CN111848510A - Synthesis method of montelukast sodium - Google Patents
Synthesis method of montelukast sodium Download PDFInfo
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- CN111848510A CN111848510A CN201910331439.5A CN201910331439A CN111848510A CN 111848510 A CN111848510 A CN 111848510A CN 201910331439 A CN201910331439 A CN 201910331439A CN 111848510 A CN111848510 A CN 111848510A
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- montelukast sodium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/18—Halogen atoms or nitro radicals
Abstract
The invention provides a synthesis method of montelukast sodium, which comprises the following steps: (1) asymmetric reduction of the compound of formula (VII) to give the compound of formula (VI); (2) reacting the compound shown in the formula (VI) with methylsulfonyl chloride to obtain an intermediate compound shown in the formula (V), wherein the intermediate directly undergoes a substitution reaction with 1-mercaptomethylcyclopropylacetic acid without separation to obtain a compound shown in the formula (III); (3) carrying out Heck coupling reaction on a compound of a formula (III) and a compound of a formula (IV) under the action of a palladium catalyst to obtain a compound of a formula (II); (4) the compound of the formula (II) and a methyl Grignard reagent are subjected to direct addition reaction to obtain montelukast sodium. The synthesis method has the advantages of short steps, mild conditions and simple and convenient operation, is beneficial to reducing the process cost and realizing industrial production.
Description
1. Field of the invention
The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of montelukast sodium.
2. Background of the invention
Montelukast Sodium (Montelukast Sodium) is an anti-asthma drug developed by the american merck company and is marketed under the approval of the U.S. Food and Drug Administration (FDA) on 20/2/1998 under the trade name of sunless (Singulair). The montelukast sodium as a selective leukotriene receptor antagonist can be selectively combined with leukotriene receptors in respiratory tracts, and is a high-efficiency, low-toxicity and safe antiasthmatic, anti-inflammatory and antiallergic drug.
The chemical name of montelukast sodium is: 1- [ [ [ (1R) -1- [3- [ (1E) -2- (7-chloro-2-quinoline) ethenyl ] phenyl ] -3- [2- (1-hydroxy-1-methylethyl) phenyl ] propyl ] thio ] methyl ] cyclopropane sodium acetate, the chemical structural formula is shown in the following formula I.
WO2008058118 discloses a method for preparing montelukast sodium from m-phthalaldehyde and 7-chloro-2-methylquinoline as initial raw materials, wherein a preparation route is shown as follows, and the synthesis route is tedious (12 steps), reaction steps are long, and the overall yield is low, so that the production period is long, the environmental protection pressure is high, the cost is high, and the method is not suitable for industrial production.
Therefore, it is urgently needed to develop a new process route which has simple reaction method and high yield and is suitable for industrial production.
3. Summary of the invention
The invention aims to solve the problems in the prior art and provides a novel synthesis method of montelukast sodium. The synthesis method has the advantages of short steps, mild conditions and simple and convenient operation, is beneficial to reducing the process cost and realizing industrial production.
Specifically, the invention provides a novel synthesis method of montelukast sodium, which comprises the following steps:
(1) asymmetric reduction of the compound of formula (VII) to give the compound of formula (VI);
(2) Reacting the compound shown in the formula (VI) with methylsulfonyl chloride to obtain an intermediate compound shown in the formula (V), wherein the intermediate directly undergoes a substitution reaction with 1-mercaptomethylcyclopropylacetic acid without separation to obtain a compound shown in the formula (III);
(3) carrying out Heck coupling reaction on a compound of a formula (III) and a compound of a formula (IV) under the action of a palladium catalyst to obtain a compound of a formula (II);
(4) the compound of the formula (II) and a methyl Grignard reagent are subjected to direct addition reaction to obtain montelukast sodium.
Wherein the content of the first and second substances,
in the step (1), the reducing agent for the asymmetric reduction reaction is (-) -diisopinocampheylchloroborane.
In the step (2), the molar ratio of the methylsulfonyl chloride to the compound of formula (VI) is (1-1.5): 1. preferably (1-1.2): 1.
In the step (2), the molar ratio of the 1-mercaptomethylcyclopropyl acetic acid to the compound of the formula (VI) is (1-1.5): 1, preferably (1-1.2): 1.
in the step (3), the palladium catalyst is selected from one or more of palladium acetate, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium and 1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride.
In the step (4), the methyl Grignard reagent is methyl magnesium chloride, methyl magnesium bromide or methyl magnesium iodide.
In the step (4), the molar ratio of the compound shown in the formula (II) to the methyl Grignard reagent is 1: (3-10). Preferably 1: (3-6).
In the step (4), the montelukast sodium is prepared by the compound shown in the formula (II) and a methyl Grignard reagent under the catalysis of Lewis acid. The Lewis acid catalyst is one or more of cerium trichloride, zinc chloride, lithium chloride, cobalt chloride, lanthanum chloride and chromium chloride. Preferably, the Lewis acid catalyst is cerium trichloride.
Compared with the prior art, the invention has the beneficial effects that due to the adoption of the technical scheme:
(1) the process route is short, and 5 steps of reaction are carried out;
(2) the reaction condition is mild;
(3) the obtained product has good purity, high quality and low cost, and is suitable for industrial production.
4. Detailed description of the preferred embodiments
The following detailed description of specific embodiments of the present invention is provided for illustrative purposes only and is not intended to limit the scope of the present invention.
Example 1: synthesis of Compounds of formula (VI)
The compound of formula (VII) (100g, 0.288mol) was dissolved in dichloromethane (1L), (-) -diisopinocampheylchloroborane (254mL, about 1.7mol/L n-heptane solution, 0.432mol) was added, the reaction was stirred at 25 ℃ for 10h, and TLC was used to check the completion of the starting material reaction. Pouring the reaction solution into 25% cold ammonia water solution (1.5L), quenching the reaction, stirring at 25 ℃ for 1h, separating liquid, washing an organic phase with saturated saline solution for 3 times, drying, decoloring, concentrating under reduced pressure, adding 1L of n-heptane into the concentrated solution, cooling to 0 ℃, stirring for 5h, gradually separating out a solid, filtering, and drying to obtain 82g of a white solid compound of the formula (VI), wherein the yield is 82%. MS 349[ M + H ]
Example 2: synthesis of Compounds of formula (III)
Dissolving a compound (80g, 0.23mol) of a formula (VI) and diisopropylethylamine (45.2g, 0.35mol) in dichloromethane (0.8L), cooling to-20 ℃, adding methylsulfonyl chloride (32.2g, 0.28mol) under the protection of nitrogen, heating to-15 to-10 ℃ after addition, and stirring for reaction for 0.5h to obtain an intermediate reaction solution of a formula (V).
Simultaneously, dissolving 1-mercaptomethylcyclopropylacetic acid (40.9g, 0.28mol) in tetrahydrofuran, dropwise adding sodium methoxide solution (137.5g, 30 wt%, 0.84mol) under the protection of nitrogen, stirring for 0.5h after the addition is finished, and cooling to-15 to-10 ℃. Dropwise adding the intermediate reaction solution shown in the formula (V) into a reaction system, keeping the temperature of-15 to-10 ℃ after adding, stirring for 0.5h, heating to 5 to 10 ℃, continuing stirring for 6h, detecting by TLC, and completely reacting. Controlling the temperature to be below 10 ℃, pouring the reaction liquid into 1N hydrochloric acid, separating an organic phase, washing the organic phase for 1 time by using saturated sodium bicarbonate and water in sequence, drying the organic phase by using magnesium sulfate, and performing spin drying to obtain an oily substance, and separating and purifying by using a rapid adsorption column to obtain 70g of a compound shown in the formula (III), wherein the yield is as follows: 61.1 percent. MS:477[ M + H ]
Example 3: synthesis of Compounds of formula (II)
Under the protection of nitrogen, a compound (30g, 63mmol) of a formula (III), a compound (12g, 63mmol) of a formula (IV), palladium acetate (0.7g, 3.2mmol), triphenylphosphine (1.7g, 6.4mmol) and triethylamine (19.1g, 189mmol) are added into N, N-dimethylformamide (300mL) in sequence, the mixture is heated to 100 ℃, stirred and reacted for 6 hours, and TLC detection shows that the raw materials are completely reacted. Adding water into the reaction liquid, extracting and separating by dichloromethane, washing an organic phase by saturated saline solution for 1 time, drying and decoloring, concentrating under reduced pressure to obtain a crude oily substance of the compound shown in the formula (II), dissolving the crude product in toluene, salifying with isopropylamine, separating out a solid, filtering and drying to obtain 30.5g of isopropylamine salt of the compound shown in the formula (II), wherein the yield is as follows: 75 percent. MS:586[ M + H ]
Example 4: synthesis of montelukast sodium
Adding cerium trichloride (18g, 69.7mmol) into tetrahydrofuran (600ml) under the protection of nitrogen, heating to 65 ℃, stirring for 1h, cooling, slowly dropwise adding methyl magnesium chloride (96.0ml, about 3mol/L tetrahydrofuran solution, 279.0mmol) at the temperature of below 5 ℃, preserving heat for reaction for 1h after dropwise adding, adding compound (II) isopropylamine salt (30g, 46.5mmol) into the system in batches, controlling the temperature to be 0 ℃, after adding, preserving heat for reaction for 1h, monitoring by HPLC, and enabling the raw materials to react completely. Pouring the reaction solution into 1M hydrochloric acid, controlling the temperature to be below 10 ℃, extracting twice by dichloromethane, combining organic phases, washing by saturated sodium bicarbonate solution, 0.5M tartaric acid solution and water respectively, drying by magnesium sulfate, spin-drying to obtain 34.4g of oily matter, dissolving the oily matter in 200ml of toluene, dropwise adding 3.8g of isopropylamine, stirring overnight for crystallization under the protection of nitrogen. The next day, suction filtration is carried out, the filter cake is washed by 20ml of toluene and 50ml of n-hexane respectively, vacuum drying is carried out at 45 ℃, 25g of white solid is obtained, and the yield is as follows: 83.3 percent. MS 584[ M-H ]
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention; those skilled in the art can make various changes, modifications and alterations without departing from the scope of the invention, and all equivalent changes, modifications and alterations to the disclosed technology are equivalent embodiments of the present invention; meanwhile, any changes, modifications, and evolutions of the equivalent changes of the above embodiments according to the actual techniques of the present invention are still within the protection scope of the technical solution of the present invention.
Claims (9)
1. A method for synthesizing montelukast sodium is characterized by comprising the following steps:
(1) asymmetric reduction of the compound of formula (VII) to give the compound of formula (VI);
(2) reacting the compound shown in the formula (VI) with methylsulfonyl chloride to obtain an intermediate compound shown in the formula (V), wherein the intermediate directly undergoes a substitution reaction with 1-mercaptomethylcyclopropylacetic acid without separation to obtain a compound shown in the formula (III);
(3) carrying out Heck coupling reaction on a compound of a formula (III) and a compound of a formula (IV) under the action of a palladium catalyst to obtain a compound of a formula (II);
(4) the compound of the formula (II) and a methyl Grignard reagent are subjected to direct addition reaction to obtain montelukast sodium.
2. The method for synthesizing montelukast sodium according to claim 1, comprising the steps of: in the step (1), the reducing agent for the asymmetric reduction reaction is (-) -diisopinocampheylchloroborane.
3. The method for synthesizing montelukast sodium according to claim 1, comprising the steps of: in the step (2), the molar ratio of the methylsulfonyl chloride to the compound of the formula (VI) is (1-1.5): 1.
4. the method for synthesizing montelukast sodium according to claim 1, comprising the steps of: in the step (2), the molar ratio of the 1-mercaptomethylcyclopropyl acetic acid to the compound of the formula (VI) is (1-1.5): 1.
5. The method for synthesizing montelukast sodium according to claim 1, comprising the steps of: in the step (3), the palladium catalyst is selected from one or more of palladium acetate, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium and 1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride.
6. The method for synthesizing montelukast sodium according to claim 1, comprising the steps of: in the step (4), the methyl Grignard reagent is methyl magnesium chloride, methyl magnesium bromide or methyl magnesium iodide.
7. The method for synthesizing montelukast sodium according to claim 1, comprising the steps of: in the step (4), the molar ratio of the compound shown as the formula (II) to the methyl Grignard reagent is 1: (3-10).
8. The method for synthesizing montelukast sodium according to claim 1, comprising the steps of: in the step (4), the montelukast sodium is prepared by the compound shown in the formula (II) and a methyl Grignard reagent under the catalysis of Lewis acid.
9. The method for synthesizing montelukast sodium according to claim 8, comprising the steps of: the Lewis acid catalyst in the step (4) is one or more of cerium trichloride, zinc chloride, lithium chloride, cobalt chloride, lanthanum chloride and chromium chloride.
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| CN113387884A (en) * | 2021-07-05 | 2021-09-14 | 艾美科健（中国）生物医药有限公司 | Preparation method of montelukast sodium impurity H |
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| CN113387884A (en) * | 2021-07-05 | 2021-09-14 | 艾美科健（中国）生物医药有限公司 | Preparation method of montelukast sodium impurity H |
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Application publication date: 20201030 |