匹伐他汀钙及其中间体非对映异构体的合成

目的：为控制匹伐他汀钙的质量,合成匹伐他汀钙及其中间体非对映异构体中的C-5位差向异构体。方法：以（3R,5S,6E）-7-[2-环丙基-4-(4-氟苯基)-3-喹啉基]-3,5-二羟基-3,5-O-亚异丙基庚-6-烯酸叔丁酯（2）为原料经脱缩酮、氧化、反立体选择性还原得（3R,5R,6E）-7-[2-环丙基-4-(4-氟苯基)-3-喹啉基]-3,5-二羟基-6-庚烯酸叔丁酯（5）。5水解成盐得（+）-双-[（3R,5R,6E）-7-[2-环丙基-4-（4-氟苯基）-3-喹啉基]-3,5-二羟基-6-烯庚酸]单钙盐（1）。5与2,2-二甲氧基丙烷形成缩酮得化合物（3R,5R,6E）-7-[2-环丙基-4-（4-氟苯基）-3-喹啉基]-3,5-二羟基-3,5-O-亚异丙基-6-庚烯酸叔丁酯（4）。结果与结论：合成了匹伐他汀钙及其中间体的C-5位差向异构体,并经核磁共振氢谱、碳谱、质谱和比旋光度等确证结构,3个目标化合物5、1和4的总收率分别为70%、68%和56%（以2计）,纯度经HPLC检测均在97.5%以上,可以作为匹伐他汀钙原料药质量控制的对照品。     

Diastereomeric and enantiomeric high-performance liquid chromatographic separation of synthetic anisodamine

In order to investigate the enantiomeric pharmacokinetics and biotransformation of synthetic anisodamine (654-2), a cholinoceptor antagonist widely used in clinic in China, it has been preparatively separated into two racemates (I and II) by using ZORBAX Eclipse XDB-C18 column. The diastereo- and/or enantioseparations of 654-2, I and II were carried out by HPLC using CHIRALPAK AD-H as chiral stationary phase (CSP) and acetonitrile-2-propanol-DEA 97:3:0.1 (v/v/v) as mobile phase. The methods were optimized by studying mobile phase modifiers, concentration of modifier and column temperature. The HPLC method for the simultaneous separation of two pairs of enantiomers of 654-2 has been validated.     

Development and validation of an HPLC-UV method for the separation of entecavir optical isomers

A simple and effective high-performance liquid chromatography with ultraviolet detection (HPLC-UV) method was established to determine entecavir optical isomers. With 3 chiral carbon atoms, entecavir had 7 optical isomers, including 6 diastereoisomers and 1 enantiomer. The separations were performed on a Symmetrix ODS-AQ C₁₈ column (4.6 mm×250 mm, 5 µm) and a Daicel CHIRALPAK AD column (4.6 mm×250 mm,10 µm), respectively. The detection wavelength was set at 254 nm.The limit of detection (LOD) and the limit of quantification (LOQ) of diastereoisomers (diastereoisomer-1, diastereoisomer-2, diastereoisomer-3) were 0.0371, 0.0376, 0.0377, and 0.124, 0.125, 0.126 µg/mL, respectively. The LOD and LOQ of enantiomer were 0.14 and 0.46 µg/mL, respectively. The precision was within 0.36%, 0.44%, 1.04%, and 0.67% for diastereoisomer-1, diastereoisomer-2, diastereoisomer-3, and enantiomer, respectively. The recoveries of enantiomers ranged from 98.4% to 100.5%. The method could be applied to control the quality of entecavir.     

Bronchoselective actions of a new series of trimetoquinol analogues

In selected beta 1- (guinea pig atrial) and beta 2- (guinea pig trachea and lung parenchyma) adrenoceptor systems, we have examined the interaction of isoproterenol (ISO), trimetoquinol (TMQ), erythro- and threo-diastereoisomers of 1-(3,4,5-trimethoxy-alpha-methylbenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (alpha-methylTMQ), alpha-dimethylTMQ, N-methylTMQ and N-[2-methyl-2-(3,4,5-trimethoxyphenyl)propyl]dopamine (open chain dimethylTMQ analogue). The rank order of potency for agonists in trachea was threo-alpha-methylTMQ greater than (+/-)-TMQ greater than ISO greater than erythro-alpha-methylTMQ greater than N-methylTMQ greater than alpha-dimethylTMQ. Only N-methylTMQ gave an intrinsic activity similar to ISO, whereas the alpha-methylated TMQ analogues were partial agonists in this beta 2-system. In atria, the rank order of beta 1-potency was ISO greater than (+/-)-TMQ greater than threo-alpha-methylTMQ greater than N-methylTMQ = erythro-alpha-methylTMQ. Maximal chronotropic effects of all compounds, with the exception of threo-alpha-methylTMQ, were similar to ISO in this preparation. Both alpha-dimethylTMQ and open chain dimethylTMQ analogues were inactive as agonists in this beta 1-system. The ratio of beta 2 : beta 1 selectivity (trachea vs. atria), relative to ISO for threo-alpha-methylTMQ, erythro-alpha-methylTMQ, TMQ and N-methylTMQ was 106.5, 27, 7 and 5.8, respectively. Whereas the rank order of potency for selected compounds in lung parenchyma was ISO greater than threo-alpha-methylTMQ = TMQ greater than erythro-alpha-methylTMQ, the comparative beta 2-selectivity (lung parenchyma vs. atria) relative to ISO, for erythro-alpha-methylTMQ, threo-alpha-methylTMQ and TMQ was 2.5, 1.9 and 0.24, respectively. It is concluded that lipophilic substitutions on the alpha-carbon of the 1-(3,4,5-trimethoxybenzyl)-substituent of TMQ can generate compounds which are potent bronchoselective adrenoceptor agonists. Threo-alpha-methylTMQ and erythro-alpha-methylTMQ were more beta 2-selective than (+/-)-TMQ.     

Impact of the simultaneous administration of the (+)- and (−)-forms of formyl-tetrahydrofolic acid on plasma and intracellular pharmacokinetics of (−)-tetrahydrofolic acid

Purpose: To detect possible interactions between (−)-formyl-tetrahydrofolic acid (leucovorin, (−)-fTHF) and (+)-formyl-tetrahydrofolic acid ((+)-fTHF) on the plasma and intracellular pharmacokinetics following their simultaneous administration. Methods: Plasma levels of (−)-fTHF, (−)-methyl-THF, and (+)-fTHF were determined in samples from four volunteers following the administration of both (−)-fTHF and (±)-fTHF and in seven patients during a 5-fluorouracil (5-FU)/fTHF combination chemotherapy. In addition, the intracellular uptake of ¹⁴C-(−)-mTHF in the presence of (+)-mTHF at increasing concentrations was measured in vitro. Analyses were performed using a highly specific high-performance liquid chromatography procedure. Results: The pharmacokinetic parameters obtained for (−)-fTHF following the administration of (−)-fTHF only were: terminal half-life, 1.2 h; area under the curve, 10 μg · h/ml; maximum concentration, 12 μg/ml; clearance, 305 ml/min; volume of distribution, 19 l. The parameters did not differ significantly as compared with those obtained following the administration of (±)-fTHF to both volunteers and patients. There were no differences in the pharmacokinetics of (−)-mTHF or in the protein binding of both substances with the different forms of administration. The intracellular uptake of ¹⁴C-(−)-mTHF did not depend on the presence of (+)-mTHF at either concentration. Conclusions: These data suggest that (−)-fTHF is not therapeutically superior to (±)-fTHF and that the latter is appropriate during combination chemotherapy with 5-FU/fTHF in patients with colorectal cancers. Received: 12 March 1999 / Accepted: 9 August 1999     

强效镇痛剂研究 Ⅶ.1-β-羟基-3-甲基芬太尼(7302)及有关化合物非对映异构体的合成及镇痛活性

本文报道N-[1-(β-羟基-β-苯乙基)-3-甲基-4-哌啶基]-N-丙酰苯胺(简称1-β-羟基-3-甲基芬太尼,编号7302)及N-[1-苯甲酰基甲基-3-甲基-4-哌啶基]-N-丙酰苯胺(7303)非对映异构体的合成及镇痛活性。初步结果表明(小鼠,ip,热板法),7302分子中三个手性中心的构型对镇痛活性影响都至关重要。顺-A-7302的强度为顺-B-7302的5.3倍,反-A-7302为反-B-7302的2倍左右。顺-A-7302为四个非对映异构体中作用最强者,为吗啡的6000多倍,为依托芬的3倍左右。