CN112441942B - Debromination method of sartan intermediate polybrominated substituent - Google Patents
Debromination method of sartan intermediate polybrominated substituent Download PDFInfo
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- CN112441942B CN112441942B CN202011554293.XA CN202011554293A CN112441942B CN 112441942 B CN112441942 B CN 112441942B CN 202011554293 A CN202011554293 A CN 202011554293A CN 112441942 B CN112441942 B CN 112441942B
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- polybrominated
- substituent
- sartan
- debromination
- reaction
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- 238000000034 method Methods 0.000 title claims abstract description 17
- 238000007256 debromination reaction Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 20
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000002994 raw material Substances 0.000 claims abstract description 14
- 239000012452 mother liquor Substances 0.000 claims abstract description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 10
- 238000010992 reflux Methods 0.000 claims abstract description 10
- 238000001035 drying Methods 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 5
- 238000005406 washing Methods 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 239000008247 solid mixture Substances 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- LFFIEVAMVPCZNA-UHFFFAOYSA-N 2-[4-(bromomethyl)phenyl]benzonitrile Chemical group C1=CC(CBr)=CC=C1C1=CC=CC=C1C#N LFFIEVAMVPCZNA-UHFFFAOYSA-N 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 239000003513 alkali Substances 0.000 abstract description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 abstract description 8
- 239000000203 mixture Substances 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 abstract description 4
- 239000003638 chemical reducing agent Substances 0.000 abstract description 3
- 239000003960 organic solvent Substances 0.000 abstract description 3
- 239000013078 crystal Substances 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 15
- 239000007787 solid Substances 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/32—Separation; Purification; Stabilisation; Use of additives
- C07C253/34—Separation; Purification
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a debromination method of a sartan polybrominated intermediate, which comprises the following steps: taking a brominated crystal mother liquor of a sartan intermediate containing a polybrominated substituent as a raw material, mixing the raw material with diethyl phosphite and alkali, wherein the alkali is selected from any one or more than two mixtures of potassium carbonate or sodium carbonate; the reaction mole ratio of the polybrominated substituent in the raw materials to the alkali is 1:1-3; the reaction molar ratio of the polybrominated substituent in the raw materials to the diethyl phosphite serving as the reducing agent is 1:1-3; reflux reaction in organic solvent for 8-16 hr, water washing, drying, desolventizing and crystallizing to obtain high purity monobromo substituent. The method of the invention achieves the ideal debromination effect of the polybrominated substituent. The monobromo substituent after debromination can be recycled, and the utilization rate of the sartan intermediate is obviously improved.
Description
Technical Field
The invention belongs to the technical field of medical intermediates, and particularly relates to a debromination method of a sartan intermediate polybrominated substituent.
Background
The intermediate of the bromosartan is a series of common medical intermediates. The intermediate of the bromosartan used in the process of synthesizing the sartan is usually obtained by brominating the intermediate of the bromosartan. The byproduct polybrominated substances are generated in the bromination process, so that the purity of the product is reduced, and the production benefit is reduced.
Therefore, it is necessary to provide a debromination method of a sartan polybrominated intermediate to improve the purity and the production benefit of the product.
Disclosure of Invention
Aiming at the problems related to the background technology, the invention provides a debromination method of a polybrominated substituent of a sartan intermediate, so that the polybrominated substituent of the sartan intermediate can be reused, and the utilization rate of the sartan intermediate can be obviously improved.
In order to solve the technical problems, the invention adopts the following technical scheme:
a process for debrominating a sartan polybrominated intermediate comprising: the preparation method comprises the steps of taking a brominated crystallization mother liquor of a sartan intermediate containing a polybrominated substituent as a raw material, mixing the raw material with diethyl phosphite and alkali, carrying out reflux reaction in an organic solvent for 8-16 hours, and washing, drying, desolventizing and crystallizing the reacted product to obtain the high-purity monobrominated substituent.
In order to further improve the debromination efficiency of the polybrominated substituent, a preferred embodiment of the present invention further comprises spin-drying and desolventizing the raw material to obtain a solid mixture containing the polybrominated substituent.
In the scheme of the invention, the alkali is taken as an acid binding agent to participate in the reaction, and can be selected from any one or more than two mixtures of potassium carbonate or sodium carbonate; preferably potassium carbonate.
In the scheme of the invention, the reaction molar ratio of the polybrominated substituent in the raw materials to the alkali is 1:1-3; preferably 1:1.5-3; most preferably 1:3.
In the scheme of the invention, the diethyl phosphite is taken as a reducing agent to participate in the reaction, and the reaction mole ratio of the polybrominated substituent in the raw material to the diethyl phosphite serving as the reducing agent is 1:1-3; preferably 1:1.5-3; most preferably 1:1.5.
In the scheme of the invention, the reaction temperature is 35-80 ℃, and the reaction time is preferably 16 hours.
In the scheme of the invention, the organic solvent can be esters, hydrocarbons, ethers or alcohols; preferably hydrocarbons; further preferred is dichloromethane or dichloroethane.
In a preferred embodiment of the invention, a brominated crystal mother liquor of a sartan intermediate containing a polybrominated substituent is taken as a raw material, the raw material is spin-dried and desolventized to obtain a solid mixture containing the polybrominated substituent, the solid mixture is mixed with diethyl phosphite and potassium carbonate, so that the molar ratio of the polybrominated substituent to the potassium carbonate in the solid mixture is 1:1.5-3, and the molar ratio of the polybrominated substituent to the diethyl phosphite is 1:1.5-3; after mixing, the mixture is reacted in a hydrocarbon solvent for 16 hours under reflux, and the product after the reaction is washed, dried, desolventized and crystallized to obtain the high-purity monobromo substituent.
Compared with the prior art, the method of the invention furthest promotes the reaction by adding the alkali with proper types and proper proportions as the acid-binding agent in the reaction process. Experiments prove that the inventor can properly increase the use amount of the alkali to ensure that the polybrominated substituent can obtain an ideal debromination effect, but the debromination effect is poor when the use amount of the alkali is too large (the molar ratio of the alkali to the polybrominated substituent exceeds 1:3); furthermore, a particular class of base has desirable effects on the debromination reaction of the invention. In a word, the monobromo substituent obtained by debrominating through the method can be recycled, and the utilization rate of the sartan intermediate is obviously improved.
Detailed Description
The following is a further description of the solution of the invention by way of examples. The solution of the invention is not limited to the examples listed.
Example 1
The synthesis process of the 2-cyano-4' -bromomethyl biphenyl is shown in the following formula (I):
during production of b, byproduct c is produced. During purification of b, the byproduct c is present in the crystallization mother liquor in a large amount.
According to the present invention, there is provided a method for debrominating a polybrominated by-product c contained in the above-mentioned crystallization mother liquor, comprising:
taking 100ml of the crystallization mother liquor as a raw material, spin-drying and desolventizing by a rotary evaporator to obtain 36g of yellow solid, wherein the purity of the yellow solid is a:5%, b:60.24%, c:28.62%. The solid was added with 200ml of methylene chloride to a 500ml flask, followed by addition of 12.2g of potassium carbonate (88.3 mmol) and 6.09g of diethyl phosphite (44.15 mmol), heating to reflux and reaction at a constant temperature for 16 hours. Samples were analyzed for purity by HPLC: a:8%, b:81%, c:5.1%. 100ml×2 water was added to wash twice. 10g of anhydrous magnesium sulfate was added to the mixture to dry the mixture, the mixture was filtered, and the filtrate was cooled to-5℃with stirring. Crystallizing for 2 hours. Filtering, washing the filter cake with 10ml of dichloromethane for 1 time, pumping and drying to obtain the product. The reaction process is shown in the following formula (II):
comparative example 1
100ml of the mother liquor described in example 1 was taken and spin-dried with a rotary evaporator to give 36g of yellow solid with purity a:5%, b:60.24%, c:28.62%. The solid was added with 200ml of dichloromethane to a 500ml vial, 6.98g of ammonium bicarbonate (88.3 mmol) and 6.09g of diethyl phosphite (44.15 mmol) were added continuously, the temperature was raised to reflux, the reaction was kept at rest for 16 hours, and samples were taken for HPLC analysis: a:41.6%, b:2.1%, c:40.09%, and the result shows that the product is destroyed and has no debromination effect.
Comparative example 2
100ml of the mother liquor described in example 1 was taken and spin-dried with a rotary evaporator to give 36g of yellow solid with purity a:5%, b:60.24%, c:28.62%. The solid was added with 200ml of dichloromethane to a 500ml vial, 18.3g of potassium carbonate (132.5 mmol) and 6.09g of diethyl phosphite (44.15 mmol) were added successively, the temperature was raised to reflux, the reaction was kept at rest for 16 hours, and samples were taken for HPLC analysis: a:31%, b:59.0%, c:2.5%.
Comparative example 3
100ml of the mother liquor described in example 1 was taken and spin-dried with a rotary evaporator to give 36g of yellow solid with purity a:5%, b:60.24%, c:28.62%. The solid was added with 200ml of dichloromethane to a 500ml vial, followed by 24.4g of potassium carbonate (176.6 mmol) and 6.09g of diethyl phosphite (44.15 mmol), warmed to reflux, incubated for 16 hours, and sampled for HPLC analysis: a:31.0%, b:61.88%, c:1.68%.
Comparative example 4
100ml of the mother liquor described in example 1 was taken and spin-dried with a rotary evaporator to give 36g of yellow solid with purity a:5%, b:60.24%, c:28.62%. The solid was added with 200ml of dichloromethane to a 500ml vial, 18.7g of sodium carbonate (176.6 mmol) and 6.09g of diethyl phosphite (44.15 mmol) were added successively, the temperature was raised to reflux, the reaction was kept for 16 hours, and samples were taken for HPLC analysis: a:30.0%, b:56.88%, c:5.21%.
Comparative example 5
100ml of the mother liquor described in example 1 was taken and spin-dried with a rotary evaporator to give 36g of yellow solid with purity a:5%, b:60.24%, c:28.62%. The solid was added with 200ml of dichloromethane to a 500ml vial, 18.7g of sodium carbonate (176.6 mmol) and 11.09g of diethyl phosphite (80.3 mmol) were added successively, the mixture was warmed to reflux, the reaction was kept for 16 hours, and samples were taken for HPLC analysis: a:28%, b:65.2%, c:0.56%.
The above embodiments are only for illustrating the technical solution of the present invention and not for limiting the conception and the protection scope of the present invention, and the technical solution of the present invention is modified or equivalent by those of ordinary skill in the art without departing from the spirit and scope of the technical solution, which should be covered in the scope of the claims of the present invention.
Claims (1)
1. A debromination method of a sartan polybrominated intermediate is characterized in that a brominated crystallization mother liquor of the sartan intermediate containing polybrominated substituents, which is generated in the synthesis process of 2-cyano-4' -bromomethyl biphenyl shown in the following formula (I), is taken as a raw material,
the debromination method specifically comprises the following steps:
spin-drying and desolventizing the crystallization mother liquor raw material containing b and c to obtain a solid mixture containing a polybrominated substituent c,
mixing the solid mixture with diethyl phosphite and potassium carbonate so that the molar ratio of polybrominated substituent c to potassium carbonate in the solid mixture is 1:3 and the molar ratio of polybrominated substituent c to diethyl phosphite is 1:1.5; after mixing, carrying out reflux reaction for 16 hours in dichloromethane, and washing, drying, desolventizing and crystallizing the reacted product to obtain a monobromo substituent; the reaction process is shown in the following formula (II):
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| CN202011554293.XA CN112441942B (en) | 2020-12-24 | 2020-12-24 | Debromination method of sartan intermediate polybrominated substituent |
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| CN114478313A (en) * | 2021-12-24 | 2022-05-13 | 浙江华洲药业有限公司 | Method for synthesizing high-purity bromosartanbiphenyl |
| CN114478315B (en) * | 2022-02-25 | 2023-10-31 | 山东艾孚特科技有限公司 | Method for catalytic reduction of irosartan biphenyl waste residues by using halogen-modified Pd/C catalyst |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103626677A (en) * | 2013-12-05 | 2014-03-12 | 天津大学 | Crystallizing method for preparing high-purity 4-bromomethyl-2-cyanobiphenyl |
| CN104876836A (en) * | 2015-06-12 | 2015-09-02 | 山东金城医药化工股份有限公司 | Method for utilizing 4-bromomethyl-2-cyanobiphenyl waste residues to prepare 4-bromomethyl-2-cyanobiphenyl |
| CN108947870A (en) * | 2018-07-23 | 2018-12-07 | 湖北宇阳药业有限公司 | A kind of preparation method of bromo sartanbiphenyl |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103626677A (en) * | 2013-12-05 | 2014-03-12 | 天津大学 | Crystallizing method for preparing high-purity 4-bromomethyl-2-cyanobiphenyl |
| CN104876836A (en) * | 2015-06-12 | 2015-09-02 | 山东金城医药化工股份有限公司 | Method for utilizing 4-bromomethyl-2-cyanobiphenyl waste residues to prepare 4-bromomethyl-2-cyanobiphenyl |
| CN108947870A (en) * | 2018-07-23 | 2018-12-07 | 湖北宇阳药业有限公司 | A kind of preparation method of bromo sartanbiphenyl |
Non-Patent Citations (1)
| Title |
|---|
| Atherton-Todd 反应及其立体化学机理研究进展;曹书霞 等;《中国科学：化学》;第45卷(第3期);283-294页 * |
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