CN102617568B - Stable moxifloxacin hydrochloride compound and preparation method thereof - Google Patents

Stable moxifloxacin hydrochloride compound and preparation method thereof Download PDF

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CN102617568B
CN102617568B CN 201210056150 CN201210056150A CN102617568B CN 102617568 B CN102617568 B CN 102617568B CN 201210056150 CN201210056150 CN 201210056150 CN 201210056150 A CN201210056150 A CN 201210056150A CN 102617568 B CN102617568 B CN 102617568B
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严洁
王�华
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天津市汉康医药生物技术有限公司
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Abstract

本发明公开了一种盐酸莫西沙星化合物,本发明制备的盐酸莫西沙星化合物通过3-甲氧基-2,4,5-三氟苯腈进行Reformatsky反应化,得到3-甲氧基-2,4,5-三氟苯甲酰乙酸乙酯,经过烯胺化、胺交换、亲核取代、水解和螯合得到(8-甲氧基-1-环丙基-6,7-二氟-4-氧代-1,4-二氢喹啉-3-羧酸)二氟化硼,其进行亲核取代反应得到盐酸莫西沙星。 The present invention discloses one kind of hydrochloric acid compound moxifloxacin, moxifloxacin hydrochloride compound of the present invention prepared by reaction of 3-methoxy-2,4,5-fluorobenzonitrile of Reformatsky reaction carried out, to give 3-methoxy - 2,4,5-trifluoro-benzoyl acetate, after amination of alkylene, amine exchange, nucleophilic substitution, hydrolysis and the chelating give (8-methoxy-1-cyclopropyl-6,7- fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid) boron difluoride, subjected to a nucleophilic substitution reaction to obtain moxifloxacin hydrochloride. 本发明的有益效果是操作简便,各步中间体纯度都很高。 Advantageous effect of the invention is easy to operate, each of the intermediate steps are high purity. 本发明的方法使反应进行的充分,副反应少,且容易纯化。 The method of the present invention is that the reaction to proceed sufficiently, less side effects, and is readily purified. 本发明减少了反应步骤,易于实现工业化生产。 The present invention reduces reaction steps, is easy to realize industrial production.

Description

一种稳定的盐酸莫西沙星化合物、其制备方法 A stabilized moxifloxacin hydrochloride compounds, methods for their preparation

技术领域 FIELD

[0001] 本发明涉及医药领域中的药品,尤其是涉及一种稳定性好的盐酸莫西沙星化合物、其制备方法。 [0001] The present invention relates to the field of pharmaceutical drug, particularly good in stability relates to Moxifloxacin hydrochloride star compounds, methods for their preparation.

背景技术 Background technique

[0002] 随着抗菌剂的广泛使用甚至滥用,细菌耐药性逐年增加,耐药性细菌感染不仅严重危害人类健康,而且已成为世界范围的棘手问题。 [0002] With the widespread use of antimicrobial agents and even abuse, bacterial resistance increases every year, not only drug-resistant bacterial infections serious harm to human health, but also has become a thorny problem worldwide. 据报道,在美国住院患者中每年发生院内感染约200万例,其中约9万例死亡。 It is reported that nosocomial infections in hospitalized patients in the United States each year about 2 million cases, of which about 90,000 cases of death. 70%以上的院内获得性感染已经对临床上常用的抗菌药物产生耐药,因此,加快研发能够有效对付革兰阳性菌特别是耐甲氧西林金葡菌(MRSA)所致重度感染以及耐药性递增的革兰阴性菌(铜绿假单胞菌和鲍氏不动杆菌等)引起的院内感染的口服抗菌药已迫在眉睫。 More than 70% of hospital-acquired infections have been resistant to commonly used antibiotics clinically, therefore, possible to accelerate the development of effective against Gram-positive bacteria especially methicillin-resistant Staphylococcus aureus (MRSA) and drug-induced severe infection of increasing gram-negative bacteria (Pseudomonas aeruginosa and Acinetobacter baumannii, etc.) caused by nosocomial infections oral antibiotics is imminent.

[0003] 2006年初,美国感染病协会(IDSA)公布了对人类健康威胁最大的6种耐药性致病菌,其中MRSA高居榜首,以下依次为大肠埃希菌、克雷伯菌属、鲍氏不动杆菌、耐万古霉素屎肠球菌和铜绿假单胞菌。 [0003] In early 2006, the Infectious Diseases Society of America (IDSA) announced the largest of six kinds of pathogenic bacteria resistant to human health threats, MRSA topped the list, the following were Escherichia coli, Klebsiella, abalone baumannii, vancomycin-resistant Enterococcus and Pseudomonas aeruginosa feces. 60%以上的院内肺炎是由革兰阴性菌引起的。 More than 60% of nosocomial pneumonia is caused by Gram-negative bacteria. 据统计,2002-2003年度临床分离的肺炎克雷伯菌对甲氧亚氨基-β —内酰胺类抗生素(第三代头孢菌素)的耐药率高达47%。 According to statistics in 2002 - Annual 2003 clinical isolates of Klebsiella pneumoniae methoxyimino -β - resistance rates lactam antibiotics (third generation cephalosporin) of up to 47%. 由不动杆菌属引起的院内获得性肺炎的比率不断增大,且死亡率高达20% -50%,而由铜绿假单胞菌弓丨起的院内获得性肺炎的发生率已从1975年的 The ratio obtained from the genus Acinetobacter nosocomial pneumonia caused increasing, and the mortality rate as high as 20% -50%, while the bow Shu played Pseudomonas aeruginosa hospital-acquired pneumonia incidence rate from 1975

9.6%提高至2003年的18.1%,增长近I倍。 9.6% increase to 18.1% in 2003, an increase of nearly I fold.

[0004] 细菌感染是许多疾病常见的并发症,是威胁危重病患者生命的主要因素之一。 [0004] Bacterial infection is a common complication of many diseases, is one of the main factors threatening the life of critically ill patients. 危重病患者由于长期住院,病情危重,抵抗力低,对抗菌药的耐药性强,病情反复发作易感染等原因造成。 Due to long-term critically ill patients hospitalized in critical condition, low resistance, resistance to antibiotics is strong, resulting in recurrent disease susceptible to infection and other reasons. 危重病患者的下呼吸道感染在综合性重症ICU (S ICU )是一个相当突出的问题,据国内资料统计约占所有感染的50%以上,这主要与I⑶的患者大多病情危重、许多人需要建立人工气道和进行机械通气有关。 Lower respiratory tract infections in critically ill patients in general intensive ICU (S ICU) is a very prominent issue, according to national statistics account for about 50% of all infections, mainly in patients with I⑶ mostly in critical condition, many people need to build artificial airway and mechanically ventilated related.

[0005] 由于耐甲氧西林金黄色葡萄球菌、耐甲氧西林表皮葡萄球菌的医院感染发生率不断上升以及耐药率的迅速增加,已成为医院感染的危险因素。 [0005] Since the methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis hospital infection rates rising and the rapid increase in resistance rates, has become a risk factor for nosocomial infection. 有资料表明,尽管抗生素的开发使用大量增加,但葡萄球菌的耐药率却越来越广,它与抗生素使用的种类、剂量、疗程及医院的规模成为正比关系。 Some data indicate that, despite a significant increase in the development of the use of antibiotics, but staphylococci rate is increasingly wide scale and it kind of antibiotic use, dosage, treatment and hospital becomes proportional relationship.

[0006] 盐酸莫西沙星是第四代广谱8-甲氧基氟喹诺酮类抗菌药,是近年来临床应用比较广泛的抗菌药物,也是一类较新的合成抗菌药。 [0006] Moxifloxacin hydrochloride is the fourth generation of a broad spectrum of 8-methoxy-fluoroquinolone antibiotics, in recent years widespread clinical application of antibiotics, is a relatively new class of synthetic antibacterial agents. 盐酸莫西沙星能直接对抗肺炎链球菌(最常引起RTIs)、流感嗜血杆菌和卡他莫拉菌。 Moxifloxacin hydrochloride directly against S. pneumoniae (the most common cause RTIs), Haemophilus influenzae and Moraxella catarrhalis. 与目前所用的氟喳诺酮类不同。 Connaught fluorine chirp currently used in different ketones.

[0007] 盐酸莫西沙星可增强抗少见G—菌的活性,包括金黄色葡萄球菌、非典型病原体如支原体、衣原体及军团菌。 [0007] Moxifloxacin hydrochloride can enhance the activity of anti-G- rare bacteria, including Staphylococcus aureus, atypical pathogens such as Mycoplasma, Legionella and Chlamydia. 此外,对β_内酰胺类和大环内酯类已耐药的细菌也有效。 Further, the effective β_ amides and macrolide resistant bacteria have. 原研公司强调,盐酸莫西沙星可杀灭细菌,作用迅速,具有浓度依赖性,不像大环内酯类仅对细菌起抑制生长作用。 Stressed originator, moxifloxacin hydrochloride can kill bacteria, the role of rapid, concentration-dependent, not only macrolides from inhibition of growth of bacteria.

[0008] 盐酸莫西沙星服用方便,每日用药一次即可奏效,因而具有良好的耐受性。 [0008] moxifloxacin hydrochloride easy to take daily medication once worked, which has a good tolerability. 此药无光毒性和肝毒性,与其它喹诺酮类相同,其最明显的副作用为恶心、腹泻。 Matt drug toxicity and liver toxicity, the same as with other quinolones, its most significant side effects were nausea, diarrhea. [0009] 盐酸莫西沙星的另一优点是,比其它喹诺酮类药物产生的耐药性程度要低得多。 Another advantage of [0009] Moxifloxacin hydrochloride is the degree of resistance than other quinolones produced much lower. 不过,要使用适当的剂量以及正确的服药次数和间隔时间。 However, to use appropriate doses of medication and the correct number of times and intervals. 例如,针对适应证,口服400mg, qd,连用5-10 天。 For example, for the indications oral 400mg, qd, once every 5-10 days.

[0010] 通用名:盐酸莫西沙星; [0010] Generic name: Moxifloxacin hydrochloride;

[0011]英文名:Moxifloxacin Hydrochloride ; [0011] English name: Moxifloxacin Hydrochloride;

[0012]化学名:1-环丙基-7-{(5,5)-2,8-重氮-二环[4.3.0]壬 _8_ 基} _6_ 氟_8_ 甲氧-1,4- 二氢-4-氧-3-喹啉羧酸氢氯化物; [0012] Chemical name: 1-cyclopropyl-7 - {(5,5) -2,8-diazo - bicyclo [4.3.0] non-yl} _6_ _8_ methoxy-1,4-difluoro-_8_ - dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride;

[0013] 结构式为: [0013] of the formula:

Figure CN102617568BD00051

[0015]分子式=C21H24FN3O4.HCl [0015] Molecular Formula = C21H24FN3O4.HCl

[0016]分子量:436.9 [0016] Molecular weight: 436.9

[0017] 理化性质:淡黄色至黄色结晶性粉末,略溶于水和甲醇,微溶于乙醇,几乎不溶于丙酮。 [0017] Properties: pale yellow to yellow crystalline powder, slightly soluble in water and methanol, slightly soluble in ethanol, practically insoluble in acetone.

[0018] 药理类型:盐酸莫西沙星是具有广谱活性和杀菌作用的8 -甲氧基氟喹诺酮类抗菌药。 [0018] Pharmacology Type: moxifloxacin hydrochloride is a broad spectrum of activity and bactericidal effect of 8 - methoxy fluoroquinolone antibiotics. 盐酸莫西沙星在体外显示出对革兰阳性菌、革兰阴性菌、厌氧菌、抗酸菌和非典型微生物如支原体、衣原体和军团菌具有广谱抗菌活性。 Exhibits moxifloxacin hydrochloride in vitro against Gram-positive bacteria, Gram-negative bacteria, anaerobic bacteria, atypical acid-fast bacteria and microorganisms such as mycoplasma, chlamydia, and legionella with broad-spectrum antibacterial activity.

[0019] 作用机制:杀菌作用机制为干扰拓扑异构酶II和IV。 [0019] Mechanism: Mechanism of bactericidal action of topoisomerase II and interference IV. 拓扑异构酶是控制DNA拓扑和在DNA复制、修复和转录中关键的酶。 Topoisomerase repair and transcription is a key enzyme in the replication control DNA topology and DNA,. 盐酸莫西沙星表现为浓度依赖性的杀菌活性。 Moxifloxacin hydrochloride showed concentration-dependent bactericidal activity. 最低杀菌浓度和最低抑菌浓度基本一致。 Basically the same minimum inhibitory concentration and minimum bactericidal concentration. 盐酸莫西沙星对β —内酰胺类和大环内酯类耐药的细菌亦有效。 Moxifloxacin hydrochloride of β - lactam and also effective macrolide-resistant bacteria. 通过感染的实验动物模型证实,盐酸莫西沙星体内活性高。 Experimental animal models of infection confirmed high moxifloxacin hydrochloride in vivo activity.

[0020] 适应证:盐酸莫西沙星的适应症为治疗患有上呼吸道和下呼吸道感染的成人18岁),如:急性窦炎,慢性支气管炎急性发作、社区获得性肺炎,以及皮肤和软组织感染。 [0020] Indications: moxifloxacin hydrochloride is indicated for the treatment of patients with upper respiratory tract and lower respiratory tract infections in adults 18 years of age), such as: acute sinusitis, acute exacerbation of chronic bronchitis, community-acquired pneumonia, and skin and soft tissue infection.

[0021] 用法用量:剂量范围:任何适应症均推荐一次400mg(l片),一日I次。 [0021] Dosage: Dose Range: any of the indications are the recommended time 400mg (l tablet), I-th day. 成年人服用方法:片剂用一杯水送下,服用时间不受饮食影响。 Adults: Take a tablet with a glass of water sent to the next, taking time from eating affected. 治疗时间:治疗时间应根据症状的严重程度或临床反应决定。 Treatment time: treatment time should be determined according to the severity of the symptoms or clinical response. 治疗上呼吸道和下呼吸道。 The treatment of respiratory and lower respiratory tract.

[0022] 感染时可按照下列方法:慢性气管炎急性发作:5天;社区获得性肺炎:10天;急性窦炎-J天;治疗皮肤和软组织感染的推荐治疗时间为7天;盐酸莫西沙星400mg片剂在临床试验中最多用过14天疗程。 [0022] When the infection in the following ways: acute exacerbation of chronic bronchitis: 5 days; community-acquired pneumonia: 10 days; acute sinusitis -J days; treatment of skin and soft tissue infections of the recommended treatment for 7 days; moxifloxacin hydrochloride Star 400mg tablets used in clinical trials for up to 14-day course.

[0023] 老年人不必调整用药剂量,儿童和青少年禁用;肝功能损伤的患者不必调整盐酸莫西沙星的剂量。 [0023] do not have to adjust the dosage elderly, children and disabled young people; in patients with liver dysfunction do not have to adjust the dose of moxifloxacin hydrochloride. 任何程度的肾功能受损的病人均不必调整盐酸莫西沙星的剂量(包括肌酐清除率≥30ml/min/l.73m2)。 Any degree of renal impairment patients were having to adjust the dose of moxifloxacin hydrochloride (including creatinine clearance ≥30ml / min / l.73m2). 目前缺乏透析病人的药代动力学数据。 The current lack of dialysis patients pharmacokinetic data. 不同种族间不必调整药物剂量。 Between different races do not have to adjust the dose.

[0024] 盐酸莫西沙星片由拜耳公司1999年12月在美国FDA上市,而后2001年盐酸莫西沙星注射液在美国上市。 [0024] moxifloxacin hydrochloride tablets marketed by Bayer AG in December 1999. FDA in the United States, then in 2001 moxifloxacin hydrochloride injection in the United States. 2002年,盐酸莫西沙星片经SFDA批准进口并在中国上市,商品名拜复乐' 目前SFDA未批准国内厂家生产。 In 2002, imports of moxifloxacin hydrochloride tablets approved by SFDA in China and marketed under the trade name thanks to complex music 'is currently not approved SFDA domestic manufacturers.

[0025] 已知莫西沙星的合成方法如下: [0025] Moxifloxacin known synthetic methods are as follows:

[0026] 专利US4997943在合成关键中间体化合物6中,以3_甲氧基_2,4,5_三氟苯腈为 [0026] Patent US4997943 key intermediate in the synthesis of compound 6, to three 3_ methoxy-fluorobenzonitrile as _2,4,5_

起始原料,经8步反应得到化合物6,其合成路线如下。 Starting material, was obtained from compound 8 by 6, which scheme is as follows.

[0027] [0027]

Figure CN102617568BD00061

[0028] 该法优点是原料易得但是其路线较长,总收率不高且要使用毒性较大的二氯亚砜和乙酸酐做反应试剂。 [0028] An advantage of this method is a readily available raw material, but its long route, the total yield is not high toxicity and to use thionyl chloride and acetic anhydride to make a reagent.

[0029] 专利US2003008894在合成关键中间体化合物6中,以3_甲氧基_2,4,5_三氟苯甲酸为起始原料,经6步反应得到化合物6,其合成路线如下。 [0029] Patent US2003008894 key intermediate compounds in the synthesis of 6 to 3_ methoxy _2,4,5_ trifluoroacetic acid as a starting material, was obtained from compound 6 by 6, which scheme is as follows.

[0030] [0030]

Figure CN102617568BD00062

[0031] 该法优点是原料易得,但是其路线较长,总收率不高,且第二步需在_10°C下进行,增加了操作难度。 [0031] An advantage of this method is a readily available raw material, but the route is long, the total yield is not high, and the need for a second step at _10 ° C, increasing the difficulty of the operation.

[0032] 专利US4997943在合成关键中间体化合物6中,以2,3_ 二氟_5_硝基苯酚为原料,经5步反应得化合物6,合成路线如下。 [0032] Patent US4997943 key intermediate in the synthesis of compound 6, to _5_ 2,3_-difluoro-nitrophenol as starting material, by reaction of the compound 5 Step 6, the following synthetic route.

[0033] [0033]

Figure CN102617568BD00071

[0034] 该法优点是反应路线短,但起始原料不易得,反应过程中需使用剧毒的碘甲烷和无水乙醇。 [0034] An advantage of this method is the short reaction scheme, the starting material but not easy, during the reaction of the need to use highly toxic methyl iodide and ethanol.

[0035] 专利US855292在合成关键中间体化合物6中,以3_甲氧基_2,4,5_三氟硝基苯 [0035] Patent US855292 key intermediate compounds in the synthesis of 6 to 3_ methoxy _2,4,5_ Trifluoronitrobenzene

为起始原料,经4步反应得化合物6,合成路线如下。 As a starting material, by reaction of the compound 4-step 6, the following synthetic route.

[0036] [0036]

Figure CN102617568BD00072

[0037] 该法优点是反应路线较短,反应条件温和,但反应时间过长,反应起始物不易得,且使用无水溶剂。 [0037] An advantage of this method is a shorter reaction scheme, mild reaction conditions, but the reaction time is too long, the reaction was not easy starting and using anhydrous solvents.

[0038] 专利US4855292,US5639886, CN1212256在合成关键中间体化合物6中,采用下面 [0038] Patent US4855292, US5639886, CN1212256 key intermediate in the synthesis of Compound 6, using the following

这条路线。 This route.

[0039] [0039]

Figure CN102617568BD00073

[0040] 该法优点是反应路线较短,但是其采用了有毒的二氯亚砜和有机碱做反应试剂。 [0040] An advantage of this method is the reaction route is shorter, but it uses a toxic thionyl chloride and an organic base reagents do.

[0041] 在合成盐酸西他沙星中,专利CN101941969采用化合物6与化合物8在有机碱存在下进行亲核取代反应,此方法直接简单,但反应中生成性质相近的杂质,难以分离,影响了莫西沙星的收率和纯度。 [0041] In the synthesis of cetirizine hydrochloride He gatifloxacin in Patent CN101941969 using compound 6 and compound 8 nucleophile in the presence of an organic base substitution reaction, this method is straightforward, but produced in the reaction similar nature of the impurities, is difficult to separate, the influence of the moxifloxacin yield and purity.

[0042] 专利W02008059521将化合物6的羧酸转换成酰胺,然后与化合物8反应,在依次用氢氧化钠和盐酸处理,得到莫西沙星;此法使用了强致癌物物质DCC和昂贵的DBU,不利于工业化生产。 [0042] Patent W02008059521 Compound 6 is converted into a carboxylic acid amide, and then reacted with compound 8, treated sequentially with sodium hydroxide and hydrochloric acid to give moxifloxacin; this method uses the highly carcinogenic substance DCC and expensive DBU, It is not conducive to industrial production. [0043] 专利W0200500970采用三氟化硼的乙醚溶液与化合物6形成螯合物,然后与化合 [0043] Patent No. W0200500970 using boron trifluoride diethyl ether solution with a chelate forming compound 6, and then compound

物8反应,后处理得到莫西沙星。 8 was reaction, after-treatment to obtain moxifloxacin. 此法有大量的强腐蚀性的氟化氢生成,给生成带来了不便。 This method has a large number of highly corrosive hydrogen fluoride generation to generation inconvenience.

[0044] 专利W02005012285,W02008059223采用硼酸、酸酐与化合物6形成螯合物,然后与化合物8反应,接着用无机碱和无机酸处理,得到莫西沙星。 [0044] Patent W02005012285, W02008059223 use boric acid, acid anhydride and forming a chelate compound 6, and then reacted with compound 8, followed by a mineral acid and an inorganic base to give moxifloxacin. 专利CN101973992,EP1832587分别采用加入氯化锌和三甲基硅化物对其进行了改进。 Patent CN101973992, EP1832587 respectively added zinc chloride and trimethyl silicide thereof is improved. 但是其采用收率不高和操作繁琐,且使用较毒的硼酸和酸酐作为反应试剂。 But which employs the operation is complicated and the yield is not high, and the use of more toxic and acid anhydride as a reactant. CNlO 1830921用苯硼酸直接与化合物6形成螯合物,虽然简化了操作,但其成本高,不利于工业化生产。 CNlO 1830921 phenylboronic acid forming a chelate compound 6 directly, while simplifying the operation, but its high cost, is not suitable for industrial production.

[0045] 本发明人经过长期研究,制得盐酸莫西沙星化合物,操作简便,各步中间体纯度都很高。 Al. [0045] The present inventors have long studied to prepare a moxifloxacin hydrochloride compound, easy to operate, each of the intermediate steps are high purity. 本发明的方法使反应进行的充分,副反应少,且容易纯化。 The method of the present invention is that the reaction to proceed sufficiently, less side effects, and is readily purified. 本发明减少了反应步骤,易于实现工业化生产。 The present invention reduces reaction steps, is easy to realize industrial production.

发明内容 SUMMARY

[0046] 本发明的目的是提供一种合成盐酸莫西沙星的方法,以克服现有技术存在的上述缺陷。 Objective [0046] The present invention is to provide a method for the synthesis of moxifloxacin hydrochloride, to overcome the above drawbacks of the prior art.

[0047] 本发明的方法,包括如下步骤: [0047] The method of the present invention, comprising the steps of:

[0048] 反应方程式: [0048] Scheme:

[0049] [0049]

Figure CN102617568BD00081

[0050] 1、化合物2 , 3-甲氧基-2,4,5_三氟苯腈进行Reformatsky反应化得到化合物 [0050] 1, Compound 2, three-fluorophenyl 3-methoxy--2,4,5_ nitrile Reformatsky reaction to give a compound of

3 ; 3;

[0051] 2、化合物3,3-甲氧基_2,4,5-三氟苯甲酰乙酸乙酯与N,N-二甲基甲酰胺二甲缩醒反应得到化合物4 ; [0051] 2, the compound 3,3-trifluoro-methoxy-benzoyl acetate _2,4,5- N, N- dimethylformamide dimethyl wake condensation reaction with the compound 4;

[0052] 3、化合物4,3- 二甲基胺-2- (3_甲氧基_2,4,5_三氟苯甲酰基)丙烯酸乙酯进行胺交换得到化合物5 ;[0053] 4、化合物5,3-环丙胺-2- (3_甲氧基_2,4,5_三氟苯甲酰基)丙烯酸乙酯经过亲核取代和水解得到化合物6 ; [0052] 3, the compound 4,3-dimethyl-amine-2- (trifluoromethyl _2,4,5_ 3_ methoxy-benzoyl) acrylate compound to give the amine exchange 5; [0053] 4 , 5,3- cyclopropylamine compound 2- (methoxy 3_ _2,4,5_ trifluorobenzoyl) acrylate via a nucleophilic substitution and hydrolysis to give compound 6;

[0054] 5、化合物6,8-甲氧基-1-环丙基_6,7_ 二氟_4_氧代-1,4_ 二氢喹啉_3_羧酸螯合得到化合物7 ; [0054] 5. A compound methoxy-1-cyclopropyl-6,8-difluoro-_4_ _6,7_ -1,4_ dihydroquinoline-oxo acid chelating _3_ give compound 7;

[0055] 6、化合物7,(8-甲氧基-1-环丙基_6,7_ 二氟_4_氧代-1,4_ 二氢喹啉_3_羧酸)二氟化硼发生亲核取代反应得到盐酸莫西沙星。 [0055] 6, compound 7, (8-methoxy-difluoro-1-cyclopropyl _6,7_ _4_ oxo -1,4_ dihydroquinoline _3_ acid) occurs boron difluoride nucleophilic substitution reaction to obtain moxifloxacin hydrochloride.

[0056] 具体反应条件是: [0056] Specific reaction conditions are:

[0057] 1、称取化合物2:锌:无机酸的摩尔比=1:(1-5); (0.01-0.5);将化合物2、锌加入到溶剂中,在搅拌下加入酸,加热至回流,缓慢滴加溴乙酸乙酯。 [0057] 1. Weigh Compound 2: zinc: the molar ratio of mineral acid = 1: (1-5); (0.01-0.5); Compound 2, zinc added to the solvent, the acid is added under stirring and heated to refluxed, ethyl bromoacetate was slowly added dropwise. 在回流下反应完全,冷却至室温,依次加入6M盐酸和水,搅拌,冷却,过滤,烘干,得到化合物3。 At reflux the reaction was complete, cooled to room temperature, 6M hydrochloric acid and water were successively added, with stirring, cooling, filtering and drying, to give compound 3.

[0058] 上述所用的溶剂为四氢呋喃、二恶烷等;所选的酸为有机酸如:对甲基苯磺酸、甲磺酸等;无机酸为氯化氢气体等;反应温度为40-100°C之间。 [0058] The above solvent used is tetrahydrofuran, dioxane and the like; organic acids are selected as: p-toluenesulfonic acid, methanesulfonic acid and the like; inorganic acid is hydrogen chloride gas or the like; the reaction temperature is 40-100 ° between C.

[0059] 2、称取化合物3 =DMFDMA的摩尔比=1:(1-30);将化合物3、N, N- 二甲基甲酰胺二甲缩醛和溶剂搅拌,室温反应完全后。 [0059] 2, said molar ratio of compound of 3 = DMFDMA = 1: (1-30); The compound 3, N, N- dimethylformamide dimethyl acetal and the solvent was stirred at room temperature reaction was complete. 减压浓缩得化合物4,将其溶于溶剂中备用。 Concentrated under reduced pressure to give compound 4, which was dissolved in a solvent for use.

[0060] 上述所用的溶剂为甲醇、乙醇、异丙醇等,温度为20_50°C。 [0060] The solvent used is methanol, ethanol, isopropanol, etc., temperature 20_50 ° C.

[0061] 3、称取化合物4和环丙胺的摩尔比=1: (0.9-3);将环丙胺溶解在溶剂中,滴加化合物4的溶液,搅拌直至反应完全。 [0061] 3, said molar ratio of compound 4 and cyclopropylamine = 1: (0.9 to 3); cyclopropylamine dissolved in a solvent, a solution of Compound 4 was added dropwise, stirred until the reaction was complete. 向反应液中加入水,搅拌,静置分液,有机相用10%碳酸氢钠水溶液洗涤,分液。 Water was added to the reaction mixture, stirred, allowed to separate, and the organic phase washed with 10% aqueous sodium bicarbonate solution, liquid separation. 合并水相,水相用溶剂萃取,合并有机相,无水硫酸钠干燥,过滤,滤液浓缩至干,得到化合物5。 The combined aqueous phase, the aqueous phase is extracted with a solvent, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness to give compound 5. 将其溶于溶剂中备用。 Which was dissolved in a solvent for use.

[0062] 上述所用的溶剂为二氯甲烷、四氢呋喃等,温度为20_50°C。 [0062] The above solvent used is methylene chloride, tetrahydrofuran and the like at a temperature of 20_50 ° C.

[0063] 4、称取化合物5:无机碱的摩尔比=1: (1-10);在搅拌下,将无机碱加到化合物5的溶液中,搅拌直至反应完全。 [0063] 4, Compound 5 was weighed: the molar ratio of inorganic base = 1: (1-10); under stirring, an inorganic base added to the solution of compound 5, the reaction was stirred until complete. 加入溶剂,搅拌,过滤,滤饼用溶剂洗涤,滤液浓缩,得到中间体的溶液。 Solvent was added, stirred, filtered, the filter cake was washed with solvent, and the filtrate was concentrated to give intermediate solution.

[0064] 上述所用无机碱为碳酸钾、碳酸铯、碳酸钠等,温度为20_50°C,反应溶剂为二甲基亚砜,N,N-二甲基甲酰胺等,洗涤溶剂为二氯甲烷、乙酸乙酯等。 [0064] The inorganic base used is potassium carbonate, cesium carbonate, sodium carbonate, and temperature 20_50 ° C, the reaction solvent is dimethyl sulfoxide, N, N- dimethylformamide and the like, the washing solvent is dichloromethane and ethyl acetate.

[0065] 称取上述溶液:无机酸的摩尔比=1:(3-30);在搅拌下,将无机酸加到上述溶液中,加热回流直至反应完全。 [0065] The solution weighed: the molar ratio of mineral acid = 1: (3-30); stirring, the mineral acid added to the solution, heated to reflux until the reaction was complete. 降温,加入水,搅拌,过滤,重结晶得中间体6。 Cooling, water was added, stirred, filtered, and recrystallized to give intermediate 6.

[0066] 上述所用无机酸为盐酸等,温度为80-150°C.[0067] 5、称取化合物6:三氟化硼:无机碱的摩尔比=1:(1-2): (1_5);将化合物6、溶剂和无机碱,在氮气保护下搅拌,滴加三氟化硼的乙醚溶液。 [0066] The inorganic acid used is hydrochloric acid and the like, a temperature of 80-150 ° C [0067] 5, 6 weighed compounds: boron trifluoride: molar ratio of inorganic base = 1: (1-2): (1_5 ); compound 6, a solvent and an inorganic base, stirred under nitrogen, was added dropwise a solution of boron trifluoride diethyl ether. 加热,在回流下反应完全。 It was heated at reflux the reaction was complete. 降至室温,加入溶剂,搅拌,过滤,溶剂冲洗,减压干燥,得到粗品。 Cooled to room temperature, the solvent was added, stirred, filtered, rinsed with solvent, and dried under reduced pressure to give the crude product. 用溶剂打浆,过滤,减压干燥得中间体7。 Slurried with a solvent, filtered and dried under reduced pressure to give intermediate 7.

[0068] 上述所用的无机碱为碳酸钾、碳酸钠、碳酸铯等,所用溶剂为四氢呋喃、乙腈、异丙醚、甲基叔丁基醚等。 [0068] The above inorganic base used is potassium carbonate, sodium carbonate, cesium carbonate, the solvent is tetrahydrofuran, acetonitrile, diisopropyl ether, methyl tert-butyl ether.

[0069] 6、称取化合物7:化合物8:有机碱的摩尔比=1: (0.95-2): (1_5);将化合物7、化合物8、有机碱和溶剂混合,搅拌,加热至回流至反应完全。 [0069] 6, weighed Compound 7: Compound 8: 1 molar ratio of organic base = 1: (0.95-2): (1_5); and 7, Compound 8, an organic base compound and a solvent mixture stirred and heated to reflux until the reaction is complete. 降温,减压蒸馏回收溶剂,向残留物中加入溶剂,搅拌溶解,滴加盐酸至PH为2,室温搅拌,在低于(TC下搅拌析晶,过滤,450C干燥,得到盐酸莫西沙星。 Cool, evaporated under reduced pressure to recover the solvent, the solvent added to the residue, dissolved with stirring, hydrochloric acid was added dropwise to a PH of 2, stirred at room temperature, below (TC under stirring crystallization, filtration, 450C and dried, to obtain moxifloxacin hydrochloride.

[0070] 有机碱为三乙胺、吡啶等,无机碱为碳酸钾、碳酸钠等,反应溶剂为乙腈、四氢呋喃等,后处理溶剂为乙醇、乙腈等。 [0070] The organic base is triethylamine, pyridine, etc., an inorganic base is potassium carbonate, sodium carbonate, the reaction solvent is acetonitrile, tetrahydrofuran, etc., post-treatment solvent is ethanol, acetonitrile and the like.

[0071] 本设计路线的优势: [0071] The advantage of this design line:

[0072] 本发明的有益效果是操作简便,各步中间体纯度都很高。 [0072] Advantageous effects of the present invention is a simple, very high purity of the intermediate in each step. 本发明的方法使反应进行的充分,副反应少,且容易纯化。 The method of the present invention is that the reaction to proceed sufficiently, less side effects, and is readily purified. 本发明减少了反应步骤,易于实现工业化生产。 The present invention reduces reaction steps, is easy to realize industrial production.

[0073] 1.本发明合成化合物3采取Reformatsky反应,避免了使用较贵的起始原料,且减少了反应步骤,提高了收率,溶剂为四氢呋喃等极性非质子溶剂。 Synthesis of Compound [0073] 1. The present invention taken 3 Reformatsky reaction, avoiding the use of expensive starting materials and reaction steps is reduced, increasing the yield, the solvent is a polar aprotic solvent such as tetrahydrofuran.

[0074] 2.本发明合成化合物4采用N,N-二甲基甲酰胺二甲缩醛(DMFDMA),避免了使用有毒的试剂如:乙酸酐和高温反应,简化了操作。 Synthesis of Compound [0074] 2. The present invention uses 4 N, N- dimethylformamide dimethylacetal (DMFDMA), avoiding the use of toxic reagents such as: acetic anhydride and the reaction temperature, the operation is simplified.

[0075] 3.本发明合成化合物6,中间不提纯可以直接从化合物3经简单处理得到化合物6。 [0075] 3. Synthesis of Compound 6 of the present invention, without intermediate purification to give compound 6 directly by a simple process from compound 3.

[0076] 4.本发明合成化合物7在无机碱作用下发生,避免了有毒的有机碱,提高了收率,溶剂为四氢呋喃等极性非质子溶剂。 Synthesis of Compound [0076] 4. The present invention is an inorganic base to act in the 7 occurs, avoid the toxic organic bases, increasing the yield, the solvent is a polar aprotic solvent such as tetrahydrofuran.

[0077] 5.本发明简化了工艺操作,提高了收率。 [0077] The present invention simplifies the process operation, increasing the yield.

[0078] 说明书附图: [0078] accompanying drawings:

[0079] 图1盐酸莫西沙星化合物的反应方程式; The reaction [0079] FIG 1 compound moxifloxacin hydrochloride equation;

[0080] 具体实施方式: [0080] DETAILED DESCRIPTION:

[0081] 下面结合实施例对本发明做进一步的说明,使本领域专业技术人员更好的理解本发明。 [0081] The following embodiments in conjunction with embodiments of the present invention will be further described, enables those skilled in the art a better understanding of the present invention. 实施例仅为解释性的,决不意味着它以任何方式限制本发明的范围。 The examples are merely illustrative, it is by no means limit the scope of the present invention in any way.

[0082] 实施例1 [0082] Example 1

[0083] 在3L三口瓶中加入187g3_甲氧基_2,4,5_三氟苯腈、97.5g锌和IL四氢呋喃,在搅拌下加入8.6g对甲基苯磺酸,室温搅拌0.5h。 [0083] In 3L three-neck flask was added 187g3_ _2,4,5_ three methoxy-fluorobenzonitrile, 97.5 g of zinc and IL tetrahydrofuran was added with stirring 8.6g p-toluenesulfonic acid, stirred 0.5h at room temperature . 加热至回流,缓慢滴加217.1g溴乙酸乙酯。 It was heated to reflux and 217.1g of ethyl bromoacetate was slowly added dropwise. 在回流下反应2小时,冷却至室温,依次加入500mL6M盐酸和IOOmL水,搅拌2h,冷却至5°C,有大量固体析出,过滤,100 mL乙醇冲洗,40°C下鼓风干燥,得223.5g3_甲氧基-2,4,5-三氟苯甲酰乙酸乙酯,收率80.9%,纯度98.5%。 The reaction at reflux for 2 hours, cooled to room temperature, and hydrochloric acid were added 500mL6M IOOmL water, stirred for 2h, cooled to 5 ° C, with a large amount of solid precipitated was filtered, 100 mL of ethanol rinsing, blast drying at 40 ° C, to give 223.5 g3_-2,4,5-trifluoro benzoyl acetate in a yield of 80.9%, 98.5% purity.

[0084] 实施例2: [0084] Example 2:

[0085] 在3L三口瓶中加入220g3_甲氧基-2,4,5-三氟苯甲酰乙酸乙酯、1.1L甲醇和142.8gN, N- 二甲基甲酰胺二甲缩醛,室温反应2h,TLC显示反应完成,减压浓缩得270g3_ 二甲基胺-2-(3-甲氧基-2,4,5-三氟苯甲酰基)丙烯酸乙酯。 [0085] 220g3_ added benzoyl-2,4,5-trifluoro ethyl, and 1.1 L of methanol 142.8gN, N- dimethylformamide dimethyl acetal, 3L three-necked flask at room temperature reaction 2h, TLC showed complete reaction, concentrated under reduced pressure to give amine 270g3_ dimethyl-2- (3-methoxy-2,4,5-trifluorobenzoyl) acrylate. 将270g3- 二甲基胺-2-(3-甲氧基-2,4,5-三氟苯甲酰基)丙烯酸乙酯溶于1.35L 二氯甲烷中备用。 The 270g3- dimethyl amine 2- (3-methoxy-2,4,5-trifluorobenzoyl) acrylate was dissolved in 1.35L of dichloromethane standby.

[0086] 实施例3: [0086] Example 3:

[0087] 在5L三口瓶中加入54.7g环丙胺,IL 二氯甲烷,在室温下滴加3- 二甲基胺-2- (3-甲氧基_2,4,5-三氟苯甲酰基)丙烯酸乙酯的二氯甲烷溶液,搅拌Ih,TLC检测反应完全,停止反应。 [0087] 54.7g of cyclopropylamine was added, IL dichloromethane 5L three-neck flask, a solution of 3-methyl amine at room temperature 2- (3-methoxy-trifluoromethyl benzoic _2,4,5- acyl) acrylate in methylene chloride was stirred Ih, TLC the reaction was complete, the reaction was stopped. 向反应液中加入2L水,搅拌20分钟,静置分液,有机相用IL 10%碳酸氢钠水溶液洗涤,分液。 To the reaction mixture were added 2L of water, stirred for 20 minutes, allowed to separate, and the organic phase was washed with aqueous sodium bicarbonate IL 10%, liquid separation. 合并水相,水相用IL 二氯甲烷萃取,合并有机相,无水硫酸钠干燥,过滤,滤液浓缩至干,得到280.5g3-环丙胺-2- (3-甲氧基-2,4,5-三氟苯甲酰基)丙烯酸乙酯。 The combined aqueous phase, the aqueous phase was extracted with IL dichloromethane and the combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness, 280.5g3- cyclopropylamine to give 2- (3-methoxy-2,4, 5-trifluoromethyl-benzoyl) acrylate. 3-环丙胺-2- (3-甲氧基-2,4,5-三氟苯甲酰基)丙烯酸乙酯用3 L DMSO溶解备用。 3-amine 2- (3-methoxy-2,4,5-trifluorobenzoyl) acrylate was dissolved with 3 L DMSO standby.

[0088] 实施例4: [0088] Example 4:

[0089] 在5L三口瓶中加入220.8g碳酸钾,3-环丙胺-2- (3-甲氧基_2,4,5_三氟苯甲酰基)丙烯酸乙酯的DMSO溶液,室温下搅拌反应I小时,TLC检测反应结束。 [0089] Potassium carbonate was added 220.8g 5L three-neck flask, 3-amine 2- (3-methoxy _2,4,5_ trifluorobenzoyl) acrylate in DMSO was stirred at room temperature reaction I h, TLC detection reaction was completed. 加入IL 二氯甲烷,搅拌5分钟,过滤,滤饼用2L 二氯甲烷洗涤,滤液浓缩将二氯甲烷蒸出。 IL methylene chloride was added, stirred for 5 minutes, filtered, the filter cake washed with 2L of methylene chloride, the methylene chloride was distilled off and the filtrate was concentrated.

[0090] 在IOL三口瓶中加入二甲基亚砜的溶液,200mL浓盐酸,搅拌升温,回流反应5小时,TLC检测反应完全后,停止反应。 [0090] in dimethyl sulfoxide was added a solution of IOL three-neck flask, 200 mL concentrated hydrochloric acid, stirred and heated to reflux for 5 hours, After the completion of the reaction by TLC, the reaction was stopped. 降温至室温,向反应液加入24 L水,搅拌I h,过滤,干燥,乙腈重结晶得201.6g8-甲氧基-1-环丙基-6,7- 二氟-4-氧代-1,4- 二氢喹啉_3_羧酸,收率85.4%ο Cooling to room temperature, 24 L of water was added to the reaction mixture, stirred for I h, filtered, dried, and recrystallized from acetonitrile to give 201.6g8- methoxy-1-cyclopropyl-6,7-difluoro-4-oxo-1 , 4-dihydro-quinoline-carboxylic acid _3_, yield 85.4% ο

[0091] 实施例5: [0091] Example 5:

[0092] 在IOL三口瓶中加入200g8_甲氧基_1_环丙基_6,7_ 二氟_4_氧代_1,4_ 二氢喹啉-3-羧酸、2.4L四氢呋喃和103.2g碳酸钾,在氮气保护下搅拌IOmindfW 153.7mL三氟化硼的乙醚溶液。 [0092] IOL three-neck flask was added _1_ 200g8_ methoxy-difluoro-cyclopropyl _6,7_ _4_ oxo _1,4_ dihydroquinoline-3-carboxylic acid, 2.4L of tetrahydrofuran and 103.2 g of potassium carbonate, stirred IOmindfW 153.7mL of boron trifluoride ether solution under nitrogen. 加热,在回流下反应4h,HPLC显示99%的化合物7已经反应。 Heating the reaction at reflux for 4h, HPLC of Compound 7 show 99% had reacted. 降至室温,加入4L甲基叔丁基醚并搅拌lOmin,过滤,IL甲基叔丁基醚冲洗,减压干燥(50°C,-0.095MPa)2h,得到粗品334.5g。 Cooled to room temperature, was added 4L MTBE and stirred for lOmin, filtered, IL methyl t-butyl ether, dried under reduced pressure (50 ° C, -0.095MPa) 2h, to give a crude product 334.5g. 用3.3L乙腈1000mL*3打浆,过滤,减压干燥(50°C,-0.095MPa)至恒重,得225g (8-甲氧基-1-环丙基_6,7- 二氟-4-氧代-1,4- 二氢喹啉_3_羧酸)二氟化硼,收率96.8%, HPLC 纯度99.5%。 3.3L with 1000mL * 3 beating acetonitrile, filtered, and dried under reduced pressure (50 ° C, -0.095MPa) to constant weight to give 225g (8- methoxy-1-cyclopropyl-difluoro-4 _6,7- - oxo-1,4-dihydro-quinoline-carboxylic acid _3_) boron difluoride, yield 96.8%, HPLC purity 99.5%.

[0093] 实施例6: [0093] Example 6:

[0094] 在三口瓶中加入220g (8-甲氧基-1-环丙基_6,7_ 二氟_4_氧代-1,4_ 二氢喹啉-3-羧酸)二氟化硼、84.7g (4as-顺)-八氢-M-吡咯并[3,4_b]吡啶、2.2L乙腈和133.5mL三乙胺,加热至回流,搅拌3h,TLC检测反应完全后。 [0094] In the three-neck flask was added 220g (8- methoxy-1-cyclopropyl-difluoro _4_ _6,7_ oxo -1,4_ dihydroquinoline-3-carboxylic acid) boron difluoride , 84.7g (4as- cis) - octahydro-pyrrolo -M- [3,4_b] pyridine, triethylamine 133.5mL 2.2L of acetonitrile and heated to reflux, stirred for 3h, TLC the reaction was complete after. 降温至45°C,减压蒸馏回收溶剂,向残留物中加入2.2L乙醇,搅拌溶解,与30°C下滴加6moL/L的盐酸至pH为2,室温搅拌2h,然后在低于0°C下搅拌2h析晶,过滤,用乙醇洗,45°C干燥,得到259.6g盐酸莫西沙星,收率92.4%ο Cooling to 45 ° C, recovery of the solvent by distillation under reduced pressure, 2.2L of ethanol was added to the residue, dissolved with stirring at 30 ° C and added dropwise 6moL / L hydrochloric acid to pH 2 and stirred at rt for 2h, and then below 0 stirring crystallization ° C 2h, filtered, washed with ethanol, 45 ° C and dried to obtain moxifloxacin hydrochloride star 259.6g, a yield of 92.4% ο

Claims (7)

  1. 1.一种合成盐酸莫西沙星化合物的方法,其特征在于,包括以下步骤: Moxifloxacin hydrochloride A star method of synthesizing a compound, wherein, comprising the steps of:
    Figure CN102617568BC00021
    反应方程式: Reaction equation:
    Figure CN102617568BC00022
    1).化合物2,3-甲氧基-2,4,5-三氟苯腈进行Reformatsky反应化得到化合物3 ; 2).化合物3,3-甲氧基-2,4,5-三氟苯甲酰乙酸乙酯与N,N- 二甲基甲酰胺二甲缩醛反应得到化合物4 ; 3).化合物4,3-二甲基胺-2- (3-甲氧基_2,4,5-三氟苯甲酰基)丙烯酸乙酯进行胺交换得到化合物5 ; 4).化合物5,3_环丙胺-2- (3-甲氧基_2,4,5-三氟苯甲酰基)丙烯酸乙酯经过亲核取代和水解得到化合物6 ; 5).化合物6,8-甲氧基-1-环丙基_6,7- 二氟-4-氧代-1,4- 二氢喹啉_3_羧酸螯合得到化合物7 ; 6).化合物7,(8-甲氧基-1-环丙基_6,7- 二氟-4-氧代-1,4- 二氢喹啉_3_羧酸)二氟化硼发生亲核取代反应得到盐酸莫西沙星。 1) -2,4,5-methoxy compound 2,3-difluorobenzonitrile for Reformatsky reaction to give a compound of 3; 2) 3,3-2,4,5-trifluoro compound. benzoyl acetate and N, N- dimethylformamide dimethyl acetal to give compound 4; 3) the compound 4,3-dimethyl-amine 2- (3-methoxy _2,4. , 5-trifluoromethyl-benzoyl) acrylate compound to give the amine exchange 5; 4) cyclic amine compound 5,3_ 2- (3-methoxy-benzoyl _2,4,5- trifluoromethyl. ) acrylate via a nucleophilic substitution and hydrolysis to give compound 6; 5) compounds methoxy-1-cyclopropyl-6,8-difluoro-_6,7- oxo-1,4-dihydro. quinoline _3_ acid chelating compound to give 7; 6) of compound 7, (8-methoxy-1-cyclopropyl _6,7--difluoro-4-oxo-1,4-dihydro. quinoline _3_ acid) boron difluoride nucleophilic substitution reaction to obtain moxifloxacin hydrochloride.
  2. 2.根据权利要求1所述的方法,其特征在于,其中,步骤I)包括如下步骤:称取化合物2:锌:酸的摩尔比=1:1-5:0.01-0.5 ;将化合物2、锌加入到溶剂中,在搅拌下加入酸,加热至回流,在40-100°C之间缓慢滴加溴乙酸乙酯,在回流下反应完全,冷却至室温,依次加入6M盐酸和水,搅拌,冷却,过滤,烘干,得到化合物3。 The method according to claim 1, wherein, wherein step I) comprises the steps of: Weigh Compound 2: zinc: acid molar ratio = 1: 1-5: 0.01-0.5; Compound 2, zinc was added to the solvent, the acid is added under stirring, and heated to reflux at 40-100 ° C between ethyl bromoacetate was slowly added dropwise, at reflux the reaction was complete, cooled to room temperature, 6M hydrochloric acid and water were successively added, stirring , cooling, filtering and drying, to give compound 3.
  3. 3.根据权利要求1所述的方法,其特征在于,其中,步骤2)包括如下步骤:称取化合物3 =DMFDMA的摩尔比=1:1_30 ;将化合物3、N,N-二甲基甲酰胺二甲缩醛和溶剂搅拌,在20-50°C之间反应完全后,减压浓缩得化合物4,将其溶于溶剂中备用。 3. The method according to claim 1, wherein, wherein step 2) comprises the steps of: said molar ratio of compound of 3 = DMFDMA = 1: 1_30; The compound 3, N, N- dimethylformamide dimethyl acetal was stirred and the solvent, after completion of the reaction between 20-50 ° C, concentrated under reduced pressure to give compound 4, which was dissolved in a solvent for use.
  4. 4.根据权利要求1所述的方法,其特征在于,其中,步骤3)包括如下步骤:称取化合物4:环丙胺的摩尔比=1:0.9-3 ;将环丙胺溶解在溶剂中,在20-50°C之间滴加化合物4的溶液,搅拌直至反应完全,向反应液中加入水,搅拌,静置分液,有机相用10%碳酸氢钠水溶液洗涤,分液,合并水相,水相用溶剂萃取,合并有机相,无水硫酸钠干燥,过滤,滤液浓缩至干,得到化合物5,将其溶于溶剂中备用。 4. The method according to claim 1, wherein, wherein step 3) comprises the steps of: Weigh Compound 4: molar ratio of cyclopropylamine = 1: 0.9 to 3; cyclopropylamine dissolved in a solvent, in the compound 4 is added dropwise a solution of between 20-50 ° C, stirred until the reaction was complete, water was added to the reaction mixture, stirred, allowed to separate, and the organic phase washed with 10% aqueous sodium bicarbonate, separated, the aqueous phase was combined the aqueous phase is extracted with a solvent, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness to give compound 5, which was dissolved in a solvent for use.
  5. 5.根据权利要求1所述的方法,其特征在于,其中,步骤4)包括如下步骤:称取化合物5:无机碱的摩尔比=1:1-10 ;在20-50°C搅拌下,将无机碱加到化合物5的溶液中,搅拌直至反应完全,加入二氯甲烷或乙酸乙酯,搅拌,过滤,滤饼用二氯甲烷或乙酸乙酯洗涤,滤液浓缩,得到中间体的溶液;称取上述溶液:无机酸的摩尔比=1:3-30 ;在搅拌下,将无机酸加到上述溶液中,在80-150°C下反应完全,降温,加入水,搅拌,过滤,重结晶得中间体6。 5. The method according to claim 1, wherein, wherein step 4) comprises the steps of: Weigh Compound 5: molar ratio of inorganic base = 1: 1-10; under stirring at 20-50 ° C, inorganic base is added to a solution of compound 5 and stirred until the reaction was complete, dichloromethane or ethyl acetate, stirred, filtered, the filter cake was washed with methylene chloride or ethyl acetate, and the filtrate was concentrated to give intermediate solution; the solution weighed: the molar ratio of mineral acid = 1: 3-30; under stirring, an inorganic acid was added to the above solution at 80-150 ° C the reaction was completed, cooling, water was added, stirred, filtered, heavy intermediate 6 to give crystals.
  6. 6.根据权利要求1所述的方法,其特征在于,其中,步骤5)包括如下步骤:称取化合物6:三氟化硼:无机碱的摩尔比=1:1-2:1-5 ;将化合物6、溶剂和无机碱,在氮气保护下搅拌,滴加三氟化硼的乙醚溶液,加热,在回流下反应完全,降至室温,加入溶剂,搅拌,过滤,溶剂冲洗,减压干燥,得到粗品,用溶剂打浆,过滤,减压干燥得中间体7。 6. The method according to claim 1, wherein, wherein step 5) comprises the steps of: Weigh Compound 6: boron trifluoride: molar ratio of inorganic base = 1: 1-2: 1-5; compound 6, a solvent and an inorganic base, stirred under nitrogen, was added dropwise boron trifluoride ether solution was heated at reflux the reaction was complete, cooled to room temperature, the solvent was added, stirred, filtered, rinsed with solvent, and dried under reduced pressure to give the crude product, slurried with a solvent, filtered and dried under reduced pressure to give intermediate 7.
  7. 7.根据权利要求1所述的方法,其特征在于,其中,步骤6)包括如下步骤:称取化合物7:化合物8:有机碱的摩尔比=1:0.95-2:1-5 ;将化合物7、化合物8、有机碱和溶剂混合,搅拌,加热至回流至反应完全,降温,减压蒸馏回收溶剂,向残留物中加入溶剂,搅拌溶解,滴加盐酸至PH为2,室温搅拌,在低于0°C下搅拌析晶,过滤,45°C干燥,得到盐酸莫西沙星。 The method according to claim 1, wherein, wherein step 6) comprises the steps of: Weigh Compound 7: Compound 8: 1 molar ratio of organic base = 1: 0.95-2: 1-5; Compound 7, 8, organic base compound and a solvent mixture, stirred and heated to reflux until the reaction was complete, cooled, evaporated under reduced pressure to recover the solvent, the solvent added to the residue, dissolved with stirring, hydrochloric acid was added dropwise to a PH of 2, stirred at room temperature, at was stirred below 0 ° C under crystallization, filtration, 45 ° C and dried to obtain moxifloxacin hydrochloride.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4855292A (en) 1986-02-25 1989-08-08 Otsuka Pharmaceutical Company, Limited 1-cyclopropyl-6-fluoro-8-alkyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid derivatives
US4997943A (en) 1986-03-31 1991-03-05 Sankyo Company Limited Quinoline-3-carboxylic acid derivatives
WO2005012285A1 (en) 2003-08-05 2005-02-10 Matrix Laboratories Ltd An improved process for the preparation of moxifloxacin hydrochloride

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ES2249489T3 (en) * 2000-12-14 2006-04-01 THE PROCTER & GAMBLE COMPANY quinolone antimicrobial.

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4855292A (en) 1986-02-25 1989-08-08 Otsuka Pharmaceutical Company, Limited 1-cyclopropyl-6-fluoro-8-alkyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid derivatives
US4997943A (en) 1986-03-31 1991-03-05 Sankyo Company Limited Quinoline-3-carboxylic acid derivatives
WO2005012285A1 (en) 2003-08-05 2005-02-10 Matrix Laboratories Ltd An improved process for the preparation of moxifloxacin hydrochloride

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