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WO2018177048A1 - 头孢菌素中间体7α-甲氧基头孢噻吩的结晶及其制备方法 - Google Patents

头孢菌素中间体7α-甲氧基头孢噻吩的结晶及其制备方法 Download PDF

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WO2018177048A1
WO2018177048A1 PCT/CN2018/077000 CN2018077000W WO2018177048A1 WO 2018177048 A1 WO2018177048 A1 WO 2018177048A1 CN 2018077000 W CN2018077000 W CN 2018077000W WO 2018177048 A1 WO2018177048 A1 WO 2018177048A1
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methoxy
cefotaxime
crystal
acid
cephalosporin intermediate
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French (fr)
Inventor
侯传山
汤沸
范美菊
王欣
付景龙
时米超
雷熹
徐红梅
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Qilu Anti Pharmaceutical Co Ltd
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Qilu Anti Pharmaceutical Co Ltd
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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
    • 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
    • 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
    • C07D501/57—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with a further substituent in position 7, e.g. cephamycines
    • 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

Definitions

  • the invention belongs to the field of drug synthesis, relates to crystallization of a cephalosporin intermediate and a preparation method thereof, and particularly relates to crystallization of 7 ⁇ -methoxy cefotaxime and a preparation method thereof.
  • 7 ⁇ -methoxy cefotaxime (I) is called (6R,7S)-3-acetyloxymethyl-7-methoxy-8-oxo-7-[2-(2-thienyl)acetamide 5-]thia-1-nitrobicyclo[4.2.0]oct-2-ene-2-carboxylic acid is an important cephalosporin intermediate mainly used for the synthesis of cefoxitin.
  • 7 ⁇ -methoxy cefotaxime is isolated as a cyclohexylamine salt, as shown in Formula II.
  • the following preparation procedure is disclosed in US Pat. No. 7,662,955: cefotaxime is subjected to a methoxylation reaction in a mixed solvent of dichloromethane and methanol at 90 ° C to form 7 ⁇ -methoxy cefotaxime; after quenching and acid extraction, 7 ⁇ -A is obtained.
  • a solution of oxycephalosporin in methylene chloride is concentrated, and cyclohexylamine is added to precipitate a cyclohexylamine salt.
  • the X-ray powder is diffracted in a 2 ⁇ angle using Cu-Ka radiation, and the crystals of the 7 ⁇ -methoxy cefotaxime are at 7.34°, 12.71°, 13.84°, 14.25°, 14.68°, Characteristic absorption peaks at 15.14°, 15.51°, 16.52°, 16.85°, 17.99°, 19.45°, 19.98°, 20.80°, 21.12°, 21.54°, 22.21°, 22.69°, 22.99°, 23.77° and 25.59°.
  • the X-ray powder diffraction spectrum of the 7 ⁇ -methoxy cefotaxime crystal is 7.34°, 10.54° at 2 ⁇ angle using X-ray powder diffraction expressed by 2 ⁇ angle using Cu-Ka radiation.
  • the X-ray powder diffraction spectrum of the 7 ⁇ -methoxy cefotaxime crystal is as shown in FIG.
  • a preparation method of a cephalosporin intermediate 7 ⁇ -methoxy cefotaxime crystal is one of the following three methods:
  • the organic solvent of the organic solution of 7 ⁇ -methoxycephalosporin in the method (1) is selected from one or a combination of dichloromethane or ethyl acetate.
  • the aqueous solution of 7 ⁇ -methoxy cefotaxime described in the method (2) is prepared by the following method: extracting 7 ⁇ -methoxy cefotaxime from an organic solution with an alkali to obtain an aqueous phase; or Is obtained by dissolving crystalline, amorphous or oily 7 ⁇ -methoxy cefotaxime base in water;
  • the organic solvent of the organic solution is selected from one or a combination of dichloromethane or ethyl acetate; the base is selected from the group consisting of ammonia water, sodium hydroxide, sodium hydrogencarbonate, sodium carbonate, hydrogen.
  • the base is selected from the group consisting of ammonia water, sodium hydroxide, sodium hydrogencarbonate, sodium carbonate, hydrogen.
  • the acid described in the method (2) or (3) is selected from one or a combination of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid or methanesulfonic acid.
  • 7 ⁇ -methoxy cefotaxime crystals are prepared by the method of the present invention, and seed crystals may or may not be seeded. Seed crystals can be prepared with reference to relevant embodiments of the invention, such as Example 1.
  • the preparation method of the cephalosporin intermediate 7 ⁇ -methoxycephalosporin crystal is one of the following three types:
  • the dichloromethane solution containing 7 ⁇ -methoxy cefotaxime and the cyclohexylamine salt of 7 ⁇ -methoxy cefotaxime in the preparation method of the present invention can be prepared by referring to US7662955.
  • the 7 ⁇ -methoxy cefotaxime crystal provided by the invention is easy to prepare, and the related detection data show that 7 ⁇ -methoxy cefotaxime has high crystal purity, low impurity content and good stability.
  • the quality stability of the 7 ⁇ -methoxy cefotaxime crystal provided by the present invention is significantly improved compared with the cyclohexylamine salt, and is more suitable for industrial production, transportation, storage and application.
  • the preparation method involved in the invention no longer uses cyclohexylamine, thereby saving raw material cost; no need to consider the recovery of cyclohexylamine, which is beneficial to reduce environmental pressure and process complexity; and the quality of the product does not exist in the residue of cyclohexylamine risk.
  • the solvent required for the preparation method according to the present invention is a conventional solvent, the preparation cost is low, the preparation method is simple, the conditions are mild and easy to control, and the crystal of 7 ⁇ -methoxy cefotaxime can be stably obtained, which is suitable for industrial production.
  • Example 1 is an X-ray powder diffraction pattern of 7 ⁇ -methoxycephalosporin crystals in Example 1.
  • Test instrument PANalytical powder X-ray diffractometer (model: X'Pert PRO MPD).
  • the target material is copper
  • the light pipe is set to 40KV, 40mA
  • the diffraction mode is reflection
  • the scanning mode is continuous
  • the divergence slit is 1/8°
  • the anti-scatter slit is 1/4°
  • the scanning range is 3 ⁇ 45°
  • scanning step length is 0.026°
  • scanning speed is 8°/min.
  • the X-ray powder diffraction pattern is substantially identical to that of Figure 1.
  • the X-ray powder diffraction pattern is substantially identical to that of Figure 1.
  • Example 3 The preparation method as described in Example 3 was carried out except that the layer was adjusted to pH 4.0 with an aqueous solution of sodium hydrogencarbonate. Final filtration without drying gave 71.7 g of 7 ⁇ -methoxy cefotaxime wet product.
  • the X-ray powder diffraction pattern is substantially identical to that of Figure 1.
  • Example 3 The preparation method as described in Example 3 was carried out except that the layer was adjusted to pH 10.0 with an aqueous solution of potassium carbonate. Finally, 79.5 g of 7 ⁇ -methoxy cefotaxime was obtained.
  • the X-ray powder diffraction pattern is substantially identical to that of Figure 1.
  • Example 3 The preparation method as described in Example 3, except that the aqueous phase obtained by layering is dropped into 110 ml of an aqueous solution of 2 mol/L formic acid, crystallized for 30 minutes, and hydrochloric acid is continuously added to adjust the pH to 2.0, and the temperature is lowered to 0-5. After filtration, washing, and drying, 78.9 g of 7 ⁇ -methoxy cefotaxime was obtained.
  • the X-ray powder diffraction pattern is substantially identical to that of Figure 1.
  • the X-ray powder diffraction pattern is substantially identical to that of Figure 1.
  • the X-ray powder diffraction pattern is substantially identical to that of Figure 1.
  • Example 9 The 7 ⁇ -methoxycephalosporin crystal prepared in Example 1 and the 7 ⁇ -methoxy cefotaxime cyclohexylamine salt prepared in Example 9 were subjected to a 6-month stability accelerated comparison study, and the two products were found to be in appearance and hygroscopicity. There are significant differences in the stability of the content, as shown in Table 1-2:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

本发明涉及一种头孢菌素中间体7α-甲氧基头孢噻吩(I)的结晶及其制备方法。所述的7α-甲氧基头孢噻吩(I)的结晶使用Cu-Ka辐射，以2θ角度表示的X射线粉末衍射，所述的7α-甲氧基头孢噻吩的结晶在7.34°±0.20°，12.71°±0.20°，14.25°±0.20°，14.68°±0.20°，16.52°±0.20°，17.99°±0.20°，19.98°±0.20°和22.69°±0.20°位置有特征吸收峰。本发明提供的7α-甲氧基头孢噻吩结晶易于制备，相关检测数据显示7α-甲氧基头孢噻吩结晶纯度高，杂质含量低，稳定性好。制备成本低廉，制备方法操作简单，条件温和容易控制，可以稳定的获得7α-甲氧基头孢噻吩的结晶，适用于工业化生产。

Description

头孢菌素中间体7α-甲氧基头孢噻吩的结晶及其制备方法 技术领域
本发明属于药物合成领域，涉及一种头孢菌素中间体的结晶及其制备方法，具体涉及7α-甲氧基头孢噻吩的结晶及其制备方法。
背景技术
7α-甲氧基头孢噻吩(Ⅰ)全称为(6R,7S)-3-乙酰基氧甲基-7-甲氧基-8-氧代-7-[2-(2-噻吩基)乙酰胺基]-5-硫杂-1-杂氮双环[4.2.0]辛-2-烯-2-羧酸，是重要的头孢菌素中间体，主要用于头孢西丁的合成。
现有技术中7α-甲氧基头孢噻吩是以环己胺盐的形式分离，如式II所示。US7662955中公开了如下制备流程：零下90℃下，头孢噻吩在二氯甲烷和甲醇的混合溶剂中进行甲氧化反应，生成7α-甲氧基头孢噻吩；经过淬灭和酸化萃取，得到7α-甲氧基头孢噻吩的二氯甲烷溶液，浓缩后加入环己胺即析出其环己胺盐。
Figure PCTCN2018077000-appb-000001
现有技术以环己胺盐形式分离7α-甲氧基头孢噻吩存在如下不足：首先，7α-甲氧基头孢噻吩的工艺原子经济性不好，额外使用环己胺显然会导致成本增加，却不能对最终产物头孢西丁的结构有任何贡献；其次，环己胺可能残留到最终产品中，带来额外的质量风险；再次，该环己胺盐吸湿性强，储存稳定性差，实际上应用于工业生产也并非最佳选择；最后，环己胺盐的分离以及下一步环己胺盐的使用，均需考虑环己胺的回收、纯化和回用以降低成本和减少环境污染，从而增加了整体工艺的复杂性。
现有技术中未见关于7α-甲氧基头孢噻吩的晶体以及其制备方法的报道。
发明内容
针对现有技术的不足，本发明的一个目的在于提供了一种头孢菌素中间体的结晶，即7α-甲氧基头孢噻吩的结晶，本发明的另一个目的在于提供了7α-甲氧基头孢噻吩结晶的制备方法。
本发明的技术方案为：
一种头孢菌素中间体7α-甲氧基头孢噻吩的结晶，使用Cu-Ka辐射，以2θ角度表示的X射线粉末衍射，所述的7α-甲氧基头孢噻吩的结晶在7.34°±0.20°，12.71°±0.20°， 14.25°±0.20°，14.68°±0.20°，16.52°±0.20°，17.99°±0.20°，19.98°±0.20°和22.69°±0.20°位置有特征吸收峰。
根据本发明优选的，使用Cu-Ka辐射，以2θ角度表示的X射线粉末衍射，所述的7α-甲氧基头孢噻吩的结晶在7.34°，12.71°，13.84°，14.25°，14.68°，15.14°，15.51°，16.52°，16.85°，17.99°，19.45°，19.98°，20.80°，21.12°，21.54°，22.21°，22.69°，22.99°，23.77°和25.59°位置有特征吸收峰。
根据本发明进一步优选的，使用Cu-Ka辐射，以2θ角度表示的X射线粉末衍射，所述的7α--甲氧基头孢噻吩结晶的X射线粉末衍射光谱在2θ角为7.34°，10.54°，11.02°，11.51°，12.71°，13.84°，14.25°，14.68°，15.14°，15.51°，16.52°，16.85°，17.99°，18.36°，18.63°，18.98°，19.45°，19.98°，20.80°，21.12°，21.54°，22.21°，22.69°，22.99°，23.77°，24.49°，24.98°，25.59°，26.33°，27.50°，27.81°，28.04°，28.31°，29.15°，29.57°，29.87°，30.42°，31.08°，31.37°，31.97°，33.54°，34.41°，36.29°，37.69°和38.66°位置有特征吸收峰。
根据本发明更进一步优选的，所述的7α-甲氧基头孢噻吩结晶的X射线粉末衍射光谱的图谱如图1所示。
一种头孢菌素中间体7α-甲氧基头孢噻吩结晶的制备方法，为以下三种方法之一：
(1)将7α-甲氧基头孢噻吩的有机溶液减压浓缩结晶；或者
(2)将pH值为4～10的7α-甲氧基头孢噻吩水溶液与酸混合，结晶；或者
(3)将7α-甲氧基头孢噻吩环己胺盐溶于水后酸化结晶。
根据本发明优选的，方法(1)中所述7α-甲氧基头孢噻吩的有机溶液的有机溶剂选自二氯甲烷或乙酸乙酯之一或其组合。
根据本发明优选的，方法(2)中所述的7α-甲氧基头孢噻吩水溶液由如下方法制备：将7α-甲氧基头孢噻吩从其有机溶液中加碱萃取到水相后得到；或者是将结晶的、无定型的或油状的7α-甲氧基头孢噻吩加碱溶于水后得到；
根据本发明进一步优选的，所述的有机溶液的有机溶剂选自二氯甲烷或乙酸乙酯之一或其组合；所述的碱选自氨水、氢氧化钠、碳酸氢钠、碳酸钠、氢氧化钾、碳酸钾、碳酸氢钾或三乙胺中的一种或几种的组合。
根据本发明优选的，方法(2)或(3)中所述的酸选自盐酸、硫酸、磷酸、甲酸、醋酸或甲磺酸中的一种或几种的组合。
根据本发明优选的，采用本发明所述的方法制备7α-甲氧基头孢噻吩结晶，可以加入晶种，也可以不加晶种。晶种可以参考本发明的相关实施例制备，例如实施例1。
根据本发明进一步优选的，头孢菌素中间体7α-甲氧基头孢噻吩结晶的制备方法，为如下三种之一：
(1)将含7α-甲氧基头孢噻吩约85.7g的二氯甲烷溶液1064g，减压浓缩至365g，养晶 180min，继续浓缩至200g，降温到0～5℃，过滤，洗涤，干燥得7α-甲氧基头孢噻吩；
(2)将含7α-甲氧基头孢噻吩85.2g的二氯甲烷溶液1050g，加入质量浓度7％的碳酸氢钠水溶液，至pH7.0，分层，有机相弃去，所得水相即为pH7.0的7α-甲氧基头孢噻吩的水溶液；向该水溶液中加入盐酸调节pH至3.0，加入晶种，养晶30min，继续加入盐酸调节pH至2.0，降温到0～5℃，过滤，洗涤，干燥得7α-甲氧基头孢噻吩；
(3)将7α-甲氧基头孢噻吩环己胺盐100.0g，溶解到300ml水中，加入3mol/L硫酸调节pH至3.0，结晶析出，养晶30min，继续加入3mol/L硫酸调节pH至2.0，降温到0～5℃，过滤，干燥得7α-甲氧基头孢噻吩。
本发明制备方法中的含7α-甲氧基头孢噻吩的二氯甲烷溶液以及7α-甲氧基头孢噻吩的环己胺盐均可参照US7662955制备。
本发明相比现有技术的有益效果如下：
1.本发明提供的7α-甲氧基头孢噻吩结晶易于制备，相关检测数据显示7α-甲氧基头孢噻吩结晶纯度高，杂质含量低，稳定性好。
2.本发明提供的7α-甲氧基头孢噻吩结晶的质量稳定性相比其环己胺盐有显著提高，更适合工业生产、运输、储存和应用。
3.本发明所涉及的制备方法不再使用环己胺，从而节约原料成本；无需考虑环己胺的回收，有利于减小环保压力和工艺复杂性；且产品不存在环己胺残留的质量风险。
4.本发明所涉及的制备方法所需的溶剂是常规溶剂，制备成本低廉，制备方法操作简单，条件温和容易控制，可以稳定的获得7α-甲氧基头孢噻吩的结晶，适用于工业化生产。
附图说明
图1是实施例1中的7α-甲氧基头孢噻吩结晶的X射线粉末衍射图。
具体实施方式
下面结合实施例对本发明做进一步阐述，但本发明所保护范围不限于此。
X射线粉末衍射试验依据：中国药典2015年版通则0451第二法。
试验仪器：PANalytical粉末X射线衍射仪(型号：X’Pert PRO MPD)。
试验方法：靶材料为铜，光管设定为40KV、40mA，衍射模式为反射，扫描方式为连续；发散狭缝为1/8°，防散射狭缝为1/4°，扫描范围为3～45°，扫描步长为0.026°，扫描速度为8°/min。
实施例1
参照US7662955制备得到含7α-甲氧基头孢噻吩约85.7g的二氯甲烷溶液1064g，减压浓缩至365g，养晶180min，继续浓缩至200g，降温到0～5℃，过滤，洗涤，干燥得7α-甲氧基头孢噻吩72.1g。
所得7α-甲氧基头孢噻吩的X射线粉末衍射光谱见图1。
实施例2
参照US7662955制备得到含7α-甲氧基头孢噻吩约84.9g的二氯甲烷溶液1070g，加入7％碳酸氢钠水溶液，至pH7.0，分层，有机相弃去。向水相中加入乙酸乙酯500ml，用6mol/L盐酸调节pH至2.0，分层，有机相即为7α-甲氧基头孢噻吩的乙酸乙酯溶液。将该溶液减压浓缩至250g，加入晶种，养晶30min，结晶析出，继续浓缩至180g，降温到0～5℃，过滤，干燥得7α-甲氧基头孢噻吩78.7g。
X射线粉末衍射图与图1基本一致。
实施例3
参照US7662955制备得到含7α-甲氧基头孢噻吩85.2g的二氯甲烷溶液1050g，加入7％碳酸氢钠水溶液，至pH7.0，分层，有机相弃去，所得水相即为pH7.0的7α-甲氧基头孢噻吩的水溶液。向该水溶液中加入盐酸调节pH至3.0，加入晶种，养晶30min，继续加入盐酸调节pH至2.0，降温到0～5℃，过滤，洗涤，干燥得7α-甲氧基头孢噻吩79.4g。
X射线粉末衍射图与图1基本一致。
实施例4
如实施例3所述的制备方法，不同之处在于：用碳酸氢钠水溶液调节到pH4.0分层。最终过滤而不干燥，得7α-甲氧基头孢噻吩湿品71.7g。
取少许湿品，干燥后进行衍射实验，其余湿品直接用于头孢西丁的下一步合成。
X射线粉末衍射图与图1基本一致。
实施例5
如实施例3所述的制备方法，不同之处在于：用碳酸钾水溶液调节到pH10.0分层。最终得7α-甲氧基头孢噻吩79.5g。
X射线粉末衍射图与图1基本一致。
实施例6
如实施例3所述的制备方法，不同之处在于：将分层所得水相滴入到2mol/L甲酸的水溶液110ml中，养晶30min，继续加入盐酸调节pH至2.0，降温到0～5℃，过滤，洗涤，干燥得得7α-甲氧基头孢噻吩78.9g。
X射线粉末衍射图与图1基本一致。
实施例7
参照US7662955制备得到7α-甲氧基头孢噻吩环己胺盐100.0g，溶解到300ml水中，加入3mol/L硫酸调节pH至3.0，结晶析出，养晶30min，继续加入3mol/L硫酸调节pH至2.0，降温到0～5℃，过滤，干燥得7α-甲氧基头孢噻吩70.4g。
X射线粉末衍射图与图1基本一致。
实施例8
将2mol/L醋酸的水溶液200ml和6mol/L盐酸10ml混合均匀，将7α-甲氧基头孢噻吩环己胺盐100.0g分次投入其中，加入晶种，养晶30min，继续加入盐酸调节pH至2.0，降温到 0～5℃，过滤，洗涤，干燥得7α-甲氧基头孢噻吩74.9g。
X射线粉末衍射图与图1基本一致。
实施例9
参照US7662955制备7α-甲氧基头孢噻吩的二氯甲烷溶液以及7α-甲氧基头孢噻吩环己胺盐：
将100g头孢噻吩钠加入到二氯甲烷806ml和甲醇83ml的混合溶剂中，降温到-20℃，加入甲磺酸25.3g。降温到-90℃，控温加入N-氯代琥珀酰亚胺60.8g，再加入30％甲醇钠溶液(337.3g)和甲醇160ml混合形成的溶液。反应完成后，加入焦亚硫酸钠20.6g、80％醋酸的水溶液150ml和氯化钠溶液(189g溶于1164ml水)。在0℃加入6N盐酸23.5ml，静止分层。所得有机相用水洗涤去除其中的少量甲醇，即得到7α-甲氧基头孢噻吩的二氯甲烷溶液约1070g，其中含7α-甲氧基头孢噻吩约86g。将该溶液减压浓缩至500ml，加入环己胺至pH6.5，然后加入异丙醚，于0℃搅拌120min，过滤，丙酮洗涤，干燥得到7α-甲氧基头孢噻吩环己胺盐101.0g。
实施例10
将实施例1制备的7α-甲氧基头孢噻吩结晶与实施例9制备的7α-甲氧基头孢噻吩环己胺盐进行6个月稳定性加速对比研究，发现两种产品在外观、吸湿性和含量稳定性方面存在明显差异，具体见表1-2：
表1实施例1的7α-甲氧基头孢噻吩结晶实验结果
Figure PCTCN2018077000-appb-000002
由实施例2-8制备的7α-甲氧基头孢噻吩结晶进行6个月稳定性加速实验，所得的结果同表1基本一致。
表2实施例9制备的7α-甲氧基头孢噻吩环己胺盐实验结果
Figure PCTCN2018077000-appb-000003
结论：通过以上6个月稳定性加速对比研究实验可知，本发明制备的7α-甲氧基头孢噻吩结晶与实施例9制备的7α-甲氧基头孢噻吩环己胺盐在外观、吸湿性和含量稳定性方面存在明显差异，本发明的结晶纯度高，质量稳定性更好。

Claims (10)

  1. 一种头孢菌素中间体7α-甲氧基头孢噻吩的结晶，其特征在于，使用Cu-Ka辐射，以2θ角度表示的X射线粉末衍射，所述的7α-甲氧基头孢噻吩的结晶在7.34°±0.20°，12.71°±0.20°，14.25°±0.20°，14.68°±0.20°，16.52°±0.20°，17.99°±0.20°，19.98°±0.20°和22.69°±0.20°位置有特征吸收峰。
  2. 如权利要求1所述的头孢菌素中间体7α-甲氧基头孢噻吩的结晶，其特征在于，使用Cu-Ka辐射，以2θ角度表示的X射线粉末衍射，所述的7α-甲氧基头孢噻吩的结晶在7.34°，12.71°，13.84°，14.25°，14.68°，15.14°，15.51°，16.52°，16.85°，17.99°，19.45°，19.98°，20.80°，21.12°，21.54°，22.21°，22.69°，22.99°，23.77°和25.59°位置有特征吸收峰。
  3. 如权利要求1或2所述的头孢菌素中间体7α-甲氧基头孢噻吩的结晶，其特征在于，使用Cu-Ka辐射，以2θ角度表示的X射线粉末衍射，所述的7α--甲氧基头孢噻吩结晶的X射线粉末衍射光谱在2θ角为7.34°，10.54°，11.02°，11.51°，12.71°，13.84°，14.25°，14.68°，15.14°，15.51°，16.52°，16.85°，17.99°，18.36°，18.63°，18.98°，19.45°，19.98°，20.80°，21.12°，21.54°，22.21°，22.69°，22.99°，23.77°，24.49°，24.98°，25.59°，26.33°，27.50°，27.81°，28.04°，28.31°，29.15°，29.57°，29.87°，30.42°，31.08°，31.37°，31.97°，33.54°，34.41°，36.29°，37.69°和38.66°位置有特征吸收峰。
  4. 如权利要求1-3任一所述的头孢菌素中间体7α-甲氧基头孢噻吩的结晶，其特征在于，所述的7α-甲氧基头孢噻吩结晶的X射线粉末衍射光谱的图谱如7α-甲氧基头孢噻吩结晶的X射线粉末衍射图所示。
  5. 如权利要求1-3任一所述的头孢菌素中间体7α-甲氧基头孢噻吩的结晶的制备方法，其特征在于，为以下三种方法之一：
    (1)将7α-甲氧基头孢噻吩的有机溶液减压浓缩结晶；或者
    (2)将pH值为4～10的7α-甲氧基头孢噻吩水溶液与酸混合，结晶；或者
    (3)将7α-甲氧基头孢噻吩环己胺盐溶于水后酸化结晶。
  6. 如权利要求5所述的头孢菌素中间体7α-甲氧基头孢噻吩的结晶的制备方法，其特征在于，方法(1)中所述7α-甲氧基头孢噻吩的有机溶液的有机溶剂选自二氯甲烷或乙酸乙酯之一或其组合。
  7. 如权利要求5所述的头孢菌素中间体7α-甲氧基头孢噻吩的结晶的制备方法，其特征在于，方法(2)中所述的7α-甲氧基头孢噻吩水溶液由如下方法制备：将7α-甲氧基头孢噻吩从其有机溶液中加碱萃取到水相后得到；或者是将结晶的、无定型的或油状的7α-甲氧基头孢噻吩加碱溶于水后得到。
  8. 如权利要求7所述的头孢菌素中间体7α-甲氧基头孢噻吩的结晶的制备方法，其特征在于，所述的有机溶液的有机溶剂选自二氯甲烷或乙酸乙酯之一或其组合；所述的碱选自氨水、氢氧化钠、碳酸氢钠、碳酸钠、氢氧化钾、碳酸钾、碳酸氢钾或三乙胺中的一种或几种的组合。
  9. 如权利要求5所述的头孢菌素中间体7α-甲氧基头孢噻吩的结晶的制备方法，其特征在于，方法(2)或(3)中所述的酸选自盐酸、硫酸、磷酸、甲酸、醋酸或甲磺酸中的一种或几种的组合；采用本发明所述的方法制备7α-甲氧基头孢噻吩结晶，加入晶种或不加晶种。
  10. 如权利要求5所述的头孢菌素中间体7α-甲氧基头孢噻吩的结晶的制备方法，其特征在于，为如下三种之一：
    (1)将含7α-甲氧基头孢噻吩约85.7g的二氯甲烷溶液1064g，减压浓缩至365g，养晶180min，继续浓缩至200g，降温到0～5℃，过滤，洗涤，干燥得7α-甲氧基头孢噻吩；
    (2)将含7α-甲氧基头孢噻吩85.2g的二氯甲烷溶液1050g，加入质量浓度7％的碳酸氢钠水溶液，至pH7.0，分层，有机相弃去，所得水相即为pH7.0的7α-甲氧基头孢噻吩的水溶液；向该水溶液中加入盐酸调节pH至3.0，加入晶种，养晶30min，继续加入盐酸调节pH至2.0，降温到0～5℃，过滤，洗涤，干燥得7α-甲氧基头孢噻吩；
    (3)将7α-甲氧基头孢噻吩环己胺盐100.0g，溶解到300ml水中，加入3mol/L硫酸调节pH至3.0，结晶析出，养晶30min，继续加入3mol/L硫酸调节pH至2.0，降温到0～5℃，过滤，干燥得7α-甲氧基头孢噻吩。
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