Process for the preparation of an atazanavir intermediate

Abstract

The application provides a preparation method of an atazanavir intermediate and relates to the technical field of organic synthesis. The application takes p-halogenated toluene as a starting material, uses NiCl2(dppe), tetraphenylphosphonium palladium or PdCl2(dppe) as a catalyst, and obtains N-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone through Grignard coupling reaction, substitution reaction, Sommelet reaction (aldehyde) and aldehyde amine condensation reaction, and finally obtains the target product atazanavir intermediate 2-[4-(2-pyridyl)benzyl]-hydrazine carboxylic acid tert-butyl ester through hydrogenation reduction reaction. Compared with the prior art, the starting material and the catalyst (especially NiCl2(dppe)) used in the application are cheap and easy to obtain, so that the synthesis cost is reduced, and the product yield and purity of the method are high, the purity is greater than 99% (HPLC), and the highest single impurity is less than 0.1%.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a preparation method of an atazanavir intermediate. BACKGROUND

[0002] 2-[4-(2-pyridyl)benzyl]-hydrazinecarboxylic acid tert-butyl ester, CAS: 198904-85-7, molecular weight: 299.37, molecular formula: C 17 H 21 N3O2, the chemical structural formula is as follows:

[0003]

[0004] 2-[4-(2-pyridyl)benzyl]-hydrazinecarboxylic acid tert-butyl ester is a key intermediate for synthesizing atazanavir. Atazanavir, with the trade name Reyataz, is a protease inhibitor (PI) type antiretroviral drug, mainly used for treating AIDS. Due to its half-life, it can be administered once a day, and its use frequency is greatly reduced compared to other types of AIDS drugs. At the same time, it has the characteristics of high bioavailability, long drug effect duration and low drug resistance.

[0005] Up to now, there are few synthesis methods of 2-[4-(2-pyridyl)benzyl]-hydrazinecarboxylic acid tert-butyl ester in China, and all of them are relatively complicated, which is difficult to meet the subsequent industrial production. The existing technology about the synthesis method of 2-[4-(2-pyridyl)benzyl]-hydrazinecarboxylic acid tert-butyl ester mainly has the following two routes:

[0006] Route 1: taking p-bromophenylboronic acid as a raw material, N-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone is obtained through a Suzuki-Miyaura coupling reaction and an amine aldehyde condensation, and then the target product 2-[4-(2-pyridyl)benzyl]-hydrazinecarboxylic acid tert-butyl ester is obtained by catalytic hydrogenation. The specific synthesis route is as follows:

[0007]

[0008] Route 2: taking p-bromobenzaldehyde as a raw material, N-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone is obtained through an acetal reaction, a Grignard coupling reaction and an amine aldehyde condensation reaction, and then the target product 2-[4-(2-pyridyl)benzyl]-hydrazinecarboxylic acid tert-butyl ester is obtained by catalytic hydrogenation. The specific synthesis route is as follows:

[0009]

[0010] The reaction route of route 1 and route 2 is mature, but the raw material compound is expensive, and a catalyst with high cost is used (a noble metal catalyst is needed for coupling in route 1, and Pd(PPh3)4 catalyst is needed for Grignard coupling in route 2), and in addition, there is the problem of low yield, which is not conducive to industrial production. SUMMARY

[0011] Therefore, the present application aims to provide a preparation method of an atazanavir intermediate.

[0012] In order to achieve the above-mentioned application purposes, the present application provides the following technical solutions.

[0013] The present application provides a preparation method of an atazanavir intermediate, comprising the following steps:

[0014] (1) mixing zinc chloride, a catalyst, 2-halogenated pyridine, a Grignard reagent and a first solvent to perform Grignard coupling reaction to obtain 4-(2-pyridyl)-toluene; the Grignard reagent is prepared by reacting p-halogenated toluene and magnesium, and the catalyst is NiCl2(dppe), tetrakis triphenylphosphine palladium or PdCl2(dppe);

[0015] (2) mixing the 4-(2-pyridyl)-toluene, a halogenated reagent and a second solvent to perform substitution reaction to obtain 4-(2-pyridyl)-halogenated toluene;

[0016] mixing the 4-(2-pyridyl)-halogenated toluene and urotropin to perform Sommelet reaction to obtain 4-(2-pyridyl)-benzaldehyde;

[0017] mixing the 4-(2-pyridyl)-benzaldehyde, tert-butyl hydrazine formate and a third solvent to perform condensation reaction to obtain N-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone;

[0018] (3) mixing the N-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone, palladium-carbon and a fourth solvent, and performing hydrogenation reduction under the condition of hydrogen being introduced to obtain atazanavir intermediate 2-[4-(2-pyridyl)benzyl]-hydrazine carboxylic acid tert-butyl ester.

[0019] Preferably, in step (1), the 2-halogenated pyridine is 2-chloropyridine, 2-bromopyridine or 2-iodopyridine, and the p-halogenated toluene is p-chlorotoluene or p-bromotoluene; the molar ratio of the p-halogenated toluene, the 2-halogenated pyridine and the catalyst used for preparing the Grignard reagent is 1:(0.8-1.2):(0.03-0.1), and the molar ratio of the 2-halogenated pyridine and zinc chloride is 1:(0.5-0.7).

[0020] Preferably, the temperature of Grignard coupling in step (1) is 60-90℃, and the time is 3-4h.

[0021] Preferably, the halogenating agent in step (2) comprises one or more of N-bromosuccinimide, N-chlorosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, 1,3-dichloro-5,5-dimethylhydantoin and bromine; and the molar ratio of 4-(2-pyridyl)-toluene, halogenating agent, urotropine and tert-butyl hydrazinecarboxylate is 1:(1.0-1.5):(1.0-2.0):(0.75-1.1).

[0022] Preferably, in step (2), the temperature of substitution reaction is 75-85℃, and the time is 4-6h; and the temperature of condensation reaction is room temperature, and the time is 6-10h.

[0023] Preferably, the Sommelet reaction in step (2) comprises:

[0024] After the completion of substitution reaction, urotropine is added to the reaction solution of obtained 4-(2-pyridyl)-halogenated toluene to perform salt formation reaction, and then the dry solvent is removed; and the obtained product is hydrolyzed in an acidic aqueous solution with pH value of 4-5 to obtain 4-(2-pyridyl)-benzaldehyde.

[0025] Preferably, the temperature of salt formation reaction is room temperature, and the time is 3-4h; and the temperature of hydrolysis reaction is 100℃, and the time is 2-4h.

[0026] Preferably, the first solvent comprises one or more of tetrahydrofuran, 2-methyltetrahydrofuran and methyl tert-butyl ether; the second solvent and the third solvent independently comprise one or more of carbon tetrachloride, dichloroethane, water, acetic acid, methanol, ethanol and isopropanol; and the fourth solvent comprises one or more of methanol, ethanol, isopropanol, acetone and acetonitrile.

[0027] Preferably, in step (3), the mass ratio of N-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone and palladium carbon is 1:(0.005-0.01).

[0028] Preferably, in step (3), the temperature of hydrogenation reduction is 30-40℃, the time is 3-4h, and the pressure is 0.1-0.3MPa.

[0029] The application provides a preparation method of an atazanavir intermediate, and the atazanavir intermediate is prepared from p-halogen toluene as a starting material, NiCl2(dppe), tetraphenylphosphonium palladium or PdCl2(dppe) as a catalyst, through Grignard coupling reaction, substitution reaction, Sommelet reaction (aldehyde conversion) and aldehyde amine condensation reaction to obtain N-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone, and finally through hydrogen reduction reaction to obtain the target product tert-butyl 2-[4-(2-pyridyl)benzyl]-hydrazine carboxylate. Compared with the prior art, the starting material and the catalyst (especially NiCl2(dppe)) used in the application are cheap and easy to obtain, so that the synthesis cost is reduced, and the product yield and purity of the method are high.

[0030] The results of the examples show that the purity of the tert-butyl 2-[4-(2-pyridyl)benzyl]-hydrazine carboxylate prepared by the method provided by the application is greater than 99% (HPLC), and the highest single impurity is less than 0.1%. BRIEF DESCRIPTION OF DRAWINGS

[0031] Figure 1 The HPLC spectrum of the tert-butyl 2-[4-(2-pyridyl)benzyl]-hydrazine carboxylate synthesized for Example 3;

[0032] Figure 2 The H-NMR spectrum of the tert-butyl 2-[4-(2-pyridyl)benzyl]-hydrazine carboxylate synthesized for Example 3. DETAILED DESCRIPTION

[0033] The application provides a preparation method of an atazanavir intermediate, and the atazanavir intermediate is prepared from p-halogen toluene as a starting material, NiCl2(dppe), tetraphenylphosphonium palladium or PdCl2(dppe) as a catalyst, through Grignard coupling reaction, substitution reaction, Sommelet reaction (aldehyde conversion) and aldehyde amine condensation reaction to obtain N-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone, and finally through hydrogen reduction reaction to obtain the target product tert-butyl 2-[4-(2-pyridyl)benzyl]-hydrazine carboxylate. Compared with the prior art, the starting material and the catalyst (especially NiCl2(dppe)) used in the application are cheap and easy to obtain, so that the synthesis cost is reduced, and the product yield and purity of the method are high.

[0034] (1) mixing zinc chloride, a catalyst, 2-halogenated pyridine, a Grignard reagent and a first solvent to perform Grignard coupling reaction to obtain 4-(2-pyridyl)-toluene; the Grignard reagent is prepared by reacting p-halogen toluene with magnesium, and the catalyst is NiCl2(dppe), tetraphenylphosphonium palladium or PdCl2(dppe);

[0035] (2) mixing the 4-(2-pyridyl)-toluene, a halogenated reagent and a second solvent to perform substitution reaction to obtain 4-(2-pyridyl)-halogenated toluene;

[0036] mixing the 4-(2-pyridyl)-halogenated toluene and urotropine to perform Sommelet reaction to obtain 4-(2-pyridyl)-benzaldehyde;

[0037] mixing the 4-(2-pyridyl)-benzaldehyde, tert-butyl hydrazine carboxylate and a third solvent to perform aldehyde amine condensation reaction to obtain N-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone;

[0038] (3) mixing the N-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone, palladium on carbon and a fourth solvent, and performing hydrogen reduction under hydrogen atmosphere to obtain the atazanavir intermediate tert-butyl 2-[4-(2-pyridyl)benzyl]-hydrazinecarboxylate.

[0039] In the present application, the raw materials involved are all commercially available products well known to those skilled in the art, unless otherwise specified.

[0040] In the present application, the zinc chloride, catalyst, 2-halogenated pyridine, Grignard reagent and first solvent are mixed to perform Grignard coupling reaction to obtain 4-(2-pyridyl)-toluene.

[0041] In the present application, the 2-halogenated pyridine is preferably 2-chloropyridine, 2-bromopyridine or 2-iodopyridine, more preferably 2-chloropyridine.

[0042] In the present application, the Grignard reagent is prepared by reacting p-halogenated toluene and magnesium, and the p-halogenated toluene is preferably p-chlorotoluene or p-bromotoluene, more preferably p-chlorotoluene. The present application does not have special requirements for the preparation method of the Grignard reagent, and the preparation method well known to those skilled in the art can be used; in the present application, the preparation method of the Grignard reagent is preferably as follows: 2.87 g of magnesium chips, 50 mL of anhydrous 2-methyltetrahydrofuran and 0.5-2 mL of initiator are mixed, 1-2 g of p-halogenated toluene is added dropwise, after initiation, 18-20 g of p-halogenated toluene is continuously added dropwise at a temperature of 30-60°C, and the reaction is continued until the magnesium chips are consumed to obtain the Grignard reagent. In the present application, the initiator is preferably p-tolylmagnesium bromide, which is preferably added in the form of a 2-methyltetrahydrofuran solution.

[0043] In the present application, the catalyst is NiCl2(dppe) (1,2-bis(diphenylphosphinoethane) nickel chloride), tetrakis(triphenylphosphine)palladium or PdCl2(dppe) (1,2-bis(diphenylphosphino)ethane palladium chloride), preferably NiCl2(dppe).

[0044] In the present application, the zinc chloride is preferably anhydrous zinc chloride. In the present application, the Grignard coupling reaction is specifically Negishi coupling reaction, in which the Grignard reagent and zinc chloride generate hydrocarbyl zinc halide, which then reacts with 2-halogenated pyridine.

[0045] In the present application, the molar ratio of p-halogen toluene, 2-halogen pyridine and catalyst used for preparing the Grignard reagent is preferably 1 : (0.8-1.2) : (0.03-0.1), more preferably 1 : (0.8-0.9) : (0.04-0.06), and the molar ratio of 2-halogen pyridine and zinc chloride is preferably 1 : (0.5-0.7). In the present application, the first solvent preferably comprises one or more of tetrahydrofuran, 2-methyltetrahydrofuran and methyl tert-butyl ether, more preferably tetrahydrofuran or 2-methyltetrahydrofuran; the present application does not have special requirements for the amount of the first solvent, as long as it can ensure the smooth progress of the reaction. In the present application, the method for mixing the zinc chloride, catalyst, 2-halogen pyridine, Grignard reagent and first solvent is preferably as follows: zinc chloride and catalyst are sequentially added in the first solvent, the resulting mixture is stirred for 30 min, then 2-halogen pyridine is added to the mixture, and then the Grignard reagent is added dropwise.

[0046] In the present application, the temperature of the Grignard coupling reaction is preferably 60-90°C, and the time is preferably 3-4 h. The time of the Grignard coupling reaction is calculated from the start of the dropwise addition of the Grignard reagent.

[0047] After the completion of the Grignard coupling reaction, the present application preferably performs post-treatment on the obtained Grignard coupling reaction liquid, and the post-treatment preferably comprises the following steps:

[0048] The obtained Grignard coupling reaction liquid is subjected to reduced pressure recovery of part of the solvent to obtain a concentrated liquid;

[0049] Ammonium chloride saturated aqueous solution is added to the concentrated liquid, and the mixture is subjected to layer separation to obtain an organic layer and an aqueous layer, wherein the aqueous layer is extracted with 2-methyltetrahydrofuran for 3 times, and all the organic layers are combined;

[0050] The organic layer is evaporated to dryness, carbon tetrachloride is added to the remaining oily residue, and after dissolution, anhydrous sodium sulfate is added for drying, followed by filtration and evaporation to dryness under reduced pressure to obtain a red viscous liquid;

[0051] The red viscous liquid is subjected to rectification, and the fraction of 107-110°C / 12mmHg is collected to obtain a light yellow transparent liquid, i.e. 4-(2-pyridyl)-toluene.

[0052] After obtaining the 4-(2-pyridyl)-toluene, the present application carries out a substitution reaction by mixing the 4-(2-pyridyl)-toluene, a halogenating agent and a second solvent to obtain a 4-(2-pyridyl)-halogenated toluene. In the present application, the halogenating agent preferably includes one or more of N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), 1,3-dibromo-5,5-dimethylhydantoin, 1,3-dichloro-5,5-dimethylhydantoin and bromine; in the embodiments of the present application, the halogenating agent is preferably a brominating agent, and specifically NBS or 1,3-dibromo-5,5-dimethylhydantoin. In the present application, the second solvent preferably includes one or more of carbon tetrachloride, dichloroethane, water, acetic acid, methanol, ethanol and isopropanol, and more preferably carbon tetrachloride. The present application does not have a specific requirement for the amount of the second solvent, as long as the reaction can proceed smoothly. The present application does not have a specific requirement for the mixing method of the 4-(2-pyridyl)-toluene, the halogenating agent and the second solvent.

[0053] In the present application, the temperature of the substitution reaction is preferably 75-85°C, and the time is preferably 4-6h. After the completion of the substitution reaction, the present application preferably cools the obtained substitution reaction solution to room temperature and then filters it, and the obtained filtrate is directly subjected to the next reaction.

[0054] After obtaining the 4-(2-pyridyl)-halogenated toluene, the present application carries out a Sommelet reaction by mixing the 4-(2-pyridyl)-halogenated toluene and urotropine (hexamethylenetetramine) to obtain a 4-(2-pyridyl)-benzaldehyde. In the present application, the Sommelet reaction preferably includes: after the completion of the substitution reaction, adding urotropine to the obtained 4-(2-pyridyl)-halogenated toluene reaction solution to carry out a salt formation reaction, removing the dry solvent, and carrying out a hydrolysis reaction of the obtained product in an acidic aqueous solution having a pH value of 4-5 to obtain a 4-(2-pyridyl)-benzaldehyde. In the present application, the temperature of the salt formation reaction is preferably room temperature, and the time is preferably 3-4h, and the salt formation reaction is preferably carried out under stirring. In the present application, the acidic aqueous solution is preferably an aqueous hydrochloric acid solution; the temperature of the hydrolysis reaction is preferably 100°C, and the time is preferably 2-4h. After the hydrolysis reaction, the obtained reaction solution is preferably cooled to room temperature and then directly subjected to the next reaction.

[0055] After obtaining 4-(2-pyridyl)-benzaldehyde, the present application mixes the 4-(2-pyridyl)-benzaldehyde, tert-butyl hydrazine carbonate and a third solvent into an aldehyde amine condensation reaction to obtain N-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone. In the present application, the molar ratio of the 4-(2-pyridyl)-toluene, halogenated reagent, urotropine and tert-butyl hydrazine carbonate is preferably 1:(1.0-1.5):(1.0-2.0):(0.75-1.1), more preferably 1:(1.0-1.1):(1.8-1.9):(0.75-1.0); the third solvent preferably includes one or more of carbon tetrachloride, dichloroethane, water, acetic acid, methanol, ethanol and isopropanol, more preferably ethanol, and the present application does not have a special requirement for the amount of the third solvent, as long as the reaction can proceed smoothly.

[0056] In the present application, the temperature of the aldehyde amine condensation reaction is preferably room temperature, and the time is preferably 6-10h, more preferably 8h. In the present application, the specific operation of the aldehyde amine condensation reaction is preferably as follows: after the Sommelet reaction, the obtained reaction liquid (i.e. the reaction liquid after the hydrolysis reaction) is cooled to room temperature, the pH value of the reaction liquid is adjusted to 8 with liquid alkali, then the third solvent and tert-butyl hydrazine carbonate are added, and the aldehyde amine condensation reaction is carried out at room temperature under stirring.

[0057] After the aldehyde amine condensation reaction is completed, the present application preferably filters, washes with water and dries the obtained aldehyde amine condensation reaction product in sequence to obtain a solid product, and recrystallizes the solid product to obtain N-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone; the solvent for the recrystallization is preferably 95% ethanol.

[0058] After obtaining N-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone, the present application mixes the N-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone, palladium carbon and a fourth solvent, and hydrogenates under hydrogen to obtain atazanavir intermediate 2-[4-(2-pyridyl)benzyl]-hydrazine tert-butyl ester. In the present application, the mass ratio of the N-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone and palladium carbon is preferably 1:(0.005-0.01); in the examples of the present application, the palladium carbon used is 10% Pd / C. In the present application, the fourth solvent preferably includes one or more of methanol, ethanol, isopropanol, acetone and acetonitrile, and more preferably is methanol. The present application does not have a particular requirement for the amount of the fourth solvent, as long as the reaction can proceed smoothly. The present application preferably adds the N-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone to the fourth solvent, stirs to dissolve and clarify, and adds palladium carbon to the obtained solution to hydrogenate.

[0059] In the present application, the hydrogenation temperature is preferably 30-40℃, the time is preferably 3-4h, and the pressure is preferably 0.1-0.3MPa. After the hydrogenation is completed, the present application preferably filters the obtained reaction liquid to remove the palladium carbon, evaporates the filtrate to dryness, refines the obtained residue with a methanol aqueous solution to obtain a white solid, and then dries to obtain 2-[4-(2-pyridyl)benzyl]-hydrazine tert-butyl ester. In the present application, the mass fraction of the methanol aqueous solution is preferably 50%, and the operation method of the refining specifically includes: dissolving the residue with 3-5 times the volume of the methanol aqueous solution of the raw material used in the hydrogenation reaction, adding an equal volume of pure water dropwise under stirring until the solution concentration reaches 50%, precipitating a large amount of solid, cooling to 0℃, stirring for another 1h, and filtering to obtain the white solid.

[0060] Taking 2-halogenated pyridine as 2-chloropyridine and para-halogenated toluene as para-chlorotoluene used for preparing Grignard reagent as examples, the reaction route for preparing 2-[4-(2-pyridyl)benzyl]-hydrazine tert-butyl ester in the present application is as follows:

[0061]

[0062] The preparation method provided by the present application has the advantages of easy-to-obtain raw materials, low cost, high efficiency, controllability and easy operation, can continuously produce high-quality products, and the product purity is greater than 99%(HPLC) and the highest single impurity is less than 0.1%.

[0063] In order to further illustrate the present application, the preparation method of the atazanavir intermediate provided by the present application is described in detail below in combination with examples, but they should not be understood as limiting the scope of protection of the present application.

[0064] Example 1

[0065] Synthesis of 4-(2-pyridyl)-toluene

[0066] Mix 2.87g magnesium turnings, 50mL anhydrous 2-methyltetrahydrofuran and 1 mL initiator (2-methyltetrahydrofuran solution of p-tolyl magnesium bromide), drop 2g p-chlorotoluene, after initiation, continue drop 18g p-chlorotoluene at 30°C, continue reaction until magnesium turnings are consumed, get Grignard reaction solution (i.e. Grignard reagent).

[0067] Add 8.58g anhydrous zinc chloride into 50mL 2-methyltetrahydrofuran, add catalyst 5.16g NiCl2(dppe), after stirring for 30min, add 14.3g 2-chloropyridine, drop the prepared Grignard reagent above, after drop completion, recover part of solvent under reduced pressure, add saturated aqueous ammonium chloride solution, separate layers, extract water layer with 2-methyltetrahydrofuran for 3 times, combine organic layers, evaporate to dryness, add carbon tetrachloride into the remaining oily residue, dissolve, then add anhydrous sodium sulfate for drying, then filter, evaporate to dryness under reduced pressure, get red viscous liquid. Distill, collect 107-110°C / 12mmHg fraction, get 24.1g light yellow oily liquid. Yield 90%, purity >98% (HPLC).

[0068] Example 2

[0069] Synthesis of N-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone

[0070] Take 6g 4-(2-pyridyl)-toluene prepared in Example 1, 160mL carbon tetrachloride and 6.4g NBS, reflux reaction for 4h, TLC detection reaction complete, cool to room temperature, filter to remove the reaction produced succinimide solid, add 9.2g urotropine into the filtrate, stir reaction at room temperature for 4h, recover carbon tetrachloride to dryness, add 50mL water, dilute hydrochloric acid to adjust solution pH to 4.5±0.5, reflux reaction for 2h, cool to room temperature, liquid alkali to adjust pH value to 8, add 50mL 95% ethanol and 3.5g tert-butyl hydrazine carboxylate, stir reaction at room temperature for 8h. After filtration, water washing and drying, get 8.2g white solid product, then recrystallize with 95% ethanol, yield 77%, purity >98% (HPLC).

[0071] Example 3

[0072] Synthesis of 2-[4-(2-pyridyl)benzyl]-hydrazine carboxylic acid tert-butyl ester

[0073] To 6.3 g of N-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone prepared in Example 2 in 150 mL of methanol, 0.63 g of 10% Pd / C was added and the mixture was stirred to dissolve. Hydrogenation reduction was carried out at 35 ± 5 °C for 3 h. The reaction was monitored by HPLC. The amount of starting material was less than 0.2%. The Pd / C was removed by filtration. The filtrate was evaporated to dryness and purified with methanol in water to give a white solid which was dried to give 5.89 g. The yield was 93% and the purity was greater than 99% (HPLC) with less than 0.1% of a single impurity.

[0074] Figure 1 and Figure 2 are the HPLC and H-NMR chromatograms of the synthesized 2-[4-(2-pyridyl)benzyl]-hydrazine carboxylic acid tert-butyl ester, respectively.

[0075] Example 4

[0076] Synthesis of 4-(2-pyridyl)-toluene

[0077] To 2.87 g of magnesium turnings, 50 mL of anhydrous tetrahydrofuran and 1 mL of initiator (2-methyltetrahydrofuran solution of p-tolylmagnesium bromide) were added dropwise 2 g of p-chlorotoluene. After initiation, 18 g of p-chlorotoluene was added dropwise at 30 °C. The reaction was continued until the magnesium turnings were consumed to give the Grignard reagent.

[0078] To 8.58 g of anhydrous zinc chloride in 50 mL of tetrahydrofuran, 5.16 g of NiCl2(dppe) was added as a catalyst. After stirring for 30 min, 14.3 g of 2-chloropyridine was added and the Grignard reagent prepared above was added dropwise. After the addition was completed, the solvent was recovered under reduced pressure. The reaction mixture was saturated with an aqueous solution of ammonium chloride and separated into layers. The aqueous layer was extracted with tetrahydrofuran three times. The combined organic layers were evaporated to dryness. Carbon tetrachloride was added to the remaining oily residue. After dissolution, anhydrous sodium sulfate was added for drying. The mixture was filtered and evaporated to dryness under reduced pressure to give a red viscous liquid. The liquid was distilled to collect the fraction at 107-110 °C / 12 mm Hg to give 25.34 g of a yellowish oily liquid. The yield was 94.8% and the purity was greater than 98% (HPLC).

[0079] Example 5

[0080] Synthesis of N-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone

[0081] To 6 g of 4-(2-pyridyl)-toluene prepared in Example 4, 160 mL of carbon tetrachloride and 4.8 g of NCS, reflux for 4 h, TLC test reaction complete, cool to room temperature, filter (filter out the succinimide solid produced after NCS reaction), add 9.2 g of urotropine to the filtrate, stir at room temperature until salification is complete, recover carbon tetrachloride to dryness, add 50 mL of water, adjust the solution pH to 4.5 ± 0.5 with dilute hydrochloric acid, reflux for 2 h, cool to room temperature, adjust the pH to 8 with liquid alkali, add 50 mL of 95% ethanol and 3.5 g of tert-butyl hydrazine carboxylate, stir at room temperature for 8 h. Filter, wash with water, dry to obtain 8.0 g of white solid product, recrystallize from 95% ethanol, yield 75%, purity > 98% (HPLC).

[0082] Example 6

[0083] Synthesis of N-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone

[0084] To 6 g of 4-(2-pyridyl)-toluene prepared in Example 4, 160 mL of carbon tetrachloride and 10.4 g of 1,3-dibromo-5,5-dimethylhydantoin, reflux for 4 h, TLC test reaction complete, cool to room temperature, filter, add 9.2 g of urotropine to the filtrate, stir at room temperature until salification is complete, recover carbon tetrachloride to dryness, add 50 mL of water, adjust the solution pH to 4.5 ± 0.5 with dilute hydrochloric acid, reflux for 2 h, cool to room temperature, adjust the pH to 8 with liquid alkali, add 50 mL of 95% ethanol and 3.5 g of tert-butyl hydrazine carboxylate, stir at room temperature for 8 h. Filter, wash with water, dry to obtain 8.5 g of white solid product, recrystallize from 95% ethanol, yield 78%, purity > 98% (HPLC).

[0085] Example 7

[0086] Synthesis of tert-butyl 2-[4-(2-pyridyl)benzyl]hydrazine carboxylate

[0087] To 6.3 g of N-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone prepared in Example 6, add to 150 mL of methanol, stir to dissolve and clarify, add 0.63 g of 10% Pd / C, hydrogen reduction at 35 ± 5 °C for 3 h, HPLC test reaction process, raw material less than 0.2%, filter to remove palladium carbon, evaporate the filtrate to dryness, refine with methanol aqueous solution to obtain white solid, dry to obtain 5.30 g. Yield 84%, purity > 99% (HPLC), single impurity less than 0.1%. The HPLC spectrum and H-NMR spectrum of the product are consistent with Figure 1 and Figure 2 .

[0088] The above merely describes the preferred embodiments of the present application, and does not limit the present application in any form. It should be noted that, for those skilled in the art, several improvements and refinements can be made without departing from the principles of the present application, and these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. A method for preparing an atazanavir intermediate, characterized in that, Includes the following steps: (1) Zinc chloride, catalyst, 2-halopyridine, Grignard reagent and first solvent are mixed and subjected to Grignard coupling reaction to obtain 4-(2-pyridyl)-toluene; the Grignard reagent is prepared by reacting para-halopyridine with magnesium, the catalyst is NiCl2 (dppe); the 2-halopyridine is 2-chloropyridine, the para-halopyridine is para-chlorotoluene; the first solvent is tetrahydrofuran; (2) The 4-(2-pyridyl)-toluene, the halogenating agent, and the second solvent are mixed and subjected to a substitution reaction to obtain 4-(2-pyridyl)-halotoluene; the halogenating agent is 1,3-dibromo-5,5-dimethylhydantoin; and the second solvent is carbon tetrachloride. The 4-(2-pyridyl)-halotoluene and hexamethylenetetramine were mixed and subjected to a Sommelet reaction to obtain 4-(2-pyridyl)-benzaldehyde. The Sommelet reaction included: after the substitution reaction was completed, hexamethylenetetramine was added to the obtained 4-(2-pyridyl)-halotoluene reaction solution to carry out a salt formation reaction, and the solvent was removed. The obtained product was hydrolyzed in an acidic aqueous solution with a pH of 4 to 5 to obtain 4-(2-pyridyl)-benzaldehyde. The 4-(2-pyridyl)-benzaldehyde, tert-butyl hydrazinocarboxylate, and a third solvent were mixed in an aldehyde-amine condensation reaction to obtain N-1-(tert-butyloxycarbonyl)-N-2-[4-(2-pyridyl)benzylene]hydrazone; (3) The N-1-(tert-butyloxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone, palladium on carbon and the fourth solvent are mixed and hydrogenated under hydrogen gas to obtain the atazanavir intermediate 2-[4-(2-pyridyl)benzylidene]-hydrazide tert-butyl ester.

2. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of para-halotoluene, 2-halopyridine and catalyst used to prepare Grignard reagent is 1:(0.8~1.2):(0.03~0.1), and the molar ratio of 2-halopyridine to zinc chloride is 1:(0.5~0.7).

3. The preparation method according to claim 1 or 2, characterized in that, The temperature of the Grignard coupling reaction in step (1) is 60~90℃ and the time is 3~4h.

4. The preparation method according to claim 1, characterized in that, In step (2), the molar ratio of 4-(2-pyridyl)-toluene, halogenated reagent, hexamethylenetetramine, and tert-butyl hydrazide carboxylate is 1:(1.0~1.5):(1.0~2.0):(0.75~1.1).

5. The preparation method according to claim 1 or 4, characterized in that, In step (2), the temperature of the substitution reaction is 75~85℃ and the time is 4~6h, and the temperature of the aldehyde-amine condensation reaction is room temperature and the time is 6~10h.

6. The preparation method according to claim 1, characterized in that, The salt formation reaction is carried out at room temperature for 3-4 hours; the hydrolysis reaction is carried out at 100°C for 2-4 hours.

7. The preparation method according to claim 1, characterized in that, The third solvent independently includes one or more of carbon tetrachloride, dichloroethane, water, acetic acid, methanol, ethanol, and isopropanol; the fourth solvent includes one or more of methanol, ethanol, isopropanol, acetone, and acetonitrile.

8. The preparation method according to claim 1, characterized in that, In step (3), the mass ratio of N-1-(tert-butyloxycarbonyl)-N-2-[4-(2-pyridyl)benzylidene]hydrazone to palladium on carbon is 1:(0.005~0.01).

9. The preparation method according to claim 1 or 8, characterized in that, In step (3), the hydrogenation reduction temperature is 30~40℃, the time is 3~4h, and the pressure is 0.1~0.3MPa.

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