Preparation process of key intermediate of nemategravir raw material medicine

Abstract

The invention discloses a nemategravir bulk drug key intermediate preparation process, which comprises: 1, dissolving a compound I in an organic solvent under nitrogen protection, introducing ammonia gas, carrying out a heating reaction at a temperature of 35-40 DEG C, carrying out HPLC monitoring on the reaction, and after the reaction is detected, separating the product to obtain a compound II; and 2, dissolving the compound II in an organic solvent, adding an alkali reagent, adding a catalyst, reacting in an ice bath at 0 DEG C for 10-12 hours, and separating a product after the reaction is finished to obtain a compound III. The method has the beneficial effects that the reaction route is simple to operate, the reaction raw materials are easy to obtain, the product yield is high, the reaction route is short, the method is suitable for industrial expanded-scale production, the generation of pollutants is effectively reduced, and the post-treatment difficulty and time of the product are reduced.

Description

Technical Field

[0001] The present invention relates to the technical field related to pharmaceutical synthesis, and in particular to a process for preparing a key intermediate of a Namatevir raw material drug. Background Art

[0002] Nirmatrelvir, chemical name: (1R,2S,5S)-N-[(1S)-1-cyano-2-(2-oxo-pyrrolidin-3-yl)ethyl]-3-[(S)-3,3-dimethyl-2-(trifluoroacetamido)butyryl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-amide; the structural formula is as follows:

[0003]

[0004] The original research company Pfizer Pharmaceuticals reported the synthesis route and method of Nirmatrelvir in Science (2021 Dec 24; 374 (6575): 1586-1593). The total yield of the product Nirmatrelvir was 50.11%. The synthesis route is as follows:

[0005] Route 1

[0006]

[0007] The following is an optimized preparation route for preparing Namatevir, using caron anhydride as raw material, through optimizing the process route, replacing excipients, and optimizing the process, the Namatevir API is finally prepared: Route 2

[0008]

[0009] The intermediate compound C in the above preparation route is one of the key intermediate raw materials for the synthesis of Nirmatrelvir, and is mainly used to construct the pyrrolidone core structure in the Nirmatrelvir molecule. In Pfizer's early route, bromoacetonitrile was used to introduce a cyano group, which was reduced by high-pressure hydrogenation (palladium-carbon catalyst) to generate an amine intermediate, and then a cyclization reaction was performed to form a pyrrolidone structure. The reaction steps were many, and the reaction used many dangerous or expensive reagents. The production cost was high and the product yield was extremely low. In addition, many by-products were generated and there were different degrees of racemic products, resulting in a low final yield. Summary of the Invention

[0010] Aiming at the deficiencies of the above reaction route, the present invention aims to provide a preparation process for a key intermediate of nirmatrelvir raw material drug, effectively reducing the reaction steps, optimizing the reaction process, introducing a cyano group and a chiral structure through the method of Schiff base chiral synthesis to introduce a cyano group, effectively improving the selectivity of the reaction, reducing the production cost in production, and reducing the generation of by-products and waste. The technical solution of the present invention is as follows:

[0011] A preparation process for a key intermediate of nirmatrelvir raw material drug, comprising the following steps:

[0012] A preparation process for a key intermediate of nirmatrelvir raw material drug, including the following steps:

[0013]

[0014] In the first step, under nitrogen protection, dissolve compound I in an organic solvent, introduce ammonia gas, heat and react at 35-40 °C, monitor the progress of the reaction by HPLC, and after detecting the end of the reaction, separate the product to obtain compound II;

[0015] In the second step, dissolve compound II in an organic solvent, add a base reagent, add a catalyst, and react at 0 °C in an ice bath, monitor the progress of the reaction by HPLC, and after detecting the end of the reaction, separate the product after the reaction ends to obtain compound IV;

[0016] Further, the solvent used in the first-step reaction is one of dichloromethane, chloroform, and benzene.

[0017] Further, the solvent used in the second-step reaction is DMSO or DMF.

[0018] Further, the base reagent used in the second-step reaction is triethylamine.

[0019] Further, the cyanation reagent in the second-step reaction is methyl thiocyanate MeSCN.

[0020] Further, the heating temperature of the first-step reaction is 35-40 °C.

[0021] Further, the catalyst used in the second-step reaction is L-proline.

[0022] Further, the dosage of the catalyst used in the second-step reaction is 3-8 mol% of compound II.

[0023] Further, the dosage of the base reagent of the reactant in the second-step reaction is 2-3 eq of compound II.

[0024] Further, the molar ratio of the reactants in the second-step reaction is compound II: cyanation reagent = 1: 1.0-2.0.

[0025] The beneficial effects of the present invention are as follows: 1. The reaction route of the present invention has fewer reaction steps, the reaction raw materials are easily available, and the reaction process is simple, which is suitable for industrial large-scale production; 2. The reaction route of the present invention is easy to operate, reduces the difficulty and time of post-treatment of the product, and can effectively improve the selectivity of the reaction, further reducing the production cost in production and reducing the generation of by-products and waste. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 It is a schematic structural diagram of nirmatrelvir of the present invention;

[0027] Figure 2 It is a process flow chart of the preparation process of Route 1 of nirmatrelvir of the present invention;

[0028] Figure 3 It is a process flow chart of the preparation process of Route 2 of nirmatrelvir of the present invention;

[0029] Figure 4 It is a schematic diagram of the process flow of the preparation process of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0030] 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 making creative efforts fall within the protection scope of the present invention.

[0031] Example 1

[0032] In the first step, under nitrogen protection, 12.7 g (0.1 mol) of compound I was dissolved in 300 ml of the organic solvent dichloromethane, ammonia gas was slowly introduced, and the reaction was heated at 35-40 °C. The progress of the reaction was monitored by HPLC. When the content of the reactant compound I was detected to be less than 1% wt of the dosage, the reaction was terminated. The solvent was evaporated, and the product was recrystallized with 50 ml of toluene to obtain 12.0 g of compound II, with a yield of 95.2% and a purity of 98.3%;

[0033] In the second step, 12.6 g (0.1 mol) of compound III was dissolved in 250 ml of the organic solvent anhydrous DMSO, 0.2 mol of the base reagent triethylamine was added, 0.005 mol / L of L-proline as the catalyst was added, 0.1 mol of the cyanide reagent methyl thiocyanate MeSCN was added, and 0.1 mol of anhydrous sodium sulfate as the desiccant was added. The reaction was carried out in an ice bath at 0 °C. The progress of the reaction was monitored by HPLC. After the reaction was detected to be completed, brine was added for washing, dichloromethane was added for extraction, the organic phase was separated, distilled under reduced pressure at low temperature, and vacuum dried. The product was recrystallized with 50 ml of toluene to obtain 14.5 g of compound IV, with a yield of 94.7% and a purity of 98.6%;

[0034] Example 2

[0035] Step 1: Under nitrogen protection, dissolve 12.7 g (0.1 mol) of Compound I in 300 ml of the organic solvent chloroform, slowly introduce ammonia gas, heat and react at 35 - 40 °C, monitor the progress of the reaction by HPLC, when the content of the reactant Compound I is lower than 1% wt of the dosage, end the reaction, evaporate the solvent, and recrystallize the product with 50 ml of toluene to obtain 11.8 g of Compound II, with a yield of 93.6% and a purity of 97.8%.

[0036] Example 3

[0037] Step 2: Dissolve 12.6 g (0.1 mol) of Compound III in 250 ml of the organic solvent anhydrous DMSO, add 0.2 mol of the base reagent triethylamine, add 0.01 mol of the catalyst L - proline, add 0.1 mol of the cyanation reagent methyl thiocyanate MeSCN, add 0.1 mol of the drying agent anhydrous sodium sulfate, react at 0 °C in an ice - water bath, monitor the progress of the reaction by HPLC, after detecting the end of the reaction, filter, wash with saturated brine, add dichloromethane for extraction, separate the organic phase, distill under reduced pressure at low temperature, dry in vacuo, and recrystallize the product with 50 ml of toluene to obtain 14.6 g of Compound IV, with a yield of 95.4% and a purity of 98.5%;

[0038] Example 4

[0039] Step 2: Dissolve 12.6 g (0.1 mol) of Compound III in 250 ml of the organic solvent anhydrous DMSO, add 0.3 mol of the base reagent triethylamine, add 0.005 mol of the catalyst L - proline, add 0.1 mol of the cyanation reagent methyl thiocyanate MeSCN, add 0.1 mol of the drying agent anhydrous sodium sulfate, react at 0 °C in an ice - water bath, monitor the progress of the reaction by HPLC, after detecting the end of the reaction, filter, wash with saturated brine, add dichloromethane for extraction, separate the organic phase, distill under reduced pressure at low temperature, dry in vacuo, and recrystallize the product with 50 ml of toluene to obtain 14.45 g of Compound IV, with a yield of 94.1% and a purity of 98.3%;

[0040] Example 5

[0041] Step 2: Dissolve 12.6 g (0.1 mol) of Compound III in 250 ml of anhydrous DMSO, an organic solvent. Add 0.2 mol of the base reagent triethylamine, 0.005 mol of the catalyst L-proline, 0.2 mol of the cyanation reagent methyl thiocyanate (MeSCN), and 0.1 mol of the desiccant anhydrous sodium sulfate. React under an ice-water bath at 0 °C, monitor the progress of the reaction by HPLC. After detecting the end of the reaction, filter, wash with saturated brine, extract with dichloromethane, separate the organic phase, distill under reduced pressure at low temperature, and dry in vacuo. Recrystallize the product with 50 ml of toluene to obtain 14.6 g of Compound IV, with a yield of 95.4% and a purity of 98.0%.

[0042] For those skilled in the art, it is obvious that the present invention is not limited to the details of the above exemplary embodiments, and the present invention can be implemented in other specific forms without departing from the spirit or basic characteristics of the present invention. Therefore, from any point of view, the embodiments should be regarded as exemplary and non-restrictive. The scope of the present invention is defined by the appended claims rather than the above description. Therefore, all changes falling within the meaning and scope of the equivalent elements of the claims are intended to be embraced within the present invention. Any reference signs in the claims should not be regarded as limiting the claims involved.

[0043] In addition, it should be understood that although this specification is described according to embodiments, not every embodiment only contains an independent technical solution. This narrative way of the specification is only for clarity. Those skilled in the art should regard the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A preparation process for a key intermediate of nirmatrelvir API, characterized in that It includes the following steps: In the first step, under nitrogen protection, dissolve Compound I in an organic solvent, introduce ammonia gas, heat and react at 35 - 40 °C, monitor the progress of the reaction by HPLC. After detecting the end of the reaction, separate the product to obtain Compound II; In the second step, dissolve Compound II in an organic solvent, add a base reagent and a catalyst, react at 0 °C in an ice bath, monitor the progress of the reaction by HPLC. After detecting the end of the reaction, separate the product to obtain Compound III.

2. The preparation process of a key intermediate of nirmatrelvir raw material medicine according to claim 1, characterized in that: The solvent used in the first step reaction is one of dichloromethane, chloroform, and benzene.

3. The preparation process of a key intermediate of nirmatrelvir API according to claim 1, characterized in that: The solvent used in the second step reaction is DMSO or DMF.

4. The preparation process of a key intermediate of nirmatrelvir raw material drug according to claim 1, characterized in that: The base reagent used in the second step reaction is triethylamine.

5. The preparation process of a key intermediate of nirmatrelvir raw material drug according to claim 1, characterized in that: The cyanating reagent in the second step reaction is methyl thiocyanate MeSCN.

6. A process for preparing a key intermediate of nirmatrelvir API according to claim 1, characterized in that: The heating temperature of the first step reaction is 35 - 40 °C.

7. The preparation process of a key intermediate of nirmatrelvir raw material drug according to claim 1, characterized in that: The catalyst used in the second step reaction is L-proline.

8. A preparation process for a key intermediate of nirmatrelvir API, characterized in that: The dosage of the catalyst used in the second step reaction is 3 - 8 mol% of Compound II.

9. The preparation process of a key intermediate of nirmatrelvir API according to claim 1, characterized in that: The dosage of the base reagent of the reactants in the second step reaction is 2 - 3 eq of Compound II.

10. A preparation process for a key intermediate of nirmatrelvir API, characterized in that: The molar ratio of the reactants in the second step reaction is Compound II: cyanating reagent = 1: 1.0 - 2.0.

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