A preparation process of montelukast sodium intermediate

Abstract

The present invention relates to the technical field of pharmaceutical intermediates, and in particular to a process for preparing a montelukast sodium intermediate. The montelukast sodium intermediate #imgabs0# is finally synthesized by subjecting tribromoneopentyl alcohol to the steps of chlorination, ring closure, accession with potassium thioacetate, enzymatic cyanidation, hydrolysis, and the like. The synthesis route is: #imgabs1##imgabs2#. Compared with existing preparation methods, the preparation process of the present invention has simpler procedures, easier reactions, and reduced raw material costs.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical intermediates, and specifically relates to a preparation process of a montelukast sodium intermediate. Background Art

[0002] Montelukast sodium is an anti-asthmatic, anti-inflammatory, and anti-allergic drug used for the prevention and long-term treatment of asthma, including prevention of daytime and nighttime asthma symptoms, treatment of aspirin-sensitive asthma patients, and prevention of exercise-induced bronchoconstriction. Its chemical name is sodium 1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetate, and its structural formula is as follows:

[0003]

[0004] Among them, 1-(mercaptomethyl)cyclopropylacetic acid is one of the important intermediates for the preparation of montelukast sodium.

[0005] Patent US200720817 reports a method for preparing 1-(mercaptomethyl)cyclopropylacetic acid, the synthesis route of which is as follows:

[0006]

[0007] Using diethyl malonate as the starting material, the process goes through cyclization and reduction steps, followed by the action of thionyl chloride, sodium cyanide, liquid bromine, and thiourea, and finally hydrolysis to obtain 1-(mercaptomethyl)cyclopropylacetic acid. This method uses a wide variety of materials, among which auxiliary materials such as lithium chloride and sodium iodide are expensive, and the post-processing operation is complicated, generating a lot of three wastes. Summary of the Invention

[0008] The purpose of the present invention is to provide a preparation process of a montelukast sodium intermediate, wherein tribromoneopentyl alcohol is subjected to chlorination, ring closure, access to potassium thioacetate, enzymatic cyanidation, hydrolysis and other steps to finally synthesize a montelukast sodium intermediate. The invention adopts an enzymatic method to introduce a cyano group, which has milder conditions, controls the dosage of potassium thioacetate to reduce the generation of disubstitution products, and controls the acid adjustment temperature to improve the conversion rate.

[0009] To achieve the above object, the present invention provides the following technical solutions:

[0010] A preparation process of a montelukast sodium intermediate, the synthesis route of which is as follows:

[0011]

[0012] The specific preparation steps are as follows:

[0013] (1) Compound 1 was synthesized by chlorination using tribromoneopentyl alcohol as a raw material;

[0014] (2) Compound 1 is cyclized to synthesize compound 2 under the action of zinc powder;

[0015] (3) Compound 2 was docked with potassium thioacetate to synthesize compound 3;

[0016] (4) Compound 3 is then enzymatically cyanided to synthesize compound 4;

[0017] (5) Compound 4 was hydrolyzed under the action of alkali to synthesize compound 5.

[0018] Furthermore, in the step (1), the molar ratio of 4-tribromoneopentyl alcohol, the chlorination reagent, and the acid binding agent is 1:1-1.5:1-1.5, and the chlorination reagent is any one of thionyl chloride, phosphorus trichloride, phosphorus pentachloride, triphosgene, oxalyl chloride, and sulfuryl chloride.

[0019] Furthermore, in step (2), the molar ratio of compound 1 to zinc powder is 1:1-2.

[0020] Furthermore, in step (3), the molar ratio of compound 2 to potassium thioacetate is 1:1 to 1.2.

[0021] Furthermore, in step (4), the molar ratio of compound 3 to the cyaniding agent is 1:1-1.5, the mass ratio of compound 3 to the enzyme solution is 1:0.05-0.2, the pH during the reaction is 7-7.5, and the cyaniding agent is sodium cyanide or potassium cyanide. The enzyme is a wild-type Halohydrin Dehalogenases (Crude Enzyme)

[0022] Furthermore, in step (5), the molar ratio of compound 4 to the base is 1:1-1.5, the acid adjustment temperature is 0-10°C, and the base is one or more of alkali metal hydroxides and alkali metal carbonates.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] (1) The preparation process of the present invention adopts an enzymatic method to introduce cyano groups, which can react at room temperature, has mild and simple conditions, emits less three wastes, is environmentally friendly, and has a high conversion rate.

[0025] (2) The preparation process of the present invention achieves unilateral substitution by controlling the amount of potassium thioacetate and the activity difference of different halogens, thereby reducing the impurity generation of disubstituted products during the preparation of compound 3.

[0026] (3) The preparation process of the present invention improves the conversion yield of the target product by controlling the acid adjustment temperature in step (5). BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is the spot plate result of Example 3. DETAILED DESCRIPTION

[0028] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0029] Example 1 Synthesis of Compound 1

[0030]

[0031] Add tribromoneopentyl alcohol (32.84 g, 0.1 mol), triethylamine (11.13 g, 0.11 mol), dichloromethane (100 ml), and DMF (0.7 g, 0.01 mol) into the reactor, stir and mix, protect with nitrogen, cool to 0-10°C, add thionyl chloride (13.09 g, 0.11 mol) dropwise into the system, raise the temperature to reflux after the addition is complete, and mix and react for 4 hours.

[0032] After the reaction, dichloromethane and excess thionyl chloride were evaporated, and dichloromethane (100 ml) and water (100 ml) were added to the residue. The organic layer was washed twice with saturated sodium bicarbonate and twice with water. The organic layer was spin-dried to dry the solvent to obtain compound 1 (30.07 g, 0.0876 mol) with a yield of 87.6%.

[0033] Example 2 Synthesis of Compound 2

[0034]

[0035] Compound 1 (34.33 g, 0.1 mol) and methanol (150 ml) were added to a reactor and stirred to dissolve. Zinc powder (9.8 g, 0.15 mol) was added and nitrogen was applied. The system was heated to 70-80°C and stirred for 12 h. The reaction was filtered and the filtrate was cooled to below 10°C. The excess zinc powder was filtered out and ammonia gas (8.5 g, 0.5 mol) was introduced into the filtrate. The mixture was stirred for 30 min and the precipitated solid was filtered. The solvent in the filtrate was dried to obtain compound 2 (14.37 g, 0.0783 mol) in a yield of 78.3%.

[0036] Example 3 Synthesis of Compound 3

[0037]

[0038] Compound 2 (18.35 g, 0.1 mol) and anhydrous methanol (80 ml) were added to the reactor and stirred at room temperature (20-30°C) to dissolve completely under nitrogen. Potassium thioacetate (11.42 g, 0.1 mol) was added all at once and the temperature was raised to reflux for about 15-20 hours until the reaction of the raw materials was complete.

[0039] After the reaction was completed, dry methanol was recovered under reduced pressure to obtain compound 3 (15.24 g, 0.0853 mol) with a yield of 85.3%.

[0040] like Figure 1 As shown, the three points from left to right are compound 2, the system after reaction, and the reference substance of compound 3, the condition of DCM: methanol = 10:1, and potassium permanganate staining. The control shows that the reaction successfully synthesized compound 3.

[0041] Example 4 Synthesis of Compound 4

[0042]

[0043] A 30% aqueous sodium cyanide solution (16.3 g, 0.1 mol) was added to the reactor, followed by the slow dropwise addition of dilute sulfuric acid until the pH reached 7.0-7.5. Compound 3 (17.7 g, 0.1 mol) was then added, followed by the addition of wild-type halohydrin dehalogenases (Crude Enzyme) (1.3 g, commercially available from Codexis) enzyme solution. The reaction was heated to 30-35°C and maintained for 24 hours, with sodium cyanide solution maintaining the pH at 7-7.5.

[0044] After the reaction, vacuum dehydrocyanate was removed for 20 minutes. The temperature was then lowered to 30°C and filter press was initiated. The filtrate became transparent and the temperature was then lowered to below 30°C. Methyl tert-butyl ether (80 ml) was added to the filtrate and extracted twice. The organic layers were combined and the methyl tert-butyl ether was recovered to dryness to obtain compound 4 (14.01 g, 0.0828 mol), with a yield of 82.8%.

[0045] Example 5 Synthesis of Compound 5

[0046]

[0047] Compound 4 (16.92 g, 0.1 mol) and methanol (100 ml) were added to the reactor and stirred to dissolve. A 30% NaOH aqueous solution (14.7 g, 0.11 mol) was added to the system and the mixture was refluxed and stirred for 20 hours.

[0048] The system was cooled naturally to room temperature, water was added to obtain a clear system, and the temperature was lowered to 0-10°C. Dilute hydrochloric acid was slowly added dropwise to adjust the pH to 1-2. The mixture was stirred for 30 minutes and extracted three times with n-hexane. The organic phases were combined, the solvent was recovered under reduced pressure, and the residue was recrystallized from n-hexane to obtain compound 5 (12.41 g, 0.0849 mol), with a yield of 84.9%.

[0049] Example 6-8 Synthesis of Compound 1

[0050] Other conditions were the same as those in Example 1. The molar ratio of tribromoneopentyl alcohol, chlorination reagent, and acid binding agent, and the type of chlorination reagent were changed. The reaction conditions and yields of Example 1 and Examples 6-8 are detailed in Table 1.

[0051] Table 1 Different conditions and results of Example 1 and Examples 6-8

[0052] Example Tribromoneopentyl alcohol, chlorination reagent, acid binding agent Types of chlorination reagents Yield / % 1 1:1.1:1.1 Thionyl chloride 87.6 6 1:1:1 Thionyl chloride 86.8 7 1:1.5:1.5 Thionyl chloride 85.5 8 1:1.1:1.1 Phosphorus trichloride 85.2

[0053] Example 9-10 Synthesis of Compound 2

[0054] Other conditions were the same as in Example 2, except that the molar ratio of compound 1 to zinc powder was changed. The reaction conditions and yields of Example 2 and Examples 9-10 are detailed in Table 2.

[0055] Table 2 Different conditions and results of Example 2, Example 9-10

[0056] Example Compound 1: Zinc powder Yield / % 2 1:1.5 78.3 9 1:1 72.6 10 1:2 75.5

[0057] Synthesis of Compound 3 in Examples 11-12

[0058] Other conditions were the same as those in Example 3, except that the molar ratio of compound 2 to potassium thioacetate was changed. The reaction conditions and yields of Example 3 and Examples 11-12 are detailed in Table 3.

[0059] Table 3 Different conditions and results of Example 3 and Example 11-12

[0060] Example Compound 2: Potassium thioacetate Total yield / % 3 1:1.1 85.3 11 1:1 83.4 12 1:1.2 84.7

[0061] Synthesis of Compound 4 in Examples 13-16

[0062] Other conditions were the same as those in Example 4. The molar ratio of compound 3 to the cyaniding agent, the mass ratio of compound 3 to the enzyme, and the type of cyaniding agent were changed. The reaction conditions and yields of Example 4 and Examples 13-16 are detailed in Table 4.

[0063] Table 4 Different conditions and results of Example 4 and Examples 13-16

[0064] Example Compound 3: cyaniding reagent Compound 3: Enzyme Types of cyanide reagents Yield / % 4 1:1 1:0.08 Sodium cyanide 82.8 13 1:1.5 1:0.08 Sodium cyanide 81.2 14 1:1 1:0.05 Sodium cyanide 80.7 15 1:1 1:0.2 Sodium cyanide 82.2 16 1:1 1:0.08 Potassium cyanide 81.6

[0065] Synthesis of Compound 5 in Examples 17-19

[0066] Other conditions were the same as those in Example 5, except that the molar ratio of compound 4 to the base and the acid temperature were changed. The reaction conditions and results of Example 5 and Examples 17-19 are detailed in Table 5.

[0067] Table 5 Different conditions and results of Example 5 and Examples 17-19

[0068] Example Compound 4: Base Acid adjustment temperature Yield / % 5 1:1.1 0～10℃ 84.9 17 1:1 0～10℃ 83.5 18 1:1.5 0～10℃ 83.1 19 1:1.1 25～35℃ 75.4

[0069] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A process for preparing a montelukast sodium intermediate, characterized in that: The following steps are involved: (1) Compound 1 was synthesized by chlorination using tribromoneopentyl alcohol as a raw material; (2) Compound 1 is cyclized to synthesize compound 2 under the action of zinc powder; (3) Compound 2 was docked with potassium thioacetate to synthesize compound 3; (4) Compound 3 is then enzymatically cyanided to synthesize compound 4; (5) Compound 4 is hydrolyzed under the action of alkali to synthesize compound 5; 2. The process for preparing the montelukast sodium intermediate according to claim 1, wherein: In the step (1), the molar ratio of tribromoneopentyl alcohol, the chlorination reagent and the acid binding agent is 1:1-1.5:1-1.5, and the chlorination reagent is any one of thionyl chloride, phosphorus trichloride, phosphorus pentachloride, triphosgene, oxalyl chloride and sulfuryl chloride.

3. The process for preparing the montelukast sodium intermediate according to claim 1, wherein: In the step (2), the molar ratio of compound 1 to zinc powder is 1:1-2.

4. The process for preparing the montelukast sodium intermediate according to claim 1, wherein: In the step (3), the molar ratio of compound 2 to potassium thioacetate is 1:1 to 1.

2.

5. The process for preparing the montelukast sodium intermediate according to claim 1, wherein: In the step (4), the molar ratio of compound 3 to the cyaniding agent is 1:1-1.5, the mass ratio of compound 3 to the enzyme solution is 1:0.05-0.2, the pH value during the reaction is 7-7.5, the cyaniding agent is sodium cyanide or potassium cyanide, and the enzyme is wild-type Halohydrin Dehalogenases(Crude Enzymes).

6. The process for preparing the montelukast sodium intermediate according to claim 1, wherein: In the step (5), the molar ratio of compound 4 to the base is 1:1-1.5, the acid adjustment temperature is 0-10°C, and the base is one or more of alkali metal hydroxides and alkali metal carbonates.

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