WO2018028496A1 - 一种甲氨蝶呤或其盐的纯化工艺 - Google Patents

一种甲氨蝶呤或其盐的纯化工艺 Download PDF

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WO2018028496A1
WO2018028496A1 PCT/CN2017/095805 CN2017095805W WO2018028496A1 WO 2018028496 A1 WO2018028496 A1 WO 2018028496A1 CN 2017095805 W CN2017095805 W CN 2017095805W WO 2018028496 A1 WO2018028496 A1 WO 2018028496A1
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water
solution
methotrexate
organic solvent
purification process
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PCT/CN2017/095805
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English (en)
French (fr)
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毛文纲
严伟
顾贤德
唐波
赵栩强
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浙江海正药业股份有限公司
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Priority to CN201780042040.4A priority Critical patent/CN109641905B/zh
Publication of WO2018028496A1 publication Critical patent/WO2018028496A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
    • C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2

Definitions

  • the invention relates to a purification process of a compound, in particular to a purification process of methotrexate or a salt thereof.
  • Methotrexate is an immunosuppressive agent that works by competitive inhibition of dihydrofolate reductase. It has been used to treat childhood leukemia since its discovery in the 1940s. It has been used in the treatment of psoriasis since the 1950s. It is now a commonly used anti-malignant drug in clinical practice, mainly for acute leukemia, breast cancer, and chorionic epithelium. Cancer and malignant mole, head and neck tumor, bone tumor, leukemia meningeal spinal cord infiltration, lung cancer, reproductive system tumor, liver cancer, intractable common psoriasis, rheumatoid arthritis / autoimmune disease.
  • tetraaminopyrimidine sulfate, p-methylaminobenzoyl L-glutamic acid and tribromoacetone are synthesized into methotrexate.
  • the alkali is adjusted with ammonia water, and the filtrate is repeatedly passed.
  • Multiple acid-base adjustments two consecutive After adjusting the acid, and then adjusting the alkali and acid), filtering the obtained filter cake and adjusting the alkali, filtering, adding the filtrate to acetone to prepare the methotrexate sodium salt, and then adding sulfuric acid crystal to obtain the methotrexate product.
  • the method has good yield and purity, but the post-treatment and purification process is extremely cumbersome, and due to repeated adjustment of acid and alkali, it is necessary to use a large amount of ammonia water and a large amount of hydrochloric acid, etc., which has a great impact on the environment.
  • Zhou Wei et al. published an improvement in the purification process of methotrexate in the Journal of Chinese Pharmaceutical Industry 1990, 21 (12).
  • the methotrexate sample was adjusted with ammonia water, filtered, and the filtrate was acid-treated, filtered, and filtered.
  • the cake was adjusted with alkali and filtered, and the obtained filtrate was crystallized from acetone, and the cake was crystallized with sulfuric acid to obtain pure methotrexate.
  • the method still uses hydrochloric acid and ammonia water to adjust the acid and alkali, and requires more ammonia water and environmental pollution. Therefore, there is an urgent need for an economical, environmentally friendly, and commercially viable methotrexate
  • the object of the present invention is to provide a purification process of methotrexate or a salt thereof which has simple process, convenient operation, high yield and good reproducibility, and the process has the advantages of economy, environmental protection and commercialization.
  • the invention provides a purification process of methotrexate or a salt thereof, comprising the following steps:
  • the pH of the aqueous solution of methotrexate is adjusted to 1.0 to 3.0 at a temperature of 0 to 60 ° C, and filtered to obtain a filter cake;
  • step b) alkali adjustment: the filter cake obtained in step b) is added to water or an aqueous solution of an organic solvent to adjust the pH to a basic range to obtain a lye;
  • step a) comprises reacting tetraaminopyrimidine sulfate, p-methylaminobenzoyl L-glutamate zinc salt and tribromoacetone under acidic conditions with water as a reaction solvent , an aqueous solution of methotrexate was obtained.
  • the organic solvents in steps c) and d) may be the same organic solvent or a mixture of the same organic solvent.
  • the organic solvent mixture may be a mixture of two or more organic solvents.
  • the acidic conditions in step a) are preferably pH between 1.5 and 2.5.
  • the reagent used to adjust the pH of the reaction solution in step b) is hydrochloric acid water.
  • the solution or aqueous sodium hydroxide; additionally and independently, the pH is preferably controlled in the range of 1.5 to 2.5, more preferably 1.8 to 2.0.
  • the temperature in step b) is preferably controlled at 40 to 60 ° C, more preferably 45 to 55 ° C.
  • the pH is adjusted in step c) with an alkaline solution
  • the alkaline solution is an aqueous solution of an inorganic strong base, preferably an aqueous solution of sodium hydroxide or potassium hydroxide, more preferably an aqueous solution of sodium hydroxide.
  • the amount of the alkaline solution in the step c) is 3% to 30%, preferably 5%, based on the total mass of the system obtained by adding the filtered cake to water or an aqueous solution of an organic solvent. 20%, more preferably 8 to 15%.
  • the basic range described in step c) is 7.0 ⁇ pH ⁇ 10.0, preferably pH 8.0 to 9.0.
  • the organic solvent employed in steps c) and d) is a water-miscible organic solvent, preferably acetone, tetrahydrofuran, acetonitrile or an alcohol, more preferably acetone.
  • the volume ratio of water to organic solvent in the aqueous solution of the organic solvent in step c) is from 1:0 to 1:3, preferably 1:1.
  • the organic solvent is used in step d) in an amount of from 3 to 10 times the volume of water added in step c) or the volume of water contained in the aqueous solution of organic solvent added in step c) It is preferably 5 to 7 times.
  • the purification process of the present invention controls the pH and temperature of the reaction liquid by the reaction liquid pretreatment step of step b), and the pretreatment step of the reaction liquid can synergistically control the methotrexate isomer (structure is as follows) in the reaction liquid
  • the solubility in the solution is further filtered to remove the methotrexate isomer to solve the problem of difficult removal of subsequent isomers.
  • the main purpose of repeating the acid crystallization is to remove the methotrexate isomer.
  • the invention simplifies the separation and purification process of methotrexate or its salt, avoids the use of a large amount of ammonia water and hydrochloric acid, and at the same time, the obtained product has high yield and good quality reproducibility, and the solvent used can be recycled. It is suitable for industrial production; the purification method of the invention has the advantages of economy, environmental protection, and commercialization.
  • liquid phase test conditions involved in the present invention are:
  • the column is C18 5 ⁇ m 4.6 ⁇ 250mm;
  • pH 6.0 buffer Prepare a mixture of 0.2 M disodium hydrogen phosphate and 0.1 M citric acid (volume ratio: 630:370), if necessary, 0.1 M citric acid or 0.2 M hydrogen phosphate Sodium adjusts the pH to 6.0;
  • Preparation of mobile phase a mixture of pH 6.0 buffer and acetonitrile prepared above (volume ratio of 90:10), filtered and degassed;
  • the detection wavelength was 302 nm; the flow rate was 1.2 ml/min; the injection amount was 20 ⁇ l; and the column temperature was room temperature.
  • the temperature of the reaction solution is controlled to 45 ° C, the pH is adjusted to 1.8 with dilute hydrochloric acid, filtered, washed with water, and the filter cake is added with 35 ml of water and 35 ml of acetone, and a 10% (mass%) aqueous solution of NaOH is added dropwise to adjust the pH to 8.5, and filtered.
  • the temperature of the reaction solution is controlled to 30 ° C, the pH is adjusted to 1.5 with dilute hydrochloric acid, filtered, washed with water, the filter cake is added with 35 ml of water and 35 ml of acetone, and 10% (mass percent) aqueous NaOH solution is added dropwise to adjust the pH to 8.5, and filtered.
  • the temperature of the reaction solution is controlled to 40 ° C, the pH is adjusted to 1.7 with dilute hydrochloric acid, filtered, washed with water, and the filter cake is added with 35 ml of water and 35 ml of acetone, and a 10% (mass%) aqueous solution of NaOH is added dropwise to adjust the pH to 8.5, and filtered.
  • the temperature of the reaction solution is controlled to 50 ° C, the pH is adjusted to 2.0 with dilute hydrochloric acid, filtered, washed with water, and the filter cake is added with 35 ml of water and 35 ml of acetone, and a 10% (mass%) aqueous solution of NaOH is added dropwise to adjust the pH to 8.5, and filtered.
  • the temperature of the reaction solution is controlled to be 55 ° C, 20% (mass%) aqueous NaOH solution is adjusted to pH 2.5, filtered, washed with water, and the filter cake is added with 35 ml of water and 35 ml of acetone, and 10% (by mass) of aqueous NaOH solution is added dropwise.
  • the methotrexate disodium salt yellow solid was 10.3 g, the yield was 64.8%, the purity was 97.35%, and the isomer content was 0.17%.
  • the temperature of the reaction solution is controlled to 50 ° C, the pH is adjusted to 2.0 with dilute hydrochloric acid, filtered, washed with water, and the filter cake is added with 35 ml of water and 70 ml of acetone, and 10% (by mass) of aqueous NaOH solution is added dropwise to adjust the pH to 9.0, and filtered.
  • the filter cake was washed with a small amount of acetone/water (1:1 by volume), and the filtrate was added with 180 ml of acetone crystals, and the mixture was further stirred for 1 hour, filtered, and the filter cake was washed with a small amount of acetone, and the filter cake was vacuum dried at room temperature overnight to obtain methotrexate.
  • the disodium salt yellow solid was 10.9 g, the yield was 68.5%, the purity was 98.78%, and the isomer content was 0.16%.
  • the temperature of the reaction solution is controlled to 50 ° C, the pH is adjusted to 2.0 with dilute hydrochloric acid, filtered, washed with water, and the filter cake (sampled, which is sample 2) is added with 35 ml of water and 105 ml of acetone, and 10% by mass of NaOH is added dropwise.
  • the aqueous solution was adjusted to pH 8.5, filtered, and the filter cake was washed with a small amount of acetone/water (1:1 by volume).
  • the filtrate (sampled, sample 3) was added dropwise with 130 ml of acetone crystals, stirring was continued for 1 h, filtered, and the filter cake was used.
  • Sample 1, sample 2, sample 3 and sample 4 were subjected to HPCL test to obtain the content of methotrexate (or methotrexate disodium salt) and methotrexate isomer, as shown in Table 1.
  • the reaction solution was cooled to 35 ° C, adjusted to pH 9.5 with 60 ml of concentrated aqueous ammonia, keeping the temperature below 40 ° C and stirring at room temperature for 15 min. 10 g of diatomaceous earth was added, stirring was continued for 15 min, filtered, washed with water, and the cake was discarded.
  • the pH of the filtrate (sampled as sample 2A) was adjusted to 6.0 at room temperature under concentrated hydrochloric acid, and solids were precipitated, filtered, and washed with water.
  • the filter cake (sampled, sample 3A) was added with 400 ml of water, concentrated hydrochloric acid to adjust the pH to 1.5, dissolved, stirring was continued for 1.5 h, solids were precipitated, filtered, and washed with water; the filter cake was adjusted to pH with 20% (mass%) aqueous NaOH solution. 10, filtration; the filtrate was slowly adjusted to pH 1.5 with concentrated hydrochloric acid, stirring was continued for 1.5 h, solids were precipitated, filtered, washed with water; the filter cake (sampled, which is sample 4A) was redissolved in 20% by mass aqueous sodium hydroxide solution.
  • Sample 1A, sample 2A, sample 3A, sample 4A, sample 5A, and sample 6A were subjected to HPCL detection to obtain a content of methotrexate (or methotrexate disodium salt) and methotrexate isomer. As shown in table 2.
  • Example 9 prepared according to the preparation method of US 4374987, the purification process of the present invention is purified
  • the temperature of the reaction solution is controlled to 50 ° C, the pH is adjusted to 2.0 with dilute hydrochloric acid, filtered, washed with water, and the filter cake is added with 35 ml of water and 35 ml of acetone, and a 10% (mass%) aqueous solution of NaOH is added dropwise to adjust the pH to 8.5, and filtered.
  • the filter cake was washed with a small amount of 1:1 acetone/water, and the filtrate was added with 210 ml of acetone crystals, and the mixture was further stirred for 1 hour, filtered, and the filter cake was washed with a small amount of acetone, and the filter cake was dried at room temperature overnight to obtain methotrexate disodium salt yellow.
  • the solid was 10.3 g, the yield was 64.8%, the purity was 98.2%, and the content of methotrexate isomer was 0.06%.
  • the temperature of the reaction solution is controlled to 50 ° C, the pH is adjusted to 2.0 with dilute hydrochloric acid, filtered, and washed with water.
  • Add 35 ml of water and 70 ml of tetrahydrofuran to the filter cake add 10% (mass%) aqueous NaOH solution, adjust the pH to 9.0, filter, wash the filter cake with a small amount of tetrahydrofuran / water (1:1 by volume), add 250 ml of tetrahydrofuran crystals. Stirring was continued for 1 h, filtered, and the filter cake was washed with a small amount of tetrahydrofuran.
  • the filter cake was dried under vacuum overnight at room temperature to obtain 9.6 g of methotrexate disodium salt yellow solid.
  • the yield was 60.4%, the purity was 98.52%, and the isomer content was 0.22%.
  • Example 8 shows that the methotrexate isomer can be well removed by the method of the present invention, and the methotrexate isomer removal effect and methylamine of the method of the present invention are well removed.
  • the yield of pterin disodium salt is superior to the repeated acid-alkali treatment method of US Pat. No. 4,374,987;
  • Example 10 is compared with Example 8: both are equivalent in the removal effect of methotrexate isomers, but examples The purity of the obtained methotrexate disodium salt is higher than that of Example 8, and the method of the present invention greatly simplifies the purification process of methotrexate disodium salt.
  • Example 8 shows that the reaction solution of US Pat. No. 4,374,987 is treated by the post-treatment method of the present invention, and the method of the invention simplifies the separation and purification process of methotrexate salt, avoiding the use of a large amount of ammonia water and hydrochloric acid, and simultaneously The yield of methotrexate salt is obviously increased, and the content of methotrexate isomer is low, and the removal effect of methotrexate isomer is better than that of US4374987.
  • the temperature of the reaction solution is controlled to 50 ° C, the pH is adjusted to 1.9 with dilute hydrochloric acid, filtered, washed with water, and the filter cake is added with 1750 ml of water and 1750 ml of acetone, and a 10% (mass%) aqueous solution of NaOH is added dropwise to adjust the pH to 9.0, and filtered.
  • the filter cake was washed with a small amount of acetone/water (1:1 by volume), and the filtrate was added with 11.0 L of acetone crystals, stirring was continued for 1 h, filtered, and the filter cake was washed with a small amount of acetone, and the filter cake was dried at room temperature overnight to obtain methotrexate.
  • the bismuth sodium salt yellow solid was 523.1 g, the yield was 65.8%, the purity was 98.08%, and the isomer content was 0.01%.

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Abstract

涉及一种工艺简单，便于操作、收率较高、质量重现性较好的甲氨蝶呤或其盐的纯化工艺。该工艺包括提供甲氨蝶呤的水性溶液、预处理及过滤、调碱和结晶四个步骤。

Description

一种甲氨蝶呤或其盐的纯化工艺
本申请要求于2016年8月9日提交中国专利局、申请号201610649766.1，发明名称为“一种甲氨蝶呤盐的纯化工艺”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及一种化合物的纯化工艺，具体涉及一种甲氨蝶呤或其盐的纯化工艺。
背景技术
甲氨蝶呤是一种免疫抑制剂，通过对二氢叶酸还原酶的竞争性抑制而发挥作用。其自20世纪40年代发现以来即用于治疗儿童白血病，20世纪50年代开始用于银屑病的治疗，现在是临床常用的抗恶性肿瘤药物，主要适用于急性白血病、乳腺癌、绒毛膜上皮癌及恶性葡萄胎、头颈部肿瘤、骨肿瘤、白血病脑膜脊髓浸润、肺癌、生殖系统肿瘤、肝癌、顽固性普通牛皮癣、类风湿性关节炎/自体免疫病。
Figure PCTCN2017095805-appb-000001
现有技术中甲氨蝶呤有两条合成路线：1.专利US4080325、US422446和US3989703公开了一种三步合成方法，将四氨基嘧啶和1,3-二羟基丙酮合成6-羟基蝶啶，再经溴化或氯化后与对甲氨基苯甲酰L-谷氨酸进行对接，得甲氨蝶呤，但这些方法收率均不高；2.US 4374987公开了甲氨蝶呤的一锅合成法，将四氨基嘧啶硫酸盐、对甲氨基苯甲酰L-谷氨酸和三溴丙酮合成甲氨蝶呤，反应液经冷却后，用氨水调碱，过滤，所得滤液需反复经过多次酸碱调节(连续两 次调酸，再紧接着先后调碱和酸)，过滤所得到滤饼再调碱，过滤，所得滤液加入丙酮制备得到甲氨蝶呤钠盐精品，再加入硫酸结晶得到甲氨蝶呤成品，该方法收率和纯度均较好，但其后处理纯化工艺极其的繁琐，且由于反复的调酸碱，需要使用大量氨水和大量盐酸等，对环境影响较大。周蓓等人在《中国医药工业杂志》1990,21(12)发表了甲氨蝶呤纯化工艺的改进，其甲氨蝶呤样品用氨水调碱，过滤，滤液调酸析晶，过滤，滤饼经调碱，过滤，所得滤液用丙酮析晶，滤饼再用硫酸结晶，得甲氨蝶呤纯品。该方法依旧使用了盐酸和氨水进行调酸碱，所需氨水较多，环境污染较大。因此，迫切需要一种经济、环保、适宜商业化的甲氨蝶呤纯化工艺。
发明内容
本发明的目的在于提供了一种工艺简单、便于操作、收率较高、重现性较好的甲氨蝶呤或其盐的纯化工艺，该工艺具有经济、环保、适宜商业化等优点。
本发明提供一种甲氨蝶呤或其盐的纯化工艺，包括步骤如下：
a)提供甲氨蝶呤的水性溶液；
b)预处理及过滤：在0～60℃的温度下将甲氨蝶呤的水性溶液的pH调节至1.0～3.0，过滤，得滤饼；
c)调碱：将步骤b)所得滤饼加入水或有机溶剂水溶液中，调节pH至碱性范围，得调碱液；
d)结晶：将步骤c)所得调碱液过滤，向滤液中加入有机溶剂进行结晶。
在本发明的优选实施方案中，其中步骤a)包括：将四氨基嘧啶硫酸盐、对甲氨基苯甲酰L-谷氨酸锌盐和三溴丙酮在酸性条件下以水为反应溶剂进行反应，得到甲氨蝶呤水溶液。
在本发明的优选实施方案中，在步骤c)和d)中的有机溶剂可以为同一种有机溶剂，或者为同一有机溶剂混合物。所述有机溶剂混合物可以是两种或更多种有机溶剂的混合物。
在本发明的优选实施方案中，步骤a)中所述酸性条件优选为pH在1.5～2.5。
在本发明的优选实施方案中，步骤b)中调节反应液pH所用试剂为盐酸水 溶液或氢氧化钠水溶液；另外地以及独立地，所述pH优选控制在1.5～2.5，更优选为1.8～2.0的范围内。
在本发明的优选实施方案中，步骤b)中的温度优选控制在40～60℃，更优选为45～55℃。
在本发明的优选实施方案中，步骤c)中利用碱性溶液调节pH，并且所述碱性溶液为无机强碱水溶液，优选为氢氧化钠、氢氧化钾水溶液，更优选氢氧化钠水溶液。
在本发明的优选实施方案中，步骤c)中碱性溶液的用量为基于所调节的滤饼加入水或有机溶剂水溶液中后所得体系的总质量的3％～30％，优选为5％～20％，更优选为8～15％。
在本发明的优选实施方案中，步骤c)中所述的碱性范围为7.0＜pH≤10.0，优选pH为8.0～9.0。
在本发明的优选实施方案中，步骤c)和d)中采用的有机溶剂为与水互溶的有机溶剂，优选为丙酮、四氢呋喃、乙腈或醇类，更优选为丙酮。
在本发明的优选实施方案中，步骤c)中有机溶剂水溶液中水与有机溶剂的体积比为1:0～1:3，优选为1:1。
在本发明的优选实施方案中，步骤d)中所述有机溶剂的用量为步骤c)中所加入水的体积或步骤c)中所加入有机溶剂水溶液中所含水的体积的3～10倍，优选为5～7倍。
本发明的纯化工艺通过步骤b)的反应液预处理步骤来控制反应液的pH和温度，该反应液的预处理步骤可协同控制甲氨蝶呤同分异构体(结构如下)在反应液中的溶解度，再进行过滤，除去甲氨蝶呤同分异构体，以便解决后续同分异构体难去除的问题。此外，通过对专利US4374987纯化工艺的跟踪，其反复进行调酸结晶的主要目的也是为了除去甲氨蝶呤同分异构体。
Figure PCTCN2017095805-appb-000002
本发明简化了甲氨蝶呤或其盐的分离与纯化工艺，避免了大量氨水及盐酸的使用，同时所得的产物的收率较高、质量重现性较好，所采用的溶剂可以回收利用，适合工业化生产；本发明的纯化方法具有经济、环保、适宜商业化等优点。
具体实施方式
以下实施例仅用于进一步说明本发明，而非用于限制本发明。在本发明的构思前提下对本发明制备方法的简单改进都属于本发明要求保护的范围。
本发明涉及的液相测试条件为：
色谱柱为C18 5μm 4.6×250mm；
pH6.0的缓冲液的制备：制备0.2M的磷酸氢二钠与0.1M的柠檬酸的混合液(体积比为630:370)，必要时用0.1M的柠檬酸或0.2M的磷酸氢二钠调节pH至6.0；
流动相的制备：上述制备得到的pH6.0的缓冲液与乙腈的混合液(体积比为90:10)，过滤并脱气；
检测波长为302nm；流速为1.2ml/min；进样量为20μl；柱温为室温。
实施例1
将450ml水、24.2g四氨基嘧啶硫酸盐和15.9g对甲氨基苯甲酰L-谷氨酸锌盐加入1.0L烧瓶中，搅拌，加热至50±5℃，继续搅拌1.0h，再加入1/3的26.6g三溴丙酮，温度控制在50±5℃，用20％(质量百分比)NaOH水溶液控制pH＝2.35±0.15，每隔30min加入1/3的三溴丙酮，继续用20％(质量百分比)NaOH水溶液维持pH，反应3.5h。
反应完毕后，控制反应液温度为45℃，用稀盐酸调pH至1.8，过滤，水洗，滤饼加入35ml水和35ml丙酮，滴加10％(质量百分比)NaOH水溶液，调pH至8.5，过滤，用少量的丙酮/水(体积比1:1)洗涤滤饼，滤液滴加210ml丙酮结晶，继续搅拌1h，过滤，滤饼用少量丙酮洗涤，滤饼室温真空干燥过夜，得甲氨蝶呤二钠盐黄色固体9.8g，收率61.6％，纯度98.49％，同分异构体含量为0.06％。
实施例2
将450ml水、24.2g四氨基嘧啶硫酸盐和15.9g对甲氨基苯甲酰L-谷氨酸锌盐加入1.0L烧瓶中，搅拌，加热至50±5℃，继续搅拌1.0h，再加入1/3的26.6g三溴丙酮，温度控制在50±5℃，用20％(质量百分比)NaOH水溶液控制pH＝2.35±0.15，每隔30min加入1/3的三溴丙酮，继续用20％(质量百分比)NaOH水溶液维持pH，反应3.5h。
反应完毕后，控制反应液温度为30℃，用稀盐酸调pH至1.5，过滤，水洗，滤饼加入35ml水和35ml丙酮，滴加10％(质量百分比)NaOH水溶液，调pH至8.5，过滤，用少量的丙酮/水(体积比1:1)洗涤滤饼，滤液滴加210ml丙酮结晶，继续搅拌1h，过滤，滤饼用少量丙酮洗涤，滤饼室温真空干燥过夜，得甲氨蝶呤二钠盐黄色固体9.1g，收率57.2％，纯度98.63％，同分异构体含量为0.01％。
实施例3
将450ml水、24.2g四氨基嘧啶硫酸盐和15.9g对甲氨基苯甲酰L-谷氨酸锌盐加入1.0L烧瓶中，搅拌，加热至50±5℃，继续搅拌1.0h，再加入1/3的26.6g三溴丙酮，温度控制在50±5℃，用20％(质量百分比)NaOH水溶液控制pH＝2.35±0.15，每隔30min加入1/3的三溴丙酮，继续用20％(质量百分比)NaOH水溶液维持pH，反应3.5h。
反应完毕后，控制反应液温度为40℃，用稀盐酸调pH至1.7，过滤，水洗，滤饼加入35ml水和35ml丙酮，滴加10％(质量百分比)NaOH水溶液，调pH至8.5，过滤，用少量的丙酮/水(体积比1:1)洗涤滤饼，滤液滴加210ml丙酮 结晶，继续搅拌1h，过滤，滤饼用少量丙酮洗涤，滤饼室温真空干燥过夜，得甲氨蝶呤二钠盐黄色固体9.4g，收率59.1％，纯度99.08％，同分异构体含量为0.18％。
实施例4
将450ml水、24.2g四氨基嘧啶硫酸盐和15.9g对甲氨基苯甲酰L-谷氨酸锌盐加入1.0L烧瓶中，搅拌，加热至50±5℃，继续搅拌1.0h，再加入1/3的26.6g三溴丙酮，温度控制在50±5℃，用20％(质量百分比)NaOH水溶液控制pH＝2.35±0.15，每隔30min加入1/3的三溴丙酮，继续用20％(质量百分比)NaOH水溶液维持pH，反应3.5h。
反应完毕后，控制反应液温度为50℃，用稀盐酸调pH至2.0，过滤，水洗，滤饼加入35ml水和35ml丙酮，滴加10％(质量百分比)NaOH水溶液，调pH至8.5，过滤，用少量的丙酮/水(体积比1:1)洗涤滤饼，滤液滴加210ml丙酮结晶，继续搅拌1h，过滤，滤饼用少量丙酮洗涤，滤饼室温真空干燥过夜，得甲氨蝶呤二钠盐黄色固体10.8g，收率67.9％，纯度98.50％，同分异构体含量为0.09％。
实施例5
将450ml水、24.2g四氨基嘧啶硫酸盐和15.9g对甲氨基苯甲酰L-谷氨酸锌盐加入1.0L烧瓶中，搅拌，加热至50±5℃，继续搅拌1.0h，再加入1/3的26.6g三溴丙酮，温度控制在50±5℃，用20％(质量百分比)NaOH水溶液控制pH＝2.35±0.15，每隔30min加入1/3的三溴丙酮，继续用20％(质量百分比)NaOH水溶液维持pH，反应3.5h。
反应完毕后，控制反应液温度为55℃，20％(质量百分比)NaOH水溶液调pH为2.5，过滤，水洗，滤饼加入35ml水和35ml丙酮，滴加10％(质量百分比)NaOH水溶液，调pH至8.0，过滤，用少量的丙酮/水(体积比1:1)洗涤滤饼，滤液滴加210ml丙酮结晶，继续搅拌1h，过滤，滤饼用少量丙酮洗涤，滤饼室温真空干燥过夜，得甲氨蝶呤二钠盐黄色固体10.3g，收率64.8％，纯度97.35％，同分异构体含量为0.17％。
实施例6
将450ml水、24.2g四氨基嘧啶硫酸盐和15.9g对甲氨基苯甲酰L-谷氨酸锌盐加入1.0L烧瓶中，搅拌，加热至50±5℃，继续搅拌1.0h，再加入1/3的26.6g三溴丙酮，温度控制在50±5℃，用20％(质量百分比)NaOH水溶液控制pH＝2.35±0.15，每隔30min加入1/3的三溴丙酮，继续用20％(质量百分比)NaOH水溶液维持pH，反应3.5h。
反应完毕后，控制反应液温度为50℃，用稀盐酸调pH为2.0，过滤，水洗，滤饼加入35ml水和70ml丙酮，滴加10％(质量百分比)NaOH水溶液，调pH至9.0，过滤，用少量的丙酮/水(体积比1:1)洗涤滤饼，滤液滴加180ml丙酮结晶，继续搅拌1h，过滤，滤饼用少量丙酮洗涤，滤饼室温真空干燥过夜，得甲氨蝶呤二钠盐黄色固体10.9g，收率68.5％，纯度98.78％，同分异构体含量为0.16％。
实施例7
将450ml水、24.2g四氨基嘧啶硫酸盐和15.9g对甲氨基苯甲酰L-谷氨酸锌盐加入1.0L烧瓶中，搅拌，加热至50±5℃，继续搅拌1.0h，再加入1/3的26.6g三溴丙酮，温度控制在50±5℃，用20％(质量百分比)NaOH水溶液控制pH＝2.35±0.15，每隔30min加入1/3的三溴丙酮，继续用20％(质量百分比)NaOH水溶液维持pH，反应3.5h，得反应液(取样，其为样品1)。
反应完毕后，控制反应液温度为50℃，用稀盐酸调pH为2.0，过滤，水洗，滤饼(取样，其为样品2)加入35ml水和105ml丙酮，滴加10％(质量百分比)NaOH水溶液，调pH至8.5，过滤，用少量的丙酮/水(体积比1:1)洗涤滤饼，滤液(取样，其为样品3)滴加130ml丙酮结晶，继续搅拌1h，过滤，滤饼用少量丙酮洗涤，滤饼室温真空干燥过夜，得甲氨蝶呤二钠盐黄色固体(取样，其为样品4)10.6g，收率66.7％，纯度98.36％。
表1
Figure PCTCN2017095805-appb-000003
Figure PCTCN2017095805-appb-000004
将样品1、样品2、样品3及样品4进行HPCL检测，得到甲氨蝶呤(或甲氨蝶呤二钠盐)、甲氨蝶呤同分异构体的含量，如表1所示。
实施例8(根据US 4374987的制备方法及纯化工艺)
将270ml水、24.2g四氨基嘧啶硫酸盐和15.9g对甲氨基苯甲酰L-谷氨酸锌盐加入500ml烧瓶中，搅拌，加热至50℃，用浓盐酸调pH至2.0，再加入1/2事先用27ml乙醇溶解26.6g三溴丙酮的溶液，温度控制在50±1℃，用20％(质量百分比)NaOH水溶液控制pH＝2.0±0.05，15min后加入剩下的三溴丙酮乙醇溶液，继续用20％(质量百分比)NaOH水溶液维持pH，反应3.5h，得反应液(取样，其为样品1A)。
反应液冷却至35℃，用60ml的浓氨水调pH至9.5，保持温度低于40℃，室温搅拌15min。加入10g硅藻土，继续搅拌15min，过滤，水洗，弃滤饼，室温下浓盐酸调节滤液(取样，其为样品2A)的pH至6.0，有固体析出，过滤，水洗。滤饼(取样，其为样品3A)加入400ml水，浓盐酸调节pH至1.5，溶解，继续搅拌1.5h，析出固体物，过滤，水洗；滤饼用20％(质量百分比)NaOH水溶液调pH＝10，过滤；滤液用浓盐酸缓慢调PH至1.5，继续搅拌1.5h，固体析出，过滤，水洗；将滤饼(取样，其为样品4A)重新溶解在20％(质量百分比)氢氧化钠水溶液中得到pH＝10的100g溶液，搅拌下加入125ml丙酮稀释溶液，继续搅拌30min，过滤，滤液(取样，其为样品5A)在充分搅拌下加入175ml丙酮结晶，继续搅拌1h，过滤，用3:1的丙酮/水溶液进行洗涤，再用丙酮洗，真空干燥，得甲氨蝶呤二钠盐黄色固体(取样，其为样品6A)5.91g，收率37.2％，纯度98.18％。
表2
Figure PCTCN2017095805-appb-000005
Figure PCTCN2017095805-appb-000006
将样品1A、样品2A、样品3A、样品4A、样品5A、样品6A进行HPCL检测，得到甲氨蝶呤(或甲氨蝶呤二钠盐)、甲氨蝶呤同分异构体的含量，如表2所示。
实施例9(根据US 4374987的制备方法制备，本发明的纯化工艺纯化)
270ml水、24.2g四氨基嘧啶硫酸盐和15.9g对甲氨基苯甲酰L-谷氨酸锌盐加入500ml烧瓶中，搅拌，加热至50℃，用浓盐酸调pH至2.0，再加入1/2事先用27ml乙醇溶解26.6g三溴丙酮的溶液，温度控制在50±1℃，用20％(质量百分比)NaOH水溶液控制pH＝2.0±0.05，15min后加入剩下的三溴丙酮乙醇溶液，继续用20％(质量百分比)NaOH水溶液维持pH，反应3.5h。
反应完毕后，控制反应液温度为50℃，用稀盐酸调pH为2.0，过滤，水洗，滤饼加入35ml水和35ml丙酮，滴加10％(质量百分比)NaOH水溶液，调pH至8.5，过滤，用少量1:1的丙酮/水洗涤滤饼，滤液滴加210ml丙酮结晶，继续搅拌1h，过滤，滤饼用少量丙酮洗涤，滤饼室温真空干燥过夜，得甲氨蝶呤二钠盐黄色固体10.3g，收率64.8％，纯度98.2％，甲氨蝶呤同分异构体的含量为0.06％。
实施例10
将450ml水、24.2g四氨基嘧啶硫酸盐和15.9g对甲氨基苯甲酰L-谷氨酸锌盐加入1.0L烧瓶中，搅拌，加热至50±5℃，继续搅拌1.0h，再加入1/3的26.6g三溴丙酮，温度控制在50±5℃，用20％(质量百分比)NaOH水溶液控制pH＝2.35±0.15，每隔30min加入1/3的三溴丙酮，继续用20％(质量百分比)NaOH水溶液维持pH，反应3.5h。
反应完毕后，控制反应液温度为50℃，用稀盐酸调pH为2.0，过滤，水洗， 滤饼加入35ml水和70ml四氢呋喃，滴加10％(质量百分比)NaOH水溶液，调pH至9.0，过滤，用少量的四氢呋喃/水(体积比1:1)洗涤滤饼，滤液滴加250ml四氢呋喃结晶，继续搅拌1h，过滤，滤饼用少量四氢呋喃洗涤，滤饼室温真空干燥过夜，得甲氨蝶呤二钠盐黄色固体9.6g，收率60.4％，纯度98.52％，同分异构体含量为0.22％。
实施例1～7、与实施例8对比表明：采用本发明方法能很好地去除甲氨蝶呤同分异构体，本发明方法的甲氨蝶呤同分异构体去除效果和甲氨蝶呤二钠盐的收率优于US4374987专利的反复调酸碱的处理方法；实施例10与实施例8相比：两者在甲氨蝶呤同分异构体去除效果上相当，但实例10所得的甲氨蝶呤二钠盐的纯度高于实施例8，本发明方法大大简化了甲氨蝶呤二钠盐的纯化工艺。
实施例8和实施例9对比表明：利用本发明的后处理方法处理US4374987专利的反应液，本发明方法简化了甲氨蝶呤盐的分离与纯化工艺，避免了大量氨水及盐酸的使用，同时所得的甲氨蝶呤盐的收率明显增加，并且甲氨蝶呤同分异构体含量较低，甲氨蝶呤同分异构体去除效果优于US4374987的方法。
实施例11(本发明的放大反应)
将22.5L水、1210g四氨基嘧啶硫酸盐和795g对甲氨基苯甲酰L-谷氨酸锌盐加入30L反应釜中，搅拌，加热至50±5℃，继续搅拌1.0h，再加入1/3的1330g三溴丙酮，温度控制在50±5℃，用20％(质量百分比)NaOH水溶液控制pH＝2.35±0.15，每隔30min加入1/3的三溴丙酮，继续用20％(质量百分比)NaOH水溶液维持pH，反应3.5h。
反应完毕后，控制反应液温度为50℃，用稀盐酸调pH为1.9，过滤，水洗，滤饼加入1750ml水和1750ml丙酮，滴加10％(质量百分比)NaOH水溶液，调pH至9.0，过滤，用少量的丙酮/水(体积比1:1)洗涤滤饼，滤液滴加11.0L丙酮结晶，继续搅拌1h，过滤，滤饼用少量丙酮洗涤，滤饼室温真空干燥过夜，得甲氨蝶呤二钠盐黄色固体523.1g，收率65.8％，纯度98.08％，同分异构体含量为0.01％。

Claims (12)

  1. 一种甲氨蝶呤或其盐的纯化工艺，包括以下步骤：
    a)提供甲氨蝶呤的水性溶液；
    b)预处理及过滤：在0～60℃的温度下将甲氨蝶呤的水性溶液的pH调节至1.0～3.0，过滤，得滤饼；
    c)调碱：将步骤b)所得滤饼加入水或有机溶剂水溶液中，调节pH至碱性范围，得调碱液；
    d)结晶：将步骤c)所得调碱液过滤，向滤液中加入有机溶剂进行结晶。
  2. 根据权利要求1所述的纯化工艺，其中步骤a)包括：将四氨基嘧啶硫酸盐、对甲氨基苯甲酰L-谷氨酸锌盐和三溴丙酮在酸性条件下以水为反应溶剂进行反应，得到甲氨蝶呤水溶液。
  3. 根据权利要求1或2所述的纯化工艺，其中在步骤c)和d)中的有机溶剂为同一种有机溶剂或同一有机溶剂混合物。
  4. 根据权利要求2或3所述的纯化工艺，其中所述步骤a)中的酸性条件为pH在1.5～2.5的范围内。
  5. 根据前述权利要求中任一项所述的纯化工艺，其中在所述步骤b)中使用盐酸水溶液或氢氧化钠水溶液调节pH，和/或所述pH调节至1.5～2.5、优选为1.8～2.0的范围内。
  6. 根据前述权利要求中任一项所述的纯化工艺，其中所述步骤b)中的温度控制在40～60℃，优选为45～55℃。
  7. 根据前述权利要求中任一项所述的纯化工艺，其中在所述步骤c)中利用碱性溶液调节pH，并且所述碱性溶液为无机强碱水溶液，优选为氢氧化钠、氢氧化钾水溶液，更优选为氢氧化钠水溶液。
  8. 根据权利要求7所述的纯化工艺，其中所述碱性溶液的用量为基于所调节的滤饼加入水或有机溶剂水溶液中后所得体系的总质量的3％～30％，优选为 5％～20％，更优选为8～15％。
  9. 根据前述权利要求中任一项所述的纯化工艺，其中所述步骤c)中所述的碱性范围为7.0＜pH≤10.0，优选为8.0～9.0。
  10. 根据前述权利要求中任一项所述的纯化工艺，其中所述步骤c)和d)中的有机溶剂为与水互溶的有机溶剂，优选为丙酮、四氢呋喃、乙腈或醇类，更优选为丙酮。
  11. 根据前述权利要求中任一项所述的纯化工艺，其中所述步骤c)中的有机溶剂水溶液中水与有机溶剂的体积比为1:0～1:3，优选为1:1。
  12. 根据前述权利要求中任一项所述的纯化工艺，其中步骤d)中所述有机溶剂的用量为步骤c)中所加入水的体积或步骤c)中所加入有机溶剂水溶液中所含水的体积的3～10倍，优选为5～7倍。
PCT/CN2017/095805 2016-08-09 2017-08-03 一种甲氨蝶呤或其盐的纯化工艺 WO2018028496A1 (zh)

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