CN114605437A - Synthesis process for preparing three telaprevir medicaments by continuous one-pot method - Google Patents

Synthesis process for preparing three telaprevir medicaments by continuous one-pot method Download PDF

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CN114605437A
CN114605437A CN202210349198.9A CN202210349198A CN114605437A CN 114605437 A CN114605437 A CN 114605437A CN 202210349198 A CN202210349198 A CN 202210349198A CN 114605437 A CN114605437 A CN 114605437A
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telaprevir
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赵长阔
王先恒
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Zunyi Medical University
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    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Abstract

The invention provides a synthesis process for preparing 3 telaprevir medicaments by a continuous one-pot method, which comprises the following steps: (1) the compound 4 is synthesized by the one-pot reaction of 4-methoxy methyl acetoacetate, DMF-DMA, dimethyl oxalate and aminoacetaldehyde dimethyl acetal; (2) the compound 4, the corresponding salt of the chiral amino alcohol and the acid catalyst react in a reaction solvent in one pot to synthesize a compound VI; (3) the compound VI and the corresponding fluorobenzylamine are coupled under the action of a coupling agent and organic base, and are reacted in a pot under the action of LiBr to respectively obtain three 'telaprevir' anti-AIDS medicaments, namely cabozeprevir, doritaevir and bicipreprevir. In the one-pot process for synthesizing the compounds 4, VI and VIII, the separation and purification of any intermediate products are not required in each pot of reaction, so that the flow and the cost of the production process are greatly simplified, the industrial production is easy to realize, and the like.

Description

Synthesis process for preparing three telaprevir medicaments by continuous one-pot method
Technical Field
The invention belongs to the field of preparation and synthesis of chemical raw material medicines. In particular to a synthesis process for preparing three 'telaprevir' anti-AIDS medicaments (including cabozeprevir, doritaevir and biciprevir) by a continuous one-pot method.
Background
The HIV virus is a retrovirus and the enzymes involved in its proliferation are reverse transcriptase, protease and integrase. The emergence of reverse transcriptase inhibitors and protease inhibitors of the HIV virus in the 80 to 90 th century transformed AIDS from a disease that rapidly led to death to a chronic disease, but both drugs had some defects, such as drug toxicity and drug resistance. Integrase inhibitors are the latest generation of anti-AIDS drugs. Dolutegravir (the text is interpreted as multiclatavir) was first approved by the U.S. FDA in 2013 by ViiV Healthcare, while Bictegravir (the text is interpreted as biclatavir) was developed by Gilead; cabotegravir (the text is interpreted as caboziravir) was also developed by the company ViiV Healthcare.
Figure BDA0003578676050000011
The company of Gellan reports in patent application WO2011119566 a process for the synthesis of doriravir starting from methyl 4-methoxyacetoacetate comprising the following 8 steps of reaction, detailed in the following formula.
Figure BDA0003578676050000012
Figure BDA0003578676050000021
The synthesis method of the doramevir shown in the reaction formula comprises 8 steps of reaction, more reaction steps and high production cost.
In order to reduce the steps of drug synthesis and the generation cost, the subject group develops a synthesis process for preparing doritavir by a continuous one-pot method. Because the 3 medicaments of the cabozavir, the dortiramivir and the bictiramivir are very similar in chemical structure and have a common synthetic intermediate, namely the compound 4, the method is successfully applied to the synthesis and preparation of the three 'tiramivir' anti-AIDS medicaments.
Disclosure of Invention
The invention provides a synthesis process for preparing three 'telaprevir' anti-AIDS drugs (including caboziravir, doritaevir and bicipristar) by a one-pot method, which comprises the following operation processes in a one-pot reaction container:
compound 4 was prepared in the first pot reaction vessel.
Intermediate VI was prepared in a second pot reaction vessel.
Preparing the target telaprevir medicament VIII in a third pot reaction container.
Further, the invention provides a synthesis process for preparing 3 telaprevir medicaments by a continuous one-pot method, which comprises the following steps:
1) the compound 4 is synthesized by the one-pot reaction of 4-methoxy methyl acetoacetate, DMF-DMA, dimethyl oxalate and aminoacetaldehyde dimethyl acetal;
2) the compound 4, the salt of the chiral amino alcohol and the acid catalyst react in a reaction solvent in one pot to synthesize a compound VI;
3) the compound VI and the fluorobenzylamine are coupled under the action of a coupling agent and an organic base, and are reacted in one pot under the catalysis of Lewis acid to synthesize the telaprevir medicament. As follows.
Figure BDA0003578676050000022
The "one-pot" reaction for synthesizing the compounds 4, VI and VIII described above refers to a reaction carried out in a one-pot reaction vessel, and the essence of the "one-pot" reaction is that it is not necessary to separate and purify the intermediate product obtained by the "one-pot" reaction.
In an embodiment of the present invention, the process for preparing compound 4 in the first pot reaction vessel is: 4-methoxy methyl acetoacetate is placed in a reaction vessel, and is synthesized with DMF-DMA, dimethyl oxalate and aminoacetaldehyde dimethyl acetal in one pot in the reaction vessel to obtain a compound 4. In the process for synthesizing the compound 4, the separation and purification of any intermediate products are not needed, and the flow and the cost of the production process are greatly simplified.
In an embodiment of the present invention, the process for preparing compound VI in the second pot reaction vessel is: and (3) placing the compound 6 in a reaction container, and reacting with corresponding chiral amino alcohol and an acid catalyst in a reaction solvent in one pot to synthesize the compound VI. In the process for synthesizing the compound VI, the separation and purification of any intermediate products are not needed, and the flow and the cost of the production process are greatly simplified.
In the second pot reaction, when the chiral amino alcohol is respectively selected from (S) -2-aminopropanol, (R) -3-aminobutanol and (1R,3S) -3-aminocyclopentanol, intermediate compounds VIa, VIb and VIc for synthesizing the caboziravir, the doriravir and the biciravir are respectively obtained.
Further, in the second pot reaction, the salt of the chiral amino alcohol is selected from one of hydrochloride and sulfate; the hydrochloride salt is preferred.
Further, in the second pot reaction, the acid catalyst is selected from one of p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid and trifluoroacetic acid, and is a mixed acid formed by acetic acid, preferably a mixed acid of methanesulfonic acid and acetic acid.
In an embodiment of the present invention, the process for preparing the "telaprevir" drug (compound number VIII in this application) in the third-pot reaction vessel is: placing the compound VI in a reaction vessel, coupling with fluorobenzylamine under the action of a coupling agent and an organic base catalyst, and reacting with a Lewis acid (such as MgBr)2LiCl or LiBr) under the action of the solvent to obtain the telaprevir medicament VIII. In the process for synthesizing the compound VI, the separation and purification of any intermediate products are not needed, and the flow and the cost of the production process are greatly simplified.
In the second pot reaction, when the fluorobenzylamine is selected from 2, 4-difluoroaniline, the compound is used for synthesizing caboziravir (compound VIIIa) and dortiriravir (compound VIIIb), and when the fluorobenzylamine is selected from 2,4, 6-trifluoroaniline, the compound is used for synthesizing bictiriravir (compound VIIIc), and the detailed reaction formula is shown in the following.
Further, in the third pot reaction, the coupling agent is selected from one of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), Dicyclohexylcarbodiimide (DCC), 2- (7-azabenzotriazole) -N, N, N ', N ' -tetramethylurea Hexafluorophosphate (HATU), 1-Hydroxybenzotriazole (HOBT), N, N ' -Carbonyldiimidazole (CDI), preferably EDCI.
Further, in the third pot reaction, the organic base catalyst is selected from triethylenediamine (DABCO), 1, 8-diazabicycloundec-7-ene (DBU), 4-dimethylaminopyridine (abbreviated as DMAP), pyridine; DMAP is preferred.
Further, in the third-pot reaction, the Lewis acid is selected from MgBr2One of LiCl and LiBr, preferably MgBr2， LiBr。
In the above synthesis and preparation processes, the reaction solvent, the reaction temperature, and the reaction time can be appropriately selected by those skilled in the art according to the basic principle of organic chemistry. For example, the reaction solvent may be selected from N, N-dimethylformamide (abbreviated as DMF), dimethylsulfoxide (abbreviated as DMSO), dichloromethane (abbreviated as DCM), chloroform, acetonitrile, tetrahydrofuran, etc., depending on the temperature required for the reaction and the polarity of the solvent. The reaction temperature may be appropriately selected depending on the type of the reaction. In the reaction, the progress of the reaction can be monitored by chromatography and HPLC-MS. In the chromatography, thin layer chromatography can be used, and gas chromatography or liquid chromatography such as HPLC can be used instead. The reaction time can be obtained by tracking the reaction condition by monitoring means such as thin layer chromatography TLC, high performance liquid chromatography HPLC or LC-MS liquid mass spectrum combination and the like. In the present invention, (S) -2-aminopropanol, (R) -3-aminobutanol and (1R,3S) -3-aminocyclopentanol may be used as hydrochloride thereof.
The invention has the advantages that: the invention provides a new synthesis process of 3 telaprevir medicaments shown in formula I, and in the one-pot process for synthesizing the compounds 4, VI and VIII, the separation and purification of any intermediate product are not needed in each one-pot reaction, so that the flow and the cost of the production process are greatly simplified, and the industrial production is easy to realize.
Detailed Description
The invention will be further illustrated by the following specific examples, which are not intended to limit the scope of the invention. Without departing from the inventive concept, a person skilled in the art may make modifications or combinations of the parameters or conditions of the claims, which modifications or combinations shall also be considered as the protective scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Ethyl 4-methoxyacetoacetate, dimethyl oxalate, methanesulfonic acid, DMF-DMA (N, N-dimethylformamide dimethyl acetal), (S) -2-aminopropanol, (R) -3-aminobutanol and (1R,3S) -3-aminocyclopentanol hydrochloride, acetic acid, MgBr2, LiBr from the chinese pharmacopoeia group.
In the following examples, the English abbreviation h stands for hour, TLC stands for thin layer chromatography, mL stands for milliliter, and N stands for mol/L concentration.
A first part: first pot reaction
Figure BDA0003578676050000041
Example 1 preparation of Compound 4
8mL (61.80mmol) of methyl 4-methoxyacetoacetate and 9.6mL (72.26mmol) of N, N-dimethylformamide dimethyl acetal (DMF-DMA) were stirred in a 150mL round-bottomed flask at room temperature for 1.5 hours, the solution changed from yellow to brown, and the R of compound 1 (structural formula 1, which does not need to be isolated in this pot reaction) was monitored by TLC thin layer chromatographyf0.137 (developing solvent: ethyl acetate: petroleum ether: 5: 1, observed at 254nm under ultraviolet lamp). Adding 20mL of methanol into the reaction solution for dilution, adding 6.68mL (61.31mmol) of aminoacetaldehyde dimethyl acetal, stirring at room temperature for 1h to obtain wine red solution, tracking by TLC thin layer chromatography, and collecting R of compound 2 (structural formula 1, without separation in the reaction kettle)f0.557 (viewing at 254nm under an ultraviolet lamp, developing solvent: ethyl acetate). The reaction was stopped and concentrated by evaporation to a reddish brown oily liquid. Adding 45.2mL of methanol to the residue for dissolution, adding 18.34g (155.34mmol) of dimethyl oxalate, controlling the temperature below 25 ℃ after the dimethyl oxalate is completely dissolved, adding 108.67mmol of lithium hydride LiH in batches to obtain a brownish red suspension, and after the addition is finished, placing the reaction solution in an oil bath kettle at 40 ℃ for reaction for 14 hours to obtain a brick red solution from the suspension; and cooling the obtained reaction liquid to-5 ℃, adding 5.94g (123.8mmol) of anhydrous lithium hydroxide, controlling the temperature in an environment of 3-5 ℃, changing the brick red reaction liquid into orange suspension, reacting for 2 hours, adding 146.8mL of 2N hydrochloric acid to carry out quenching reaction, and controlling the reaction temperature to be lower than 5 ℃. Adding 180mExtracting with ethyl acetate L, heating to 20 deg.C, vacuum filtering, and removing solid; collecting liquid phase, separating liquid phase, collecting organic phase, adding 90mL water into organic phase, concentrating under reduced pressure, vacuum filtering, collecting filter cake, and vacuum drying at 50 deg.C to obtain compound 4 as white solid, Rf0.35 (developing agent: ethyl acetate, observed under uv lamp 254 nm), 12.51g, yield: 65%, m.p.111.3 ℃.1H NMR (400MHz,CDCl3)δ＝8.40-8.42(m,1H),4.49-4.53(m,1H),4.10-4.14(m,2H),3.98(s,3H),3.97 (s,3H),3.38(s,3H),3.37(s,3H)；13C NMR(100MHz,CDCl3)δ＝174.86,165.99,161.60, 148.65,145.47,136.59,116.53,102.31,60.97,57.26,55.97,53.77.
A second part: second pot reaction
Example 2 preparation of Compound VIa (intermediate for the Synthesis of Cabotegravir)
The intermediate acetal obtained in example 1 (compound 4,1g,3.2mmol) was weighed out and dissolved in 50mL of CH3In CN. HOAc (1mL) and CH were added at room temperature3SO3H (0.3mL, 5.7mmol) in CH3CN (50mL) solution and (S) -2-aminopropanol (705mg, 9.4mmol), and the mixture was refluxed for 30 hours. Concentrating the mixture and redissolving the residue in CH2Cl2(100 mL). After addition of 1N HCl (50mL), the resulting mixture was partitioned, and the aqueous layer was replaced with CH2Cl2(150 mL. times.2) and the organic layers were combined and concentrated. MeOH (80mL) was added and the resulting mixture was concentrated again. After addition of MeOH (50mL), the resulting mixture was heated at reflux for 2 h, gradually cooled to 20 ℃ and held at 20 ℃ for 15 h. The product was collected by filtration and dried in vacuo to give the title compound VIa (746mg, 80%) as a white solid, Rf0.69 (developing solvent: ethyl acetate, observed under an ultraviolet lamp at 254 nm).1H NMR(400MHz,Chloroform-d)δ＝8.43(s,1H),5.39(dd,J＝9.9, 3.4Hz,1H),4.56(dd,J＝12.4,3.4Hz,1H),4.47–4.33(m,2H),4.07(s,3H),3.96(dd,J＝12.1, 10.2Hz,1H),3.71(t,J＝7.5Hz,1H),1.42(d,J＝6.0Hz,3H).13C NMR(101MHz,CDCl3)δ＝176.16,165.78,153.85,152.48,143.04,131.51,116.04,82.38,73.15,61.60,55.74,52.20,17.02.
Example 3 preparation of Compound VIb (intermediate for the Synthesis of Dolutegravir)
The intermediate acetal obtained in example 1 (compound 4,20g,63mmol) was weighed out and dissolved in 100mL CH3In CN. HOAc (100mL) and CH were added at room temperature3SO3H (1.2mL, 18.5mmol) and (R) -3-amino-1-butanol (16.73g, 188mmol) in CH3CN solution (100mL) and the mixture refluxed for 15 hours. The mixture was concentrated and the residue was redissolved in CH2Cl2(200 mL). Dilute HCl (1N, 100mL) was added and the layers were separated. CH for aqueous layer2Cl2(100 mL. times.2) and the organic layers were combined and concentrated. MeOH (50mL) was added and the resulting mixture was heated under reflux for 2 h, and a yellow solid precipitated from the reaction. The reaction was stopped, cooled to room temperature, the product collected by filtration and dried in vacuo to give the title compound VIb (12.6g, yield 65%) as a yellow solid.1H NMR(400MHz,CDCl3)δ＝15.02(d, J＝16.7Hz,1H),8.42(d,J＝11.8Hz,1H),5.29(dd,J＝5.4,3.9Hz,1H),4.97(q,J＝6.4Hz,1H), 4.52(t,J＝4.5Hz,1H),4.43(dd,J＝13.6,3.5Hz,1H),4.26(dd,J＝13.6,5.8Hz,1H),4.13(d,J ＝4.5Hz,1H),4.05(d,J＝13.0Hz,2H),3.98(d,J＝2.2Hz,3H),3.96(d,J＝2.9Hz,1H),3.39(s, 3H),2.22-2.09(m,1H),1.52(dd,J＝13.9,1.6Hz,1H),1.35(d,J＝7.0Hz,2H)；13C NMR(100 MHz,CDCl3)δ＝173.23,164.17,162.24,149.45,144.64,135.03,130.77,130.73,130.67,119.35, 111.34,111.30,111.13,111.09,103.81,102.73,60.78,56.81,55.72,53.47,36.60,36.56.HRMS (ESI-TOF):309.1166[M+1].
Example 4 preparation of Compound VIc (intermediate for the Synthesis of Bictegravir)
The intermediate acetal obtained in example 1 (compound 4,1g,3.2mmol) was weighed out and dissolved in 50mL of CH3And (C) in CN. HOAc (1mL) and CH were added at room temperature3SO3H (0.3mL, 5.7mmol) in CH3CN (50mL) solution and (1R,3S) -3-aminocyclopentanol (1.29g, 9.4mmol), and the mixture was refluxed for 30 hours. Concentrating the mixture and redissolving the residue in CH2Cl2(100 mL). After addition of 1N HCl (50mL), the resulting mixture was partitioned, and the aqueous layer was replaced with CH2Cl2(150 mL. times.2) and the organic layers were combined and concentrated. MeOH (80mL) was added and the resulting mixture was concentrated again. After addition of MeOH (50mL), the resulting mixture was heated to reflux for 2 h, gradually cooled to 20 ℃ and held at 20 ℃ for 15 h. The product was collected by filtration and dried in vacuo to give the title compound VIa (634mg, 62%) as a yellowish solid, Rf0.38 (developing solvent: DCM: CH)3OH 97:3, observed under uv lamp 254 nm).1H NMR(400MHz,DMSO-d6)δ＝8.70(s,1H),5.40(dd,J ＝9.7,3.8Hz,1H),5.07(d,J＝4.0Hz,1H),4.70(dd,J＝12.9,3.8Hz,1H),4.07(dd,J＝12.8,9.7 Hz,1H),3.81(s,3H),1.89(s,2H),1.88(s,1H),1.76(d,J＝10.7Hz,2H),1.52(dt,J＝12.3,3.3 Hz,1H).13C NMR(101MHz,DMSO-d6)δ＝176.04,165.67,153.30,151.69,144.06,133.00, 115.10,76.61,74.13,60.94,54.09,51.01,38.10,28.90,27.86.
And a third part: third pot reaction
Example 5 preparation of Compound VIIIa (Cabotegravir)
The compound VIa (2g,6.8mmol) obtained in example 2 was dissolved in 100mL of CH3To CN, EDCI (3.87g,20.2mmol), DMAP (334mg,2.7mmol) and 2, 4-difluorobenzylamine (1.17g,8.2mmol) were added to form a suspension. The mixture was heated to 80 ℃ in an oil bath and after 2 hours was completely dissolved. LiBr (1g,12mmol) was then added. After 4 hours, the product was collected by filtration and dried in vacuo to give the title compound VIIIa (Cabotegravir) (2.5g, yield 90%) as a white solid. Rf＝0.31(DCM:CH3OH＝97:3).1H NMR(400MHz,DMSO-d6)δ＝10.24(s,1H), 7.86(s,1H),7.31(d,J＝8.1Hz,1H),7.16(t,J＝9.4Hz,1H),7.02–6.92(m,1H),5.16(dd,J＝ 9.9,4.0Hz,1H),4.67(dt,J＝20.1,10.3Hz,2H),4.29(t,J＝7.7Hz,1H),4.17(d,J＝14.4Hz, 2H),3.60(t,J＝7.6Hz,1H),3.54–3.42(m,1H),1.25(d,J＝6.0Hz,3H).13C NMR(101MHz, DMSO-d6)δ＝177.55,165.46,164.68,159.27,136.60,131.16,115.15,111.83,111.61,109.99, 109.78,104.42,104.16,103.91,81.52,72.67,54.19,51.59,35.90,17.28.
Example 6 preparation of Compound VIIIb (intermediate of Dolutegravir)
The compound VIb (10g,32mmol) obtained in example 3 was weighed out and dissolved in 300mL of CH3To CN, EDCI (20.0g,104mmol), DMAP (1.72g,14.1mmol) and 2, 4-difluorobenzylamine (5.85g,40.9mmol) were added to form a suspension. The mixture was heated to 80 ℃ in an oil bath and after 2 hours was completely dissolved. LiBr (5.5g,62mmol) was then added. After 4 hours, the product was collected by filtration and dried in vacuo to give the title compound VIIIb (Dolutegravir (8.0g, 59% yield) as a white solid.1H NMR(400MHz,CDCl3)δ＝12.48(s,1H),10.33(t,J＝4Hz,1H),8.47(s,1H),7.35 (q,J＝4Hz,1H),7.20(td,J＝8Hz,4Hz,1H),7.02(dd,J＝8Hz,4Hz,1H),5.42(t,J＝8Hz,1H), 4.76(t,J＝8Hz,1H),4.57(d,J＝4Hz,1H),4.51(d,J＝4Hz,2H),4.33(q,J＝8Hz,1H),4.00(t,J ＝12Hz,1H),3.88-3.85(d,J＝4Hz，1H),2.03-1.94(m,1H),1.51(d,J＝12Hz,3H).13C NMR(100 MHz,CDCl3)δ＝174.23,170.89,164.35,164.15,162.22,155.74,153.63,142.92,140.43,130.58, 130.07,121.65,116.88,116.80,115.52,115.42,110.99,110.77,103.51,103.26,102.99,76.43, 76.28,62.36,62.01,60.34,53.07,52.04,48.08,45.05,44.85,36.00,29.12,14.74,14.27.
Example 7 preparation of Compound VIIIc (Bictegravir)
The compound VIc (1.80g,5.6mmol) obtained in example 4 was weighed out and dissolved in 100mL of CH3To CN, EDCI (3.87g,20.2mmol), DMAP (334mg,2.7mmol) and 2,4, 6-trifluorobenzylamine (1.32g, 8.2mmol) were added to form a suspension. The mixture was heated to 80 ℃ in an oil bath and after 2 hours was completely dissolved. LiBr (1g,12mmol) was then added. After 4 hours, the product was collected by filtration and dried in vacuo to give the title compound viiic (bictegravir) (2.14g, 85% yield) as a white solid. Rf＝0.38(DCM:CH3OH＝97:3).1H NMR(400MHz,DMSO-d6)δ＝12.32(s,1H), 10.25(s,1H),8.25(s,1H),6.61(t,J＝8.0Hz,2H),5.36(dd,J＝9.4,4.0Hz,1H),5.25(d,J＝9.5 Hz,1H),4.65–4.58(m,2H),4.24(dd,J＝13.1,4.1Hz,1H),3.95(dd,J＝12.8,9.3Hz,1H),3.43 (d,J＝1.1Hz,1H),2.12–1.89(m,6H).13C NMR(101MHz,CDCl3)δ＝171.13,163.70,160.45, 155.68,140.21,116.27,115.78,100.48,100.23,100.20,100.18,99.95,99.93,77.28,74.24,53.36, 51.27,37.89,30.59,28.98,27.85.
The foregoing is merely an example of the present invention and common general knowledge of known specific structures and features of the embodiments is not described herein in any greater detail. It should be noted that, for those skilled in the art, without departing from the structure of the present invention, several changes and modifications can be made, which should also be regarded as the protection scope of the present invention, and these will not affect the effect of the implementation of the present invention and the practicability of the patent. The scope of the claims of the present application shall be determined by the contents of the claims, and the description of the embodiments and the like in the specification shall be used to explain the contents of the claims.

Claims (11)

1. A synthesis process for preparing three 'telaprevir' medicaments, namely caboziravir, doriravir and bicistrivir, by a one-pot method comprises the following operation processes in a one-pot reaction container: compound 4 was prepared in the first pot reaction vessel.
2. The synthesis process of the telaprevir medicament according to claim 1, comprising the following operation processes in a one-pot reaction vessel: intermediate VI was prepared in a second pot reaction vessel.
3. The synthesis process of telaprevir drug according to claim 1, comprising the following operating processes in a one-pot reaction vessel: preparing the target telaprevir medicament VIII in a third-pot reaction vessel.
4. The synthesis process of telaprevir medicament according to any one of claims 1-3, which is characterized by comprising the following three operation processes in a one-pot reaction vessel in succession:
1) the compound 4 is synthesized by the one-pot reaction of 4-methoxy methyl acetoacetate, DMF-DMA, dimethyl oxalate and aminoacetaldehyde dimethyl acetal;
2) the compound 4, the salt of the chiral amino alcohol and the acid catalyst react in a reaction solvent in one pot to synthesize a compound VI;
3) the compound VI and the fluorobenzylamine are coupled under the action of a coupling agent and an organic base, and are reacted in one pot under the catalysis of Lewis acid to synthesize the telaprevir medicament;
Figure FDA0003578676040000011
5. the synthesis process of the telaprevir medicament according to any one of claims 1-3, wherein in a first-pot reaction vessel: 4-methoxy methyl acetoacetate is placed in a reaction vessel, and is synthesized with DMF-DMA, dimethyl oxalate and aminoacetaldehyde dimethyl acetal in one pot in the reaction vessel to obtain a compound 4.
6. The synthesis process of telaprevir drug according to any one of claims 1-3, wherein the process for preparing compound VI in the second pot reaction vessel is as follows: and (3) placing the compound 6 in a reaction container, and reacting with corresponding chiral amino alcohol and an acid catalyst in a reaction solvent in one pot to synthesize the compound VI.
7. The synthesis process of telaprevir medicament according to claim 6, wherein in the second-pot reaction, when the chiral amino alcohol is respectively selected from (S) -2-aminopropanol, (R) -3-aminobutanol and (1R,3S) -3-aminocyclopentanol, the intermediate compounds VIa, VIb and VIc for synthesizing the caboziravir, the dorivavir and the bicecavir are respectively prepared.
8. The synthesis process of the telaprevir medicament according to claim 7, wherein the acid catalyst is selected from one of p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid and trifluoroacetic acid, and is a mixed acid formed by acetic acid, preferably a mixed acid of methanesulfonic acid and acetic acid.
9. The synthesis process of telaprevir drug according to any one of claims 1-3, characterized in that in a third-pot reaction: putting a compound VI in a reaction container, coupling the compound VI with fluorobenzylamine under the action of a coupling agent and an organic base catalyst, and carrying out one-pot reaction under the action of Lewis acid to synthesize the telaprevir medicament VIII; when the fluorobenzylamine is selected from 2, 4-difluoroaniline, the synthesis method is used for synthesizing caboziravir and dortiramer, and when the fluorobenzylamine is selected from 2,4, 6-trifluoroaniline, the synthesis method is used for synthesizing bictiramer.
10. The process for the synthesis of a "telaprevir" drug according to claim 9, wherein in a third pot reaction: the coupling agent is selected from 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide, 2- (7-azabenzotriazole) -N, N, N ', N ' -tetramethylurea hexafluorophosphate, 1-hydroxybenzotriazole and N, N ' -carbonyldiimidazole, preferably EDCI.
11. The process for synthesizing a telaprevir drug according to claim 9, wherein in a third-pot reaction: the Lewis acid is MgBr2One of LiCl and LiBr, preferably MgBr2，LiBr。
CN202210349198.9A 2022-04-01 2022-04-01 Synthesis process for preparing three telaprevir medicaments by continuous one-pot method Pending CN114605437A (en)

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