WO2020034945A1 - Method for preparing cyclohexane derivative - Google Patents

Abstract

The present invention provides a method for preparing a cyclohexane derivative, comprising the following steps: (1) subjecting a compound SM01 and a compound SM02 or a salt thereof to a nucleophilic substitution reaction to obtain a compound A; (2) deprotecting the compound A to obtain a compound B; and (3) subjecting the compound B and an acylation reagent to an acylation reaction to obtain a cyclohexane derivative. The method provided by the present invention has less side reactions, high product yield, and high product purity, and are suitable for industrial-scale production.

Description

Preparation method of cyclohexane derivative Technical field

The invention belongs to the field of pharmaceutical synthesis, and particularly relates to a method for preparing a cyclohexane derivative.

Background technique

CN106518841A discloses a class of cyclohexane derivatives or stereoisomers or salts thereof. The structures of these cyclohexane derivatives are shown in the following formula IB:

Where X is N or C; R is:

These cyclohexane derivatives have strong affinity for dopamine D ₃ receptor and serotonin, but have weak affinity for D ₂ receptor, showing high selectivity for D ₃ / D ₂ receptor and strong It has anti-schizophrenic symptoms and has only very low toxicity and good safety.

In CN106518841A, piperazine is first docked with R-Br to form a compound of formula IV, and then subjected to a reductive amination reaction with 4-amino-protected cyclohexaneacetaldehyde to form compound V. These cyclohexane derivatives are obtained by further reaction Property II:

The 4-amino protected cyclohexaneacetaldehyde used in the reaction is, for example, trans-2- {1- [4- (N-tert-butoxycarbonyl) amino] cyclohexyl} -acetaldehyde:

Although the reductive amination route has mild reaction conditions and simple operation, the raw material is trans-2- {1- [4- (N-tert-butoxycarbonyl) -amino] -cyclohexyl} acetaldehyde, The formula 2- {1- [4- (N-tert-butoxycarbonyl) -amino] -cyclohexyl} ethanol is prepared by Swern oxidation; or by trans-2- {1- [4- (N-tert- Butoxycarbonyl) -amino] -cyclohexyl} ethyl acetate was prepared by reduction of diisobutylaluminum hydride. Swern oxidation requires low-temperature operation and harsh reaction conditions; the reduction of diisobutylaluminum hydride also requires low-temperature operation, and the product needs to be purified by column chromatography, which is complicated and unsuitable for scale-up.

Summary of the Invention

In order to overcome the disadvantages of harsh process conditions and low product purity for the preparation of cyclohexane derivatives of formula IB in the prior art, the present invention provides a new method for preparing cyclohexane derivatives, which can react mildly. Conditions and higher yields yielded cyclohexane derivative IB with low impurity content in the product. Specifically, the present invention adopts the following technical solutions.

A method for preparing a cyclohexane derivative represented by Formula IB includes the following steps:

(1) Compound SM01 is subjected to a nucleophilic substitution reaction with compound SM02 or a salt thereof to obtain compound A;

(2) deprotection of compound A to obtain compound B or a salt of compound B;

(3) Compound B or a salt of compound B is subjected to an acylation reaction with an acylating agent containing N, N-dimethylcarbamoyl to obtain compound IB,

The synthetic route is:

Where R is:

R ₂ is an amino protecting group; L is a leaving group L 'or -OH.

Preferably, the aforementioned R ₂ is tert-butoxycarbonyl Boc.

The leaving group L 'may be a conventional leaving group in a nucleophilic substitution reaction in the art, and is preferably -OTs, -OMs, -Br, -Cl, or -I.

In one embodiment, when L is L ′ in the step (1), the solvent of the nucleophilic substitution reaction is selected from acetonitrile, N, N-dimethylformamide, acetone, or two or more of them. mixture.

The aforementioned nucleophilic substitution reaction is performed in the presence of a base selected from potassium carbonate, sodium carbonate, triethylamine, or diisopropylethylamine.

The reaction temperature of the nucleophilic substitution reaction is -20 to 180 ° C, and the reaction time is 1-48h.

In another embodiment, when L is -OH in step (1), the solvent of the nucleophilic substitution reaction is selected from toluene, xylene, or a mixture thereof.

The aforementioned nucleophilic substitution reaction is performed under the catalysis of a ruthenium catalyst such as Ru ₃ (CO) ₁₂ , and the phosphine ligand is selected from Xantphos, Ruphos, Xphos, and the like.

The reaction temperature of the nucleophilic substitution reaction is -20 to 180 ° C, and the reaction time is 1-48h.

In one embodiment, when L is L 'in the step (1), the compound SM01 is commercially available or can be prepared according to a conventional method in the art. For example, the compound SM01 is preferably prepared by the following reaction:

The solvent for the above reaction is selected from methylene chloride, tetrahydrofuran, toluene, chloroform, or a mixture of two or more thereof.

In one embodiment, the reagent for the above reaction is selected from p-toluenesulfonyl chloride, methanesulfonyl chloride, NBS, dichlorosulfoxide, phosphorus oxychloride, iodine, or phosphorus tribromide.

The above reaction is performed in the presence of a base selected from triethylamine, diisopropylethylamine or imidazole.

The reaction temperature of the above reaction is -20 to 180 ° C, and the reaction time is 1-48h.

In one embodiment, in step (1) above, in addition to the compound SM01, another reaction raw material is the compound SM02 or a salt of the compound SM02. Among them, the salt of compound SM02 is preferably selected from hydrochloride, sulfate, acetate, sulfonate, mesylate or p-toluenesulfonate.

The salt of compound SM02 can be prepared by reacting compound SM02 with an acid selected from hydrochloric acid, sulfuric acid, acetic acid, sulfonic acid, methanesulfonic acid, or p-toluenesulfonic acid.

The compound SM02 or a salt thereof can be prepared according to a conventional method in the art. For example, the salt of the SM02 compound can be prepared by reacting the SM02 compound with an acid, or can also be prepared by directly reacting SM02-A of the following formula. Correspondingly, the SM02 free base can be prepared by directly reacting SM02-A, or it can also be prepared by further freeing the salt of SM02-A. For example, the compound SM02 is preferably prepared by a method comprising the following steps:

① R-X is coupled with R ₁ -piperazine to form SM02-A;

②SM02-A is deprotected to obtain the compound SM02 or SM02 salt,

The synthetic route is:

Wherein, X is Cl, Br or I; R ₁ is an amino protecting group.

R _{1 is} preferably Boc.

The coupling reaction in the above step ① is performed under the catalysis of a palladium catalyst selected from Pd ₂ (dba) ₃ , tetratriphenylphosphine palladium or dppf palladium dichloride, and the phosphine ligand is BINAP.

The coupling reaction in the above step ① is performed in the presence of a base. The base used is preferably potassium tert-butoxide, sodium tert-butoxide, potassium carbonate or cesium carbonate.

The solvent of the coupling reaction in step ① is selected from toluene, xylene or a mixture thereof.

In one embodiment, the methods and conditions for the deprotection of the deprotection reaction in step (2) may be the conventional methods and conditions for such reactions in the art. The solvent is selected from methylene chloride, tetrahydrofuran, methyltetrahydrofuran, methanol, ethanol, ethyl acetate, or a mixture of two or more thereof.

The deprotection reaction in step (2) can be performed in the presence of an acid, and the acid used is selected from hydrogen chloride (such as a hydrogen chloride ethanol solution), hydrochloric acid, sulfuric acid, or p-toluenesulfonic acid.

The salt of the compound B may be a salt conventional in the art, such as a hydrochloride, a sulfate, or a p-toluenesulfonate.

The reaction temperature of the deprotection reaction in the above step (2) is -80 to 100 ° C, and the reaction time is 1-48h.

In one embodiment, the methods and conditions of the acylation reaction described in step (3) above may be conventional methods and conditions of such reactions in the art. The solvent for the acylation reaction is preferably from dichloromethane, tetrahydrofuran, methyltetrahydrofuran, DMF, acetonitrile, toluene, or a mixture of two or more thereof.

The acylating reagent in the acylation reaction in step (3) is selected from the group consisting of N, N-dimethylcarbamoyl chloride, CDI (N, N'-carbonyldiimidazole), and dimethylamine, triphosgene, and dimethylamine.

The acylation reaction in the above step (3) is performed in the presence of a base. The base used is selected from the group consisting of an organic base such as triethylamine, DIPEA (N, N-diisopropylethylamine), or DBU (diazabicyclo). ), Etc., for inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or sodium bicarbonate, the equivalent of the base is 1 to 10 eq.

The reaction temperature of the acylation reaction in the step (3) is preferably -20 to 100 ° C, and the reaction time is preferably 1-48 h.

The preparation method of the present invention can prepare a cyclohexane derivative of Formula IB under mild reaction conditions and high yields, and impurities in the product such as dimer impurities (also known as disubstituted impurities) imp6 and imp8, and mono The content of methyl impurity imp1 is low, for example, the content of imp1 is less than 0.1%, the content of imp6 is less than 0.3%, and imp8 is almost undetectable. Therefore, the product has high purity, easily meets drug quality standards, and is more suitable for industrial large-scale production with low content.

detailed description

Herein, the term "compound X" is sometimes expressed as "compound X", which can be understood by those skilled in the art. For example, the compound represented by formula A and compound A both refer to the same compound. Similarly, both the compound represented by Formula IB and Compound IB refer to the same compound.

In this paper, the compounds imp6 and imp8 belong to the dimer impurity, and the compound imp1 belongs to the monomethyl impurity (also called methyl impurity, demethyl impurity, mono impurity).

In a preferred embodiment, after the reaction of the above steps is completed, purification operations such as filtration, washing, and drying may be performed according to common knowledge in the art.

It should be understood that when the cyclohexane derivative of Formula IB has a specific stereo configuration, according to common knowledge in the art, the compound SM01 and its corresponding reaction raw material have corresponding stereo configurations. For example, in a specific embodiment, the compound of Formula IB is N '-[trans-4- [2- [7- (benzo [b] thiophene) -7-piperazinyl] ethyl] cyclohexyl]- In the case of N, N-dimethylurea (the following formula IB-1), SM01 is 1,1-dimethyl-3- (trans-4- (2-oxoethyl) cyclohexyl) urea, but The SM01 was prepared using trans-2- (4-aminocyclohexyl) ethyl acetate.

On the basis of conforming to common knowledge in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain each preferred embodiment of the present invention.

The invention is further illustrated by the following examples. It should be understood that these examples are for illustrative purposes only and are not a limitation on the present invention. Various changes or adjustments made by those skilled in the art according to the concept of the present invention shall fall within the protection scope of the present invention.

This article refers to the added amount, content and concentration of various substances, where the percentage content, unless otherwise specified, refers to the mass percentage content.

In the examples herein, if no specific description is made as to the reaction temperature or the operating temperature, the temperature generally refers to room temperature (15-30 ° C).

Examples

Reagents: The reactants and catalysts used in the examples of the present invention are chemically pure and can be used directly or simply purified as required; organic solvents and the like are all analytically pure and used directly. Reagents were purchased from China Pharmaceutical (Group) Shanghai Chemical Reagent Company.

Testing equipment:

Model of nuclear magnetic resonance instrument: Bruker AV HD 600MHz, Bruker AV III III 400MHz;

Mass spectrometer (liquid mass spectrometry (LCMS)), model: Agilent 6120, B, and detector is DAD.

Example 1 Preparation of Compound SM02

In a 500ml single-necked flask, add 7-bromobenzothiophene (21.2g, 0.1mol), Boc piperazine (20.5g, 0.11mol, 1.1eq), potassium tert-butoxide (16.8g, 0.15mol, 1.5eq) Toluene (300 ml) was mixed and stirred, and replaced with nitrogen three times. After adding BINAP (3.74 g) and Pd ₂ (dba) ₃ (2 g), nitrogen was substituted 3 times. The temperature was raised to 100 ° C in an oil bath, and the reaction was stirred overnight (8h). Sampling point plate (developing solvent: petroleum ether: ethyl acetate = 10: 1), the raw material reaction was basically complete. Stop heating, and after the reaction solution was cooled to room temperature, filter through diatomaceous earth, rinse the filter cake with toluene (300ml), combine the filtrate, wash with saturated brine, and spin dry (water bath 45 ℃ ～ 60 ℃) to obtain a brown-red oil.物 38g. Purified by column chromatography, eluent: petroleum ether: ethyl acetate = 50: 1 to 30: 1, to obtain 21.2 g of a pale yellow oil, which is the intermediate SM02-A.

In a 500L single-necked flask, the intermediate SM02-A (21.2 g), a hydrogen chloride ethanol solution (20 ml), and anhydrous ethanol (150 ml) were added and mixed. The oil bath was heated at 55 ° C for 2 hours to react, and a white solid precipitated during the reaction. Sampling point plate (developing solvent: petroleum ether: ethyl acetate = 10: 1), the raw material reaction was basically complete. Stop heating. After the reaction solution was cooled to room temperature, suction filtration was performed. The filter cake was rinsed with ethanol. After drying, 15 g of off-white solid was obtained as SM02 hydrochloride.

After 15 g of the above-mentioned hydrochloride was freed with sodium hydroxide solution, it was extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered and spin-dried to obtain 12 g of a yellow oily compound SM02.

Example 2 Preparation of trans-2- {1- [4- (N-tert-butoxycarbonyl) -amino] -cyclohexyl} ethyl-4-methylbenzenesulfonate (compound SM01)

In a 100 ml single-necked flask, add trans-2- {1- [4- (N-tert-butoxycarbonyl) -amino] -cyclohexyl} ethanol (3.74 g, 0.0154 mol), and triethylamine (4.7 g, 0.0463). mol, 3 eq), dichloromethane (40 ml) and stirred, and p-toluenesulfonyl chloride (3.5 g, 0.0185 mol, 1.2 eq) was added in portions. After the addition, the reaction was stirred overnight. Sampling to check the reaction of the raw materials, the reaction solution was poured into iced 1N dilute hydrochloric acid (50ml), stirred for 15min, the liquid phase was separated, the aqueous phase was extracted with dichloromethane (40ml * 2), the organic phases were combined, and saturated sodium bicarbonate was used The aqueous solution was washed once, and then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product. After beating with petroleum ether, it was filtered to obtain 3.8 g of a white solid, which was trans-2- {1- [4 -(N-tert-butoxycarbonyl) -amino] -cyclohexyl} ethyl-4-methylbenzenesulfonate SM01.

Example 3 Preparation of Compound A

In a 500ml single-necked flask, add SM02 (12g, 0.055mol, 1eq), potassium carbonate (15.2g, 0.11mol, 2eq), and acetonitrile (300ml) and stir; add SM01 (24.0g, 0.0605mol, 1.1eq) and add. The oil bath was warmed to 75 ° C and the reaction was stirred overnight (8h). Sampling point plate (developing solvent: dichloromethane: methanol = 10: 1), SM02 basically completed the reaction, stop heating, after the reaction solution was cooled to room temperature, the solvent was spin-dried, the residue was dissolved by adding water and ethyl acetate, and stirred to dissolve. Then, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and dried to obtain 28 g of a pale yellow solid, which was the crude compound A.

Purified by column chromatography, eluent: petroleum ether: ethyl acetate = 5: 1 to 2: 1 to 0: 1, to obtain 23.3 g of a pale yellow solid.

Example 4 Preparation of Compound B

In a 2L single-necked flask, add compound A (100g), 700ml of absolute ethanol, mix and stir, add hydrogen chloride ethanol solution (100ml), and stir the reaction at 55 ° C in an oil bath. A white solid precipitates with the reaction. Samples were taken to test that the reaction of intermediate A was complete. The heating was stopped. After the reaction solution was cooled to room temperature, suction filtration was performed. The filter cake was rinsed with ethanol.

Example 5 Preparation of Compound IB

N, N-dimethylcarbamoyl chloride method:

In a 2L single-necked flask, add the dihydrochloride (62.28 g, 0.15 mol) of compound B, an aqueous sodium hydroxide solution (sodium hydroxide 60 g, 1.5 mol, 10 eq, dissolved in 375 ml of water), and dichloromethane (375 ml) and mixed Add tetrabutylphosphonium bromide (6g) and stir to dissolve. It was cooled to 5 ° C in an ice bath, and N, N-dimethylcarbamoyl chloride (64.2 g, 0.6 mol, 4 eq) was added dropwise, and the drop was completed in about 45 minutes. After the dropwise addition was completed, the reaction was stirred overnight (8 h) in an oil bath at 25 ° C. Sampling and detection, the basic reaction of the raw materials is complete, the reaction liquid is separated, the aqueous phase is extracted with dichloromethane (200ml * 2), the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and spin-dried to obtain 100 g of pale yellow viscous Thick solid, crude compound IB.

The crude product was purified by column chromatography, eluent: dichloromethane: methanol = 50: 1 to 30: 1, to obtain 80 g of a pale yellow solid, and the solid was recrystallized from 800 ml of ethyl acetate to obtain 35 g of compound IB as a white solid.

¹ H NMR (400MHz, CDCl ₃ ) δ: 7.52 1H d, 7.41 1H d, 7.32 2H m, 6.94 1H d, 4.12 1H d, 3.59 1H m, 3.29 4H s, 2.88 6H s, 2.72 4H m, 2.50 2H m , 2.03 2H m, 1.79 2H m, 1.50 2H m, 1.26 1H m, 1.11 4H m;

MS (EI) m / z: M + 1 = 415

By HPLC detection, HPLC purity: imp1 0.06%; IB 99.64%; imp6 0.28%.

Contains impurities

CDI law:

In a 100 ml single-necked flask, add Compound B free base (3.43 g, 0.01 mol), CDI (1.78 g, 0.011 mol, 1.1 eq) and dissolve in N, N-dimethylformamide (30 ml). Stir the reaction at room temperature for 2 h. . The solvent was spin-dried and purified by column chromatography. The eluent: dichloromethane: methanol = 50: 1 to 30: 1, 3.3 g (intermediate) was obtained as a white solid.

In a 100 ml single-necked flask, the above intermediate (3.3 g, 0.0076 mol) was added, dissolved in dichloromethane (50 ml), and dimethylamine hydrochloride (0.92 g, 0.0113 mol, 1.5 eq) and triethylamine ( 2.1 ml, 0.0152 mol, 2 eq) were added and the reaction was stirred overnight. The reaction solution was spin-dried and purified by column chromatography. The eluent: dichloromethane: methanol = 50: 1 to 30: 1, 2.8 g of a pale yellow solid was obtained. The solid was recrystallized from ethyl acetate to obtain 1.2 g of a white solid. This is compound IB.

Example 6 Another Preparation Method of Compound IB

In a 100 ml single-necked flask, add trans-2- {1- [4- (N-tert-butoxycarbonyl) -amino] -cyclohexyl} ethanol (compound SM01C) (2.43 g, 0.01 mol), and compound SM02 free base (2.4 g, 0.011 mol, 1.1 eq), Ru ₃ (CO) ₁₂ (0.25 g, 0.0004 mol, 0.04 eq), Xantphos (0.35 g, 0.0006 mol, 0.06 eq), toluene (20 ml) and mixed with stirring. After replacing with nitrogen, the reaction was heated at reflux overnight. The solvent was spin-dried, purified by column chromatography, and purified by column chromatography. The eluent: petroleum ether: ethyl acetate = 1: 1 to 0: 1. 2.6 g of a white solid was obtained, which is compound A.

Subsequent operations The dihydrochloride of compound B and compound IB were prepared according to the methods of Examples 4 and 5.

Examples 7-11 Synthesis of IB Compounds with Different R Substituents

Referring to the synthesis methods in Examples 1-6, IB compounds having different R substituents were synthesized according to the following synthetic routes. The corresponding structure and yield are shown in Table 1 below.

Where X is Br, R ₁ and R ₂ are both -Boc, and L is -OTs.

Table 1. Yields of various IB compounds

By HPLC detection, there was no imp1 greater than 0.1% in the final product, and the IB compound accounted for more than 99.5%.

Comparative Example 1

In a 100 ml single-necked flask, add the compounds SM01A (1.47 g, 0.004 mol), SM02 (0.96 g, 0.0044 mol, 1.1 eq), potassium carbonate (1.1 g, 0.008 mol, 2 eq), acetonitrile (40 ml) and mix well. Oil The reaction was heated in a bath at 75 ° C overnight. Sampling test, after the reaction of the raw materials is complete, stop heating. After the reaction solution was cooled to room temperature, the solvent was spin-dried, and the residue was stirred with water (50 ml) and dichloromethane (30 ml), and the solution was separated. The aqueous phase was extracted with dichloromethane (50 ml * 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and dried to give 2.5 g of a brown solid.

Purified by column chromatography, eluent: dichloromethane: methanol = 50: 1 to 30: 1, 1.8 g of a pale yellow solid was obtained, and 0.8 g of a white solid was obtained by recrystallization from ethyl acetate, which is compound IB.

HPLC detection: IB 86.35%; imp8 13.22%.

Imp8 with dimer impurities:

Comparative Example 2

Synthesis of trans-2- {1- [4- (N-tert-butoxycarbonyl) -amino] -cyclohexyl} acetaldehyde (Compound 9-SM01):

In a 250 ml three-necked flask, DMSO (4.37 g, 0.056 mol, 3 eq) was added, dissolved in 50 ml of dichloromethane, replaced with nitrogen, and cooled to -78 ° C in a dry ice bath. Oxalyl chloride (4.74 g, 0.0373 mol, 2 eq) was added dropwise, and the temperature was controlled to not exceed -65 ° C. After dripping, the reaction was held at -70 to -78 ° C for 1 hour. A solution of trans-2- {1- [4- (N-tert-butoxycarbonyl) -amino] -cyclohexyl} ethanol in dichloromethane (trans-2- {1- [4- (N-tert-butyl) Oxycarbonyl) -amino] -cyclohexyl} ethanol, 4.55 g, 0.0187 mol in 30 ml of dichloromethane), and the temperature is controlled to not exceed -65 ° C. After dripping, the reaction was held at -70 to -78 ° C for 1 hour. Add triethylamine (26ml, 0.1867mol, 10eq), and control the temperature not to exceed -45 ° C. After the addition was completed, the dry ice bath was removed, and the temperature was naturally raised to -20 ° C. The reaction solution was poured into ice-cold 1N hydrochloric acid (100 ml) and stirred for 15 min. The layers were separated, and the aqueous phase was extracted with dichloromethane (50 ml * 2). The organic phases were combined, washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and dried to give 5.2 g of a pale yellow solid.

Purified by column chromatography, eluent: petroleum ether: ethyl acetate = 10: 1 to 5: 1, 3g of white solid was obtained, which is trans-2- {1- [4- (N-tert-butoxycarbonyl) ) -Amino] -cyclohexyl} acetaldehyde (Compound 9-SM01).

Synthesis of compound A:

In a 100 ml single-necked flask, add trans-2- {1- [4- (N-tert-butoxycarbonyl) -amino] -cyclohexyl} acetaldehyde (1.5 g, 0.00622 mol), SM02 free base (1.36 g, 0.00622 mol, 1 eq), and dichloromethane (50 ml) was stirred and dissolved. Sodium triacetoxyborohydride (1.98 g, 0.00933 mol, 1.5 eq) was added in portions. After the addition was complete, the reaction was stirred overnight. Sampling to check the basic reaction is complete, the reaction solution was added 60ml saturated sodium bicarbonate and stirred for 30min, the liquid phase was separated, and the aqueous phase was extracted with dichloromethane (50ml * 2). , Spin-dried, purified by column chromatography, eluent: petroleum ether: ethyl acetate = 1: 1 to 0: 1, 1.42 g of white solid was obtained, which is compound A.

Subsequent operations: Compound B and compound IB were prepared according to the methods of Examples 4 and 5.

The above experiments show that the product IB prepared by the method of the present invention has high purity, which greatly reduces the content of impurities, especially the content of dimer impurities and monomethyl impurities (mono impurity is less than 0.1%), and easily meets drug quality standards. Moreover, the post-processing is simple, which can significantly reduce the production cost, so it is more suitable for industrial large-scale production.

Claims (10)

1. A method for preparing a cyclohexane derivative represented by Formula IB includes the following steps:

   (1) Compound SM01 is subjected to a nucleophilic substitution reaction with compound SM02 or a salt thereof to obtain compound A;

   (2) deprotection of compound A to obtain compound B or a salt of compound B;

   (3) Compound B or a salt of compound B is subjected to an acylation reaction with an acylating agent containing N, N-dimethylcarbamoyl to obtain compound IB,

   The synthetic route is:

   

   Where R is:

   

   R ₂ is an amino protecting group; L is a leaving group L 'or -OH.
2. The method according to claim 1, wherein R ₂ is tert-butoxycarbonyl Boc.
3. The method according to claim 1, wherein the L 'is -OTs, -OMs, -Br, -Cl, or -I.
4. The method according to claim 1, characterized in that when L is L 'in step (1), the nucleophilic substitution reaction is performed in the presence of a base selected from the group consisting of potassium carbonate, sodium carbonate, and triethyl Amine or diisopropylethylamine.
5. The method according to claim 1, characterized in that when L is -OH in step (1), the nucleophilic substitution reaction is carried out under the catalysis of Ru ₃ (CO) ₁₂ ruthenium catalyst, and the phosphine ligand is selected From Xantphos, Ruphos or Xphos.
6. The method according to claim 1, characterized in that when L is L 'in step (1), the compound SM01 is prepared by the following reaction:

   
7. The method according to claim 6, wherein the reagent for the reaction is selected from the group consisting of p-toluenesulfonyl chloride, methanesulfonyl chloride, NBS, dichlorosulfoxide, phosphorus oxychloride, iodine, or phosphorus tribromide.
8. The method according to claim 1, wherein the compound SM02 is prepared by a method comprising the following steps:

   ① R-X is coupled with R ₁ -piperazine to form SM02-A;

   ②SM02-A is deprotected to obtain the compound SM02 or SM02 salt;

   The synthetic route is:

   

   Wherein, X is Cl, Br or I; R ₁ is an amino protecting group.
9. The method according to claim 1, wherein the deprotection reaction in step (2) is performed in the presence of an acid, and the acid used is selected from hydrogen chloride, hydrochloric acid, sulfuric acid, or p-toluenesulfonic acid.
10. The method according to claim 1, characterized in that the acylating reagent in the acylation reaction in step (3) is N, N-dimethylcarbamoyl chloride, CDI and dimethylamine, or triphosgene and dimethylamine .