A method for the solid phase preparation of nirmatrelvir
By using a solid-phase synthesis method and treating it with amide resin and a dehydrating agent, the synthesis steps of nematradil were simplified, the yield and purity were improved, the problem of complicated operation in existing liquid-phase synthesis was solved, and large-scale production was realized.
Patent Information
- Application Number
- CN202210489078.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2022-05-07
- Publication Date
- 2025-11-21
- Estimated Expiration
- 2042-05-07
AI Technical Summary
Existing methods for the liquid-phase synthesis of nematriberi are complex to operate, with frequent deprotection and purification steps resulting in long synthesis cycles, low yields, and high costs, making it difficult to achieve large-scale production.
Using amide resin as a solid-phase support, solid-phase coupling reaction was carried out using Fmoc-T12-OH, Fmoc-SM1-OH, and Tfa-SM2-OH as starting materials. Combined with pyrolysis and dehydration agent treatment, the synthesis steps were simplified and the yield and purity were improved.
The synthesis process has been simplified, production costs have been reduced, and this is conducive to the large-scale industrial production of nematoside.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the field of synthesis of new coronal drugs, in particular to a method for preparing nirmatrelvir by solid phase TECHNICAL BACKGROUND
[0002] Paxlovid, a new coronavirus treatment drug of Pfizer. This product is an oral small molecule new coronavirus treatment drug, which is used for treating adult patients with mild to moderate new coronavirus infection (COVID-19) with high risk factors for developing severe illness, such as patients with high risk factors for developing severe illness, such as high age, chronic kidney disease, diabetes, cardiovascular disease, chronic lung disease, etc. On December 22, 2021, the U.S. Food and Drug Administration approved Paxlovid for marketing.
[0003] Nirmatrelvir is one of the active ingredients of Paxlovid (nirmatrelvir tablets / ritonavir tablets combination), a specific drug for treating adult patients with mild to moderate new coronavirus infection (COVID-19) with high risk factors for developing severe illness, and its chemical name is: (1R, 2S, 5S)-N-((1S)-1-oxyl-2-((3S)-2-oxyl-pyrrolidine-3-yl]ethyl)-3-((2S)-3(3-dimethyl-2-yl 2,2-trifluoroacetyl) amide acetyl) 6-dimethyl-diazabicyclo [3.0] hexane-2-carboxamide, and its structural formula is:
[0004]
[0005] Patent US20220062232 provides a synthetic route thereof:
[0006]
[0007]
[0008] In this synthetic route, SM1, SM2 and T13 are used as starting materials, and 7-step liquid phase synthesis is adopted to obtain the target product. In the above synthesis method, the operation process is complicated, frequent deprotection, deprotection and purification, the synthesis cycle is long, and the production investment is large.
[0009] The present inventors found that the purity and yield of the existing synthesis method in the process of preparing nirmatrelvir are not high, the production cost is high, and the subsequent treatment is complicated, and it is difficult to realize the synthesis automation and large-scale production. Therefore, the present inventors have carried out research on the updating and improvement of the synthesis method of nirmatrelvir, and thus obtained the technical scheme of the present application. SUMMARY
[0010] The application aims to provide a method for preparing nirmatrelvir by solid phase.
[0011] To achieve the above-mentioned application purposes, the application provides the following technical solutions.
[0012] A method for preparing nirmatrelvir by solid phase comprises the following steps:
[0013] (a) using an amide resin as a solid phase carrier, and coupling Fmoc-T12-OH as a raw material to prepare Fmoc-T12-amide resin, and then sequentially coupling Fmoc-SM1-OH and Tfa-SM2-OH to obtain a nirmatrelvir precursor resin;
[0014] (b) cleaving the nirmatrelvir precursor resin to obtain a nirmatrelvir precursor;
[0015] (c) treating the nirmatrelvir precursor with a dehydrating agent to obtain a crude nirmatrelvir product; and recrystallizing and drying the crude nirmatrelvir product to obtain fine nirmatrelvir.
[0016] Preferably, the specific operation steps of step (a) are as follows: the solid phase carrier amide resin is Rink amide resin, Rink amide-AM resin, Sieber Amide resin or Rink amide-MBHA resin with a substitution degree of 0.2-0.9 mmol / g; the resin is coupled with Fmoc-T12-OH to obtain Fmoc-T12-amide resin; after removing the Fmoc protection, 1.5-3 times the feeding ratio of the corresponding Fmoc-SM1-OH and Tfa-SM2-OH is added for coupling reaction; each coupling reaction is a solid phase peptide reaction in the presence of a condensing agent; each coupling reaction is detected by Kaiser reagent to determine the reaction end point; after the reaction is completed, the Fmoc is removed by a deprotection reagent, and then coupled with the next starting material; the operation is repeated until the nirmatrelvir precursor resin Tfe-SM2-SM1-T12-amide resin is synthesized.
[0017] The deprotection reagent is preferably 20% (volume ratio) piperidine in DMF; the condensing agent used in the coupling reaction is one of the following combinations: DIC / HOBT, DIC / HOAT, TBTU / HOBT / DIPEA, HBTU / HOBT / DIPEA and HATU / HOAT / DIPEA; the structures of Fmoc-T12-OH, Fmoc-SM1-OH and Tfa-SM2-OH are as follows:
[0018]
[0019] Preferably, in step (b), the cleavage reagent is a TFA solution with a volume ratio of 1-5% scavenger, which is one or more of anisole, thioanisole, phenol, water and TIS; more preferably, the cleavage reagent is TFA / thioanisole / water / TIS = 90 / 2.5 / 5.0 / 2.5.
[0020] The structure of the nirmatrelvir precursor is Tfe-SM2-SM1-T12-NH2:
[0021]
[0022] Preferably, in step (c), the dehydrating agent is one or more of Burgess Reagent, TFAA-alkaline reagent, EtOPOCl2 / DBU; the alkaline reagent is one or more of triethylamine, pyridine, DMAP, 2,6-lutidine.
[0023] More preferably, in step (c), when the dehydrating agent is Burgess Reagent, the specific operation steps are as follows: nirmatrelvir precursor and dichloromethane are added to a reactor, then Burgess Reagent (1 eq-2 eq) is added, the reaction is stirred at room temperature, the reaction is monitored by HPLC until it reaches the end point, water is slowly added to terminate the reaction, the organic phase is washed with saturated aqueous ammonium chloride and water three times respectively, then dried and distilled under reduced pressure to obtain the crude product, which is recrystallized in ethyl acetate / methyl tert-butyl ether to obtain the product.
[0024]
[0025] More preferably, in step (c), when the dehydrating agent is TFAA-alkaline reagent, the specific operation steps are as follows: nirmatrelvir precursor and dichloromethane are added to a reactor, then triethylamine (4 eq-6 eq) is added to the reactor, after stirring, TFAA (2-3 eq) is added dropwise in an ice water bath, the reaction is stirred at room temperature, the reaction is monitored by HPLC until it reaches the end point, water is slowly added to terminate the reaction, the organic phase is washed with saturated brine and water three times respectively, then dried and distilled under reduced pressure to obtain the crude product, which is recrystallized in ethyl acetate / methyl tert-butyl ether to obtain the product.
[0026] More preferably, when the dehydrating agent in step (c) is EtOPOCl2 / DBU reagent, the specific operation steps are as follows: adding the nimitaprevir precursor and dichloromethane into a reactor, then adding DBU (2 eq-3 eq) into the reactor, stirring uniformly, then adding EtOPOCl2 (2-3 eq) dropwise in an ice water bath, stirring the reaction at room temperature, monitoring the reaction end point by HPLC, slowly adding water to terminate the reaction, washing the organic phase with saturated aqueous ammonium chloride solution and water respectively three times, then drying and distilling under reduced pressure to obtain the crude product, recrystallizing in ethyl acetate / methyl tert-butyl ether to obtain the product.
[0027] The beneficial effects of the present application relative to the prior art are:
[0028] The present application first uses Fmoc-T12-OH, Fmoc-SM1-OH and Tfa-SM2-OH as starting materials to synthesize nimitaprevir by solid phase synthesis, simplifies the cumbersome crystallization and purification steps in liquid phase synthesis, can obtain nimitaprevir by repeating the solid phase deprotection, washing, coupling and washing operation steps, reduces the equipment investment, and is conducive to the large-scale production of nimitaprevir. DETAILED DESCRIPTION
[0029] The present application will be described in detail below with specific examples, but is not limited to the patent; according to the present application, changing the feeding ratio of raw materials, or reaction solvents and condensing agents, etc. are all within the protection scope of the present application.
[0030] The meanings of the abbreviations used in the specification and claims are as follows:
[0031]
[0032] Example 1: Synthesis of nimitaprevir precursor resin
[0033] The present example provides a synthesis process of nimitaprevir precursor resin, which is specifically as follows:
[0034] Accurately weigh Rink amide AM-resins with substitution degree of 0.89 mmol / g 2247 g (synthesis scale 2.0 mol) into a 50 L reaction kettle, add 20 L DCM to swell for 30 min; after the DCM is filtered out, wash twice with 20 L DMF, add 20% piperidine / DMF solution 20 L to deprotect twice, wash 6 times with 20 L DMF; add Fmoc-T12-OH 1577.7 g (4.0 mol), 594 g (4.4 mol) HOBT and 700 ml (4.4 mol) DIC in DMF solution 20 L, stir and react under N2for 2 h, and the reaction end point is determined by Kaiser reagent; after the reaction reaches the end point, the reaction solution is removed (Fmoc-T12-OH is recovered), and 20 L DMF, DCM and DMF are used for washing twice, respectively, and stand by.
[0035] Add 20% piperidine / DMF solution 20 L to deprotect twice, wash 6 times with 20 L DMF; add Fmoc-SM1-OH 1509.8 g (4.0 mol), 594 g (4.4 mol) HOBT and 700 ml (4.4 mol) DIC in DMF solution 20 L, stir and react under N2for 2 h, and the reaction end point is determined by Kaiser reagent; after the reaction reaches the end point, the reaction solution is removed (Fmoc-SM1-OH is recovered), and 20 L DMF, DCM and DMF are used for washing twice, respectively, and stand by.
[0036] Add 20% piperidine / DMF solution 20 L to deprotect twice, wash 6 times with 20 L DMF; add Tfa-SM2-OH 900.8 g (4.0 mol), 594 g (4.4 mol) HOBT and 700 ml (4.4 mol) DIC in DMF solution 20 L, stir and react under N2for 2 h, and the reaction end point is determined by Kaiser reagent; after the reaction reaches the end point, the reaction solution is removed (Fmoc-SM1-OH is recovered), and 20 L DMF, DCM and methanol are used for washing 3 times, respectively, and then vacuum dried to obtain nirmatrelvir precursor resin 2839.8 g.
[0037] Example 2: Synthesis of nirmatrelvir precursor resin
[0038] This example provides another synthesis process of nirmatrelvir precursor resin, which is as follows:
[0039] Accurately weigh Rink amide resins with a substitution degree of 0.92 mmol / g, 2174 g (synthesis scale 2.0 mol) into a 50 L reaction kettle, add 20 L DCM and swell for 30 min; after the DCM is filtered out, wash twice with 20 L DMF, add 20% piperidine / DMF solution 20 L and deprotect twice, wash 6 times with 20 L DMF; add Fmoc-T12-OH 1577.7 g (4.0 mol), 594 g (4.4 mol) HOBT and 700 ml (4.4 mol) DIC in DMF solution 20 L, stir under N2 for 2 h, and the reaction end point is determined by Kaiser reagent test result, after the reaction reaches the end point, the reaction liquid is removed (Fmoc-T12-OH is recovered), and 20 L DMF, DCM and DMF are washed twice respectively, and stand by.
[0040] Add 20% piperidine / DMF solution 20 L and deprotect twice, wash 6 times with 20 L DMF; add Fmoc-SM1-OH 1509.8 g (4.0 mol), 594 g (4.4 mol) HOBT and 700 ml (4.4 mol) DIC in DMF solution 20 L, stir under N2 for 2 h, and the reaction end point is determined by Kaiser reagent test result, after the reaction reaches the end point, the reaction liquid is removed (Fmoc-SM1-OH is recovered), and 20 L DMF, DCM and DMF are washed twice respectively, and stand by.
[0041] Add 20% piperidine / DMF solution 20 L and deprotect twice, wash 6 times with 20 L DMF; add Tfa-SM2-OH 900.8 g (4.0 mol), 594 g (4.4 mol) HOBT and 700 ml (4.4 mol) DIC in DMF solution 20 L, stir under N2 for 2 h, and the reaction end point is determined by Kaiser reagent test result, after the reaction reaches the end point, the reaction liquid is removed (Fmoc-SM1-OH is recovered), and 20 L DMF, DCM and methanol are washed 3 times respectively, and after vacuum drying, obtain 2767.2 g of nirmatrelvir precursor resin.
[0042] Example 3: Preparation of nirmatrelvir precursor
[0043] This example is based on the preparation of nirmatrelvir precursor in the preceding example 1:
[0044] Take the obtained nirmatrelvir precursor resin 2830 g in Example 1 and add it to the frozen 12 L lysis solution (volume ratio of TFA / TIS / H2O = 95 / 2.5 / 2.5), stir the reaction at room temperature for 2 h; after the lysis reaction is completed, filter the resin, wash the resin with 2 L of TFA twice, combine the filtrate and the washing liquid, pour into 160 L of frozen methyl tert-butyl ether, and precipitate white sediment; after standing for 60 min, centrifugal separation, wash with methyl tert-butyl ether for 6 times, and vacuum dry to obtain the crude product 1020.2 g, with a crude peptide yield of 98.9% and a purity of 98.2%.
[0045] Example 4: Preparation of nirmatrelvir precursor
[0046] This example is based on the previous Example 2, and the preparation of nirmatrelvir precursor is as follows:
[0047] Take the obtained nirmatrelvir precursor resin 2830 g in Example 1 and add it to the frozen 12 L lysis solution (volume ratio of TFA / TIS / H2O = 95 / 2.5 / 2.5), stir the reaction at room temperature for 2 h; after the lysis reaction is completed, filter the resin, wash the resin with 2 L of TFA twice, combine the filtrate and the washing liquid, pour into 160 L of frozen methyl tert-butyl ether, and precipitate white sediment; after standing for 60 min, centrifugal separation, wash with methyl tert-butyl ether for 6 times, and vacuum dry to obtain the crude product 1020.2 g, with a crude peptide yield of 98.9% and a purity of 98.2%.
[0048] Example 5: Preparation of nirmatrelvir
[0049] This example provides a preparation process of nirmatrelvir, and the specific steps are as follows:
[0050] In a 20 L reaction kettle, add nirmatrelvir precursor 1000 g and dichloromethane 20 L, then slowly add Burgess Reagent 717.9 g (3 mol), stir the reaction at room temperature for 2 h, monitor the reaction endpoint by HPLC, slowly add 1000 ml of water to terminate the reaction, wash the organic phase with 4 L of saturated ammonium chloride aqueous solution and water respectively three times, then dry and distill under reduced pressure to obtain the crude product, then add 2 L of ethyl acetate to redissolve, filter out the insoluble matter, slowly add 38 L of methyl tert-butyl ether to crystallize, filter, vacuum dry to obtain the product 735.5 g, with a purity of 99.2% and a yield of 76.2%.
[0051] Example 6: Preparation of nirmatrelvir
[0052] This example provides a preparation process of nirmatrelvir, and the specific steps are as follows:
[0053] In a 20 L reaction kettle, 500 g of the nimitaprevir precursor and 10 L of dichloromethane were added, then 358.9 g (1.5 mol) of triethylamine was slowly added at low temperature 0°C, then 358.9 g (1.5 mol) of triethylamine was slowly added, and 420 g (2.0 mol) of TFFA was slowly added at low temperature 0°C. After the dropwise addition was completed, the reaction was stirred at room temperature for 2 h. HPLC monitoring showed that the reaction reached the end point. 500 ml of water was slowly added to terminate the reaction. The organic phase was washed with 2 L of saturated ammonium chloride aqueous solution and water three times, then dried and distilled under reduced pressure to obtain the crude product. Then 1 L of ethyl acetate was added to dissolve it. After the insoluble matter was filtered out, 19 L of methyl tert-butyl ether was slowly added for crystallization. After filtration and vacuum drying, 369.7 g of product was obtained with a purity of 99.1% and a yield of 76.6%.
[0054] Example 7: Preparation of nimitaprevir
[0055] This example provides a preparation process of nimitaprevir, and the specific steps are as follows:
[0056] In a 20 L reaction kettle, 500 g of the nimitaprevir precursor and 10 L of dichloromethane were added, then 358.9 g (1.5 mol) of triethylamine was slowly added at low temperature 0°C, then 358.9 g (1.5 mol) of triethylamine was slowly added, and 420 g (2.0 mol) of TFFA was slowly added at low temperature 0°C. After the dropwise addition was completed, the reaction was stirred at room temperature for 2 h. HPLC monitoring showed that the reaction reached the end point. 500 ml of water was slowly added to terminate the reaction. The organic phase was washed with 2 L of saturated ammonium chloride aqueous solution and water three times, then dried and distilled under reduced pressure to obtain the crude product. Then 1 L of ethyl acetate was added to dissolve it. After the insoluble matter was filtered out, 19 L of methyl tert-butyl ether was slowly added for crystallization. After filtration and vacuum drying, 369.7 g of product was obtained with a purity of 99.1% and a yield of 76.6%.
Claims
1. A method for solid-phase preparation of nermatevi, characterized in that, Includes the following steps: (a) Using amide resin as solid support and Fmoc-T12-OH as raw material, Fmoc-T12-amide resin was prepared by coupling reaction in the presence of condensing agent. Then, it was sequentially coupled with Fmoc-SM1-OH and Tfa-SM2-OH to obtain nematribe precursor resin. (b) Nematovir precursor resin was pyrolyzed to obtain nematovir precursor; (c) The nematetravir precursor was treated with a dehydrating agent to obtain crude nematetravir; the crude product was recrystallized and dried to obtain refined nematetravir. In step (a), the solid-phase carrier amide resin is a Rink amide resin with a substitution degree of 0.2-0.9 mmol / g.
2. The method for solid-phase preparation of nematradiate according to claim 1, characterized in that: The Rink amide resin is Rink amide-AM resin.
3. The method for solid-phase preparation of nermatevi according to claim 1, characterized in that: The condensing agent mentioned in step (a) is one of the following combinations: DIC / HOBT, DIC / HOAT, TBTU / HOBT / DIPEA, HBTU / HOBT / DIPEA, and HATU / HOAT / DIPEA.
4. The method for solid-phase preparation of nermatevi according to claim 1, characterized in that: In step (b), the lysis reagent is a TFA solution containing 1-5% by volume of a scavenging agent, wherein the scavenging agent is one or more of anisole, anisole sulfide, phenol, water, and TIS.
5. The method for solid-phase preparation of nermatevi according to claim 4, characterized in that: The ratio of lysis reagent in step (b) is: TFA / water / TIS = 95 / 2.5 / 2.
5.
6. The method for solid-phase preparation of nermatevi according to claim 1, characterized in that: In step (c), the dehydrating agent is one or more of Burgess Reagent, TFAA-alkaline reagent, and EtOPOCl2 / DBU.
7. The method for solid-phase preparation of nermatevi according to claim 6, characterized in that: In step (c), the alkaline reagents are triethylamine, pyridine, and DMAP.
8. The method for solid-phase preparation of nermatevi according to claim 7, characterized in that: The pyridine is 2,6-dimethylpyridine.
9. The method for solid-phase preparation of nermatevi according to claim 6, characterized in that: In step (c), when the dehydrating agent is Burgess Reagent, the specific operating steps are as follows: add nemateviprogenitor and dichloromethane to the reactor, then add Burgess Reagent 1eq-2eq, stir the reaction at room temperature, monitor the reaction until the endpoint is reached by HPLC, slowly add water to terminate the reaction, wash the organic phase three times with saturated ammonium chloride aqueous solution and water, then dry and distill under reduced pressure to obtain the crude product, recrystallize in ethyl acetate / methyl tert-butyl ether to obtain the product.
10. A method for solid-phase preparation of nermatevi according to claim 6, characterized in that: In step (c), when the dehydrating agent is TFAA-alkaline reagent, the specific operating steps are as follows: add nematradine precursor and dichloromethane to the reactor, then add 4 eq-6 eq of alkaline reagent to the reactor, stir evenly, add 2-3 eq of TFAA dropwise in an ice-water bath, stir the reaction at room temperature, monitor the reaction to the endpoint by HPLC, slowly add water to terminate the reaction, wash the organic phase three times with saturated brine and water, then dry and distill under reduced pressure to obtain crude product, recrystallize in ethyl acetate / methyl tert-butyl ether to obtain the product.
11. The method for solid-phase preparation of nermatevi according to claim 6, characterized in that: In step (c), when the dehydrating agent is EtOPOCl2 / DBU reagent, the specific operating steps are as follows: add nematevisc precursor and dichloromethane to the reactor, then add DBU2eq-3eq to the reactor, stir evenly, add EtOPOCl22-3eq dropwise in an ice-water bath, stir the reaction at room temperature, monitor the reaction to reach the endpoint by HPLC, slowly add water to terminate the reaction, wash the organic phase three times with saturated ammonium chloride aqueous solution and water, then dry and distill under reduced pressure to obtain crude product, recrystallize in ethyl acetate / methyl tert-butyl ether to obtain the product.
Citation Information
Patent Citations
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CN114409727A