with out S9 activationat concentrations between 500 and 1750 µg/ml using bothCHO and L5178Y cells. These results indicate that BVDU is apotential human clastogen.