Process for the preparation of zanorelin hydrochloride bulk drug

Abstract

The application provides a preparation method of zanaburimab hydrochloride, which comprises the following steps: performing a chlorination reaction on compound 1 and oxalyl chloride to obtain compound 2; performing a substitution reaction on compound 2 and compound 3 in an organic solvent to obtain compound 4; performing a deacetoxy reaction on compound 4 to obtain compound 5; performing a coupling reaction on compound 5 and compound 6 to obtain compound 7; performing a de-Boc reaction on compound 7 to obtain compound 8; performing an amine group reduction reaction on compound 8, formaldehyde and sodium triacetoxyborohydride to obtain a compound shown in formula (I), i.e., zanaburimab; and performing a salt formation reaction on the compound shown in formula (I) and hydrochloric acid to obtain a compound shown in formula (II), i.e., zanaburimab hydrochloride. The method has the advantages of high safety, high purity of a final product, high yield and the like, and is easy to be industrialized; and the prepared zanaburimab hydrochloride has the advantages of high purity and controllable quality.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biological medicine, in particular, the present application relates to a preparation method of zanabrutinib hydrochloride drug substance, more particularly, the present application relates to a method for preparing zanabrutinib (a compound shown in formula (I)) and a method for preparing zanabrutinib hydrochloride (a compound shown in formula (II)). BACKGROUND

[0002] Lung cancer is a malignant tumor originating from the bronchial mucosa or glands of the lung, and its incidence and mortality are increasing fastest, which is the main cause of cancer death in the world, and is considered to be one of the malignant tumors that pose the greatest threat to human health and life. In the past 50 years, many countries have reported that the incidence and mortality of lung cancer have increased significantly, and the incidence and mortality of male lung cancer account for the first place of all malignant tumors, and the incidence of female lung cancer accounts for the second place, and the mortality accounts for the second place.

[0003] Zanabrutinib hydrochloride is a treatment drug for lung cancer brain metastasis designed by AstraZeneca and developed by Jiangsu Chentai Pharmaceutical Technology Co., Ltd., which has a blood-brain barrier permeability of 100%, and performs very well in preclinical research and clinical trials, and can effectively treat lung cancer brain metastasis patients.

[0004] However, the current synthesis method of zanabrutinib hydrochloride has the disadvantages of high cost, high impurity content and low yield. Therefore, it is necessary to develop a preparation method of zanabrutinib hydrochloride with mild conditions and high yield. SUMMARY

[0005] The present application aims to at least partially solve at least one of the technical problems existing in the prior art. To this end, the present application provides a preparation method of zanabrutinib hydrochloride drug substance, which has the advantages of mild conditions, low cost, environmental protection, high product purity, stable and controllable quality and high yield, and is easy to industrialize.

[0006] In one aspect of the present application, a method for preparing a compound shown in formula (I) is provided. According to an embodiment of the present application, the method comprises: performing an amine group reduction reaction on compound 8 with formaldehyde and sodium triacetoxyborohydride, so as to obtain a compound shown in formula (I);

[0007]

[0008] According to the method of the present application, by performing an amine group reduction reaction on compound 8 with formaldehyde and sodium triacetoxyborohydride, the generation of toxic substances can be avoided; the solubility of the reduction substance in the organic phase is improved, and the safety is improved; the homogeneous reaction is creatively performed in the mixed solvent, the reaction time is shortened; and the obtained compound shown in formula (I) - zanabrutinib has the advantages of high purity and high yield, and is easy to industrialize.

[0009] According to the embodiment of the present application, the method can further include at least one of the following technical features:

[0010] According to the embodiment of the present application, the amine group reduction reaction is performed at 15-40°C.

[0011] According to the embodiment of the present application, the molar ratio of formaldehyde, sodium triacetoxyborohydride and compound 8 is (1-2):(1.5-3.5):1.

[0012] According to the embodiment of the present application, the amine group reduction reaction is performed in a first solvent, and the first solvent includes methanol, dichloromethane and water.

[0013] According to the embodiment of the present application, the volume ratio of methanol and dichloromethane is (10-20):(3-5).

[0014] According to the embodiment of the present application, the compound 8 is obtained by the following steps:

[0015] a) performing a substitution reaction on compound 2 and compound 3 in an organic solvent to obtain compound 4;

[0016] b) performing a deacetoxy reaction on compound 4 to obtain compound 5;

[0017] c) performing a coupling reaction on compound 5 and compound 6 to obtain compound 7;

[0018] d) performing a de-Boc reaction on compound 7 to obtain compound 8;

[0019]

[0020] According to the embodiment of the present application, in step (a), the substitution reaction is performed at 68-80°C.

[0021] According to the embodiment of the present application, the molar ratio of compound 3 and compound 2 is (1.0-1.2):1.

[0022] According to the embodiment of the present application, the organic solvent is at least one of acetonitrile and tetrahydrofuran.

[0023] According to the embodiment of the present application, in step (b), the deacetoxy reaction is performed at 15-35°C.

[0024] According to the embodiment of the present application, the deacetoxy reaction is performed in a methanol and potassium carbonate system.

[0025] According to an embodiment of the present application, the molar ratio of potassium carbonate and compound 4 is (1.6-2.4):1.

[0026] According to an embodiment of the present application, in step (c), the coupling reaction is carried out at 10-35°C.

[0027] According to an embodiment of the present application, the coupling reaction is carried out in a first base and a first inert solvent.

[0028] According to an embodiment of the present application, the first inert solvent is at least one selected from N,N-dimethylformamide and N,N-dimethylacetamide.

[0029] According to an embodiment of the present application, the first base is an alkali metal carbonate, preferably potassium carbonate or sodium carbonate.

[0030] According to an embodiment of the present application, the Boc removal reaction is carried out between compound 7 and HCl in a second inert solvent.

[0031] According to an embodiment of the present application, the Boc removal reaction is carried out at 10-40°C.

[0032] According to an embodiment of the present application, the second inert solvent is at least one selected from methanol and tetrahydrofuran.

[0033] According to an embodiment of the present application, compound 2 is obtained by carrying out a chlorination reaction between compound 1 and oxalyl chloride;

[0034]

[0035] According to an embodiment of the present application, the chlorination reaction is carried out at 10-40°C.

[0036] According to an embodiment of the present application, the catalyst for the chlorination reaction is at least one selected from N,N-dimethylformamide and N,N-dimethylacetamide.

[0037] According to an embodiment of the present application, the molar ratio of the catalyst and compound 1 is (0.02-0.2):1.

[0038] According to an embodiment of the present application, the chlorination reaction is carried out in a fourth solvent, which is at least one selected from dichloromethane and trichloromethane.

[0039] In another aspect of the present application, a method for preparing a compound represented by formula (II) is provided. According to an embodiment of the present application, the method comprises: carrying out a salt formation reaction between the compound represented by formula (I) prepared according to the aforementioned method of the present application and hydrochloric acid to obtain the compound represented by formula (II);

[0040]

[0041] As can be seen from the foregoing, the aforementioned method can prepare the compound represented by formula (I) - zanabosin, and has the advantages of high safety, high purity, high yield, and easy industrial production. Thus, the method of the present application can prepare the compound represented by formula (II) - zanabosin hydrochloride from the zanabosin obtained above, and has the advantages of high purity and high yield.

[0042] According to an embodiment of the present application, the salt formation reaction is carried out at 0-60°C.

[0043] According to an embodiment of the present application, the salt formation reaction is carried out in a fifth solvent.

[0044] According to an embodiment of the present application, the fifth solvent is acetone.

[0045] Additional aspects and advantages of the present application will be set forth in part in the description that follows, and in part will become apparent to those skilled in the art upon examination of the following and / or can be learned by practice of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0046] The foregoing and / or additional aspects and advantages of the present application will become apparent and be readily understood upon consideration of the following description of the embodiments, taken in conjunction with the accompanying drawings.

[0047] Figure 1 is a purity chromatogram of compound 2 of step 1 in Example 1 of the present application;

[0048] Figure 2 is a purity chromatogram of compound 2 of step 1 in Example 1 of the present application;

[0049] Figure 3 is a purity chromatogram of compound 4 of step 2 in Example 1 of the present application;

[0050] Figure 4 is a purity chromatogram of compound 4 of step 2 in Example 1 of the present application;

[0051] Figure 5 is a purity chromatogram of compound 5 of step 3 in Example 1 of the present application;

[0052] Figure 6 is a purity chromatogram of compound 5 of step 3 in Example 1 of the present application;

[0053] Figure 7 is a purity chromatogram of compound 7 of step 4 in Example 1 of the present application;

[0054] Figure 8 is a purity chromatogram of compound 7 of step 4 in Example 1 of the present application;

[0055] Figure 9 The middle control chromatogram for Step 5 in Example 1 of the present application;

[0056] Figure 10 The purity chromatogram of Compound 8 for Step 5 in Example 1 of the present application;

[0057] Figure 11 The middle control chromatogram for Step 6 in Example 1 of the present application;

[0058] Figure 12 The purity chromatogram of Compound I for Step 6 in Example 1 of the present application;

[0059] Figure 13 The purity chromatogram of Compound II for Step 7 in Example 1 of the present application. DETAILED DESCRIPTION

[0060] Embodiments of the present application are described in detail below. The embodiments described below are examples for explaining the present application and should not be understood as limiting the present application.

[0061] It should be noted that the terms "first", "second" are used only for the purpose of description and should not be understood as indicating or implying relative importance or implying the number of the technical features indicated. Thus, the features defined with "first", "second" can explicitly or implicitly include one or more of the features. Further, in the description of the present application, the meaning of "a plurality of" is two or more, unless otherwise specified.

[0062] In this document, the term "comprising" or "including" is an open expression that includes the indicated content, but does not exclude other aspects.

[0063] In this document, the term "optionally", "optional" or "optional" generally means that the event or condition described thereafter can but does not necessarily occur, and the description includes both cases where the event or condition occurs and cases where it does not occur.

[0064] The present application proposes a method for preparing Zolmitriptan (a compound represented by Formula (I)) and a method for preparing Zolmitriptan hydrochloride bulk drug (a compound represented by Formula (II)), which will be described in detail below.

[0065] Method for preparing a compound represented by Formula (I)

[0066] In one aspect of the present application, the present application proposes a method for preparing a compound represented by Formula (I). According to an embodiment of the present application, the method comprises: subjecting Compound 8 to an amine group reduction reaction with formaldehyde and sodium triacetoxyborohydride, so as to obtain a compound represented by Formula (I);

[0067]

[0068] Traditional synthesis methods involve the amino reduction reaction of compound 8 with paraformaldehyde and sodium cyanoborohydride. During the reaction, hydrogen cyanide, a highly toxic inorganic substance classified as Class A, is generated, resulting in low safety. Furthermore, this reaction is a solid-liquid two-phase reaction with a low reaction rate and long reaction time (greater than 16 hours). The reaction product (compound zolitinib shown in formula (I)) is slightly soluble in the reaction solution (e.g., methanol solution), and precipitates out in solid form, encapsulating the reaction substrate (compound 8, paraformaldehyde, or sodium cyanoborohydride), leading to low reaction conversion (below 95%) and a low yield of qualified product (approximately 58%).

[0069] However, the method of the present invention avoids the generation of hydrogen cyanide, a highly toxic inorganic substance of Class A, by using sodium triacetoxyborohydride as a reaction reagent, thus improving production safety. At the same time, based on the solubility of the reaction substrate and the reaction product, a mixed solvent is creatively used to make the reaction a homogeneous reaction, which can increase the reaction rate, shorten the reaction time (about 1-3 hours), and increase the reaction conversion rate (to more than 99.9%). The purity of the compound represented by formula (I) obtained can reach 99.95%, and the yield can reach 95% (at least more than 90%).

[0070] Therefore, the method of the present invention has advantages such as high safety, fast reaction rate, short reaction time, and the obtained compound (I) - zolitinib has high purity and high yield, and is easy to industrialize.

[0071] According to embodiments of the present invention, the above method may further include at least one of the following technical features:

[0072] According to an embodiment of the present invention, the amino reduction reaction is carried out at 15–40°C. This further shortens the reaction time, increases the reaction rate, and improves the product yield.

[0073] According to an embodiment of the present invention, the reaction time of the amino reduction reaction is 1 to 3 hours.

[0074] According to an embodiment of the present invention, the molar ratio of formaldehyde, sodium triacetoxyborohydride, and compound 8 is (1-2):(1.5-3.5):1. This further improves the product yield.

[0075] According to an embodiment of the present application, the amine group reduction reaction is performed in a first solvent, and the first solvent comprises methanol, dichloromethane and water. In this way, the solubility of the reaction substrate and the reaction product in the present application can be further improved, so that the reaction becomes a homogeneous reaction, and the reaction product can not wrap the reaction substrate, thereby further improving the reaction rate and shortening the reaction time.

[0076] According to an embodiment of the present application, the volume ratio of the methanol and the dichloromethane is (10-20):(3-5). In this way, the reaction rate can be further improved and the reaction time can be shortened.

[0077] According to an embodiment of the present application, the amine group reduction reaction product is further subjected to a fifth purification treatment to obtain the compound shown in formula (I).

[0078] It should be noted that the fifth purification treatment can be performed by using conventional means in the art, as long as the impurities in the amine group reduction reaction product can be partially or completely removed to obtain the compound shown in formula (I), and the specific purification method is not limited, and is within the protection scope of the present application.

[0079] Exemplarily, the fifth purification treatment is performed by using acetonitrile. In this way, the amine group reduction reaction product can be purified by using acetonitrile (for example, acetonitrile crystallization, hot washing and beating purification), so that the product purity can be further improved.

[0080] According to an embodiment of the present application, the compound 8 is obtained by using the following steps:

[0081] a) performing a substitution reaction on the compound 2 and the compound 3 in an organic solvent to obtain the compound 4;

[0082] b) performing a deacetoxy reaction on the compound 4 to obtain the compound 5;

[0083] c) performing a coupling reaction on the compound 5 and the compound 6 to obtain the compound 7;

[0084] d) performing a de-Boc reaction on the compound 7 to obtain the compound 8;

[0085]

[0086]

[0087] According to an embodiment of the present application, in step (a), the substitution reaction is performed at 68-80°C. In this way, the purity and the yield of the compound 4 can be improved.

[0088] According to an embodiment of the present application, the reaction time of the substitution reaction is 2-24h.

[0089] According to an embodiment of the present application, the molar ratio of the compound 3 and the compound 2 is (1.0-1.2):1.

[0090] According to an embodiment of the present application, the organic solvent is at least one of acetonitrile and tetrahydrofuran.

[0091] According to an embodiment of the present application, the step a) further comprises: performing a first purification treatment on the substitution reaction product to obtain the compound 4.

[0092] It should be noted that the first purification treatment can be purified by conventional means in the art, as long as the impurities in the substitution reaction product can be removed partially or completely to obtain the compound 4, and the specific purification method is not limited, which is within the protection scope of the present application.

[0093] According to an embodiment of the present application, in the step (b), the deacetoxy reaction is performed at 15-35℃. Thus, the purity (up to 99%) and yield (up to 95.6%, at least above 94%) of the compound 5 can be improved.

[0094] According to an embodiment of the present application, the reaction time of the deacetoxy reaction is 2-5h.

[0095] According to an embodiment of the present application, the deacetoxy reaction is performed in a methanol and potassium carbonate system.

[0096] According to an embodiment of the present application, the molar ratio of the potassium carbonate and the compound 4 is (1.6-2.4):1. Compared with the molar ratio of the potassium carbonate and the compound 4 being 2.5:1, the above molar ratio of the present application can further prolong the reaction time and improve the reaction conversion rate, i.e., the reaction conversion rate is improved from 98% to above 99.5%.

[0097] According to an embodiment of the present application, the step b) further comprises: performing a second purification treatment on the deacetoxy reaction product to obtain the compound 5.

[0098] It should be noted that the second purification treatment can be purified by conventional means in the art, as long as the impurities in the deacetoxy reaction product can be removed partially or completely to obtain the compound 5, and the specific purification method is not limited, which is within the protection scope of the present application.

[0099] In some optional embodiments of the present application, the second purification treatment is performed in a methanol-water system.

[0100] In some alternative embodiments of the present application, the second purification treatment comprises: lowering the temperature of the deacetoxy reaction product to 10-40℃, adding a predetermined amount of water, and performing a second crystallization treatment to obtain the compound 5. In this way, the purity and yield of the compound 5 can be further improved.

[0101] According to an embodiment of the present application, in step (c), the coupling reaction is performed at 10-35℃. In this way, the purity and yield of the compound 7 can be improved.

[0102] According to an embodiment of the present application, the reaction time of the coupling reaction is 5-20h.

[0103] According to an embodiment of the present application, the coupling reaction is performed in a first base and a first inert solvent.

[0104] According to an embodiment of the present application, the first inert solvent is selected from at least one of N,N-dimethylformamide and N,N-dimethylacetamide.

[0105] According to an embodiment of the present application, the first base is an alkali metal carbonate, preferably potassium carbonate or sodium carbonate.

[0106] According to an embodiment of the present application, step c) further comprises: performing a third purification treatment on the coupling reaction product to obtain the compound 7.

[0107] It should be noted that the third purification treatment can be performed by conventional means in the art, as long as the impurities in the coupling reaction product can be partially or completely removed to obtain the compound 7, and the specific purification method is not limited, which is within the protection scope of the present application.

[0108] According to an embodiment of the present application, the de-Boc reaction is performed between the compound 7 and HCl in a second inert solvent. In this way, the purity and yield of the compound 8 can be improved.

[0109] According to an embodiment of the present application, the de-Boc reaction is performed at 10-40℃.

[0110] According to an embodiment of the present application, the reaction time of the de-Boc reaction is 8-10h.

[0111] According to an embodiment of the present application, the second inert solvent is selected from at least one of methanol and tetrahydrofuran.

[0112] According to an embodiment of the present application, step d) further comprises: performing a fourth purification treatment on the de-Boc reaction product to obtain the compound 8.

[0113] It should be noted that the fourth purification treatment can be performed by using conventional means in the art, as long as the impurities in the de-Boc reaction product can be removed partially or completely to obtain the compound 8, and the specific purification method is not limited, which is within the protection scope of the present application.

[0114] Exemplarily, the de-Boc reaction product and sodium bicarbonate are mixed, and the pH value is adjusted to 7.5-8.0, and then filtered through activated carbon to obtain the compound 8.

[0115] According to an embodiment of the present application, the compound 2 is obtained by performing a chlorination reaction on the compound 1 with oxalyl chloride;

[0116]

[0117] The conventional synthesis method of the compound 2 is to use POCl3 or SOCl2 as a chlorination reagent, which is both a reaction reagent and a reaction solvent, and the amount of the chlorination reagent is large, and high-concentration wastewater containing phosphorus or sulfur is generated, which greatly pollutes the environment; and the reaction is performed under reflux, the reaction temperature is greater than 90 degrees, and the reaction is exothermic, which has safety risks such as material spraying and explosion. In addition, the above reaction state is a suspension liquid, a two-phase reaction, and the reaction process has many uncontrollable factors, which leads to a low product yield (only 67%).

[0118] However, by analyzing the stability and activity of the compound 1, the present application finally uses oxalyl chloride as a chlorination reagent to perform a chlorination reaction, and the by-product of the reaction is carbon dioxide, which can reduce the pollution to the environment. In addition, the reaction of the present application is a homogeneous reaction, the reaction conversion rate is greater than 99%, and the subsequent obtained product has the advantages of high purity (up to 99.8%) and high yield (up to 96.8%).

[0119] According to an embodiment of the present application, the molar ratio of the oxalyl chloride to the compound 1 is (1.2-1.7):1. When POCl3 or SOCl2 is used as a chlorination reagent, the added molar amount is 18 times that of the compound 1, so that the amount of the chlorination reagent can be reduced, and the cost can be reduced.

[0120] According to an embodiment of the present application, the chlorination reaction is performed at 10-40℃. When POCl3 or SOCl2 is used as a chlorination reagent, the reaction temperature is 90-110℃; and the reaction temperature of the above method of the present application is below 40℃, which is mild and gentle, and can improve the safety of the reaction.

[0121] According to an embodiment of the present application, the reaction time of the chlorination reaction is 20-40h.

[0122] According to an embodiment of the present application, the catalyst for the chlorination reaction is at least one of N,N-dimethylformamide and N,N-diethylformamide.

[0123] According to an embodiment of the present application, the molar ratio of the catalyst to compound 1 is (0.02-0.2):1.

[0124] According to an embodiment of the present application, the chlorination reaction is performed in a fourth solvent, which is at least one of dichloromethane and trichloromethane.

[0125] According to an embodiment of the present application, the chlorination reaction product is further subjected to a sixth purification treatment to obtain compound 2.

[0126] It should be noted that the sixth purification treatment can be performed by using conventional means in the art, as long as the impurities in the chlorination reaction product can be removed partially or completely to obtain compound 2, and the specific purification method is not limited, which is within the protection scope of the present application.

[0127] In another aspect of the present application, a method for preparing a compound represented by formula (II) is provided. According to an embodiment of the present application, the method comprises: subjecting the compound represented by formula (I) prepared by the method described above to a salt formation reaction with hydrochloric acid to obtain the compound represented by formula (II).

[0128]

[0129] As can be seen from the foregoing, the method described above can be used to prepare compound-zanorelin represented by formula (I), and has the advantages of high safety, high purity, high yield and easy industrial production. Thus, the method of the present application can be used to prepare compound-zanorelin hydrochloride represented by formula (II) from zanorelin obtained above, and has the advantages of high purity and high yield.

[0130] According to an embodiment of the present application, the salt formation reaction is performed at a temperature of 0-60°C.

[0131] According to an embodiment of the present application, the reaction time of the salt formation reaction is 15-120 min.

[0132] According to an embodiment of the present application, the salt formation reaction is performed in a fifth solvent.

[0133] According to an embodiment of the present application, the fifth solvent is acetone.

[0134] According to an embodiment of the present application, before the compound represented by formula (I) is contacted with hydrochloric acid, the compound represented by formula (I) is subjected to a dissolution treatment in acetone in advance.

[0135] The schemes of the present application will be explained below with examples. Those skilled in the art will understand that the following examples are only for illustration of the present application and should not be considered as limiting the scope of the present application. If no specific technique or condition is mentioned in the examples, the technique or condition described in the literature in the art or according to the product manual is used. If no manufacturer of the reagent or instrument is mentioned, it is a conventional product available in the market.

[0136] Example 1:

[0137] The synthetic route of solitinib hydrochloride is shown as follows:

[0138]

[0139] First step: synthesis of compound 2

[0140]

[0141] Into a reaction kettle, DCM (dichloromethane, 2250 ml), compound 1 (150 g, 0.64 mol) and DMF (N, N-dimethylformamide, 7.02 g, 0.096 mol) were sequentially added, the temperature was controlled at 25 °C, (COCl)2(oxalyl chloride, 121.9 g, 0.96 mol) was added dropwise for reaction, after the end of the reaction, the cooled reaction solution was added dropwise into the pre-prepared buffer solution (about 3300 g, K2HPO4: KH2PO4 = 2: 1), the liquid was separated, the organic layer was washed with saturated sodium chloride solution and separated, anhydrous sodium sulfate (about 300 g) was added to the organic layer for drying, the mother liquor was filtered and vacuum desolvated, n-heptane (1500 ml) was added, filtered, and the filter cake was vacuum dried to obtain compound 2 (yield 91%, purity 99.9%). The HPLC chromatogram of the intermediate control of this step is shown in Figure 1 , and the purity chromatogram of compound 2 is shown in Figure 2 (retention time 9.145 min is compound 2).

[0142] Second step: synthesis of compound 4

[0143]

[0144] Into a reaction kettle, acetonitrile (1456 ml) and compound 2 (145.6 g, 0.58 mol) were added, the temperature was adjusted to 23 °C, compound 3 (92.3 g, 0.63 mol) was slowly added, the temperature was raised to 75 °C, after reaction, the temperature was lowered to 28 °C, filtered, the filter cake was taken, acetonitrile (1456 ml) was added for recrystallization, filtered, and the filter cake was vacuum dried to obtain compound 4 (yield 96%, purity 99.5%). The HPLC chromatogram of the intermediate control of this step is shown in Figure 3 , and the purity chromatogram of compound 4 is shown in Figure 4 .

[0145] Step 3: Synthesis of compound 5

[0146]

[0147] Into a reactor, methanol (1281 ml) was added, the temperature was adjusted to 21 °C, compound 4 (213.5 g, 0.54 mol) was added, potassium carbonate (148.2 g, 1.07 mol) was added, the temperature was adjusted to 27 °C, water (1778 ml) was added dropwise after the reaction, filtered, the filter cake was dried to obtain compound 5 (yield 94%, purity 99.3%). The HPLC chromatogram of the intermediate control of this step is shown in Figure 5 , and the purity chromatogram of compound 5 is shown in Figure 6 .

[0148] Step 4: Synthesis of compound 7

[0149]

[0150] Into a reactor, DCM (1128 ml) and triphosgene (131.6 g, 0.44 mol) were added, the temperature was adjusted to 3 °C, pyridine (106.9 g, 1.35 mol) was added dropwise, and then compound SM1 (135.3 g 0.68 mol) was added dropwise; after the addition was completed, the temperature was adjusted to 22.0 °C, and the reaction was completed. Directly filtered, the filter cake was dissolved with DMF to obtain a DMF solution containing compound 6.

[0151] The temperature was adjusted to 22 °C, and into another reactor, the DMF solution (1289 ml) was added, compound 5 (161.2 g, 0.50 mol) and potassium carbonate (139.3 g, 1.01 mol) were added, and the DMF solution containing compound 6 was added dropwise. After the reaction was completed, DCM-water extraction was performed to separate the organic layer, which was concentrated under reduced pressure to about 500 ml, MTBE (methyl tert-butyl ether, 1289 ml) was added, filtered, and the filter cake was dried under vacuum to obtain compound 7 (yield 95%, purity 99.9%). The HPLC chromatogram of the intermediate control of this step is shown in Figure 7 , and the purity chromatogram of compound 7 is shown in Figure 8 .

[0152] Step 5: Synthesis of compound 8

[0153]

[0154] Into a reactor, add compound 7 (253.2 g, 0.46 mol) and methanol (1519 ml). Adjust the temperature to 17 °C, add HCl / methanol (2025 ml, HCl concentration is 3.2 mol / L). After the reaction, concentrate to about 600 ml, add sodium bicarbonate (about 750 g) to adjust the pH to 7.6. Adsorb with activated carbon, filter. Add water to the organic layer, crystallize, filter, and dry to obtain compound 8 (yield 93%, purity 99.6%). The HPLC chromatogram of the intermediate control in this step is shown in Figure 9 , and the purity chromatogram of compound 8 is shown in Figure 10 .

[0155] Step 6: Synthesis of compound I

[0156]

[0157] Into a reactor, add methanol (2250 ml), then add compound 8 (150 g, 0.34 mol), dissolve, then add DCM (600 ml) and 37% formaldehyde solution (40.9 ml), then add sodium triacetoxyborohydride (156.8 g, 0.74 mol), and adjust the temperature to 26 °C after the addition is complete. React, after the reaction is complete, concentrate to about 350 ml, add DCM (900 ml) and water (150 ml). Adjust the pH to 7.1 with Na2CO3 solution. Separate the layers, concentrate the organic phase to about 300 ml, add acetonitrile (1500 ml), cool to 4 °C, filter, add acetonitrile to the filter cake, reflux, cool to crystallize, filter, and dry the filter cake to obtain compound I (yield 90%, purity 99.96%). The HPLC chromatogram of the intermediate control in this step is shown in Figure 11 , and the purity chromatogram of compound I is shown in Figure 12 .

[0158] Step 7: Synthesis of compound II

[0159]

[0160] Into a reactor, add acetone (3900 ml), add compound I (130 g, 0.26 mol), reflux until the solid is completely dissolved, control the temperature to 44 °C, add HCl / acetone (390 ml, 5.41%) dropwise, cool to 17 °C, filter, and dry to obtain compound II (yield 93%, purity 99.9%). The purity chromatogram of compound II is shown in Figure 13 .

[0161] In the description of the specification, the description of the terms "one embodiment", "some embodiments", "an example", "a specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are contained in at least one embodiment or example of the present application. In the specification, the illustrative description of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any suitable manner in any one or more embodiments or examples. In addition, the person skilled in the art can combine and combine the different embodiments or examples described in the specification and the features of the different embodiments or examples without contradiction.

[0162] Although the embodiments of the present application have been shown and described above, it is understood that the above-described embodiments are exemplary and are not to be construed as limiting the present application, and those skilled in the art can make changes, modifications, replacements and variations to the above-described embodiments within the scope of the present application.

Claims

1. A process for the preparation of a compound of formula (I) ###000001### (I) characterized in that, The method comprises the following steps: carrying out amine group reduction reaction on compound 8, formaldehyde and sodium triacetoxyborohydride to obtain a compound shown in formula (I); ； The amine group reduction reaction is carried out at 15-40℃; The amine group reduction reaction is carried out in a first solvent, wherein the first solvent is a mixed solvent of methanol, dichloromethane and water, and the volume ratio of methanol to dichloromethane is (10-20):(3-5).

2. The method of claim 1, wherein, The molar ratio of formaldehyde, sodium triacetoxyborohydride and compound 8 is (1-2):(1.5-3.5):

1.

3. The method according to claim 1 or 2, characterized in that, The compound 8 is obtained by the following steps: a) carrying out substitution reaction on compound 2 and compound 3 in an organic solvent to obtain compound 4; b) carrying out deacetoxy reaction on compound 4 to obtain compound 5; c) carrying out coupling reaction on compound 5 and compound 6 to obtain compound 7; d) carrying out de-Boc reaction on compound 7 to obtain compound 8; 。 4. The method of claim 3, wherein, In step (a), the substitution reaction is carried out at 68-80℃; Optionally, the molar ratio of compound 3 to compound 2 is (1.0-1.2):1; Optionally, the organic solvent is at least one of acetonitrile and tetrahydrofuran.

5. The method of claim 3, wherein, In step (b), the deacetoxy reaction is carried out in a methanol and potassium carbonate system; Optionally, the molar ratio of potassium carbonate to compound 4 is (1.6-2.4):1; Optionally, the deacetoxy reaction is carried out at 15-35℃.

6. The method of claim 3, wherein, In step (c), the coupling reaction is carried out at 10-35℃; Optionally, the coupling reaction is carried out in a first base and a first inert solvent; Optionally, the first inert solvent is at least one of N,N-dimethylformamide and N,N-dimethylacetamide; Optionally, the first base is an alkali metal carbonate.

7. The method of claim 6, wherein, The first base is potassium carbonate or sodium carbonate.

8. The method of claim 3, wherein, The de-Boc reaction is carried out on compound 7 with HCl in a second inert solvent; Optionally, the de-Boc reaction is carried out at 10-40℃; Optionally, the second inert solvent is at least one of methanol and tetrahydrofuran.

9. The method of claim 3, wherein, The compound 2 is obtained by carrying out chlorination reaction on compound 1 with oxalyl chloride; ； Optionally, the molar ratio of oxalyl chloride to compound 1 is (1.2-1.7):1; Optionally, the chlorination reaction is carried out at 10-40℃; Optionally, the catalyst of the chlorination reaction is at least one of N,N-dimethylformamide and N,N-dimethylacetamide; Optionally, the molar ratio of the catalyst to compound 1 is (0.02-0.2):1; Optionally, the chlorination reaction is carried out in a fourth solvent, wherein the fourth solvent is at least one of dichloromethane and trichloromethane.

10. A process for the preparation of a compound of formula (II) ###00010### (II) characterized in that, The method comprises the following steps: carrying out salt formation reaction on the compound shown in formula (I) prepared by the method according to any one of claims 1-9 with hydrochloric acid to obtain a compound shown in formula (II); 。 11. The method of claim 10, wherein, The salt formation reaction is carried out at 0-60℃. Optionally, the salt formation reaction is carried out in a fifth solvent; Optionally, the fifth solvent is acetone.

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