CN112745246A - Purification method of shakubiqu intermediate - Google Patents
Purification method of shakubiqu intermediate Download PDFInfo
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- CN112745246A CN112745246A CN202011604219.4A CN202011604219A CN112745246A CN 112745246 A CN112745246 A CN 112745246A CN 202011604219 A CN202011604219 A CN 202011604219A CN 112745246 A CN112745246 A CN 112745246A
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- toluene
- shakubiqu
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/08—Separation; Purification; Stabilisation; Use of additives
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- 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
- C07B2200/07—Optical isomers
Abstract
A method for purifying a shakubiqu intermediate, wherein the shakubiqu intermediate is (R, E) -5- ([1,1' biphenyl ] -4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl-2-pentenoic acid, comprises the following steps: 1) adding ethanol into the crude product of the shakubitqu intermediate, and heating to dissolve to obtain a solution; 2) under the condition of stirring, dropwise adding toluene into the solution obtained in the step 1), and continuing stirring after dropwise adding; 3) continuously dripping toluene into the solution, and continuously stirring after dripping is finished; 4) the reaction system is cooled to 10-15 ℃ in a gradient way within 5-6h, and is kept warm and stirred for 1.5-2 h; 5) filtering, washing with ethanol and toluene mixed solution to obtain the shakubiqu intermediate product. The purification method can greatly reduce the content of impurities, especially optical enantiomer impurities, in the Sacubitril intermediate, so that the prepared Sacubitril intermediate meets the requirements of medical synthesis.
Description
Technical Field
The invention relates to the field of medicine synthesis, and particularly relates to a purification method of a shakubiqu intermediate.
Background
The shakubiqu is an anti-heart failure drug, and the (R, E) -5- ([1,1' biphenyl ] -4-yl) -4- ((tert-butyloxycarbonyl) amino) -2-methyl-2-pentenoic acid is a key intermediate of the drug, and has the following structural formula:
and the Sacubitril is also an important component of LCZ-696 (sodium valsartan of Sacubitril) medicaments. The medicine has great advantages compared with the existing cardiovascular treatment medicines due to the unique dual action mechanism of enkephalinase and angiotensin receptors, thereby gaining high attention of the pharmaceutical industry and various boundaries of the market, and each main intermediate of the LCZ-696 series also becomes the object of controversial research of each large medicine enterprise company.
At present, (R, E) -5- ([1,1' biphenyl ] -4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl-2-pentenoic acid is still produced and sold as an important intermediate of LCZ-696 in the domestic market. Regarding the preparation of the intermediate (R, E) -5- ([1,1' biphenyl ] -4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl-2-pentenoic acid, there are several patent reports at home and abroad, among which WO2014032627A1 reports a patent route: taking (R) -tert-butyl (1- ([1,1 '-biphenyl ] -4-yl) -3-hydroxypropane-2-yl) carbamate as a starting material, and obtaining an intermediate (R, E) -5- ([1,1' -biphenyl ] -4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl-2-pentenoic acid through TEMPO oxidation reaction, Wittig reaction, saponification hydrolysis, post-treatment crystallization; the route has simple equipment requirement and appropriate cost economy, and is suitable for industrial production, but the main defect problem of the process is that an S-type optical enantiomer impurity generated by simultaneous reaction with the intermediate is easily generated in the reaction, the impurity is named as (2E,4S) -5- ([1,1' biphenyl ] -4-yl) -4- [ (tert-butoxycarbonyl) amino ] -2-methylpentenoic acid, and the structure is as follows:
although the reaction has certain stereoselectivity to control the impurity, the impurity is generally generated in about 3-5% after the reaction is finished, the impurity is difficult to remove after the generation in the reaction, the post-treatment is difficult, and the quality standard of related substances of the intermediate (R, E) -5- ([1,1' biphenyl ] -4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl-2-pentenoic acid is influenced.
Disclosure of Invention
The invention aims to provide a purification method of a shakubiqu intermediate aiming at the defects of the prior art, which can greatly reduce the content of impurities, particularly optical enantiomer impurities, in the shakubiqu intermediate, so that the prepared shakubiqu intermediate meets the requirements of medical synthesis.
The technical scheme of the invention is as follows: a method for purifying a shakubiqu intermediate, wherein the shakubiqu intermediate is (R, E) -5- ([1,1' biphenyl ] -4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl-2-pentenoic acid, comprises the following steps:
1) adding ethanol into the crude product of the shakubitqu intermediate, and heating to dissolve to obtain a solution;
2) under the condition of stirring, dropwise adding toluene into the solution obtained in the step 1), and continuing stirring after dropwise adding;
3) continuously dripping toluene into the solution, and continuously stirring after dripping is finished;
4) the reaction system is cooled to 10-15 ℃ in a gradient way within 5-6h, and is kept warm and stirred for 1.5-2 h;
5) filtering, washing with ethanol and toluene mixed solution to obtain the shakubiqu intermediate product.
The crude product of the shakubiqu intermediate in the step 1) contains an optical enantiomer, the content of the optical enantiomer is 10-15 wt%, and the optical enantiomer is (2E,4S) -5- ([1,1' biphenyl ] -4-yl) -4- [ (tert-butoxycarbonyl) amino ] -2-methylpentene-oic acid.
Step 1), the mass ratio of the ethanol to the crude intermediate of the shakubiqu is 8: 1, the temperature rise is 75-78 ℃.
Step 2), the mass ratio of the toluene to the crude product of the shakuibiqu intermediate is 7: 1, the dropping temperature is 75-78 ℃, the dropping time is 1-1.5h, and after the dropping is finished, the stirring is continued for 1h under the condition of heat preservation.
Step 3), the mass ratio of the toluene to the crude product of the shakuibiqu intermediate is 8: 1, the dropping temperature is 75-78 ℃, the dropping time is 1-1.5h, and after the dropping is finished, the stirring is continued for 1h under the condition of heat preservation.
And 4) performing gradient cooling, wherein the temperature is reduced for 10-13h per hour.
Step 5), in the ethanol-toluene mixed solution, the mass ratio of ethanol to toluene is 1:2, the mass ratio of the mixed solution to the crude intermediate of the shakubiqu is 1.5: 1.
adopt above-mentioned technical scheme to have following beneficial effect:
1. the intermediate (R, E) -5- ([1,1 'biphenyl ] -4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl-2-pentenoic acid and its optical enantiomer impurity (2E,4S) -5- ([1,1' biphenyl ] -4-yl) -4- [ (tert-butoxycarbonyl) amino ] -2-methylpentenoic acid have similar solubility in various solvents due to the similar properties of the two, have good solubility in polar solvents such as ethanol, methanol, DMF and the like, and are usually difficult to separate. The purification method of the invention removes the impurities containing the optical enantiomer by utilizing the principles of dissolution in a mixed solvent system, re-precipitation and recrystallization of the product according to the solubility difference between the target product and the optical enantiomer impurities in the crude product of the shakubiqu intermediate in a recrystallization mode. Adding a crude product of the shakubiqu intermediate containing impurities and optical enantiomer impurities into ethanol, heating to dissolve, then dropwise adding toluene at 75-78 ℃, stirring for a period of time, utilizing the characteristic that the toluene has poor solubility for the toluene in the temperature range, but the solubilities of the toluene and the toluene are different to a certain extent, so that most of the optical enantiomer impurities are in a dissolved state, part of target products are separated out, continuously dropwise adding the toluene, continuously stirring, keeping most of the optical enantiomer impurities in a dissolved state, more target products are separated out, then reducing the temperature to 10-15 ℃ in a gradient manner within 5-6 hours, most of the optical enantiomer impurities are still in a dissolved state, and most of the target products are separated out and crystallized. Keeping the temperature and stirring for 1.5-2h to obtain the Sacubitril intermediate, wherein the optical purity of the target product is more than 99.9%, the optical enantiomer is as low as less than 0.1%, and the yield of the target product is more than 82%.
2. The Sacubitril intermediate obtained by purification is washed by ethanol-toluene mixed liquor, and the mass ratio of ethanol to toluene in the mixed liquor is 1:2, the ratio of the crystal system used in recrystallization is close to (8: 8+7), the optical isomer impurities in the residual mother liquor can be effectively removed, and the target product is obtained, wherein the content of the impurities is less than 0.1%, and the requirements of medical synthesis can be effectively met. If the mixed liquid with other proportion is used, the effect of removing the impurities of the residual mother liquid in the washed filter cake cannot be achieved, and the yield of the target product is seriously reduced.
The applicant verifies that the main impurities in the crude product of the shakubiqu intermediate and the optical enantiomer impurities can be reduced from 15% to more than 0.1% by adopting the purification method.
The following is a further description with reference to specific examples.
Detailed Description
In the invention, the used raw material A is from Zhengzhou Jexon chemical product limited company (the purity is more than or equal to 98 percent, and the moisture is less than or equal to 0.1 percent). (ii) a The ethanol used is from Chongqing Duzhou chemical products Co., Ltd (purity is more than or equal to 99%, and water content is less than or equal to 0.1%).
Example 1
Taking a crude product of the intermediate (R, E) -5- ([1,1' biphenyl ] -4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl-2-pentenoic acid, and sampling to detect that the content of the optical enantiomer of the main impurity is 15.02 percent before purification preparation.
Taking 50g of crude intermediate (R, E) -5- ([1,1' biphenyl ] -4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl-2-pentenoic acid, adding 400g of absolute ethyl alcohol, stirring, heating to 75-78 ℃, dissolving the system, then dropwise adding 350g of toluene, controlling the temperature to 75-78 ℃, finishing dropwise adding for 70min, preserving the temperature to 75-78 ℃, and continuing to stir for 1 h; then dropwise adding 400g of toluene, controlling the temperature to be 75-78 ℃, keeping the temperature to be 75-78 ℃ after dropwise adding is finished for 60min, and continuously stirring for 1 h; starting gradient slow cooling, controlling the temperature to be reduced by 10-13 ℃ per hour, controlling the total cooling time to be 5-6 hours, keeping the temperature to be 10-15 ℃ after the temperature is reduced to 10-15 ℃, stirring for 1.5-2.0 h, keeping the temperature for a while, filtering, washing a filter cake with 75g of ethanol-toluene mixed liquor (the weight ratio of the mixed liquor is 1:1) to obtain a white-like solid, drying at 55 ℃ in a vacuum drying oven to obtain purified (R, E) -5- ([1,1' biphenyl ] -4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl-2-pentenoic acid, the optical purity was 99.94%, the optical enantiomeric impurity (2E,4S) -5- ([1,1' biphenyl ] -4-yl) -4- [ (tert-butoxycarbonyl) amino ] -2-methylpentenoic acid: 0.06% and yield 82.6%.
Example 2
Taking a crude product of the intermediate (R, E) -5- ([1,1' biphenyl ] -4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl-2-pentenoic acid, and sampling and detecting the content of main impurities and optical enantiomers to be 11.50 percent before purification preparation.
Taking 70g of crude intermediate (R, E) -5- ([1,1' biphenyl ] -4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl-2-pentenoic acid, adding 560g of absolute ethyl alcohol, stirring, heating to 75-78 ℃, dissolving the system, then dropwise adding 490g of toluene, controlling the temperature to 75-78 ℃, finishing dropwise adding for 90min, preserving the temperature to 75-78 ℃, and continuing to stir for 1 h; then, 560g of toluene is dripped, the temperature is controlled to be 75-78 ℃, the dripping is finished for 75min, the temperature is kept at 75-78 ℃ and the stirring is continued for 1h, the heat preservation time is finished, the temperature is slowly reduced to 10-15 ℃ within 5-6h, the temperature is reduced to 10-13 ℃ per hour, the temperature is kept at 10-15 ℃, the crystallization is stirred for 1.5-2.0 h, the filtration is carried out, a filter cake is washed by ethanol-toluene mixed liquor (the weight ratio of the two is 1:2)105g, a white solid is obtained, a wet product is dried in a vacuum oven, the temperature is 55 ℃, and the drying is carried out, so that the purified (R, E) -5- ([1,1 'biphenyl ] -4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl-2-pentenoic acid with the optical purity of 99.96 percent and the optical enantiomer impurity (2E,4S) -5- ([1,1' biphenyl ] -4-yl) -4 Pentenoic acid: 0.04% and purification yield 83.4%.
Example 3
Taking a crude product of the intermediate (R, E) -5- ([1,1' biphenyl ] -4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl-2-pentenoic acid, and sampling and detecting the content of main impurities and optical enantiomers to be 12.20 percent before purification preparation.
Taking 40g of crude intermediate (R, E) -5- ([1,1' biphenyl ] -4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl-2-pentenoic acid, adding 320g of absolute ethanol, stirring, heating to 75-78 ℃, dissolving the system, beginning to dropwise add 280g of toluene, controlling the temperature to 75-78 ℃, completing dropwise addition, then preserving the temperature to 75-78 ℃ and continuing to stir for 1h, then dropwise adding 320g of toluene, controlling the temperature to 75-78 ℃, completing dropwise addition for 70min, still preserving the temperature to 75-78 ℃ and continuing to stir for 1h, after the heat preservation time is completed, slowly cooling to 10-15 ℃ within 5-6h, reducing the temperature to about 10-13 ℃ per hour, then preserving the temperature to 10-15 ℃, crystallizing and stirring for 1.5-2.0 h, filtering, washing a filter cake by 105g of ethanol-toluene mixed solution (the weight ratio of the two is 1:2), obtaining a white-like solid, drying the wet product in a vacuum oven at 55 ℃, and drying to obtain the purified (R, E) -5- ([1,1 'biphenyl ] -4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl-2-pentenoic acid with the optical purity of 99.98 percent, and the optical enantiomer impurity (2E,4S) -5- ([1,1' biphenyl ] -4-yl) -4- [ (tert-butoxycarbonyl) amino ] -2-methylpentene-noic acid: 0.02% and a purification yield of 82.1%.
Claims (7)
1. A method for purifying a shakubiqu intermediate, which is characterized in that the shakubiqu intermediate is (R, E) -5- ([1,1' biphenyl ] -4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl-2-pentenoic acid, and comprises the following steps:
1) adding ethanol into the crude product of the shakubitqu intermediate, and heating to dissolve to obtain a solution;
2) under the condition of stirring, dropwise adding toluene into the solution obtained in the step 1), and continuing stirring after dropwise adding;
3) continuously dripping toluene into the solution, and continuously stirring after dripping is finished;
4) the reaction system is cooled to 10-15 ℃ in a gradient way within 5-6h, and is kept warm and stirred for 1.5-2 h;
5) filtering, washing with ethanol and toluene mixed solution to obtain the shakubiqu intermediate product.
2. The purification method according to claim 1, wherein the crude sabotabifrazole intermediate of step 1) contains an optical enantiomer in an amount of 10-15 wt%, and the optical enantiomer is (2E,4S) -5- ([1,1' biphenyl ] -4-yl) -4- [ (tert-butoxycarbonyl) amino ] -2-methylpentenoic acid.
3. The purification method according to claim 1, wherein the mass ratio of ethanol in step 1) to the crude shakubitrex intermediate is 8: 1, the temperature rise is 75-78 ℃.
4. The purification method according to claim 1, wherein the mass ratio of the toluene in the step 2) to the crude shakubiqu intermediate is 7: 1, the dropping temperature is 75-78 ℃, the dropping time is 1-1.5h, and after the dropping is finished, the stirring is continued for 1h under the condition of heat preservation.
5. The purification method according to claim 1, wherein the mass ratio of the toluene in the step 3) to the crude shakubiqu intermediate is 8: 1, the dropping temperature is 75-78 ℃, the dropping time is 1-1.5h, and after the dropping is finished, the stirring is continued for 1h under the condition of heat preservation.
6. The purification method according to claim 1, wherein the gradient cooling in step 4) is performed for 10-13h per hour.
7. The purification method according to claim 1, wherein in the ethanol-toluene mixed solution in the step 5), the mass ratio of ethanol to toluene is 1:2, the mass ratio of the mixed solution to the crude intermediate of the shakubiqu is 1.5: 1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114409558A (en) * | 2022-02-15 | 2022-04-29 | 重庆市碚圣医药科技股份有限公司 | Sacubitril intermediate impurity and synthetic method thereof |
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