CN110078640B - Synthesis method of valsartan intermediate - Google Patents
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- CN110078640B CN110078640B CN201910249453.0A CN201910249453A CN110078640B CN 110078640 B CN110078640 B CN 110078640B CN 201910249453 A CN201910249453 A CN 201910249453A CN 110078640 B CN110078640 B CN 110078640B
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- 239000004072 C09CA03 - Valsartan Substances 0.000 title claims abstract description 26
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 title claims abstract description 26
- 229960004699 valsartan Drugs 0.000 title claims abstract description 26
- 238000001308 synthesis method Methods 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 26
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims abstract description 24
- XGISHOFUAFNYQF-UHFFFAOYSA-N pentanoyl chloride Chemical compound CCCCC(Cl)=O XGISHOFUAFNYQF-UHFFFAOYSA-N 0.000 claims abstract description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229910001868 water Inorganic materials 0.000 claims abstract description 21
- 238000005406 washing Methods 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000011780 sodium chloride Substances 0.000 claims abstract description 13
- 239000001103 potassium chloride Substances 0.000 claims abstract description 12
- 235000011164 potassium chloride Nutrition 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 12
- -1 2' -cyanobiphenyl-4-yl Chemical group 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 10
- 239000011230 binding agent Substances 0.000 claims abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 238000004321 preservation Methods 0.000 claims abstract description 5
- 238000004821 distillation Methods 0.000 claims abstract description 3
- 238000010791 quenching Methods 0.000 claims abstract description 3
- 230000000171 quenching effect Effects 0.000 claims abstract description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 7
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 5
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 7
- 238000003786 synthesis reaction Methods 0.000 claims 7
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 claims 1
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 239000010410 layer Substances 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- SUQNCOFVJNHEKQ-DEOSSOPVSA-N methyl (2s)-2-[[4-(2-cyanophenyl)phenyl]methyl-pentanoylamino]-3-methylbutanoate Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(=O)OC)=CC=C1C1=CC=CC=C1C#N SUQNCOFVJNHEKQ-DEOSSOPVSA-N 0.000 description 1
- AZQXUWUZQLZNIM-FYZYNONXSA-N methyl (2s)-2-[[4-(2-cyanophenyl)phenyl]methylamino]-3-methylbutanoate;hydrochloride Chemical compound Cl.C1=CC(CN[C@H](C(=O)OC)C(C)C)=CC=C1C1=CC=CC=C1C#N AZQXUWUZQLZNIM-FYZYNONXSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
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Classifications
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- 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 relates to a synthesis method of a valsartan intermediate, which comprises the following steps: (1) dissolving a compound shown in the following formula II in an organic solvent, adding an acid binding agent, sodium chloride or potassium chloride and water, uniformly stirring, dropwise adding n-valeryl chloride, and carrying out heat preservation reaction; (2) after the reaction is finished, water is added for quenching, and the target product, namely the N- [ (2' -cyanobiphenyl-4-yl) methyl ] -N- (1-oxo-pentyl) -L-valine methyl ester, is obtained by sequentially carrying out alkali washing, acid washing and alkali washing, and finally carrying out reduced pressure distillation. According to the method, a proper amount of sodium chloride or potassium chloride is added into a reaction system, and the occurrence of n-valeryl chloride hydrolysis reaction is inhibited by utilizing the same ion effect, so that the use amount of n-valeryl chloride is reduced, the purity and yield of a product are improved, the production cost is reduced, the pollution to the environment is reduced, and the method is more suitable for industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical preparation, in particular to a method for synthesizing a valsartan intermediate.
Background
Valsartan (Valsartan), chemical name: n- (1-oxypentyl) -N- [4- [2- (1H-tetrazol-5-yl) phenyl ] benzyl ] -L-valine, which is an angiotensin II receptor antagonist developed by Nowa company, and has the characteristics of stable blood pressure reduction, strong curative effect, long action time, good tolerance of patients and the like.
The compound N- [ (2' -cyanobiphenyl-4-yl) methyl ] -N- (1-oxopentyl) -L-valine methyl ester is a key intermediate for synthesizing valsartan, and the structure of the compound is shown as a formula I.
In the prior art, the preparation of valsartan intermediate N- [ (2' -cyanobiphenyl-4-yl) methyl ] -N- (1-oxopentyl) -L-valine methyl ester is carried out by reacting N- [ (2' -cyanobiphenyl-4-yl) methyl ] - (L) -valine methyl ester hydrochloride (structure shown in formula II) with N-valeryl chloride in the presence of an inorganic base aqueous solution and a suitable solvent to obtain (N- [ (2' -cyanobiphenyl-4-yl) -methyl ] -N-valeryl- (L) -valine methyl ester (formula I), wherein the synthetic route is shown as follows:
due to the presence of water in the reaction system, n-valeryl chloride undergoes hydrolysis, which leads to an increase in its amount. In addition, in the feeding molar ratio of the compound of the formula II to the n-valeryl chloride in the prior art, the dosage of the n-valeryl chloride is too high, the residue of n-valeric acid as an impurity in a product is increased, and ammonia water washing is needed for multiple times, so that the quality control of the product is not facilitated, the product purity and yield are lower, the production cost and the discharge amount of nitrogen-containing wastewater are increased, and the environmental pollution is greater.
Therefore, further improvement is needed for the current synthesis method of the valsartan intermediate.
Disclosure of Invention
The invention aims to solve the technical problem of the prior art and provides a synthesis method of a valsartan intermediate, which can effectively inhibit hydrolysis of n-valeryl chloride so as to reduce the dosage of the n-valeryl chloride, further improve the purity and yield of the product and reduce environmental pollution.
The technical scheme adopted by the invention for solving the technical problems is as follows: a synthetic method of a valsartan intermediate is characterized by comprising the following steps: comprises the following steps
(1) Dissolving a compound shown in the following formula II in an organic solvent, adding an acid binding agent, sodium chloride or potassium chloride and water, uniformly stirring, dropwise adding n-valeryl chloride, and carrying out heat preservation reaction;
(2) after the reaction is finished, adding water for quenching, sequentially carrying out alkali washing, acid washing and alkali washing, and finally carrying out reduced pressure distillation to obtain a target product, namely a compound shown as a formula I, namely N- [ (2' -cyanobiphenyl-4-yl) methyl ] -N- (1-oxo-pentyl) -L-valine methyl ester;
preferably, the organic solvent in step (1) is any one of toluene, xylene and dichloromethane.
Preferably, the acid-binding agent in the step (1) is sodium carbonate or potassium carbonate.
Preferably, the feeding molar ratio of the sodium carbonate or the potassium carbonate to the compound of the formula II is 2.2-4: 1.
Preferably, the mass ratio of the sodium chloride or the potassium chloride to the compound of the formula II in the step (1) is 0.3-1: 1. By adopting the feed ratio, sodium chloride or potassium chloride can better inhibit the hydrolysis of the n-valeryl chloride.
Preferably, the feeding mass ratio of the water to the compound of the formula II in the step (1) is 3-5: 1.
Preferably, the feeding molar ratio of the compound of formula II in the step (1) to the n-valeryl chloride is 1: 1.05-1.2. Because the sodium chloride or the potassium chloride is adopted in the step (1), the hydrolysis of the n-valeryl chloride is effectively reduced, so that the dosage of the n-valeryl chloride can be reduced and controlled within the above charge ratio.
Preferably, the temperature of the heat preservation reaction in the step (1) is 15-35 ℃.
Preferably, in the step (2), the solvent used for alkali washing is an aqueous ammonia solution with a concentration of 2.5%, the solvent used for acid washing is an aqueous hydrochloric acid solution with a concentration of 5%, and the solvent used for alkali washing is a sodium bicarbonate solution with a concentration of 2%.
Compared with the prior art, the invention has the advantages that: according to the method, a proper amount of sodium chloride or potassium chloride is added into a reaction system, and the occurrence of n-valeryl chloride hydrolysis reaction is inhibited by utilizing the same ion effect, so that the use amount of n-valeryl chloride is reduced, the purity and yield of a product are improved, the production cost is reduced, the pollution to the environment is reduced, and the method is more suitable for industrial production.
Drawings
FIG. 1 is an HPLC profile of a valsartan intermediate of formula I of example 1 of the present invention;
FIG. 2 is an HPLC chromatogram of the valsartan intermediate of formula I in example 2 of the present invention;
fig. 3 is an HPLC profile of valsartan intermediate of formula I shown in example 3 of the present invention.
Detailed Description
The invention is described in further detail below with reference to the accompanying examples.
Example 1:
the synthesis method of the valsartan intermediate comprises the following steps:
(1) adding 30g of the compound shown in the formula II and 200mL of toluene into a 500mL four-mouth bottle, and uniformly stirring; adding 21g of sodium carbonate and 18g of sodium chloride into 120mL of water, stirring to dissolve the sodium carbonate and the sodium chloride, and then dropwise adding the sodium carbonate and the sodium chloride into the four-mouth bottle; controlling the internal temperature to be 20-28 ℃, slowly dripping 12g of n-valeryl chloride and 20mL of toluene mixed solution, keeping the temperature and stirring after dripping, and detecting the compound residue in the formula II by HPLC;
(2) detecting the residue of the compound shown in the formula II by HPLC (high performance liquid chromatography) to be less than or equal to 0.10%, adding 120mL of water, separating a water layer, washing an organic phase by using 120 mL2.5% ammonia water, and separating the water layer; the organic phase was washed with 50mL of 5% aqueous hydrochloric acid solution and the aqueous layer was separated; the organic phase was washed with 50mL of 2% sodium bicarbonate and the aqueous layer was separated; the organic layer was distilled under reduced pressure to give the compound of formula I, yield: 99.0%, as shown in fig. 1, purity (HPLC): 99.76 percent.
Example 2:
the synthesis method of the valsartan intermediate comprises the following steps:
(1) adding 30g of the compound shown as the formula II and 200mL of dimethylbenzene into a 500mL four-mouth bottle, and uniformly stirring; adding 30g of potassium carbonate and 20g of sodium chloride into 150mL of water, stirring to dissolve, and then dropwise adding into the four-mouth bottle; controlling the internal temperature to be 20-28 ℃, slowly dripping 11g of n-valeryl chloride and 20mL of dimethylbenzene mixed solution, keeping the temperature and stirring after dripping, and detecting the residue of the compound shown in the formula II by HPLC;
(2) after HPLC detection shows that the residue of the compound shown in the formula II is less than or equal to 0.10%, 120mL of water is added, and a water layer is removed; washing the organic phase with 120ml of 2.5% ammonia water, and separating the water layer; the organic phase was washed with 50mL of 5% aqueous hydrochloric acid solution and the aqueous layer was separated; the organic phase was washed with 50mL of 2% sodium bicarbonate and the aqueous layer was separated; the organic layer was distilled under reduced pressure to give the compound of formula I, yield: 99.2%, as shown in fig. 2, purity (HPLC): 99.73 percent.
Example 3:
the synthesis method of the valsartan intermediate comprises the following steps:
(1) adding 50g of the compound shown in the formula II and 335mL of dichloromethane into a 1000mL four-mouth bottle, and uniformly stirring; adding 35g of sodium carbonate and 39g of potassium chloride into 200mL of water, stirring to dissolve the sodium carbonate and the potassium chloride, and then dropwise adding the sodium carbonate and the potassium chloride into the four-mouth bottle; controlling the internal temperature to be 20-28 ℃, slowly dripping a mixed solution of 20g of n-valeryl chloride and 33.5mL of dichloromethane, keeping the temperature and stirring after dripping, and detecting the residue of the compound shown in the formula II by HPLC;
(2) after HPLC detection shows that the residue of the compound shown in the formula II is less than or equal to 0.10%, 200mL of water is added, and a water layer is removed; washing the organic phase with 200ml of 2.5% ammonia water, and separating the water layer; the organic phase was washed with 85mL of 5% aqueous hydrochloric acid solution and the aqueous layer was separated; the organic phase was washed with 85mL of 2% sodium bicarbonate and the aqueous layer was separated; the organic layer was distilled under reduced pressure to give the compound of formula I, yield: 98.8%, as shown in FIG. 3, purity (HPLC): 99.81 percent.
Claims (9)
1. A synthetic method of a valsartan intermediate is characterized by comprising the following steps: comprises the following steps
(1) Dissolving a compound shown in the following formula II in an organic solvent, adding an acid binding agent, sodium chloride or potassium chloride and water, uniformly stirring, dropwise adding n-valeryl chloride, and carrying out heat preservation reaction;
(2) after the reaction is finished, adding water for quenching, sequentially carrying out alkali washing, acid washing and alkali washing, and finally carrying out reduced pressure distillation to obtain a target product, namely a compound shown as a formula I, namely N- [ (2' -cyanobiphenyl-4-yl) methyl ] -N- (1-oxo-pentyl) -L-valine methyl ester;
wherein, the solvent adopted by the first alkali washing is ammonia water solution.
2. A process for the synthesis of valsartan intermediate according to claim 1, characterised in that: the organic solvent in the step (1) is any one of toluene, xylene and dichloromethane.
3. A process for the synthesis of valsartan intermediate according to claim 1, characterised in that: the acid-binding agent in the step (1) is sodium carbonate or potassium carbonate.
4. A process for the synthesis of valsartan intermediate according to claim 3, characterised in that: the feeding molar ratio of the sodium carbonate or the potassium carbonate to the compound of the formula II is 2.2-4: 1.
5. A process for the synthesis of valsartan intermediate according to claim 1, characterised in that: in the step (1), the feeding mass ratio of the sodium chloride or the potassium chloride to the compound of the formula II is 0.3-1: 1.
6. A process for the synthesis of valsartan intermediate according to claim 1, characterised in that: the feeding mass ratio of the water to the compound of the formula II in the step (1) is 3-5: 1.
7. A process for the synthesis of valsartan intermediate according to claim 1, characterised in that: the feeding molar ratio of the compound of the formula II in the step (1) to the n-valeryl chloride is 1: 1.05-1.2.
8. A process for the synthesis of valsartan intermediate according to claim 1, characterised in that: the temperature of the heat preservation reaction in the step (1) is 15-35 ℃.
9. A method of synthesizing the valsartan intermediate as claimed in any one of claims 1 to 8, wherein: in the step (2), the solvent used for alkali washing is an ammonia water solution with the concentration of 2.5%, the solvent used for acid washing is a hydrochloric acid water solution with the concentration of 5%, and the solvent used for alkali washing is a sodium bicarbonate solution with the concentration of 2%.
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| WO2012056294A1 (en) * | 2010-10-29 | 2012-05-03 | Jubilant Life Sciences Ltd. | An improved process for the preparation of n-pentanoyl-n-[[2'-(1h-tetrazol-5-yi)[1,1'-biphenyl]-4-yi]methyl]-l-valine |
| CN102417486A (en) * | 2012-01-04 | 2012-04-18 | 合肥工业大学 | Synthesis method of valsartan |
| CN102911128A (en) * | 2012-09-25 | 2013-02-06 | 苏州天绿生物制药有限公司 | Synthetic method of valsartan |
| CN104045602A (en) * | 2014-06-28 | 2014-09-17 | 浙江华海药业股份有限公司 | Improved method for preparing tetrazole for valsartan |
| CN107056720A (en) * | 2016-12-30 | 2017-08-18 | 湖南千金湘江药业股份有限公司 | A kind of preparation and purification method of Valsartan |
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