头孢拉宗的合成

4-乙基-2,3-二氧代哌嗪经三光气氯代、与D-苏氨酸缩合、甲酸氧化及草酰氯酰氯化制得2-[(4-乙基-2,3-二氧代-1-哌嗪基)甲酰胺基]-3-甲酰氧基丁酰氯(6),6再与7β-氨基-7α-甲氧基-3-(1-甲基-1H-四唑-5-基硫甲基)-8氧代-5-硫-1-氮杂二环[4.2.0]辛-2-烯-2-甲酸二苯甲酯(7-MAC)经缩合、脱二苯甲基保护基和脱甲酰基等反应得到抗菌剂头孢拉宗,总收率约5%.     

(6R,7R)-7-[2-呋喃基(甲氧亚氨基)乙酰氨基]-3-羟甲基-8-氧代-5-硫杂-1-氮杂二环[420]辛-2-烯-2-甲酸的合成研究

目的　制备(6R,7R) - 7-[2 -呋喃基(甲氧亚氨基)乙酰氨基] - 3-羟甲基- 8-氧代- 5 -硫杂- 1-氮杂二环[4 2 0]辛- 2 -烯- 2 -甲酸。方法　通过7-氨基头孢烷酸的水解,生成去乙酰基7-氨基头孢烷酸,再与2 - (2 -呋喃基)- 2 -甲氧亚胺基乙酸氯反应进行7位氨基的酰化制备上述医药中间体。结果及结论　适宜的反应条件为:7-氨基头孢烷酸在- 2 5℃水解,与2 - (2 -呋喃基) - 2 -甲氧亚胺基乙酰氯在- 10℃反应,二者的摩尔比为1 0∶1. 15,收率可达80 %。     

7β-叔丁氧羰基氨基-3-氯甲基-3-头孢烯-4-羧酸二苯甲酯的合成

7-ACA经水解、氨基保护得到的7β-叔丁氧羰基氨基-3-羟甲基-3-头孢烯-4-羧酸,与二苯基重氮甲烷反应保护羧基得7β-叔丁氧羰基氨基-3-羟甲基-3-头孢烯-4-羧酸二苯甲酯,最后经氯代制得硫酸头孢噻利等的中间体7β-叔丁氧羰基氨基-3-氯甲基-3-头孢烯-4-羧酸二苯甲酯,总收率约29%(以7-ACA计).     

7β-氨基-3-氯甲基-7α-甲氧基-1-氧代-3-头孢烯-4-羧酸二苯甲酯的合成路线图解

7β-氨基-3-氯甲基-7α-甲氧基-1-氧代-3-头孢烯-4-羧酸二苯甲酯（1）是合成拉氧头孢（1atamoxef）和氟氧头孢（flomoxef）等注射用头孢菌素的母核。从6-氨基青霉烷酸（6-APA，2）制取1的合成路线可归纳如下（图1）。     

注射用氧哌嗪青霉素钠

【化学名】 (2S,5R,6R)-6-{(R)-2-[(4-乙基-2,3-双氧代-1-哌嗪基)-甲酰胺]-2-苯乙酰胺}-3,3-二甲基-7-氧代-4-噻-1-氮杂二环-[3,2,0]庚烷-2-羧酸钠【结构式】     

头孢唑肟丙匹酯的合成

（6R，7R）-7-氨基-8-氧代-5-硫-1-氮杂二环[4．2．0]辛-2-烯-2-羧酸与（Z）-2-[[[（S）-2-（叔丁氧羰基）氨基-1-氧代丙基]氨基]-4-噻唑基]-2-甲氧亚氨基乙酸（2-巯基苯并噻唑）酯反应制得（6R，7R）-7-[[[2（S）-[（N-叔丁氧羰基-2-氨基-1-氧代丙基）-氨基]-4-噻唑基][（Z）-甲氧基亚氨基]乙酰基]氨基-8-氧代-5-硫-1-氮杂二环[4．2．0]辛-2-烯-2-羧酸，与特戊酸碘甲酯成酯后，再脱保护、成盐制得头孢唑肟丙匹酯单盐酸盐，总收率为72％。     

头孢泊肟酯的研究进展

头孢泊肟酯（CPDX-PR）是日本三共公司开发的第3代口服头孢菌素,1990年在日本首次上市。化学名为（6R,7R）-7-[（2Z）-（2-氨基-4-噻唑基）（甲氧亚氨基）乙酰胺基]-3-（甲氧基甲基）-8-氧代-5硫杂-1-氮杂二环[4．2．0]辛-2-烯2-羧酸1[[（1-甲基乙氧基）羰基]氧基]乙酯,     

比阿培南的合成

水合肼经缩合、烯丙基化、脱保护后甲酰化、溴加成、环合、取代、醇解、氧化、去甲酰化、环合、还原得到6，7-二氢-6-巯基-5H-吡唑并[1，2-a][1,2，4]三唑鎓氯化物（12），收率12％。12与（4R，5S，6S）-3-二苯氧磷酰氧基-6-[（1R）-1-羟乙基]-4-甲基-7-氧代-1-氮杂二环[3．2．0]庚-2-烯-2-羧酸对硝基苄酯（13）经缩合、脱保护得到比阿培南，收率67．5％（以13计）。     

莫西沙星8-二氟甲氧基类似物的合成与体内外抗菌作用

1-环丙基-6，7-二氟-8-甲氧基-1，4-二氢．4-氧代喹啉．3-羧酸乙酯依次经醚键断裂、酯化、二氟甲基醚化得1．环丙基-6，7-二氟-8-二氟甲氧基-1，4-二氢-4-氧代喹啉．3-羧酸乙酯，然后经过螫合、与[1S，6S]-2．叔丁氧羰基．2，8．二氮杂双环[4，3，0]壬烷缩合、最后脱除叔丁氧羰基保护得到1-环丙基．8．二氟甲氧基-7-[（1S，6S）．2，8．二氮杂双环[4，3，0]壬烷．8．基]-6-氟．1，4-二氢-4-氧代喹啉-3-羧酸。目标化合物的结构经核磁共振氢谱和质谱（ESI）所确证，并测定了其体内外抗菌作用，结果表明该化合物优于对照药环丙沙星，与莫西沙星相当或略优，尤其对肺炎链球菌29074的体内活性突出，值得深入评价。     

头孢米诺有关物质的合成及结构鉴定

在头孢米诺钠无菌粉质量研究中,通过HPLC-MS解析鉴定出一个新杂质,推测其结构为:(6R,7S)-7-[[[(2S)-2-氨基-2-羧乙基]硫基]乙酰胺基]-3-[[(1-甲基-1H-四唑-5-基)硫基]甲基]-7-甲硫基-8-氧代-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸钠.并以(6R,7S)-7-氨基-7-甲氧基-3-[[(1-甲基-1H-四唑-5-基)硫基]甲基]-8-氧代-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸二苯甲酯和甲硫醇为原料,经取代、酰化、脱保护及取代反应得到该杂质,经1H NMR和MS确证结构,而且与头孢米诺钠新杂质HPLC保留时间相同.     

The hypoglycemic effect of (7R*,9aS*)-7-phenyl-octahydroquinolizin-2-one in mice

(-)-Multiflorine (1), which was isolated from leguminous plants, produced a hypoglycemic effect when administered to mice with streptozotocin-induced diabetes. (-)-Multiflorine has an enaminone type conjugation on the A-ring, which is unusual in lupine alkaloids. Proceeding on the assumption that the A-B ring is responsible for the activity, several compounds bearing quinolizidin-2-one were synthesized and their hypoglycemic effects were examined. The hypoglycemic effect of (7R*,9aS*)-7-phenyl-octahydroquinolizin-2-one was approximately 4 times stronger than that of (-)-multiflorine measured by oral glucose tolerance test in normal mice. This result indicates that compounds possessing the quinolizidin-2-one ring system as the basic structure may be possible lead compounds for a new type of diabetes drug.     

The autoradiographic studies on the distribution of 14C-labeled pivaloyloxymethyl (+)-(6R,7R)- 7-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]- 3-[(5-methyl-2H-tetrazol-2-yl)methyl]-8-o xo-5-thia- 1-azabicyclo [4.2.0]oct-2-ene-2-carboxylate (14C-T-2588) in mice

The distribution of T-2588 was studied with whole body autoradiography in normal male mice and pregnant mice using two radioactive T-2588 labeled at the aminothiazole or pivaloyloxymethyl moieties. When (aminothiazole-2-14C) T-2588 was orally administered, the radioactivity was distributed widely to whole tissues except central nervous systems such as brain and spinal cord. In pregnant mice, no detectable radioactivity was present in the fetus. These results suggested that T-2588 was well absorbed and hardly crossed the blood-brain barrier and placenta. At 4 hours after administration, radioactivity was only observed in gastrointestinal tract implying rapid excretion of T-2588. When (pivaloyloxymethyl-14C) T-2588 was orally administered, radioactivity was accumulated to all tissues and fetus. From these results we speculated that formaldehyde formed by hydrolysis at the pivaloyloxymethyl ester and entered the C1-metabolic pathway.     

Studies on absorption, distribution and excretion of 14C labeled pivaloyloxymethyl (+)-(6R,7R)- 7-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]- 3-[(5-methyl-2H-tetrazol-2-yl)methyl]-8-oxo-5-thia- 1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (14C-T-2588) in rats and mice

Absorption, distribution and excretion of T-2588 were studied in rats and mice using (aminothiazole-2-14C) T-2588 and (pivaloyloxymethyl-14C) T-2588. Results are summarized below. The binding rate of 14C-T-2525, an activated form of 14C-T-2588 in vivo, to serum protein was 90 approximately 100% in rats and mice after an oral administration of (aminothiazole-2-14C) T-2588. Blood levels of radioactivity reached to the highest concentration at 1 hour after an oral administration of (aminothiazole-2-14C) T-2588 to rats, and then gradually diminished. After an oral administration of (aminothiazole-2-14C) T-2588 to rats and mice, the highest radioactivity distribution was found in kidney among all the organs except stomach, intestine and bladder. Radioactivity was widely distributed into other organs such as adrenal, lung, liver, heart and pancreas. But little radioactivity was found in the brain. In new born rats, tissue levels of radioactivity were lower and diminished slower than those of adult rats. After an oral administration of (aminothiazole-2-14C) T-2588 to rats and mice, urinary excretion of radioactivity was about 26% and 35% of the dosed radioactivity in rats and mice, respectively, and fecal excretion was about 76% and 63% of the dosed radioactivity in rats and mice, respectively. Urinary and fecal excretion patterns of radioactivity after multiple oral administration of (aminothiazole-2-14C) T-2588 for 7 days to mice were similar to those after a single administration. This result suggests that T-2588 did not accumulate in the body. After an oral administration of (pivaloyloxymethyl-14C) T-2588 to rats and mice, urinary excretion was both about 8% of the dosed radioactivity, and fecal excretion was both about 6%. Then excretion of 14CO2 into respiratory air was about 55% and 66% of the dosed radioactivity in rats and mice, respectively. Biliary excretion was about 6.5% of the dosed radioactivity after an oral administration of (aminothiazole-2-14C) T-2588 to rats. Small amount of radioactivity was secreted to the milk after intravenous administration of (aminothiazole-2-14C) T-2525 to nursing rats. After an administration of (aminothiazole-2-14C) T-2588 to pregnant mice, radioactivity hardly transferred into the fetus.     

Hepatobiliary Transport of a Nonpeptidic Endothelin Antagonist, (+)-(5S,6R, 7R)-2-Butyl-7-[2((2S)-2-Carboxypropyl)-4-Methoxyphenyl]-5-(3,4-Methylenedioxyphenyl) Cyclopentenol[1,2-b]Pyridine-6-Carboxylic Acid: Uptake by Isolated Rat Hepatocytes and Canalicular Membrane Vesicles

Purpose. Hepatobiliary excretions of drugs from the blood to the bile include two essential transmembrane processes: uptake into hepatocytes and secretion from hepatocytes. The purpose of this study was to clarify the transport mechanisms underlying these processes for a new non-peptide endothelin antagonist, (+)-(5S,6R,7R)-2-butyl-7-[2((2S)-2-carboxypropyl)-4-methoxyphenyl]-5-(3,4-methylenedioxy- phenyl)cyclopentenol[1,2-b]pyridine-6-carboxylic acid (J-104132). Methods. Biliary excretion of J-104132 was assessed in rats after intravenous injection. To evaluate the hepatic uptake process, J-104132 was incubated with freshly isolated rat hepatocytes and the uptake of J-104132 was calculated. To evaluate the biliary secretion process, the uptake of J-104132 into rat canalicular membrane vesicles that were isolated from normal Sprague-Dawley rats or Eisai hyperbilirubinemic rats was measured. Results. After intravenous injection, J-104132 was recovered from the bile quantitatively (99.7 ± 1.3%) as its intact form. J-104132 was taken up by isolated rat hepatocytes in a time- and temperature-dependent manner. The uptake was saturable with K _m and V _max of 5.7 M and 564 pmol/min/10⁶ cells, respectively. The uptake was Na⁺ independent and was reduced in the presence of ATP depleters (rotenone and carbonyl cyanide-p-(trifluoromethoxy)-phenylhydra- zone), organic anions (dibromosulfophthalein, indocyanine green, BQ-123, and pravastatin), and bile acids (taurecholate and cholate). In Sprague-Dawley rats, J-104132 was taken up by canalicular membrane vesicle ATP-dependently with K_m and V_max values of 6.1 M and 552 pmol/min/mg protein, respectively. However, ATP-dependent uptake disappeared in Eisai hyperbilirubinemic rats. Conclusions. These data suggest that energy-dependent and carrier-mediated transport systems play important roles in hepatobiliary excretion of J-104132 (both uptake and secretion processes), which is the main excretion route in rats. As for the secretion process of J-104132, an involvement of mrp2 was demonstrated.     

Pseudopolymorphism and phase stability in four solid forms of (6R,7R)-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxy- iminoacetamid]-3- [(4-carbamoyl-1-quinuclidinio)methyl]-8-oxo-5-thia-1-azabicyclo - [4,2,0]oct-2-ene-2-carboxylate (E1040)

(6R,7R)-7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxy- iminoacetamid]-3- [(4-carbamoyl-1-quinuclidinio)methyl]-8-oxo-5-thia-1-azabicyclo [4,2,0]oct-2-ene-2-carboxylate (1; E1040) was isolated as alpha-(decahydrate), beta-(pentahydrate), and gamma-form (anhydrate) crystals and the X-ray amorphous form. The relationship between the pseudopolymorphic crystal forms of this compound and water content was studied by X-ray diffractometry, coulometric moisture analysis, thermal analysis, and hygroscopic and vacuum-freeze-drying experiments. The phase transition of crystalline 1 clearly indicated the effect of water content on dehydration. During dehydration, hydrated alpha-form (decahydrate) crystals and beta-form (pentahydrate) crystals became anhydrate gamma-form crystals, with the diffraction angle shifting toward shorter spacing accompanied by line broadening. These results indicate conversion of hydrate 1 crystals to the anhydrous form and contraction of the crystal lattice. It was estimated that the decahydrate (alpha-form) crystals contain 8 mol/mol crystal water and 2 mol/mol adhesion water, and that the pentahydrate (beta-form) crystals contain 4 mol/mol crystal water and 1 mol/mol adhesion water. These estimates were made by comparing the data from equilibrium hydration experiments and vacuum-freeze-drying experiments. It thus follows that gamma-form crystals are anhydrate and the X-ray amorphous form exists in either the hydrous or anhydrous form.     

(2R,4R)-4-甲基-2-哌啶甲酸乙酯的合成工艺改进

目的 优化(2R,4R)-4-甲基-2-哌啶甲酸乙酯的合成工艺.方法 以S-(-)-α-甲基苄胺为原料,与乙醛酸乙酯反应得到[(S)-1-苯乙基亚胺基]乙酸乙酯,与异戊二烯进行环合后,再经不对称氢化和脱保护反应制得(2R,4R)-4-甲基-2-哌啶甲酸乙酯.结果 总收率从17.0％提高至47.6％.结论 本工艺可有效地降低生产成本.