Process for the preparation of an intermediate of amuvirtide

Abstract

The application discloses a preparation method of an intermediate of Axitinib. The application specifically discloses a preparation method of a compound as shown in formula III, which comprises the following steps: adding a reaction solution containing a compound as shown in formula I into a reaction solution containing a compound as shown in formula IX, and carrying out a substitution reaction as shown in the following formula III. The preparation method of the intermediate of Axitinib can avoid using expensive reagents, save cost, and significantly improve the yield of the compound III, and is beneficial to industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to a preparation method of an Alectinib intermediate. BACKGROUND

[0002] Alectinib, also known as Alecensa, is an ALK inhibitor used for the treatment of advanced (metastatic) non-small cell lung cancer (NSCLC) with ALK gene mutation, or patients resistant to crizotinib. The chemical name is 9-ethyl-6,6-dimethyl-8-[4-(4-morpholinyl)-1-piperidinyl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile, and its molecular structure is as follows:

[0003]

[0004] WO2010143664 and WO2012023597 reported two synthetic routes of Alectinib.

[0005] Route one: 7-methoxy-3,4-dihydro-2-naphthalenone is used as the raw material, and Alectinib is prepared through 9 steps, the route step is long, the operation is complicated, the production cost is high, and it is not conducive to commercialization, and the synthetic route is as follows:

[0006]

[0007] Route two: 2-methyl-2-(4-ethyl-3-iodophenyl)-propionic acid is used as the raw material (compound I), and Alectinib is prepared through six steps, and the route is greatly simplified compared with the route one step, but in the preparation of compound III, not only the expensive cesium carbonate is used, but also the yield of compound I to compound IV is only 63%, and the yield is not high.

[0008]

[0009] Therefore, exploring a preparation method of Alectinib with higher yield and lower cost has been the direction of efforts of medical workers. SUMMARY

[0010] The present application provides a preparation method of an Alectinib intermediate to overcome the problems of low yield and high cost in the preparation method of Alectinib in the prior art, and the preparation method has high yield and low cost, and is beneficial to industrial production.

[0011] The present application solves the above technical problems through the following technical scheme.

[0012] The present application also provides a preparation method of a compound as shown in formula III, which comprises the following steps:

[0013] adding a reaction solution containing a compound of Formula I to a reaction solution containing a compound of Formula IX, to undergo a substitution reaction as shown below, to obtain a compound of Formula III;

[0014] The reaction solution containing a compound of Formula I comprises a compound of Formula I, a condensation activator, and an organic solvent.

[0015] The reaction solution containing a compound of Formula IX comprises a compound of Formula IX, an organic base, and an organic solvent.

[0016]

[0017] In the method for preparing a compound of Formula III, the raw materials for the substitution reaction consist of the organic solvent in the reaction solution containing a compound of Formula I, the organic solvent in the reaction solution containing a compound of Formula IX, the compound of Formula I, the compound of Formula IX, the condensation activator, and the organic base.

[0018] The reaction solution containing a compound of Formula I consists of the compound of Formula I, the condensation activator, and the organic solvent.

[0019] The reaction solution containing a compound of Formula IX consists of the compound of Formula IX, the organic base, and the organic solvent.

[0020] In the method for preparing a compound of Formula III, the condensation activator can be a condensation activator for substitution reactions in the art, preferably thionyl chloride, oxalyl chloride, CDI, DCC, or EDC; for example, CDI.

[0021] In the method for preparing a compound of Formula III, the molar ratio of the condensation activator to the compound of Formula I can be a conventional amount used in substitution reactions in the art, preferably (1.0-1.5): 1, more preferably (1.0-1.3): 1, for example 1.0:1, 1.05:1, or 1.3:1.

[0022] In the method for preparing a compound of Formula III, the organic solvent in the reaction solution containing a compound of Formula I can be a conventional solvent used in substitution reactions in the art, preferably acetonitrile, ethylene glycol dimethyl ether, or dichloromethane, for example, acetonitrile.

[0023] In the preparation method of the compound of formula III, the molar volume ratio of the compound of formula I to the organic solvent in the reaction solution containing the compound of formula I can be the conventional amount used in substitution reactions in the art, preferably 0.67-1.0 mol / L, for example 0.8 mol / L.

[0024] In the preparation method of the compound of formula III, the temperature when the compound of formula I and the condensation activator are mixed can be the conventional temperature when mixing is performed in substitution reactions in the art, preferably 20-30°C.

[0025] In the preparation method of the compound of formula III, the organic base can be a conventional organic base used in substitution reactions in the art, preferably triethylamine or diisopropylethylamine, for example triethylamine.

[0026] In the preparation method of the compound of formula III, the molar ratio of the organic base to the compound of formula IX can be the conventional amount used in substitution reactions in the art, preferably (1-2):1, for example 1.5:1.

[0027] In the preparation method of the compound of formula III, the organic solvent in the reaction solution containing the compound of formula IX can be a conventional solvent used in substitution reactions in the art, preferably acetonitrile, dichloromethane, ethylene glycol dimethyl ether or tetrahydrofuran, for example acetonitrile.

[0028] In the preparation method of the compound of formula III, the molar volume ratio of the compound of formula IX to the organic solvent in the reaction solution containing the compound of formula IX can be the conventional amount used in substitution reactions in the art, preferably 0.67-1.0 mol / L, for example 0.8 mol / L.

[0029] In the preparation method of the compound of formula III, the temperature when the compound of formula IX and the organic base are mixed can be the conventional temperature when mixing is performed in substitution reactions in the art, preferably 20-30°C.

[0030] In the preparation method of the compound of formula III, the molar ratio of the compound of formula I to the compound of formula IX can be the conventional amount used in substitution reactions in the art, preferably (0.5-1.5):1, for example 1:1 or 1.05:1.

[0031] In the preparation method of the compound of formula III, the temperature when the reaction solution containing the compound of formula I is added to the reaction solution containing the compound of formula IX can be the conventional temperature when the same operation is performed in substitution reactions in the art, preferably 20-30°C.

[0032] The adding is preferably dropwise.

[0033] The reaction temperature of the substitution reaction in the preparation method of the compound of formula III can be the conventional reaction temperature of the substitution reaction in the art, preferably 60-80°C, for example 65-70°C.

[0034] The preparation method of the compound of formula III can further comprise a post-treatment after the substitution reaction.

[0035] The post-treatment can further comprise the following steps: concentration (for example, concentration under reduced pressure), dilution with an organic solvent (for example, isopropyl acetate), acidification to pH 5-6, liquid separation, and concentration of the organic phase to obtain the compound of formula III.

[0036] In the post-treatment, the acidification is preferably hydrochloric acid acidification, and the concentration of the hydrochloric acid is preferably 2 mol / L.

[0037] In a preferred embodiment, the preparation method of the compound of formula III further comprises a preparation method of a compound of formula IX, which comprises the following steps:

[0038] In a solvent, a compound of formula VIII is subjected to a condensation reaction with tert-butyl alcohol in the presence of a condensation reagent and a catalyst to obtain a compound of formula IX.

[0039]

[0040] In the preparation method of the compound of formula IX, the raw materials of the condensation reaction consist of the solvent, the compound of formula VIII, the tert-butyl alcohol, the catalyst, and the condensation reagent.

[0041] In the preparation method of the compound of formula IX, the condensation reagent can be a conventional condensation reagent in the art, preferably DCC or EDC, for example DCC.

[0042] In the preparation method of the compound of formula IX, the catalyst can be a conventional catalyst in the art, preferably DMAP.

[0043] In the preparation method of the compound of formula IX, the molar ratio of the condensation reagent to the compound of formula VIII can be the conventional usage in the art, preferably (1-1.5):1, for example 1.05:1 or 1.1:1.

[0044] In the preparation method of the compound of formula IX, the molar ratio of the catalyst to the compound of formula VIII can be the conventional amount used in condensation reactions in the art, preferably (0.03-0.1):1, for example 0.05:1.

[0045] In the preparation method of the compound of formula IX, the molar ratio of the tert-butyl alcohol to the compound of formula VIII can be the conventional amount used in condensation reactions in the art, preferably (1-2):1, for example 1:1 or 2:1.

[0046] In the preparation method of the compound of formula IX, the solvent can be the conventional solvent used in condensation reactions in the art, preferably dichloromethane.

[0047] In the preparation method of the compound of formula IX, the molar volume ratio of the compound of formula VIII to the solvent can be the conventional amount used in condensation reactions in the art, preferably 1-2 mol / L, for example 1 mol / L.

[0048] In the preparation method of the compound of formula IX, the reaction temperature of the condensation reaction can be the conventional reaction temperature of condensation reactions in the art, preferably 15-35℃, for example 15-25℃.

[0049] In the preparation method of the compound of formula IX, the condensation reaction can further include post-treatment, which can refer to the conventional operation method of post-treatment in the art.

[0050] The post-treatment can further include filtration, acidification of the filtrate, liquid-liquid separation, concentration of the organic phase, and recrystallization to obtain the compound of formula IX.

[0051] In the post-treatment, the acidification can be acidification with hydrochloric acid; the concentration of the hydrochloric acid can be 1 mol / L.

[0052] In the post-treatment, the solvent used in recrystallization can be ethanol and water.

[0053] The present application also provides a preparation method of a compound of formula IX, which comprises the following steps: condensation reaction of a compound of formula VIII with tert-butyl alcohol in a solvent in the presence of a condensation reagent and a catalyst to obtain a compound of formula IX;

[0054]

[0055] In the preparation method of the compound of formula IX, the conditions and parameters are as described in any one of the present application.

[0056] The present application also provides a compound of formula IX,

[0057]

[0058] In the present application, the synthesis route of the compound as shown in formula III is as follows:

[0059]

[0060] The preparation method, conditions and parameters of the compound as shown in formula IX and the compound as shown in formula III are as described in any one of the present application.

[0061] On the basis of not violating the common sense of the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e. to obtain each preferred example of the present application.

[0062] The reagents and raw materials used in the present application are commercially available.

[0063] The positive progress effect of the present application is that the preparation method of the Alectinib intermediate of the present application can avoid the use of expensive reagents, save costs, and significantly improve the yield of compound III, which is conducive to industrialized production. DETAILED DESCRIPTION

[0064] The present application will be further described below by way of examples, but the present application is not limited in the scope of the examples. The experimental methods in the following examples without specific conditions are selected according to conventional methods and conditions, or according to the instructions of the goods.

[0065] Example 1:

[0066]

[0067] Into 100 mL of dichloromethane, 20.6 g of the compound as shown in formula VIII (0.1 mol), 15.8 g of tert-butyl alcohol (0.2 mol), and 0.611 g of 4-dimethylaminopyridine (0.005 mol) were added and cooled to 0-5°C. The temperature was controlled not to be higher than 5°C, and 21.6 g of DCC (0.105 mol) dissolved in 100 mL of dichloromethane was added to the above solution. After the dropwise addition was completed, the reaction was carried out at 15-25°C for 4-6 hours. Filtration was carried out, and the filter cake was rinsed with dichloromethane (41 mL*2). The organic phase was washed with 1 mol / L hydrochloric acid (41 mL*2), 5% sodium bicarbonate (41 mL*1), and water (41 mL*1) in sequence. The organic phase was concentrated to dryness, 40 mL of ethanol was added, and stirred until dissolved. 200 mL of water was added dropwise at 20-30°C, and after the dropwise addition was completed, the stirring was carried out at 0-5°C for 2-3 hours. Filtration was carried out, and the filter cake was rinsed with 41 mL of petroleum ether, and dried under vacuum at 40-50°C to obtain 24.2 g of the compound as shown in formula IX, with a yield of 92.0%.

[0068] 1H NMR (400 MHz, DMSO-d6): 1.51 (s, 9H), 4.20 (s, 2H), 7.82 (d, 1H), 8.23 (d, 1H), 8.65 (s, 1H).

[0069] Example 2:

[0070]

[0071] Compound I, 33.4 g (0.105 mol), 17.0 g N,N-carbonyldiimidazole (CDI, 0.105 mol) were added into 125 mL acetonitrile, and the reaction was controlled at 20-30 °C for 2 hours. Compound IX, 26.2 g (0.1 mol), 15.2 g triethylamine (0.15 mol) were dissolved in 125 mL acetonitrile, and stirred at 20-30 °C for 1 hour. The reaction solution of compound I was added dropwise into the reaction solution of compound IX at 20-30 °C, and after the dropwise addition was completed, the temperature was raised to 65-70 °C, and the reaction was stirred for 3 hours. After the reaction was completed, the temperature was lowered to 40-50 °C, and the external temperature was controlled to be not higher than 50 °C, and the pressure was reduced to 60-80 mL. 318 mL isopropyl acetate was added, and the solution was acidified to pH = 5-6 with 2 mol / L dilute hydrochloric acid under stirring, and the solution was separated. The aqueous phase was extracted with 65 mL isopropyl acetate, and the combined organic phase was washed with 100 mL 5% sodium bicarbonate, and 10% sodium chloride (100 mL*2). The organic phase was concentrated under reduced pressure to almost no liquid flow to obtain an oily liquid, and the purity of the oily liquid was measured by the following HPLC: 99.2%, and the oily liquid was directly used in the next step without further treatment.

[0072] Table 1. HPLC test conditions

[0073]

[0074] The compound as shown in formula III prepared by the above preparation method is an oily liquid, which contains solvents and the like. The purity of the oily liquid is nearly 99% (excluding solvents) measured by the above HPLC detection method, which indicates that the product is substantially free of raw materials (compound IX), and the reaction is substantially complete.

[0075] Considering that the oily liquid is directly used in the next step reaction, and does not affect the preparation of the product in the next step, the oily liquid is directly used in the next step reaction without further purification.

[0076] Example 3:

[0077]

[0078] The same procedure as described in CN201080025574, paragraph 7029, was followed to dissolve all the product of compound III from Example 2 in 112 mL of tetrahydrofuran, 224 mL of water was added to the reaction flask, the temperature was adjusted to 25-35°C, and 56.2 g of sodium dithionite (88% content) was added in portions while the temperature was controlled to be no higher than 35°C. After the addition was completed, the reaction was allowed to proceed for 4 hours while the temperature was controlled to be 25-35°C. After the reaction was completed, the lower aqueous phase was removed by liquid separation. The organic phase was washed successively with 224 mL of 10% sodium chloride, 224 mL of 1 mol / L hydrochloric acid, 224 mL of 5% sodium bicarbonate, and 224 mL of water, and then concentrated to dryness under reduced pressure. To the concentrate was added 224 mL of ethanol, and the mixture was stirred to dissolve, and 1120 mL of water was added dropwise while the temperature was controlled to be 20-30°C. The mixture was allowed to stand and stir for 2-3 hours, filtered, washed with 336 mL of an ethanol / water solution (V:V=1:2), and dried under reduced pressure at 40-50°C to obtain 47.4 g of the product, which had a total yield of 92.2% for Examples 2 and 3, and a purity of 98.9% as determined by HPLC. MS: (M+H) + : 515.2.

[0079] Table 2. HPLC test conditions

[0080]

[0081]

[0082] Example 4:

[0083] Referring to the method for preparing the compound of formula IX in Reference Example 1, the compound of formula IX-Me, IX-Et, IX-Bu was prepared from the compound of formula VIII, and the yield and purity of the obtained product were as shown in Table 3. 1 H NMR was as shown in Table 3.

[0084] Table 3. Structure and yield data of the compound of formula IX-Me, IX-Et, IX-Bu

[0085]

[0086] Example 5:

[0087] Referring to the method for preparing the compound of formula III in Reference Example 2 and the HPLC test method, the compound of formula III-Me, III-Et, III-Bu was prepared from the compound of formula I, and the yield and purity of the obtained product were as shown in Table 4.

[0088] Table 4. Structure and purity data of the compound of formula III-Me, III-Et, III-Bu

[0089]

[0090] Note: The compounds as shown in Formula III-Me, III-Et, III-Bu prepared by the above preparation method are all oily liquid, which contains solvent. The purity of the product is nearly 99% (excluding solvent) by the above HPLC detection method during HPLC test, which indicates that the product is substantially free of raw materials and the reaction is substantially complete.

[0091] Considering that the above oily liquid is directly used for the next step reaction without affecting the preparation of the next product, no further purification is made and the obtained oily liquid is directly used for the next step reaction.

[0092] Example 6:

[0093] Referring to the preparation method of the compound as shown in Formula IV and the HPLC test method of Reference Example 3, the compound as shown in Formula IV-Me, IV-Et, IV-Bu is prepared by the reduction ring closure reaction of the compound as shown in Formula III-Me, III-Et, III-Bu. The yield and purity of the obtained product are shown in Table 3 below.

[0094] Table 3. Structure and yield data of the compound as shown in Formula IV-Me, IV-Et, IV-Bu

[0095]

[0096] Note: The total yield in the above table refers to the yield of preparing the compound as shown in Formula IV-Me, IV-Et, IV-Bu from the compound as shown in Formula III-Me, III-Et, III-Bu, i.e. the product oily liquid obtained in Example 5.

[0097] Example 7:

[0098]

[0099] Into 100 mL of dichloromethane, 20.6 g of the compound as shown in formula VIII (0.1 mol), 7.9 g of tert-butyl alcohol (0.1 mol), and 0.611 g of 4-dimethylaminopyridine (0.005 mol) were added and cooled to 0-5 °C. A solution of 21.6 g of DCC (0.105 mol) dissolved in 100 mL of dichloromethane was added to the above solution at a temperature not higher than 5 °C. After the dropwise addition was completed, the reaction was carried out at 15-25 °C for 4-6 hours. TLC showed that the reaction was complete. 10 mL of water was added and stirred for 1 hour. The filter cake was rinsed with dichloromethane (41 mL*2). The organic phase was washed successively with 1 mol / L hydrochloric acid (41 mL*2), 5% sodium bicarbonate (41 mL*1), and water (41 mL*1). The organic phase was concentrated to dryness. 40 mL of ethanol was added and stirred until dissolved. 200 mL of water was added dropwise at a temperature of 20-30 °C. After the dropwise addition was completed, the stirring was carried out at a temperature of 0-5 °C for 2-3 hours. The filter cake was rinsed with 41 mL of petroleum ether and dried under vacuum at 40-50 °C to obtain 23.1 g of the compound as shown in formula IX with a yield of 88.2%.

[0100] Example 8:

[0101]

[0102] Into 125 mL of acetonitrile, 31.8 g of compound I (0.1 mol) and 16.2 g of N,N-carbonyldiimidazole (CDI) were added and reacted at a temperature of 20-30 °C for 2 hours. Into 125 mL of acetonitrile, 26.2 g of compound IX (0.1 mol) and 15.2 g of triethylamine (0.15 mol) were dissolved and stirred at a temperature of 20-30 °C for 1 hour. The reaction solution of compound I was added dropwise to the reaction solution of compound IX at a temperature of 20-30 °C. After the dropwise addition was completed, the temperature was raised to 65-70 °C and the stirring was carried out for 3 hours. After the reaction was completed, the temperature was lowered to 40-50 °C and the solution was concentrated under reduced pressure to 60-80 mL. 318 mL of isopropyl acetate was added and acidified to pH = 5-6 with 2 mol / L dilute hydrochloric acid while stirring. The mixture was separated. The aqueous phase was extracted with 65 mL of isopropyl acetate. The combined organic phase was washed successively with 100 mL of 5% sodium bicarbonate and 100 mL of 10% sodium chloride. The organic phase was concentrated under reduced pressure to obtain an oily liquid. The purity was 96.7% as measured by the HPLC detection method of Example 2.

[0103] Example 9:

[0104]

[0105] A solution of the compound III from Example 8 was dissolved in 112 mL of tetrahydrofuran, 224 mL of water was added to the reaction flask, and the temperature was adjusted to 25-35°C. The temperature was controlled to be no higher than 35°C, and 56.2 g of sodium dithionite (88% content) was added in portions. After the addition was completed, the temperature was controlled to be 25-35°C, and the reaction was allowed to proceed for 4 hours. After the reaction was completed, the lower aqueous phase was removed by separation. The organic phase was washed successively with 224 mL of 10% sodium chloride, 224 mL of 1 mol / L hydrochloric acid, 224 mL of 5% sodium bicarbonate, and 224 mL of water, and then concentrated to dryness under reduced pressure. To the concentrate was added 224 mL of ethanol, and the mixture was stirred to dissolve. The temperature was controlled to be 20-30°C, and 1120 mL of water was added dropwise. The mixture was stirred for 2-3 hours, filtered, washed with 336 mL of an ethanol / water solution (V:V=1:2), and dried under reduced pressure at 40-50°C to obtain 45.1 g, which was a total yield of 87.7% of Example 8 and Example 9, and had a purity of 98.5%. MS: (M+H) + : 515.2.

[0106] Example 10:

[0107]

[0108] A solution of 20.6 g of a compound as shown in Formula VIII (0.1 mol), 15.8 g of tert-butyl alcohol (0.2 mol), and 0.611 g of 4-dimethylaminopyridine (0.005 mol) was added to 100 mL of dichloromethane, and cooled to 0-5°C. A solution of 20.6 g of DCC (0.10 mol) dissolved in 100 mL of dichloromethane was added to the above solution at a temperature controlled to be no higher than 5°C. After the dropwise addition was completed, the temperature was controlled to be 15-25°C, and the reaction was allowed to proceed for 4-6 hours. TLC showed that a small amount of starting material remained. 2.06 g of DCC (0.01 mol) was added, and the reaction was allowed to proceed for 2 hours. TLC showed that the starting material was completely reacted. 10 mL of water was added, and the mixture was stirred for 1 hour. The mixture was filtered, and the filter cake was rinsed with dichloromethane (41 mL*2). The organic phase was washed successively with 1 mol / L hydrochloric acid (41 mL*2), 5% sodium bicarbonate (41 mL*1), and water (41 mL*1). The organic phase was concentrated to dryness, 40 mL of ethanol was added, and the mixture was stirred to dissolve. The temperature was controlled to be 20-30°C, and 200 mL of water was added dropwise. After the dropwise addition was completed, the temperature was controlled to be 0-5°C, and the mixture was stirred for 2-3 hours. The mixture was filtered, the filter cake was rinsed with 41 mL of petroleum ether, and the filter cake was dried under vacuum at 40-50°C to obtain 24.5 g of a compound as shown in Formula IX, which had a yield of 93.2%.

[0109] Example 11:

[0110]

[0111] To 125 mL of acetonitrile, add 33.4 g of compound I (0.105 mol) and 17.8 g of N,N-carbonyldiimidazole (CDI), and react at 20-30 °C for 2 hours. Dissolve 26.2 g of compound IX (0.1 mol) and 15.2 g of triethylamine (0.15 mol) in 125 mL of acetonitrile, and stir at 20-30 °C for 1 hour. Add the reaction solution of compound I dropwise to the reaction solution of compound IX at 20-30 °C, and after the dropwise addition is completed, raise the temperature to 65-70 °C, and stir for 3 hours. After the reaction is completed, lower the temperature to 40-50 °C, and concentrate under reduced pressure to 60-80 mL while controlling the external temperature to be not higher than 50 °C. Add 318 mL of isopropyl acetate, and acidify to pH = 5-6 with 2 mol / L dilute hydrochloric acid while stirring, and separate the layers. Extract the aqueous phase with 65 mL of isopropyl acetate, and wash the combined organic phase with 100 mL of 5% sodium bicarbonate, 100 mL of 10% sodium chloride, and 100 mL of water. Concentrate the organic phase under reduced pressure to an oily liquid, and measure the purity by the HPLC detection method of Example 2 to be 98.8%.

[0112] Example 12:

[0113]

[0114] Dissolve the solution of compound III obtained in Example 11 in 112 mL of tetrahydrofuran, and add 224 mL of water to the reaction flask, and adjust the temperature to 25-35 °C. Add 56.2 g of sodium dithionite (88% content) in portions while controlling the temperature to be not higher than 35 °C. After the addition is completed, react at 25-35 °C for 4 hours. After the reaction is completed, separate the lower aqueous phase. Wash the organic phase with 224 mL of 10% sodium chloride, 224 mL of 1 mol / L hydrochloric acid, 224 mL of 5% sodium bicarbonate, and 224 mL of water, and concentrate under reduced pressure to dryness. Add 224 mL of ethanol to the concentrate, and dissolve by stirring, and add 1120 mL of water dropwise while controlling the temperature to be 20-30 °C. Stir for 2-3 hours while maintaining the temperature, filter, wash with 336 mL of an ethanol / water solution (V:V = 1:2), and dry under reduced pressure at 40-50 °C to obtain 47.0 g. The total yield of Example 11 and Example 12 is 91.4%, and the purity is 98.5%. MS: (M+H) + : 515.2.

[0115] Example 13:

[0116]

[0117] Into a 500 mL flask, 31.8 g of compound I (0.1 mol) and 21.4 g of N,N-carbonyldiimidazole (CDI) were added into 125 mL of acetonitrile, and the reaction was carried out at 20-30 °C for 2 hours. Into another 500 mL flask, 26.2 g of compound IX (0.1 mol) and 15.2 g of triethylamine (0.15 mol) were dissolved in 125 mL of acetonitrile, and the reaction was carried out at 20-30 °C for 1 hour. The reaction solution of compound I was added dropwise into the reaction solution of compound IX at 20-30 °C, and after the dropwise addition was completed, the temperature was raised to 65-70 °C, and the reaction was carried out at this temperature for 3 hours. After the reaction was completed, the temperature was lowered to 40-50 °C, and the reaction solution was concentrated under reduced pressure to 60-80 mL. 318 mL of isopropyl acetate was added, and the solution was acidified to pH = 5-6 with 2 mol / L dilute hydrochloric acid under stirring, and the solution was separated. The aqueous phase was extracted with 65 mL of isopropyl acetate, and the combined organic phase was washed with 100 mL of 5% sodium bicarbonate, 100 mL of 10% sodium chloride, and 100 mL of water. The organic phase was concentrated under reduced pressure to an oily liquid, and the purity was determined to be 89.3% by the HPLC detection method of Example 2.

[0118] Example 14:

[0119]

[0120] Into a 500 mL flask, 31.8 g of compound I (0.1 mol) and 21.4 g of N,N-carbonyldiimidazole (CDI) were added into 125 mL of acetonitrile, and the reaction was carried out at 20-30 °C for 2 hours. Into another 500 mL flask, 26.2 g of compound IX (0.1 mol) and 15.2 g of triethylamine (0.15 mol) were dissolved in 125 mL of acetonitrile, and the reaction was carried out at 20-30 °C for 1 hour. The reaction solution of compound I was added dropwise into the reaction solution of compound IX at 20-30 °C, and after the dropwise addition was completed, the temperature was raised to 65-70 °C, and the reaction was carried out at this temperature for 3 hours. After the reaction was completed, the temperature was lowered to 40-50 °C, and the reaction solution was concentrated under reduced pressure to 60-80 mL. 318 mL of isopropyl acetate was added, and the solution was acidified to pH = 5-6 with 2 mol / L dilute hydrochloric acid under stirring, and the solution was separated. The aqueous phase was extracted with 65 mL of isopropyl acetate, and the combined organic phase was washed with 100 mL of 5% sodium bicarbonate, 100 mL of 10% sodium chloride, and 100 mL of water. The organic phase was concentrated under reduced pressure to an oily liquid, and the purity was determined to be 89.3% by the HPLC detection method of Example 2. + :515.2.

Claims

1. A method for preparing a compound as shown in formula III, characterized in that: It comprises the following steps: The reaction solution containing the compound as shown in formula I is added into the reaction solution containing the compound as shown in formula IX, and a substitution reaction as shown below occurs to obtain the compound as shown in formula III; The reaction solution containing the compound as shown in formula I comprises the compound as shown in formula I, a condensation activator and an organic solvent; The reaction solution containing the compound as shown in formula IX comprises the compound as shown in formula IX, an organic base and an organic solvent; The condensation activator is DCC, CDI or EDC; The organic base is triethylamine or diisopropyl ethylamine; The molar ratio of the condensation activator to the compound as shown in formula I is (1.0-1.5):1; The molar ratio of the organic base to the compound as shown in formula IX is (1-2):1; The molar ratio of the compound as shown in formula I to the compound as shown in formula IX is (0.5-1.5):1; The reaction temperature of the substitution reaction is 60-80℃; 2. The production method according to claim 1, wherein The substitution reaction meets one or more of the following conditions: ①The raw materials of the substitution reaction consist of the organic solvent in the reaction solution containing the compound as shown in formula I, the organic solvent in the reaction solution containing the compound as shown in formula IX, the compound as shown in formula I, the compound as shown in formula IX, the condensation activator and the organic base; ②The reaction solution containing the compound as shown in formula I consists of the compound as shown in formula I, the condensation activator and the organic solvent; ③The reaction solution containing the compound as shown in formula IX consists of the compound as shown in formula IX, the organic base and the organic solvent.

3. The production method according to claim 1, wherein The substitution reaction meets one or more of the following conditions: ①The molar ratio of the condensation activator to the compound as shown in formula I is (1.0-1.3):1; ②The organic solvent in the reaction solution containing the compound as shown in formula I is acetonitrile, ethylene glycol dimethyl ether or dichloromethane; ③The molar volume ratio of the compound as shown in formula I to the organic solvent in the reaction solution containing the compound as shown in formula I is 0.67-1.0 mol / L; ④The temperature when the compound as shown in formula I and the condensation activator are mixed is 20-30℃; ⑤The organic solvent in the reaction solution containing the compound as shown in formula IX is acetonitrile, dichloromethane, ethylene glycol dimethyl ether or tetrahydrofuran; ⑥The molar volume ratio of the compound as shown in formula IX to the organic solvent in the reaction solution containing the compound as shown in formula IX is 0.67-1.0 mol / L; ⑦The temperature when the compound as shown in formula IX and the organic base are mixed is 20-30℃; ⑧The temperature when the reaction solution containing the compound as shown in formula I is added into the reaction solution containing the compound as shown in formula IX is 20-30℃; ⑨The adding mode is dropwise adding; ⑩After the substitution reaction, post-treatment is further included, and the post-treatment further comprises the following steps: concentration, organic solvent dilution, acidification to pH 5-6, liquid separation, concentration of the organic phase to obtain the compound as shown in formula III.

4. The production method according to claim 3, wherein The substitution reaction meets one or more of the following conditions: ① The condensation activator is CDI; ② The molar ratio of the condensation activator to the compound of formula I is 1.0:1, 1.05:1 or 1.3:1; ③ The organic solvent in the reaction solution containing the compound of formula I is acetonitrile; ④ The molar volume ratio of the compound of formula I to the organic solvent in the reaction solution containing the compound of formula I is 0.8 mol / L; ⑤ The organic base is triethylamine; ⑥ The molar ratio of the organic base to the compound of formula IX is 1.5:1; ⑦ The organic solvent in the reaction solution containing the compound of formula IX is acetonitrile; ⑧ The molar volume ratio of the compound of formula IX to the organic solvent in the reaction solution containing the compound of formula IX is 0.8 mol / L; ⑨ The molar ratio of the compound of formula I to the compound of formula IX is 1:1 or 1.05:1; ⑩ The reaction temperature of the substitution reaction is 65-70℃; The acidification is with hydrochloric acid.

5. The production method according to any one of claims 1 to 4, wherein It also includes a preparation method of the compound of formula IX, which comprises the following steps: In a solvent, a compound of formula VIII is subjected to a condensation reaction with tert-butyl alcohol in the presence of a condensation reagent and a catalyst to obtain a compound of formula IX; 6. The production method according to claim 5, wherein The condensation reaction meets one or more of the following conditions: ① The raw materials of the condensation reaction consist of the solvent, the compound of formula VIII, the tert-butyl alcohol, the catalyst and the condensation reagent; ② The condensation reagent is DCC or EDC; ③ The catalyst is DMAP; ④ The molar ratio of the condensation reagent to the compound of formula VIII is (1-1.5):1; ⑤ The molar ratio of the catalyst to the compound of formula VIII is (0.03-0.1):1; ⑥ The molar ratio of the tert-butyl alcohol to the compound of formula VIII is (1-2):1; ⑦ The solvent is dichloromethane; ⑧ The molar volume ratio of the compound of formula VIII to the solvent is 1-2 mol / L; ⑨ The reaction temperature of the condensation reaction is 15-35℃; ⑩ After the condensation reaction, post-treatment is further included, which comprises filtration, acidification of the filtrate, liquid separation, concentration of the organic phase, recrystallization to obtain the compound of formula IX.

7. The production method according to claim 6, wherein The condensation reaction meets one or more of the following conditions: ① The condensation reagent is DCC; ② The catalyst is DMAP; ③ The molar ratio of the condensation reagent to the compound of formula VIII is 1.05:1 or 1.1:1; ④ The molar ratio of the catalyst to the compound of formula VIII is 0.05:1; ⑤ The molar ratio of the tert-butyl alcohol to the compound of formula VIII is 1:1 or 2:1; ⑥ The molar volume ratio of the compound of formula VIII to the solvent is 1 mol / L; ⑦ The reaction temperature of the condensation reaction is 15-25℃; ⑧ In the post-treatment, the solvent used for recrystallization is ethanol and water. ​

Images