Industrial production method of nemategravir key intermediate

Abstract

The invention relates to the technical field of organic synthesis industrialization, in particular to an industrial production method of a nemategravir key intermediate, and the target product alpha-amino-2-oxo-3-pyrrolidine propanamide hydrochloride is obtained by taking t-butyloxycarbonyl-L-glutamic acid dimethyl ester as an initial raw material through coupling, reduction ring closing, amine ester exchange and Boc removal. Compared with the prior art, the method has the advantages that the reaction route is reliable, industrial production is easy to realize, the used reagent is low in cost, the obtained product is high in yield and purity, and the product quality can meet the subsequent requirements.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis industrialization, and specifically refers to an industrial production method of a key intermediate of nirmatrelvir. Background Art

[0002] Paxlovid is a compound preparation composed of nirmatrelvir tablets (2 tablets of 150 mg) and ritonavir tablets (1 tablet of 100 mg). It is taken orally 2 times a day for 5 consecutive days. A box of the drug contains 5 blister packages of Paxlovid, which is a combined package of nirmatrelvir tablets and ritonavir tablets, providing all the doses required for a complete 5-day treatment.

[0003] As one of the key intermediates for the synthesis of nirmatrelvir, it is particularly important to invent an efficient, low-cost, environmentally friendly, and easily industrializable method for α-amino-2-oxo-3-pyrrolidinepropanamide hydrochloride.

[0004] Patent CN116283706A proposes the application of cobalt chloride hexahydrate / potassium borohydride in the reaction path to reduce the exotherm in the reduction cyclization reaction of dimethyl (2S,4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)pentanedioate, and to increase the methyl tert-butyl ether and n-heptane recrystallization system. It uses inorganic salts and sodium borohydride, resulting in serious three-waste problems and difficult filtration problems in the production process.

[0005] In the existing reaction path, in the aminolysis step, the amount of ammonia, methanol or ammonia water used is large, the reaction temperature is high, and the yield is low. For example, in US Patent US20210355111, ammonia methanol is used at 80 °C and the amount of ammonia methanol used is more than 100 equivalents; Chinese Patent CN114230504 reports the reaction in an ammonia water and methanol system, with the amount of ammonia water used ranging from 20 to 100 equivalents and the reaction temperature of 150 °C. Summary of the Invention

[0006] (I) Technical Problems

[0007] The present invention aims to solve at least the problems of high cost and difficulty in industrialization existing in the prior art.

[0008] (II) Technical Content

[0009] This solution provides an industrial production method of a key intermediate of nirmatrelvir. Using dimethyl tert-butoxycarbonyl-L-glutamate as the starting material, through coupling, reduction cyclization, amine ester exchange, and de-Boc, the target product α-amino-2-oxo-3-pyrrolidinepropanamide hydrochloride is obtained. The specific steps are as follows:

[0010] Step 1: Add tetrahydrofuran (C 4 H 8O) 160 g, and then add dimethyl tert-butoxycarbonyl-L-glutamate (C 12 H 21 O 6 N) 20 g, and cool down to -65 to -100 °C;

[0011] 130 g of lithium bis(trimethylsilyl)amide is pressured into reaction flask 2 with argon (C 6 H 18 LiNSi 2 ) and cool down to -65 to -100 °C. After the temperature of reaction flask 2 is lowered, lithium bis(trimethylsilyl)amide is added dropwise to reaction flask 1 with argon (C 6 H 18 LiNSi 2 ) ;

[0012] Then add 60 g of tetrahydrofuran (C 4 H 8 O), 10 g of bromoacetonitrile (C 2 H 2 BrN) to reaction flask 3, and cool down to -65 to -100 °C. After the temperature of reaction flask 3 is lowered, the solution in reaction flask 3 is added dropwise to reaction flask 1;

[0013] After the reaction is completed, glacial acetic acid (C 2 H 4 O 2 ) is used to terminate the reaction, and the temperature is returned to room temperature. It is quenched into brine, and ethyl acetate (C 4 H 8 O 2 ) is used for extraction, and concentration gives the compound (2S,4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)dimethyl glutarate (C 14 H 22 O 6 N 2 ) 21 kg;

[0014] Step 2, charge 21 g of the compound (2S,4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)dimethyl glutarate (C 14 H 22 O 6 N 2 ) into an autoclave, and then add 200 g of methanol (CH 4 O), 2 g of catalyst, add 6 g of ammonia-methanol, displace with nitrogen and hydrogen (H 2 ) and heat up to 40 - 50 °C for hydrogenation for 8 h until the reaction is completed. Filter, concentrate, and use methyl tert-butyl ether (C 5 H 12O) The solution material crystallizes, is filtered and dried to obtain methyl (S)-2-(Boc-amino)-3-[(S)-2-oxo-3-pyrrolidinyl] propionate (C 13 H 22 O 5 N 2 ) 16.2 g;

[0015] Step 3: Add 16.2 g of methyl (S)-2-(Boc-amino)-3-[(S)-2-oxo-3-pyrrolidinyl] propionate (C 13 H 22 O 5 N 2 ) to reaction flask 4, add 162 g of methanol (CH 4 O), add 3 g of ammonia gas (NH 3 ), add 0.16 g of DMAP (4-dimethylaminopyridine (C 7 H 10 N 2 ), heat up to 25 - 35 °C and react for 1 h to finish, concentrate to obtain N-Boc-α-amino-2-oxo-3-pyrrolidine propionamide (C 12 H 21 O 4 N 3 ) 15.3 g;

[0016] Step 4: Add 30 g of methanol and 75 g of ethyl acetate (C 4 H 8 O 2 ) to reaction flask 5, then add 15.3 g of N-Boc-α-amino-2-oxo-3-pyrrolidine propionamide (C 12 H 21 O 4 N 3 ), dropwise add 12.7 g of hydrogen chloride ethyl acetate solution, control the temperature at 25 - 35 °C and react for 5 h, then cool down to crystallize, filter, wash with methanol and filter and dry to obtain α-amino-2-oxo-3-pyrrolidine propionamide hydrochloride (C 7 H 14 O 2 ClN 3 ) 10.4 g.

[0017] Preferred technical solution 1: In step 1, the pre-cooling temperature in reaction flasks 1, 2, and 3 is -80 - -85 °C.

[0018] Preferred technical solution 2: In step 2, the catalyst is Raney nickel.

[0019] Preferred technical solution 3: In step 4, the concentration of the hydrogen chloride ethyl acetate solution is 13%.

[0020] Preferred Technical Solution Four: In Step 1, the purity of the obtained compound (2S,4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)pentanedioic acid dimethyl ester (C 14 H 22 O 6 N 2 ) is ≥80%, and the yield is 92.1%.

[0021] Preferred Technical Solution Five: In Step 2, the yield of the compound methyl (S)-2-(Boc-amino)-3-[(S)-2-oxo-3-pyrrolidinyl]propionate is 85%, and the purity is ≥98%.

[0022] Preferred Technical Solution Six: In Step 3, the purity of the compound N-Boc-α-amino-2-oxo-3-pyrrolidinepropanamide is ≥98%, and the yield is 100%.

[0023] Preferred Technical Solution Seven: In Step 4, the purity of the compound α-amino-2-oxo-3-pyrrolidinepropanamide hydrochloride is 99.8%, and the yield is 90%.

[0024] Preferred Technical Solution Eight: In Step 2, the concentration of ammonia in methanol is 10%.

[0025] (III) Technical Effects

[0026] Adopting the above structure enables this solution to have the following beneficial effects:

[0027] 1. This method adopts a pre-cooling operation mode for the materials, which increases the product purity by more than 20% and significantly improves the yield. Using a conventional reaction kettle, high quality and high yield can be achieved; the effect of cost reduction and efficiency improvement is achieved

[0028] 2. This method uses a Raney nickel catalyst, avoiding the use of platinum dioxide catalyst, palladium carbon catalyst, sodium borohydride, and cobalt chloride by users, making the production operation simple, significantly improving the production efficiency, with controllable costs, and reducing the generation of three wastes;

[0029] 3. This method uses an inexpensive catalyst, significantly improving the reaction rate, shortening the cycle by more than half, avoiding the use of high pressure and excessive single amount of ammonia, reducing the three wastes, and having good economy. Description of the Drawings

[0030] The drawings are used to provide a further understanding of the present invention and constitute a part of the specification. Together with the embodiments of the present invention, they are used to explain the present invention and do not constitute a limitation to the present invention. In the drawings:

[0031] Figure 1 is the overall reaction route diagram of this solution;

[0032] Figure 2 This is the reaction roadmap for Step 1 of the solution;

[0033] Figure 3 This is the reaction roadmap for Step 2 of the solution;

[0034] Figure 4 This is the reaction roadmap for Step 3 of the solution;

[0035] Figure 5 This is the reaction roadmap for Step 4 of the solution. Detailed implementation method

[0036] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. 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 creative efforts belong to the scope of protection of the present invention.

[0037] Embodiment

[0038] As Figure 1 shown, an industrial production method for a key intermediate of nirmatrelvir specifically includes the following steps:

[0039] Refer to Figure 2 , Step 1, add 160 g of tetrahydrofuran (C 4 H 8 O) to reaction flask 1, and then add 20 g of tert-butoxycarbonyl-L-glutamic acid dimethyl ester (C 12 H 21 O 6 N), and cool down to -85 to -80 °C;

[0040] Press 130 g of lithium bis(trimethylsilyl)amide with argon (C 6 H 18 LiNSi 2 ) into reaction flask 2, and cool down to -85 °C to -80 °C. After the temperature of reaction flask 2 is lowered, drip lithium bis(trimethylsilyl)amide with argon (C 6 H 18 LiNSi 2 ) into reaction flask 1;

[0041] Then add 60 g of tetrahydrofuran (C 4 H 8 O), 10 g of bromoacetonitrile (C 2 H 2 BrN) to reaction flask 3, and cool down to -85 °C to -80 °C. After the temperature of reaction flask 3 is lowered, drip the solution in reaction flask 3 into reaction flask 1;

[0042] The reaction was terminated using glacial acetic acid (C 2 H 4 O 2 ). After warming back to room temperature, it was quenched into brine and extracted with ethyl acetate (C 4 H 8 O 2 ). After concentration, dimethyl (2S,4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)pentanedioate (C 14 H 22 O 6 N 2 ) was obtained with a yield of 21 kg, a purity of ≥80%, and a recovery rate of 92.1%;

[0043] See Figure 3 , Step 2. Charge 21 g of dimethyl (2S,4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)pentanedioate (C 14 H 22 O 6 N 2 ) into an autoclave, then add 200 g of methanol (CH 4 O), 2 g of Raney nickel as a catalyst, 6 g of 10% ammonia in methanol. After purging with nitrogen and hydrogen (H 2 ), the temperature was raised to 40 - 50 °C and hydrogenation was carried out for 8 h until the reaction ended. After filtration and concentration, the product was dissolved in methyl tert-butyl ether (C 5 H 12 O) and crystallized. After filtration and drying, 16.2 g of methyl (S)-2-(Boc-amino)-3-[(S)-2-oxo-3-pyrrolidinyl]propionate (C 13 H 22 O 5 N 2 ) was obtained with a yield of 85% and a purity of ≥98%;

[0044] See Figure 4 , Step 3. Add 16.2 g of methyl (S)-2-(Boc-amino)-3-[(S)-2-oxo-3-pyrrolidinyl]propionate (C 13 H 22 O 5 N 2 ) to Reaction Flask 4, add 162 g of methanol (CH 4 O), 3 g of ammonia gas (NH 3 ), and 0.16 g of DMAP (4-dimethylaminopyridine (C 7 H 10 N 2 ). Heat to 25 - 35 °C and react for 1 h until the reaction ends. After concentration, N-Boc-α-amino-2-oxo-3-pyrrolidinepropanamide (C12 H 21 O 4 N 3 ) 15.3 g, purity ≥ 98%, yield 100%;

[0045] See Figure 5 , Step 4, add 30 g of methanol and 75 g of ethyl acetate (C 4 H 8 O 2 ) to reaction flask 5, then add 15.3 g of compound N-Boc-α-amino-2-oxo-3-pyrrolidinepropanamide (C 12 H 21 O 4 N 3 ), dropwise add 12.7 g of ethyl acetate solution of hydrogen chloride (concentration 13%), control the temperature at 25 - 35 °C and react for 5 h. After completion, cool down to crystallize, filter, wash with methanol, filter and dry to obtain 10.4 g of compound α-amino-2-oxo-3-pyrrolidinepropanamide hydrochloride (C 7 H 14 O 2 ClN 3 ), purity 99.8%, yield 90%.

[0046] Compared with the prior art, the reaction route of this solution is reliable, easy to realize industrial production, the reagents used have low cost, the obtained product has high yield and high purity, and the product quality can meet the subsequent requirements.

[0047] Although the embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions and variations can be made therein without departing from the principles and spirit of the present invention, and the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. An industrial production method for a key intermediate of Namatevir, characterized in that: The steps include: Step 1: Add tetrahydrofuran and then tert-butyloxycarbonyl-L-glutamic acid dimethyl ester to reaction bottle 1, and precool to -65 to -100°C; Lithium bistrimethylsilylamide is pressed into reaction bottle 2 with argon gas, precooled to -65 to -100°C, and then lithium bistrimethylsilylamide is dripped into reaction bottle 1 with argon gas; Then, tetrahydrofuran and bromoacetonitrile were added to reaction bottle 3, precooled to -65 to -100°C, and then the solution in reaction bottle 3 was dripped into reaction bottle 1; After the reaction was completed, glacial acetic acid was used to terminate the reaction, the mixture was warmed to room temperature, quenched into brine, extracted with ethyl acetate, and concentrated to obtain the compound (2S,4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)pentanedioic acid dimethyl ester; Step 2: Add compound (2S, 4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)pentanedioic acid dimethyl ester into the autoclave, then add methanol and catalyst, add ammonia methanol, replace with nitrogen and hydrogen, heat to 40-50°C and hydrogenate for 8h until the reaction is completed, filter, concentrate, crystallize the methyl tert-butyl ether solution, filter and dry to obtain 16.2g of compound (S)-2-(Boc-amino)-3-[(S)-2-oxo-3-pyrrolidinyl]propionic acid methyl ester; Step 3, add compound (S)-2-(Boc-amino)-3-[(S)-2-oxo-3-pyrrolidino]propionic acid methyl ester to reaction bottle 4, add methanol, add ammonia, add DMAP, heat to 25-35°C and react for 1 hour, and concentrate to obtain compound N-Boc-α-amino-2-oxo-3-pyrrolidinopropionamide; Step 4, add methanol and ethyl acetate to the reaction bottle 5, then add the compound N-Boc-α-amino-2-oxo-3-pyrrolidinepropionamide, add hydrogen chloride ethyl acetate solution dropwise, control the temperature at 25-35°C to react for 5 hours, cool and crystallize, filter, slurry with methanol, filter and dry to obtain the compound α-amino-2-oxo-3-pyrrolidinepropionamide hydrochloride.

2. The industrial production method of a key intermediate of Namatevir according to claim 1, characterized in that: In step 1, the pre-cooling temperature in reaction bottle 1, reaction bottle 2 and reaction bottle 3 is preferably -80--85°C.

3. The industrial production method of a key intermediate of Namatevir according to claim 1, characterized in that: In step 1, in reaction bottle 1, the weight amount of tetrahydrofuran is 160 parts, and the weight amount of tert-butyloxycarbonyl-L-glutamic acid dimethyl ester is 20 parts; In reaction bottle 2, the weight amount of argon gas for lithium bis(trimethylsilylamide) is 130 parts; In reaction bottle 3, the weight amount of tetrahydrofuran is 60 parts, and the weight amount of bromoacetonitrile is 10 parts; The solution was concentrated to give 21 parts by weight of dimethyl (2S,4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)pentanedioate.

4. The industrial production method of a key intermediate of Namatevir according to claim 1, characterized in that: In step 2, the weight amount of dimethyl (2S, 4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)pentanedioate is 21 parts; The amount of methanol by weight is 200 parts; The catalyst weight portion is 2 parts; The amount of ammonia methanol by weight is 6 parts; The weight of the compound (S)-2-(Boc-amino)-3-[(S)-2-oxo-3-pyrrolidinyl]propionic acid methyl ester was 16.2 parts by weight.

5. The industrial production method of a key intermediate of Namatevir according to claim 1, characterized in that: Step 3, in reaction bottle 4: The weight amount of the compound (S)-2-(Boc-amino)-3-[(S)-2-oxo-3-pyrrolidinyl]propionic acid methyl ester is 16.2 parts; The amount of methanol by weight is 162 parts; The amount of ammonia by weight is 3 parts; The weight portion of DMAP is 0.16 parts; The weight parts of the compound N-Boc-α-amino-2-oxo-3-pyrrolidinepropionamide produced were 15.3 parts.

6. The industrial production method of a key intermediate of Namatevir according to claim 4, characterized in that: In step 2, the catalyst is Raney nickel; The amount of Raney nickel used is 0.1 times that of the compound (2S,4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)pentanedioic acid dimethyl ester.

7. The industrial production method of a key intermediate of Namatevir according to claim 1, characterized in that: Step 4, in reaction bottle 5: The amount of methanol by weight is 30 parts; The weight portion of ethyl acetate is 75 parts; The weight amount of N-Boc-α-amino-2-oxo-3-pyrrolidine propionamide is 15.3 parts; The weight portion of hydrogen chloride ethyl acetate solution is 12.7 parts; The weight parts of the compound α-amino-2-oxo-3-pyrrolidinepropionamide hydrochloride produced were 10.4 parts.

8. The industrial production method of a key intermediate of Namatevir according to claim 7, characterized in that: In step 4, the concentration of the hydrogen chloride ethyl acetate solution is 13%.

9. The industrial production method of a key intermediate of Namatevir according to claim 1, characterized in that: In step 2, the concentration of ammonia methanol is 10%.

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