CN114133350A - Preparation method of anti-neocorolla drug Paxlovid intermediate - Google Patents
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Abstract
The invention discloses a preparation method of a new crown resistant drug Paxlovid intermediate. The preparation method takes N-Boc-trans-4-hydroxy-L-proline methyl ester (compound II) which is cheap and easy to obtain as an initial raw material, and the Paxlovid intermediate can be obtained through reaction in a plurality of steps, wherein the structural formula of the anti-corona drug Paxlovid intermediate is shown as a formula I. The invention has the advantages of simple process, low production cost, easy industrial production and the like.
Description
Technical Field
The invention relates to a preparation method of a new crown resistant drug Paxlovid intermediate, and particularly relates to a preparation method of (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3,1,0] hexyl-2-carboxylic acid methyl ester hydrochloride (CAS: 565456-77-1). The invention belongs to the field of pharmaceutical synthetic chemistry.
Background
Paxlovid is an anti-neocrown drug developed by the company Perey, and the active ingredients of the Paxlovid consist of a small molecular compound PF07321332 and ritonavir. On day 5/11 of 2021, pfeik announced phase II/III clinical findings of Paxlovid, suggesting that Paxlovid may reduce the risk of COVID-19-related hospitalization or death for any reason by 89% three days of symptom onset. It is expected that by the end of 2021, the FDA will be expected to approve the Emergency Use Authorization (EUA) for Paxlovid.
The chemical structure of PF07321332 is shown below:
wherein (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3,1,0] hexyl-2-carboxylic acid methyl ester hydrochloride (compound I, CAS: 565456-77-1) is a key chiral intermediate of PF 07321332. The synthesis of compound I is currently reported in the following patents/literature:
patent WO2004113295a1 reports a process for the synthesis of compound I starting from ethyl first chrysanthemate. The entire route involving KMnO4Oxidative resolution, LiAlH4Reduction, TEMPO-NaClO oxidation, Pd/C catalytic hydrogenolysis, etc., using trifluoroacetic anhydride, LiAlH4And highly toxic and dangerous reagents such as TMSCN. Because the reaction route is long and the steps are complicated, the energy consumption and the occupancy rate of equipment are high, the three-waste treatment cost is high, the total yield is low, and the comprehensive production cost is high.
Patent WO2007075790a1 reports a process for the synthesis of compound I starting from caronic anhydride. Similar to scheme 1, the reaction uses LiAlH4KCN and other reagents with high toxicity/danger, Oxone/silver nitrate oxidation, chemical resolution and other steps, low total yield and high comprehensive production cost.
Scheme 2 was modified in the literature (j.am. chem. soc.2012,134, 6467-6472) by oxidation of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane (CAS: 943516-54-9) with monoamine oxidase (MAON) followed by asymmetric addition of the C ═ N double bond with NaCN. Although the resolution of the route 2 is avoided, the starting material is expensive, the NaCN is high in toxicity, and the industrial application is still to be studied further.
The literature (J.Med.chem.2006,49,6074-6086) reports a synthesis of compound I starting from L-pyroglutamine derivative (CAS: 103201-79-2)The route of (1). The whole synthesis needs 8 steps of reaction, and oxidation, cyclopropanation and LiAlH are involved4Reduction, Pd/C hydrogenation debenzylation and other processes. The starting materials and some reagents in the route are expensive, the risk of the oxidation step is high, the amount of three wastes is large, and the comprehensive cost is high.
In conclusion, the existing synthesis steps of the compound I are complicated, the amount of three wastes is large, and the comprehensive cost is high. Therefore, it is very important to develop a synthetic route of compound I, which has a simple route, a simple and reliable process, a low cost and is suitable for industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3,1,0] hexyl-2-carboxylic acid methyl ester hydrochloride (compound I) which has simple steps, simple and reliable process and easy industrial production.
The synthetic route of the invention is as follows:
the invention comprises the following steps:
1) reacting the compound II with alkyl or aryl sulfonyl chloride to generate a sulfonate intermediate III; and carrying out elimination reaction on the sulfonate intermediate III under the action of alkali to obtain a compound IV.
2) And (3) performing cyclopropanation reaction on the compound IV and a phosphine ylide reagent to obtain an intermediate compound V.
3) And removing the Boc protecting group of the compound V in a hydrogen chloride solution to obtain a compound I.
In the step 1), the compound II reacts with alkyl or aryl sulfonyl chloride to obtain a reaction product (containing sulfonate intermediate III), which can directly undergo elimination reaction under the action of alkali without purification, or can be purified to obtain the sulfonate intermediate III. The elimination reaction preferably takes place directly under the action of a base without purification.
Further, the alkyl or aryl sulfonyl chloride in step 1) is one of sulfonyl chlorides such as methanesulfonyl chloride, ethanesulfonyl chloride, p-toluenesulfonyl chloride and p-nitrobenzenesulfonyl chloride.
Further, in the step 1), the molar ratio of the alkyl or aryl sulfonyl chloride to the compound II is 1: 1-1.5: 1, and the reaction temperature is 0-50 ℃.
Further, in the step 1), the base is one or more of potassium tert-butoxide, sodium tert-butoxide, DBU and the like.
Further, in the step 1), the molar ratio of the alkali to the compound III is 1: 1-20: 1, and the reaction temperature is 0-120 ℃.
In the step 2), the phosphine ylide reagent is isopropyl triphenyl phosphonium bromide or isopropyl triphenyl phosphonium iodide and organic lithium which are generated in situ, and the generation reaction temperature is-80 ℃ to 50 ℃; the organic lithium is one of methyl lithium, ethyl lithium, n-butyl lithium and sec-butyl lithium, preferably n-butyl lithium.
Further, in the step 2), the molar ratio of the phosphine ylide reagent to the compound IV is 1: 1-5: 1, and the cyclopropanation reaction temperature is 80-50 ℃.
In the step 3), the hydrogen chloride solution is one or more of hydrogen chloride/methanol, hydrogen chloride/ethanol, hydrogen chloride/ethyl acetate and hydrogen chloride/dioxane solution.
Further, in the step 3), the molar ratio of the hydrogen chloride to the compound V is 1: 1-10: 1, and the reaction temperature is-10 ℃ to 50 ℃.
Compared with the prior art, the invention has the following remarkable advantages:
1) because the invention directly adopts N-Boc-trans-4-hydroxy-L-proline methyl ester as a chiral source, and realizes the cyclopropanation reaction of the compound IV with high enantioselectivity, the invention avoids the defects of long synthetic route, complicated reaction steps and low chiral resolution yield, and has lower cost;
2) because the invention has no dangerous processes such as oxidation, reduction and the like, the LiAlH does not need to be used4NaCN, TMSCN and the likeDangerous or extremely toxic reagents, and stronger operability in actual production;
3) because the steps of the invention are short, the three wastes are greatly reduced, and the whole preparation process is more environment-friendly;
4) the comprehensive production cost of the invention is greatly reduced compared with the prior art, so the route of the invention has more market competitiveness.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be noted that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention, and it should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Example 1
Preparation of Compound IV
981g of compound II, 450g of triethylamine and 3L of dichloromethane are added into a 5L round-bottom flask, 801g of p-toluenesulfonyl chloride is added under ice bath, the mixture is stirred until the compound II disappears, water is added for quenching, the liquid is extracted and separated, and the water phase is extracted once again by 2L of dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure.
The obtained p-toluenesulfonate intermediate is dissolved in 4L of dioxane solution, 672g of potassium tert-butoxide is added under ice bath, and the mixture is heated and refluxed until the intermediate disappears. Quench with 1L of 10% aqueous ammonium chloride, remove dioxane under reduced pressure and extract the aqueous phase 2 times with 2L of ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 710g of compound IV in 78% yield.
1H NMR(CDCl3,600MHz)δ5.80-5.64(m,1H),4.35-4.13(m,1H),3.73(s,3H),1.46(m,9H)；
13C NMR(CDCl3,101MHz)δ171.0,152.7,129.5,124.6,79.4,66.2,53.2,52.0,27.9；
HRMS(ESI):m/z calcd for C11H17NO4[M+H]+227.1158,found:227.1162.
Example 2
Preparation of Compound IV
981g of compound II, 450g of triethylamine and 3L of dichloromethane are added into a 5L round-bottom flask, 930g of p-nitrobenzenesulfonyl chloride is added under ice bath, the mixture is stirred until the compound II disappears, water is added for quenching, the separated liquid is extracted, and the water phase is extracted once again by 2L of dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure.
The obtained p-nitrobenzenesulfonate intermediate is dissolved in 4L dioxane solution, 576g sodium tert-butoxide is added under ice bath, and the mixture is heated and refluxed until the intermediate disappears. Quench with 1L of 10% aqueous ammonium chloride, remove dioxane under reduced pressure and extract the aqueous phase 2 times with 2L of ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 655g of compound IV in a yield of 72%.
Example 3
Preparation of Compound IV
981g of compound II, 450g of triethylamine and 3L of dichloromethane are added into a 5L round-bottom flask, 481g of methanesulfonyl chloride is added under ice bath, stirring is carried out until the compound II disappears, water is added for quenching, liquid separation is carried out by extraction, and the water phase is extracted once again by 2L of dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure.
The resulting mesylate intermediate was dissolved in 4L of toluene, added 1220g of 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) in an ice bath and refluxed at elevated temperature until the intermediate disappeared. Quenching with 1L 10% hydrochloric acid aqueous solution, separating the solution, extracting the aqueous phase with 2L toluene for 1 time. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to obtain 745g of compound IV in 82% yield.
Example 4
Preparation of Compound IV
981g of compound II, 450g of triethylamine and 3L of dichloromethane are added into a 5L round-bottom flask, 540g of ethanesulfonyl chloride is added under ice bath, stirring is carried out until the compound II disappears, water is added for quenching, extraction and liquid separation are carried out, and the water phase is extracted once again by 2L of dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure.
The obtained p-toluenesulfonate intermediate is dissolved in 4L of dioxane solution, 672g of potassium tert-butoxide is added under ice bath, and the mixture is heated and refluxed until the intermediate disappears. Quench with 1L of 10% aqueous ammonium chloride, remove dioxane under reduced pressure and extract the aqueous phase 2 times with 2L of ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 755g of compound IV in 83% yield.
Example 5
Preparation of Compound V
Under a nitrogen atmosphere, n-butyllithium (2.5M in hexane, 880mL) was added dropwise to a solution of isopropyltriphenylphosphine iodide (864g) in tetrahydrofuran (3L). The reaction was stirred at 0 ℃ for 30 minutes, and then a tetrahydrofuran solution (1L) of Compound IV (455g) was added dropwise. After the addition, the mixture was stirred at room temperature until compound IV disappeared (TLC), and then 10% diluted hydrochloric acid was added to quench it, followed by extraction of the separated liquid, extraction of the aqueous phase once with ethyl acetate (2L), and the combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The crude product was stirred with methyl tert-ether (2L), the solid removed by suction filtration and the filtrate concentrated to dryness under reduced pressure to give 496g of compound V in 92% yield.
1H NMR(CDCl3,400MHz)δ4.50-4.43(m,1H),3.72(s,3H),3.63-3.53(m,1H),3.47-3.38(m,1H),1.67(t,J＝7.4Hz,1H),1.47(m,1H),1.45(s,9H),1.10(s,3H),0.99(s,3H)；
13C NMR(CDCl3,101MHz)δ173.1,153.7,79.9,59.7,52.1,46.4,31.9,28.3,27.3,26.6,26.2,19.3,12.5
HRMS(ESI):m/z calcd for C14H23NO4[M+H]+270.1700,found:270.1703.
Example 6
Preparation of Compound V
Under a nitrogen atmosphere, n-butyllithium (2.5M in hexane, 880mL) was added dropwise to a solution of isopropyltriphenylphosphine bromide (774g) in tetrahydrofuran (3L). The reaction was stirred at 0 ℃ for 30 minutes, and then a tetrahydrofuran solution (1L) of Compound IV (455g) was added dropwise. After the addition, the mixture was stirred at room temperature until compound IV disappeared (TLC), and then 10% diluted hydrochloric acid was added to quench it, followed by extraction of the separated liquid, extraction of the aqueous phase once with ethyl acetate (2L), and the combined organic phases were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The crude product was stirred with methyl tert-ether (2L), the solid was removed by suction filtration and the filtrate was concentrated to dryness under reduced pressure to give 485g of compound V in 90% yield.
Example 7
Preparation of Compound I
404 g of compound V are dissolved in 1000mL of methanol, 250mL of a 4N hydrogen chloride/methanol solution are added in ice bath, the mixture is stirred at room temperature until the reaction is completed, and the mixture is concentrated to dryness under reduced pressure. Then 1L of ethyl acetate was added, mechanically stirred at 50 ℃ for 30 minutes, cooled to room temperature, filtered with suction and dried in vacuo to yield 266 g of compound I (white solid) in 86% yield.
1H NMR(CDCl3,400MHz)δ9.82(brs,1H),4.14(d,J＝1.6Hz,1H),3.79(s,3H),3.62-3.57(m,1H),3.03(dd,J＝10.8Hz,J＝2Hz,1H),1.90-1.87(m,1H),1.78-1.74(m,1H),1.08(s,3H),1.04(s,3H)；
13C NMR(CDCl3,101MHz)δ170.2,61.6,54.3,47.4,34.4,30.8,26.2,23.4,14.0；
HRMS(ESI):m/z calcd for C11H22N2O2[M+H+-HCl]170.1176,found:170.1174.
Example 8
Preparation of Compound I
404 g of compound V are dissolved in 1000mL of ethyl acetate, 250mL of a 4N hydrogen chloride/ethyl acetate solution are added in an ice bath, the reaction is stirred at room temperature until completion, suction filtration and vacuum drying are carried out, 281 g of compound I (white solid) are obtained, and the yield is 91%.
Example 9
Preparation of Compound I
404 g of compound V are dissolved in 1000mL of ethyl acetate, 250mL of 4N hydrogen chloride/dioxane solution are added under ice bath, the mixture is stirred at room temperature until the reaction is completed, and the mixture is filtered, vacuum-dried to obtain 253 g of compound I (white solid) with the yield of 82%.
Claims (10)
1. The preparation method of the anti-neocrown drug Paxlovid intermediate (compound I) is characterized by comprising the following steps:
1) reacting the compound II with alkyl or aryl sulfonyl chloride to generate a sulfonate intermediate III; carrying out elimination reaction on the sulfonate intermediate III under the action of alkali to obtain a compound IV;
2) performing cyclopropanation reaction on the compound IV and a phosphine ylide reagent to obtain an intermediate compound V;
3) removing a protecting group from the compound V in a hydrogen chloride solution to obtain a compound I;
2. the method for preparing Paxlovid intermediate (compound I) as claimed in claim 1, wherein in step 1), the intermediate (compound III) of sulfonate ester obtained by reacting compound II with alkyl or arylsulfonyl chloride can be directly eliminated under the action of alkali without purification, or can be purified to obtain intermediate III of sulfonate ester, which is then eliminated under the action of alkali.
3. The method for preparing Paxlovid intermediate (compound I) as claimed in claim 1, wherein the alkyl or aryl sulfonyl chloride in step 1) is selected from methanesulfonyl chloride, ethanesulfonyl chloride, p-toluenesulfonyl chloride or p-nitrobenzenesulfonyl chloride.
4. The method for preparing the anti-neocorolla drug Paxlovid intermediate (compound I) according to claim 1, wherein the molar ratio of the alkyl or arylsulfonyl chloride to the compound II in the step 1) is 1: 1-1.5: 1, and the reaction temperature is 0-50 ℃.
5. The method for preparing Paxlovid intermediate (compound I) as claimed in claim 1, wherein the base in step 1) is one or more of potassium tert-butoxide, sodium tert-butoxide and DBU.
6. The preparation method of the anti-neocorolla drug Paxlovid intermediate (compound I) according to claim 1, wherein the molar ratio of the base to the compound III in the step 1) is 1: 1-20: 1, and the reaction temperature is 0-120 ℃.
7. The method for preparing Paxlovid intermediate (compound I) of anti-corona drug as claimed in claim 1, wherein the phosphine ylide reagent in step 2) is generated in situ from triphenyl isopropyl phosphine halide and organic lithium reagent, and the reaction temperature is-80 ℃ to 50 ℃.
8. The method for preparing the anti-new crown drug Paxlovid intermediate (compound I) according to claim 1, wherein the molar ratio of the phosphine ylide reagent to the compound IV in the step 2) is 1: 1-5: 1, and the cyclopropanation reaction temperature is-80 ℃ to 50 ℃.
9. The method for preparing Paxlovid intermediate (compound I) as claimed in claim 1, wherein the hydrogen chloride solution in step 3) is one or more of hydrogen chloride/methanol, hydrogen chloride/ethanol, hydrogen chloride/ethyl acetate or hydrogen chloride/dioxane solution.
10. The preparation method of the anti-neocorolla drug Paxlovid intermediate (compound I) according to claim 1, wherein the molar ratio of the hydrogen chloride to the compound V in the step 3) is 1: 1-10: 1, and the reaction temperature is-10 ℃ to 50 ℃.
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