WO2023202567A1 - 一种头孢噻肟钠的精制方法 - Google Patents
一种头孢噻肟钠的精制方法 Download PDFInfo
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- WO2023202567A1 WO2023202567A1 PCT/CN2023/088936 CN2023088936W WO2023202567A1 WO 2023202567 A1 WO2023202567 A1 WO 2023202567A1 CN 2023088936 W CN2023088936 W CN 2023088936W WO 2023202567 A1 WO2023202567 A1 WO 2023202567A1
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- cefotaxime
- turbulence
- temperature
- ethyl acetate
- sodium
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- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 title claims abstract description 28
- 229960002727 cefotaxime sodium Drugs 0.000 title claims abstract description 28
- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000007670 refining Methods 0.000 title claims abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000003756 stirring Methods 0.000 claims abstract description 24
- 239000013078 crystal Substances 0.000 claims abstract description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 20
- GPRBEKHLDVQUJE-VINNURBNSA-N cefotaxime Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-VINNURBNSA-N 0.000 claims abstract description 20
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 14
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims abstract description 11
- 235000017281 sodium acetate Nutrition 0.000 claims abstract description 11
- 239000001632 sodium acetate Substances 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000001914 filtration Methods 0.000 claims abstract description 8
- 238000005406 washing Methods 0.000 claims abstract description 7
- 239000012046 mixed solvent Substances 0.000 claims abstract description 5
- 239000000706 filtrate Substances 0.000 claims abstract description 3
- 229960004261 cefotaxime Drugs 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims 7
- 239000000047 product Substances 0.000 abstract description 15
- 239000012535 impurity Substances 0.000 abstract description 7
- 238000002425 crystallisation Methods 0.000 abstract description 5
- 239000002904 solvent Substances 0.000 abstract description 5
- 238000001291 vacuum drying Methods 0.000 abstract description 5
- 230000008025 crystallization Effects 0.000 abstract description 2
- 238000005352 clarification Methods 0.000 abstract 1
- 239000008213 purified water Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 206010061695 Biliary tract infection Diseases 0.000 description 1
- 206010005940 Bone and joint infections Diseases 0.000 description 1
- 241000588921 Enterobacteriaceae Species 0.000 description 1
- 206010022678 Intestinal infections Diseases 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- -1 oxime cephalosporins Chemical class 0.000 description 1
- 238000012372 quality testing Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
Classifications
-
- 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
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
-
- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to the field of medical technology, specifically to a method for refining cefotaxime sodium.
- Cefotaxime sodium is a third-generation cephalosporin. Semi-synthetic oxime cephalosporins have strong effects on Gram-negative bacteria, especially Enterobacteriaceae. It is mainly used for respiratory system infections, urinary system infections, biliary tract and intestinal infections, skin and soft tissue infections, burns and bone and joint infections caused by sensitive bacteria.
- the chemical name of cefotaxime is: 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino]-acetamido-3-cephalosporin-4 -Carboxylic acid, the structural formula is as follows:
- CN102584854A discloses a method for preparing cefotaxime sodium crystals in an anhydrous solution system. The method uses formamide, acetamide, dimethyl sulfoxide or methanol as the solvent system. This method is easy to operate and has a short production cycle, but the prepared product has a high residual amount of organic solvent, making it difficult to reuse the solvent, and the product solution has poor clarity.
- CN101486719A discloses a crystallization method that uses acetone aqueous solution as the solvent system. Although it solves the problem of poor clarity of the prepared product solution, the stability of the product prepared using this method is poor. Therefore, it is of great significance to study a high-quality cefotaxime sodium product with good clarity, few impurities and good stability.
- the object of the present invention is to provide a method for refining cefotaxime sodium to solve the problems of large impurity content, poor clarity and unsatisfactory stability of existing products.
- a method for refining cefotaxime sodium including the following steps:
- step (1) the ratio of the amount of water in the mixed solvent to the feeding amount of cefotaxime is 0.1-0.2L: 1kg; the ratio of the amount of methanol to the feeding amount of cefotaxime is 2-3L: 1kg; the amount of acetone
- the dosage ratio with cefotaxime acid is 0.5 ⁇ 1L:1kg.
- step (1) the mass ratio of the added sodium acetate to cefotaxime acid is 35-45:200; when adding sodium acetate and stirring to dissolve, the temperature is controlled at 0 to 5°C.
- step (2) the temperature is controlled between -3°C and 10°C.
- step (3) the temperature is controlled to be 0 to 5°C.
- step (3) the rapid addition is within 1 to 10 seconds.
- step (3) the ratio of the added ethyl acetate to cefotaxime acid is 2-5L:1kg.
- step (5) the slow addition of ethyl acetate has a flow rate of 20 to 40 mL/min.
- step (5) the ratio of the added ethyl acetate to cefotaxime acid is 10-14L:1kg.
- the crystal growing time is 20-40 minutes.
- the invention adopts rapid turbulent crystallization to improve the product quality of cefotaxime sodium.
- the present invention uses a variety of solvents during refining, which can increase the solubility of different impurities and reduce impurities entrained in the crystal, thereby improving product quality.
- Test conditions temperature: 40°C ⁇ 2°C, relative humidity: 75% ⁇ 5%, acceleration time: 6 months.
- the test results are shown in Table 2.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Cephalosporin Compounds (AREA)
Abstract
一种头孢噻肟钠的精制方法，包括以下步骤：(1)将头孢噻肟酸溶解到水、甲醇和丙酮的混合溶剂中，加入醋酸钠，搅拌溶解澄清；(2)加入活性炭搅拌，然后过滤；(3)在强烈湍流下向滤液中快速加入乙酸乙酯；所述强烈湍流为雷诺数在11000以上；(4)在缓和湍流下养晶；所述缓和湍流为雷诺数达到4000～6000；(5)在快速湍流下缓慢加入乙酸乙酯，并继续养晶，所述快速湍流为雷诺数达到6500～8000；(6)养晶结束后，经过滤、洗涤、真空干燥，即得所述头孢噻肟钠。上述方法采用快速湍流结晶，且采用多种溶剂，能够增加不同杂质的溶解度，减少结晶夹带杂质，提高了产品质量。
Description
本发明涉及医药技术领域，具体地说是涉及一种头孢噻肟钠的精制方法。
头孢噻肟钠为第三代头孢菌素。半合成肟型头孢菌素对革兰阴性菌、尤其对肠杆菌作用强大。主要用于敏感菌所致呼吸系统感染、泌尿系统感染、胆道及肠道感染、皮肤及软组织感染、烧伤和骨关节感染等。头孢噻肟酸化学名为：3-乙酰氧基甲基-7-[2-(2-氨基-4-噻唑基)-2-甲氧亚胺基]-乙酰胺基-3-头孢-4-羧酸，结构式如下、：
在头孢噻肟钠存放过程中，容易出现色级、杂质等变化较大的问题，影响了产品的质量。头孢噻肟钠结晶方法通常采用无水体系结晶法。如CN102584854A公开了一种在无水溶液体系中制备头孢噻肟钠晶体的方法，该方法采用甲酰胺、乙酰胺、二甲基亚砜或甲醇为溶媒体系。该方法操作简便、生产周期短，但所制备的产品有机溶剂残留量较高，溶剂重复利用难度较大，且产品溶液的澄清度较差。CN101486719A公开了一种选用丙酮水溶液作为溶媒体系的结晶方法，虽然解决了制备产品溶液的澄清度较差的问题，但使用该方法所制备的产品的稳定性较差。因此，研究一种澄清度好、杂质少且稳定性好的高质量头孢噻肟钠产品具有重要的意义。
发明内容
本发明的目的是提供一种头孢噻肟钠的精制方法，以解决现有产品杂质含量较大、澄清度差和稳定性不理想的问题。
本发明的目的是这样实现的：一种头孢噻肟钠的精制方法，包括以下步骤：
(1)将头孢噻肟酸溶解到水、甲醇和丙酮的混合溶剂中，加入醋酸钠，搅拌溶解澄清；
(2)控温，加入活性炭搅拌，然后过滤；
(3)控温，在强烈湍流下向滤液中快速加入乙酸乙酯；继续保持强烈湍流10～60s，所述强烈湍流为雷诺数在11000以上；
(4)控温，在缓和湍流下养晶；所述缓和湍流为雷诺数达到4000～6000；
(5)控温，在快速湍流下缓慢加入乙酸乙酯，并继续养晶，所述快速湍流为雷诺数达到6500～8000；
(6)养晶结束后，经过滤、洗涤、干燥，即得所述头孢噻肟钠。
步骤(1)中，所述的混合溶剂中水的用量与头孢噻肟酸投料量比例为0.1～0.2L：1kg；甲醇用量与头孢噻肟酸投料量比例为2～3L：1kg；丙酮用量与头孢噻肟酸投料量比例为0.5～1L：1kg。
步骤(1)中，加入的醋酸钠的质量与头孢噻肟酸的质量比为35-45：200；加入醋酸钠并搅拌溶解时，温度控制在0～5℃。
步骤(2)中，控温为-3～10℃。
步骤(3)至步骤(5)中，控温为0～5℃。
步骤(3)中，所述的快速加入为1～10s内加入。
步骤(3)中，加入的乙酸乙酯与头孢噻肟酸投料量的比例为2～5L：1kg。
步骤(5)中，所述的缓慢加入为乙酸乙酯流速20～40mL/min。
步骤(5)中，加入的乙酸乙酯与头孢噻肟酸投料量的比例为10～14L：1kg。
步骤(4)和步骤(5)中，养晶时间均为20-40min。
由于采用了上述技术方案，本发明取得的技术进步是：
本发明采用快速湍流结晶，提高了头孢噻肟钠的产品质量。
本发明在精制时采用多种溶剂，能够增加不同杂质的溶解度，减少结晶夹带杂质，从而提高产品质量。
下面结合实施例对本发明做进一步的阐述，下述实施例仅作为说明，并不以任何方式限制本发明的保护范围。
在下述实施例中未详细描述的过程和方法是本领域公知的常规方法，实施例中所用试剂均为分析纯或化学纯，且均可市购或通过本领域普通技术人员熟知的方法制备。下述实施例均实现了本发明的目的。
实施例1
取200g头孢噻肟酸，加入25ml纯化水，580ml甲醇，200ml丙酮，搅拌至溶清；再加入醋酸钠40g，控温2±2℃，搅拌溶解澄清。之后加入活性炭搅拌，然后过滤。
在雷诺数为12000的湍流状态下，10s内加入乙酸乙酯600ml，控制温度2±2℃，搅拌30s，降低雷诺数到4000，养晶30min，控制温度2±2℃。
再次用90min在雷诺数为6500湍流状态下加入2500ml乙酸乙酯，养晶30min，控制温度2±2℃。最后过滤、洗涤、真空干燥后，得到头孢噻肟钠成品。
实施例2
取200g头孢噻肟酸，加入20ml纯化水，400ml甲醇，150ml丙酮，搅拌至溶清；再加入醋酸钠40g，控温2±2℃，搅拌溶解澄清。之后加入活性炭搅拌，然后过滤。
雷诺数为11000的湍流状态下，10s内加入乙酸乙酯1000ml，控制温度2±2℃，搅拌30s，降低雷诺数到5000，养晶20min，控制温度2±2℃。
再次用90min在雷诺数为7000湍流状态下加入2000ml乙酸乙酯，养晶20min，控温2±2℃。最后过滤、洗涤、真空干燥后，得到头孢噻肟钠成品。
实施例3
取200g头孢噻肟酸，加入40ml纯化水，600ml甲醇，100ml丙酮，搅拌至溶清；再加入醋酸钠40g，控温2±2℃，搅拌溶解澄清。之后加入活性炭搅拌，然后过滤。
雷诺数为13000的湍流状态下，10s内加入乙酸乙酯400ml，控制温度2±2℃，搅拌30s，降低雷诺数到6000，养晶40min，控制温度2±2℃。
再次用90min在雷诺数为8000湍流状态下加入2800ml乙酸乙酯，养晶40min，控制温度2±2℃。最后过滤、洗涤、真空干燥后，得到头孢噻肟钠成品。
对比例1
取200g头孢噻肟酸，加入25ml纯化水，580ml甲醇，200ml丙酮，搅拌至溶清；再加入醋酸钠40g，控温2±2℃，搅拌溶解澄清。之后加入活性炭搅拌，然后过滤。
雷诺数为12000的湍流状态下，10s内加入乙酸乙酯600ml，控制温度2±2℃，搅拌30s，降低雷诺数到4000，养晶30min，控制温度2±2℃。再次用90min保持雷诺数为4000状态下加入2500ml乙酸乙酯，养晶30min，控制温度2±2℃。最后过滤、洗涤、真空干燥后，得到头孢噻肟钠成品。
对上述产品进行质量检测，结果见表1所示。
表1：
加速试验对比：
试验条件：温度：40℃±2℃，相对湿度：75％±5％，加速时间：6个月。试验结果见表2所示。
表2：
Claims (10)
- 一种头孢噻肟钠的精制方法，其特征在于，包括以下步骤：(1)将头孢噻肟酸溶解到水、甲醇和丙酮的混合溶剂中，加入醋酸钠，搅拌溶解澄清；(2)控温，加入活性炭搅拌，然后过滤；(3)控温，在强烈湍流下向滤液中快速加入乙酸乙酯；继续保持强烈湍流10～60s，所述强烈湍流为雷诺数在11000以上；(4)控温，在缓和湍流下养晶；所述缓和湍流为雷诺数达到4000～6000；(5)控温，在快速湍流下缓慢加入乙酸乙酯，并继续养晶，所述快速湍流为雷诺数达到6500～8000；(6)养晶结束后，经过滤、洗涤、干燥，即得所述头孢噻肟钠。
- 根据权利要求1所述的头孢噻肟钠的精制方法，其特征在于，步骤(1)中，所述的混合溶剂中水的用量与头孢噻肟酸投料量比例为0.1～0.2L：1kg；甲醇用量与头孢噻肟酸投料量比例为2～3L：1kg；丙酮用量与头孢噻肟酸投料量比例为0.5～1L：1kg。
- 根据权利要求1所述的头孢噻肟钠的精制方法，其特征在于，步骤(1)中，加入的醋酸钠的质量与头孢噻肟酸的质量比为35-45：200；加入醋酸钠并搅拌溶解时，温度控制在0～5℃。
- 根据权利要求1所述的头孢噻肟钠的精制方法，其特征在于，步骤(2)中，控温为-3～10℃。
- 根据权利要求1所述的头孢噻肟钠的精制方法，其特征在于，步骤(3)至步骤(5)中，控温为0～5℃。
- 根据权利要求1所述的头孢噻肟钠的精制方法，其特征在于，步骤(3)中，所述的快速加入为1～10s内加入。
- 根据权利要求1所述的头孢噻肟钠的精制方法，其特征在于，步骤(3)中，加入的乙酸乙酯与头孢噻肟酸投料量的比例为2～5L：1kg。
- 根据权利要求1所述的头孢噻肟钠的精制方法，其特征在于，步骤(5)中，所述的缓慢加入为乙酸乙酯流速20～40mL/min。
- 根据权利要求1所述的头孢噻肟钠的精制方法，其特征在于，步骤(5)中，加入的乙酸乙酯与头孢噻肟酸投料量的比例为10～14L：1kg。
- 根据权利要求1所述的头孢噻肟钠的精制方法，其特征在于，步骤(4)和步骤(5)中，养晶时间均为20-40min。
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| CN101486719A (zh) * | 2009-02-17 | 2009-07-22 | 福建省福抗药业股份有限公司 | 头孢噻肟酸转钠盐结晶方法 |
| CN104086569A (zh) * | 2014-07-29 | 2014-10-08 | 石药集团中诺药业（石家庄）有限公司 | 一种头孢噻肟钠的制备方法 |
| CN113024580A (zh) * | 2021-03-10 | 2021-06-25 | 苏州东瑞制药有限公司 | 一种头孢噻肟钠的制备方法 |
| CN114874237A (zh) * | 2022-04-21 | 2022-08-09 | 华北制药河北华民药业有限责任公司 | 一种头孢噻肟钠的精制方法 |
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| CN101486719A (zh) * | 2009-02-17 | 2009-07-22 | 福建省福抗药业股份有限公司 | 头孢噻肟酸转钠盐结晶方法 |
| CN104086569A (zh) * | 2014-07-29 | 2014-10-08 | 石药集团中诺药业（石家庄）有限公司 | 一种头孢噻肟钠的制备方法 |
| CN113024580A (zh) * | 2021-03-10 | 2021-06-25 | 苏州东瑞制药有限公司 | 一种头孢噻肟钠的制备方法 |
| CN114874237A (zh) * | 2022-04-21 | 2022-08-09 | 华北制药河北华民药业有限责任公司 | 一种头孢噻肟钠的精制方法 |
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