A method for preparing a Prilosec intermediate

Abstract

The present invention provides a method for preparing a pranlukast intermediate. Using compound C as a raw material, the pranlukast intermediate is obtained after reaction. The pranlukast intermediate prepared by the present invention has a high yield, and has the advantages of relatively mild reaction conditions, convenient operation, high purity and high yield of the obtained pranlukast intermediate, and is suitable for industrial production. Therefore, it provides a more valuable synthetic route for the preparation of pranlukast, which can bring good social and economic benefits and has great economic value potential.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis for pharmaceuticals, and more specifically, to a preparation method of a pranlukast intermediate used in the production of pranlukast drugs. Background Art

[0002] Pranlukast is a new anti-asthma drug launched in the mid-1990s and is one of the three leukotriene receptor antagonists that have received extensive attention internationally. Pranlukast is characterized by extremely low toxicity (oral LD50 > 2000 mg / kg), significant inhibition of LTC4, LTD4, and LTE4, especially significant inhibition of LTD4 (the main component causing human tracheal smooth muscle contraction). Clinically, it is effective not only for atopic asthma but also for infectious, mixed, chronic, episodic, and non-seasonal bronchial asthma; it has no serious adverse reactions, does not affect p450 drug-metabolizing enzymes, and has no drug interaction problems.

[0003] The structural characteristics of pranlukast determine that its synthesis mainly consists of two fragments: 4-(4-phenylbutoxy)benzoic acid (A) and 8-amino-2-(1H-tetrazol-5-yl)-4H-chromen-4-one (B). Since the structure of compound A is stable and relatively simple, the research focus is mainly on compound B.

[0004]

[0005] In the currently reported synthetic processes of pranlukast, for the synthesis of compound B, there are mainly the following routes:

[0006] ① Reported by Toda: Using 3-nitro-2-hydroxyacetophenone as the raw material, undergoing Claisen condensation with diethyl oxalate, and then heating under reflux to close the ring to construct the chromene ring; synthesizing the cyano group on the ring by dehydrating the amide, and then reacting this cyano compound with sodium azide to synthesize the tetrazole, and hydrogenating and reducing the nitro group on the compound to an amino group under the catalysis of 5% Pd / C.

[0007]

[0008] ② The Robert route and the Graham route are prepared by a carbonyl formylation reaction using a palladium ligand compound as the catalyst, condensation under the action of potassium tert-butoxide, and ring closure and dehydration under acidic conditions to obtain the chromene ring.

[0009]

[0010] ③The Masayohi synthetic route involves the addition reaction of 2-cyanobenzopyran derivatives with hydrogen sulfide gas under base catalysis to form 2-aminothiocarbonylbenzopyran derivatives, followed by reaction with anhydrous hydrazine to form aminohydrazones, and then nitrosation with sodium nitrite under acidic conditions to obtain a tetrazole ring.

[0011]

[0012] ④Giles, Hideki, and Hayler all added substituents to the tetrazole to make the condensation reaction easier, but it is difficult to synthesize tetrazoles with substituents on nitrogen. The final removal reaction uses dangerous reagents such as lithium aluminum hydride, which is not easy for industrialization.

[0013]

[0014] The above routes generally have the disadvantages of severe reaction conditions, low yield, high toxicity, and difficult removal of impurities generated by the reaction. Summary of the Invention

[0015] In view of the above-mentioned defects and problems of the prior art, the present invention provides a method for preparing a Pranlukast intermediate, and the technical problem to be solved is: to develop a synthetic method for Pranlukast intermediate compound B with mild reaction conditions and low impurities, so as to provide conditions for better preparation of Pranlukast.

[0016] In order to achieve the above object, the present invention provides the following technical solutions:

[0017] A method for preparing a Pranlukast intermediate, using compound C as a raw material, and obtaining the Pranlukast intermediate by any of the following schemes;

[0018] Scheme 1: It includes the following steps:

[0019] Q1. React with compound C as a raw material to finally obtain compound D. The characteristics of compound D are: R1 is a halogen or a group that can polymerize with a hydroxyl group to form an ether; the position of R2 is an ester group;

[0020] Q2. Condense compound D with o-acetamidophenol, and then through a ring-forming reaction and a hydrolysis reaction, finally prepare compound B with sodium azide;

[0021] Scheme 2: It includes the following steps:

[0022] Q1. React with compound C as a raw material to finally obtain compound E. The characteristics of compound E are: R1 is a halogen or a group that can polymerize with a hydroxyl group to form an ether, and the position of R3 is an ester group;

[0023] Q2. After condensing compound E with o-acetamidophenol, convert the hydroxyl group in the original compound E into a 4-nitrogenazole and then form a ring to obtain compound B;

[0024]

[0025] The structure of the said compound C is as follows:

[0026]

[0027] It is characterized in that R1 is a halogen or a group capable of polymerizing with a hydroxyl group to form an ether; R2 and R3 are hydrogen groups or groups capable of forming an ester with a carboxylic acid.

[0028] The present invention prepares a pranlukast intermediate with a high yield, having the advantages of relatively mild reaction conditions, convenient operation, high purity and high yield of the obtained pranlukast intermediate, and being suitable for industrial production. Thus, it provides a more valuable synthetic route for preparing pranlukast, which can bring good social and economic benefits and has great potential economic value. Specific Embodiments

[0029] Next, in combination with the embodiments of the present invention, the technical solutions of the present invention will be clearly and completely described. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts belong to the scope of protection of the present invention.

[0030] A method for preparing a pranlukast intermediate, comprising the following steps:

[0031] Q1. React with compound C as a raw material to finally obtain compound D. The characteristics of compound D are: R1 is a halogen or a group capable of polymerizing with a hydroxyl group to form an ether; the position of R2 is an ester group;

[0032] Q2. After condensing compound D with o-acetamidophenol, through a ring-forming reaction and a hydrolysis reaction, finally prepare compound B with sodium azide;

[0033] A method for preparing a pranlukast intermediate, comprising the following steps:

[0034] Q1. React with compound C as a raw material to finally obtain compound E. The characteristics of compound E are: R1 is a halogen or a group capable of polymerizing with a hydroxyl group to form an ether, and the position of R3 is an ester group;

[0035] Q2. After condensing compound E with o-acetamidophenol, convert the hydroxyl group in the original compound E into a 4-nitrogenazole and then form a ring to obtain compound B;

[0036]

[0037] In the above technical solution, the structure of the compound C is as follows:

[0038]

[0039] It is characterized in that R1 is a halogen or a group capable of polymerizing with a hydroxyl group to form an ether; R2 and R3 are hydrogen groups or groups capable of forming an ester with a carboxylic acid.

[0040] Accordingly, in the examples, the present invention provides two synthetic routes. The preferred structures of the compound C in the synthetic route 1 are the compound 1 and the compound 3, and their structures are as follows:

[0041]

[0042] Using the compound 1 or the compound 3 as the starting material, the specific synthetic route is as follows:

[0043]

[0044] The greatest advantage of the synthetic route 1 is that the cyclization reaction conditions of the compound 5 are mild, the specific reaction is strong, and the generated impurities are extremely easy to remove.

[0045] 1. Example of the synthetic route 1: The synthetic route for synthesizing the pranlukast intermediate compound B using the preferred compound 1 or compound 3 of the compound C as the starting material:

[0046] ① Synthesis of the compound 2: Add 800 ml of methanol to the reaction vessel, add the compound 1, dropwise add 300 ml of thionyl chloride under an ice-water bath, heat and reflux for 8 hours, concentrate to a viscous liquid, add 400 ml of methanol, raise the temperature to 40 °C, stir evenly, then concentrate to a small volume, crystallize, filter, and dry to obtain 214.6 g of the compound 2, with a yield of 107.3%.

[0047] ② Synthesis of the compound 3: Add 600 ml of an aqueous lithium hydroxide solution to the reaction vessel, and while stirring, dropwise add the methanol solution of the compound 2 (dissolve the compound 2 obtained in the previous step in 300 ml of methanol, raise the temperature and stir until dissolved), raise the temperature to 40 °C and stir for 8 hours. After the reaction is complete, cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid, extract twice with ethyl acetate, collect the organic layer, dry with anhydrous MgSO4, concentrate to a small volume, crystallize, filter, and dry to obtain 190.4 g of the compound 3, with a yield of 88.7%.

[0048] ③ Synthesis of Compound 4: Place 500 ml of saturated NaCl aqueous solution in a reaction vessel, slowly add NaOH, and after adding 180 g of o-acetylaminophenol, slowly add 190.4 g of Compound 3. Stir and react at 60 °C for 15 hours. After the reaction is complete, cool to room temperature and adjust the pH to 3 with hydrochloric acid. Extract 3 times with ethyl acetate, collect the organic phase layer, then extract 3 times with Na2CO3 aqueous solution, collect the Na2CO3 aqueous layer, adjust the pH = 2 - 3 with hydrochloric acid, and finally extract 3 times with ethyl acetate, collect the ethyl acetate layer, dry with anhydrous MgSO4, and then vacuum dry to obtain 241.4 g of Compound 4, with a yield of 126.8%.

[0049] ④ Synthesis of Compound 5: Add 490 g of concentrated sulfuric acid to Reaction Vessel A. After cooling to 5 °C, slowly dropwise add 241.4 g of Compound 4 dissolved in water, and stir and react for 16 hours. After the reaction is completed, cool the reaction mixture to room temperature. Pour 1.5 L of purified water into Reaction Vessel B, control the temperature at 0 - 5 °C, and slowly dropwise add the reaction product in Reaction Vessel A into Reaction Vessel B. Add 1.2 L of dichloromethane and stir, separate the organic layer, add 1 L of purified water, adjust the pH to about 7 with 5% sodium carbonate aqueous solution, separate the organic layer again, concentrate and filter, and vacuum dry under reduced pressure at 40 °C to obtain 172.8 g of Compound 5, with a yield of 71.6%.

[0050] ⑤ Synthesis of Compound 6: Dissolve the Compound 5 obtained in the previous step in 900 ml of DMF, and introduce dry ammonia gas while stirring. The color of the reaction solution gradually changes from yellow to red. Pour the reaction solution into cold water, adjust it to acidic with dilute hydrochloric acid, crystallize, filter, and dry to obtain 145.7 g of Compound 6, with a yield of 84.3%

[0051] ⑥ Synthesis of Compound 7: Add 800 ml of DMF, 20 ml of SOCl2 and the Compound 6 obtained in the previous step to a single-necked flask. Stir at 7.5 °C for 6 h and then pour it into cold water. Filter to obtain 127.6 g of Compound 7, with a yield of 87.6%.

[0052] ⑦ Synthesis of Compound 8: Add the Compound 7 obtained in the previous step, 27 g of ammonium chloride, 28 g of sodium azide and 1000 ml of DMF to a reaction vessel, heat for 4.5 h, cool and pour it into ice water, adjust it to acidic with dilute hydrochloric acid, and filter to obtain 117.0 g of the finished product, with a yield of 91.7%.

[0053] ⑧ Synthesis of Compound B: Add 600 ml of dichloromethane, 60 g of pyridine and 80 g of acetic anhydride to a reaction vessel, stir evenly, add the Compound 8 obtained in the previous step, heat to 35 °C, heat for 5 hours, cool and pour it into ice water, adjust the pH value to neutral, filter and dry to obtain 94 g of Compound B, with a yield of 80.3%.

[0054] 2. Examples of Synthetic Route 2: Starting from Compound 1 or Compound 9, the specific synthetic route is as follows:

[0055] In Synthetic Route 2, the preferred structures of Compound C are Compound 1 and Compound 9, and their structures are as follows:

[0056]

[0057] The specific synthetic route is as follows:

[0058]

[0059] The reaction conditions of this Synthetic Route 2 are mild, and the yield is significantly higher than that of Synthetic Route 1, which is suitable for industrial production.

[0060] 2. Examples of Synthetic Route 2:

[0061] ① Synthesis of Compound 2: Add 800 ml of methanol to the reaction vessel, add Compound 1, dropwise add 300 ml of thionyl chloride under an ice-water bath, heat under reflux for 8 hours, concentrate to a viscous liquid, add 400 ml of methanol, raise the temperature to 40 °C, stir evenly, then concentrate to a small volume, crystallize, filter, and dry to obtain 214.2 g of Compound 2 with a yield of 107.1%.

[0062] ② Synthesis of Compound 9: Add 500 ml of water to the reaction vessel, add the Compound 2 obtained in the previous step under stirring, dropwise add 300 ml of sodium hydroxide methanol solution, raise the temperature to 60 °C and stir for 2 hours. After the reaction is complete, cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid, extract twice with ethyl acetate, collect the organic layer, dry with anhydrous MgSO4, concentrate to a small volume, crystallize, filter, and dry to obtain 185.1 g of Compound 9 with a yield of 86.4%.

[0063] ③ Synthesis of Compound 10: Place 500 ml of saturated NaCl aqueous solution in the reaction vessel, slowly add NaOH, add 190 g of o-acetylaminophenol, and then slowly add 185.1 g of Compound 9. Stir and react at 60 °C for 15 hours. After the reaction is complete, cool to room temperature and adjust the pH to 3 with hydrochloric acid. Extract three times with ethyl acetate, collect the organic phase layer, then extract three times with Na2CO3 aqueous solution, collect the Na2CO3 aqueous layer, adjust the pH = 2 - 3 with hydrochloric acid, and finally extract three times with ethyl acetate, collect the ethyl acetate layer, dry with anhydrous MgSO4, and then vacuum dry to obtain 219.7 g of Compound 10 with a yield of 118.7%.

[0064] ④ Synthesis of Compound 11: Dissolve the compound 10 obtained in the previous step in 900 ml of DMF. While stirring, introduce dry ammonia gas. The color of the reaction solution gradually changes from yellow to red. Pour the reaction solution into cold water and adjust it to acidic with dilute hydrochloric acid. Crystallize, filter, and dry to obtain 211.8 g of compound 11, with a yield of 96.4%.

[0065] ⑤ Synthesis of Compound 12: Add 900 ml of DMF, 25 ml of SOCl₂, and the compound 11 obtained in the previous step to a single-necked flask. Stir at 6°C for 6 h and then pour it into cold water. Filter to obtain 189.3 g of compound 12, with a yield of 89.4%.

[0066] ⑥ Synthesis of Compound 13: Add the compound 12 obtained in the previous step, 30 g of ammonium chloride, 32 g of sodium azide, and 1000 ml of DMF to a reaction vessel. Heat for 4.5 h, cool, and pour into ice water. Adjust to acidic with dilute hydrochloric acid and filter to obtain 205.2 g of the finished product, with a yield of 108.4%.

[0067] ⑦ Synthesis of Compound 14: Add 500 ml of water to a reaction vessel. While stirring, add the compound 13 obtained in the previous step. Dropwise add 200 ml of sodium hydroxide methanol solution and heat to 60°C and stir for 2 h. After the reaction is complete, cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid, extract once with ethyl acetate, collect the organic layer, concentrate to a small volume, crystallize, filter, and dry to obtain 187.2 g of compound 14, with a yield of 91.2%.

[0068] ⑧ Synthesis of Compound 8: Add 510 g of concentrated sulfuric acid to reaction vessel A. After cooling to 5°C, slowly dropwise add 187.2 g of compound 14 dissolved in water. Stir and react for 20 h. After the reaction is complete, cool the reaction mixture to room temperature. Pour 1.5 L of purified water into reaction vessel B and control the temperature at 0 - 5°C. Slowly dropwise add the reaction product in reaction vessel A to reaction vessel B. Add 1.2 L of dichloromethane and stir. Separate the organic layer, add 1 L of purified water, adjust the pH to about 7 with 5% sodium carbonate aqueous solution, separate the organic layer again, concentrate and filter, and dry under vacuum at 40°C to obtain 158.3 g of compound 14, with a yield of 84.6%.

[0069] ⑨ Synthesis of Compound B: Add 600 ml of dichloromethane, 60 g of pyridine, and 80 g of acetic anhydride to a reaction vessel. Stir evenly, add the compound 8 obtained in the previous step, heat to 35°C, and heat for 5 h. Cool and pour into ice water, adjust the pH value to neutral, filter, and dry to obtain 112.9 g of compound B, with a yield of 71.3%.

[0070] As described above, it is only the specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention can easily think of changes or substitutions, which should all be covered within the protection scope of the present invention. Therefore, the protection scope of the present invention should be subject to the protection scope of the claims.

Claims

1. A method for preparing a Prilosec intermediate, characterized in that: Using compound 1 or compound 3 as the starting material, prepare the pranlukast intermediate compound B. The synthesis steps are as follows:

2. A preparation method of a prilosec intermediate, characterized in that: Using compound 1 or compound 9 as the starting material, prepare the pranlukast intermediate compound B. The synthesis steps are as follows: 。

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