A process for the preparation of a btk inhibitor pharmaceutical intermediate

Abstract

The application discloses a preparation method of a BTK inhibitor drug intermediate. The application provides a preparation method of a compound shown in formula I. The preparation method provided by the application is short in steps, simple in operation, high in yield, and high in purity.

Description

TECHNICAL FIELD

[0001] The present application relates to a preparation method of a BTK inhibitor drug intermediate. BACKGROUND

[0002] Mutations in the Bruton's tyrosine kinase (BTK) gene cause a rare inherited B-cell specific immunodeficiency disease, known as X-linked agammaglobulinemia (XLA). In this disease, the function of BTK is inhibited, resulting in a block in the production or maturation of B cells. Men with XLA disease have essentially no B cells in their bodies and little circulating antibody, and are prone to serious and even fatal infections. This strongly proves that BTK plays an extremely important role in the growth and differentiation of B cells.

[0003] CN107382973B provides a 5-amino pyrazole carboxamide derivative as a BTK inhibitor and a preparation method and a pharmaceutical composition thereof, as shown in formula (1):

[0004]

[0005] The compound is an effective and safe inhibitor of protein kinase BTK. However, the preparation process disclosed therein has the disadvantages of long route, low yield and being not conducive to industrialization. Therefore, there is an urgent need to provide a process route with high yield to efficiently prepare the target compound. SUMMARY

[0006] The technical problem to be solved by the present application is to provide a new preparation method of a BTK inhibitor drug intermediate, and to more effectively synthesize a BTK inhibitor drug. The preparation method provided by the present application has fewer steps, is easy to operate, and has a higher yield.

[0007] The present application solves the above technical problems through the following technical solutions.

[0008] The present application provides a preparation method of a compound as shown in formula I, which comprises the following steps:

[0009]

[0010] Step 1, reacting compound B3, ethyl formate reagent, titanate and boron trifluoride reagent in a solvent to generate compound B4;

[0011] Step 2, reacting compound B4 with an acid to generate compound B5;

[0012] Step 3, reacting compound B5 with benzyl chloroformate (CbzCl) and a base in a solvent to generate compound B6;

[0013] Step 4, compound B6 reacts with p-toluenesulfonyl chloride (TsCl) and di-tert-butyltin chloride (Bu2SnCl2) in a solvent in the presence of a base and potassium phosphate to form compound B7;

[0014] Step 5, compound B7 reacts with 3,4-dihydropyran in a solvent in the presence of an acid to form compound B7-1;

[0015] Step 6, compound B7-1 reacts with a base in a solvent to form compound B7-2;

[0016] Step 7, compound B7-2 reacts with an acid in a solvent to form compound B8;

[0017] Step 8, compound B8 reacts with compound B8-1 in a Mitsunobu reaction in a solvent to form compound B9;

[0018] Step 9, compound B9 reacts with ethanolamine in a solvent to form compound B10;

[0019] Step 10, compound B10 reacts with an acid in a solvent to form compound I.

[0020] In the preparation method, in step 1, the solvent can be a solvent conventional for such reactions in the art, for example an ether solvent, preferably methyl tert-butyl ether.

[0021] In the preparation method, in step 1, the ethyl Grignard reagent can be ethyl magnesium bromide.

[0022] In the preparation method, in step 1, the concentration of the ethyl Grignard reagent can be 1M.

[0023] In the preparation method, in step 1, the titanate can be tetraisopropyl titanate.

[0024] In the preparation method, in step 1, the boron trifluoride reagent can be boron trifluoride diethyl etherate.

[0025] In the preparation method, in step 1, the concentration of compound B3 in the solvent can be 0.1-1 kg / L; preferably 0.1 kg / L.

[0026] In the preparation method, in step 1, the molar ratio of compound B3 to the ethyl Grignard reagent can be 1:(10-20); preferably 1:16.

[0027] In the preparation method, in step 1, the molar ratio of compound B3 to the titanate can be (0.5-2):1; preferably 0.9:1.

[0028] In the preparation method, in step 1, the molar ratio of the compound B3 to the boron trifluoride reagent can be (0.5-1):1; preferably 0.52:1.

[0029] In the preparation method, in step 1, the temperature of the reaction can be 10-20°C.

[0030] In the preparation method, in step 1, the reaction is carried out under inert gas protection, for example, nitrogen.

[0031] In the preparation method, step 1 comprises the following steps: under nitrogen protection, compound B3 and titanium acid tetraisopropyl are added in methyl tert-butyl ether, ethyl magnesium bromide is added dropwise at 10-20°C, after the reaction is completed, boron trifluoride ether is continuously added dropwise at 10-20°C, to obtain a solution containing compound B4.

[0032] In the preparation method, in step 1, the compound B4 generated by the reaction is directly used in step 2 without post-treatment.

[0033] In the preparation method, in step 2, the acid can be a citric acid aqueous solution; the concentration of the citric acid aqueous solution is preferably 25% or 5%.

[0034] In the preparation method, in step 2, the molar ratio of the compound B4 to the acid can be 1:(1-2); preferably 1:1.8.

[0035] In the preparation method, in step 2, the temperature of the reaction can be 20-40°C.

[0036] In the preparation method, step 2 comprises the following steps: 25% citric acid aqueous solution is added dropwise to the solution containing compound B4 obtained by step 1 at 20-40°C, stirring is carried out at 15-35°C, and the organic phase is extracted with 5% citric acid aqueous solution, and the combined water phase is obtained to obtain a solution containing compound B5.

[0037] In the preparation method, in step 2, the compound B5 generated by the reaction is directly used in step 3 without post-treatment.

[0038] In the preparation method, in step 3, the solvent can be a solvent conventional for such reactions in the art, for example, an ether solvent, preferably tetrahydrofuran.

[0039] In the preparation method, in step 3, the base can be an inorganic base, for example, potassium bicarbonate.

[0040] In the preparation method, in step 3, the molar ratio of the compound B5 to the benzyl chloroformate can be 1:(1-2); preferably 1:1.

[0041] In the preparation method, in step 3, the molar ratio of the compound B5 to the base can be 1: (1-5), preferably 1:2.

[0042] In the preparation method, in step 3, the temperature of the reaction can be 20-30℃.

[0043] In the preparation method, step 3 comprises the following steps: at 15-25℃, 30% sodium hydroxide solution is added to the solution containing the compound B5 obtained in step 2, the pH of the system is adjusted to 7-8, and the mixture is reacted with tetrahydrofuran, benzyl chloroformate (CbzCl) and potassium bicarbonate at 20-30℃, and after treatment, the compound B6 is obtained.

[0044] In the preparation method, in step 3, the after-treatment comprises the following steps: after the reaction is completed, the pH of the reaction solution is adjusted to 1, and the ester organic solvent is extracted, and after the organic phase is concentrated, it is cooled to 20-30℃, and n-heptane is added dropwise, and then filtered to obtain the compound B6.

[0045] More preferably, the filter cake is washed with an ester organic solvent / n-heptane mixed solution and dried; or further comprising: the dried solid is recrystallized with water and ethanol to obtain the compound B6.

[0046] In the preparation method, in step 4, the solvent can be a mixed solvent of dichloromethane, tetrahydrofuran and water; the volume ratio of dichloromethane, tetrahydrofuran and water is preferably 17:3:1.

[0047] In the preparation method, in step 4, the base can be an organic base, such as triethylamine.

[0048] In the preparation method, in step 4, the molar ratio of the compound B6 to the base can be 1: (0.02-0.1), preferably 1:0.02.

[0049] In the preparation method, in step 4, the molar ratio of the compound B6 to the potassium phosphate can be 1: (1-2), preferably 1:1.2.

[0050] In the preparation method, in step 4, the molar ratio of the compound B6 to the p-toluenesulfonyl chloride can be 1: (0.4-1), preferably 1:0.46.

[0051] In the preparation method, in step 4, the molar ratio of the compound B6 to the di-t-butyl tin dichloride can be 1: (0.05-0.1), preferably 1:0.05.

[0052] In the preparation method, in step 4, the temperature of the reaction can be 20-30℃.

[0053] In the preparation method, in step 4, the reaction is carried out under inert gas protection, for example, nitrogen.

[0054] In the preparation method, in step 4, the reaction comprises the following steps: under nitrogen protection, compound B6 and potassium phosphate are mixed in a mixed solution of dichloromethane, tetrahydrofuran and water, di-tert-butyl tin dichloride, triethylamine and p-toluenesulfonyl chloride are added, after the reaction is completed, extraction is carried out, the organic phase is separated to obtain a dichloromethane solution containing compound B7; preferably, the dichloromethane solution containing compound B7 is concentrated and directly used in step 5.

[0055] In the preparation method, in step 5, the solvent can be a conventional solvent for such a reaction in the art, for example, toluene.

[0056] In the preparation method, in step 5, the acid can be one or both of glacial acetic acid and p-toluenesulfonic acid.

[0057] In the preparation method, in step 5, the molar ratio of compound B7 to 3,4-dihydropyran can be 1:(1-5); preferably 1:2.

[0058] In the preparation method, in step 5, the molar ratio of compound B7 to glacial acetic acid can be 1:(0.5-1); preferably 1:0.5.

[0059] In the preparation method, in step 5, the molar ratio of compound B7 to p-toluenesulfonic acid can be 1:(0.5-1); preferably 1:0.5. The p-toluenesulfonic acid is preferably p-toluenesulfonic acid monohydrate.

[0060] In the preparation method, in step 5, the temperature of the reaction can be 15-25°C.

[0061] In the preparation method, step 5 comprises the following steps: after the dichloromethane solution containing compound B7 obtained in step 4 is concentrated, it is mixed with toluene and concentrated, and then reacted with glacial acetic acid, p-toluenesulfonic acid monohydrate and 3,4-dihydropyran at 15-25°C to obtain a solution containing compound B7-1.

[0062] In the preparation method, in step 6, the base can be an organic base, for example, potassium tert-butoxide.

[0063] In the preparation method, in step 6, the molar ratio of compound B7-1 to the base can be 1:(1-5); preferably 1:2.

[0064] In the preparation method, in step 6, the temperature of the reaction can be 15-25°C.

[0065] In the preparation method, step 6 comprises the following steps: mixing the solution containing compound B7-1 obtained from step 5 with potassium tert-butoxide at 5-15°C, and reacting at 15-25°C; after the reaction is completed, adding an acid for neutralization, standing to separate layers, extracting the aqueous phase with toluene, and concentrating the organic phase under reduced pressure to obtain a toluene solution containing compound B7-2; preferably, directly used in step 7.

[0066] In the preparation method, in step 7, the solvent can be a solvent conventional in the art for such reactions, for example an alcohol solvent, for example methanol.

[0067] In the preparation method, in step 7, the acid can be one or both of p-toluenesulfonic acid and hydrogen chloride; the p-toluenesulfonic acid is preferably p-toluenesulfonic acid monohydrate; the hydrogen chloride is preferably hydrogen chloride ethanol solution; the concentration of the hydrogen chloride ethanol solution is preferably 4M.

[0068] In the preparation method, in step 7, the temperature of the reaction can be 15-25°C.

[0069] In the preparation method, in step 7, the molar ratio of compound B7-2 to p-toluenesulfonic acid can be 1:(0.1-1); preferably 1:0.1.

[0070] In the preparation method, in step 7, the molar ratio of compound B7-2 to hydrogen chloride can be 1:(0.5-1); preferably 1:0.77.

[0071] In the preparation method, in step 7, the reaction is carried out under inert gas protection, for example nitrogen.

[0072] In the preparation method, step 7 comprises the following steps: mixing the toluene solution containing compound B7-2 obtained from the reaction in step 6 with methanol, p-toluenesulfonic acid monohydrate and hydrogen chloride ethanol solution under nitrogen protection, and reacting at 15-25°C to obtain a toluene solution containing compound B8; preferably, directly used in step 8.

[0073] In the preparation method, in step 8, the reactants of the Mitsunobu reaction further comprise triphenylphosphine and di-tert-butyl azodicarboxylate (DBAD).

[0074] In the preparation method, in step 8, the molar ratio of compound B8 to compound B8-1 can be 1:(0.5-1.2); preferably 1:0.9.

[0075] In the preparation method, in step 8, the molar ratio of compound B8 to triphenylphosphine can be 1:(1-2); preferably 1:1.4.

[0076] In the preparation method, in step 8, the molar ratio of the compound B8 to the di-tert-butyl azodicarboxylate can be 1: (1-2), preferably 1:1.4.

[0077] In the preparation method, in step 8, the solvent can be a solvent conventional for such reactions in the art, such as toluene.

[0078] In the preparation method, in step 8, the reaction is carried out under inert gas protection, such as nitrogen.

[0079] In the preparation method, in step 8, the temperature of the Mitsunobu reaction can be -7-3℃.

[0080] In the preparation method, in step 8, the Mitsunobu reaction comprises the following steps: under nitrogen protection, the toluene solution containing the compound B8 obtained from step 7 is mixed with toluene, compound B8-1 and triphenylphosphine, and then a toluene solution of di-tert-butyl azodicarboxylate (DBAD) is added dropwise at -7-3℃, and then anhydrous magnesium chloride is added to obtain the compound B9.

[0081] In the preparation method, in step 9, the solvent can be a solvent conventional for such reactions in the art, such as toluene.

[0082] In the preparation method, in step 9, the molar ratio of the compound B9 to the ethanolamine can be 1: (2-10), preferably 1:4.

[0083] In the preparation method, in step 9, the temperature of the reaction can be 45-55℃.

[0084] In the preparation method, in step 9, the reaction is carried out under inert gas protection, such as nitrogen.

[0085] In the preparation method, in step 10, the solvent can be a solvent conventional for such reactions in the art, such as ethyl acetate.

[0086] In the preparation method, in step 10, the acid can be hydrogen chloride ethyl acetate solution.

[0087] In the preparation method, in step 10, the temperature of the reaction can be 45-55℃.

[0088] The application also provides a compound B4 or a salt thereof,

[0089] .

[0090] The application further provides a preparation method of the compound B4, comprising the following steps: reacting the compound B3, an ethyl form reagent, a titanate and a boron trifluoride reagent in a solvent to generate the compound B4.

[0091] ;

[0092] Preferably, the preparation method of the compound B5 further comprises the preparation of the compound B4, and the preparation conditions of the compound B4 are as described in any one of the application.

[0093] The application further provides a compound B5 or a salt thereof,

[0094] .

[0095] The application further provides a preparation method of the compound B5, comprising the following steps: reacting the compound B4 with an acid to generate the compound B5.

[0096]

[0097] Preferably, the preparation method of the compound B5 further comprises the preparation of the compound B4, and the preparation conditions of the compound B4 are as described in any one of the application.

[0098] Preferably, the preparation method of the compound B5 further comprises the preparation of the compound B4, and the preparation conditions of the compound B4 are as described in any one of the application.

[0099] The application further provides a compound B6 or a salt thereof,

[0100] .

[0101] The application further provides a preparation method of the compound B6, comprising the following steps: reacting the compound B5, benzyl chloroformate (CbzCl) and a base in a solvent to generate the compound B6.

[0102]

[0103] Preferably, the preparation method of the compound B6 further comprises the preparation of the compound B5, and the preparation conditions of the compound B5 are as described in any one of the application.

[0104] Preferably, the preparation method of the compound B6 further comprises the preparation of the compound B5, and the preparation conditions of the compound B5 are as described in any one of the application.

[0105] The application further provides a compound B7 or a salt thereof,

[0106] .

[0107] The application further provides a preparation method of the compound B7, which comprises the following steps: reacting the compound B6 with p-toluenesulfonyl chloride (TsCl) and di-t-butyl tin dichloride (Bu2SnCl2) in a solvent in the presence of a base and potassium phosphate to generate the compound B7.

[0108]

[0109] The preparation conditions of the preparation method of the compound B7 are as described in any one of the schemes of the application.

[0110] Preferably, the preparation method of the compound B7 further comprises the preparation of the compound B6; and the preparation conditions of the compound B6 are as described in any one of the schemes of the application.

[0111] The application further provides a compound B7-1 or a salt thereof,

[0112] .

[0113] The application further provides a preparation method of the compound B7-1, which comprises the following steps: reacting the compound B7 with 3,4-dihydropyran in a solvent in the presence of an acid to generate the compound B7-1.

[0114]

[0115] The preparation conditions of the preparation method of the compound B7-1 are as described in any one of the schemes of the application.

[0116] Preferably, the preparation method of the compound B7-1 further comprises the preparation of the compound B7; and the preparation conditions of the compound B7 are as described in any one of the schemes of the application.

[0117] The application further provides a compound B7-2 or a salt thereof,

[0118] .

[0119] The application further provides a preparation method of the compound B7-2, which comprises the following steps: reacting the compound B7-1 with a base in a solvent to generate the compound B7-2.

[0120]

[0121] The preparation conditions of the preparation method of the compound B7-2 are as described in any one of the schemes of the application.

[0122] Preferably, the preparation method of the compound B7-2 further comprises the preparation of the compound B7-1; and the preparation conditions of the compound B7-1 are as described in any one of the schemes of the application.

[0123] The application also provides a compound B8 or a salt thereof,

[0124] .

[0125] The application also provides a preparation method of the compound B8, comprising the following steps:

[0126]

[0127] The preparation conditions of the preparation method of the compound B8 are as described in any one of the schemes of the application.

[0128] Preferably, the preparation method of the compound B8 further comprises the preparation of the compound B7-2; and the preparation conditions of the compound B7-2 are as described in any one of the schemes of the application.

[0129] The application also provides a compound B9 or a salt thereof,

[0130] .

[0131] The application also provides a preparation method of the compound B9, comprising the following steps: in a solvent, the compound B8 and the compound B8-1 are subjected to Mitsunobu reaction to generate the compound B9.

[0132]

[0133] The preparation conditions of the preparation method of the compound B9 are as described in any one of the schemes of the application.

[0134] Preferably, the preparation method of the compound B9 further comprises the preparation of the compound B8; and the preparation conditions of the compound B8 are as described in any one of the schemes of the application.

[0135] The application also provides a compound B10 or a salt thereof,

[0136] .

[0137] The application also provides a preparation method of the compound B10, comprising the following steps:

[0138]

[0139] The preparation conditions of the preparation method of the compound B10 are as described in any one of the schemes of the application.

[0140] Preferably, the preparation method of the compound B10 further comprises the preparation of the compound B9; and the preparation conditions of the compound B9 are as described in any one of the schemes of the application.

[0141] The above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present application.

[0142] The reagents and raw materials used in the present application are commercially available.

[0143] The positive progress effect of the present application is that the intermediate preparation method provided by the present application has short steps, simple operation, higher yield, and higher purity. DETAILED DESCRIPTION

[0144] The present application will be further described by way of examples, but the present application is not limited to the scope of the examples. The experimental methods in the following examples are not specified, and the methods are selected according to the conventional methods and conditions or according to the product instructions.

[0145] Example 1: Synthesis of Compound I

[0146]

[0147] 1 Synthesis of Compound B6

[0148] Under nitrogen protection, 150.2 kg of methyl tert-butyl ether, 20.2 kg of compound B3 and 40.8 kg of titanium acid tetraisopropyl ester (Ti(OiPr)4) were added into a reaction kettle, 280.2 kg of 1.0 M ethyl magnesium bromide was added dropwise at a temperature of 10-20°C, and the reaction was detected by sampling until it was complete. At this temperature, 36.4 kg of boron trifluoride ether was added dropwise, and the reaction was continuously stirred for 6 hours until it was complete. A solution containing compound B4 was obtained.

[0149] After the reaction was completed, 185.2 kg of 25% citric acid aqueous solution was added dropwise into the reaction liquid at a temperature of 20-40°C, and stirred for 6 hours at a temperature of 15-35°C, and then separated by standing. The organic phase was extracted with 67.4 kg of 5% citric acid aqueous solution, and the aqueous phase was combined. The aqueous phase was added into a reaction kettle, and the pH of the system was adjusted to 7-8 with 30% sodium hydroxide solution at a temperature of 15-25°C. 57.0 kg of tetrahydrofuran, 21.6 kg of benzyl chloroformate (CbzCl) and 25.0 kg of potassium bicarbonate were added. After stirring for 30 minutes at a temperature of 20-30°C, the reaction was detected by sampling until it was complete. A solution containing compound B5 was obtained.

[0150] After the reaction is completed, the pH of the system is adjusted to 1 with 31% concentrated hydrochloric acid at 10-30°C, and then 278.4 kg of isopropyl acetate is added, stirred, and allowed to separate into layers. The aqueous phase is extracted once with 278.8 kg of isopropyl acetate, and the organic phases are combined. The organic phase is concentrated under reduced pressure to 6-7 times the volume, cooled to 20-30°C, and continuously stirred for 4 hours. 217.8 kg of n-heptane is slowly added dropwise, and the stirring is continued for 8 hours. Filtration is performed, and the filter cake is washed with a mixture of 18.4 kg of isopropyl acetate and 43.2 kg of n-heptane and dried. The dried solid, 114.4 kg of water, and 22.6 kg of ethanol are added to a reaction kettle, and the temperature is raised to 50-60°C. Stirring is performed until the solution is clear, the temperature is lowered to 35-41°C, 0.038 kg of seed crystals is added, and stirring is continued for 2 hours. 229.2 kg of water is continuously added, and the stirring is continued for 2 hours. The temperature is lowered to 15-25°C, and the stirring is continued for 4 hours. Filtration is performed, the filter cake is washed with 50 kg of water, and the wet product is dried to obtain 10.8 kg of compound B6 in the form of a white solid with a purity of 98.9%, an ee value of 99.1%, a yield of 30%, and MS: m / z = 280.18, [M+H] + .

[0151] 2 Synthesis of compound B7

[0152] Under nitrogen protection, 106.0 kg of dichloromethane, 18.2 kg of tetrahydrofuran, 6.0 kg of water, 20.2 kg of compound B6, and 18.2 kg of potassium phosphate are added to a reaction kettle, and the stirring is performed at 20-30°C for 30 minutes. 1.09 kg of di-t-butyl tin dichloride (Bu2SnCl2), 0.14 kg of triethylamine, and 15.0 kg of p-toluenesulfonyl chloride (TsCl) are added, and the stirring is performed at 20-30°C for 10-12 hours. Sampling detection is performed until the reaction is complete. 80.1 kg of water is added, and the stirring is performed for 4 hours. The organic phase is washed with 84.6 kg of a 5% sodium chloride solution to obtain 170.7 kg of a dichloromethane solution of compound B7 with a purity of 90.6% and MS: m / z = 434.15, [M+H] + .

[0153] 3 Synthesis of compound B8

[0154] Into a reaction kettle, 170.7 kg of a dichloromethane solution of compound B7 was added, concentrated under reduced pressure to 2-3 times volume, 173.4 kg of toluene was added, and the concentration was continued to 8-10 times volume, 2.2 kg of glacial acetic acid, 0.68 kg of p-toluenesulfonic acid monohydrate and 12.0 kg of 3,4-dihydropyran were added at 15-25 °C, and the stirring was continued for 2 hours, and the reaction was completed by sampling detection; a solution of compound B7-1 was obtained. The temperature was lowered to 5-15 °C, and 16.1 kg of potassium tert-butoxide was added at this temperature, and the temperature was raised to 15-25 °C, and the stirring was continued for 4 hours, and the reaction was completed by sampling detection. 160.5 kg of 1.8% hydrochloric acid solution was added to the reaction liquid at this temperature, and the stirring was continued for 2 hours, and the liquid was separated, and the aqueous phase was extracted with 33.8 kg of toluene once, and the organic phases were combined, and the organic phase was concentrated under reduced pressure to 8 times volume, and a toluene solution of compound B7-2 was obtained.

[0155] Under nitrogen protection, a toluene solution of compound B7-2, 47.8 kg of methanol, 1.4 kg of p-toluenesulfonic acid monohydrate and 11.5 kg of 4M hydrogen chloride ethanol solution were added into a reaction kettle, and the stirring was continued for 1 hour at 15-25 °C, and the reaction was completed by sampling detection. The reaction liquid was controlled at 15-25 °C, and was added dropwise into 160.5 kg of 5% potassium bicarbonate solution, and the stirring was continued for 1 hour, and the filter cake was washed with 34.9 kg of toluene, and the filtrate was combined, and the liquid was separated, and the aqueous phase was extracted with 35.2 kg of toluene once, and the organic phases were combined, and the organic phase was concentrated under reduced pressure to 4 times volume, and 76.0 kg of toluene was added, and a toluene solution of compound B8 was obtained, 153.3 kg, purity 88.6%, MS: m / z = 262.20, [M+H] + .

[0156] 4 Synthesis of compound B9

[0157] Under nitrogen protection, 210.3 kg of compound B8 toluene solution, 52.3 kg of toluene, 16.1 kg of compound B8-1 and 28.0 kg of triphenylphosphine were added into a reaction kettle, and the temperature was lowered to -7~3 ℃, then di-tert-butyl azodicarboxylate (DBAD) toluene solution (25.0 kg of DBAD and 87.3 kg of toluene) was added dropwise into the reaction solution, and the stirring was continued for 6 hours, and the sample was detected until the reaction was complete. 14.6 kg of anhydrous magnesium chloride was added, and the stirring was continued for 1 hour, and the temperature was raised to 20~30 ℃, and the stirring was continued for 60 hours, and the sample was detected until the reaction was complete. The reaction solution was filtered through diatomite, the filter cake was washed with 22.4 kg of toluene, and the filtrate was combined. 280.5 kg of 4N hydrochloric acid was added into the filtrate, and the stirring was continued at 20~30 ℃ for 24 hours, and the liquid was separated, and the organic phase was washed with 84.1 kg of 10% sodium chloride solution, then washed with 84.4 kg of 4% sodium chloride and 4% sodium bicarbonate mixed solution, and then washed with 83.4 kg of 10% sodium chloride solution, and the organic phase was concentrated under reduced pressure to 8 times the volume, to obtain 225.1 kg of compound B9 toluene solution with a purity of 80.9%, MS: m / z=506.21, [M+H] + .

[0158] 5 Synthesis of compound B10

[0159] Under nitrogen protection, 224.5 kg of compound B9 toluene solution and 12.9 kg of ethanolamine were added into a reaction kettle, and the temperature was raised to 45~55 ℃, and the stirring was continued for 16 hours, and the sample was detected until the reaction was complete. The temperature was lowered to 10~20 ℃, 175.4 kg of 3% dilute hydrochloric acid was added, and the stirring was continued, and the liquid was separated, and the organic phase was washed with 125.2 g of water twice (125.2 g*2), and the organic phase was concentrated under reduced pressure until no obvious fraction was left, and 60.0 kg of ethyl acetate was added, to obtain 93.5 kg of compound B10 ethyl acetate solution with a purity of 53.1%, MS: m / z=376.23, [M+H] + .

[0160] 6 Synthesis of compound I

[0161] Under nitrogen protection, 1255.2 kg of compound B10 ethyl acetate solution was added into a reaction bottle, and concentrated under reduced pressure until no obvious fraction was left, and 1050 kg of ethyl acetate and 315.0 kg of 4.0M hydrogen chloride ethyl acetate solution were added, and the temperature was raised to 45~55 ℃, and the stirring was continued for 6 hours, and the sample was detected until the reaction was complete. The temperature was lowered to 20~30 ℃, 205.2 kg of ethanol was added, and the stirring was continued for 2 hours, and the filtration was carried out, and the filter cake was washed with 122.2 kg of ethyl acetate, and the wet product was dried, to obtain 46.1 kg of compound I with a purity of 97.2%, and the total yield of compound B6 to I was 24.6%.

[0162] 1H NMR, DMSO-d6, 7.376~7.286(m, 9 H), 6.086(s, 2 H), 4.034~ 3.987(d, 1H),3.081~3.003(m, 2 H),2.017~1.980(m, 1 H),1.623 (m, 2 H), 1.595(m, 1 H),1.073~1.039(m, 1 H) ,0.815~0.783(m, 1 H) ,0.662~0.632(m, 1 H) ,0.558~0.527(m,1 H)。

Claims

1. A method for preparing a compound as shown in Formula I, characterized in that, It includes the following steps: ； Step 1: In a solvent, compound B3, ethyl Grignard reagent, titanate, and boron trifluoride reagent react to form compound B4; Step 2: Compound B4 reacts with acid to form compound B5; Step 3: In a solvent, compound B5 reacts with benzyl chloroformate (CbzCl) and a base to generate compound B6; Step 4: In a solvent, in the presence of an organic base and potassium phosphate, compound B6 reacts with p-toluenesulfonyl chloride (TsCl) and di-tert-butyltin dichloride to generate compound B7. Step 5: In a solvent and in the presence of an acid, compound B7 reacts with 3,4-dihydro-2H-pyran to form compound B7-1; Step 6: In a solvent, compound B7-1 reacts with a base to form compound B7-2; Step 7: In a solvent, compound B7-2 reacts with an acid to form compound B8; Step 8: In a solvent, compound B8 reacts with compound B8-1 via a Mitsunobu reaction to generate compound B9; Step 9: In a solvent, compound B9 reacts with ethanolamine to form compound B10; Step 10: In a solvent, compound B10 reacts with an acid to form compound I.

2. The preparation method according to claim 1, characterized in that, In step 1, one or more of the following conditions are satisfied: (1) The solvent is an ether solvent; (2) The ethyl Grignard reagent is ethyl magnesium bromide; (3) The concentration of the ethyl Grignard reagent is 1M; (4) The titanate is tetraisopropyl titanate; (5) The boron trifluoride reagent is boron trifluoride diethyl ether; (6) The concentration of compound B3 in the solvent is 0.1~1 kg / L; (7) The molar ratio of compound B3 to the ethyl Grignard reagent is 1:(10~20); (8) The molar ratio of compound B3 to the titanate is (0.5~2):1; (9) The molar ratio of compound B3 to the boron trifluoride reagent is (0.5~1):1; (10) The reaction temperature is 10~20℃; (11) The reaction is carried out under the protection of an inert gas; (12) The compound B4 generated by the reaction is used directly in step 2 without post-treatment.

3. The preparation method according to claim 2, characterized in that, In step 1, one or more of the following conditions are satisfied: (1) The solvent is methyl tert-butyl ether; (2) The concentration of compound B3 in the solvent is 0.1 kg / L; (3) The molar ratio of compound B3 to the ethyl Grignard reagent is 1:16; (4) The molar ratio of compound B3 to the titanate is 0.9:1; (5) The molar ratio of compound B3 to the boron trifluoride reagent is 0.52:1; (6) The reaction is carried out under nitrogen protection.

4. The preparation method according to claim 2, characterized in that, Step 1 includes the following steps: under nitrogen protection, compound B3 and tetraisopropyl titanate are added to methyl tert-butyl ether, and ethyl magnesium bromide is added dropwise at 10~20℃. After the reaction is complete, boron trifluoride ether is added dropwise at 10~20℃ to obtain a solution containing compound B4.

5. The preparation method according to claim 1, characterized in that, In step 2, one or more of the following conditions must be met: (1) The acid is an aqueous solution of citric acid; (2) The molar ratio of compound B4 to the acid is 1:(1~2); (3) The reaction temperature is 20~40℃; (4) The compound B5 generated in the reaction is used directly in step 3 without post-treatment.

6. The preparation method according to claim 5, characterized in that, In step 2, the concentration of the citric acid aqueous solution is 25% or 5%; and / or, the molar ratio of compound B4 to the acid is 1:1.

8.

7. The preparation method according to claim 5, characterized in that, Step 2 includes the following steps: adding 25% citric acid aqueous solution dropwise to the solution containing compound B4 obtained in step 1 at 20~40℃, stirring at 15~35℃, allowing to stand and separate into layers, extracting the organic phase with 5% citric acid aqueous solution, and combining the aqueous phases to obtain a solution containing compound B5.

8. The preparation method according to claim 1, characterized in that, In step 3, one or more of the following conditions must be met: (1) The solvent is an ether solvent; (2) The base is an inorganic base; (3) The molar ratio of compound B5 to benzyl chloroformate is 1:(1~2); (4) The molar ratio of compound B5 to the base is 1:(1~5); (5) The reaction temperature is 20~30℃.

9. The preparation method according to claim 8, characterized in that, In step 3, one or more of the following conditions must be met: (1) The solvent is tetrahydrofuran; (2) The alkali is potassium bicarbonate; (3) The molar ratio of compound B5 to benzyl chloroformate is 1:1; (4) The molar ratio of compound B5 to the base is 1:

2.

10. The preparation method according to claim 8, characterized in that, Step 3 includes the following steps: at 15~25℃, add 30% sodium hydroxide solution to the solution containing compound B5 obtained in step 2, adjust the pH of the system to 7~8, mix with tetrahydrofuran, benzyl chloroformate (CbzCl) and potassium bicarbonate, react at 20~30℃, and obtain compound B6 after post-treatment.

11. The preparation method according to claim 10, characterized in that, In step 3, the post-processing includes the following steps: after the reaction is completed, the pH of the reaction solution is adjusted to 1, extracted with an ester organic solvent, the organic phase is concentrated and then cooled to 20~30℃, n-heptane is added dropwise, and the mixture is filtered to obtain compound B6.

12. The preparation method according to claim 11, characterized in that, In step 3, the filter cake is washed with a mixed solution of ester organic solvent / n-heptane and dried; or, it may also include recrystallizing the dried solid with water and ethanol to obtain compound B6.

13. The preparation method according to claim 1, characterized in that, In step 4, one or more of the following conditions must be met: (1) The solvent is a mixture of dichloromethane, tetrahydrofuran and water; (2) The molar ratio of compound B6 to the organic base is 1:(0.02~0.1); (3) The molar ratio of compound B6 to potassium phosphate is 1:(1~2); (4) The molar ratio of compound B6 to p-toluenesulfonyl chloride is 1:(0.4~1); (5) The molar ratio of compound B6 to di-tert-butyltin dichloride is 1:(0.05~0.1); (6) The reaction temperature is 20~30℃; (7) The reaction is carried out under the protection of an inert gas.

14. The preparation method according to claim 13, characterized in that, In step 4, one or more of the following conditions must be met: (1) The volume ratio of dichloromethane, tetrahydrofuran and water is 17:3:1; (2) The organic base is triethylamine; (3) The molar ratio of compound B6 to the organic base is 1:0.02; (4) The molar ratio of compound B6 to potassium phosphate is 1:1.2; (5) The molar ratio of compound B6 to p-toluenesulfonyl chloride is 1:0.46; (6) The molar ratio of compound B6 to di-tert-butyltin dichloride is 1:0.05; (8) The reaction is carried out under nitrogen.

15. The preparation method according to claim 13, characterized in that, In step 4, the reaction includes the following steps: under nitrogen protection, in a mixed solution of dichloromethane, tetrahydrofuran and water, at 20-30°C, compound B6 and potassium phosphate are mixed, and di-tert-butyltin dichloride, triethylamine and p-toluenesulfonyl chloride are added. After the reaction is complete, extraction is performed, and the organic phase is separated to obtain a dichloromethane solution containing compound B7.

16. The preparation method according to claim 15, characterized in that, The dichloromethane solution containing compound B7 is concentrated and then used directly in step 5.

17. The preparation method according to claim 1, characterized in that, In step 5, one or more of the following conditions must be met: (1) The solvent is toluene; (2) The acids are glacial acetic acid and p-toluenesulfonic acid; (3) The molar ratio of compound B7 to 3,4-dihydro-2H-pyran is 1:(1~5); (4) The reaction temperature is 15~25℃.

18. The preparation method according to claim 17, characterized in that, In step 5, the molar ratio of compound B7 to glacial acetic acid is 1:(0.5~1); the molar ratio of compound B7 to p-toluenesulfonic acid is 1:(0.5~1).

19. The preparation method according to claim 17, characterized in that, In step 5, one or more of the following conditions must be met: (1) The molar ratio of compound B7 to 3,4-dihydro-2H-pyran is 1:2; (2) The molar ratio of compound B7 to glacial acetic acid is 1:0.5; (3) The molar ratio of compound B7 to p-toluenesulfonic acid is 1:0.5; (4) The p-toluenesulfonic acid is p-toluenesulfonic acid monohydrate.

20. The preparation method according to claim 17, characterized in that, Step 5 includes the following steps: mixing compound B7 obtained in step 4 with toluene, and reacting it with glacial acetic acid, p-toluenesulfonic acid monohydrate and 3,4-dihydro-2H-pyran at 15~25°C to obtain a solution containing compound B7-1.

21. The preparation method according to claim 20, characterized in that, The resulting solution containing compound B7-1 was used directly in step 6.

22. The preparation method according to claim 1, characterized in that, In step 6, one or more of the following conditions must be met: (1) The base is an organic base; (2) The molar ratio of compound B7-1 to the base is 1:(1~5); (3) The reaction temperature is 15~25℃.

23. The preparation method according to claim 22, characterized in that, In step 6, one or more of the following conditions must be met: (1) The base is potassium tert-butoxide; (2) The molar ratio of compound B7-1 to the base is 1:2; (3) Step 6 includes the following steps: at 5~15℃, the solution containing compound B7-1 obtained in step 5 is mixed with potassium tert-butoxide and reacted at 15~25℃; after the reaction is completed, acid is added to neutralize, the mixture is allowed to stand and separate into layers, the aqueous phase is extracted with toluene, and the organic phase is concentrated under reduced pressure to obtain a toluene solution containing compound B7-2.

24. The preparation method according to claim 23, characterized in that, The toluene solution containing compound B7-2 was directly used in step 7.

25. The preparation method according to claim 1, characterized in that, In step 7, one or more of the following conditions are satisfied: (1) The solvent is an alcohol solvent; (2) The acid is p-toluenesulfonic acid and hydrogen chloride; (3) The reaction temperature is 15~25℃; (4) The reaction is carried out under the protection of an inert gas.

26. The preparation method according to claim 25, characterized in that, In step 7, the molar ratio of compound B7-2 to p-toluenesulfonic acid is 1:(0.1~1); the molar ratio of compound B7-2 to hydrogen chloride is 1:(0.5~1).

27. The preparation method according to claim 25, characterized in that, In step 7, one or more of the following conditions are satisfied: (1) The solvent is methanol; (2) The p-toluenesulfonic acid is p-toluenesulfonic acid monohydrate; (3) The hydrogen chloride is a hydrogen chloride ethanol solution; (4) The molar ratio of compound B7-2 to p-toluenesulfonic acid is 1:0.1; (5) The molar ratio of compound B7-2 to hydrogen chloride is 1:0.77; (6) The reaction is carried out under nitrogen protection.

28. The preparation method according to claim 27, characterized in that, The concentration of the hydrogen chloride ethanol solution is 4M; and / or, step 7 includes the following steps: under nitrogen protection, the toluene solution containing compound B7-2 obtained from step 6 is mixed with methanol, p-toluenesulfonic acid monohydrate and hydrogen chloride ethanol solution, and reacted at 15~25°C to obtain a toluene solution containing compound B8.

29. The preparation method according to claim 28, characterized in that, The toluene solution containing compound B8 was directly used in step 8.

30. The preparation method according to claim 1, characterized in that, In step 8, one or more of the following conditions are satisfied: (1) The reactants of the Mitsunobu reaction also include triphenylphosphine and di-tert-butyl azodicarbonate; (2) The molar ratio of compound B8 to compound B8-1 is 1:(0.5~1.2); (3) The solvent is toluene; (4) The reaction is carried out under the protection of an inert gas; (5) The temperature of the Mitsunobu reaction is -7~3℃.

31. The preparation method according to claim 30, characterized in that, In step 8, one or more of the following conditions are satisfied: (1) The molar ratio of compound B8 to triphenylphosphine is 1:(1~2); (2) The molar ratio of compound B8 to di-tert-butyl azodicarbonate is 1:(1~2); (3) The molar ratio of compound B8 to compound B8-1 is 1:0.9; (4) The reaction is carried out under nitrogen protection.

32. The preparation method according to claim 30, characterized in that, In step 8, one or more of the following conditions are satisfied: (1) The molar ratio of compound B8 to triphenylphosphine is 1:1.4; (2) The molar ratio of compound B8 to di-tert-butyl azodicarbonate is 1:1.4; (3) The Mitsunobu reaction includes the following steps: under nitrogen protection, the toluene solution containing compound B8 obtained in step 7 is mixed with toluene, compound B8-1 and triphenylphosphine, and a toluene solution of di-tert-butyl azodicarbonate (DBAD) is added dropwise at -7~3℃, and anhydrous magnesium chloride is added to react and compound B9 is obtained.

33. The preparation method according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) In step 9, the solvent is toluene; (2) In step 9, the molar ratio of compound B9 to ethanolamine is 1:(2~10); (3) In step 9, the reaction temperature is 45~55℃; (4) In step 9, the reaction is carried out under the protection of an inert gas; (5) In step 10, the solvent is ethyl acetate; (6) In step 10, the acid is an ethyl hydrogen chloride solution; (7) In step 10, the reaction temperature is 45~55℃.

34. The preparation method according to claim 33, characterized in that, In step 9, the molar ratio of compound B9 to ethanolamine is 1:4; and / or, in step 9, the reaction is carried out under nitrogen protection.

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