(S)-(+)-2-氨基丙醇的KBH4还原合成法

(S) - ( + ) - 2 -氨基丙醇 ( 1 )为合成左氟沙星的关键手性中间体。本刊曾发表用 Li Al H4 为还原剂 ,把L-氨基丙酸 ( 2 )直接还原制得 1的工艺 ,及用Na BH4 或 KBH4 的 BER树脂为还原剂还原 L-氨基丙酸乙酯盐酸盐 ( 3a)来制备 1的方法 [1～ 4 ]。文献 [5]也报道了用高沸点的乙二醇二甲醚为溶剂 ,把KBH4 和 Zn Cl2 制成 Zn( BH4 ) 2 还原剂 ,还原 3a制备 1来提高收率 ( 60 % )的还原方法。除文献[1] 外 ,其它文献均从 2的乙酯盐酸盐 ( 3a)用不同的还原剂还原制得 1。还原剂 Li Al H4 和 Na BH4 价格较昂贵 ,不宜采用。KBH4 的…     

Conformational analysis and structural comparisons of (1R,3S)-(+)- and (1S,3R)-(-)-tefludazine, (S)-(+)- and (R)-(-)-octoclothepin, and (+)-dexclamol in relation to dopamine receptor antagonism and amine-uptake inhibition

Conformational analysis with molecular mechanics (MM2(85] and molecular superimposition studies of (1R,3S)-(+)- and (1S,3R)-(-)-4-[3-(4-fluorophenyl)-6-(trifluoromethyl)indan-1-yl]-1- piperazineethanol (tefludazine) and (S)-(+)- and (R)-(-)-octoclothepin have been employed to identify biologically active conformations of these compounds with respect to dopamine receptor antagonism and amine-uptake inhibition. In contrast to what is commonly assumed, these studies indicate that the conformation of (S)-(+)-octoclothepin responsible for the dopamine receptor antagonism is different from the one observed in the crystal. From least-squares molecular superimpositions with the potent and stereoselective dopamine receptor antagonist (1R,3S)-tefludazine, biologically active conformations for the two compounds on the dopamine receptor have been deduced. This analysis also rationalizes the enantioselectivity of octoclothepin on the dopamine receptor. The X-ray structure of (S)-(+)-octoclothepin is shown to correspond structurally to the 1S,3R enantiomer of tefludazine, which is an amine-uptake inhibitor. This correspondence provides a structural basis for the norepinephrine (NE) uptake blocking properties of octoclothepin. It is predicted that the enantioselectivity of the NE-uptake inhibition of octoclothepin should be low with the S-(+) enantiomer as the more active optical isomer. A comparison of the deduced biologically active conformation of (S)-(+)-octoclothepin with (+)-dexclamol is also discussed on the basis of earlier derived superimposition studies with (+)-dexclamol.     

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.     

Anti-allergic effects of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole fumarate (KB-2413)

The effects of KB-2413 on four types of allergic reactions classified by Coombs and Gell were investigated. KB-2413 inhibited homologous passive cutaneous anaphylaxis and passive anaphylactic bronchoconstriction in guinea pigs mediated by IgE-like antibody, and ED50 values were 0.0017 mg/kg, p.o., and 0.022 mg/kg, p.o., respectively. KB-2413 also inhibited IgG-mediated anaphylactic bronchoconstriction in guinea pigs actively sensitized with egg albumin. Both complement-dependent immune hemolysis and complement-independent hypotonic hemolysis were inhibited by KB-2413 in a concentration-dependent manner. KB-2413 had no effect on the Forssman systemic reaction. The passive Arthus reaction in guinea pigs sensitized with anti-egg albumin rabbit serum was unaffected by KB-2413. However, the early stage of the active Arthus reaction in rabbits sensitized with egg albumin was inhibited. KB-2413 had an inhibitory effect on the efferent phase of delayed-type hypersensitivity induced by picryl chloride (PC-DTH) in mice. On the other hand, the afferent phase of PC-DTH in mice was unaffected. These results suggest that KB-2413 strongly suppresses type I allergic reactions, and it slightly suppresses type II, III and IV allergic reactions.     

艾他培南关键中间体的合成

目的改进艾他培南关键中间体(2S,4S)-4-乙酰硫-1-对硝基苄氧羰基-2-(3-烯丙氧羰基苯氨甲酰基)吡咯烷的合成工艺。方法以反-4-羟基-L-脯氨酸为原料经氨基、羧基保护;羟基甲磺酰化和乙酰硫化;脱去羧基保护基;与3-氨基苯甲酸烯丙酯缩合得目标物。结果与结论反-4-羟基-L-脯氨酸经6步反应制得目标物,总收率为49·4%,各步反应不需繁琐的柱色谱分离,操作简便,适合工业生产。     

(S)-(+)-2-甲基哌嗪的制备

（S）-（＋）-2-甲基哌嗪（1）是卡德沙星（caderofloxacin）等氟喹诺酮类药物的原料[1]。1可利用手性源合成,也可将外消旋体用扁桃酸、酒石酸或樟脑酸衍生物为拆分剂进行拆分得到。研究选择D-（-）-酒石酸为拆分剂在乙醇-水中进行拆分，得到1·D-（-）-酒石酸盐（2）后用碱游离出1（图1）.     

(S)-(+)-2,2-二甲基环丙烷甲酰胺的合成

甘氨酸乙酯盐酸盐经重氮化反应制得重氮乙酸乙酯,与异丁烯在自制的手性催化剂—(R,R)-(+)-2,2′-亚异丙基双(4-叔丁基-2-噁唑啉)与三氟甲磺酸亚铜的络合物催化下进行不对称环丙烷化反应,制得(S)-2,2-二甲基环丙烷甲酸乙酯,碱性条件下水解,再与氯化亚砜反应得酰氯后氨解制得(S)-(+)-2,2-二甲基环丙烷甲酰胺,总收率约27%。     

(S)-(+)-2-氨基丙醇合成工艺研究

对（Ｓ）－（＋）－２－氨基丙醇的合成工艺地研究。以Ｌ－氨基丙酸为起始原料,经缩合、化学还原丙步反应,制得本品,工艺简单、易操作,收率７２．７％。     

(S)-(+)-2-氨基丙醇的硼氢化钠法制备

(S) - ( ) - 2 -氨基丙醇 (1 )是合成左氧氟沙星的重要原料之一[1] ,作者曾报道用 Li Al H4 还原 L-丙氨酸 (2 )制备 1 [2 ] 。本刊曾发表用 KBH4 制成的 BER树脂来还原 2乙酯的制备法 [3 ] 。由于 Li Al H4 价格昂贵 ,致使 1的制备成本较高。为了降低成本 ,我们参考有关文献 [4 ,5] ,采用将 2酯化后 ,用价廉的 Na BH4来还原酯而得 1的合成路线 ,并对工艺进行了改进使其更简便 ,更有利于工业化生产。　　文献[4 ] 报道 ,2在 SOCl2 参与下与无水乙醇反应 ,得到丙氨酸乙酯盐酸盐 (3)的醇溶液 ,用乙醚稀释 ,过滤出固体产物 ,用 Et OH…     

(S)-(+)-2-氨基丙醇合成工艺改进

对(S)-(+)-2-氨基丙醇的合成工艺进行了改进。以L-丙氨酸为起始原料,经缩合、KBH_4还原两步反应,制得本品,工艺简单、易操作,收率82％。     

(S)-(+)-2-氨基丙醇合成工艺改进

对(S)-(+)-2-氨基丙醇的合成工艺进行了改进.以L-丙氨酸为起始原料,经缩合、KBH4还原两步反应,制得本品,工艺简单、易操作,收率82%.     

HPLC测定(S)-4-苯基-2-噁唑烷酮的纯度

目的采用HPLC法测定(S)-4-苯基-2-噁唑烷酮(SPO)的纯度。方法采用Welchrom C18色谱柱,流动相为0.02 mol·L-1磷酸二氢钾(KOH调p H5)-乙腈(60∶40),检测波长210 nm,流速1.0 m L·min-1,柱温35℃。结果 SPO0.3036~6.072μg·m L-1与峰面积的线性关系良好(r=0.9999),检测限和定量限分别为0.9099、3.033 ng。结论所用方法准确、灵敏、快速,适用于检测SPO中的微量杂质。     

(S)-(+)-氟比洛芬的合成

目的 采用新的方法合成非甾体抗炎镇痛药氟比洛芬并拆分得到S-异构体。方法 以国内价格较低廉的2-氟苯胺为起始原料,经1,3-二溴-5,5-二甲基海因溴代、与苯缩合、再与2-溴丙酸钠进行格氏反应,酸化后得到外消旋的氟比洛芬,再经葡辛胺拆分,得（S）-（＋）-氟比洛芬。结果 成功制备得到目标产物,其结构经mp,NMR等确证。结论 该制备方法具有工艺简单、得率高、试剂价格低廉等特点,适合于工业化生产。     

（S）—（＋）—2—氨基丙醇合成工艺改进

(S) - ( ) - 2 -氨基丙醇 (1 )是合成左氟沙星的重要原料之一 ,本刊曾发表以 L-丙氨酸乙酯为原料 ,由以 KBH4 制成的 BER树脂[1] 或 Na BH4 [2 ] 还原的制备方法。但酯化需用 SOCl2 与无水乙醇 ,生产成本较高 ,同时会产生 SO2 ,在环保上需要相应的后处理装置。我们采用工业 L -丙氨酸 (2 )与盐酸成盐 ,减压浓缩除去水份 ,剩余物用 95%的工业乙醇溶解 ,加入苯 -乙醇 (55∶ 45)的混合液回流酯化 ,利用苯 -水 -乙醇三元共沸除去水层。酯化完全后 ,蒸馏回收苯和乙醇。将得到的 L-丙氨酸乙酯盐酸盐 (3)的乙醇液冷却至 65°C,加无水 Na2 …     

(4S)-1-芴甲氧羰基-4-叠氮基-L-脯氨酸的合成

目的合成用于caspofungin类似物全合成的关键中间体--(4S)-1-芴甲氧羰基-4-叠氮基-L-脯氨酸.方法以(4R)-1-叔丁氧羰基-4-羟基-L-脯氨酸乙酯(2)为原料,经羟基甲磺酰化、叠氮基取代、酯水解、氨基脱叔丁氧羰基保护及9-芴甲氧羰基再保护合成了关键氨基酸中间体(4S)-1-芴甲氧羰基-4-叠氮基-L-脯氨酸,通过质谱(MS)和氢谱(1H-NMR)确证其结构.结果该工艺反应条件温和、操作简便、收率高,总收率达62.3%.     

Pharmacological differences between R(-)- and S(+)-ibuprofen

Ibuprofen (IBU) is a non-steroidal anti-inflammatory drug exhibiting optical isomerism. Only the racemate is in clinical use. In in vitro studies it has been demonstrated that only the S(+)-enantiomer inhibits the PG synthetase system. Nevertheless, it is widely believed that the sole use of the active isomer does not comprise any advantages since the inactive isomer is converted within the human body. In a triple cross-over study (300 mg S(+), 300 mg R(-), 600 mg racemic IBU; n = 8), we could show that the converted R(-)-IBU after racemate administration provides for only one third of the AUC of S(+)-IBU obtained after S(+)-application. Highest S(+)-peak plasma levels were reached after S(+)-IBU, lower ones after racemate. We, therefore, studied 4 patients with classical rheumatoid arthritis treated with 2-3 doses of 500 mg of S(+)-IBU/day over a two week period. Significant clinical recovery (Ritchie-index p less than 0.01; analogue scale pain p less than 0.05, motion p less than 0.01) was reached after one week. The results indicate that a reduction of dose and of metabolic load is possible if the S(+)-enantiomer is administrated.