Process for the preparation of a telaprevir intermediate and telaprevir

Abstract

The application discloses a preparation method of a telaprevir intermediate and telaprevir, wherein compound 6 and compound 9 or compound 13 are subjected to 2-step reaction or 3-step reaction respectively to obtain compound 15; and 1-phenyl-3-hexanone is used as an initial raw material to obtain compound 20, i.e., telaprevir, through a Reformatsky reaction, hydrolysis, kinetic resolution, condensation, cyclization, asymmetric allylation reaction, reduction and sulfonamidation reaction. The synthesis route is short and efficient, simple to operate, safe and easy to obtain raw materials, and the reaction condition is mild, the reaction yield is high, the reaction steps and synthesis cost are reduced, and the method is more suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis and medicinal chemistry, and particularly relates to a preparation method of a tipranavir intermediate and tipranavir. BACKGROUND

[0002] Tipranavir, chemically named as N-[3-[(1R)-1-[(6R)-2-hydroxy-4-oxo-6-phenethyl-6-propyl-5H-pyranyl-3-yl]propyl]phenyl]-5-(trifluoromethyl)pyridine-2-sulfonamide, is a very representative non-peptide HIV protease inhibitor (NPPI) in anti-AIDS drugs, and has a wide anti-viral activity against various protease inhibitor-resistant HIV-1.

[0003]

[0004] The tipranavir molecule has two chiral centers, and the existence of the two chiral centers makes the molecule theoretically exist four stereoisomers, and researches show that the four stereoisomers have great activity difference. At present, the commercially available tipranavir drug is the isomer of 3αR, 6R, and therefore, the efficient and precise asymmetric synthesis of the molecules is very important.

[0005] The synthesis routes of tipranavir reported in the past literatures mainly include the following:

[0006] 1. According to the method reported by Turner et al.: starting from 1-phenylhexan-3-one, through cyclization, condensation, addition, reduction and sulfonamide, etc. 7-step reactions, the racemic tipranavir molecule is obtained. The synthesis process of the racemic molecule involves all classical reactions, and therefore the synthesis route is relatively simple. However, the chiral isomer can only be obtained by preparation HPLC separation, but this cannot be scaled up, and cannot meet the needs of research and production. (Ref: Turner S R, Strohbach J W, Tommasi R A, et al. Tipranavir (PNU-140690): a potent, orally bioavailable nonpeptidic HIV protease inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone sulfonamide class [J]. Journal of Medicinal Chemistry, 1998, 41(18): 3467-3476.)

[0007]

[0008] 2. According to the method reported by Gammill et al: starting from Evens chiral auxiliary, the target product was obtained in 25:1 dr value after 13 steps, and the ee value was well maintained. However, due to the introduction of chiral auxiliary, in order to ensure good reaction stereoselectivity under the action of chiral auxiliary, the reaction needs to be carried out at-78℃ and under anhydrous and anaerobic conditions. In this way, the reaction time is greatly prolonged, and the reaction conditions are harsh, which is very unfavorable for industrial production; and as an auxiliary group, the chiral auxiliary must be used in an equivalent amount and the reaction steps are longer, which is not economical.(Ref: Gammill R B. Asymmetric Syntheses and Absolute Stereochemistry of 5,6-Dihydro-α-pyrones, A New Class of Potent HIV Protease Inhibitors [J]. Journal of the American Chemical Society, 1997.)

[0009]

[0010] 3. According to the method reported by Romero et al: β-disubstituted unsaturated acid was synthesized from ethyl pent-2-ynoate, and further asymmetric hydrogenation reaction catalyzed by chiral metal ruthenium complex was carried out to obtain chiral intermediate with good stereoselectivity, and further through a series of chemical transformations, the PNU-140690, a similar substance of tipranavir, was synthesized in 14 steps. However, this synthesis route has several shortcomings: 1) the catalytic asymmetric hydrogenation can only obtain 90% ee value, which needs to be further recrystallized to improve the stereoselectivity of the product; 2) the effective control of the chiral center in the pyrone skeleton cannot be realized, and only the tipranavir analog can be obtained; 3) the synthesis route is long, the reaction conditions are complex, and the cost cannot be effectively reduced.(Ref: Donna L, Romero, et al. Asymmetric Synthesis of the C3α Fragment of 5,6-Dihydro-α-pyrone Nonpeptidic HIV-1 Protease Inhibitors [J]. The Journal of Organic Chemistry, 1999, 64(13): 4980-4984.)

[0011]

[0012] 4. According to the method reported by Trost et al: the strategy of twice catalytic asymmetric reaction is used to construct two chiral intermediates, and then the two chiral intermediates are connected to stereospecifically synthesize the target molecule of Tipranavir. The authors use the chiral ligand developed by the research group to catalyze the construction of two asymmetric allylic chiral centers, and the ee value is as high as 98% and 96%, which well guarantees the stereoselectivity of the product. However, in this synthesis strategy, the total reaction steps reach 18 steps, the cost of scale-up synthesis is high, and the economy is low; at the same time, the use of two kinds of chiral catalysts in the twice catalytic asymmetric synthesis further increases the synthesis cost, which seriously restricts the application in industrial production. (Ref: Barry M, Trost, et al. Utilization of Molybdenum-and Palladium-Catayzed Dynamic Kinetic Asymmetric Transformations for the Preparation of Tertiary and Quaternary Stereogenic Centers: A Concise Synthesis of Tipranavir [J]. Journal of the American Chemical Society, 2002.)

[0013]

[0014] The previous synthesis method has long reaction steps, complex conditions and high cost, which is not conducive to industrial production. Therefore, it is necessary to develop a synthesis route of Tipranavir with fewer steps, simple reaction, low cost and industrialization. SUMMARY

[0015] In order to solve the problems in the prior art, the present application provides a kind of Tipranavir intermediate and the preparation method of Tipranavir. The synthesis route of the present application is short, simple operation, raw material reagent is easy to obtain, can efficiently and accurately complete the construction of two chiral centers and stereoselectivity control, has the advantages of high yield and low cost, and is suitable for industrial production.

[0016] The present application first provides a kind of synthesis method of Tipranavir, which includes the following steps:

[0017] 1) compound 6 and compound 9 are subjected to asymmetric allylic substitution reaction in the presence of metal catalyst, ligand and acid promoter to synthesize compound 14;

[0018] 2) compound 14 is reduced by a reducing agent to synthesize compound 15;

[0019] 3) Compound 15 and compound 19 are sulfonylated to synthesize compound 20, i.e. tipranavir;

[0020] The synthetic route is shown in the following formula:

[0021]

[0022] wherein R is tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, acetyl.

[0023] Further, in the step 1), the metal catalyst is selected from 1,5-cyclooctadiene iridium chloride dimer ([Ir(COD)Cl]2); the ligand is selected from one of (R)-(+)-(3,5-dioxa-4-phosphasinorbornen-4-yl)-5-hydro-dibenzo[b,f]azepine, (R)-(-)-(3,5-dioxa-4-phosphasinorbornen-4-yl)dimethylamine, 1-(11bR)-dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-yl-1,2,3,4-tetrahydroquinoline, (2R)-1-(11bR)-dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-yl-1,2,3,4-tetrahydro-2-methylquinoline, (11bR)-N,N-bis[(1S)-1-phenylethyl]dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-amine; the acid promoter is selected from one of diphenyl phosphate, p-toluenesulfonic acid monohydrate, trifluoroacetic acid, (±)-10-camphorsulfonic acid, ytterbium triflate, bismuth triflate, lanthanum triflate, zinc triflate, copper triflate, indium triflate; the reaction is carried out in a solvent selected from one or more of ethyl acetate, dichloromethane, trichloromethane, dichloroethane, toluene, acetonitrile, methanol, tetrahydrofuran, N,N-dimethylformamide, diethyl ether, methyl tert-butyl ether, 1,4-dioxane.

[0024] Further, in the step 1), the molar ratio of compound 6 to compound 9 is 1:1.1-1:2; the molar ratio of compound 6 to metal catalyst is 1:0.02-1:0.04; the molar ratio of compound 6 to ligand is 1:0.08-1:0.016; the molar ratio of compound 6 to acid promoter is 1:0.05-1:0.1; the reaction temperature is 25-50°C; the reaction time is 28-72 hours.

[0025] Further, in the step 2), the reducing agent is selected from hydrogen; the catalyst is selected from 10% palladium on carbon; the solvent is selected from methanol; in the step 2), the mass ratio of compound 14 to catalyst is 1:0.1-1:0.2; the reaction temperature is 25-45°C; the reaction time is 2-48 hours.

[0026] The present application also provides another method for synthesizing Tipranavir, which comprises the following steps:

[0027] a) synthesizing compound 16 by asymmetric allylic substitution reaction of compound 6 with compound 13 in the presence of a metal catalyst, a ligand, and an acid promoter;

[0028] b) reducing compound 16 by a reducing agent in the presence of an acidic reagent and a solvent to obtain compound 17;

[0029] c) removing the hydroxyl protecting group of compound 17 in the presence of an acidic reagent and a solvent to obtain compound 15;

[0030] d) synthesizing compound 20, i.e. Tipranavir, by sulfonylamidation of compound 15 with compound 19;

[0031] The synthetic route is shown in the following formula:

[0032]

[0033] Further, in the step a), the metal catalyst is selected from one of 1,5-cyclooctadiene iridium chloride dimer ([Ir(COD)Cl]2); the ligand is selected from one of (R)-(+)-(3,5-dioxa-4-phospha-cyclohepta[2,1-a;3,4-a']dinaphthalen-4-yl)-5-hydro-dibenzo[b,f]azepine, (R)-(-)-(3,5-dioxa-4-phospha-cyclohepta[2,1-a:3,4-a']dinaphthalen-4-yl)dimethylamine, 1-(11bR)-dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphorinan-4-yl-1,2,3,4-tetrahydroquinoline, (2R)-1-(11bR)-dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphorinan-4-yl-1,2,3,4-tetrahydro-2-methylquinoline, (11bR)-N,N-bis[(1S)-1-phenylethyl]dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphorinan-4-amine; the acid promoter is selected from one of diphenyl phosphate, p-toluenesulfonic acid monohydrate, trifluoroacetic acid, (±)-10-camphorsulfonic acid, ytterbium triflate, bismuth triflate, lanthanum triflate, zinc triflate, copper triflate, indium triflate; the reaction is carried out in a solvent selected from one or more of ethyl acetate, dichloromethane, trichloromethane, dichloroethane, toluene, acetonitrile, methanol, tetrahydrofuran, N,N-dimethylformamide, diethyl ether, methyl tert-butyl ether, 1,4-dioxane.

[0034] Further, in the step a), the molar ratio of compound 6 to compound 13 is 1:1.2-1:2; the molar ratio of compound 6 to metal catalyst is 1:0.02-1:0.04; the molar ratio of compound 6 to ligand is 1:0.08-1:0.016; the molar ratio of compound 6 to acid promoter is 1:0.05-1:0.1; the reaction temperature is 25-50℃; and the reaction time is 36-96 hours.

[0035] Further, in the step b), the reducing agent is selected from p-toluenesulfonyl hydrazide; the acidic agent is sodium acetate; the solvent is ethanol; the molar ratio of compound 16 to p-toluenesulfonyl hydrazide is 1:2-1:5; the molar ratio of compound 16 to sodium acetate is 1:2-1:5; the reaction temperature is 25-80℃; and the reaction time is 3-48 hours.

[0036] Further, in the step c), the acidic agent is 12 mol / L concentrated hydrochloric acid; the solvent is one or both of tetrahydrofuran and water; the amount of the concentrated hydrochloric acid is 1.0-6.0 mL / mmol based on the amount of compound 17; the reaction temperature is 25-50℃; and the reaction time is 3-24 hours.

[0037] The step 3) and the step d) in the above two methods are completely the same, and specifically, compound 15 is sulfonamidated with compound 19 in the presence of a basic agent, a stabilizer and a solvent to synthesize compound 20.

[0038] Preferably, the basic agent is selected from one of pyridine, triethylamine and N,N-dimethyl aniline, and is further preferably N,N-dimethyl aniline; the stabilizer is selected from 2,6-di-tert-butyl-p-cresol; and the solvent is selected from one of dichloromethane and anhydrous dichloromethane, and is further preferably dichloromethane.

[0039] Preferably, the molar ratio of compound 15 to compound 19 is 1:1-1:2, and is further preferably 1:1.1; the molar ratio of compound 15 to the basic agent is 1:1.1-1:3, and is further preferably 1:1.2; the molar ratio of compound 15 to the stabilizer is 1:0-1:0.2, and is further preferably 1:0.2; the reaction temperature is -20-25℃, and is further preferably 0℃; the reaction time is 0.5-3 hours; and the amount of the solvent is 5.0-10.0 mL / mmol based on the amount of compound 16, and is further preferably 6 mL / mmol.

[0040] The present application also provides a intermediate compound of tipranavir, which has a structure as shown in compound 14 or compound 16:

[0041]

[0042] The beneficial effects of the present application include: the intermediate of the present application is synthesized by transition metal iridium catalyzing pyrone and allyl alcohol to perform asymmetric allylation reaction, which efficiently and quickly completes the accurate construction of chiral center, reduces reaction steps and synthesis cost. The two synthesis routes of the present application can synthesize high-purity (99.9%) and high-enantiomeric selectivity (99% ee) of the telaprevir drug molecule. The synthesis route of the present application is simple and efficient, easy to operate, and the raw materials are safe and easy to obtain. The reaction conditions are mild, the reaction yield is high, the reaction steps and synthesis cost are reduced, and it is more suitable for industrial production. DETAILED DESCRIPTION

[0043] The present application will be further described and illustrated in conjunction with the specific embodiments. The examples are only exemplary and do not limit the scope. The technical features of each embodiment in the present application can be combined accordingly without conflict.

[0044] The present application provides a synthesis method of telaprevir, which has two optional routes. One of them includes steps 1)-3):

[0045] 1) Compound 6 and compound 9 are subjected to asymmetric allyl substitution reaction in the presence of a metal catalyst, a ligand, and an acid promoter to synthesize compound 14;

[0046] 2) Compound 14 is reduced by a reducing agent to synthesize compound 15;

[0047] 3) Compound 15 and compound 19 are subjected to sulfonamide to synthesize compound 20, i.e. telaprevir.

[0048] Another route includes steps a)-d):

[0049] a) Compound 6 and compound 13 are subjected to asymmetric allyl substitution reaction in the presence of a metal catalyst, a ligand, and an acid promoter to synthesize compound 16;

[0050] b) Compound 16 is reduced by a reducing agent in the presence of an acidic reagent and a solvent to obtain compound 17;

[0051] c) Compound 17 is subjected to deprotection of the hydroxyl protecting group in the presence of an acidic reagent and a solvent to obtain compound 15;

[0052] d) Compound 15 and compound 19 are subjected to sulfonamide to synthesize compound 20, i.e. telaprevir.

[0053] The preferred reaction conditions of the foregoing steps 1), steps 2), and steps a)-c) are described in the foregoing and will not be repeated here.

[0054] The synthesis route of the raw material compound 6 in the above two synthesis routes of Tipranavir has been reported in some literatures, and in the examples of the present application, the synthesis is carried out by the following steps:

[0055] 6.1) Synthesizing compound 2 from 1-phenyl-3-hexanone, i.e. compound 1, which can be carried out by step 6.1a) or step 6.1b);

[0056] 6.1a). Synthesizing compound 2 from 1-phenyl-3-hexanone, i.e. compound 1, by reacting with ethyl acetate under alkaline condition; the alkaline reagent is selected from lithium diisopropylamide (LDA) reagent; the solvent is selected from tetrahydrofuran. The molar ratio of compound 1 to ethyl acetate is 1:1-1:1.5; the molar ratio of compound 1 to LDA is 1:1-1:2; the reaction temperature is -70-0°C; the reaction time is 1-3 hours; the amount of the solvent is 1.0-2.0 mL / mmol based on the amount of compound 1.

[0057] 6.1b). Synthesizing compound 2 from 1-phenyl-3-hexanone, i.e. compound 1, by reacting with ethyl bromoacetate in the presence of zinc and iodine. The solvent in this step is selected from one or both of toluene and dimethoxyethane. The molar ratio of compound 1 to ethyl bromoacetate is 1:1-1:1.5; the molar ratio of compound 1 to zinc powder is 1:1.2-1:2; the molar ratio of compound 1 to iodine is 1:0.0001-1:0.01; the reaction temperature is 82-130°C; the reaction time is 2-5 hours; the volume ratio of toluene to dimethoxyethane is 1:0-1:1; the amount of the solvent is 0.8-2.0 mL / mmol based on the amount of compound 1.

[0058] 6.2) Hydrolyzing compound 2 under alkaline condition to obtain compound 3. Preferably, the alkaline reagent in this step is selected from one of sodium hydroxide and potassium hydroxide; in the step (2), the molar ratio of compound 2 to the alkaline reagent is 1:1-1:2; the reaction temperature is 0-50°C; the reaction time is 3-24 hours.

[0059] 6.3) Resolving compound 3 twice by a resolving agent to obtain compound 4; preferably, the resolving agent in this step is selected from one of (R)-N-(3,4-dimethoxybenzyl)-α-phenylethylamine and (R)-N-(o-chlorophenyl)-α-phenylethylamine; the molar ratio of compound 3 to the resolving agent is 1:0.5-1:1; the reaction temperature is 0-90°C; the reaction time is 2-24 hours.

[0060] 6.4) Compound 4 is condensed in the presence of a condensing agent to react with magnesium monoethyl malonate to synthesize compound 5. Preferably, the condensing agent in this step is selected from N,N carbonyldiimidazole (CDI); the solvent is selected from tetrahydrofuran; the molar ratio of compound 4 to CDI is 1:1-1:1.5; the molar ratio of compound 4 to magnesium monoethyl malonate is 1:1-1:1.5; the reaction temperature is -20-40℃; and the reaction time is 3-12 hours.

[0061] 6.5) Compound 5 is intramolecularly condensed under basic conditions to cyclize to obtain compound 6. Preferably, the basic reagent in this step is selected from sodium hydroxide or potassium hydroxide; the molar ratio of compound 5 to the basic reagent is 1:1-1:2; the reaction temperature is 0-50℃; and the reaction time is 3-24 hours.

[0062] The synthesis route of the raw material compound 9 in the above-mentioned synthesis route of tipranavir has been reported in some literatures, and the following steps are adopted in the examples of the present application to synthesize it:

[0063] (1) Compound 8 is synthesized by reacting m-nitrobenzaldehyde, i.e. compound 7, with Grignard reagent; wherein the Grignard reagent is selected from vinylmagnesium bromide reagent; the solvent is selected from tetrahydrofuran; in the step (6), the molar ratio of compound 7 to vinylmagnesium bromide is 1:1-1:2.5; the reaction temperature is -70-0℃; and the reaction time is 1-3 hours.

[0064] (2) Compound 9 is synthesized by protecting compound 8 under basic conditions with a hydroxyl protecting group. The basic reagent for constructing the basic conditions is selected from one of triethylamine, pyridine, and diisopropylethylamine (DIPEA); this step is carried out in the presence of a catalyst and a solvent, the catalyst is selected from 4-dimethylaminopyridine (DMAP); the solvent is selected from one of dichloromethane, dichloroethane, tetrahydrofuran, and ethanol; the molar ratio of compound 8 to the basic reagent is 1:1-1:3; the molar ratio of compound 8 to the hydroxyl protecting reagent is 1:1-1:1.5; the molar ratio of compound 8 to the catalyst is 1:0-1:0.5; the reaction temperature is 0-40℃; and the reaction time is 2-12 hours.

[0065] The synthesis route of the raw material compound 13 in the above-mentioned synthesis route of tipranavir has been reported in some literatures, and the following steps are adopted in the examples of the present application to synthesize it:

[0066] (1) Compound 11 is synthesized by protecting m-aminobenzyl alcohol, i.e. compound 10, with an amino protecting group; the amino protecting reagent is selected from di-tert-butyl dicarbonate; the solvent is selected from one of dichloromethane, tetrahydrofuran, and ethanol; the molar ratio of compound 10 to the amino protecting reagent is 1:1-1:1.2; the reaction temperature is 0-40℃; and the reaction time is 2-12 hours;

[0067] (2) Compound 11 is oxidized by an oxidizing agent to obtain compound 12; the oxidizing agent is selected from pyridinium chlorochromate (PCC); the solvent is selected from one of tetrahydrofuran, dichloromethane; the molar ratio of compound 11 to PCC is 1:1-1:1.5; the reaction temperature is 0-25℃; and the reaction time is 1-12 hours;

[0068] (3) Compound 12 is reacted with a Grignard reagent to synthesize compound 13. The Grignard reagent is selected from vinylmagnesium bromide; the solvent of this step is selected from tetrahydrofuran; the molar ratio of compound 12 to vinylmagnesium bromide is 1:1-1:3; the reaction temperature is -70-0℃; and the reaction time is 1-3 hours.

[0069] In the two synthetic routes of the present application, the step 3) of route one and the step d) of route two are completely the same, i.e. compound 15 is sulfonamidated with compound 19 in the presence of a basic reagent, a stabilizer and a solvent to synthesize compound 20. Preferably, the basic reagent is selected from one of pyridine, triethylamine, N,N-dimethylaniline, and further preferably N,N-dimethylaniline; the stabilizer is selected from 2,6-di-tert-butyl-p-cresol; and the solvent is selected from one of dichloromethane and anhydrous dichloromethane, and further preferably dichloromethane. Preferably, the molar ratio of compound 15 to compound 19 is 1:1-1:2, and further preferably 1:1.1; the molar ratio of compound 15 to the basic reagent is 1:1.1-1:3, and further preferably 1:1.2; the molar ratio of compound 15 to the stabilizer is 1:0-1:0.2, and further preferably 1:0.2; the reaction temperature is -20-25℃, and further preferably 0℃; and the reaction time is 0.5-3 hours. The amount of the solvent is 5.0-10.0 mL / mmol based on the amount of compound 16, and further preferably 6 mL / mmol.

[0070] The synthetic route of compound 19 has been reported in many literatures, for example, compound 18, i.e. 5-(trifluoromethyl)-2-mercaptopyridine, can be used as a raw material to synthesize under acidic conditions. The acidic solvent for constructing the acidic conditions is selected from concentrated sulfuric acid; the chlorine source is selected from 10.5% available chlorine sodium hypochlorite solution; the amount of the 10.5% available chlorine sodium hypochlorite solution is 2.0-5.0 mL / mmol based on the amount of compound 18; the reaction temperature is -16-0℃; and the reaction time is 0.5-2 hours. The amount of the acidic solvent is 2.0-4.0 mL / mmol based on the amount of compound 18.

[0071] Based on the above information, the application further provides a full synthesis method of telaprevir, which takes 1-phenyl-3-hexanone, i.e., compound 1, m-nitrobenzaldehyde, i.e., compound 7 (or m-aminobenzyl alcohol, i.e., compound 10), and 5-(trifluoromethyl)-2-mercaptopyridine, i.e., compound 18 as starting materials; the full synthesis route is shown in the following formula:

[0072]

[0073] wherein R is tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl or acetyl.

[0074] The full synthesis route is specifically as follows: 1-phenyl-3-hexanone, i.e., compound 1, is taken as a starting material, and compound 2 is generated through two methods; compound 3 is obtained by hydrolysis of compound 2; compound 4 is obtained by resolution of compound 3; compound 5 is obtained by condensation of compound 4; and compound 6 is obtained by cyclization of compound 5.

[0075] m-nitrobenzaldehyde, i.e., compound 7, or m-aminobenzyl alcohol, i.e., compound 10, is taken as a raw material to synthesize phenyl allyl alcohol, i.e., compound 9 or compound 13, through addition and methylation of two steps or methylation, oxidation and addition of three steps; compound 6 and compound 9 or compound 13 are reacted through two steps or three steps, respectively, to obtain compound 15.

[0076] 5-(trifluoromethyl)-2-mercaptopyridine, i.e., compound 18, is taken as a raw material to obtain compound 19.

[0077] Compound 15 and compound 19 are reacted through sulfonamide reaction to obtain compound 20, i.e., telaprevir.

[0078] The full synthesis route is efficient, simple in operation, safe and easy in raw material, mild in reaction condition, high in reaction yield, low in synthesis cost, and more suitable for industrial production.

[0079] The following embodiments further illustrate some steps in the method of the application:

[0080] Example 1

[0081]

[0082] To a dry 100 mL round bottom flask under nitrogen atmosphere was added [Ir(COD)Cl]2(53.7 mg, 0.08 mmol), (R)-L (162.4 mg, 0.32 mmol) and anhydrous toluene (40 mL) and stirred for 15 min. (6R)-5,6-dihydro-4-hydroxy-6-(2- phenylethyl)-6-propyl-2H-pyran-2-one (1.041 g, 4 mmol), t-butyl (1-(3- nitrophenyl)allyl) carbonate (2.234 g, 8 mmol) and ytterbium triflate (248.1 mg, 0.4 mmol) were added and stirred at room temperature for 28 h. The solvent was removed by rotary evaporation under reduced pressure and the crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10:1 to 2:1) to obtain compound 14 (1.551 g, 92%) as a yellow solid, (R)-3-((R)-1-(3-nitrophenyl)allyl)-4-hydroxy-6-phenylethyl-6-propyl-5,6-dihydro-2H-pyran-2-one, and t-butyl (1-(3-nitrophenyl)allyl) carbonate was recovered (0.731 g)

[0083] Mp: 105.1-109.5 °C; [a] D 20 = 21.30 (c = 1.54, CH2Cl2); 99% ee as determined by HPLC (Chiralcel AD-H, 90:10 hexanes / i-PrOH, 1 mL / min), t r (major) = 23.858 min, t r (minor) = 28.918 min; 1 H NMR (500 MHz, DMSO-d6) δ 11.22 (s, 1H), 8.07 - 8.03 (m, 2H), 7.66 (dd, J = 7.7, 1.4 Hz, 1H), 7.59 - 7.55 (m, 1H), 7.27 (t, J = 7.5 Hz, 2H), 7.19 - 7.14 (m, 3H), 6.44 (ddd, J = 16.8, 10.3, 8.3 Hz, 1H), 5.21 - 5.15 (m, 2H), 4.89 (d, J = 8.2 Hz, 1H), 2.72 (d, J = 2.5 Hz, 2H), 2.58 (dt, J = 11.0, 6.4 Hz, 2H), 1.97 - 1.84 (m, 2H), 1.76 - 1.65 (m, 2H), 1.31 (ddd, J = 12.8, 11.0, 6.0 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H); 13C NMR (126 MHz, DMSO-d6) δ 166.21, 166.11, 148.05, 146.18, 141.99, 138.12, 134.60, 129.86, 128.83, 128.58, 126.30, 122.11, 121.26, 117.11, 103.61, 80.51, 44.02, 39.52, 36.10, 29.70, 16.95, 14.72; HRMS calcd for C 25 H 28 NO5[M+H] + = 422.1962, found = 422.1965.

[0084] Example 2

[0085]

[0086] To a 50 mL round-bottom flask was added (R)-3-((R)-1-(3-nitrophenyl)allyl)-4- hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one (1 g, 2.3725 mmol), 10% Pd / C (150 mg) and methanol (7.5 mL) under the protection of hydrogen atmosphere, stirred at 40 °C for 3 h. After the reaction was completed, diatomite was filtered, washed with methanol (5 mL), the filtrate was evaporated under reduced pressure to remove the solvent, and yellow solid compound 15 (0.95 g, 99%) (R)-3-((R)-1-(3-aminophenyl)propyl)-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one was obtained, which could be directly used in the next step reaction without purification.

[0087] Mp: 105.9-108.2 °C; [a] D 20 = -17.92 (c = 1.73, CH2Cl2); 1H NMR (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 7.26 (t, J = 7.5 Hz, 2H), 7.19 - 7.12 (m, 3H), 6.83 (t, J = 7.7 Hz, 1H), 6.55 (t, J = 1.9 Hz, 1H), 6.49 (d, J = 7.6 Hz, 1H), 6.32 (dd, J = 7.9, 2.2 Hz, 1H), 4.89 (s, 2H), 3.79 (dd, J = 9.8, 6.4 Hz, 1H), 2.60 (s, 2H), 2.56 (ddd, J = 9.6, 5.7, 2.2 Hz, 2H), 2.13 (ddq, J = 14.5, 9.6, 7.3 Hz, 1H), 1.93 (ddd, J = 13.9, 10.4, 6.9 Hz, 1H), 1.88 - 1.79 (m, 2H), 1.66 (ddt, J = 18.8, 13.9, 8.6 Hz, 2H), 1.34 - 1.23 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H), 0.82 (t, J = 7.3 Hz, 3H); 13 C NMR (126 MHz, DMSO-d6) δ 166.66, 164.79, 148.36, 146.20, 142.06, 128.83, 128.61, 128.47, 126.25, 116.15, 114.21, 111.67, 104.90, 79.82, 42.30, 39.53, 39.31, 36.47, 29.76, 24.94, 16.92, 14.79, 13.48; HRMS calcd for C 25 H 32 NO3[M+H] + = 394.2377, found = 394.2382.

[0088] Example 3

[0089]

[0090] Into a dry 500 mL round bottom flask under nitrogen atmosphere was added tert-butyl (3-formylphenyl)carbamate (8.2 g, 37 mmol), anhydrous tetrahydrofuran (100 mL), and cooled to -30 °C. Ethyl vinyl magnesium bromide (1 M in THF, 92.5 mL, 92.5 mmol) was added dropwise slowly, and stirred at 0 °C for 3 h. Quench with saturated ammonium chloride solution (50 mL), and allowed to warm to room temperature. Extracted with ethyl acetate (50 mL x 3), combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure to give the product compound 13 (8.21 g, 88%) as a light yellow oil, which was used in the next step without further purification.

[0091] 1 H NMR (500 MHz, Chloroform-d) δ 7.30 (s, 1H), 7.21 - 7.16 (m, 2H), 6.97 - 6.92 (m, 1H), 6.54 (s, 1H), 5.94 (ddd, J = 17.1, 10.3, 6.0 Hz, 1H), 5.26 (dt, J = 17.1, 1.4 Hz, 1H), 5.10 (dt, J = 10.3, 1.4 Hz, 1H), 5.07 (d, J = 5.9 Hz, 1H), 2.19 (s, 1H), 1.43 (s, 9H); 13 C NMR (126 MHz, Chloroform-d) δ 152.80, 143.71, 140.06, 138.56, 129.15, 120.98, 115.18, 75.14, 28.35; HRMS calcd for C 14 H 19 NNaO3[M+Na] + =

[0092] 272.1257, found = 272.1263.

[0093] Example 4

[0094]

[0095] To a dry 100 mL round bottom flask under nitrogen atmosphere was added [Ir(COD)Cl]2(60.08 mg, 0.08945 mmol), (R)-L (181.63 mg, 0.3578 mmol) and anhydrous ethyl acetate (45 mL) and stirred for 15 min. (6R)-5,6-Dihydro-4-hydroxy-6-(2- phenylethyl)-6-propyl-2H-pyran-2-one (1.164 g, 4.4725 mmol), t-butyl (3-(1- allyloxy)phenyl)carbamate (2.23 g, 8.945 mmol) and ytterbium triflate (277.45 mg, 0.44725 mmol) were added and stirred at room temperature for 36 h. The solvent was removed by rotary evaporation under reduced pressure and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1) to obtain compound 16 (1.98 g, 90%) as white solid, t-butyl (3-((R)-1-((R)-4-hydroxy-2-oxo-6-phenylethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)allyl)phenyl)carbamate, and t-butyl (3-(1-allyloxy)phenyl)carbamate (0.729 g) was recovered.

[0096] Mp: 95.8-97.3 °C; [a] D 20 = 3.02 (c = 1.79, CH2Cl2); 99% ee as determined by

[0097] HPLC (Chiralcel AD-H, 85:15 hexanes / i-PrOH, with 0.1% Diethylamine, 1 mL / min), t r (minor) = 9.153 min, t r (major) = 16.328 min; 1H NMR (500 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.20 (s, 1H), 7.42 (s, 1H), 7.28 (t, J = 7.5 Hz, 2H), 7.23 - 7.14 (m, 4H), 7.09 (t, J = 7.9 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.49 - 6.39 (m, 1H), 5.10 - 5.07 (m, 1H), 5.05 (s, 1H), 4.71 (d, J = 8.5 Hz, 1H), 2.67 (d, J = 2.1 Hz, 2H), 2.62 - 2.54 (m, 2H), 1.96 - 1.83 (m, 2H), 1.71 (ddt, J = 21.0, 9.9, 7.7 Hz, 2H), 1.46 (s, 9H), 1.31 (dq, J = 11.6, 5.7, 5.3 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H); 13 C NMR (126 MHz, DMSO-d6) δ 166.15, 165.06, 153.20, 144.28, 142.05, 139.65, 139.63, 128.83, 128.61, 128.29, 126.26, 121.43, 117.85, 116.08, 115.57, 104.66, 80.19, 79.15, 44.59, 39.56, 39.52, 36.18, 29.73, 28.60, 16.96, 14.76; HRMS calcd for C 30 H 37 NNaO5[M+Na] + =

[0098] 514.2564, found = 514.2570.

[0099] Example 5

[0100]

[0101] In a 100 mL round bottom flask, tert-butyl (3-((R)-1-((R)-4-hydroxy-2-oxo-6- phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)allyl)phenyl)carbamate (1.82 g, 3.712 mmol) was dissolved in ethanol (37 mL), sodium acetate (1.218 g, 14.848 mmol) and p-toluenesulfonylhydrazide (2.765 g, 14.848 mmol) were added, and the mixture was heated and stirred under reflux for 2.5 h. The ethanol was removed by rotary evaporation, and ethyl acetate (20 mL) and water (20 mL) were added, and the mixture was stirred for 5 min. The ethyl acetate layer was extracted (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10:1 to 3:1) to obtain Compound 17 (1.8 g, 98%) as a white solid, tert-butyl (3-((R)-1-((R)-4-hydroxy-2-oxo-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-3- yl)propyl)phenyl)carbamate.

[0102] Mp: 83.5-85.3 °C; [a] D 20 = 23.71 (c = 1.4, CH2Cl2); 99% ee as determined by HPLC (Chiralcel AD-H, 90:10 hexanes / i-PrOH, with 0.1% Diethylamine, 1 mL / min), t r (minor) = 17.997 min, t r (major) = 22.946 min; 1 H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.17 (s, 1H), 7.45 (s, 1H), 7.26 (t, J = 7.5 Hz, 2H), 7.21 - 7.15 (m, 2H), 7.15 - 7.10 (m, 2H), 7.07 (t, J = 7.9 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 3.89 (dd, J = 9.8, 6.3 Hz, 1H), 2.62 (s, 2H), 2.55 (ddd, J = 9.5, 6.1, 1.8 Hz, 2H), 2.18 - 2.10 (m, 1H), 1.95 - 1.85 (m, 2H), 1.81 (ddd, J = 13.9, 10.3, 7.0 Hz, 1H), 1.66 (dqd, J = 10.7, 8.1, 4.6 Hz, 2H), 1.46 (s, 9H), 1.29 - 1.25 (m, 2H), 0.85 (dt, J = 9.5, 7.3 Hz, 6H).13 C NMR (126 MHz, DMSO-d6) δ 166.57, 165.14, 153.22, 146.00, 142.04, 139.40, 128.82, 128.59, 128.16, 126.24, 121.95, 118.41, 115.90, 104.57, 79.90, 79.10, 42.18, 40.23, 39.35, 36.39, 29.74, 28.62, 24.78, 16.93, 14.76, 13.36; HRMS calcd for C 30 H 39 NNaO5[M+Na] + = 516.2702, found = 516.2703.

[0103] Example 6

[0104]

[0105] In a 150 mL round bottom flask, tert-butyl (3-((R)-1-((R)-4-hydroxy-2-oxo-6- phenethyl-6-propyl-5,6-dihydro-2H-pyran-3-yl)propyl)phenyl)carbamate (1.76 g, 3.566 mmol) was dissolved in tetrahydrofuran (36 mL), 6 M hydrochloric acid solution (30 mL) was added, and stirring was performed at room temperature for 6 h. A 4 M sodium hydroxide solution was added to adjust the pH to about 10. Ethyl acetate was added for extraction (60 mL x 3). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain compound 15 (1.4 g, 99%) as a light yellow solid, (R)-3-((R)-1-(3- aminophenyl)propyl)-4-hydroxy-6-phenethyl-6-propyl-5,6-dihydro-2H-pyran-2-one, which was used directly in the next reaction without purification.

[0106] Example 7

[0107]

[0108] (R)-3-((R)-1-(3-aminophenyl)propyl)-4-hydroxy-6-phenethyl-6-propyl-5,6- dihydro-2H-pyran-2-one (1.1 g, 2.8 mmol) was dissolved in dichloromethane (16 mL), N,N-dimethylaniline (390 mg, 3.22 mmol), 2,6-di-tert-butyl-p-cresol (123 mg, 0.56 mmol) were added and cooled to 0°C. 5- trifluoromethyl-2-pyridinesulfonyl chloride (825 mg, 3.36 mmol) was added and stirred for 3 h. Dilution with dichloromethane (12 mL) and washing with 2M hydrochloric acid solution (8 mL) was performed. The organic phase was dried over anhydrous Na2SO4, filtered and the solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 12:1 to 5:1) to obtain compound 20 (1.42 g, 84%) as a white solid, N-[3-[(1R)-1-[(6R)-2-hydroxy-4-oxo-6-phenethyl-6-propyl-5H-pyran-3-yl]propyl]phenyl]-5- (trifluoromethyl)pyridine-2-sulfonamide. This white solid was recrystallized from a n- hexane / dichloromethane solution and left at -20°C for 12 h. Filtration and washing with a small amount of n-hexane / dichloromethane solution at -20°C afforded high purity 99.9% of tipranavir.

[0109] Mp: 88.1-91.6 °C; [a] D 20 = (c = 1.51, MeOH); 99% ee as determined by HPLC (Chiralcel IC, 80:20 hexanes / i- PrOH, 1 mL / min), t r (minor) = 15.498 min, t r (major) = 21.835 min; 1H NMR (500 MHz, DMSO-d6) δ 10.67 (s, 2H), 9.12 (d, J = 2.2 Hz, 1H), 8.44 (dd, J = 8.3, 2.3 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.25 (t, J = 7.5 Hz, 2H), 7.18 - 7.14 (m, 2H), 7.09 - 7.05 (m, 3H), 6.97 (dt, J = 7.8, 1.2 Hz, 1H), 6.91 (dt, J = 8.4, 1.2 Hz, 1H), 3.82 (dd, J = 9.5, 6.6 Hz, 1H), 2.58 (s, 2H), 2.55 - 2.51 (m, 2H), 2.05 (ddd, J = 13.3, 9.6, 7.2 Hz, 1H), 1.89 - 1.75 (m, 3H), 1.61 (dtd, J = 14.5, 7.0, 2.9 Hz, 2H), 1.26 - 1.20 (m, 2H), 0.82 (t, J = 7.3 Hz, 3H), 0.76 (t, J = 7.3 Hz, 3H); 13 C NMR (126 MHz, DMSO-d6) δ 166.39, 165.21, 160.37, 147.64, 146.60, 141.96, 137.05, 136.88, 128.82, 128.77, 128.53, 128.17 (q, J = 32.8 Hz), 126.24, 124.41, 123.30 (q, J = 273.4 Hz), 123.26, 120.58, 118.29, 104.31, 79.87, 42.09, 39.49, 39.28, 36.38, 29.69, 24.68, 16.86, 14.70, 13.2 / 1; HRMS calcd for C 31 H 34 F3N2O5S [M+H] + = 603.2135, found = 603.2145.

[0110] The above-described embodiments only express several embodiments of the present application, which are described in more detail and in more detail, but cannot be understood as limiting the scope of the patent of the present application. For ordinary skilled in the art, without departing from the concept of the present application, a number of modifications and improvements can be made, which are within the scope of protection of the present application.

Claims

1. A method for synthesizing telanavir, characterized in that, Includes the following steps: 1) Compound 6 and Compound 9 were synthesized into Compound 14 via an asymmetric allyl substitution reaction in the presence of a metal catalyst, ligand, and acid accelerator; The metal catalyst is selected from 1,5-cyclooctadiene iridium chloride dimer ([Ir(COD)Cl]2); the ligand is selected from (R)-(+)-(3,5-dioxa-4-phosphocycloheptano[2,1-a;3,4-a']dinaphthyl-4-yl)-5-hydro-dibenzo[b,f]azapyridine; the acid accelerator is selected from ytterbium trifluoromethanesulfonate; the reaction is carried out in a solvent, which is selected from one or more of ethyl acetate and toluene; The molar ratio of compound 6 to compound 9 is 1:1.1-1:2; the molar ratio of compound 6 to the metal catalyst is 1:0.02-1:0.04; the molar ratio of compound 6 to the ligand is 1:0.08-1:0.016; the molar ratio of compound 6 to the acid accelerator is 1:0.05-1:0.1; the reaction temperature is 25-50℃; and the reaction time is 28-72 hours. 2) Compound 14 was reduced by a reducing agent to synthesize compound 15; 3) Compound 15 and compound 19 were sulfonated to synthesize compound 20, namely telanavir; The synthesis route is shown in the following formula: Wherein, R represents tert-butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, or acetyl.

2. The synthesis method according to claim 1, characterized in that, In step 2), the reducing agent is selected from hydrogen; the catalyst is selected from 10% palladium on carbon; the solvent is selected from methanol; in step 2), the mass ratio of compound 14 to catalyst is 1:0.1-1:0.2; the reaction temperature is 25-45℃; and the reaction time is 2-48 hours.

3. A method for synthesizing telanavir, characterized in that, Includes the following steps: a) Compound 6 and Compound 13 were synthesized into Compound 16 via an asymmetric allyl substitution reaction in the presence of a metal catalyst, a ligand, and an acid accelerator; The metal catalyst is selected from 1,5-cyclooctadiene iridium chloride dimer ([Ir(COD)Cl]2); the ligand is selected from (R)-(+)-(3,5-dioxa-4-phosphocycloheptano[2,1-a;3,4-a']dinaphthyl-4-yl)-5-hydro-dibenzo[b,f]azapyridine; the acid accelerator is selected from ytterbium trifluoromethanesulfonate; the reaction is carried out in a solvent, which is selected from one or more of ethyl acetate and toluene; The molar ratio of compound 6 to compound 13 is 1:1.2-1:2; the molar ratio of compound 6 to the metal catalyst is 1:0.02-1:0.04; the molar ratio of compound 6 to the ligand is 1:0.08-1:0.016; the molar ratio of compound 6 to the acid accelerator is 1:0.05-1:0.1; the reaction temperature is 25-50℃; and the reaction time is 36-96 hours. b) Compound 16 was reduced by a reducing agent in the presence of an acidic reagent and solvent to obtain compound 17; c) Compound 17 was deprotected in the presence of an acidic reagent and solvent to give compound 15; d) Compound 15 and compound 19 are sulfonated to synthesize compound 20, namely telanavir; The synthesis route is shown in the following formula:

4. The synthesis method according to claim 3, characterized in that, In step b), the reducing agent is selected from p-toluenesulfonyl hydrazine; the acidic reagent is sodium acetate; the solvent is ethanol; the molar ratio of compound 16 to p-toluenesulfonyl hydrazine is 1:2-1:5; the molar ratio of compound 16 to sodium acetate is 1:2-1:5; and the reaction temperature is 25-80℃. The reaction time is 3-48 hours.

5. The synthesis method according to claim 3, characterized in that, In step c), the acidic reagent is 12 mol / L concentrated hydrochloric acid; the solvent is one or both of tetrahydrofuran and water; based on the amount of compound 17 used, the amount of concentrated hydrochloric acid used is 1.0-6.0 mL / mmol; the reaction temperature is 25-50℃; and the reaction time is 3-24 hours.

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