CN104292146B - Telaprevir intermediate and preparation method thereof - Google Patents

Abstract

The invention discloses a telaprevir intermediate and a preparation method thereof. The telaprevir intermediate is the compound shown in 1. The preparation method of telaprevir intermediate compound 2 comprises the following steps: in an organic solvent, under the action of a desulfurizing agent, compound 1 is subjected to a desulfurization reaction to obtain compound 2; wherein, R ¹ is C ₁ -C ₆ straight chain or branched chain alkyl, n is 0, 1 or 2, Z is an amino protecting group. The preparation method of the telaprevir intermediate of the present invention is simple and easy.

Description

Telaprevir intermediate and preparation method thereof

technical field

The invention relates to the field of drug synthesis, in particular to a telaprevir intermediate and a preparation method thereof.

Background technique

Globally, the infection rate of hepatitis C virus (HCV) is about 3%, and the total number of infected people is about 200 million. Because of the high infection rate of HCV and the serious potential complications such as liver cirrhosis and liver cancer, HCV is a serious threat to human life and health. According to the Simmonds naming system, HCV can be divided into six main genotypes, namely I-VI, and each type can be divided into several subtypes (such as Ia, Ib, IIa, IIb, IIIa, IIIb, etc.). There are about 40 million HCV-infected people in my country, 69% of whom are type I infections (mainly type Ib). The current treatment of chronic hepatitis C is mainly the combination of pegylated interferon (PEG-IFNα) and ribavirin (RBV), which fails to produce sustained virological response in about 50% of HCV type I patients , and have adverse reactions, so it is urgent to develop effective therapeutic drugs. Due to this need, the research and development of new anti-HCV drugs is very active. At present, more than 50 anti-HCV drug candidates are undergoing or have been approved for clinical trials. Among these drugs, Telaprevir (Incivek (Telaprevir)) was approved by the US FDA (Food and Drug Administration) on May 23, 2011 in combination with pegylated interferon and ribavirin for the treatment of chronic Hepatitis C.

telaprevir

Telaprevir (Telaprevir) is a chronic hepatitis C treatment drug developed by Vertex Pharmaceutical Co., Ltd. of the United States. It is an orally effective HCV NS3 protease inhibitor. A small molecule inhibitor discovered by systematically truncating and modifying amino acid residues on a peptide can capture the serine in the active site of NS3, and the carbonyl carbon on the ketoamide combines with the serine to form a covalent adduct, resulting in NS3 Inactivate. A study published in the "New England Journal of Medicine" showed that for patients with previously untreated chronic HCV genotype Ⅰ infection, adding Telaprevir to the standard treatment of pegylated interferon-ribavirin was associated with Compared with standard treatment alone, it can significantly increase the sustained virological response rate.

The synthesis method of Telaprevir disclosed in the original compound patent WO02/18369A2 of Telaprevir involves the following three key intermediates:

Key Intermediate 1 Key Intermediate 2 Key Intermediate 3

Wherein the main synthetic method of key intermediate 1 has the following three kinds of reports:

(1) The original compound patent WO02/18369A2 reported (1S,3aR,6aS)-1-ethyl-2-(phenylmethyl)-4-oxohexahydrocyclopenta[c]pyrrole- Using 1,2(1H)-dicarboxylate as the starting material, the key intermediate 1 can be obtained through 4 steps. The synthetic route is as follows.

key intermediate 1

(2) Patent US2007/0087973A1 reported that (3aR,6aS)-heptahydrocyclopenta[c]pyrrole was used as the starting material to obtain the oxalate salt of the key intermediate 1 through 4 steps. The synthetic route is as follows.

Oxalate of key intermediate 1

(3) Patent WO2010/008828A2 reported that (3aR,6aS)-heptahydrocyclopenta[c]pyrrole was used as the starting material, and the key intermediate 1 was obtained through enzymatic oxidation and other five-step reactions. The synthetic route is as follows.

key intermediate 1

Given the importance of hepatitis C virus ("HCV") protease inhibitors, novel intermediates for the preparation of such inhibitors are always of interest.

Contents of the invention

The technical problem solved by the present invention is to provide a telaprevir intermediate completely different from the prior art and a preparation method thereof. The preparation method of the telaprevir intermediate of the present invention is simple and easy.

The present invention solves the above technical problems through the following technical solutions:

The present invention provides a method for preparing telaprevir intermediate compound 2, which comprises the following steps: in an organic solvent, under the action of a desulfurizing agent, desulfurize compound 1 to obtain compound 2;

Wherein, R ¹ is a C ₁ -C ₆ linear or branched alkyl group, n is 0, 1 or 2, and Z is an amino protecting group.

In the present invention, said R ¹ is preferably a C ₁ -C ₄ linear or branched alkyl group.

In the present invention, said Z is preferably tert-butoxycarbonyl, benzyloxycarbonyl or benzyl, more preferably tert-butoxycarbonyl or benzyloxycarbonyl.

Wherein, the method and condition of described desulfurization reaction all can be the conventional method and condition of this type of reaction in this area, and the present invention particularly preferably following condition:

The desulfurization agent is preferably Raney nickel.

The mass ratio between the desulfurization reagent and compound 1 is preferably (5:1-20:1), more preferably (5:1-15:1), most preferably (5:1-10:1 ).

The organic solvents are preferably ether solvents, halogenated hydrocarbon solvents, aromatic hydrocarbon solvents, alcohol solvents, acetonitrile, DMF (N,N-dimethylformamide) and DMSO (dimethyl sulfoxide) One or more of, more preferably alcoholic solvents. The ether solvent is preferably one or more of diethyl ether, tetrahydrofuran, methyl tert-butyl ether and tetrahydropyran (THP). The halogenated hydrocarbon solvent is preferably one or more of methylene chloride, chloroform, carbon tetrachloride and ethylene dichloride. The aromatic hydrocarbon solvent is preferably one or more of toluene, benzene, xylene, trimethylbenzene and chlorobenzene. The alcohol solvent is preferably one or more of methanol, ethanol and isopropanol, more preferably ethanol.

The volume mass ratio of the organic solvent and compound 1 is preferably 5-20ml/g.

The temperature of the desulfurization reaction is preferably 20-120°C, more preferably 40-100°C, most preferably 60-80°C.

The progress of the desulfurization reaction can be monitored by conventional means in the field (such as TLC or HPLC). Generally, the end point of the reaction is when compound 1 disappears. The time of the desulfurization reaction is preferably 4-8 hours.

In the present invention, the compound 1 can be prepared by the following method: compound E is reacted with a thiol reagent F under the action of a catalyst in a solvent to obtain compound 1;

Wherein, the method and condition of described reaction all can be the conventional method and condition of this type of reaction in this area, and the present invention particularly preferably following condition:

The catalyst is preferably a Lewis acid, more preferably one or more of boron trifluoride ether, aluminum trichloride and trifluoroacetic acid, most preferably boron trifluoride ether.

The molar ratio of the catalyst to compound E is preferably (0.1:1-1:1), more preferably (0.1:1-0.5:1), most preferably (0.1:1-0.3:1) .

The solvents are preferably ether solvents, halogenated hydrocarbon solvents, aromatic hydrocarbon solvents, ester solvents, acetonitrile, DMF (N,N-dimethylformamide) and DMSO (dimethyl sulfoxide) One or more, more preferably halogenated hydrocarbon solvents. The ether solvent is preferably one or more of diethyl ether, tetrahydrofuran, methyl tert-butyl ether and tetrahydropyran (THP). The halogenated solvent hydrocarbon is preferably one or more of dichloromethane, chloroform, carbon tetrachloride and dichloroethane, more preferably dichloromethane. The aromatic hydrocarbon solvent is preferably one or more of toluene, benzene, xylene, trimethylbenzene and chlorobenzene. The ester solvent is preferably ethyl acetate.

The volume mass ratio of the solvent and the compound E is preferably 5-20ml/g.

The molar ratio of the thiol reagent F to compound E is preferably (1:1-5:1), more preferably (1:1-3:1), most preferably (1:1-1.5 :1).

The reaction temperature is preferably 0-80°C, more preferably 20-60°C, most preferably 20-30°C.

The progress of the reaction can be monitored by conventional means in the art (such as TLC or HPLC). Generally, the end point of the reaction is when the compound E disappears. The reaction time is preferably 0.5-4 hours.

In the present invention, the compound E can be prepared according to the method in the document J.Org.Chem., Vol.59, No.10, 1994, and its preparation route is as follows:

Step 1. includes the following steps: Compound A is reacted with bromoacetate in an organic solvent to prepare compound B. With respect to compound A, bromoacetate can be used in about 1 molar equivalent to about 3 molar equivalents, preferably 1 molar equivalent to about 3 molar equivalents. 2 molar equivalents, more preferably 1.2 molar equivalents, available bromoacetate esters include methyl bromoacetate, ethyl bromoacetate, etc., preferably ethyl bromoacetate. Usable solvents include aromatic solvents, such as toluene, benzene, xylene, trimethylbenzene, chlorobenzene, etc.; ester solvents, such as ethyl acetate, etc.; alcohol solvents, such as methanol, ethanol, isopropanol, etc.; preferred solvents It is an alcoholic solvent, more preferably ethanol. The reaction in step ① can be carried out at a temperature of 20°C-120°C, preferably 40°C-90°C, more preferably 70°C-90°C, for 3-6 hours or until the reaction is complete.

Step ② includes the following steps: compound B and 2-cyclopentenone undergo 1,3-dipolar cycloaddition to obtain compound C under the action of an organic base in an organic solvent. 2-Cyclopentenone can be used in an amount of about 2 to 8 molar equivalents, preferably 2 to 4 molar equivalents, more preferably 3 to 4 molar equivalents, relative to compound B. The organic base can be used in an amount of about 1 to 4 molar equivalents, preferably 1 to 3 molar equivalents, more preferably about 1 to about 2 molar equivalents, relative to compound B. Usable organic bases include triethylamine, N,N-diisopropylethylamine (DIEA), tripropylamine, etc., preferably triethylamine. Usable solvents include ether solvents, such as diethyl ether, THF, methyl tert-butyl ether, THP, etc.; halogenated hydrocarbon solvents, such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, etc.; aromatic solvents, For example, toluene, benzene, xylene, trimethylbenzene, chlorobenzene, etc.; and ester solvents, such as ethyl acetate, etc.; and other solvents, such as acetonitrile, DMF, DMSO, etc. or a suitable mixture thereof. Preferred solvents are other solvents, more preferably acetonitrile. The reaction in step ② can be carried out at a temperature of about -20°C to about 80°C, preferably at a temperature of 0°C to 50°C, more preferably at a temperature of about 10°C to 30°C, for about 24 to 26 hours or until the reaction is complete.

Step 3. includes the following steps: in an organic solvent, under the action of a catalyst and tri-n-butyltin hydride, compound C obtains compound D through free radical reaction and salt-forming reaction with hydrochloric acid, wherein in the step of free radical reaction, relatively For compound C, tri-n-butyltin hydride can usually be used in about 1 molar equivalent to 5 molar equivalents, preferably 1 molar equivalent to 3 molar equivalents, more preferably about 1 molar equivalent to 1.3 molar equivalents; relative to compound C, the catalyst is usually It can be used in about 0.01 molar equivalent to about 0.5 molar equivalent, preferably in 0.05 to 0.3 molar equivalent, more preferably in about 0.1 molar equivalent to about 0.15 molar equivalent. Useful catalysts include AIBN. Available organic solvents include ether solvents, such as diethyl ether, THF, methyl tert-butyl ether, THP, etc.; halogenated hydrocarbon solvents, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, etc.; aromatic solvents , such as toluene, benzene, xylene, trimethylbenzene, chlorobenzene, etc.; and ester solvents, such as ethyl acetate, etc.; and other solvents, such as acetonitrile, DMF, DMSO, etc. or a suitable mixture thereof. Preferred solvents are aromatic solvents, more preferably toluene. In the free radical reaction step, the reaction can be carried out at about 25°C to about 150°C, preferably at 50°C to 120°C, more preferably at about 80°C to 100°C for about 8 hours or until the reaction is complete. Wherein, in the step reaction of forming a salt with hydrochloric acid, relative to compound C, hydrochloric acid can usually be used in about 1 molar equivalent to about 5 molar equivalents, preferably 1 molar equivalent to 3 molar equivalents, more preferably about 1 molar equivalent to about 1.5 molar equivalents . Usable solvents include ether solvents, such as diethyl ether, THF, methyl tert-butyl ether, THP, etc.; halogenated hydrocarbon solvents, such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, etc.; aromatic solvents, For example, toluene, benzene, xylene, trimethylbenzene, chlorobenzene, etc.; and ester solvents, such as ethyl acetate, etc.; and other solvents, such as acetonitrile, DMF, DMSO, etc. or a suitable mixture thereof. The preferred solvent is an ester solvent, more preferably ethyl acetate. The step of salt formation with hydrochloric acid can be carried out at about 0°C to about 80°C, preferably at 20°C to 60°C, more preferably at about 20°C to about 30°C, for about 14 hours or until the reaction is complete.

Step ④ includes the following steps: in an organic solvent, under the action of a base, compound D reacts with an amino-protecting group reagent to obtain compound E, and with respect to compound D, the amino-protecting group reagent can usually be about 1 molar equivalent to about 5 molar equivalents , preferably 1 molar equivalent to 3 molar equivalents, more preferably about 1 molar equivalent to about 1.5 molar equivalents, available amino protecting groups include benzyloxycarbonyl, tert-butoxycarbonyl, benzyl, etc., preferably benzyloxycarbonyl and tert-butoxy carbonyl. The base can usually be used in an amount of about 1 molar equivalent to about 5 molar equivalents, preferably 1 molar equivalent to 3 molar equivalents, more preferably about 1 molar equivalent to about 1.5 molar equivalents, relative to compound D. Useful bases include sodium carbonate, sodium bicarbonate, sodium hydroxide, preferably sodium hydroxide. Available organic solvents include ether solvents, such as ether, THF, methyl tert-butyl ether, THP, etc.; halogenated hydrocarbon solvents, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, etc.; aromatic solvents, For example, toluene, benzene, xylene, trimethylbenzene, chlorobenzene, etc.; and ester solvents, such as ethyl acetate, etc.; and other solvents, such as acetonitrile, DMF, DMSO, etc. or a suitable mixture thereof. Ester solvents are preferred, and ethyl acetate is more preferred. The reaction in step ④ can be carried out at a temperature of about -20°C to about 80°C, preferably -10°C to 50°C, more preferably about 0°C to about 30°C, for 4 to 6 hours or until the reaction is complete.

The present invention also provides a telaprevir intermediate as shown in formula 1,

Wherein, R ¹ is a C ₁ -C ₆ linear or branched alkyl group, n is 0, 1 or 2, and Z is an amino protecting group.

In the present invention, said R ¹ is preferably a C ₁ -C ₄ linear or branched alkyl group.

In the present invention, said Z is preferably tert-butoxycarbonyl, benzyloxycarbonyl or benzyl, more preferably tert-butoxycarbonyl or benzyloxycarbonyl.

The present invention also provides a preparation method of telaprevir intermediate compound 1, which comprises the following steps: in a solvent, under the action of a catalyst, compound E is reacted with a thiol reagent F to obtain compound 1 ;

Wherein, the method and condition of described reaction all can be the conventional method and condition of this type of reaction in this area, and the present invention particularly preferably following condition:

The catalyst is preferably a Lewis acid, more preferably one or more of boron trifluoride ether, aluminum trichloride and trifluoroacetic acid, most preferably boron trifluoride ether.

The molar ratio of the catalyst to compound E is preferably (0.1:1-1:1), more preferably (0.1:1-0.5:1), most preferably (0.1:1-0.3:1) .

The solvents are preferably ether solvents, halogenated hydrocarbon solvents, aromatic hydrocarbon solvents, ester solvents, acetonitrile, DMF (N,N-dimethylformamide) and DMSO (dimethyl sulfoxide) One or more, more preferably halogenated hydrocarbon solvents. The ether solvent is preferably one or more of diethyl ether, tetrahydrofuran, methyl tert-butyl ether and tetrahydropyran (THP). The halogenated hydrocarbon solvent is preferably one or more of dichloromethane, chloroform, carbon tetrachloride and dichloroethane, more preferably dichloromethane. The aromatic hydrocarbon solvent is preferably one or more of toluene, benzene, xylene, trimethylbenzene and chlorobenzene. The ester solvent is preferably ethyl acetate.

The volume mass ratio of the solvent and the compound E is preferably 5-20ml/g.

The molar ratio of the thiol reagent F to compound E is preferably (1:1-5:1), more preferably (1:1-3:1), most preferably (1:1-1.5 :1).

The reaction temperature is preferably 0-80°C, more preferably 20-60°C, most preferably 20-30°C.

The progress of the reaction can be monitored by conventional means in the art (such as TLC or HPLC). Generally, the end point of the reaction is when the compound E disappears. The reaction time is preferably 0.5-4 hours.

On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

The reagents and raw materials used in the present invention are all commercially available.

The positive and progressive effect of the present invention is that the preparation method of the telaprevir intermediate of the present invention is simple and easy.

detailed description

The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples. For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.

2-cyclopentenone was purchased from Shanghai Tebo Chemical Technology Co., Ltd., 4-methyl-5-hydroxyethylthiazole, 1,2-ethanedithiol, and Raney nickel were purchased from Shanghai Darui Fine Chemical Co., Ltd. The Raney nickel model number is RTH-3110. Tri-n-butyltin hydride and azobisisobutyronitrile were purchased from Bailingwei Chemical, and other reagents and solvents were purchased from Sinopharm Chemical Reagent Co., Ltd. Anhydrous dichloromethane is distilled from dichloromethane and phosphorus pentoxide after reflux.

Example 1

Preparation of Compound C (according to the method in J.Org.Chem., Vol.59, No.10, 1994):

At 20°C, add 4-methyl-5-hydroxyethylthiazole (40g, 0.27mol), ethyl bromoacetate (37.1ml, 0.33mol), and EtOH400ml into a three-necked flask, heat up to reflux, and stir for 3 hours , the heating was stopped, and the solvent was removed by rotary evaporation. Recrystallization from CH ₂ Cl ₂ and ether gave 50 g of white solid B.

Under the protection of _N2 , compound B (20g, 64.5mmol), 2-cyclopentenone (25g, 304.5mmol) and anhydrous acetonitrile were added to the reaction flask, and three Ethylamine (7.17g, 70.9mmol) was added dropwise and reacted at room temperature for 24h under the protection of nitrogen. Add 100ml of water to the reaction solution to quench the reaction, extract the aqueous phase with ether, combine the organic phases, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and distill off the solvent to obtain 17.9 g of brown oil. Column chromatography yielded 13.6 g of C-1 and 2.0 g of C-2.

When Z is benzyloxycarbonyl, the preparation of compound E (according to the method in the document J.Org.Chem., Vol.59, No.10, 1994):

At 20°C, add C-1 and C-2 (3.5g, 11.25mmol), AIBN (278mg, 1.69mmol), tri-n-butyltin hydride (3.9ml, 14.63mmol) and anhydrous toluene into a three-necked flask (35ml), under the protection of N ₂ , the temperature was raised to reflux, stirred for 8h, and the solvent was removed by rotary evaporation to obtain a residue. The residue, 1N HCl (15ml, 14.3mmol) and diethyl ether (15ml) were added to the reaction flask, stirred at room temperature for 14h, the aqueous phase was extracted with ethyl acetate, and the aqueous phase was used for the next reaction.

At 20°C, add the previous aqueous phase, ethyl acetate (30ml) and benzyl chloroformate (1.7ml, 12.4mmol) into the three-necked flask, and cool the biphasic solution to 0°C. 2N NaOH aqueous solution (15.8ml, 31.5mmol) was slowly added dropwise to the solution. After the dropwise addition was completed, the mixture was stirred at 0°C for 1h, then raised to 20°C for 3h. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 2.8 g of a yellow oil, and 2.4 g of a white solid (Compound E) was obtained by column chromatography. .

Example 2

When n is 0, R is ethyl, and Z is benzyloxycarbonyl, the preparation of compound ¹ :

Under the protection of _N2 , compound E (2g, 6.04mmol), 1,2-ethanedithiol (0.8ml, 9.05mmol) and anhydrous dichloromethane (20ml) were added to the three-necked flask, and the reaction was carried out at 20°C. Boron trifluoride diethyl ether (0.5ml, 3.13mmol) was slowly added dropwise into the solution. After the dropwise addition, stirred for 0.5h, the reaction was quenched by adding saturated sodium bicarbonate, the aqueous phase was extracted with dichloromethane, the organic phase was combined, and the organic phase was used for Washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain 2.6 g of light yellow oil. Column chromatography gave 2.3 g of compound 1 as a colorless oil, with a yield of 92%. m/z(M+Na ⁺ )430.01, ¹ H NMR(400MHz, CDCl ₃ )δ1.16-1.27(m,3H),1.69(s,1H),2.15-2.35(m,3H),2.81-2.86 (m,1H),3.01-3.06(m,1H),3.28(s,4H),3.51-3.59(m,1H),3.75-3.82(m,1H),4.07-4.30(m,3H)5.04- 5.16 (m, 2H), 7.26-7.36 (m, 5H).

Example 3

When n is ¹ , R is ethyl, and Z is benzyloxycarbonyl, the preparation of compound 1:

Under the protection of _N2 , compound E (0.5g, 1.51mmol), 1,3-propanedithiol (0.25ml, 2.26mmol) and anhydrous dichloromethane (8ml) were added to a three-necked flask, and the Boron trifluoride diethyl ether (0.2ml, 1.25mmol) was slowly added dropwise to the reaction solution. After the dropwise addition was completed, stir for 0.5h, then add saturated sodium bicarbonate (20ml) to quench the reaction, extract the aqueous phase with dichloromethane, and combine the organic phases , the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain 0.6 g of light yellow oil. After purification by silica gel column chromatography, 0.5 g of compound 1 was obtained as a colorless oil with a yield of 93%. m/z(M+Na ⁺ )444.01, ¹ HNMR(400MHz, CDCl ₃ )δ1.16-1.27(m,3H),1.69(s,1H),1.88-1.97(m,1H),2.11-2.13( m,3H),2.31-2.41(m,1H),2.72-2.91(m,3H),2.92-3.01(m,2H),3.26-3.32(m,1H),3.62-3.79(m,2H), 4.07-4.09 (m, 1H), 4.11-4.20 (m, 2H), 5.03-5.29 (m, 2H), 7.26-7.36 (m, 5H).

Example 4

Z is the preparation of compound E in which tert-butoxycarbonyl is prepared (compound D is prepared with the same example 1):

At 20°C, the aqueous phase containing compound D in Example 1, tetrahydrofuran (30ml) and di-tert-butyl dicarbonate (2.8ml, 12.4mmol) were added to the three-necked flask, and the two-phase solution was cooled to 0°C. 2N NaOH aqueous solution (15.8ml, 31.5mmol) was slowly added dropwise to the solution. After the addition was complete, the mixture was kept at 0°C and stirred for 1h, then raised to 20°C for 3h. The aqueous phase was extracted with ethyl acetate, the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 2.4 g of a yellow oil, and 2.0 g of a colorless oil (compound e).

Example 5

When ⁿ is 0, R is ethyl, and Z is tert-butoxycarbonyl, the preparation of compound 1:

Under the protection of _N2 , compound E (0.5g, 2.13mmol), 1,2-propanedithiol (0.27ml, 3.19mmol) and anhydrous dichloromethane (8ml) were added to the three-necked flask, and the Boron trifluoride diethyl ether (0.2ml, 1.25mmol) was slowly added dropwise to the reaction solution. After the dropwise addition was completed, stir for 0.5h, add saturated sodium bicarbonate to quench the reaction, extract the aqueous phase with dichloromethane (20ml×3), and combine The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain 0.6 g of a light yellow oil. Column chromatography gave 0.5 g of compound 1 as a colorless oil, with a yield of 93%. m/z(MH ⁺ )312.01 ¹ H NMR(400MHz,CDCl ₃ )δ1.17-1.28(m,3H),1.45(s,9H)1.70(s,1H),2.13-2.34(m,3H), 2.83-2.86(m,1H),3.03-3.08(m,1H),3.28(s,4H),3.51-3.59(m,1H),3.75-3.82(m,1H),4.07-4.30(m,3H ).

Example 6

When n is ¹ , R is ethyl, and Z is tert-butoxycarbonyl, the preparation of compound 1:

Under the protection of _N2 , compound E (0.5g, 2.13mmol), 1,3-butanedithiol (0.34ml, 3.19mmol) and anhydrous dichloromethane (8ml) were added to the three-necked flask, and the Boron trifluoride diethyl ether (0.2ml, 1.25mmol) was slowly added dropwise to the reaction solution. After the dropwise addition was completed, stir for 0.5h, add saturated sodium bicarbonate to quench the reaction, extract the aqueous phase with dichloromethane, combine the organic phase, and the organic phase Washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain 0.6 g of light yellow oil. Column chromatography gave 0.5 g of compound 1 as a colorless oil, with a yield of 93%. m/z(MH ⁺ )326.01 ¹ H NMR(400MHz,CDCl ₃ )δ1.16-1.27(m,3H),1.45(s,9H)1.69(s,1H),1.88-1.97(m,1H), 2.11-2.13(m,3H),2.31-2.41(m,1H),2.72-2.91(m,3H),2.92-3.01(m,2H),3.26-3.32(m,1H),3.62-3.79(m ,2H), 4.07-4.09(m,1H), 4.11-4.20(m,2H).

Example 7

When ⁿ is 0, R is ethyl, and Z is benzyloxycarbonyl, compound 2 is prepared from compound 1:

Under the protection of N ₂ , compound 1 (2g, 4.91mmol), absolute ethanol (20ml), and Raney nickel (20g) were added to a three-neck flask, stirred, and the temperature was raised (80°C) to reflux. After reacting for 4 hours, filter, take the filtrate, and remove the solvent by rotary evaporation to obtain 1.4 g of a colorless liquid. After silica gel column chromatography, 1.0 g of compound 2 was obtained as a colorless oil, with a yield of 64%.

Example 8

When ⁿ is 0, R is ethyl, and Z is tert-butoxy, compound 2 is prepared from compound 1:

Under the protection of N ₂ , compound 1 (2g, 6.43mmol), absolute ethanol (20ml), and Raney nickel (20g) were added to a three-neck flask, stirred, and the temperature was raised (80°C) to reflux. After reacting for 4 hours, filter, take the filtrate, and remove the solvent by rotary evaporation to obtain 1.2 g of a colorless liquid. After silica gel column chromatography, 0.86 g of compound 2 was obtained as a colorless oil, with a yield of 61%.

Claims (25)

1. a preparation method of telaprevir intermediate compound 2, is characterized in that, it comprises the following steps: (1) in solvent, under the effect of Lewis acid catalyst, compound E is reacted with thiol reagent F, Compound 1 can be obtained; the Lewis acid is boron trifluoride ether or aluminum trichloride; (2) in an organic solvent, under the action of Raney nickel, the compound 1 can be desulfurized to obtain the compound 2; Wherein, R ¹ is a C ₁ -C ₆ linear or branched chain alkyl group, n is 0, 1 or 2, and Z is an amino protecting group. 2. The preparation method according to claim 1, characterized in that, said R ¹ is a C ₁ -C ₄ linear or branched alkyl group. 3. The preparation method according to claim 1, wherein said Z is tert-butoxycarbonyl, benzyloxycarbonyl or benzyl. 4. preparation method as claimed in claim 1 is characterized in that, the Lewis acid catalyst described in step (1) is boron trifluoride diethyl ether. 5. The preparation method according to claim 1, characterized in that the molar ratio of the Lewis acid catalyst described in step (1) to compound E is 0.1:1 to 1:1. 6. The preparation method according to claim 5, characterized in that the molar ratio of the Lewis acid catalyst described in step (1) to compound E is 0.1:1 to 0.5:1. 7. The preparation method according to claim 6, characterized in that the molar ratio of the Lewis acid catalyst described in step (1) to compound E is 0.1:1 to 0.3:1. 8. preparation method as claimed in claim 1 is characterized in that, the described solvent of step (1) is one in ether solvent, halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ester solvent, acetonitrile, DMF and DMSO one or more species. 9. The preparation method according to claim 8, characterized in that, the ether solvent described in step (1) is one or more of diethyl ether, tetrahydrofuran, methyl tert-butyl ether and tetrahydropyran; Described halogenated hydrocarbon solvent is one or more in methylene dichloride, chloroform, carbon tetrachloride and ethylene dichloride; Described aromatic hydrocarbon solvent is toluene, benzene, xylene, trimethylbenzene and One or more of chlorobenzene; the ester solvent is ethyl acetate. 10. The preparation method according to claim 1, wherein the molar ratio of the thiol reagent F to the compound E in step (1) is 1:1 to 5:1. 11. The preparation method according to claim 10, wherein the molar ratio of the thiol reagent F to the compound E in step (1) is 1:1 to 3:1. 12. The preparation method according to claim 11, wherein the molar ratio of the thiol reagent F to the compound E in step (1) is 1:1˜1.5:1. 13. The preparation method according to claim 1, characterized in that the reaction temperature in step (1) is 0-80°C. 14. The preparation method according to claim 13, characterized in that the reaction temperature in step (1) is 20-60°C. 15. The preparation method according to claim 14, characterized in that the reaction temperature in step (1) is 20-30°C. 16. The preparation method according to claim 1, characterized in that the mass ratio of Raney nickel to compound 1 in step (2) is 5:1-20:1. 17. The preparation method according to claim 16, characterized in that the mass ratio of Raney nickel to compound 1 in step (2) is 5:1˜15:1. 18. The preparation method according to claim 17, characterized in that the mass ratio of Raney nickel to compound 1 in step (2) is 5:1˜10:1. 19. the preparation method as claimed in claim 1 is characterized in that, the organic solvent described in step (2) is ether solvent, halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, alcohol solvent, acetonitrile, DMF and DMSO one or more. 20. The preparation method according to claim 19, characterized in that, the ether solvent described in step (2) is one or more of diethyl ether, tetrahydrofuran, methyl tert-butyl ether and tetrahydropyran; Described halogenated hydrocarbon solvent is one or more in methylene dichloride, chloroform, carbon tetrachloride and ethylene dichloride; Described aromatic hydrocarbon solvent is toluene, benzene, xylene, trimethylbenzene and One or more of chlorobenzene; the alcoholic solvent is one or more of methanol, ethanol and isopropanol. 21. The preparation method according to claim 1, characterized in that the temperature of the desulfurization reaction in step (2) is 20-120°C. 22. The preparation method according to claim 21, characterized in that the temperature of the desulfurization reaction in step (2) is 40-100°C. 23. The preparation method according to claim 22, characterized in that the temperature of the desulfurization reaction in step (2) is 60-80°C. 24. A telaprevir intermediate as shown in formula 1, Wherein, R ¹ , n and Z are as described in claims 1-3. 25. a preparation method of telaprevir intermediate 1 as claimed in claim 24, is characterized in that, it comprises the following steps: in solvent, under the effect of catalyst, compound E is reacted with thiol reagent F , Compound 1 can be prepared; Wherein, each reaction condition is as described in any one of claims 4-15.