WO2017190609A1 - 一种高效合成西他沙星中间体(7s)-5-氮杂螺[2.4]庚烷-7-基氨基甲酸叔丁酯的制备方法 - Google Patents
一种高效合成西他沙星中间体(7s)-5-氮杂螺[2.4]庚烷-7-基氨基甲酸叔丁酯的制备方法 Download PDFInfo
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- WO2017190609A1 WO2017190609A1 PCT/CN2017/081893 CN2017081893W WO2017190609A1 WO 2017190609 A1 WO2017190609 A1 WO 2017190609A1 CN 2017081893 W CN2017081893 W CN 2017081893W WO 2017190609 A1 WO2017190609 A1 WO 2017190609A1
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- azaspiro
- heptane
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- butyl ester
- statafloxacin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/54—Spiro-condensed
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the invention relates to a method for preparing a high-efficiency synthesis of statamycin intermediate (7S)-5-azaspiro[2.4]heptane-7-ylcarbamic acid tert-butyl ester.
- sitafloxacin hydrate The chemical name of sitafloxacin hydrate is 7-[(7S)-7-amino-5-azaspiro[2.4]hept-5-yl]-8-chloro-6-fluoro-1-[(1R) , 2S)-cis-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, a broad-spectrum quinolone developed by Daiichi Sankyo Co., Ltd.
- An antibacterial agent clinically used as a monohydrate, for the treatment of severely refractory infectious diseases. This product can be developed for oral administration or injection.
- the oral quinolone drug Gracevit (sitafloxacin, sitafloxacin) (I) has been marketed in Japan, the world's first market.
- the compensation price is set at 228 yen (2.17 US dollars) per 50 mg tablet, and 10 fine granules are 576 yen per package.
- This product has good pharmacokinetic properties and can alleviate adverse reactions. Its in vitro antibacterial activity is significantly enhanced compared with most similar drugs. This product not only significantly enhances the antibacterial activity against Gram-positive bacteria, but also has antibacterial activity against many clinically isolated fluoroquinolones-resistant strains.
- this product has broad-spectrum antibacterial effect, not only antibacterial activity against Gram-negative bacteria, but also Gram-positive bacteria (methicillin-resistant Staphylococcus aureus, methicillin-resistant epidermis grapes) Cocci), anaerobic bacteria (including Bacteroides fragilis), and mycoplasma and chlamydia have strong antibacterial activity, and have good bactericidal effects against many clinically common fluoroquinolone-resistant strains.
- This product is well absorbed orally, has a bioavailability of more than 70%, and has a wide distribution of tissues. The concentration of the drug in various tissues outside the central nervous system is higher than the serum drug concentration. Therefore, this product is expected to be a therapeutic respiratory tract and genitourinary tract.
- An important drug for single or mixed bacterial infections such as the abdominal cavity and soft tissues of the skin.
- the first method is to synthesize the racemate and then split to obtain a single configuration compound, which causes waste of another chiral compound.
- the second method uses dangerous chemicals cyanide or nitromethane, which brings great safety hazards in production and is inconvenient to enlarge (CN101544581A).
- the catalyst was used to directly obtain the chiral amine, but the reduction efficiency was not high, and the ee value was only 53% (JP2004099609A).
- the object of the present invention is to provide a process for the preparation of a high-efficiency synthesis of the intermediate salt of sitafloxacin (7S)-5-azaspiro[2.4]heptane-7-ylcarbamate.
- step 1) The ratio of use to acetic acid and potassium acetate is: 1 g: (3-5) mL: (1.25-1.5) g.
- the catalyst used in the Noyori hydrogenation reaction is Ru-BINAP.
- step 3 The mass ratio of HCl to the ethanol solution of hydrochloric acid was 1: (3.5-4).
- step 4 The mass ratio to benzylamine is 1: (0.15-0.2).
- step 5 The usage ratio of DPPA is 1: (1.5-2).
- the reducing agent used for the reduction is sodium borohydride or lithium aluminum hydride.
- the reducing agent used for the reduction is Pd/C.
- the invention can obtain a single compound with high ee value, avoids unnecessary waste of materials, significantly improves yield, is simple in operation, is easy to be industrially enlarged, and reduces production cost.
- FIG. 1 is a H NMR spectrum of Compound 3
- the synthetic route of the present invention is illustrated as follows:
- the ninth step is a first step.
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种高效合成西他沙星中间体(7S)-5-氮杂螺[2.4]庚烷-7-基氨基甲酸叔丁酯的制备方法,步骤:式(I)经过反应得到式(II);式(II)经过反应得到式(III);式(III)经过反应得到式(IV);式(IV)经过反应得到式(V)。本发明能得到ee值较高的单一化合物,避免了物料不必要的浪费,显著提高了收率,操作简单,易于工业放大,降低了生产成本。
Description
本发明涉及一种高效合成西他沙星中间体(7S)-5-氮杂螺[2.4]庚烷-7-基氨基甲酸叔丁酯的制备方法。
西他沙星(sitafloxacin hydrate)化学名为7-[(7S)-7-氨基-5-氮杂螺[2.4]庚-5-基]-8-氯-6-氟-1-[(1R,2S)-cis-2-氟环丙基]-1,4-二氢-4-氧代-3-喹啉羧酸,是第一制药三共株式会社(Daiichi Sankyo)开发的一广谱喹诺酮类抗菌药,临床用其一水合物,用于治疗严重难治性感染性疾病。本品可开发成口服给药也可注射给药。该口服喹诺酮药Gracevit(sitafloxacin,西他沙星)(I)已在世界第一个市场日本上市。补偿价定在每50mg片剂228日元(2.17美元),10细颗粒剂每包576日元。
本品具有良好的药代动力学特性,并可以减轻不良反应,其体外抗菌活性较大多数同类药物明显增强。本品不仅显著增强了对革兰阳性菌的抗菌活性,而且对临床分离的许多耐氟喹诺酮类的菌株也具有抗菌活性。关于本品体外抗菌活性的研究证明,本品具有广谱抗菌作用,不仅对革兰阴性菌有抗菌活性,而且对革兰阳性菌(耐甲氧西林金黄色葡萄球菌、耐甲氧西林表皮葡萄球菌)、厌氧菌(包括脆弱类杆菌)以及支原体、衣原体等具有较强的抗菌活性,对许多临床常见耐氟喹诺酮类菌株也具有良好杀菌作用。本品口服吸收好、生物利用率大于70%,组织分布广,在中枢神经系统外的多种组织中的药物浓度均高于血清药物浓度,因此,本品可望成为治疗呼吸道、泌尿生殖道、腹腔以及皮肤软组织等单一或混合细菌感染的重要药物。
(7S)-5-氮杂螺[2.4]庚烷-7-基氨基甲酸叔丁酯作为西他沙星的重要中间体,存在合成路线长,拆分困难等一系列难点,使得市场产能有限,价格高昂。
目前合成(7S)-5-氮杂螺[2.4]庚烷-7-基氨基甲酸叔丁酯的方法有如下几种:
方法一先合成消旋体,然后拆分得到单一构型化合物,这种方法造成了另一种手性化合物的浪费。
方法二则使用了危险品氰化物或硝基甲烷,在生产上带来了很大的安全隐患,不便进行放大(CN101544581A)。
方法三则使用了催化剂还原直接得到手性胺,但是还原效率不高,ee值只有53%(JP2004099609A)。
方法四用啤酒酵母还原得手性醇,然后做mitsunobu反应得到手性胺,这种方法还原体积效率低,放大困难(Chem.Pharm.Bull.1998,46,587)。
这些方法都有着不易放大的缺点,使得生产(7S)-5-氮杂螺[2.4]庚烷-7-基氨基甲酸叔丁酯的厂家非常少,价格及其昂贵,严重阻碍了其在有机化学和生物医药上的进一步应用和发展。因此开发一条可以安全放大的工艺路线将具有很大的实用价值。
发明内容
本发明的目的在于提供一种高效合成西他沙星中间体(7S)-5-氮杂螺[2.4]庚烷-7-基氨基甲酸叔丁酯的制备方法。
本发明所采取的技术方案是:
一种高效合成西他沙星中间体(7S)-5-氮杂螺[2.4]庚烷-7-基氨基甲酸叔丁酯的制备方法,包括以下步骤:
步骤2)中,Noyori氢化反应所用催化剂为Ru-BINAP。
步骤6)中,还原所用的还原剂为硼氢化钠或氢化铝锂。
步骤8)中,还原所用到的还原剂为Pd/C。
本发明的有益效果是:
本发明能得到ee值较高的单一化合物,避免了物料不必要的浪费,显著提高了收率,操作简单,易于工业放大,降低了生产成本。
图1为化合物3的HNMR图谱;
图2为化合物4的HNMR图谱;
图3为化合物5的HNMR图谱;
图4为化合物6的HNMR图谱;
图5为化合物9的HNMR图谱;
本发明的合成路线示意如下:
下面结合具体实施例对本发明做进一步的说明:
实施例1:
第一步:
13.0克乙酰乙酸乙酯加入到250mL反应瓶中,然后依次加入DMF 130mL,1,2-二溴乙烷37.6克,碳酸钾52.44克,搅拌,反应过夜,加入650mL水中,乙酸乙酯萃取,干燥,浓缩蒸馏得13.0克化合物1。
第二步:
13.0克化合物1加入到250mL三口瓶中,加入乙醇130mL,冰浴下滴加Br2 16.0克,滴加完毕后室温搅拌2小时,加入到400mL水中,分液,下层为产品层,浓缩得15.0克化合物2。
第三步:
15.0克化合物2加入250mL三口瓶中,加入50mL醋酸和18.8克醋酸钾,搅拌,体系加热至70摄氏度,过夜,冷却,体系加热到200mL水中,乙酸乙酯萃取三次,干燥,浓缩,
蒸馏得10.0克化合物3,HNMR图谱如图1所示。
第四步:
10.0克化合物3加热到250mL高压釜中,加入无水乙醇100mL,通氮气鼓泡10分钟,加入0.1克Ru-BINAP,继续鼓泡10分钟,拧上高压釜,氢气置换三次,压力0.5MPa,温度100摄氏度,反应过夜,浓缩干的10.0克化合物4(ee.98.6%),HNMR图谱如图2所示。
第五步:
10.0克化合物4加入到250mL三口瓶中,向其中加入10N HCl EtOH 100mL,加入回流,过夜,浓缩得8.0克化合物5(ee.98.5%),HNMR图谱如图3所示。
第六步:
8.0克化合物5加入到250mL三口瓶中,依次向其中加入27.0克碳酸铯,5.3克苄胺和100mL DMF,加热至100摄氏度,过夜,冷至室温,加入500mL水中,用乙酸乙酯萃取,干燥浓缩得3.0克化合物6(ee.98.5%),HNMR图谱如图4所示。
第七步:
3.0克化合物6加入到100mL三口瓶中,依次向其中加入40mL四氢呋喃,4.3克三苯基膦和4.6克DPPA,氮气保护,冰浴下滴加2.9克DEAD,滴加完毕后撤去冰浴,室温搅拌过夜,然后浓缩,柱纯化得2.0克化合物7(ee.98.4%)。
第八步:
2.0克四氢铝锂悬浮在40mL无水四氢呋喃中,冰浴下慢慢滴加5mL含有2.0克化合物7的四氢呋喃溶液,加热回流过夜,按标准程序淬灭反应,过滤,浓缩得1.0克化合物8(ee.98.2%)。
第九步:
1.0克化合物8加入到50mL单口瓶中,依次加入10mL乙醇,1.0克三乙胺和1.6克Boc2O,室温搅拌过夜,浓缩,加入乙酸乙酯,用柠檬酸水溶液洗涤,碳酸氢钠水溶液洗涤,饱和食盐水洗涤,干燥,浓缩得1.4克化合物9(ee.98.2%),,HNMR图谱如图5所示。
第十步:
1.4克化合物9,加入50mL单口瓶中,然后加入0.15克Pd/C和15mL乙醇,氢气置换三次,氢气氛围下室温搅拌过夜,过滤,浓缩得终产品0.9克(ee.98.3%)。
Claims (10)
- 根据权利要求1所述的一种高效合成西他沙星中间体(7S)-5-氮杂螺[2.4]庚烷-7-基氨基甲酸叔丁酯的制备方法,其特征在于:步骤2)中,Noyori氢化反应所用催化剂为Ru-BINAP。
- 根据权利要求3所述的一种高效合成西他沙星中间体(7S)-5-氮杂螺[2.4]庚烷-7-基氨基甲酸叔丁酯的制备方法,其特征在于:步骤6)中,还原所用的还原剂为硼氢化钠或氢化铝锂。
- 根据权利要求3所述的一种高效合成西他沙星中间体(7S)-5-氮杂螺[2.4]庚烷-7-基氨基甲酸叔丁酯的制备方法,其特征在于:步骤8)中,还原所用到的还原剂为Pd/C。
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WO2020203609A1 (ja) | 2019-03-29 | 2020-10-08 | 日本ケミファ株式会社 | 掻痒を治療するためのt型カルシウムチャネル阻害剤の使用 |
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CN105906545A (zh) | 2016-08-31 |
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US20180370914A1 (en) | 2018-12-27 |
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