CN113387828A - Preparation method of aliskiren intermediate - Google Patents

Preparation method of aliskiren intermediate Download PDF

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CN113387828A
CN113387828A CN202010178663.8A CN202010178663A CN113387828A CN 113387828 A CN113387828 A CN 113387828A CN 202010178663 A CN202010178663 A CN 202010178663A CN 113387828 A CN113387828 A CN 113387828A
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chloro
isopropyl
trans
aliskiren
pentenoic acid
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江巨东
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/30—Only oxygen atoms
    • C07D251/34—Cyanuric or isocyanuric esters
    • 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
    • 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
    • C07B2200/09—Geometrical isomers

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Abstract

The invention relates to a preparation method of trans- (2S) -5-chloro-2-isopropyl-N, N-dimethyl-4-valeramide which is an important intermediate for synthesizing aliskiren, which takes trans- (2S) -5-chloro-2-isopropyl-4-pentenoic acid as a raw material, dichloromethane as a solvent, trans- (2S) -5-chloro-2-isopropyl-4-pentenoic acid reacts with 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine under the action of organic base, then the trans- (2S) -5-chloro-2-isopropyl-4-pentenoic acid reacts with dimethylamine hydrochloride, and the high-purity target intermediate is obtained through acid washing, alkali washing, drying and reduced evaporation. The method adopts a one-pot method, and the acyl chloride intermediate is not separated in the middle, so that the risk of racemization of trans- (2S) -5-chloro-2-isopropyl-4-pentenoyl chloride chiral carbon caused in the processes of reaction under high-temperature acidic condition and high-temperature distillation and the decomposition of acyl chloride in the separation process are avoided, and the purity and yield of the target product are improved; and the operation is simple and convenient, the same solvent is adopted in the whole synthesis process, a large amount of organic solvent is saved, the production cost is low, the production efficiency is high, and the method is more suitable for industrial production.

Description

Preparation method of aliskiren intermediate
Technical Field
The invention relates to a preparation method of a compound, and particularly relates to a preparation method of trans- (2S) -5-chloro-2-isopropyl-N, N-dimethyl-4-valeramide which is an important intermediate for synthesizing aliskiren.
Background
Aliskiren (Aliskiren) is a new and highly effective antihypertensive drug with the following names: (2S, 4S, 5S, 7S) -N- (2-carbamoyl-2-methylpropyl) -5-amino-4-hydroxy-2, 7-diisopropyl-8- [ 4-methoxy-3- (3-methoxypropoxy) benzyl]-octylamine, molecular formula C30H53N306CAS number 173334-58-2, structural formula as follows:
Figure BDA0002411729080000011
aliskiren is the second generation renin inhibitor, is an antihypertensive drug developed by norwalk, switzerland, approved in the united states and europe to be marketed in 2007, and acts on the first rate-limiting step of the renin angiotensin aldosterone system (RAS). All current research data show that aliskiren antihypertensive therapy has good safety and effectiveness, few side effects, long half-life period and convenient taking once a day. Due to the good effect of treating hypertension clinically, the preparation method of aliskiren and important intermediates thereof has attracted wide attention of various large pharmaceutical companies and research units in recent years.
Noval reported a synthetic route to aliskiren in 1995, but it was not suitable for large-scale production due to high cost and poor stereoselectivity. The Speedel PharmaAG company reported a synthetic route to be used starting from trans- (2S) -5-chloro-2-isopropyl-N, N-dimethyl-4-pentanamide to construct the aliskiren intermediate (2S,7R, E) -2-isopropyl-7- (4-methoxy-3- (3-methoxypropoxy) benzyl) -N, 8-trimethylnon-4-enamide [ proceedings of chinese medical university, 2011,42 (5): 400- & ltCHEM & gt 406 ], therefore, the search for a green and environment-friendly synthetic route of trans- (2S) -5-chloro-2-isopropyl-N, N-dimethyl-4-valeramide has important industrial value.
US2003181765a1 and WO0208172a1 disclose a synthetic route to trans- (2S) -5-chloro-2-isopropyl-N, N-dimethyl-4-pentanamide, which is shown in the chemical reaction equation:
Figure BDA0002411729080000012
the preparation method specifically comprises the steps of adding oxalyl chloride into a toluene solution of trans- (2S) -5-chloro-2-isopropyl-4-pentenoic acid at room temperature, dropwise adding DMF, heating and recovering for 1h, and concentrating to remove toluene and oxalyl chloride (the chlorination yield is 88%). Dissolving the mixture with dichloromethane, then dropwise adding a mixed solution of dimethylamine, pyridine and dichloromethane, stirring for 2 hours, concentrating to remove the solvent, adding ether, washing with 2N hydrochloric acid solution, saturated sodium bicarbonate and saturated saline, concentrating to remove the solvent, and then rectifying under reduced pressure to obtain trans- (2S) -5-chloro-2-isopropyl-N, N-dimethyl-4-valeramide (the ammoniation yield is 89%). Literature [ proceedings of chinese medical university, 2011,42 (5): 400-.
The above preparation methods all have the following disadvantages:
1. in order to improve the chlorination conversion rate, excessive oxalyl chloride or thionyl chloride needs to be used, but when the excessive chlorinating agent is removed by reduced evaporation, special reduced evaporation equipment is needed due to strong corrosivity of the oxalyl chloride and the thionyl chloride; meanwhile, a large amount of solvent containing acidic substances is generated, the treatment is difficult, and the production cost is increased.
2. As is known, a chiral compound can generate racemization under the conditions of high temperature or strong acid and strong base, so that both a chlorination reaction process and a process of removing a chlorinating agent by reduced evaporation need high-temperature operation, and thus, the chiral carbon racemization of trans- (2S) -5-chloro-2-isopropyl-N, N-dimethyl-4-pentanamide can be caused, the optical purity of aliskiren is influenced, and great risk is brought to the medication safety.
3. Trans- (2S) -5-chloro-2-isopropyl-4-pentenoyl chloride is unstable and decomposes with water, and therefore, decomposition may occur during the separation process to produce impurities and pigments, which increases the purification steps of the final product.
4. Both the chlorination reaction and the amination step need repeated solvent evaporation reduction and repeated washing, and the post-treatment is more complicated and the production efficiency is lower. Meanwhile, diethyl ether is used in the ammoniation preparation processes reported in US2003181765A1 and WO0208172A1, so that the safety coefficient is high.
Disclosure of Invention
In order to solve the problems, the invention aims to overcome the defects of the prior art, and provides a preparation method of trans- (2S) -5-chloro-2-isopropyl-N, N-dimethyl-4-valeramide which is an important intermediate for synthesizing aliskiren, wherein trans- (2S) -5-chloro-2-isopropyl-4-pentenoic acid is used as a raw material, dichloromethane is used as a solvent, and the reaction is firstly carried out with 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine under the action of organic base, then the reaction is carried out with dimethylamine hydrochloride, and the high-purity target intermediate is obtained through acid washing, alkali washing, drying and reduced evaporation. The method adopts a one-pot method, and the acyl chloride intermediate is not separated in the middle, so that the risk of racemization of trans- (2S) -5-chloro-2-isopropyl-4-pentenoyl chloride chiral carbon caused in the processes of reaction under high-temperature acidic condition and high-temperature distillation and the decomposition of acyl chloride in the separation process are avoided, and the purity and yield of the target product are improved; and the operation is simple and convenient, the same solvent is adopted in the whole synthesis process, a large amount of organic solvent is saved, the production cost is low, the production efficiency is high, and the method is more suitable for industrial production.
The synthetic route of the invention is as follows:
Figure BDA0002411729080000031
the method specifically comprises the following steps:
(1) adding trans- (2S) -5-chloro-2-isopropyl-4-pentenoic acid and 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine into dichloromethane, and dropwise adding organic base under the stirring condition to react to prepare a trans- (2S) -5-chloro-2-isopropyl-4-pentenoic acid active ester solution;
the method is characterized in that in the step (1), the trans- (2S) -5-chloro-2-isopropyl-4-pentenoic acid and the 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine are stirred and dispersed by using dichloromethane as a solvent, the volume-to-weight ratio of the use amount of the organic solvent to the trans- (2S) -5-chloro-2-isopropyl-4-pentenoic acid is 8-10 ml/g, and the molar ratio of the trans- (2S) -5-chloro-2-isopropyl-4-pentenoic acid to the 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine is 1: 1-1.5.
The method is characterized in that in the step (1), one of triethylamine, pyridine and N-methylmorpholine is adopted as the organic base, the dropping temperature is kept at 0-10 ℃, and the molar ratio of trans- (2S) -5-chloro-2-isopropyl-4-pentenoic acid to the organic base is 1: 2.5-3. After the dropwise addition, the reaction temperature is maintained at 0-10 ℃ and the reaction lasts for 1-2 h.
(2) Adding dimethylamine hydrochloride by times, wherein the adding temperature is 0-10 ℃, and the reaction time is 1-1.5 h after the adding is finished;
the method is characterized in that in the step (2), three to five parts of dimethylamine hydrochloride are uniformly divided, the adding interval time of each part is 15-30 minutes, the adding temperature is 0-10 ℃, the reaction is carried out for 1-1.5 hours after the adding is finished, and the molar ratio of trans- (2S) -5-chloro-2-isopropyl-4-pentenoic acid to dimethylamine hydrochloride is 1: 1-1.5.
(3) After the reaction is finished, adding a hydrochloric acid aqueous solution and a sodium bicarbonate aqueous solution in sequence for washing, then adding a drying agent, filtering, and concentrating the filtrate to obtain a target intermediate.
The method is characterized in that in the step (3), after the reaction is finished, the organic phase is added with a hydrochloric acid solution for washing, a water phase is discarded, the organic phase is reserved for standby application, the hydrochloric acid solution aims to remove organic base hydrochloride, excessive dimethylamine hydrochloride and organic alkali generated by condensation, the volume ratio of the use amount of the hydrochloric acid solution to the organic solvent is 1: 1-2, and the concentration of the hydrochloric acid aqueous solution is 10% -20%.
The method is characterized in that in the step (3), after the acid washing of the organic phase is finished, sodium bicarbonate aqueous solution is added for washing, the aqueous phase is discarded, the organic phase is reserved for standby, and the purpose of alkali washing is to remove 2-hydroxy-4, 6-dimethoxy-1, 3, 5-triazine and excessive 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine. The volume ratio of the alkali solution to the organic solvent is 1: 1-2, and the concentration of the alkali solution is 5-10%.
The method is characterized in that in the step (3), after the alkali washing is finished, a drying agent is added into an organic phase for drying, then the organic phase is filtered, and the filtrate is collected. The desiccant can be one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium chloride and anhydrous sodium sulfate, and the amount of the desiccant is 0.1-0.5 g per 10ml of the organic phase.
The method is characterized in that in the step (3), the filtrate is concentrated to be dry to obtain the target compound, and the concentration temperature is 20-30 ℃.
The invention has the beneficial effects that:
1. the method completely avoids the adoption of a chlorination reagent, does not generate a large amount of acid water and waste gas, and is green and environment-friendly; the reaction conditions are very mild, and only ordinary reaction equipment is adopted, so that the equipment investment is reduced;
2. the method adopts a one-pot method, and the acyl chloride intermediate is not separated in the middle, so that the risk of racemization of trans- (2S) -5-chloro-2-isopropyl-4-pentenoyl chloride chiral carbon caused in the processes of reaction under high-temperature acidic condition and high-temperature distillation and the decomposition of the substance in the separation process are avoided, and the purity and the yield of the product are improved;
3. the method has simple post-treatment, adopts the same solvent in the whole reaction, saves a large amount of organic solvent, has low production cost and high production efficiency, and is more suitable for industrial production.
Detailed Description
The present invention will be described in further detail with reference to the following examples. However, it should be understood that the above description of the present invention is not limited to the following examples.
Example 1 preparation of aliskiren intermediate
(1) To a 500mL three-necked flask, trans- (2S) -5-chloro-2-isopropyl-4-pentenoic acid (17.6g, 0.1mol), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (21.1g, 0.12mol) and 170mL of dichloromethane were added, and the mixture was stirred and cooled to 0-10 ℃. Triethylamine (36ml, 0.26mol) is added dropwise, and the dropwise adding temperature is controlled to be 0-10 ℃.
(2) Dividing dimethyl hydrochloride (9.9g, 0.12mol) into three parts, each 3.3g, maintaining the temperature at 0-10 ℃, adding the first part, and adding the second part after 30 min; after another 30min interval, the third portion was added. Reacting for 1h after the addition is finished;
(3) transferring the reaction solution into a 1000ml three-necked bottle, adding 220ml 10% hydrochloric acid aqueous solution, stirring for 5min, standing for layering, and collecting an organic phase; transferring the organic phase into a 1000ml three-necked bottle, adding 220ml 10% sodium bicarbonate solution, stirring for 5min, standing for layering, and collecting the organic phase; the organic phase was transferred to a 1000ml three-necked flask, and dried by adding 6g of anhydrous sodium sulfate.
(4) Suction filtration was carried out and the filter cake was washed with 20ml of dichloromethane. The filter cake was collected and evaporated to dryness under vacuum at 25 ℃ to give 19.5g of an oil in 95.7% yield.
Example 2 preparation of aliskiren intermediate
(1) To a 500mL three-necked flask, trans- (2S) -5-chloro-2-isopropyl-4-pentenoic acid (17.6g, 0.1mol), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (26.3g, 0.15mol) and 170mL of dichloromethane were added, and the mixture was stirred and cooled to 0-10 ℃. Dropwise adding N-methylmorpholine (33ml, 0.3mol), and controlling the dropwise adding temperature to be 0-10 ℃.
(2) Dividing dimethyl alkane hydrochloride (12.2g, 0.15mol) into five parts, each 2.4g, maintaining the temperature at 0-10 ℃, adding the first part, and adding the second part after 20min interval; after another 20min interval, the third portion was added. After the addition is finished, the reaction is carried out for 1.5 h;
(3) transferring the reaction solution into a 1000ml three-necked bottle, adding 220ml 10% hydrochloric acid aqueous solution, stirring for 5min, standing for layering, and collecting an organic phase; transferring the organic phase into a 1000ml three-necked bottle, adding 220ml 10% sodium bicarbonate solution, stirring for 5min, standing for layering, and collecting the organic phase; the organic phase was transferred to a 1000ml three-necked flask, and dried by adding 4g of anhydrous magnesium sulfate.
(4) Suction filtration was carried out and the filter cake was washed with 20ml of dichloromethane. The filter cake was collected and evaporated to dryness under vacuum at 25 ℃ to give 19.7g of an oil in 96.7% yield.
Example 3 preparation of aliskiren intermediate
(1) To a 500mL three-necked flask, trans- (2S) -5-chloro-2-isopropyl-4-pentenoic acid (17.6g, 0.1mol), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (17.6g, 0.1mol) and 170mL of dichloromethane were added, and the mixture was stirred and cooled to 0-10 ℃. Pyridine (20ml, 0.25mol) is added dropwise, and the dropping temperature is controlled to be 0-10 ℃.
(2) Dividing dimethyl hydrochloride (9.9g, 0.12mol) into three parts, each 3.3g, maintaining the temperature at 0-10 ℃, adding the first part, and adding the second part after 15 min; after another 15min interval, the third portion was added. Reacting for 2 hours after the addition is finished;
(3) transferring the reaction solution into a 1000ml three-necked bottle, adding 220ml 10% hydrochloric acid aqueous solution, stirring for 5min, standing for layering, and collecting an organic phase; transferring the organic phase into a 1000ml three-necked bottle, adding 220ml 10% sodium bicarbonate solution, stirring for 5min, standing for layering, and collecting the organic phase; the organic phase was transferred to a 1000ml three-necked flask, and dried by adding 5g of anhydrous calcium chloride.
(4) Suction filtration was carried out and the filter cake was washed with 20ml of dichloromethane. The filter cake was collected and evaporated to dryness under vacuum at 25 ℃ to give 19.1g of an oil in 93.7% yield.

Claims (8)

1. A process for the preparation of trans- (2S) -5-chloro-2-isopropyl-N, N-dimethyl-4-pentanamide, an intermediate of aliskiren, of the formula I:
(1) adding trans- (2S) -5-chloro-2-isopropyl-4-pentenoic acid and 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine into dichloromethane, and dropwise adding organic base under the stirring condition to react to prepare a trans- (2S) -5-chloro-2-isopropyl-4-pentenoic acid active ester solution;
(2) adding dimethylamine hydrochloride by times, wherein the adding temperature is 0-10 ℃, and the reaction time is 1-1.5 h after the adding is finished;
(3) after the reaction is finished, adding a hydrochloric acid aqueous solution and a sodium bicarbonate aqueous solution in sequence for washing, then adding a drying agent, filtering, and concentrating the filtrate to obtain a target intermediate.
Figure FDA0002411729070000011
2. An aliskiren intermediate preparation method according to claim 1, wherein in the step (1), the volume weight ratio of the dichloromethane dosage to the trans- (2S) -5-chloro-2-isopropyl-4-pentenoic acid is 8-10 ml/g, and the molar ratio of the trans- (2S) -5-chloro-2-isopropyl-4-pentenoic acid to the 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine is 1: 1-1.5.
3. An aliskiren intermediate preparation method according to claim 1, wherein in the step (1), the organic base is one of triethylamine, pyridine and N-methylmorpholine, the dropping temperature is maintained at 0-10 ℃, and the molar ratio of the trans- (2S) -5-chloro-2-isopropyl-4-pentenoic acid to the organic base is 1: 2.5-3.
4. The preparation method of an aliskiren intermediate as claimed in claim 1, wherein in the step (1), after the organic base is added dropwise, the reaction temperature is kept at 0-10 ℃ for reaction for 1-2 h.
5. The preparation method of an aliskiren intermediate according to claim 1, wherein in the step (2), dimethylamine hydrochloride is divided into three to five parts, the adding interval time of each part is 15-30 minutes, the adding temperature is 0-10 ℃, the reaction is carried out for 1-1.5 hours after the adding is finished, and the molar ratio of trans- (2S) -5-chloro-2-isopropyl-4-pentenoic acid to dimethylamine hydrochloride is 1: 1-1.5.
6. The method for preparing an aliskiren intermediate according to claim 1, wherein in the step (3), the volume ratio of the aqueous hydrochloric acid solution to the organic solvent is 1: 1-2, and the volume ratio of the aqueous sodium bicarbonate solution to the organic solvent is 1: 1-2. The concentration of the hydrochloric acid aqueous solution is 10 to 20 percent, and the concentration of the sodium bicarbonate aqueous solution is 5 to 10 percent.
7. The method for preparing an aliskiren intermediate according to claim 1, wherein in the step (3), the desiccant is one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium chloride and anhydrous sodium sulfate, and the amount of the desiccant is 0.1-0.5 g per 10ml of the organic phase.
8. The method for preparing an aliskiren intermediate according to claim 1, wherein in the step (3), the concentration temperature of the filtrate is 20-30 ℃.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030181765A1 (en) * 2000-07-25 2003-09-25 Stefan Stutz Process for the preparation of substituted octanoyl amides
CN105682656A (en) * 2013-11-05 2016-06-15 诺华股份有限公司 Compositions and methods for modulating farnesoid x receptors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030181765A1 (en) * 2000-07-25 2003-09-25 Stefan Stutz Process for the preparation of substituted octanoyl amides
CN105682656A (en) * 2013-11-05 2016-06-15 诺华股份有限公司 Compositions and methods for modulating farnesoid x receptors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
吴勇等: ""阿利克仑的合成"", 《中国药科大学学报》 *

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