WO2017024980A1 - 盐酸奈必洛尔中间体混合物的结晶分离方法 - Google Patents
盐酸奈必洛尔中间体混合物的结晶分离方法 Download PDFInfo
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- C07B57/00—Separation of optically-active compounds
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/20—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 hydrogenated in the hetero ring
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- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- the present invention relates to a method for crystallizing a mixture, and more particularly to a method for crystallizing a mixture of nifeilol hydrochloride RS/SR type and SS/RR type mixture.
- nebivolol hydrochloride As a third-generation ⁇ -receptor antagonist, nebivolol hydrochloride has higher selectivity than other ⁇ -receptor antagonists. It does not cause contraction of bronchial smooth muscle and vascular smooth muscle, and is suitable for mild to moderate high.
- the treatment of blood pressure patients can also be used for the treatment of angina pectoris and congestive heart failure.
- RS/SR (Formula I) and SS/RR (Formula II) are two important intermediates for the synthesis of nebivolol hydrochloride, which are a pair of diastereomers.
- the formula I and the formula II are mainly separated by column chromatography, but the method has the following problems: 1. The production efficiency is low, the production labor is large; 2. The amount of solvent used is large; The rate is low and the production cost is high. There are currently no related literatures and patents reporting other separation methods of Formula I and Formula II.
- the technical problem to be solved by the present invention is to provide a method for crystallizing a mixture of nebivolol hydrochloride intermediates.
- the technical solution adopted by the present invention is to provide a method for crystallizing a mixture of nebivolol hydrochloride intermediate, comprising the following steps:
- Step 1 Add an alcohol solvent or a mixed solvent of an alcohol and an alkane to the nebivolol hydrochloride intermediate mixture, dissolve into a clear solution at room temperature, then cool to -10 to 5 ° C for crystallization, heat for 8 to 20 h, and obtain after filtration.
- SS/RR type solid of formula II :
- Step 2 The mother liquor after the step 1 crystal filtration is concentrated to dryness, and then an alcohol solvent or a mixed solvent of an alcohol and an alkane is added, and the mixture is heated to dissolve into a clear solution, and then cooled to 0 to 15 ° C for crystallization, and kept for 2 to 20 hours, and filtered.
- the resulting RS/SR type solid of formula I is obtained:
- the mass of the alcohol solvent or the mixed solvent of the alcohol and the alkane is 5% to 25% of the mass of the mother liquor after concentration.
- the volume ratio of the alcohol to the alkane is from 1:15 to 15:1.
- the volume ratio of the alcohol to the alkane is from 1:15 to 15:1.
- the numerical ratio between the volume (mL) of the alcohol solvent or the mixed solvent of the alcohol and the alkane in the step 1 and the mass (g) of the intermediate mixture is 2:1.
- the mass of the alcohol solvent or the mixed solvent of the alcohol and the alkane is 10% to 15% of the mass of the mother liquid after concentration.
- the alcohol is a mixture of one or more of methanol, ethanol, isopropanol, n-butanol, tert-butanol, and tert-amyl alcohol.
- the alkane is a mixture of one or more of C 5 -C 9 alkanes.
- the clear solution is cooled to -5 to 0 ° C for crystallization.
- the crystallization retention time in the step 1 was 12 h.
- the clear solution is cooled to 4 to 10 ° C for crystallization.
- the crystallization retention time in the step 2 was 12 h.
- a method for crystallizing a mixture of nebivolol hydrochloride intermediates comprising the steps of:
- Step 1 Add an alcohol solvent or a mixed solvent of an alcohol and an alkane to the nebivolol hydrochloride intermediate mixture, dissolve into a clear solution at room temperature, then cool to -10 to 5 ° C for crystallization, heat for 8 to 20 h, and obtain after filtration.
- SS/RR type solid of formula II :
- Step 2 The mother liquor after the step 1 crystal filtration is concentrated to dryness, and then an alcohol solvent or a mixed solvent of an alcohol and an alkane is added, and the mixture is heated to dissolve into a clear solution, and then cooled to 0 to 15 ° C for crystallization, and kept for 2 to 20 hours, and filtered.
- the resulting RS/SR type solid of formula I is obtained:
- the volume ratio of the alcohol to the alkane is from 1:15 to 15:1.
- the volume ratio of the alcohol to the alkane is 1:5.
- the numerical ratio between the volume (mL) of the alcohol solvent or the mixed solvent of the alcohol and the alkane in the step 1 and the mass (g) of the intermediate mixture is 1:1 to 5:1.
- the numerical ratio between the volume (mL) of the alcohol solvent or the mixed solvent of the alcohol and the alkane in the step 1 and the mass (g) of the intermediate mixture is 2:1.
- the mass of the alcohol solvent or the mixed solvent of the alcohol and the alkane is 5% to 25% of the mass of the mother liquor after concentration.
- the mass of the alcohol solvent or the mixed solvent of the alcohol and the alkane is 10% to 15% of the mass of the mother liquid after concentration.
- the alcohol is one or more of methanol, ethanol, isopropanol, n-butanol, tert-butanol, and tert-amyl alcohol.
- the alcohol is one or more of methanol, ethanol, isopropanol, n-butanol, tert-butanol, and tert-amyl alcohol.
- the alkane is a mixture of one or more of C5 to C9 alkanes.
- the clear solution is cooled to -5 to 0 ° C for crystallization.
- the crystallization retention time in the step 1 was 12 h.
- the clear solution is cooled to 4 to 10 ° C for crystallization.
- the crystallization retention time in the step 2 was 12 h.
- the invention Compared with the prior art, the invention has the advantages that the invention adopts the SS/RR type and the RS/SR type diastereomer in the crystal separation intermediate mixture, has simple operation, short preparation period and reduces solvent.
- the consumption of the product reduces the production cost and the post-treatment cost of the solvent, and is advantageous for industrial production, and the single-pass yield of the separated product can reach 35 to 70%.
- Example 1 is a micrograph of the SS/RR type solid obtained in Example 1 after magnifying 10 ⁇ 10;
- Example 2 is a micrograph of the RS/SR type solid obtained in Example 1 after being magnified 40 ⁇ 10;
- Figure 3 is a SS/RR type solid DSC spectrum obtained in Example 1;
- Example 4 is a RS/SR type solid DSC spectrum obtained in Example 1.
- the single pass yield of the solid of Formula I and the solid of Formula II is 70%.
- the SS/RR type solid obtained in the above Example 1 was microscopically determined to have a crystal form as shown in Fig. 1. As shown in Fig. 1, the melting point was 45.3 ° C as shown in Fig. 3; At the same time, the obtained RS/SR type solids can be known by microscopic measurement of the crystal appearance. There is needle crystal habit, as shown in Figure 2; the DSC test results show that its melting point is 34.5 ° C, as shown in Figure 4.
- the single pass yield of the solid of formula I and the solid of formula II is 68%.
- the single pass yield of the solid of Formula I and the solid of Formula II is 70%.
- gSS/RR type solid, product purity ⁇ 95%; cyclohexane and n-butanol are mixed into a mixed solvent according to a volume ratio of 15:1, and the mother liquid of the above crystal filtration is spin-dried, supplemented with 25% mixed solvent (relative to The mass of the mother liquor after spinning is dissolved, and the mixture is heated to dissolve into a clear solution, and then cooled to 5 ° C for crystallization, and kept for 2 hours. After filtration, 28.85 g of RS/SR type solid is obtained, and the product purity is ⁇ 97%.
- the single pass yield of the solid of Formula I and the solid of Formula II is 70%.
- the solution was heated to dissolve into a clear solution, then cooled to 10 ° C for crystallization, and kept for 2 hours. After filtration, 10.41 g of RS/SR type solid was obtained, and the product purity was ⁇ 97%.
- the single pass yield of the solid of formula I and the solid of formula II is 69%.
- the single pass yield of the solid of Formula I and the solid of Formula II is 70%.
- gSS/RR type solid, product purity ⁇ 95%; cyclohexane and n-butanol are mixed into a mixed solvent according to a volume ratio of 6:1, and the mother liquid filtered by the above crystal is spin-dried, supplemented with 10% mixed solvent (relative to The mass of the mother liquor after spinning is dissolved, and the mixture is heated to dissolve into a clear solution, and then cooled to 15 ° C for crystallization, and kept for 20 hours. After filtration, 21.18 g of RS/SR type solid is obtained, and the product purity is ⁇ 97%.
- the single pass yield of the solid of Formula I and the solid of Formula II is 70%.
- the single pass yield of the solid of Formula I and the solid of Formula II is 64%.
- the solution was heated to dissolve into a clear solution, then cooled to 8 ° C for crystallization, and kept for 20 hours. After filtration, 18.39 g of RS/SR type solid was obtained, and the product purity was ⁇ 98%.
- the single pass yield of the SS/RR type solid and the RS/SR type solid was 63%.
- the single pass yield of the SS/RR type solid and the RS/SR type solid was 42%.
- the single pass yield of the SS/RR type solid and the RS/SR type solid was 55%.
- Solid, product purity ⁇ 90% the mother liquid after filtration of the above crystals is evaporated to dryness, supplemented with 5% isopropanol (relative to the mass of the mother liquor after evaporation), heated to dissolve into a clear solution, and then cooled to 8 ° C for crystallization, heat preservation After 20 hours, 15.73 g of RS/SR type solid was obtained after filtration, and the product purity was ⁇ 90%.
- the single pass yield of the SS/RR type solid and the RS/SR type solid was 40%.
- the single pass yield of the SS/RR type solid and the RS/SR type solid was 40%.
- the single pass yield of the SS/RR type solid and the RS/SR type solid was 35%.
- the single pass yield of the SS/RR type solid and the RS/SR type solid was 40%.
- product purity ⁇ 85%; n-heptane and tert-amyl alcohol are mixed into a mixed solvent in a volume ratio of 5:1, and the mother liquid after filtration of the above crystals is evaporated to dryness, and a 10% mixed solvent is added (relative to the mother liquor after evaporation) Mass), dissolved at a temperature to form a clear solution, then cooled to 8 ° C for crystallization, kept for 20 hours, filtered to obtain 5.82 g of RS / SR type solid, product purity ⁇ 85%.
- the single pass yield of SS/RR type solid and RS/SR type solid is 35%.
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Abstract
公开了一种盐酸奈必洛尔中间体混合物的结品分离方法,包括以下步骤:步骤1、向盐酸奈必洛尔中间体混合物中加入醇类溶剂或醇类与烷烃的混合溶剂,常温溶解成澄清溶液,然后降温结品,过滤后得到SS/RR型固体;步骤2、将步骤1结晶过滤后的母液浓缩至干,再加入醇类溶剂或醇类与烷烃的混合溶剂,升温溶解成澄清溶液,然后降温结晶,过滤后得到RS/SR型固体。采用结晶分离中间体混合物中的SS/RR型和RS/SR型非对映异构体,操作简单,制备周期较短,同时减少了溶剂的消耗,降低了生产成本和溶剂的后处理成本,有利于实现工业化生产,分离得到的产品的单程收率可达到35-70%。
Description
本发明涉及一种混合物的结晶分离方法,具体涉及盐酸奈必洛尔中间体RS/SR型和SS/RR型混合物的结晶分离方法。
盐酸奈必洛尔作为第三代β受体拮抗剂,与其他β受体拮抗剂不同,具有更高的选择性,其不会引起支气管平滑肌和血管平滑肌收缩,适应于轻度到中度高血压病人的治疗,同时还可以用于心绞痛和充血性心力衰竭的治疗。
RS/SR(式I)和SS/RR(式II)是合成盐酸奈必洛尔的两个重要的中间体,是一对非对映异构体。目前,式I和式II主要利用柱层析方法进行分离,但该方法存在以下几个问题:1、生产效率较低,生产劳动量较大;2、所使用的溶剂量大;3、收率较低,生产成本偏高等。目前尚未有相关文献和专利报道式I和式II的其它分离方法。
【发明内容】
本发明所要解决的技术问题是提供一种盐酸奈必洛尔中间体混合物的结晶分离方法。
为解决上述技术问题,本发明采用的技术方案是:提供一种盐酸奈必洛尔中间体混合物的结晶分离方法,包括以下步骤:
步骤1:向盐酸奈必洛尔中间体混合物中加入醇类溶剂或醇类与烷烃的混合溶剂,常温溶解成澄清溶液,然后降温至-10~5℃结晶,保温8~20h,过滤后得到式II的SS/RR型固体:
步骤2:将步骤1结晶过滤后的母液浓缩至干,再加入醇类溶剂或醇类与烷烃的混合溶剂,升温溶解成澄清溶液,然后降温至0~15℃结晶,保温2~20h,过滤后得到式I的RS/SR型固体:
其中,所述步骤1中醇类溶剂或醇类与烷烃的混合溶剂的体积(mL)与中间体混合物的质量(g)之间的数值比为1∶1~5∶1;
其中,所述步骤2中醇类溶剂或醇类与烷烃的混合溶剂的质量为浓缩后母液质量的5%~25%。
所述步骤1和步骤2的混合溶剂中,醇类与烷烃的体积比为1∶15~15∶1。
所述步骤1和步骤2的混合溶剂中,醇类与烷烃的体积比为1∶15~15∶1。
所述步骤1中醇类溶剂或醇类与烷烃的混合溶剂的体积(mL)与中间体混合物的质量(g)之间的数值比为2∶1。
所述步骤2中醇类溶剂或醇类与烷烃的混合溶剂的质量为浓缩后母液质量的10%~15%。
所述醇类为甲醇、乙醇、异丙醇、正丁醇、叔丁醇、叔戊醇中的一种或多种的混合。
所述烷烃为C5~C9烷烃中的一种或多种的混合物。
所述步骤1中澄清溶液降温至-5~0℃结晶。
所述步骤1中结晶保温时间为12h。
所述步骤2中澄清溶液降温至4~10℃结晶。
所述步骤2中结晶保温时间为12h。
为解决上述技术问题,本发明采用的另一技术方案是:
盐酸奈必洛尔中间体混合物的结晶分离方法,包括以下步骤:
步骤1:向盐酸奈必洛尔中间体混合物中加入醇类溶剂或醇类与烷烃的混合溶剂,常温溶解成澄清溶液,然后降温至-10~5℃结晶,保温8~20h,过滤后得到式II的SS/RR型固体:
步骤2:将步骤1结晶过滤后的母液浓缩至干,再加入醇类溶剂或醇类与烷烃的混合溶剂,升温溶解成澄清溶液,然后降温至0~15℃结晶,保温2~20h,过滤后得到式I的RS/SR型固体:
所述步骤1和步骤2的混合溶剂中,醇类与烷烃的体积比为1∶15~15∶1。
所述步骤1和步骤2的混合溶剂中,醇类与烷烃的体积比为1∶5。
所述步骤1中醇类溶剂或醇类与烷烃的混合溶剂的体积(mL)与中间体混合物的质量(g)之间的数值比为1∶1~5∶1。
所述步骤1中醇类溶剂或醇类与烷烃的混合溶剂的体积(mL)与中间体混合物的质量(g)之间的数值比为2∶1。
所述步骤2中醇类溶剂或醇类与烷烃的混合溶剂的质量为浓缩后母液质量的5%~25%。
所述步骤2中醇类溶剂或醇类与烷烃的混合溶剂的质量为浓缩后母液质量的10%~15%。
所述醇类为甲醇、乙醇、异丙醇、正丁醇、叔丁醇、叔戊醇中的一种或多
种的混合。
所述烷烃为C5~C9烷烃中的一种或多种的混合物。
所述步骤1中澄清溶液降温至-5~0℃结晶。
所述步骤1中结晶保温时间为12h。
所述步骤2中澄清溶液降温至4~10℃结晶。
所述步骤2中结晶保温时间为12h。
与现有技术相比,本发明的优点是:本发明采用结晶分离中间体混合物中SS/RR型和RS/SR型非对映异构体,操作简单,制备周期较短,同时减少了溶剂的消耗,降低了生产成本和溶剂的后处理成本,有利于实现工业化生产,分离得到的产品的单程收率可达到35~70%。
下面结合附图和具体实施方式对本实用新型作进一步详细描述。图1是实施例1得到的SS/RR型固体放大10x10后的显微镜图;
图2是实施例1得到的RS/SR型固体放大40x10后的显微镜图;
图3是实例1得到的SS/RR型固体DSC谱图;
图4是实例1得到的RS/SR型固体DSC谱图。
下面结合具体实施例对本发明的技术方案作进一步的说明。
实施例1
在250mL四口瓶中依次投入50g盐酸奈必洛尔的中间体混合物、100mL环己烷和20mL正丁醇,常温溶解成澄清溶液,然后降温至-2℃结晶,保温20小时,过滤后得到18.26gSS/RR型固体,产品纯度≥97%;环己烷与正丁醇按照5∶1的体积比配制成混合溶剂,将上述结晶过滤后的母液蒸干,补加10%混合溶剂(相对于蒸干后的母液质量),升温溶解成澄清溶液,然后降温至8℃结晶,保温20小时,过滤后得到20.32gRS/SR型固体,产品纯度≥98%。
该方法中,式I固体和式II固体的单程收率为70%。
上述实施实例1得到的SS/RR型固体,经过显微镜测定其晶体外观可知,均具有片状晶习,如图1所示,由DSC测试结果可知其熔点为45.3℃,如图3所示;同时,所得到的RS/SR型固体,经过显微镜测定其晶体外观可知,均具
有针状晶习,如图2所示;由DSC测试结果可知其熔点为34.5℃,如图4所示。
实施例2
在250mL四口瓶中依次投入60g盐酸奈必洛尔的中间体混合物、100mL正庚烷和20mL正丁醇,常温溶解成澄清溶液,然后降温至-2℃结晶,保温20小时,过滤后得到18.57gSS/RR型固体,产品纯度≥95%;环己烷与正丁醇按照5∶1的体积比配制成混合溶剂,将上述结晶过滤后的母液蒸干,补加10%混合溶剂(相对于蒸干后的母液质量),升温溶解成澄清溶液,然后降温至8℃结晶,保温20小时,过滤后得到21.92gRS/SR型固体,产品纯度≥98%。
该方法中,式I固体和式II固体的单程收率为68%。
实施例3
在250mL四口瓶中依次投入50g盐酸奈必洛尔的中间体混合物、10mL环己烷和150mL正丁醇,常温溶解成澄清溶液,然后降温至-5℃结晶,保温20小时,过滤后得到15.61gSS/RR型固体,产品纯度≥95%;环己烷与正丁醇按照1∶15的体积比配制成混合溶剂,将上述结晶过滤后的母液旋干,补加15%混合溶剂(相对于旋干后的母液质量),升温溶解成澄清溶液,然后降温至5℃结晶,保温20小时,过滤后得到22.51gRS/SR型固体,产品纯度≥97%。
该方法中,式I固体和式II固体的单程收率为70%。
实施例4
在500mL四口瓶中依次投入80g盐酸奈必洛尔的中间体混合物、150mL环己烷和10mL正丁醇,常温溶解成澄清溶液,然后降温至5℃结晶,保温8小时,过滤后得到30.86gSS/RR型固体,产品纯度≥95%;环己烷与正丁醇按照15∶1的体积比配制成混合溶剂,将上述结晶过滤后的母液旋干,补加25%混合溶剂(相对于旋干后的母液质量),升温溶解成澄清溶液,然后降温至5℃结晶,保温2小时,过滤后得到28.85gRS/SR型固体,产品纯度≥97%。
该方法中,式I固体和式II固体的单程收率为70%。
实施例5
在250mL四口瓶中依次投入30g盐酸奈必洛尔的中间体混合物、125mL环己烷和25mL正丁醇,常温溶解成澄清溶液,然后降温至-10℃结晶,保温8小时,过滤后得到10.57gSS/RR型固体,产品纯度≥93%;环己烷与正丁醇按照5∶1的体积比配制成混合溶剂,将上述结晶过滤后的母液旋干,补加5%混合溶剂(相
对于旋干后的母液质量),升温溶解成澄清溶液,然后降温至10℃结晶,保温2小时,过滤后得到10.41gRS/SR型固体,产品纯度≥97%。
该方法中,式I固体和式II固体的单程收率为69%。
实施例6
在500mL四口瓶中依次投入120g盐酸奈必洛尔的中间体混合物、120mL环己烷和20mL正丁醇,常温溶解成澄清溶液,然后降温至-10℃结晶,保温12小时,过滤后得到45.78gSS/RR型固体,产品纯度≥93%;环己烷与正丁醇按照6∶1的体积比配制成混合溶剂,将上述结晶过滤后的母液旋干,补加10%混合溶剂(相对于旋干后的母液质量),升温溶解成澄清溶液,然后降温至4℃结晶,保温12小时,过滤后得到50.05gRS/SR型固体,产品纯度≥97%。
该方法中,式I固体和式II固体的单程收率为70%。
实施例7
在250mL四口瓶中依次投入60g盐酸奈必洛尔的中间体混合物、120mL环己烷和20mL正丁醇,常温溶解成澄清溶液,然后降温至0℃结晶,保温20小时,过滤后得到25.56gSS/RR型固体,产品纯度≥95%;环己烷与正丁醇按照6∶1的体积比配制成混合溶剂,将上述结晶过滤后的母液旋干,补加10%混合溶剂(相对于旋干后的母液质量),升温溶解成澄清溶液,然后降温至15℃结晶,保温20小时,过滤后得到21.18gRS/SR型固体,产品纯度≥97%。
该方法中,式I固体和式II固体的单程收率为70%。
实施例8
在250mL四口瓶中依次投入50g盐酸奈必洛尔的中间体混合物和100mL叔戊醇,常温溶解成澄清溶液,然后降温至-2℃结晶,保温20小时,过滤后得到15.19gSS/RR型固体,产品纯度≥97%;将上述结晶过滤后的母液蒸干,补加10%叔戊醇(相对于蒸干后的母液质量),升温溶解成澄清溶液,然后降温至4℃结晶,保温20小时,过滤后得到16.92gRS/SR型固体,产品纯度≥98%。
该方法中,式I固体和式II固体的单程收率为64%。
实施例9
在250mL四口瓶中依次投入55g盐酸奈必洛尔的中间体混合物、100mL正庚烷和20mL叔戊醇,常温溶解成澄清溶液,然后降温至-2℃结晶,保温20小时,过滤后得到16.06gSS/RR型固体,产品纯度≥95%;正庚烷与叔戊醇按照5∶1的体积比配制成混合溶剂,将上述结晶过滤后的母液蒸干,补加10%混合溶剂
(相对于蒸干后的母液质量),升温溶解成澄清溶液,然后降温至8℃结晶,保温20小时,过滤后得到18.39gRS/SR型固体,产品纯度≥98%。
该方法中,SS/RR型固体和RS/SR型固体的单程收率为63%。
实施例10
在250mL四口瓶中依次投入50g盐酸奈必洛尔的中间体混合物、50mL甲醇和50mL叔丁醇,常温溶解成澄清溶液,然后降温至-3℃结晶,保温20小时,过滤后得到20.12gSS/RR型固体,产品纯度≥90%;甲醇与叔丁醇按照1∶1的体积比配制成混合溶剂,将上述结晶过滤后的母液蒸干,补加5%混合溶剂(相对于蒸干后的母液质量),升温溶解成澄清溶液,然后降温至10℃结晶,保温20小时,过滤后得到19.31gRS/SR型固体,产品纯度≥90%。
该方法中,SS/RR型固体和RS/SR型固体的单程收率为42%。
实施例11
在250mL四口瓶中依次投入50g盐酸奈必洛尔的中间体混合物、50mL乙醇和50mL叔丁醇,常温溶解成澄清溶液,然后降温至-4℃结晶,保温20小时,过滤后得到16.88gSS/RR型固体,产品纯度≥95%;乙醇与叔丁醇按照1∶1的体积比配制成混合溶剂,将上述结晶过滤后的母液蒸干,补加8%混合溶剂(相对于蒸干后的母液质量),升温溶解成澄清溶液,然后降温至8℃结晶,保温20小时,过滤后得到14.65gRS/SR型固体,产品纯度≥98%。
该方法中,SS/RR型固体和RS/SR型固体的单程收率为55%。
实施例12
在250mL四口瓶中依次投入50g盐酸奈必洛尔的中间体混合物、100mL异丙醇,常温溶解成澄清溶液,然后降温至-2℃结晶,保温20小时,过滤后得到16.38gSS/RR型固体,产品纯度≥90%;将上述结晶过滤后的母液蒸干,补加5%异丙醇(相对于蒸干后的母液质量),升温溶解成澄清溶液,然后降温至8℃结晶,保温20小时,过滤后得到15.73gRS/SR型固体,产品纯度≥90%。
该方法中,SS/RR型固体和RS/SR型固体的单程收率为40%。
实施例13
在250mL四口瓶中依次投入50g盐酸奈必洛尔的中间体混合物、50mL乙醇和50mL正庚烷,常温溶解成澄清溶液,然后降温至-3℃结晶,保温20小时,过滤后得到13.93gSS/RR型固体,产品纯度≥90%;乙醇与正庚烷按照1∶1的体积比配制成混合溶剂,将上述结晶过滤后的母液蒸干,补加3%混合溶剂(相对
于蒸干后的母液质量),升温溶解成澄清溶液,然后降温至6℃结晶,保温20小时,过滤后得到12.03gRS/SR型固体,产品纯度≥90%。
该方法中,SS/RR型固体和RS/SR型固体的单程收率为40%。
实施例14
在250mL四口瓶中依次投入50g盐酸奈必洛尔的中间体混合物、10mL乙醇和100mL环己烷,常温溶解成澄清溶液,然后降温至-2.5℃结晶,保温20小时,过滤后得到15.48gSS/RR型固体,产品纯度≥85%;乙醇与环己烷按照1∶10的体积比配制成混合溶剂,将上述结晶过滤后的母液蒸干,补加5%混合溶剂(相对于蒸干后的母液质量),升温溶解成澄清溶液,然后降温至5℃结晶,保温20小时,过滤后得到15.19gRS/SR型固体,产品纯度≥90%。
该方法中,SS/RR型固体和RS/SR型固体的单程收率为35%。
实施例15
在250mL四口瓶中依次投入55g盐酸奈必洛尔的中间体混合物、50mL乙醇和50mL石油醚,常温溶解成澄清溶液,然后降温至-2℃结晶,保温20小时,过滤后得到14.32gSS/RR型固体,产品纯度≥90%;乙醇与石油醚按照1∶1的体积比配制成混合溶剂,将上述结晶过滤后的母液蒸干,补加2%混合溶剂(相对于蒸干后的母液质量),升温溶解成澄清溶液,然后降温至10℃结晶,保温20小时,过滤后得到12.05gRS/SR型固体,产品纯度≥90%。
该方法中,SS/RR型固体和RS/SR型固体的单程收率为40%。
实施例16
在250mL四口瓶中依次投入20g盐酸奈必洛尔的中间体混合物、80mL乙醇,常温溶解成澄清溶液,然后降温至-4℃结晶,保温20小时,过滤后得到7.03g SS/RR型固体,产品纯度≥85%;正庚烷与叔戊醇按照5∶1的体积比配制成混合溶剂,将上述结晶过滤后的母液蒸干,补加10%混合溶剂(相对于蒸干后的母液质量),升温溶解成澄清溶液,然后降温至8℃结晶,保温20小时,过滤后得到5.82gRS/SR型固体,产品纯度≥85%。
该方法中,SS/RR型固体和RS/SR型固体的单程收率为35%
上述各实施例并非是限定本发明的实施范围,对于本领域技术人员,只要是不脱离本发明技术原理,只是对本发明做出的非本质性的改变或者修改,均视为本发明权利要求的范围。
Claims (24)
- 盐酸奈必洛尔中间体混合物的结晶分离方法,其中,包括以下步骤:步骤1:向盐酸奈必洛尔中间体混合物中加入醇类溶剂或醇类与烷烃的混合溶剂,常温溶解成澄清溶液,然后降温至-10~5℃结晶,保温8~20h,过滤后得到式II的SS/RR型固体:步骤2:将步骤1结晶过滤后的母液浓缩至干,再加入醇类溶剂或醇类与烷烃的混合溶剂,升温溶解成澄清溶液,然后降温至0~15℃结晶,保温2~20h,过滤后得到式I的RS/SR型固体:其中,所述步骤1中醇类溶剂或醇类与烷烃的混合溶剂的体积(mL)与中间体混合物的质量(g)之间的数值比为1∶1~5∶1;其中,所述步骤2中醇类溶剂或醇类与烷烃的混合溶剂的质量为浓缩后母液质量的5%~25%。
- 根据权利要求1所述的盐酸奈必洛尔中间体混合物的结晶分离方法,其中,所述步骤1和步骤2的混合溶剂中,醇类与烷烃的体积比为1∶15~15∶1。
- 根据权利要求2所述的盐酸奈必洛尔中间体混合物的结晶分离方法,其中,所述步骤1和步骤2的混合溶剂中,醇类与烷烃的体积比为1∶15~15∶1。
- 根据权利要求1所述的盐酸奈必洛尔中间体混合物的结晶分离方法,其中,所述步骤1中醇类溶剂或醇类与烷烃的混合溶剂的体积(mL)与中间体混合物的质量(g)之间的数值比为2∶1。
- 根据权利要求1所述的盐酸奈必洛尔中间体混合物的结晶分离方法,其中,所述步骤2中醇类溶剂或醇类与烷烃的混合溶剂的质量为浓缩后母液质量的10% ~15%。
- 根据权利要求1所述的盐酸奈必洛尔中间体混合物的结晶分离方法,其中,所述醇类为甲醇、乙醇、异丙醇、正丁醇、叔丁醇、叔戊醇中的一种或多种的混合。
- 根据权利要求1所述的盐酸奈必洛尔中间体混合物的结晶分离方法,其中,所述烷烃为C5~C9烷烃中的一种或多种的混合物。
- 根据权利要求1所述的盐酸奈必洛尔中间体混合物的结晶分离方法,其中,所述步骤1中澄清溶液降温至-5~0℃结晶。
- 根据权利要求1所述的盐酸奈必洛尔中间体混合物的结晶分离方法,其中,所述步骤1中结晶保温时间为12h。
- 根据权利要求1所述的盐酸奈必洛尔中间体混合物的结晶分离方法,其中,所述步骤2中澄清溶液降温至4~10℃结晶。
- 根据权利要求1所述的盐酸奈必洛尔中间体混合物的结晶分离方法,其中,所述步骤2中结晶保温时间为12h。
- 根据权利要求12所述的盐酸奈必洛尔中间体混合物的结晶分离方法,其中, 所述步骤1和步骤2的混合溶剂中,醇类与烷烃的体积比为1∶15~15∶1。
- 根据权利要求13所述的盐酸奈必洛尔中间体混合物的结晶分离方法,其中,所述步骤1和步骤2的混合溶剂中,醇类与烷烃的体积比为1∶5。
- 根据权利要求12所述的盐酸奈必洛尔中间体混合物的结晶分离方法,其中,所述步骤1中醇类溶剂或醇类与烷烃的混合溶剂的体积(mL)与中间体混合物的质量(g)之间的数值比为1∶1~5∶1。
- 根据权利要求15所述的盐酸奈必洛尔中间体混合物的结晶分离方法,其中,所述步骤1中醇类溶剂或醇类与烷烃的混合溶剂的体积(mL)与中间体混合物的质量(g)之间的数值比为2∶1。
- 根据权利要求12所述的盐酸奈必洛尔中间体混合物的结晶分离方法,其中,所述步骤2中醇类溶剂或醇类与烷烃的混合溶剂的质量为浓缩后母液质量的5%~25%。
- 根据权利要求17所述的盐酸奈必洛尔中间体混合物的结晶分离方法,其中,所述步骤2中醇类溶剂或醇类与烷烃的混合溶剂的质量为浓缩后母液质量的10%~15%。
- 根据权利要求12所述的盐酸奈必洛尔中间体混合物的结晶分离方法,其中,所述醇类为甲醇、乙醇、异丙醇、正丁醇、叔丁醇、叔戊醇中的一种或多种的混合。
- 根据权利要求12所述的盐酸奈必洛尔中间体混合物的结晶分离方法,其中,所述烷烃为C5~C9烷烃中的一种或多种的混合物。
- 根据权利要求12所述的盐酸奈必洛尔中间体混合物的结晶分离方法,其中,所述步骤1中澄清溶液降温至-5~0℃结晶。
- 根据权利要求12所述的盐酸奈必洛尔中间体混合物的结晶分离方法,其中,所述步骤1中结晶保温时间为12h。
- 根据权利要求12所述的盐酸奈必洛尔中间体混合物的结晶分离方法,其中,所述步骤2中澄清溶液降温至4~10℃结晶。
- 根据权利要求12所述的盐酸奈必洛尔中间体混合物的结晶分离方法,其中,所述步骤2中结晶保温时间为12h。
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CN105085499A (zh) * | 2015-08-07 | 2015-11-25 | 上海现代制药海门有限公司 | 盐酸奈必洛尔中间体混合物的结晶分离方法 |
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