N6-苯甲酰基-2'-叔丁基二甲基硅氧基腺苷-3'-H-膦酸的合成工艺研究

目的 研究N~6-苯甲酰基-2′-叔丁基二甲基硅氧基腺苷-3′-H-膦酸的合成工艺。方法 以腺苷为起始原料,先对腺苷的嘌呤氨基进行苯甲酰基保护,再分别向腺苷的5′位和2′位引入二甲氧基三苯甲基(DMT)和叔丁基二甲基硅基(TBDMS)保护基,制备得到关键中间体N~6-苯甲酰基-5′-二甲氧基三苯甲氧基-2′-叔丁基二甲基硅氧基腺苷(3)。中间体3与磷试剂2-氯-4H-1,3,2-苯并二氧磷杂环己烷-4-酮反应引入膦酸基团,最后使用二氯乙酸脱除DMT保护基得到目标产物。结果 经过5步反应得到了目标化合物N~6-苯甲酰基-2′-叔丁基二甲基硅氧基腺苷-3′-H-膦酸,并利用~1H-NMR、~(31)P-NMR、质谱等方法确证了其结构。本合成工艺的总收率为35.7%,目标化合物的质量分数为98.5%。结论 该合成工艺与原有方法相比步骤短,操作简单,具有良好的应用前景。     

瑞舒伐他汀钙合成的新工艺

目的研究一种新的瑞舒伐他汀钙合成工艺。方法以3-O-叔丁基二甲基硅基戊二酸酐为原料,经酰胺化、活性酯制备、Wittig反应、脱保护、还原、水解及成盐等8步反应合成瑞舒伐他汀钙。结果与结论关键中间体及目标化合物的结构经~1H-NMR、~(13)C-NMR和MS谱确证,总收率22.5%(以3-O-叔丁基二甲基硅基戊二酸酐计),HPLC纯度99.9%。该合成路线操作简单、原料廉价易得、反应条件温和、收率高,适合工业化生产。     

卡泊三醇的合成

(5E,7E,22E)-24-环丙基-1α,3β-双(叔丁基二甲基硅氧基)-9,10-开环胆甾-5,7,10(19),22-四烯-24-酮(2)经二氧化硫保护后,在手性助剂(1S,2R)-(-)-顺-1-氨基-2-茚满醇存在下,以N,N-二乙基苯胺-硼烷为还原剂进行立体选择性还原,然后脱二氧化硫保护得(5E,7E,22E,24S)-24-环丙基-1α,3β-双(叔丁基二甲基硅氧基)-9,10-开环胆甾-5,7,10(19),22-四烯-24-醇(5),5脱硅烷保护基后,经光异构化反应得卡泊三醇,总收率42%(以2计)。     

对羟基苯硼酸频哪醇酯的合成

用叔丁基二甲基氯硅烷保护对溴苯酚的酚羟基,制成Grignard试剂后与硼酸三甲酯反应制得对叔丁基二甲基硅氧基苯硼酸二甲酯,再与频哪醇进行酯交换反应后脱去保护基得到对羟基苯硼酸频哪醇酯,总收率28.2%.     

法罗培南钠的合成

（3R，4R）-4-乙酰氧基-3-[（1R）-（叔丁基二甲基硅氧基）乙基]氮杂环丁-2-酮与（R）-四氢呋喃-2-硫代羧酸经缩合、酰化、Wittig反应、脱保护、水解等反应制得青霉烯类抗生素法罗培南钠，总收率约37％。     

溴甲纳曲酮的合成

盐酸纳曲酮与乙二醇缩合、叔丁基二甲基氯硅烷保护,再与碘甲烷进行N-甲基化反应得(R)-3-[(叔丁基二甲基硅基)氧基]-17-环丙甲基-4,5a-环氧-14-羟基-6-(1,3-二氧戊烷-2-基)-N-甲基吗啡喃碘化物,再经氢溴酸水解、溴离子交换得溴甲纳曲酮,总收率53％,HPLC纯度大于99％.     

3-{[(叔丁基二甲基硅基)氧基]甲基}环丁烷-1-羧酸的合成工艺研究

目的研究3-{[(叔丁基二甲基硅基)氧基]甲基}环丁烷-1-羧酸的合成工艺路线。方法以3-亚甲基环丁基腈为起始原料,经过水解、还原、硅醚保护、硼氢化氧化、氧化等实验操作合成3-{[(叔丁基二甲基硅基)氧基]甲基}环丁烷-1-羧酸。结果合成了目标化合物,并利用NMR、HR-MS确证了结构。结论 3-{[(叔丁基二甲基硅基)氧基]甲基}环丁烷-1-羧酸合成工艺操作性好,条件温和,无需贵重试剂和柱色谱操作,适于工业化生产。     

新型1β-甲基碳青霉烯母核的合成

以(2R)-2-[(3S,4R)-3-[(1R)-1-叔丁基二甲基硅氧乙基]氮杂环丁-2-酮-4-基]丙酸为原料,研究了新型1β-甲基碳青霉烯母核的合成方法,总收率达到24%,本方法收率高,适合于大规模制备.     

青霉烯类抗生素法罗培南的合成工艺研究

目的：研究法罗培南（faropenem),(5R,6S)-6-[1(R)-羟乙基]-2-[2(R)-四氢呋喃]青霉烯－3－羧酸单钠盐的合成工艺。方法：以光学活性试剂（3R,4R）－3－（R）－1－叔丁基二甲基硅氧乙基－4－乙酰氧基氮杂环丁－2－酮为原料,经取代,缩合,金属有机化,诱导环化,水解等7步反应合成了目标化合物法罗培南。结果：在诱导环化反应中,加入对苯二酚,简化了操作。水解脱羟基保护基时,用稀盐酸代替了四正丁基氟化受,使产率增加,成本降低,结论：该合成工艺条件温和,操作简单,收率提高到35．2％。     

法罗培南的合成

以光学活性试剂（3R,4R）-3-（R）-1-叔丁基二甲基硅氧乙基-4-乙酰氧基氮杂环丁-2-酮为原料,经酰基取代、缩合、金属有机化、置换、三苯磷诱导环化、脱羟基和烯丙基保护等7步反应合成了具有4个手性中心的目标化合物法罗培南,总收率29.8%。     

A population pharmacokinetic/pharmacodynamic analysis of regadenoson, an adenosine A2A-receptor agonist, in healthy male volunteers

OBJECTIVES: The aims of this study were to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of regadenoson (CVT-3146) in healthy, male volunteers. METHODS: Thirty-six healthy, male volunteers aged 18-50 years were included in this randomised, double-blind, crossover, placebo-controlled study to evaluate single intravenous bolus doses of regadenoson that ranged from 0.1 to 30.0 micro g/kg. Subjects received one dose of regadenoson or placebo on successive days while supine, then the same dose of regadenoson or placebo on successive days while standing. As part of the safety evaluation, vital signs and adverse events were monitored and recorded throughout the course of the study in all subjects. Up to 20 plasma samples were collected for regadenoson concentration determination within the 24 hours after each supine dosage. All urine was collected during the 24-hour time period post-dose and an aliquot was used for the determination of the regadenoson concentration. Heart rate and blood pressure were recorded at many of the same timepoints that the samples for the pharmacokinetic analysis were taken. A non linear mixed-effect modelling approach, using the software NONMEM, was utilised in modelling the plasma and urine concentration-time profiles and temporal changes in heart rate after regadenoson administration in the supine position. The influences of several covariates, including bodyweight, body mass index and age, on pharmacokinetic model parameters were investigated. RESULTS: Adverse events were more prevalent at regadenoson doses above 3 micro g/kg, and the increase in the occurrence of adverse events was dose-related. Most of the adverse events were related to vasodilation and an increase in heart rate and were generally of mild to moderate severity. Based on the severity and frequency of adverse events, the maximum tolerated doses of regadenoson were deemed to be 10 micro g/kg in the standing position and 20 micro g/kg in the supine position. The pharmacokinetics of regadenoson were successfully described by a three-compartment model with linear clearance. Following intravenous bolus dose administration, regadenoson was rapidly distributed throughout the body, followed by relatively slower elimination (terminal elimination half-life of approximately 2 hours). The clearance was estimated to be 37.8 L/h, with renal excretion accounting for approximately 58% of the total elimination. The volume of distribution of the central compartment and the volume of distribution at steady state were estimated to be 11.5L and 78.7L, respectively. Individual pharmacokinetic parameter estimates were fixed in the pharmacodynamic model, where changes in heart rate were related to plasma drug concentrations using a Michaelis-Menten model. The maximum heart rate increase (Emax) and plasma regadenoson concentration causing a 50% increase in the maximum heart rate (EC50) were estimated to be 76 beats per minute and 12.3 ng/mL, respectively. None of the tested covariates was found to be correlated with any of the pharmacokinetic model parameters. CONCLUSIONS: The pharmacokinetics and the effects of regadenoson on heart rate were successfully described using pharmacokinetic/pharmacodynamic modelling. The lack of a correlation between the model estimates and various baseline patient demographics supports unit-based dose administration of regadenoson.     

Regadenoson pharmacokinetics and tolerability in subjects with impaired renal function

The authors have investigated the pharmacokinetics and tolerability of regadenoson, a selective A2A adenosine receptor agonist for use in drug-stressed myocardial perfusion imaging in subjects with varying degrees of renal function. Sixteen subjects with different creatinine clearance values (range: 15-132 mL/min) received a single intravenous bolus dose of 400 microg regadenoson. A population pharmacokinetic model was developed to describe the pharmacokinetics of regadenoson in these subjects. Regadenoson elimination half-life was prolonged with decreasing renal function. However, maximum plasma concentrations, number, or severity of adverse events did not differ significantly between the subjects. Heart rate increased in all subjects after regadenoson injection but returned to normal within 150 minutes. There were no blood pressure pattern differences with respect to renal function. Results from this study do not indicate that dose adjustments are necessary when subjects with decreased renal function are administered the clinically relevant dose of 400 microg regadenoson.     

米铂的合成工艺改进

本研究对米铂(1)的合成工艺进行了改进。十四烷酸(2)和氢氧化钠在乙酸乙酯/纯化水混合溶剂中反应,经静置析晶得十四烷酸钠(3)。3和奥沙利铂(4)在水中反应,经静置析晶、抽滤、热纯化水淋洗和精制后得1,纯度达99.91%,总收率79%(以2计),并且将1中3和草酸的含量均降至0.05%以下。优化后的工艺对原料2的质量要求降低:同系物十至十六烷酸单杂含量不超过0.2%,各杂质含量之和不超过1.0%即可得到合格产品,后处理简单,易于工业化生产。     

Caffeine attenuates the duration of coronary vasodilation and changes in hemodynamics induced by regadenoson (CVT-3146), a novel adenosine A2A receptor agonist

Effects of caffeine on regadenoson-induced coronary vasodilation and changes in hemodynamics were examined in conscious dogs. Sixteen dogs were chronically instrumented for measurements of coronary blood flow (CBF), mean arterial pressure (MAP), and heart rate (HR). Regadenoson (5 microg/kg, IV) increased CBF from 34 +/- 2 to 191 +/- 7 mL/min. The duration of the 2-fold increase in CBF was 515 +/- 71 seconds. Regadenoson decreased MAP by 15 +/- 2% and increased HR by 114 +/- 14%. Regadenoson-induced maximum increases in CBF were not significantly lower in the presence of caffeine at 1, 2, 4, and 10 mg/kg (2 +/- 3, 0.7 +/- 3, 16 +/- 5, and 13 +/- 8%, respectively; all P > 0.05). Caffeine at 1, 2, 4, and 10 mg/kg significantly decreased the duration of the 2-fold increase in CBF induced by regadenoson by 17% +/- 4%, 48% +/- 8%, 62% +/- 5%, and 82% +/- 5%, respectively (all P < 0.05). Caffeine at 4 and 10 mg/kg significantly attenuated the effects of regadenoson on MAP and HR. The results indicate that 1 to 10 mg/kg caffeine dose-dependently reduced the duration, but not the peak increase of CBF caused by 5 microg/kg regadenoson.     

3-乙酰硫基-2-甲基丙酰基-L-脯氨酸的结晶体拆分工艺改进

目的　提高D - 3-乙酰硫基 - 2 -甲基丙酰基 -L -脯氨酸的质量和收率。方法　考察了不同结晶工艺水添加量,溶液pH值,温度及搅拌速度对D - 3-乙酰硫基 - 2 -甲基丙酰基 -L -脯氨酸收率和质量的影响。结果　新工艺在产品质量和收率方面均优于老工艺。结论　新工艺操作简便易行,稳定性好。     

1-甲基-3-正丙基吡唑-5-甲酸乙酯的合成

目的：合成标题化合物,并进行工艺改进。方法：以2－戊酮和草酸二乙酯为原料,经三步反应合成了产物。结果：反应的总收率为47．7％。合成的各步产品经元素分析、红外和核磁共振光谱确证。结论：改进的工艺具有反应温度低、时间短等优点,并提高了收率。     

正交设计优化帕珠沙星Hofmann重排反应工艺

目的：优化帕珠沙星Hofmann重排反应的合成工艺。方法：按L9（3^4）正交表设计考察帕珠沙星Hofmann重排反应影响因素，并对反应时间（A）、反应温度（B）、次氯酸钠的浓度（C）、次氯酸钠的用量（D）4个主要因素进行优选，每个因素各取3个水平。结果：合成帕珠沙星的Hofmann重排反应最优反应条件为A1B1C2D2，收率可达70．5％。结论：最佳工艺参数简单易控制，提高了收率，适合工业化生产。     

6-氟-2-乙基-3-(3,5-二溴-4-羟基)苯甲酰基苯并呋喃的合成

目的优化6-氟-2-乙基-3-(3,5-二溴-4-羟基)苯甲酰基苯并呋喃的合成工艺。方法以4-氟水杨醛为起始原料,经环合、还原、在伊顿试剂中酰化、三氯化铝脱甲基、溴代得到目标化合物。结果经五步合成了目标产物,总收率为18.7%,目标化合物结构经1H-NMR和MS确证。结论改进后的工艺操作简单,条件温和,收率较高,更适合工业化生产。     

头孢唑林钠中间体TDA溶剂化物的工艺改进

对头孢唑林钠中间体TDA溶剂化物的工艺进行改进。将TDA进行真空干燥,提高反应温度,优化盐酸用量,反应过程采用气体保护,收率提高了2％,产品质量得到较大提高。     

左乙拉西坦的合成

目的：研究左乙拉西坦的合成方法。方法：采用后闭环路线，优化氨解反应的工艺条件。结果：该路线的反应条件温和，副反应少，产品质量得到提高，总收率达46％左右。结论：该工艺路线适合于工业化大规模生产。