A preparation method of nirmatrelvir intermediate

Abstract

The present invention relates to the field of chemical drug synthesis, and specifically discloses a preparation method of a nirmatrelvir intermediate, which comprises the following steps: (1) The raw material (2S,4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)dimethyl glutarate is subjected to a reduction cyclization reaction under the action of a potassium borohydride / cobalt chloride system, and then undergoes post-treatments such as extraction washing, concentration and recrystallization to obtain compound (Ⅱ); (2) An ammonolysis reaction is carried out at a relatively low temperature in an ammonia methanol solution, and then filtration is carried out to prepare an isopropanol solution of compound (Ⅲ); (3) Acetyl chloride is dropped into isopropanol to prepare an isopropanol solution of hydrogen chloride, and compound (Ⅲ) is added to the prepared isopropanol solution of hydrogen chloride. A deprotection and salt formation reaction is carried out at a low temperature, and the product precipitates. Filtration and drying are carried out to obtain a high-purity finished compound (Ⅳ), which is the nirmatrelvir intermediate.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical intermediates, and specifically discloses a preparation method of a nirmatrelvir intermediate. Background Art

[0002] In the reaction path of the prior art, 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 and methanol are used at 80 °C, and the amount of ammonia and methanol used is more than 100 equivalents; Chinese Patent CN114230504 reports the reaction in an ammonia water and methanol system, the amount of ammonia water used is 20 to 100 equivalents, and the reaction temperature is 150 °C.

[0003] In the deprotection and salt formation reaction step, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid, etc. are mostly used and then converted into hydrochloride. Not only is the yield of the finished product low, but the acids used are prone to residue and cannot be completely converted into hydrochloride. Summary of the Invention

[0004] In view of the above problems, the present invention 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 increase the methyl tert-butyl ether and n-heptane recrystallization system, which is more suitable for the requirements of large-scale industrial production.

[0005] The inventor first proposes a method for preparing a nirmatrelvir intermediate, including,

[0006] , the alcoholic solution of compound (I) undergoes a reduction cyclization reaction in the presence of cobalt chloride hexahydrate / potassium borohydride to obtain compound (II), as shown in formula (A),

[0007]

[0008] Compound (II) is used as a reaction substrate and is synthesized into nirmatrelvir intermediate compound (IV) in one or more steps

[0009]

[0010] In some embodiments, for the step of synthesizing compound (II) from compound (I), the step further includes,

[0011] Step 1: Distill the solution of compound (II), add ethyl acetate and dilute hydrochloric acid to the residue, and adjust the pH.

[0012] Step 2: Extract and distill.

[0013] Step 3: Add one or more of methyl tert-butyl ether, ethyl acetate, and propyl acetate, and one or more of n-heptane, n-hexane, cyclohexane, and cyclopentane to the residue of Step 2, reflux to dissolve, cool down to precipitate solids, and obtain Compound (II).

[0014] In some embodiments, for the step of synthesizing Compound (II) from Compound (I), Compound (I) is synthesized into Compound (II) in an inert gas atmosphere, and / or the inert gas atmosphere is any one or a combination of nitrogen and argon, and / or cobalt chloride is added at -5 to 5 °C, preferably at 0 °C, and / or potassium borohydride is added at 25 to 30 °C, preferably at 25 °C.

[0015] In some embodiments, in the step of synthesizing Compound (II) from Compound (I), the concentration of the dilute hydrochloric acid added is 14 to 17% by mass, preferably 16.6%, and / or the distillation method is vacuum distillation, and / or the extraction is triple extraction.

[0016] In some embodiments, for the step of synthesizing Compound (II) from Compound (I), the molar ratio of Compound (I) to potassium borohydride in the feed is 1:4 to 1:6, preferably 1:4 to 1:5, particularly preferably 1:4, and / or the molar ratio of Compound (I) to cobalt chloride hexahydrate in the feed is 4:1 to 1:1, preferably 4:1 to 2:1, particularly preferably 2:1, and / or the mass fraction of the methanol solution of Compound (I) is 5 to 15%, preferably 10%.

[0017] In some embodiments, for the step of synthesizing Compound (III) from Compound (II), it includes

[0018] , Compound (II) is catalytically ammonolyzed in an alcoholic solution of ammonia to obtain Compound (III), as shown in Formula (B),

[0019]

[0020] In some embodiments, for the step of synthesizing Compound (III) from Compound (II), the reaction temperature for preparing Compound (III) from Compound (II) is 45 to 65 °C, preferably 50 to 55 °C, particularly preferably 55 °C, and / or the reaction time for preparing Compound (III) from Compound (II) is 1 to 3 hours, preferably 2 hours, and / or the concentration of the alcoholic solution of ammonia is 20 to 30 mol / L, preferably 29.4 mol / L, and / or the alcohol in the alcoholic solution of ammonia is selected from one or more of methanol, ethanol, and isopropanol.

[0021] In some embodiments, for the step of synthesizing compound (III) from compound (II), the catalyst for preparing compound (III) from compound (II) is molecular sieve, and / or the molecular sieve is 3A molecular sieve, and / or the mass ratio of the molecular sieve to the charged compound (II) is 1:20 to 1:10, preferably 1:10.

[0022] In some embodiments, for the step of synthesizing compound (IV) from compound (III), it includes

[0023] , compound (III) is mixed with an alcoholic solution of hydrogen chloride to deprotect and form a salt, obtaining compound (IV), as shown in formula (C),

[0024] In some embodiments, for the step of synthesizing compound (IV) from compound (III), the alcoholic solution of hydrogen chloride is prepared by adding acetyl chloride to alcohol to obtain the alcoholic solution of hydrogen chloride, and / or the alcohol is selected from any one or more of methanol, ethanol or isopropanol, and / or the concentration of the alcoholic solution of hydrogen chloride is 1.0 mol / L to 1.5 mol / L, preferably 1.28 mol / L.

[0025] Term definition:

[0026] In the foregoing text herein, all the numbers disclosed herein are approximate values, whether or not the words "about" or "approximate" are used. Based on the disclosed numbers, the numerical value of each number may have a difference of less than ±10% or a reasonable difference considered by those skilled in the art, such as a difference of ±1%, ±2%, ±3%, ±4% or ±5%.

[0027] The term "and / or" should be understood to mean any one of the options or a combination of any two or more of the options.

[0028] The term "wt%" refers to mass percentage.

[0029] The term "%vol" represents volume percentage.

[0030] To enable those skilled in the art to better understand the technical solutions herein, some non-limiting embodiments are further disclosed below for further detailed description of this article. All the reagents used herein can be purchased from the market or can be prepared by the methods described in this application. The term "rpm" represents the rotational speed "revolutions per minute"; "℃" represents the temperature unit "degree Celsius"; "L" represents the volume unit "liter"; "mL" represents the volume unit "milliliter"; "pH" represents the acidity and alkalinity; "g" represents the mass unit "gram"; "Mpa" represents the pressure unit "megapascal", and room temperature is defined as -5 to 45℃.

[0031] The reagents used in the present invention are all purchased from the publicly legal market and have not been further purified and optimized.

[0032] Advantages of the present invention:

[0033] (1) In the reduction cyclization step, potassium borohydride is used instead of sodium borohydride. The reaction process is milder and more controllable, with a higher conversion rate. A methyl tert-butyl ether and n-heptane recrystallization system is added to separate out the solid intermediate. The product purity is significantly improved.

[0034] (2) A catalyst is added to the ammonolysis reaction, greatly reducing the reaction time, reducing the amount of ammonia methanol solution used, and the reaction conditions are milder and the safety is higher.

[0035] (3) For deprotection, hydrogen chloride solution is prepared by reacting acetyl chloride with alcohol for deprotection and salt formation reactions. The reaction reagents are more stable and easily available.

[0036] (4) This synthesis method greatly reduces the production cost, improves the production capacity, and is more suitable for large-scale industrial production requirements. Description of the drawings

[0037] Figure 1 HPLC chart of the compound (IV) synthesized in Example 2 of the present invention Detailed implementation manners

[0038] Preparation of compound (II) from compound (I):

[0039]

[0040] Step 1: Under a nitrogen and argon atmosphere, compound (I) is dissolved in methanol to prepare a methanol solution of compound (I) with a mass fraction of 5-15%.

[0041] Cobalt chloride is added at a temperature of -5 to 5 °C. The molar ratio of compound (I) to cobalt chloride hexahydrate is 4:1 to 1:1. Potassium borohydride is added at 25 to 30 °C. The molar ratio of compound (I) to potassium borohydride is 1:4 to 1:6. After the reaction is completed, vacuum distillation is carried out. The residue is added with ethyl acetate and dilute hydrochloric acid with a concentration mass fraction of 14-17%, and the pH is adjusted to 5-8.

[0042] Step 2: Let it stand for layering. The aqueous layer is extracted with ethyl acetate, propyl acetate, or propyl formate, washed with any one of 20-30% sodium chloride solution or sodium carbonate solution, dried, filtered, and distilled.

[0043] Step 3: Add one or more of methyl tert-butyl ether, ethyl acetate, and propyl acetate, and one or more of n-heptane, n-hexane, cyclohexane, and cyclopentane to the residue of Step 2, reflux to dissolve, cool to 35 - 40 °C to precipitate a solid, filter, and dry to obtain a white solid powder compound (II).

[0044] Preparation of compound (III) from compound (II):

[0045]

[0046] Step 1: 3A molecular sieve and compound (II) with a mass ratio of 1:20 - 1:10 are ammonolyzed in an ammonia methanol solution with a mass fraction of 10% - 14% to obtain an alcohol solution of compound (III) with a mass fraction of 18% - 27%.

[0047] Preparation of nirmatrelvir intermediate compound (IV) from compound (III):

[0048] Step 1: Add acetyl chloride to any one of methanol, ethanol, and isopropanol to obtain an alcohol solution of hydrogen chloride.

[0049] Step 2: Dissolve compound (III) in the alcohol solution described in Step 1, react at 45 - 65 °C for 1 - 3 hours, deprotect and precipitate as a salt, filter, and dry under reduced pressure at 50 °C to obtain compound (IV).

[0050]

[0051] The following is an illustration with specific examples:

[0052] Example 1:

[0053] Preparation of compound (II) from compound (I):

[0054]

[0055] Under nitrogen protection, add 100g (0.32mol) of (2S,4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)pentanedioic acid dimethyl ester compound (Ⅰ) (CAS No.: 328086-57-3) and 1000.0g of methanol to the reaction flask, stir and cool to 0℃. Add 7.9g (0.16mol) of cobalt chloride hexahydrate and stir to dissolve. Then keep the temperature at 0~10℃, add 68.8g (1.28mol) of potassium borohydride in batches, keep the temperature and stir for 20 minutes. Heat to 25~30℃, stir and react for 15 hours, take samples for central control, TLC or HPLC, the raw material reaction is complete. Control the temperature to less than 45℃ and distill under reduced pressure until there is no fraction. Add 800 ml of ethyl acetate to the residue, cool to 15°C, control the temperature below 20°C, add 154.8 g of dilute hydrochloric acid dissolved in 774 g of water, adjust the pH to 5-6, keep warm and stir for 1 hour, re-measure the pH to 5-6, and the system turns wine red. Let stand to separate, add 400 ml of ethyl acetate to the water layer and extract again. Combine the organic phases, wash with a sodium bicarbonate solution prepared by dissolving 20 g of sodium bicarbonate in 380 g of water and (100 g of sodium chloride dissolved in 300 g of water) sodium chloride, dry with 30 g of anhydrous sodium sulfate, filter, and distill the filtrate under reduced pressure until there is no fraction, to obtain 125.19 g of crude compound (II).

[0056] Purification of crude compound (II):

[0057] The residue was added with 250 mL of methyl tert-butyl ether and 100 mL of n-heptane, heated to 55°C and refluxed to dissolve, cooled to 35-40°C to precipitate a solid, and then cooled to 5-10°C and stirred for 1 hour, filtered, and the wet product was dried under reduced pressure at 45°C to obtain 84.86.0 g of compound (II) as a white solid powder, with a yield of 93.1% and a purity of >90%.

[0058] Preparation of compound (III) from compound (II):

[0059]

[0060] Add 50.0 g (about 0.17 mol) of compound (II), 5.0 g of 3A molecular sieve and about 365 mL (about 7 mol) of ammonia methanol solution into the reaction bottle, stir and react at room temperature for 7 hours, take a sample to detect the completion of the reaction of compound (II). Filter the system, wash the filter cake with methanol, combine the filtrate, and distill under reduced pressure until there is no fraction, to obtain 47.0 g of compound (III), with a yield of 99%.

[0061] Preparation of compound (IV) from compound (III):

[0062]

[0063] Add 200 ml of isopropanol to the reaction flask, add 20.0 g of acetyl chloride dropwise with stirring in an ice-water bath, keep warm and stir after the addition to obtain a hydrogen chloride solution. Dissolve 47.0 g of about 0.17 mol of compound (III) in 200 ml of isopropanol solution and add it to the above hydrogen chloride solution. Raise the temperature to 50°C for reaction for 2 hours, and take a sample to detect whether the reaction of compound (III) is complete. Stir at room temperature for 1 hour, filter with suction, rinse with isopropanol, and dry the solid wet product under reduced pressure at 50°C to obtain 35 g of compound (IV), which is the finished product of namatevir intermediate (yield 96.7%, purity >98%)

[0064] Embodiment 2:

[0065] Preparation of compound (II) from compound (I):

[0066]

[0067] Under nitrogen protection, add 400.0 kg of (2S, 4R)-2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)pentanedioic acid dimethyl ester compound (Ⅰ) and 4000 kg of methanol to the reaction flask, stir and cool to 0°C. Add 151.6 kg of cobalt chloride hexahydrate and stir to dissolve. Then keep the temperature at 0-10°C, add 275.2 kg of potassium borohydride in batches, keep the temperature and stir for 20 minutes. Heat to 25-30°C, stir and react for 15 hours, take samples for central control, TLC or HPLC, and the raw materials react completely.

[0068] The temperature was controlled to be less than 45°C, and the mixture was distilled under reduced pressure until no fraction was found. 2880.0 kg of ethyl acetate was added to the residue, the temperature was lowered to 15°C, and the temperature was controlled to be less than 20°C. Dilute hydrochloric acid with a mass fraction of 16.6% was added dropwise, and the pH was adjusted to 5-6. The mixture was stirred for 1 hour at room temperature, and the pH was re-measured to be 5-6. The system turned to wine red. The mixture was allowed to stand for stratification, and 1440 kg of ethyl acetate was added to the aqueous layer for extraction and stratification. The organic phases were combined, washed with 5 w% aqueous sodium bicarbonate solution and 25 w% brine in turn, dried with 120 kg of anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure until no fraction was found.

[0069] The residue was added with 700 kg of ethyl acetate and 280 kg of n-hexane, heated to 55 °C and refluxed to dissolve, cooled to 35-40 °C to precipitate solid, and continued to cool to 5-10 °C and stirred for 1 hour, filtered, and the wet product was dried under reduced pressure at 45 °C to obtain 342.2 kg of the compound as a white solid powder with a yield of 94.1% and a purity of >90%.

[0070] Preparation of compound (III) from compound (II):

[0071]

[0072] Add 3650 kg of methanol to the reaction kettle, start stirring to cool down, and introduce 500 kg of liquid ammonia through the bottom to obtain an ammonia-methanol solution; then add 500 kg of compound (II) and 50 kg of 3A molecular sieve, stir and react at room temperature for 7 hours, take a sample, and detect by HPLC that the peak area of compound (II) < 0.5%. The system is filtered through a filter press, and the filtrate is transferred to the concentration kettle. Wash the reaction kettle and the filter press with methanol. The filtrates are combined and transferred to the concentration kettle. Below 50 °C, distill under reduced pressure until there is no distillate, add 1500 kg of isopropanol, and stir to dissolve to obtain an isopropanol solution of compound (III).

[0073] Preparation of compound (IV) from compound (III):

[0074]

[0075] Add 1500 kg of isopropanol to the reaction kettle, stir to cool down. Keep the temperature below 15 °C and dropwise add 200 kg of acetyl chloride. After the addition is complete, keep stirring to obtain a hydrogen chloride solution. Add the isopropanol solution of compound (III) from the previous step to the reaction kettle. Heat up and react for 2 - 3 hours, take a sample, and detect by HPLC that the peak area of compound (IV) < 0.5%. Cool down and stir for 1 hour, discharge the material to a centrifuge for centrifugation, wash the reaction kettle and the filter cake with isopropanol, and dry the solid wet product under reduced pressure at 45 - 50 °C to obtain 355 kg of compound (IV), which is the finished product of nirmatrelvir intermediate. Calculate the yield to be 98.0% and the purity > 98.9%. See the HPLC detection for details Figure 1 。

[0076] Comparative Example 1:

[0077] Take 125 g of the crude product of compound (II) prepared in Example 1 above for purification:

[0078] Add the crude product of compound (II) to any one of 350 mL of toluene, DMF, and acetone, heat up to 55 °C and reflux to dissolve, cool down to 35 - 40 °C to precipitate solids, continue to cool down to 5 - 10 °C and stir for 1 hour, filter, and dry the wet product under reduced pressure at 45 °C to obtain white solid powder of compound (II). The results are shown in Table 1

[0079] Table 1

[0080]

[0081] For the purification of compound (II), compared with traditional solvents such as toluene, DMF, and acetone, the mixed recrystallization system of methyl tert-butyl ether, ethyl acetate, propyl acetate, n-heptane, n-hexane, cyclohexane, and cyclopentane adopted in the present invention can effectively reduce the ring-opening phenomenon of compound (II), as shown in formula (D).

[0082]

[0083] The method of the present application has been described through preferred embodiments. It is obvious that relevant personnel can make changes, appropriate modifications and combinations to the methods and applications described herein within the content, spirit and scope of the present application to implement and apply the technology of the present application. Those skilled in the art can draw on the content of this article and appropriately improve the process parameters to achieve it. It should be particularly noted that all such similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present application.

Claims

1. A method for synthesizing nirmatrelvir intermediate, comprising ， Step 1: , in the presence of cobalt(II) chloride hexahydrate / potassium borohydride, the alcoholic solution of compound (I) undergoes a reductive cyclization reaction to obtain a solution of compound (II), as shown in formula (C). ； Step 1: Distill the solution of the compound (II), add ethyl acetate and dilute hydrochloric acid to the first residue, and adjust the pH; Step 2: Extract and distill; Step 3: The second residue obtained in Step 2; The second residue is added to a mixed solvent, and the mixed solvent is selected from a mixed solvent of methyl tert-butyl ether and n-heptane, or a mixed solvent of ethyl acetate and n-hexane, or a mixed solvent of propyl acetate and cyclopentane, reflux and dissolve, cool down to precipitate a solid, and obtain the solid of the compound (II); Step 2: , compound (II) is catalytically ammonolyzed in an alcoholic solution of ammonia under the action of a catalyst to obtain compound (III), as shown in formula (B). ； The catalyst is 3A molecular sieve; The compound (III) is used as a reaction substrate and is synthesized into the nirmatrelvir intermediate compound (IV) in one step or multiple steps; 。 2. The synthesis method according to claim 1, characterized in that, The compound (I) is synthesized into the compound (II) in an inert gas atmosphere, and the inert gas atmosphere is any one or a combination of nitrogen and argon. The cobalt chloride is added at -5 to 5 °C, and the potassium borohydride is added at 25 to 30 °C.

3. The synthesis method according to claim 2, characterized in that, The concentration mass fraction of the added dilute hydrochloric acid is 14 to 17%, the distillation method is vacuum distillation, and the extraction is ternary extraction.

4. The synthesis method according to claim 1, characterized in that, The molar ratio of the compound (I) to potassium borohydride in the feed is 1:4 to 1:6, the molar ratio of the compound (I) to cobalt chloride hexahydrate in the feed is 4:1 to 1:1, the alcohol solution of the compound (I) is the methanol solution of the compound (I), and the mass fraction of the methanol solution of the compound (I) is 5 to 15%.

5. The synthesis method according to claim 1, characterized in that, The reaction temperature for preparing the compound (III) from the compound (II) is 45 to 65 °C.

6. The synthesis method according to claim 1, characterized in that, The reaction temperature for preparing the compound (III) from the compound (II) is 50 to 55 °C.

7. The synthesis method according to claim 1, characterized in that, The reaction time for preparing the compound (III) from the compound (II) is 1 to 3 hours.

8. The synthesis method according to claim 1, characterized in that, The concentration of the ammonia alcohol solution is 20 to 30 mol / L.

9. The synthesis method according to claim 1, characterized in that, The concentration of the ammonia alcohol solution is 29.4 mol / L.

10. The synthesis method according to claim 1, characterized in that, The alcohol in the ammonia alcohol solution is selected from one or more of methanol, ethanol, and isopropanol.

11. The synthesis method according to claim 1, characterized in that, The mass ratio of the molecular sieve to the compound (II) in the feed is 1:20 to 1:

10.

12. The synthesis method according to claim 1, characterized in that, The mass ratio of the molecular sieve to the compound (II) in the feed is 1:

10.

13. The synthesis method according to claim 1, characterized in that, including, , acetyl chloride is added to an alcohol to obtain an alcoholic solution of hydrogen chloride. Compound (III) is mixed with the alcoholic solution of hydrogen chloride to obtain Compound (IV), as shown in Formula (C). 。 14. The synthesis method according to claim 13, characterized in that, The alcohol is selected from any one or more of methanol, ethanol, or isopropanol, and the concentration of the hydrogen chloride alcohol solution is 1.0 mol / L to 1.5 mol / L.

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