WO2017140072A1 - 一种采用粒子过程晶体产品分子组装与形态优化技术的头孢呋辛钠新晶型化合物及制剂 - Google Patents

一种采用粒子过程晶体产品分子组装与形态优化技术的头孢呋辛钠新晶型化合物及制剂 Download PDF

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WO2017140072A1
WO2017140072A1 PCT/CN2016/085300 CN2016085300W WO2017140072A1 WO 2017140072 A1 WO2017140072 A1 WO 2017140072A1 CN 2016085300 W CN2016085300 W CN 2016085300W WO 2017140072 A1 WO2017140072 A1 WO 2017140072A1
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sodium
cefuroxime
cefuroxime sodium
crystalline form
acid
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PCT/CN2016/085300
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French (fr)
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陶灵刚
王静康
尹秋响
郝红勋
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海南灵康制药有限公司
天津大学
陶灵刚
王静康
尹秋响
郝红勋
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/02—Preparation
    • C07D501/12—Separation; Purification
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/02—Preparation
    • C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • C07D501/06—Acylation of 7-aminocephalosporanic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
    • C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • the invention belongs to the technical field of medicine, and particularly relates to a novel crystalline form compound and preparation of cefuroxime sodium prepared by molecular assembly and morphology optimization technology of a particle process crystal product.
  • Cefuroxime sodium (6R,7R)-7-[2-furyl(methoxyimino)acetylamino]-3-carbamoyloxymethyl-8-oxo-5 - thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylate.
  • Cefuroxime sodium belongs to the second generation of broad-spectrum cephalosporins. It was first developed and marketed by Glaxo in 1975 under the trade name Xi Lixin. It was approved by the US FDA on December 28, 1987 and listed in the US in 1988. It is effective against a variety of Gram-positive and Gram-negative bacteria and is stable against most ⁇ -lactamases. Multi-national pharmacopoeia such as BP, USP, JP, EP and CP2005 are included.
  • cephalosporin antibiotics has become the focus of the development of Chinese medicine, especially the efficacy of cefuroxime sodium, which is the drug of choice for the treatment of mixed infection of Gram-negative bacteria and positive bacteria, so the synthesis of cefuroxime sodium It has a very significant meaning.
  • cefuroxime sodium was proposed by Glaxo Company of the United Kingdom and was prepared by 7-step reaction of 7-aminocephalosporanic acid, mainly due to the introduction of protective groups of amino and carboxyl groups in the intermediate step, but the final deprotection was required. Base, low yield, and many impurities.
  • Cefuroxime acid and finally salted with sodium isooctanoate, sodium lactate or sodium acetate to prepare cefuroxime sodium.
  • 7-ACA is first reacted with SMIF-C1 to form 7-FCA, and then hydrolyzed with sodium hydroxide to form 7-FHCA, and then reacted with trichloroacetyl isocyanate to form cefuroxime acid, and finally formed into a salt process. Converted to cefuroxime sodium.
  • cephalosporin C as a starting material, deacetylating by enzymatic hydrolysis, reacting with isocyanate of chlorosulfonic acid, and deactivating 7-amino acid bond to prepare 7-amino-3-carbamoyloxymethyl-3-cephem
  • the acid is condensed with SMIF-Cl to form cefuroxime acid, and finally converted to cefuroxime sodium by salt formation with sodium isooctanoate. All of the above methods have the problems that the prepared cefuroxime sodium has a dark color and poor stability.
  • the conventional crystal form of cefuroxime sodium has poor stability and is unstable to heat, acid environment and alkaline environment. It is characterized by easy discoloration, reduced content and degradation products. To solve this problem, it is necessary to develop a new crystallization production technology to optimize process parameters such as solvent, temperature, reaction time, additives, etc., so that crystallization can be carried out under suitable conditions, thereby obtaining a more reliable cefuroxime sodium crystal form.
  • the invention mainly aims at the above problems of the cefuroxime sodium compound, and based on the sufficient consideration of the solvent, temperature, external force, additives and the like in the crystal formation process, a purity is obtained by molecular assembly and morphology optimization technology of the particle process crystal product.
  • the preparation prepared by using the novel crystalline form compound described in the present invention has better stability than the conventional preparation.
  • a first object of the present invention is to provide a novel crystalline compound of cefuroxime sodium which is prepared by molecular assembly and morphology optimization techniques of a particle process crystal product, and has the characteristics of high purity, good color grade and good stability.
  • the X-ray powder diffraction pattern represented by the 2 ⁇ diffraction angle is 6.52° ⁇ 0.2°, 6.84° ⁇ 0.2°, 12.74° ⁇ 0.2°, as determined by X-ray powder diffraction according to the present invention. 15.57° ⁇ 0.2°, 17.32° ⁇ 0.2°, 20.31° ⁇ 0.2°, 20.96° ⁇ 0.2°, 22.40° ⁇ 0.2°, 23.11° ⁇ 0.2°, 23.82° ⁇ 0.2°, 28.10° ⁇ 0.2°, 32.10° Characteristic diffraction peaks are shown at ⁇ 0.2° and 35.40° ⁇ 0.2°.
  • the preparation of the novel crystalline form of cefuroxime sodium according to the present invention comprises the following steps:
  • the reagent 1 is one of dichloromethane, acetone, chloroform or a mixture thereof. More preferably, the organic solvent 1 is chloroform.
  • the aqueous alkali solution is selected from one of sodium hydroxide, sodium hydrogencarbonate, sodium carbonate or a mixture thereof. More preferably, the aqueous alkali solution is an aqueous solution of sodium carbonate.
  • the aqueous alkali solution in the step (3) is adjusted to have a pH ranging from 7.0 to 9.0. More preferably, the pH is in the range of 8.0 to 8.5.
  • the hydrochloric acid in the step (3) is adjusted to have a pH ranging from 2.0 to 4.0. More preferably, the pH ranges from 3.0 to 3.5.
  • the reagent 2 in the (4) is one of sodium lactate, sodium acetate, and sodium isooctanoate. More preferably, the reagent 2 is sodium isooctanoate.
  • a second object of the present invention is to provide a preparation comprising the novel crystalline form of cefuroxime sodium according to the present invention, which has better stability and less side effects than the conventional products.
  • the preparation of the cefuroxime sodium preparation of the present invention is mainly for aseptically dispensing the fresh crystalline compound of cefuroxime sodium prepared above. Specifications are 0.25 ⁇ 2.5g.
  • Figure 1 X-ray powder diffraction pattern of a new crystalline form of cefuroxime sodium. The 2 ⁇ values corresponding to the diffraction peak numbers in the figure are shown in Table 1.
  • X-ray powder diffraction was used to study and characterize the new crystalline form of cefuroxime sodium.
  • the X-ray powder diffraction pattern of the cefuroxime sodium of Example 1 was 6.52°, 6.84°, 12.74°, 15.57°, 17.32°, 20.31°, 20.96°, 22.40°, 23.11°, 23.82° at 2 ⁇ diffraction angles. Characteristic diffraction peaks were displayed at 28.10°, 32.10°, and 35.40°. See Figure 1 of the specification for details.
  • the X-ray powder diffraction pattern of the cefuroxime sodium of Example 2 was 6.52°, 6.84°, 12.74°, 15.57°, 17.32°, 20.31°, 20.96°, 22.40°, 23.11°, 23.82° at 2 ⁇ diffraction angles. Characteristic diffraction peaks were displayed at 28.10°, 32.10°, and 35.40°.
  • the X-ray powder diffraction pattern of the cefuroxime sodium of Example 3 was 6.52°, 6.84°, 12.74°, 15.57°, 17.32°, 20.31°, 20.96°, 22.40°, 23.11°, 23.82° at 2 ⁇ diffraction angles. Characteristic diffraction peaks were displayed at 28.10°, 32.10°, and 35.40°.
  • the cefuroxime sodium compound was prepared according to the procedure of Example 1, and the raw material was used to prepare cefuroxime for injection.
  • the cefuroxime sodium compound was prepared according to the method described in CN 101955492A.
  • the sodium liquid was controlled at a temperature of 28 to 30 ° C, and the cefuroxime acid filtrate was slowly added to the sodium solution, stirred, and a precipitate was formed, stirred for 45 minutes, and filtered to obtain a wet product of cefuroxime sodium.
  • the cefuroxime sodium wet product was washed twice with a mixture of anhydrous ethanol 1250 ml and acetone 1000 ml, and washed twice with acetone 1750 ml, and dried to obtain 605 g of cefuroxime sodium.
  • cefuroxime sodium compound was prepared in the same manner as in Comparative Example 1, and cefuroxime sodium for injection was prepared using this raw material in a specification of 0.25 g.
  • the present inventors studied the hygroscopicity of the cefuroxime sodium compound prepared in Example 1 of the present invention and Comparative Example 1.
  • the conditions of investigation were a relative humidity of 92.5% (RH) and a temperature of 40 ° C, and the indicator was the water content in the cefuroxime sodium compound.
  • the new crystalline form of cefuroxime sodium prepared by the present invention has a low water content and a hygroscopicity which is significantly lower than that of the cefuroxime sodium compound prepared by the prior art. It is indicated that the novel crystalline form of cefuroxime sodium according to the present invention has good stability and is suitable for the manufacture and long-term storage of pharmaceutical preparations.
  • the inventors conducted a purity test on the cefuroxime sodium compound prepared in Example 1 of the present invention and Comparative Example 1.
  • the present inventors conducted an accelerated stability test on the cefuroxime sodium for injection prepared in Example 4 and Comparative Example 2 of the present invention.
  • the conditions of investigation were temperature 40 ° C ⁇ 2 ° C, relative humidity 75% ⁇ 5%. After 6 months of storage, samples were taken at the end of 0, 1, 2, 3, and 6 months, respectively.
  • the indicators are traits, clarity, alkalinity, content and related substances.
  • cefuroxime sodium new crystal form compound and the preparation thereof of the invention have been tested by various indexes and accelerated tests, and the stability is good and the quality is reliable.

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Abstract

公开了一种头孢呋辛钠新晶型化合物及其结晶制备方法，所述头孢呋辛钠新晶型化合物采用粒子过程晶体产品分子组装与形态优化技术制备而成。通过稳定性试验证明本新晶型化合物具有纯度高、杂质含量低、引湿性低、稳定性好的特点。同时，还公开了一种采用上述头孢呋辛钠制备的制剂—注射用头孢呋辛钠。

Description

一种采用粒子过程晶体产品分子组装与形态优化技术的头孢呋辛钠新晶型化合物及制剂 技术领域
本发明属于医药技术领域，具体涉及一种采用粒子过程晶体产品分子组装与形态优化技术制备的头孢呋辛钠新晶型化合物及制剂。
背景技术
头孢呋辛钠(Cefuroxime sodium)化学名称为：(6R,7R)-7-[2-呋喃基(甲氧亚氨基)乙酰氨基]-3-氨基甲酰氧甲基-8-氧代-5-硫杂-1-氮杂二环[4.2.0]辛-2-烯-2-甲酸钠盐。分子式：C16H15N4NaO8S，分子量：446.37。其化学结构式为：
Figure PCTCN2016085300-appb-000001
头孢呋辛钠属于第二代广谱头孢菌素类药物，1975年由英国葛兰素(Glaxo)公司首先研制开发上市，商品名西力欣。1987年12月28日通过美国FDA审批，1988年在美国上市。它对多种革兰氏阳性菌和革兰氏阴性菌有效，对大多数β-内酰胺酶稳定。BP、USP、JP、EP及CP2005等多国药典均有收载。目前头孢类抗生素药物的研究开发已是中国医药发展的重点，特别是头孢呋辛钠疗效确切，为治疗革兰氏阴性菌和阳性菌混合感染的首选药物，因此对头孢呋辛钠的合成研究具有非常重大的意义。
头孢呋辛钠最初的制备路线由英国的Glaxo公司提出，由7-氨基头孢烷酸经过8步反应制备，主要是由于在中间步骤引入了氨基和羧基的保护基团，但需要最终脱去保护基，收率较低，杂质多。随后出现了许多其它制备方法的研究，如(1)7-ACA的3-位乙酰氧基采用NaOH水解生成中间体3-脱乙酰基-7-氨基-头孢酸(DACA)，DACA与Z-呋喃基-2-甲氧亚胺乙酰氯基(SMIF-Cl)反应生成7-FHCA，之后FHCA与二氯磷酰氰酸酯、氯磺酸异氰酸酯和三氯乙酰异氰酸酯进行氨甲酰化反应生成头孢呋辛酸，最后与异辛酸钠、乳酸钠或乙酸钠成盐制备头孢呋辛钠。(2)由7-ACA先与SMIF-C1反应生成7-FCA，再用氢氧化钠水解生成7-FHCA，而后与三氯乙酰异氰酸酯反应生成头孢呋辛酸，最后经成盐过程 转化为头孢呋辛钠。(3)以头孢菌素C为起始原料，经酶解脱乙酰基，与氯磺酸异氰酸酯反应，酶解脱7位酰胺键制备7-氨基-3-氨甲酰氧甲基-3-头孢烷酸，与SMIF-Cl缩合反应生成头孢呋辛酸，最后与异辛酸钠成盐转化为头孢呋辛钠。上述方法均存在制备的头孢呋辛钠色泽较深，稳定性较差的问题。
头孢呋辛钠常规晶型的稳定性较差，对热、偏酸环境、偏碱环境均不稳定，表现在外观易变色、含量降低、出现降解产物等问题。解决这个问题必须研发新型结晶生产技术，以优化溶剂、温度、反应时间、添加剂等过程工艺参数，使结晶在适合的条件下进行，从而得到一种质量更加可靠的头孢呋辛钠晶型。
粒子过程晶体产品分子组装与形态优化技术，此技术旨在针对特定的功能产品形态优化的要求，进行分子有序组装与规则排列。
本发明主要针对头孢呋辛钠化合物存在的以上问题，对晶体形成过程中溶剂、温度、外力、添加剂等因素充分考察的基础上，采用粒子过程晶体产品分子组装与形态优化技术得到了一种纯度高、色级好、流动性好、稳定性好的头孢呋辛钠新晶型化合物，该合成步骤较以往的制备过程更注重合成过程中的试剂及参数的控制，步骤简单，使用的原料等均为价格便宜、无毒或低毒产品，适于工业化规模生产。利用本发明中所述的新晶型化合物制成的制剂，较以往制剂具有更好的稳定性。
发明内容
本发明的第一目的在于提供一种头孢呋辛钠新晶型化合物，该化合物采用粒子过程晶体产品分子组装与形态优化技术制备而来，具有纯度高、色级好、稳定性好的特点。
本发明所述的头孢呋辛钠新晶型化合物用X射线粉末衍射测定，以2θ衍射角表示的X射线粉末衍射图谱在6.52°±0.2°，6.84°±0.2°，12.74°±0.2°，15.57°±0.2°，17.32°±0.2°，20.31°±0.2°，20.96°±0.2°，22.40°±0.2°，23.11°±0.2°，23.82°±0.2°，28.10°±0.2°，32.10°±0.2°，35.40°±0.2°处显示特征衍射峰。
本发明所述的头孢呋辛钠新晶型化合物制备包括下列步骤：
(1)将7-ACA溶于试剂1中，加入三乙胺和SMIF-Ts，保温反应，加入蒸馏水搅拌萃取，取水层，脱色，过滤，滤液用盐酸溶液调pH值，过滤、洗涤、真空干燥，得7-FCA。
(2)将7-FCA溶于甲醇中，缓慢加入碱水溶液，用乙酸乙酯萃取，取有机 层，洗涤，脱色，真空干燥得7-FHCA。
(3)7-FHCA溶于丙酮中，缓慢加入三氯乙酰异氰酸酯，保温反应，加入碱水溶液调pH值，乙醚萃取，取水层，脱色，过滤，滤液用盐酸调pH值，析出类白色结晶，过滤，洗涤，40℃真空干燥得头孢呋辛酸。
(4)将头孢呋辛酸溶于异丙醇、甲醇和去离子水的混合液中，采用活性炭脱色、过滤；将滤液加入异丙醇、甲醇和试剂2混合溶液中进行结晶，调节pH值，静置、过滤、洗涤，真空干燥得到头孢呋辛钠。
优选地，上述制备方法中，所述试剂1为二氯甲烷、丙酮、三氯甲烷中的一种或者它们的混合物。更优选地，有机溶剂1为三氯甲烷。
优选地，上述制备方法中，所述碱水溶液选自氢氧化钠、碳酸氢钠、碳酸钠中的一种或者它们的混合物。更优选地，碱水溶液为碳酸钠水溶液。
优选地，上述制备方法中，所述步骤(3)中碱水溶液调节pH值范围为7.0～9.0。更优选地，pH值范围为8.0～8.5。
优选地，上述制备方法中，所述步骤(3)中盐酸调节pH值范围为2.0～4.0。更优选地，pH值范围为3.0～3.5。
优选地，上述制备方法中，所述(4)中试剂2为乳酸钠、醋酸钠、异辛酸钠中的一种。更优选地，试剂2为异辛酸钠。
本发明的第二目的在于提供一种包含本发明所述头孢呋辛钠新晶型化合物的制剂，该制剂较以往产品具有更好的稳定性且副作用小。
本发明所述的头孢呋辛钠制剂的制备主要是对上述所制备的头孢呋辛钠新晶型化合物进行无菌分装。规格为0.25～2.5g。
附图说明
图1：头孢呋辛钠新晶型化合物的X-射线粉末衍射图，图中衍射峰编号对应的2θ值参见表1。
具体实施方式
下面将通过具体实施方式对本发明做进一步说明，但并不因此将本发明限制在所述的实施例范围中，本领域的技术人员应理解，对本发明内容所做的等同替换，或相应的改进，仍属于本发明的保护范围之内。
实施例1：头孢呋辛钠新晶型化合物的制备
(1)将7-ACA 54.4g溶于三氯甲烷1000ml，搅拌状态下，向上述溶液中加 入三乙胺60.6g，搅拌30min,，缓慢加入SMIF-Ts50.1g，保温0～5℃，反应2h，加入蒸馏水500ml，搅拌反应10min，取水层，室温下活性炭5g脱色10min，过滤，滤液冷至0～5℃，缓慢加入2mol/L盐酸溶液，调pH值至3.0，析出结晶，搅拌反应1h，过滤，冰水洗涤至中性，40℃真空干燥，得7-FCA 74.9g。
(2)向反应瓶中加入7-FCA 70.0g和甲醇600ml，搅拌下冷至0～5℃，缓慢加入4％的NaCO3水溶液700ml，加完后升温至10℃反应30min，用乙酸乙酯萃取2次，每次1000ml，合并有机层，蒸馏水洗涤2次，每次1000ml，活性炭5g脱色10min，40℃真空干燥，得7-FHCA 49.2g。
(3)向反应瓶中加入丙酮600ml和7-FHCA 45.7g搅拌溶解冷至0℃，缓慢加入三氯乙酰异氰酸酯48.4g，保温反应30min，加入4％的碳酸钠溶液500ml，升温至35℃反应2h，冷至室温，调节pH至8.3，乙醚萃取3次，每次300ml，取水相，室温下活性炭1.5g脱色10min，过滤，滤液用3mol/L盐酸调pH值至3.2，继续搅拌30min，过滤，蒸馏水洗涤2次，每次200ml，40℃真空干燥得头孢呋辛酸42.7g。
(4)将头孢呋辛酸40.0g溶于异丙醇1000ml、甲醇500ml和去离子水50ml的混合液中，采用活性炭3.0g脱色10min后过滤。将上述滤液加入异丙醇250ml、甲醇500ml和异辛酸钠14.2g混合溶液中进行结晶，加入4％的氢氧化钠溶液调节pH值至8.8，静置15min，过滤，滤饼使用异丙醇500ml洗涤一次，抽干，无水乙醇洗涤2次，每次500ml，经真空干燥得到头孢呋辛钠41.2g。
采用X-射线粉末衍射法(XRPD)来研究和表征头孢呋辛钠的新的结晶形式。
仪器设备：EMPYREAN(锐影)X射线衍射仪(荷兰Panalytical公司)。
测定结果：实施例1头孢呋辛钠的X射线粉末衍射图谱在2θ衍射角为6.52°，6.84°，12.74°，15.57°，17.32°，20.31°，20.96°，22.40°，23.11°，23.82°，28.10°，32.10°，35.40°处显示特征衍射峰。具体参见说明书附图1。
所述XRPD衍射的具体数据如下表所示：
表1头孢呋辛钠晶型
编号 d值 2θ(°) I/I0％
1 13.55 6.52 48.49
2 12.92 6.84 76.61
3 6.95 12.74 22.59
4 5.69 15.57 17.43
5 5.12 17.32 34.48
6 4.37 20.31 66.21
7 4.24 20.96 100.00
8 3.97 22.40 63.55
9 3.85 23.11 58.79
10 3.74 23.82 34.84
11 3.18 28.10 32.44
12 2.79 32.10 23.02
13 2.54 35.40 17.98
实施例2：头孢呋辛钠新晶型化合物的制备
(1)将7-ACA 53.8g溶于三氯甲烷1000ml，搅拌状态下，向上述溶液中加入三乙胺61.5g，搅拌30min后，缓慢加入SMIF-Ts 52.1g，保温0～5℃，反应2h，加入蒸馏水500ml，搅拌反应10min，取水层，室温下活性炭5g脱色10min，过滤，滤液冷至0～5℃，缓慢加入2mol/L盐酸溶液调pH至3.1，析出结晶，搅拌反应1h，过滤，冰水洗涤至中性，40℃真空干燥，得7-FCA 75.8g。
(2)向反应瓶中加入7-FCA 70.5g和甲醇600ml，搅拌下冷至0～5℃，缓慢加入4％的NaCO3水溶液700ml，加完后升温至10℃反应30min，用乙酸乙酯萃取2次，每次1000ml，合并有机层，蒸馏水洗涤2次，每次1000ml，活性炭5g脱色10min，40℃真空干燥，得7-FHCA 51.1g。
(3)向反应瓶中加入丙酮600ml和7-FHCA.50.1g搅拌溶解冷至0℃，缓慢加入三氯乙酰异氰酸酯50.0g，保温反应30min，加入4％的碳酸钠溶液50ml，升温至35℃反应2h，冷至室温，调节pH值至7.5，乙醚萃取3次，每次300ml，取水相，室温下活性炭1.5g脱色10min，过滤，滤液用3mol/L盐酸调pH值至3.4，继续搅拌30min，过滤，蒸馏水洗涤2次，每次200ml，40℃真空干燥得头孢呋辛酸43.1g。
测定结果：实施例2头孢呋辛钠的X射线粉末衍射图谱在2θ衍射角为6.52°，6.84°，12.74°，15.57°，17.32°，20.31°，20.96°，22.40°，23.11°，23.82°，28.10°，32.10°，35.40°处显示特征衍射峰。
(4)将头孢呋辛酸43.1g溶于异丙醇1000ml、甲醇500ml和去离子水50ml 的混合液中，采用活性炭3.0g脱色10min后过滤。将上述滤液加入异丙醇250ml、甲醇500ml和异辛酸钠15.4g混合溶液中进行结晶，加入4％的氢氧化钠溶液调节pH值至8.9，静置15min，过滤。滤饼使用异丙醇500ml洗涤一次，抽干，无水乙醇洗涤2次，每次500ml，经真空干燥得到头孢呋辛钠45.5g。
实施例3：头孢呋辛钠新晶型化合物的制备
(1)将7-ACA 50.5g溶于三氯甲烷1000ml，搅拌状态下，向上述溶液中加入三乙胺51.5g，搅拌30min后，缓慢加入SMIF-Ts 51.1g，保温0～5℃，反应2h，加入蒸馏水500ml，搅拌反应10min。取水层，室温下活性炭5g脱色10min，过滤，滤液冷至0～5℃，缓慢加入2mol/L盐酸溶液调pH值至3.3，析出结晶，搅拌反应1h，过滤，冰水洗涤至中性，40℃真空干燥，得7-FCA 74.9g。
(2)向反应瓶中加入7-FCA 70.1g和甲醇600ml，搅拌下冷至0～5℃，缓慢加入4％的NaCO3水溶液700ml，加完后升温至10℃反应30min，用乙酸乙酯萃取2次，每次1000ml，合并有机层，蒸馏水洗涤2次，每次1000ml，活性炭5g脱色10min，40℃真空干燥，得7-FHCA 50.2g。
(3)向反应瓶中加入丙酮600ml和7-FHCA.45.4g搅拌溶解冷至0℃，缓慢加入三氯乙酰异氰酸酯45.0g，保温反应30min，加入4％的碳酸钠溶液50ml，升温至35℃，反应2h，冷至室温，调节pH至8.7，乙醚萃取3次，每次300ml，取水相，室温下活性炭1.5g脱色10min，过滤，滤液用3mol/L盐酸调pH值至3.3，继续搅拌30min，过滤，蒸馏水洗涤2次，每次200ml，40℃真空干燥得头孢呋辛酸41.8g。
(4)将头孢呋辛酸40.1g溶于异丙醇1000ml、甲醇500ml和去离子水50ml的混合液中，采用活性炭3g脱色10min后过滤。将上述滤液加入异丙醇250ml、甲醇500ml和异辛酸钠13.4g混合溶液中进行结晶，加入4％的氢氧化钠溶液调节pH值至8.8，静置15min，过滤。滤饼使用异丙醇500ml洗涤一次，抽干，无水乙醇洗涤2次，每次500ml，经真空干燥得到头孢呋辛钠41.8g。
测定结果：实施例3头孢呋辛钠的X射线粉末衍射图谱在2θ衍射角为6.52°，6.84°，12.74°，15.57°，17.32°，20.31°，20.96°，22.40°，23.11°，23.82°，28.10°，32.10°，35.40°处显示特征衍射峰。
实施例4：注射用头孢呋辛钠的制备
按照实施例1的步骤制备头孢呋辛钠化合物，采用此原料制备注射用头孢呋 辛钠，规格0.25g。
处方：
Figure PCTCN2016085300-appb-000002
制备过程：
(1)备料：根据原料药含量及水分折算后，按处方量称取头孢呋辛钠；
(2)分装：在充氮的保护下将其分装于洗净并干燥灭菌的西林瓶中，压塞；
(3)轧盖；
对比例1：头孢呋辛钠化合物的制备
按照CN 101955492A中所述的方法制备头孢呋辛钠化合物。
制备过程：
在反应瓶中加入无水乙醇1000ml、异辛酸钠2.6g和含乳酸钠170g的70％乳酸钠水溶液，搅拌至异辛酸钠全部溶解，得到钠液。向另外的一只反应瓶中加入丙酮1350ml、纯化水150ml和头孢呋辛酸680.5g，升温至34-35℃，搅拌使头孢呋辛酸完全溶解；再加入活性炭40g，搅拌脱色，过滤，得到头孢呋辛酸滤液。钠液控温28～30℃，将头孢呋辛酸滤液缓缓加入到钠液中，搅拌，产生沉淀，搅拌45min，过滤，得到头孢呋辛钠湿品。头孢呋辛钠湿品用无水乙醇1250ml和丙酮1000ml的混合液洗涤2次，再用丙酮1750ml洗涤2次，烘干，得到头孢呋辛钠605g。
对比例2：注射用头孢呋辛钠的制备
取对比例1制备头孢呋辛钠化合物，采用此原料制备注射用头孢呋辛钠，规格0.25g。
处方：
Figure PCTCN2016085300-appb-000003
制备过程：
(1)备料：根据原料药含量及水分折算后，按处方量称取头孢呋辛钠；
(2)分装：在充氮的保护下将其分装于洗净并干燥灭菌的西林瓶中，压塞；
(3)轧盖；
试验例1：
本发明人对本发明实施例1和对比例1所制备头孢呋辛钠化合物吸湿性进行了研究。考察条件为相对湿度92.5％(RH)，温度为40℃，考察指标为头孢呋辛钠化合物中的含水量。
检测结果见下表：
表2含水量检测结果
Figure PCTCN2016085300-appb-000004
结果：本发明制备的头孢呋辛钠新晶型化合物本身含水量低且吸湿性明显低于现有技术制备的头孢呋辛钠化合物。说明本发明所述的头孢呋辛钠新晶型化合物稳定性良好，适合药物制剂的制造及长期储存。
试验例2：
本发明人对本发明实施例1和对比例1所制备头孢呋辛钠化合物进行了纯度检测。
纯度检测结果见下表：
表3纯度检测结果
Figure PCTCN2016085300-appb-000005
结果：本发明制备的头孢呋辛钠新晶型化合物纯度明显高于现有技术制备的头孢呋辛钠化合物。
试验例3：
本发明人对本发明实施例4和对比例2所制备注射用头孢呋辛钠进行了加速稳定性考察试验。考察条件为温度40℃±2℃、相对湿度75％±5％。放置6个月，分别于0、1、2、3、6月末取样。考察指标为性状、澄清度、碱度、含量及有关物质。
加速试验考察结果见下表：
表4加速试验考察结果
Figure PCTCN2016085300-appb-000006
Figure PCTCN2016085300-appb-000007
结果：实施例与对比例产品在上述试验条件下放置6个月，含量和有关物质及其他各项指标均未出现明显变化，质量稳定。实施例的颜色较对比例好，且含量较对比例高。
本发明的头孢呋辛钠新晶型化合物及其制剂经各项指标检验和加速试验考察表明稳定性好，质量可靠。

Claims (8)

  1. 一种头孢呋辛钠新晶型化合物，其特征在于，以2θ衍射角表示的X射线粉末衍射图谱在6.52°±0.2°，6.84°±0.2°，12.74°±0.2°，15.57°±0.2°，17.32°±0.2°，20.31°±0.2°，20.96°±0.2°，22.40°±0.2°，23.11°±0.2°，23.82°±0.2°，28.10°±0.2°，32.10°±0.2°，35.40°±0.2°处显示特征衍射峰。
  2. 如权利要求1所述的一种头孢呋辛钠新晶型化合物，其特征在于，制备方法具体步骤为：
    (1)将7-氨基头孢烷酸(7-ACA)溶于试剂1中，加入三乙胺和Z-2-呋喃基-2-甲氧基亚胺乙酸对甲苯磺酸酐(SMIF-Ts)，保温反应，加入蒸馏水搅拌萃取，取水层，脱色，过滤，滤液用盐酸溶液调pH值，过滤、洗涤、真空干燥，得7-[(Z)-2-呋喃基-2-甲氧亚胺乙酰氨基]-3-乙酰氧甲基-3-头孢烷酸(7-FCA)；
    (2)将7-FCA溶于甲醇中，缓慢加入碱水溶液，用乙酸乙酯萃取，取有机层，洗涤，脱色，真空干燥得7-[(Z)-2-呋喃基-2-甲氧亚胺乙酰氨基]-3-羟甲基-3-头核-3-烯-4-羧酸(7-FHCA)；
    (3)7-FHCA溶于丙酮中，缓慢加入三氯乙酰异氰酸酯，保温反应，加入碱水溶液调pH值，乙醚萃取，取水层，脱色，过滤，滤液用盐酸调pH值，析出类白色结晶，过滤，洗涤，40℃真空干燥得头孢呋辛酸；
    (4)将头孢呋辛酸溶于异丙醇、甲醇和去离子水的混合液中，采用活性炭脱色、过滤；将滤液加入异丙醇、甲醇和试剂2混合溶液中进行结晶，调节pH值，静置、过滤、洗涤，真空干燥得到头孢呋辛钠。
  3. 如权利要求2所述的一种制备头孢呋辛钠新晶型化合物的方法，其特征在于步骤(1)中试剂1为二氯甲烷、丙酮、三氯甲烷中的一种或者它们的混合物。
  4. 如权利要求2所述的一种制备头孢呋辛钠新晶型化合物的方法，其特征在于碱水溶液选自氢氧化钠、碳酸氢钠、碳酸钠中的一种或者它们的混合物。
  5. 如权利要求2所述的一种制备头孢呋辛钠新晶型化合物的方法，其特征在于步骤(3)中碱水溶液调节pH值范围为7.0～9.0。
  6. 如权利要求2所述的一种制备头孢呋辛钠新晶型化合物的方法，其特征在于步骤(3)中盐酸调节pH值范围为2.0～4.0。
  7. 如权利要求2所述的一种制备头孢呋辛钠新晶型化合物的方法，其特征在于步骤(4)中试剂2为乳酸钠、醋酸钠、异辛酸钠中的一种。
  8. 一种注射用头孢呋辛钠，其特征在于其含有权利要求1所述的头孢呋辛钠新晶型化合物或权利要求2～7任意一项所述的制备方法制得的头孢呋辛钠新晶型化合物，规格为0.25～2.5g。
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