A preparation method of montelukast sodium side chain

Abstract

The present invention discloses a preparation method of montelukast sodium side chain, and high-quality montelukast sodium side chain 1-(mercaptomethyl)cyclopropylacetic acid (MLM) is obtained. This process uses 1-bromo-cyclopropaneacetonitrile (MLM-5) as a raw material, and under alkaline conditions, reacts with thioacetic acid to generate benzoyl (1-cyanoethylcyclopropyl)methyl mercaptan ester (MLM-6), which is directly subjected to base hydrolysis reaction without treatment to obtain the product 1-(mercaptomethyl)cyclopropylacetic acid (MLM). This process has simple operation, cheap raw materials, mild reaction conditions, low ammonia nitrogen in wastewater, easy biodegradation, and the product yield and purity have been greatly improved.

Description

Technical Field

[0001] The present invention belongs to the field of chemical synthesis, and particularly relates to a preparation method of a montelukast sodium side chain. Background Art

[0002] Montelukast Sodium, chemically named sodium [R-(E)-1-[[[1-[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetate, has the following structural formula:

[0003]

[0004] Montelukast Sodium was developed by Merck & Co., Inc. in the United States, and its trade name is "Singulair". It was first launched in Finland and Mexico in February 1998, and then in the UK and the US in April and October of the same year, and in China in 2002. This product is a selective leukotriene D4 receptor antagonist, which can selectively bind to leukotrienes in the airway, block the action of allergic mediators, improve airway inflammation, and keep the airway unobstructed. It is an anti-asthmatic, anti-inflammatory and anti-allergic drug with high efficiency, low toxicity and good safety, and has broad application prospects.

[0005] Through the retrosynthetic analysis of montelukast sodium, it can be known that the key intermediates for synthesizing montelukast sodium include 1-(mercaptomethyl)cyclopropaneacetic acid or its derivatives in the side chain part, and 2-[2-[3R-[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-hydroxypropyl]phenyl]propanol in the main chain part. As the key precursor compound of the montelukast sodium side chain and also the key intermediate of montelukast sodium, 1-(mercaptomethyl)cyclopropaneacetic acid is relatively active, and its mercapto group is easily oxidized, so the synthesis is difficult, and it has always been the focus and hotspot of research.

[0006] WO9518107 and US5523477 reported an improved method for synthesizing 1-(mercaptomethyl)cyclopropaneacetic acid by first converting 1,1-cyclopropanedimethanol into the corresponding cyclic sulfite using thionyl chloride and then ring-opening, and the specific synthesis route is as follows:

[0007]

[0008] This method has many by-products and is difficult to separate. It requires multiple aqueous solution extractions and solvent conversions, resulting in low product yield and poor atom utilization rate.

[0009] Five methods for preparing 1-(mercaptomethyl)cyclopropylacetic acid were reported in EP480717 / US5270324. One relatively feasible method is to reduce diethyl 1,1-cyclopropanedicarboxylate to 1,1-cyclopropanedimethanol, and then prepare 1-(mercaptomethyl)cyclopropylacetic acid through multiple steps of transformation. The specific synthetic route is as follows:

[0010]

[0011] This method uses highly toxic CH2N2, which is not ideal for the pharmaceutical industry. The selectivity for obtaining benzoyl-protected diol is poor, and there are many steps with a low overall yield, so it is not suitable for large-scale production.

[0012] J. Org. Chem (1993, 58(11), 3140 - 3147) reported a method using 1,1-cyclopropanedimethanol as the starting material, which was monoacetylated with acetic anhydride / pyridine, and the yield of the product methyl 1-(mercaptomethyl)cyclopropylacetate was only 28%, not suitable for industrial production.

[0013] The present invention aims to solve the problems of high production cost, mostly liquid intermediates, cumbersome separation and purification steps, and unsuitability for industrialization in the existing methods for preparing 1-(mercaptomethyl)cyclopropylacetic acid, and aims to develop a new synthetic method for 1-(mercaptomethyl)cyclopropylacetic acid with low cost, high yield and high purity. Summary of the Invention

[0014] A method for preparing the side chain of montelukast sodium, wherein the side chain of montelukast sodium is 1-(mercaptomethyl)cyclopropylacetic acid (MLM). It is characterized in that the chemical reaction formula for the synthesis is as follows:

[0015]

[0016] According to the method for preparing the side chain of montelukast sodium described in claim 1, it is characterized by comprising the following steps:

[0017] Step 1: Add a solvent, 1-bromocyclopropylacetonitrile (MLM-5), inorganic base 1 and thiobenzoic acid into the reaction kettle, replace with nitrogen for protection, stir and heat up, and keep the temperature for reaction for 6 hours;

[0018] Step 2: Add an aqueous solution of inorganic base 2, stir and heat up, and keep the temperature for reaction for 8 hours;

[0019] Step 3: Cool down to about 20 °C, adjust the pH value to 3 - 4 with an acid, add ethyl acetate for extraction, evaporate the organic layer under reduced pressure to dryness, add isopropanol for recrystallization, then centrifuge and dry to obtain the product 1-(mercaptomethyl)cyclopropylacetic acid (MLM).

[0020] The solvent in Step 1 is methanol, ethanol, isopropanol, or tert-butanol, and the reaction temperature is 30°C to 50°C; the reaction temperature in Step 2 is 60°C to 90°C; the inorganic bases 1 and 2 in Step 1 and Step 2 are lithium hydroxide, sodium hydroxide, or potassium hydroxide; the acid in Step 3 is dilute hydrochloric acid, dilute sulfuric acid, or acetic acid aqueous solution; the molar ratio of MLM-5, inorganic base 1, inorganic base 2, and thiobenzoic acid used is 1∶(1.2 - 2.0)∶(1.2 - 2.0)∶(1.05 - 1.6); the amount of the solvent used is 5 to 10 times the mass of MLM-5.

[0021] Advantages of the present invention:

[0022] The present invention ingeniously uses thiobenzoic acid to carry out a substitution reaction with 1-bromocyclopropylacetonitrile, and then removes the benzoyl group by base hydrolysis to obtain the product 1-(mercaptomethyl)cyclopropaneacetic acid, reducing the reaction steps, increasing the total yield of the product, being suitable for industrial-scale production of montelukast sodium, simultaneously reducing the synthesis cost and sales price of montelukast sodium drugs, improving the treatment level of asthma, and accelerating the construction of domestic medical and health undertakings. Specific embodiments

[0023] All the reagents used are commercially available.

[0024] Example 1:

[0025] Add 50 ml of ethanol, 10 g (0.057 mol) of 1-bromocyclopropylacetonitrile (MLM-5), 1.65 g (0.069 mol) of lithium hydroxide, and 8.34 g (0.060 mol) of thiobenzoic acid to a reaction flask, protect with nitrogen replacement, stir and heat up to 50°C, keep the temperature for reaction for 6 hours; add 33 g of 5% lithium hydroxide aqueous solution, stir and heat up to 60°C, keep the temperature for reaction for 8 hours; cool down to about 20°C, adjust the pH value to 3 - 4 with dilute hydrochloric acid, add ethyl acetate for extraction, evaporate the organic layer under reduced pressure to dryness, add isopropanol for recrystallization, then centrifuge and dry to obtain 7.81 g of the product 1-(mercaptomethyl)cyclopropaneacetic acid (MLM), with a yield of 92.98%, HPLC: 99.35%.

[0026] Example 2:

[0027] Add 100 ml of methanol, 10 g (0.057 mol) of 1-bromocyclopropylacetonitrile (MLM-5), 4.59 g (0.115 mol) of sodium hydroxide, and 12.7 g (0.092 mol) of thiobenzoic acid to the reaction flask. Protect with nitrogen displacement, stir and heat to 30 °C, and keep the temperature for 6 hours; add 30.6 g of 15% aqueous sodium hydroxide solution, stir and heat to 90 °C, and keep the temperature for 8 hours; cool to about 20 °C, adjust the pH value to 3-4 with dilute sulfuric acid, add ethyl acetate for extraction, evaporate the organic layer under reduced pressure to dryness, add isopropanol for recrystallization, then centrifuge and dry to obtain 7.84 g of 1-(mercaptomethyl)cyclopropylacetic acid (MLM), with a yield of 93.33% and HPLC: 99.30%.

[0028] Example 3:

[0029] Add 80 ml of isopropanol, 10 g (0.057 mol) of 1-bromocyclopropylacetonitrile (MLM-5), 4.84 g (0.086 mol) of potassium hydroxide, and 10.4 g (0.075 mol) of thiobenzoic acid to the reaction flask. Protect with nitrogen displacement, stir and heat to 40 °C, and keep the temperature for 6 hours; add 48.4 g of 10% aqueous potassium hydroxide solution, stir and heat to 70 °C, and keep the temperature for 8 hours; cool to about 20 °C, adjust the pH value to 3-4 with dilute acetic acid, add ethyl acetate for extraction, evaporate the organic layer under reduced pressure to dryness, add isopropanol for recrystallization, then centrifuge and dry to obtain 7.79 g of 1-(mercaptomethyl)cyclopropylacetic acid (MLM), with a yield of 92.73% and HPLC: 99.32%.

[0030] Example 4:

[0031] Add 70 ml of tert-butanol, 10 g (0.057 mol) of 1-bromocyclopropylacetonitrile (MLM-5), 1.95 g (0.081 mol) of lithium hydroxide, and 9.69 g (0.070 mol) of thiobenzoic acid to the reaction flask. Protect with nitrogen displacement, stir and heat to 45 °C, and keep the temperature for 6 hours; add 45 g of 12% aqueous potassium hydroxide solution, stir and heat to 80 °C, and keep the temperature for 8 hours; cool to about 20 °C, adjust the pH value to 3-4 with dilute hydrochloric acid, add ethyl acetate for extraction, evaporate the organic layer under reduced pressure to dryness, add isopropanol for recrystallization, then centrifuge and dry to obtain 7.75 g of 1-(mercaptomethyl)cyclopropylacetic acid (MLM), with a yield of 92.26% and HPLC: 99.27%.

[0032] Example 5:

[0033] Add 70 ml of methanol, 10 g (0.057 mol) of 1-bromocyclopropylacetonitrile (MLM-5), 3.85 g (0.096 mol) of sodium hydroxide, and 11.0 g (0.080 mol) of thiobenzoic acid to the reaction flask. Protect with nitrogen replacement, stir and heat up to 50 °C, and keep the reaction at this temperature for 6 hours; add 30 g of 7% lithium hydroxide aqueous solution, stir and heat up to 65 °C, and keep the reaction at this temperature for 8 hours; cool down to about 20 °C, adjust the pH value to 3 - 4 with dilute acetic acid, add ethyl acetate for extraction, evaporate the organic layer under reduced pressure to dryness, add isopropanol for recrystallization, then centrifuge and dry to obtain 7.80 g of the product 1-(mercaptomethyl)cyclopropaneacetic acid (MLM), with a yield of 92.85% and HPLC purity of 99.39%.

Claims

1. A preparation method of montelukast sodium side chain, wherein the montelukast sodium side chain is 1-(mercaptomethyl)cyclopropylacetic acid (MLM), and its synthetic chemical equation is as follows: It is characterized in that It includes the following steps: Step 1: Add a solvent, 1-(bromomethyl)cyclopropylacetonitrile (MLM-5), inorganic base 1, and thiobenzoic acid into a reaction kettle, displace and protect with nitrogen, stir and heat up to 30°C - 50°C, and keep the reaction at this temperature for 6 hours; Step 2: Add an aqueous solution of inorganic base 2, stir and heat up to 60°C - 90°C, and keep the reaction at this temperature for 8 hours; Step 3: Cool down to about 20°C, adjust the pH to 3 - 4 with an acid, add ethyl acetate for extraction, evaporate the organic layer under reduced pressure to dryness, add isopropanol for recrystallization, then centrifuge and dry to obtain the product 1-(mercaptomethyl)cyclopropylacetic acid (MLM); Among them, the solvent described in Step 1 is one of methanol, ethanol, isopropanol, and tert-butanol; The inorganic base 1 and inorganic base 2 described in Step 1 and Step 2 are one of lithium hydroxide, sodium hydroxide, and potassium hydroxide.

2. The preparation method of a montelukast sodium side chain according to claim 1, characterized in that: In Step 2, the concentration of the aqueous solution of inorganic base 2 is 5% - 15%.

3. The preparation method of a montelukast sodium side chain according to claim 2, characterized in that: The acid described in Step 3 is one of dilute hydrochloric acid, dilute sulfuric acid, and acetic acid aqueous solution.

4. The preparation method of a montelukast sodium side chain according to claim 3, characterized in that: The molar ratio of MLM-5, inorganic base 1, inorganic base 2, and thiobenzoic acid used is 1:(1.2 - 2.0):(1.2 - 2.0):(1.05 - 1.6).

5. The preparation method of a montelukast sodium side chain according to claim 4, characterized in that: The dosage of the solvent is 5 - 10 times the mass of MLM.

Images