CN105085499A - Crystal separation method for nebivolol hydrochloride intermediate mixture - Google Patents

Abstract

The invention discloses a method for crystallization and separation of a nebivolol hydrochloride intermediate mixture, comprising the following steps: step 1, adding an alcohol solvent or a mixed solvent of alcohol and alkane to the nebivolol hydrochloride intermediate mixture, and dissolving at room temperature into Clarify the solution, then lower the temperature to crystallize, and obtain SS/RR solid after filtration; step 2, concentrate the mother liquor after crystallization and filtration in step 1 to dryness, then add alcohol solvent or a mixed solvent of alcohol and alkanes, and heat up to dissolve into a clear solution , and then cooled to crystallize, and filtered to obtain a RS/SR solid. The present invention uses crystallization to separate SS/RR type and RS/SR type diastereoisomers in the intermediate mixture, has simple operation, short preparation cycle, reduces solvent consumption, reduces production cost and solvent post-treatment low cost, it is beneficial to realize industrial production, and the single-pass yield of the separated product can reach 35-70%.

Description

The crystallization separation method of nebivolol hydrochloride intermediate mixture

technical field

The invention relates to a method for crystallization and separation of a mixture, in particular to a method for crystallization and separation of a mixture of nebivolol hydrochloride intermediate RS/SR type and SS/RR type.

Background technique

As a third-generation β-receptor antagonist, nebivolol hydrochloride is different from other β-receptor antagonists and has higher selectivity. 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.

Formula I

Formula II

RS/SR (formula I) and SS/RR (formula II) are two important intermediates for the synthesis of nebivolol hydrochloride, which are a pair of diastereoisomers. At present, formula I and formula II are mainly separated by column chromatography, but this method has the following problems: 1, the production efficiency is low, and the production labor is large; 2, the amount of solvent used is large; 3, the yield The rate is low and the production cost is high. At present, there are no other separation methods of formula I and formula II reported in relevant literature and patents.

Contents of the invention

The technical problem to be solved by the present invention is to provide a method for crystallization and separation of the intermediate mixture of nebivolol hydrochloride.

In order to solve the problems of the technologies described above, the technical solution adopted in the present invention is:

The crystallization separation method of nebivolol hydrochloride intermediate mixture comprises the following steps:

Step 1: Add an alcohol solvent or a mixed solvent of alcohol and alkane to the intermediate mixture of nebivolol hydrochloride, dissolve at room temperature to form a clear solution, then cool down to -10~5°C to crystallize, keep warm for 8~20h, and filter A solid of type SS/RR of formula II is obtained:

Formula II;

Step 2: Concentrate the mother liquor after crystallization and filtration in step 1 to dryness, then add alcohol solvent or a mixed solvent of alcohol and alkanes, heat up and dissolve into a clear solution, then cool down to 0~15°C to crystallize, keep warm for 2~20h, and filter After obtaining the RS/SR type solid of formula I:

Formula I.

In the mixed solvent of step 1 and step 2, the volume ratio of alcohols to alkanes is 1:15-15:1.

In the mixed solvent of step 1 and step 2, the volume ratio of alcohols to alkanes is 1:5.

In the step 1, the numerical ratio between the volume (ml) of the alcohol solvent or the mixed solvent of alcohol and alkanes to the mass (g) of the intermediate mixture is 1:1-5:1.

In the step 1, the numerical ratio between the volume (ml) of the alcohol solvent or the mixed solvent of alcohol and alkanes to the mass (g) of the intermediate mixture is 2:1.

The mass of the alcohol solvent or the mixed solvent of alcohol and alkane in the step 2 is 5%-25% of the mass of the concentrated mother liquor.

The mass of the alcohol solvent or the mixed solvent of alcohol and alkane in the step 2 is 10%-15% of the mass of the concentrated mother liquor.

The alcohols are one or more of methanol, ethanol, isopropanol, n-butanol, tert-butanol and tert-amyl alcohol.

The alkanes are C ₅ -C ₉ alkanes or one or more mixtures.

In the step 1, the clear solution is cooled to -5~0°C to crystallize.

The crystallization holding time in the step 1 is 12h.

In the step 2, the clear solution cools down to 4-10° C. to crystallize.

The crystallization holding time in the step 2 is 12h.

Compared with the prior art, the present invention has the advantages that: the present invention adopts crystallization to separate SS/RR type and RS/SR type diastereoisomers in the intermediate mixture, the operation is simple, the preparation period is short, and the solvent is reduced simultaneously. consumption, reduces the production cost and solvent post-treatment cost, and is conducive to the realization of industrial production, and the single-pass yield of the separated product can reach 35-70%.

Description of drawings

The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments. Fig. 1 is the microscope picture after the SS/RR type solid that embodiment 1 obtains is enlarged 10x10;

Fig. 2 is the microscope picture after the RS/SR type solid that embodiment 1 obtains is enlarged 40x10;

Fig. 3 is the DSC spectrogram of the SS/RR type solid that example 1 obtains;

Fig. 4 is the DSC spectrogram of the RS/SR type solid that example 1 obtains.

Detailed ways:

The technical solutions of the present invention will be further described below in conjunction with specific embodiments.

Example 1

Put 50g of nebivolol hydrochloride intermediate mixture, 100mL cyclohexane and 20mL n-butanol into a 250mL four-necked bottle successively, dissolve at room temperature to form a clear solution, then cool down to -2°C to crystallize, keep warm for 20 hours, and filter Obtain 18.26gSS/RR type solid, product purity ≥ 97%; Hexanaphthene and n-butanol are formulated into mixed solvent according to the volume ratio of 5:1, the mother liquor after the above-mentioned crystallization filter is evaporated to dryness, add 10% mixed solvent ( Relative to the quality of the mother liquor after evaporation), the temperature was raised to dissolve into a clear solution, then cooled to 8°C to crystallize, kept for 20 hours, and 20.32g of RS/SR solid was obtained after filtration, with a product purity of ≥98%.

In this method, the single-pass yield of the formula I solid and the formula II solid is 70%.

The SS/RR type solid that above-mentioned implementation example 1 obtains, it can be seen that its crystal appearance is measured through a microscope, and all has flaky crystal habit, as shown in Figure 1; It can be known that its fusing point is 45.3 ℃ by DSC test result, as shown in Figure 3 Simultaneously, obtained RS/SR type solid, through its crystal appearance of microscopic measurement, all have acicular crystal habit, as shown in Figure 2; It can be known that its fusing point is 34.5 ℃ by DSC test result, as shown in Figure 4 .

Example 2

Put 60g of nebivolol hydrochloride intermediate mixture, 100mL of n-heptane and 20mL of n-butanol into a 250mL four-neck bottle successively, dissolve at room temperature to form a clear solution, then cool down to -2°C to crystallize, keep warm for 20 hours, and filter Obtain 18.57gSS/RR type solid, product purity ≥ 95%; Hexanaphthene and n-butanol are formulated into mixed solvent according to the volume ratio of 5:1, the mother liquor after the above-mentioned crystallization filter is evaporated to dryness, add 10% mixed solvent ( Relative to the quality of the mother liquor after evaporation), the temperature was raised to dissolve into a clear solution, then cooled to 8°C to crystallize, kept for 20 hours, and 21.92g of RS/SR solid was obtained after filtration, with a product purity of ≥98%.

In this method, the single-pass yield of the formula I solid and the formula II solid is 68%.

Example 3

Put 50g of nebivolol hydrochloride intermediate mixture, 10mL cyclohexane and 150mL n-butanol into a 250mL four-neck bottle successively, dissolve at room temperature to form a clear solution, then cool down to -5°C to crystallize, keep warm for 20 hours, and filter Obtain 15.61gSS/RR type solid, product purity ≥ 95%; Hexanaphthene and n-butanol are formulated into mixed solvent according to the volume ratio of 1:15, the mother liquor after the above-mentioned crystallization filter is spin-dried, add 15% mixed solvent ( Relative to the quality of the mother liquor after spin-drying), the temperature was raised to dissolve into a clear solution, and then the temperature was lowered to 5°C to crystallize, and the temperature was kept for 20 hours. After filtration, 22.51g of RS/SR solid was obtained, and the product purity was greater than or equal to 97%.

In this method, the single-pass yield of the formula I solid and the formula II solid is 70%.

Example 4

80g of nebivolol hydrochloride intermediate mixture, 150mL of cyclohexane and 10mL of n-butanol were successively put into a 500mL four-neck bottle, dissolved at room temperature to form a clear solution, then cooled to 5°C for crystallization, kept for 8 hours, and filtered to obtain 30.86gSS/RR type solid, product purity ≥ 95%; cyclohexane and n-butanol are formulated into a mixed solvent according to the volume ratio of 15:1, the mother liquor after the above-mentioned crystallization and filtration is spin-dried, and an additional 25% mixed solvent (relatively The quality of the mother liquor after spin-drying), heated up to dissolve into a clear solution, then cooled to 5°C to crystallize, kept warm for 2 hours, and obtained 28.85g RS/SR type solid after filtration, product purity ≥ 97%.

In this method, the single-pass yield of the formula I solid and the formula II solid is 70%.

Example 5

Put 30g of nebivolol hydrochloride intermediate mixture, 125mL cyclohexane and 25mL n-butanol into a 250mL four-necked bottle successively, dissolve at room temperature to form a clear solution, then cool down to -10°C to crystallize, keep warm for 8 hours, and filter Obtain 10.57gSS/RR type solid, product purity ≥ 93%; Hexanaphthene and n-butanol are formulated into mixed solvent according to the volume ratio of 5:1, the mother liquor after the above-mentioned crystallization filter is spin-dried, add 5% mixed solvent ( Relative to the quality of the mother liquor after spin-drying), the temperature was raised to dissolve into a clear solution, and then the temperature was lowered to 10°C to crystallize, kept for 2 hours, and 10.41g of RS/SR solid was obtained after filtration, with a product purity of ≥97%.

In this method, the single-pass yield of the formula I solid and the formula II solid is 69%.

Example 6

Put 120g of nebivolol hydrochloride intermediate mixture, 120mL of cyclohexane and 20mL of n-butanol into a 500mL four-necked bottle successively, dissolve at room temperature to form a clear solution, then cool down to -10°C to crystallize, keep warm for 12 hours, and filter Obtain 45.78gSS/RR type solid, product purity ≥ 93%; Hexanaphthene and n-butanol are formulated into mixed solvent according to the volume ratio of 6:1, the mother liquor after the above-mentioned crystallization filter is spin-dried, add 10% mixed solvent ( Relative to the quality of the mother liquor after spin-drying), the temperature was raised to dissolve into a clear solution, and then cooled to 4°C to crystallize, kept for 12 hours, and 50.05g of RS/SR solid was obtained after filtration, and the product purity was ≥97%.

In this method, the single-pass yield of the formula I solid and the formula II solid is 70%.

Example 7

60g of nebivolol hydrochloride intermediate mixture, 120mL of cyclohexane and 20mL of n-butanol were successively put into a 250mL four-necked bottle, dissolved at room temperature to form a clear solution, then cooled to 0°C to crystallize, kept for 20 hours, and filtered to obtain 25.56g SS/RR type solid, product purity ≥ 95%; cyclohexane and n-butanol are formulated into a mixed solvent according to the volume ratio of 6:1, the mother liquor after the above-mentioned crystallization and filtration is spin-dried, and an additional 10% mixed solvent (relatively The mass of the mother liquor after spin-drying) was heated up to dissolve into a clear solution, then cooled to 15°C to crystallize, kept for 20 hours, and 21.18g of RS/SR solid was obtained after filtration, with a product purity of ≥97%.

In this method, the single-pass yield of the formula I solid and the formula II solid is 70%.

Example 8

Put 50g of the intermediate mixture of nebivolol hydrochloride and 100mL of tert-amyl alcohol into a 250mL four-neck bottle successively, dissolve at room temperature to form a clear solution, then cool down to -2°C to crystallize, keep warm for 20 hours, and obtain 15.19gSS/RR after filtration Type solid, product purity ≥ 97%; evaporate the mother liquor after the above-mentioned crystallization and filtration to dryness, add 10% tert-amyl alcohol (relative to the quality of the mother liquor after evaporation), heat up and dissolve into a clear solution, and then cool down to 4°C to crystallize , keep warm for 20 hours, and get 16.92g RS/SR type solid after filtration, product purity ≥ 98%.

In this method, the single-pass yield of the formula I solid and the formula II solid is 64%.

Example 9

55g of nebivolol hydrochloride intermediate mixture, 100mL of n-heptane and 20mL of tert-amyl alcohol were successively put into a 250mL four-necked bottle, dissolved at room temperature to form a clear solution, then cooled to -2°C to crystallize, kept for 20 hours, and filtered Obtain 16.06gSS/RR type solid, product purity ≥ 95%; N-heptane and tert-amyl alcohol are formulated into mixed solvent according to the volume ratio of 5:1, the mother liquor after the above-mentioned crystallization filter is evaporated to dryness, add 10% mixed solvent ( Relative to the quality of the mother liquor after evaporation), the temperature was raised to dissolve into a clear solution, then cooled to 8°C to crystallize, kept for 20 hours, and 18.39g of RS/SR solid was obtained after filtration, with a product purity of ≥98%.

In this method, the single-pass yield of SS/RR type solid and RS/SR type solid is 63%.

Example 10

Drop into the intermediate mixture of 50g nebivolol hydrochloride, 50mL methanol and 50mL tert-butanol successively in 250mL four-necked bottle, dissolve into clear solution at room temperature, then cool down to -3°C to crystallize, keep warm for 20 hours, obtain 20.12 after filtration gSS/RR type solid, product purity ≥ 90%; methanol and tert-butanol are formulated into a mixed solvent according to a volume ratio of 1:1, the mother liquor after the above-mentioned crystallization and filtration is evaporated to dryness, and 5% mixed solvent is added (relative to evaporation to dryness) The quality of mother liquor after heating), the temperature rises and dissolves into a clear solution, then cools down to 10°C to crystallize, keeps warm for 20 hours, obtains 19.31g RS/SR type solid after filtration, and the product purity is ≥ 90%.

In this method, the single-pass yield of SS/RR type solid and RS/SR type solid is 42%.

Example 11

In a 250mL four-necked bottle, drop into the intermediate mixture of 50g nebivolol hydrochloride, 50mL ethanol and 50mL tert-butanol successively, dissolve into a clear solution at room temperature, then cool down to -4°C to crystallize, keep warm for 20 hours, and obtain 16.88 gSS/RR type solid, product purity ≥ 95%; ethanol and tert-butanol are formulated into a mixed solvent according to a volume ratio of 1:1, the mother liquor after the above-mentioned crystallization and filtration is evaporated to dryness, and an additional 8% mixed solvent is added (relative to evaporation to dryness) The quality of the mother liquor after), the temperature rises and dissolves into a clear solution, then cools down to 8°C to crystallize, keeps warm for 20 hours, and obtains 14.65g RS/SR type solid after filtration, and the product purity is ≥98%.

In this method, the single-pass yield of SS/RR type solid and RS/SR type solid is 55%.

Example 12

Put 50g of the intermediate mixture of nebivolol hydrochloride and 100mL of isopropanol into a 250mL four-necked bottle in turn, dissolve at room temperature to form a clear solution, then cool down to -2°C to crystallize, keep warm for 20 hours, and obtain 16.38gSS/RR after filtration Type solid, product purity ≥ 90%; evaporate the mother liquor after the above-mentioned crystallization and filtration, add 5% isopropanol (relative to the quality of the mother liquor after evaporation), heat up and dissolve into a clear solution, and then cool down to 8°C to crystallize , heat preservation for 20 hours, after filtration, 15.73g RS/SR type solid was obtained, and the product purity was ≥90%.

In this method, the single-pass yield of SS/RR type solid and RS/SR type solid is 40%.

Example 13

In a 250mL four-necked bottle, drop into the intermediate mixture of 50g of nebivolol hydrochloride, 50mL of ethanol and 50mL of n-heptane successively, dissolve into a clear solution at room temperature, then cool down to -3°C to crystallize, keep warm for 20 hours, and obtain 13.93 gSS/RR type solid, product purity ≥ 90%; ethanol and n-heptane are formulated into a mixed solvent according to the volume ratio of 1:1, the mother liquor after the above-mentioned crystallization and filtration is evaporated to dryness, and 3% mixed solvent is added (relative to evaporation to dryness) The quality of the mother liquor after heating), the temperature was raised to dissolve into a clear solution, and then the temperature was lowered to 6°C to crystallize, and the temperature was kept for 20 hours. After filtration, 12.03g of RS/SR type solid was obtained, and the product purity was ≥90%.

In this method, the single-pass yield of SS/RR type solid and RS/SR type solid is 40%.

Example 14

50g of nebivolol hydrochloride intermediate mixture, 10mL of ethanol and 100mL of cyclohexane were successively dropped into a 250mL four-necked bottle, dissolved at room temperature into a clear solution, then cooled to -2.5°C for crystallization, kept for 20 hours, and obtained 15.48 gSS/RR type solid, product purity ≥ 85%; ethanol and cyclohexane are formulated into a mixed solvent according to the volume ratio of 1:10, the mother liquor after the above-mentioned crystallization and filtration is evaporated to dryness, and 5% mixed solvent is added (relative to evaporation to dryness) The quality of mother liquor after heating), the temperature rises and dissolves into a clear solution, then cools down to 5°C to crystallize, keeps warm for 20 hours, obtains 15.19g RS/SR type solid after filtration, and the product purity is more than 90%.

In this method, the single-pass yield of SS/RR type solid and RS/SR type solid is 35%.

Example 15

Put 55g of nebivolol hydrochloride intermediate mixture, 50mL of ethanol and 50mL of petroleum ether into a 250mL four-necked bottle successively, dissolve into a clear solution at room temperature, then cool down to -2°C to crystallize, keep warm for 20 hours, and obtain 14.32gSS after filtration /RR type solid, product purity ≥ 90%; ethanol and petroleum ether are formulated into a mixed solvent according to the volume ratio of 1:1, the mother liquor after the above-mentioned crystallization and filtration is evaporated to dryness, and 2% mixed solvent is added (relative to the evaporated to dryness) quality of mother liquor), heated up to dissolve into a clear solution, then cooled to 10°C to crystallize, kept warm for 20 hours, and obtained 12.05g RS/SR type solid after filtration, product purity ≥ 90%.

In this method, the single-pass yield of SS/RR type solid and RS/SR type solid is 40%.

Example 16

Put 20g of the intermediate mixture of nebivolol hydrochloride and 80mL of ethanol into a 250mL four-necked bottle successively, dissolve at room temperature to form a clear solution, then cool down to -4°C to crystallize, keep warm for 20 hours, and obtain 7.03g of SS/RR solid after filtration , product purity ≥ 85%; n-heptane and tert-amyl alcohol are formulated into a mixed solvent according to a volume ratio of 5:1, the mother liquor after the above-mentioned crystallization and filtration is evaporated to dryness, and 10% mixed solvent is added (relative to the mother liquor after evaporation to dryness Quality), heated up to dissolve into a clear solution, then cooled to 8°C to crystallize, kept for 20 hours, and filtered to obtain 5.82g RS/SR solid, product purity ≥ 85%.

In this method, the single-pass yield of SS/RR type solid and RS/SR type solid is 35%.

The above-mentioned embodiments are not intended to limit the scope of implementation of the present invention. For those skilled in the art, as long as they do not depart from the technical principle of the present invention, only non-essential changes or modifications made to the present invention are considered as claims of the present invention. scope.

Claims (13)

1. the crystallization separation method of nebivolol hydrochloride intermediate mixture is characterized in that, may further comprise the steps: Step 1: Add an alcohol solvent or a mixed solvent of alcohol and alkane to the intermediate mixture of nebivolol hydrochloride, dissolve at room temperature to form a clear solution, then cool down to -10~5°C to crystallize, keep warm for 8~20h, and filter A solid of type SS/RR of formula II is obtained: Formula II; Step 2: Concentrate the mother liquor after crystallization and filtration in step 1 to dryness, then add alcohol solvent or a mixed solvent of alcohol and alkanes, heat up and dissolve into a clear solution, then cool down to 0~15°C to crystallize, keep warm for 2~20h, and filter After obtaining the RS/SR type solid of formula I: Formula I. 2. the crystallization separation method of nebivolol hydrochloride intermediate mixture according to claim 1, is characterized in that, in the mixed solvent of described step 1 and step 2, the volume ratio of alcohols and alkane is 1:15～ 15:1. 3. the crystallization separation method of nebivolol hydrochloride intermediate mixture according to claim 2, is characterized in that, in the mixed solvent of described step 1 and step 2, the volume ratio of alcohols and alkane is 1:5. 4. the crystallization separation method of nebivolol hydrochloride intermediate mixture according to claim 1, is characterized in that, the volume (ml) of the mixed solvent of alcoholic solvent or alcohols and alkane in described step 1 and intermediate The numerical ratio between the mass (g) of the mixture is 1:1~5:1. 5. the crystallization separation method of nebivolol hydrochloride intermediate mixture according to claim 4, is characterized in that, the volume (ml) of the mixed solvent of alcoholic solvent or alcohols and alkane in described step 1 and intermediate The numerical ratio between the mass (g) of the mixture is 2:1. 6. the crystallization separation method of nebivolol hydrochloride intermediate mixture according to claim 1, is characterized in that, the quality of the mixed solvent of alcoholic solvent or alcohols and alkane in described step 2 is mother liquor quality after concentrating 5%~25%. 7. the crystallization separation method of nebivolol hydrochloride intermediate mixture according to claim 6, is characterized in that, the quality of the mixed solvent of alcoholic solvent or alcohols and alkane in described step 2 is mother liquor quality after concentrating 10%~15%. 8. according to the crystallization separation method of the nebivolol hydrochloride intermediate mixture described in any one in claim 1 to 7, it is characterized in that, described alcohols are methanol, ethanol, Virahol, n-butanol, tert- A mixture of one or more of butanol and tert-amyl alcohol. 9. according to the crystallization separation method of the nebivolol hydrochloride intermediate mixture described in any one in claim 1 to 7, it is characterized in that, described alkane is C ₅ ～C ₉ alkane or one or more mixtures. 10. The crystallization separation method of nebivolol hydrochloride intermediate mixture according to claim 1, is characterized in that, in described step 1, clarified solution cools down to-5～0 ℃ of crystallization. 11. the crystallization separation method of nebivolol hydrochloride intermediate mixture according to claim 1, is characterized in that, in described step 1, crystallization heat preservation time is 12h. 12. The method for crystallization and separation of nebivolol hydrochloride intermediate mixture according to claim 1, characterized in that, in the step 2, the clarified solution is cooled to 4-10° C. for crystallization. 13. the crystallization separation method of nebivolol hydrochloride intermediate mixture according to claim 1, is characterized in that, in described step 2, crystallization holding time is 12h.