CN114437043B - Preparation method of anti-new crown drug Nirmatrelvir - Google Patents
Preparation method of anti-new crown drug Nirmatrelvir Download PDFInfo
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- CN114437043B CN114437043B CN202210115087.1A CN202210115087A CN114437043B CN 114437043 B CN114437043 B CN 114437043B CN 202210115087 A CN202210115087 A CN 202210115087A CN 114437043 B CN114437043 B CN 114437043B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a preparation method of an anti-neocrown drug Nirmatrelvir (compound I). The preparation method is cheap and easily available trifluoroacetyl-L-tertiary leucine (compound II) is used as a starting material, and Nirmatrelvir can be obtained through a plurality of steps of reactions. The invention has the advantages of simple and reliable process, low comprehensive cost, easy commercial production and the like.
Description
Technical Field
The invention belongs to the field of pharmaceutical synthetic chemistry, and particularly relates to a preparation method of an anti-neocrown drug Nirmatrelvir.
Background
The chemical name of Nirmatrelvir is (1 r,2S, 5S) -N- [ (1S) -1-cyano-2- [ (3S) -2-oxo-3-pyrrolidinyl ] ethyl ] -3- [ (2S) -3, 3-dimethyl-1-oxo-2- [ (2, 2-trifluoroacetyl) amino ] butyl ] -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxamide, the chemical structure of which is shown below:
the current data for the synthesis of Nirmatrelvir is very limited and only one method for synthesizing compound I has been reported by the original J.M.in Science impurity (Science 2021,374,1586-1593). The method takes Boc-L-tertiary leucine as a starting material, and obtains methyl tertiary ether solvate of Nirmatrelvir through 6 steps of reactions such as condensation, hydrolysis, removal of Boc protecting group, trifluoroacetylation, condensation, dehydration of a Bogis reagent and the like, and finally obtains anhydrous crystal form 1 of Nirmatrelvir through crystallization. Overall, this route, although partially in high yields, requires column chromatography separation and purification in the first step and the use of air/moisture sensitive bergs reagents, greatly limits commercial production of this route. The route is specifically as follows:
considering the great use of Nirmatrelvir in resisting new coronaries, it is important to develop a Nirmatrelvir synthesis route which is simple and reliable in route, simple and reliable in process, low in comprehensive cost and suitable for industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of Nirmatrelvir (compound I) with simple and reliable process and easy commercial production.
The synthetic route of the invention is as follows:
the invention comprises the following steps:
1) And (3) reacting the compound II with the compound III under the action of a condensing agent to obtain a compound IV.
2) And (3) carrying out hydrogenolysis reaction on the compound IV under the action of a catalyst to obtain a compound V.
3) And (3) carrying out condensation/dehydration reaction on the compound V and the compound VI under a condensing agent to obtain a compound I.
The condensing agent in step 1) is carbodiimide condensing agent such as DCC and EDC · HCl, one of onium salt condensing agents such as HATU, HBTU, and T3P (tripropylphosphoric anhydride);
further, in the step 1), the molar ratio of the compound II to the condensing agent is 1:1-1:5.
Further, the temperature of the condensation reaction in step 1) is-20 to 50 ℃.
Further, in the step 1), the molar ratio of the compound II to the compound III is 2:1-1:2.
The catalyst in the step 2) is one of palladium/carbon, palladium hydroxide/carbon, platinum/carbon, ruthenium/carbon and rhodium/carbon.
Further, the weight ratio of the catalyst to the compound IV in the step 2) is 1:20 to 1:1000.
Further, the temperature of the hydrogenolysis reaction in step 2) is 20 to 80 ℃.
The condensing agent in step 3) is carbodiimide condensing agent such as DCC, EDC · HCl, onium salt condensing agents such as HATU, HBTU and PyBOP, and T 3 One of P (tripropyl phosphoric anhydride);
further, in step 3), the molar ratio of the compound V to the condensing agent is 1:1 to 1:5.
Further, the condensation reaction temperature is reduced in step 3) to-10 ℃ to 80 ℃.
Further, the molar ratio of compound V to compound VI in step 3) is from 2:1 to 1:2.
Compared with the prior art, the invention has the following remarkable advantages:
1) The invention directly adopts the trifluoroacetyl-L-tertiary leucine as a chiral source, realizes the high-selectivity condensation of the compound IV, can crystallize and remove process impurities, avoids the defect of column chromatography, and is more beneficial to industrialization;
2) The invention adopts catalytic hydrogenation to remove benzyl, has high yield and less process impurities, and is favorable for meeting the requirement of API on purity;
3) Because the method has short steps, the three wastes are greatly reduced, and the whole preparation process is more environment-friendly;
4) The invention has simple and reliable process and low comprehensive production cost, thus having good market competitiveness.
Detailed Description
The invention will be further illustrated with reference to specific examples. It should be noted that these examples are only for illustrating the present invention and are not to be construed as limiting the scope of the present invention, and the scope of the above-described subject matter of the present invention should not be construed as being limited to the following examples. All techniques implemented based on the above description of the invention are within the scope of the invention.
Example 1
Preparation of Compound IV
454g of Compound II, 564g of Compound III and 774g of diisopropylethylamine were dissolved in 2L of ethyl acetate, and 1650g of 50% T was added dropwise with stirring at room temperature 3 The P/ethyl acetate solution was stirred at 45℃until the reaction was complete (HPLC control), cooled, quenched with 300mL of water and separated. The organic phase was washed with dilute hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product obtained was recrystallized from methyl tertiary ether/n-heptane to give 837g of compound IV in 92% yield and 99.0% purity by HPLC.
1 H NMR(DMSO-d6,400MHz)δ9.48(s,1H),7.40-7.24(m,5H),5.17(s,2H),4.42(s,1H),4.29(s,1H),3.88-3.84(m,1H),3.74(d,J＝10.5Hz,1H),1.60-1.53(m,1H),1.45(d,J＝7.5Hz,1H),0.96(s,9H),0.83(s,6H)；
HRMS(ESI):m/z calcd for C 23 H 29 F 3 N 2 O 4 [M+H] + 455.2152,found:455.2157.
Example 2
Preparation of Compound IV
227g of compound II, 282g of compound III and 260g of diisopropylethylamine were dissolved in 1.5L of DMF and stirred to reduce the temperature to 0℃and then 420g of HATU were added and stirred at 25℃for 12 hours. 2L of water and 2L of methyl tertiary ether were added, and the mixture was stirred to separate the liquid. The aqueous phase was extracted once more with 2L of methyl tertiary ether. The combined organic phases were washed with 200mL of 1N hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained is recrystallized from isopropyl acetate/heptane to give 428g of compound IV in 94% yield and 98.8% purity by HPLC.
Example 3
Preparation of Compound IV
227g of Compound II, 282g of Compound III, 164g of 1-hydroxy-7-azabenzotriazol (HOAT) and 260g of diisopropylethylamine were dissolved in 1.5L of dichloromethane, and the mixture was stirred and cooled to 0℃and then 187g of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (EDCI) was added thereto, followed by stirring at 25℃for 16 hours. 1L of water is added for quenching reaction, and the solution is separated. The organic phase was washed with dilute hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product obtained is recrystallized from isopropyl acetate/heptane to give 405g of compound IV in 89% yield with 98.7% purity by HPLC.
Example 4
Preparation of Compound V
909g of compound IV is dissolved in 5L of ethyl acetate, 10g of 5% palladium/carbon catalyst is added, hydrogenolysis reaction (1.0 Mpa pressure) is carried out under 25 ℃ hydrogen atmosphere, after the reaction is finished, the palladium/carbon catalyst is recovered by suction filtration, and the filtrate is concentrated to dryness under reduced pressure. The crude product is recrystallized by ethyl acetate/n-heptane and dried to obtain 714 compound V with the yield of 98% and the HPLC purity of 99.2%.
1 H NMR(DMSO-d6,400MHz)δ12.73(s,1H),9.43(d,J＝8.5Hz,1H),4.42(d,J＝8.5Hz,1H),4.13(s,1H),3.83(dd,J＝10.5,5.3Hz,1H),3.70(d,J＝10.5Hz,1H),1.51(dd,J＝7.5,5.1Hz,1H),1.41(d,J＝7.6Hz,1H),0.99(d,J＝2.8Hz,12H),0.82(s,3H)；
HRMS(ESI):m/z calcd for C 16 H 23 F 3 N 2 O 4 [M+H] + 365.1683,found:365.1681.
Example 5
Preparation of Compound V
455g of compound IV is dissolved in 3L of tetrahydrofuran, 10g of 5% palladium hydroxide/carbon catalyst is added, hydrogenolysis reaction (1.0 Mpa pressure) is carried out under 45 ℃ hydrogen atmosphere, after the reaction is finished, the palladium hydroxide/carbon catalyst is recovered by suction filtration, and the filtrate is concentrated to dryness under reduced pressure. The crude product was recrystallized from ethyl acetate/n-heptane and dried to give 353 compound V in 97% yield and 99.1% purity by HPLC.
Example 6
Preparation of Compound V
455g of compound IV is dissolved in 3L of methanol, 20g of 10% ruthenium/carbon catalyst is added, hydrogenolysis reaction (2.0 Mpa pressure) is carried out under 45 ℃ hydrogen atmosphere, after the reaction is finished, the ruthenium/carbon catalyst is recovered by suction filtration, and the filtrate is concentrated to dryness under reduced pressure. The crude product was recrystallized from ethyl acetate/n-heptane and dried to give 353 compound V in 97% yield and 99.2% purity by HPLC.
Example 7
Preparation of Compound V
455g of compound IV is dissolved in 3L of methanol, 10g of 5% rhodium/carbon catalyst is added, hydrogenolysis reaction (2.0 Mpa pressure) is carried out under 45 ℃ hydrogen atmosphere, after the reaction is finished, the rhodium/carbon catalyst is recovered by suction filtration, and the filtrate is concentrated to dryness under reduced pressure. The crude product was recrystallized from ethyl acetate/n-heptane and dried to give 353 compound V in 96% yield with 99.2% HPLC purity.
Example 8
Preparation of Compound I
364g of compound V, 207g of compound VI, 164g of 1-hydroxy-7-azabenzotriazole (HOAT) and 260g of diisopropylethylamine were dissolved in 3L of dichloromethane, stirred and cooled to 0℃and then 187g of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (EDCI) were added and stirred for 16 hours at 25 ℃. Cooling to 0 ℃, dropwise adding 500mL of water, stirring for 1h, and separating. The organic phase was washed with dilute acid, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was recrystallized from isopropyl acetate/n-heptane to give 459.5g of compound I in 92% yield and 99.4% purity by HPLC.
1 H NMR(DMSO-d6,400MHz)δ9.46(d,J＝8.0Hz,1H),9.05(d,J＝8.6Hz,1H),7.71(s,1H),4.98(ddd,J＝11.0,8.5,5.0Hz,1H),4.42(d,J＝8.1Hz,1H),4.16(s,1H),3.92(dd,J＝10.4,5.5Hz,1H),3.70(d,J＝10.4Hz,1H),3.15(t,J＝9.1Hz,1H),3.04(td,J＝9.4,7.1Hz,1H),2.46-2.33(m,1H),2.21-2.01(m,2H),1.77-1.65(m,2H),1.58(dd,J＝7.6,5.4Hz,1H),1.33(d,J＝7.6Hz,1H),1.03(s,3H),0.99(s,9H),0.86(s,3H)；
HRMS(ESI):m/z calcd for C 23 H 32 F 3 N 5 O 4 [M+H + ]500.2479,found:500.2476.
Example 9
Preparation of Compound I
182g of compound V, 104g of compound VI and 260g of diisopropylethylamine were dissolved in 1L of ethyl acetate and 50% T was added dropwise with stirring at 0 ℃ 3 Ethyl P acetate solution (500 g), stirring for 5 hours at 45 ℃. Cooling to 0 ℃, dropwise adding 300mL of water, stirring for 1h, and separating. The organic phase was washed with dilute acid, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was recrystallized from methyl tertiary ether/n-heptane to give 207.4g of compound I in 83% yield with HPLC purity of more than 99%.
Example 10
Preparation of Compound I
182g of compound V, 104g of compound VI and 260g of diisopropylethylamine were dissolved in 2L of dichloromethane, 420g of HATU were added with stirring at 0℃and stirring at 25℃for 12 hours. Cooling to 0 ℃, dropwise adding 300mL of water, stirring for 1h, and separating. The organic phase was washed with dilute acid, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Recrystallisation of the crude product from ethyl acetate/isooctane gives 212.3g of compound I in 85% yield with HPLC purity greater than 99%.
The foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of the invention should be assessed as that of the appended claims.
Claims (2)
1. The preparation method of the anti-neocrown drug Nirmatrelvir (compound I) is characterized by comprising the following steps:
1) The compound II reacts with the compound III under the action of a condensing agent to obtain a compound IV; the condensing agent in the step 1) is a carbodiimide condensing agent, an onium salt condensing agent or T 3 One or more of P (tripropylphosphoric anhydride); the molar ratio of the compound II to the condensing agent is 1:1-1:5; the condensation reaction temperature is between 20 ℃ below zero and 50 ℃; the molar ratio of the compound II to the compound III is 2:1-1:2;
2) The compound IV undergoes hydrogenolysis reaction under the action of a catalyst to obtain a compound V: step 2) the catalyst is selected from palladium on carbon, palladium hydroxide on carbon, platinum on carbon, ruthenium on carbon or rhodium on carbon; the weight ratio of the catalyst to the compound IV is 1:20-1:1000; the temperature of the hydrogenolysis reaction is 20-80 ℃;
3) The compound V and the compound VI undergo condensation reaction under the condensing agent to obtain a compound I: the condensing agent in the step 3) is a carbodiimide condensing agent, an onium salt condensing agent or T 3 One or more of P (tripropylphosphoric anhydride); the molar ratio of the compound V to the condensing agent is 1:1-1:5, and the reaction temperature is-10-100 ℃; the molar ratio of the compound V to the compound VI is 2:1-1:2;
2. the process for the preparation of compound I according to claim 1, wherein the carbodiimide condensing agent is selected from DCC or EDC +.hcl and the onium salt condensing agent is selected from HATU, HBTU or PyBOP.
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