Olatinib intermediate and preparation method thereof, and preparation method of Olatinib

Abstract

The invention belongs to the technical field of organic synthesis, and provides an oxiratinib intermediate and a preparation method thereof, and a preparation method of oxiratinib. The preparation method comprises the following steps: taking p-chlorobenzyl chloride as a raw material, reacting with sodium sulfite to obtain the sodium 4-chlorobenzenemethanesulfonate, then taking the sodium 4-chlorobenzenemethanesulfonate as a raw material, and carrying out reactions such as first methylamine substitution, hydrogenation reduction, condensation, chlorination, dimethylamine substitution and the like to obtain the sodium 4-chlorobenzenemethanesulfonate. The p-chlorobenzyl chloride is used as a starting raw material, and compared with p-bromobenzyl bromide used as a raw material in the prior art, the raw material is easy to obtain, low in cost and more suitable for industrial production. And meanwhile, after the chlorination reaction, the obtained chlorination reaction feed liquid is directly added into the dimethylamine aqueous solution to carry out the dimethylamine reaction without post-treatment, so that the post-treatment is simple, and time and labor are saved. Besides, the cuprous salt is combined with the ligand to catalyze the substitution reaction of the first methylamine, so that the yield of the 4-methylaminobenzene methanesulfonic acid is increased, and finally, the yield of the olotinib is increased.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to an oclacitinib intermediate and a preparation method thereof, and a preparation method of oclacitinib. Background Art

[0002] Oclacitinib, chemically named N-methyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide, is a novel non-receptor tyrosine kinase (JAK) inhibitor that works by inhibiting a variety of itch-inducing, inflammatory cytokines and allergy-related cytokines that are dependent on the activity of JAK1 and JAK3 enzymes. The drug was approved by the US FDA in 2013 for the control of pruritus and atopic dermatitis caused by canine allergic dermatitis.

[0003] The relevant patent reports a synthetic route for preparing oclacitinib maleate using 4-bromobenzyl bromide as the starting material, which is costly. Summary of the invention

[0004] In view of this, the object of the present invention is to provide an oclacitinib intermediate and a preparation method thereof and a preparation method of oclacitinib. The present invention uses the oclacitinib intermediate of the structure shown in Formula 2 as a raw material to prepare oclacitinib, and the cost is low.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0006] The present invention provides an oclacitinib intermediate having a structure shown in Formula 2:

[0007]

[0008] The present invention also provides a method for preparing the oclacitinib intermediate described in the above technical scheme, comprising the following steps:.

[0009] The p-benzyl chloride, sodium sulfite and the first solvent are mixed and subjected to a sodium sulfite substitution reaction to obtain the oclacitinib intermediate.

[0010] Preferably, the molar ratio of p-benzyl chloride to sodium sulfite is 1:1-2;

[0011] The sodium sulfite substitution reaction is carried out under heating reflux conditions, and the time of the sodium sulfite substitution reaction is 1 to 20 hours.

[0012] The present invention also provides a method for preparing oclacitinib, comprising the following steps:

[0013] Using the preparation method described in the above technical solution, p-chlorobenzyl chloride is subjected to a sodium sulfite substitution reaction to obtain an oclacitinib intermediate;

[0014] The oclacitinib intermediate, the first catalyst, the ligand and the first methylamine aqueous solution are mixed to carry out a first methylamine substitution reaction to obtain 4-methylaminobenzene methanesulfonic acid;

[0015] The 4-methylaminobenzene methanesulfonic acid, the second catalyst and water are mixed, and hydrogenation reaction is carried out under the condition of introducing hydrogen to obtain trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid;

[0016] The trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid, 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, an organic base and a second solvent are mixed to carry out a condensation reaction to obtain (trans-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid;

[0017] The (trans-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid, a chlorinating agent and a third solvent are mixed to carry out a chlorination reaction to obtain a chlorination reaction feed liquid;

[0018] adding the chlorination reaction feed liquid into a second methylamine aqueous solution, and sequentially performing a second methylamination reaction and liquid separation to obtain an organic layer;

[0019] The organic layer is mixed with an inorganic base and deprotected to obtain the oclacitinib.

[0020] Preferably, after the sodium sulfite substitution reaction, the method further comprises: cooling the obtained liquid to room temperature, filtering, and drying the obtained filter cake to obtain the oclacitinib intermediate.

[0021] Preferably, the first catalyst is a cuprous salt, the chemical formula of the cuprous salt is CuX, and X in CuX is a halogen or trifluoromethanesulfonic acid;

[0022] The ligand is (CONHR) 2 or (CH 2 NHCOR) 2 , said (CONHR) 2 or (CH 2 NHCOR) 2 R in which is independently aryl, alkyl or hydrogen;

[0023] The mass fraction of the first methylamine aqueous solution is 10 to 50%;

[0024] The mass ratio of the oclacitinib intermediate to the first catalyst is 1:0.005-0.2;

[0025] The mass ratio of the oclacitinib intermediate to the ligand is 1:0.005-0.2;

[0026] The molar ratio of the oclacitinib intermediate to the methylamine in the first methylamine aqueous solution is 1:1-15;

[0027] The temperature of the first methylamine substitution reaction is 50-150° C. and the time is 3-48 hours.

[0028] Preferably, the second catalyst is palladium carbon, platinum carbon or (Ph 3 P) 4 Pd; the mass ratio of the 4-methylaminobenzenesulfonic acid to the second catalyst is 1:0.01 to 0.1;

[0029] The temperature of the hydrogenation reaction is 30-120° C., the pressure is 0.5-2 MPa, and the time is 12-48 hours.

[0030] Preferably, the organic base comprises one or more of triethylamine, diisopropylethylamine, 1,8-diazobispiro[5.4.0]undec-7-ene, dimethylaniline, N-methylmorpholine, dimethylpiperidine and triethylenediamine;

[0031] The molar ratio of the trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid and 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine is 1:0.5-2;

[0032] The molar ratio of the trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid and the organic base is 1:1-5;

[0033] The condensation reaction temperature is 50-100° C. and the reaction time is 5-15 hours.

[0034] Preferably, the chlorinating agent comprises one or more of thionyl chloride, oxalyl chloride, phosphorus oxychloride and triphosgene;

[0035] The molar ratio of the trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid to the chlorinating agent is 1:0.5-3;

[0036] The temperature of the chlorination reaction is 0-40° C., and the time is 10-120 min.

[0037] Preferably, the molar ratio of the trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid to the methylamine in the second methylamine aqueous solution is 1:1 to 10;

[0038] The mass fraction of the second methylamine aqueous solution is 10 to 50%;

[0039] The temperature of the second methylamination reaction is 0 to 30° C. and the time is 0.5 to 3 hours;

[0040] The inorganic base includes sodium hydroxide and / or potassium hydroxide;

[0041] The molar ratio of the trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid and the inorganic base is 1:0.5-10;

[0042] The deprotection is carried out under heating reflux conditions, and the deprotection time is 1 to 10 hours.

[0043] The present invention provides an oclacitinib intermediate having a structure shown in Formula 2:

[0044]

[0045] The oclacitinib intermediate provided by the present invention uses p-chlorobenzyl chloride as a raw material, which is lower in cost than 4-bromobenzyl bromide prepared from sodium 4-bromobenzyl methanesulfonate in the prior art. The oclacitinib is prepared using sodium 4-chlorobenzyl methanesulfonate as a raw material, which has a lower cost.

[0046] The present invention also provides a method for preparing oclacitinib, comprising the following steps:

[0047] The preparation method described in the above technical scheme is used to perform a sodium sulfite substitution reaction on p-chlorobenzyl chloride to obtain an oclacitinib intermediate; the oclacitinib intermediate, the first catalyst, the ligand and the first methylamine aqueous solution are mixed to perform a first methylamine substitution reaction to obtain 4-methylaminobenzene methanesulfonic acid; the 4-methylaminobenzene methanesulfonic acid, the second catalyst and water are mixed, and hydrogenation reaction is performed under the condition of passing hydrogen to obtain trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid; the trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid, 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, an organic base and The (trans-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid is mixed with the second solvent for condensation reaction to obtain (trans-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid; the (trans-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid, a chlorinating agent and a third solvent are mixed for chlorination reaction to obtain a chlorination reaction liquid; the chlorination reaction liquid is added to a second methylamine aqueous solution, and a second methylamination reaction and liquid separation are performed in sequence to obtain an organic layer; the organic layer is mixed with an inorganic base and deprotected to obtain the oclacitinib.

[0048] The preparation method of the present invention uses p-chlorobenzyl chloride as the starting raw material, which is easy to obtain and has lower cost than the prior art which uses p-bromobenzyl bromide as the raw material. At the same time, after the chlorination reaction, the obtained chlorination reaction feed liquid is directly added to the second methylamine aqueous solution without post-treatment to carry out the second methylation reaction, and the post-treatment is simple, saving time and labor. In addition, the present invention uses the first catalyst (cuprous salt) in combination with the ligand to catalyze the first methylamine substitution reaction, thereby increasing the yield of 4-methylaminobenzene methanesulfonic acid and ultimately increasing the yield of oclacitinib. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 This is the H NMR spectrum of the intermediate 2 (sodium 4-chlorobenzene methanesulfonate) obtained in Example 1. DETAILED DESCRIPTION

[0050] The present invention provides an oclacitinib intermediate having a structure shown in Formula 2:

[0051]

[0052] In the present invention, the chemical name of the oclacitinib intermediate is sodium 4-chlorobenzene methanesulfonate or sodium 4-chlorobenzyl sulfonate.

[0053] The present invention also provides a method for preparing the oclacitinib intermediate described in the above technical scheme, comprising the following steps:.

[0054] The p-benzyl chloride, sodium sulfite and the first solvent are mixed and subjected to a sodium sulfite substitution reaction to obtain the oclacitinib intermediate.

[0055] In the present invention, unless otherwise specified, the raw materials used in the present invention are preferably commercially available products.

[0056] In the present invention, the first solvent preferably includes one or more of water and an organic solvent. In the present invention, the organic solvent preferably includes one or more of acetonitrile, ethanol, acetone, tetrahydrofuran and N,N-dimethylformamide (DMF). In a specific embodiment of the present invention, the first solvent is preferably an acetonitrile aqueous solution or a tetrahydrofuran aqueous solution.

[0057] In the present invention, the molar ratio of p-benzyl chloride to sodium sulfite is preferably 1:1-2.

[0058] In the present invention, the sodium sulfite substitution reaction is preferably carried out under heating reflux conditions, and the time of the sodium sulfite substitution reaction is preferably 1 to 20 hours.

[0059] After the sodium sulfite substitution reaction, the present invention preferably further comprises: cooling the obtained feed liquid to below 30° C. and filtering, and drying the obtained filter residue to obtain the oclacitinib intermediate.

[0060] The present invention also provides a method for preparing oclacitinib, comprising the following steps:

[0061] Using the preparation method described in the above technical solution, p-chlorobenzyl chloride is subjected to a sodium sulfite substitution reaction to obtain an oclacitinib intermediate;

[0062] The oclacitinib intermediate, the first catalyst, the ligand and the first methylamine aqueous solution are mixed to carry out a first methylamine substitution reaction to obtain 4-methylaminobenzene methanesulfonic acid;

[0063] The 4-methylaminobenzene methanesulfonic acid, the second catalyst and water are mixed, and hydrogenation reaction is carried out under the condition of introducing hydrogen to obtain trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid;

[0064] The trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid, 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, an organic base and a second solvent are mixed to carry out a condensation reaction to obtain (trans-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid;

[0065] The (trans-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid, a chlorinating agent and a third solvent are mixed to carry out a chlorination reaction to obtain a chlorination reaction feed liquid;

[0066] adding the chlorination reaction feed liquid into a second methylamine aqueous solution, and sequentially performing a second methylamination reaction and liquid separation to obtain an organic layer;

[0067] The organic layer is mixed with an inorganic base and deprotected to obtain the oclacitinib.

[0068] The present invention utilizes the preparation method described in the above technical scheme to carry out a sodium sulfite substitution reaction on p-chlorobenzyl chloride to obtain an oclacitinib intermediate.

[0069] In the present invention, the material ratio and reaction parameters of the sodium sulfite substitution reaction are preferably consistent with the above technical solution, which will not be described in detail here.

[0070] After the sodium sulfite substitution reaction, the present invention preferably further comprises: cooling the obtained feed liquid to room temperature and filtering it, and drying the obtained filter residue to obtain the oclacitinib intermediate.

[0071] After obtaining the oclacitinib intermediate, the present invention mixes the oclacitinib intermediate, the first catalyst, the ligand and the first methylamine aqueous solution, and performs a first methylamine substitution reaction to obtain 4-methylaminobenzene methanesulfonic acid.

[0072] In the present invention, the first catalyst is preferably a cuprous salt, the chemical formula of the cuprous salt is preferably CuX, X in the CuX is preferably a halogen or trifluoromethanesulfonic acid; the halogen is preferably chlorine, bromine or iodine. In the present invention, the first catalyst is specifically preferably CuI, CuBr, CuI or cuprous trifluoromethanesulfonate. In the present invention, the mass ratio of the oclacitinib intermediate to the first catalyst is preferably 1:0.005-0.2.

[0073] In the present invention, the ligand is preferably (CONHR) 2 or (CH 2 NHCOR) 2 , said (CONHR) 2 or (CH 2 NHCOR) 2 R in which is independently preferably an aryl group, an alkyl group or hydrogen. In a specific embodiment of the present invention, the ligand is preferably oxalyl diamine, N,N'-diphenyl oxalamide, N,N'-diethyl oxalamide, N,N'-dibenzoyl-1,2-ethylenediamine or N,N'-diacetylethylenediamine. In the present invention, the mass ratio of the oclacitinib intermediate to the ligand is preferably 1:0.005-0.2.

[0074] In the present invention, the mass fraction of the first methylamine aqueous solution is preferably 10 to 50%, more preferably 20 to 40%. In the present invention, the molar ratio of the oclacitinib intermediate to the methylamine in the first methylamine aqueous solution is preferably 1:1 to 15.

[0075] In the present invention, the temperature of the first methylamine substitution reaction is preferably 50 to 150° C., and the time is preferably 3 to 48 hours.

[0076] After the first methylamine substitution reaction, the present invention preferably further comprises: cooling the obtained feed liquid to below 50°C, adding water and citric acid, carrying out complex reaction, filtering the obtained complex reaction feed liquid, and collecting the filtrate; adjusting the pH value of the filtrate to 3-4, then freezing and crystallizing, filtering, and collecting crystals; washing and drying the crystals to obtain the 4-methylaminobenzene methanesulfonic acid. The present invention does not specifically limit the amount of citric acid added, as long as the first catalyst can be completely complexed. In the present invention, the temperature of the complex reaction is preferably below 50°C, more preferably room temperature, the time is preferably 0.5-5h, and the complex reaction is preferably carried out under stirring; the purpose of the complex reaction is to remove the first catalyst. In the present invention, the reagent for adjusting the pH value of the filtrate to 3-4 is preferably concentrated hydrochloric acid. In the present invention, the temperature of the freezing and crystallization is preferably 0-10°C, and the freezing and crystallization is preferably carried out under stirring; the present invention does not specifically limit the time of the freezing and crystallization, until the crystals are fully precipitated. In the present invention, the washing agent is preferably water; the present invention does not specifically limit the amount of the washing agent and the number of washing times, as long as the impurities on the crystal surface are completely removed.

[0077] After obtaining 4-methylaminobenzene methanesulfonic acid, the present invention mixes the 4-methylaminobenzene methanesulfonic acid, a second catalyst and water, and carries out a hydrogenation reaction under the condition of introducing hydrogen to obtain trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid.

[0078] In the present invention, the second catalyst is preferably palladium carbon, platinum carbon or (Ph 3 P) 4 Pd. In the present invention, the palladium carbon is preferably 5% palladium carbon or 10% palladium carbon, and the 5% palladium carbon means that the weight of the palladium element accounts for 5% of the total weight of the palladium carbon catalyst. In the present invention, the platinum carbon is preferably 10% platinum carbon, and the 10% platinum carbon means that the weight of the platinum element accounts for 10% of the total weight of the platinum carbon catalyst. In the present invention, the mass ratio of the 4-methylaminobenzene methanesulfonic acid to the second catalyst is preferably 1:0.01-0.1.

[0079] In the present invention, the temperature of the hydrogenation reaction is preferably 30 to 120° C., more preferably 50 to 100° C.; the pressure is preferably 0.5 to 2 MPa; and the time is preferably 12 to 48 h.

[0080] After the hydrogenation reaction, the present invention preferably further comprises: cooling the obtained feed liquid to room temperature, filtering to remove the second catalyst, and obtaining a reduction reaction liquid; and post-treating the reduction reaction liquid to obtain the trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid.

[0081] In the present invention, the post-treatment preferably includes: distilling the reduction reaction liquid until 10-20% of the liquid remains to obtain a viscous liquid; mixing the viscous liquid and ethanol, heating for the first time, and obtaining a first clarified liquid; performing a first cooling crystallization on the first clarified liquid, filtering, and obtaining a filter cake; mixing the filter cake, water, and ethanol, and heating for the second time to obtain a second clarified liquid; cooling the second clarified liquid to 60°C, keeping it warm for 2h, and then keeping it warm below 0°C through the final cooling procedure, filtering, and collecting the filter cake; washing the filter cake with ice ethanol, and drying to obtain the trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid. In the present invention, during the first heating process, the volume of the ethanol is 5 to 20 times the volume of the viscous liquid. In the present invention, the temperature of the first heating is preferably 60 to 90°C; the present invention does not specifically limit the time of the first heating, as long as a clarified liquid can be obtained. In the present invention, the temperature of the first cooling crystallization is preferably below 0°C. In the present invention, the temperature of the second heating is preferably consistent with the temperature of the first heating, which will not be repeated here. In the present invention, the final cooling procedure is preferably: each temperature drop of 10°C is preferably kept for 1 hour. In the present invention, the time of keeping the temperature below 0°C is preferably 1 to 10 hours.

[0082] After obtaining trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid, the present invention mixes the trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid, 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, an organic base and a second solvent to carry out a condensation reaction to obtain (trans-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid.

[0083] In the present invention, the organic base preferably includes one or more of triethylamine, diisopropylethylamine, 1,8-diazobispiro[5.4.0]undec-7-ene, dimethylaniline, N-methylmorpholine, dimethylpiperidine and triethylenediamine, and triethylamine is further preferred. In the present invention, the dimethylpiperidine is preferably 3,5-dimethylpiperidine. In the present invention, the amount ratio of the trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid and the organic base is preferably 1:1 to 5.

[0084] In the present invention, the molar ratio of trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid to 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine is preferably 1:0.5-2.

[0085] In the present invention, the second solvent is preferably one or more of water and an organic solvent. In the present invention, the organic solvent preferably includes one or more of acetonitrile, ethanol, acetone, tetrahydrofuran and DMF. In a specific embodiment of the present invention, the second solvent is specifically preferably an acetonitrile aqueous solution or a tetrahydrofuran aqueous solution.

[0086] In the present invention, the temperature of the condensation reaction is preferably 50 to 100° C., and the time is preferably 5 to 15 hours. In the present invention, the condensation reaction is preferably carried out under stirring.

[0087] After the condensation reaction, the present invention preferably further comprises: evaporating the solvent in the obtained feed solution to obtain the (trans-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid.

[0088] After obtaining (trans-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid, the present invention mixes the (trans-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid, a chlorinating agent and a third solvent to carry out a chlorination reaction to obtain a chlorination reaction feed solution.

[0089] In the present invention, the chlorinating agent preferably includes one or more of thionyl chloride, oxalyl chloride, phosphorus oxychloride and triphosgene. In the present invention, the amount ratio of the trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid to the chlorinating agent is preferably 1:0.5-3.

[0090] In the present invention, the third solvent preferably includes one or more of dichloromethane, dichloroethane, tetrahydrofuran, DMF and dimethyl sulfoxide (DMSO), and further preferably includes dichloromethane and / or DMF.

[0091] In the present invention, the temperature of the chlorination reaction is preferably 0 to 40° C., and the time is preferably 10 to 120 min.

[0092] After the chlorination reaction, the present invention preferably further comprises: cooling the obtained material to 0-30° C. to obtain the chlorination reaction feed liquid.

[0093] After obtaining the chlorination reaction liquid, the present invention adds the chlorination reaction liquid into a second methylamine aqueous solution, and sequentially performs a second methylamination reaction and liquid separation to obtain an organic layer.

[0094] In the present invention, the mass fraction of the second methylamine aqueous solution is preferably 10 to 50%, more preferably 20 to 40%. In the present invention, the molar ratio of the trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid to the methylamine in the second methylamine aqueous solution is preferably 1:1 to 10.

[0095] In the present invention, the temperature of the second methylamination reaction is preferably 0 to 30° C., and the time is preferably 0.5 to 3 hours.

[0096] After the second methylamination reaction, the present invention directly performs liquid separation, and the organic layer is directly obtained after the liquid separation.

[0097] After obtaining the organic layer, the present invention mixes the organic layer with an inorganic base and performs deprotection to obtain the oclacitinib.

[0098] In the present invention, the inorganic base preferably includes sodium hydroxide and / or potassium hydroxide, and more preferably potassium hydroxide. In the present invention, the inorganic base is preferably used in the form of an inorganic base aqueous solution, and the mass fraction of the inorganic base aqueous solution is preferably 10 to 60%, more preferably 20 to 50%, and more preferably 30 to 40%.

[0099] In the present invention, the molar ratio of the trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid to the inorganic base is preferably 1:0.5-10.

[0100] In the present invention, the deprotection is preferably carried out under heating reflux conditions, and the deprotection time is preferably 1 to 10 hours.

[0101] After the deprotection, the present invention preferably further comprises: adding a saturated sodium bicarbonate aqueous solution to the obtained feed liquid, stirring and then standing to separate the layers, separating the layers, washing the obtained organic layer with water, distilling to remove the solvent, and drying to obtain the oclacitinib.

[0102]

[0103] The oclacitinib intermediate and its preparation method and the preparation method of oclacitinib provided by the present invention are described in detail below in conjunction with the examples, but they should not be construed as limiting the scope of protection of the present invention.

[0104] Example 1

[0105] Preparation of sodium 4-chlorobenzene methanesulfonate:

[0106] Add 96.6 g of p-benzyl chloride, 80 g of sodium sulfite, 300 mL of water and 100 mL of acetonitrile to the reactor, heat to reflux for 2 h, cool to below 30° C., filter, wash with water, and dry the obtained solid to obtain 138.8 g of the solid of the oclacitinib intermediate 2 (sodium 4-chlorobenzene methanesulfonate).

[0107] Figure 1 is the H NMR spectrum of the intermediate 2 (sodium 4-chlorobenzene methanesulfonate), from Figure 1 It can be seen that the embodiment of the present invention successfully synthesized sodium 4-chlorobenzene methanesulfonate.

[0108] Preparation of 4-methylaminobenzene methanesulfonic acid:

[0109] 138.8 g of the intermediate 2 obtained above, 1.0 g of CuCl, 1.0 g of oxalyl diamide, and 300 mL of a 50% aqueous solution of methylamine were added to the reactor, heated to 120° C. for reaction for 5 h. After the reaction, the reaction system was cooled to below 50° C., and then 200 mL of water was added to the system, and then 2 g of citric acid was added. The mixture was stirred at room temperature for 3 h and filtered. The pH of the filtrate was adjusted to 3-4 with concentrated hydrochloric acid, and then cooled to 0° C. The mixture was stirred until the solid was fully precipitated, filtered, the filter cake was washed with water, and dried to obtain 106.2 g of the intermediate 3 (4-methylaminobenzenesulfonic acid) as a solid with a yield of 88%.

[0110] Example 2

[0111] Preparation of sodium 4-chlorobenzene methanesulfonate:

[0112] 96.6 g of p-benzyl chloride, 91.2 g of sodium sulfite and 400 mL of DMF were added to the reactor, heated to 60° C. for reaction for 15 h, cooled to below 30° C., filtered, washed with water, and the obtained solid was dried to obtain 124.8 g of the solid of the oclacitinib intermediate 2 (sodium 4-chlorobenzene methanesulfonate).

[0113] Preparation of 4-methylaminobenzene methanesulfonic acid:

[0114] Add 124.8g of intermediate 2 obtained in the above steps, 4.2g of CuBr, 7.0g of N,N'-diphenyloxamide, and 300mL of 30% methylamine aqueous solution into the reactor, heat to 50°C and react for 30h. After the reaction, cool the reaction system, then add 200mL of water to the system, then add 5.6g of citric acid, stir at room temperature for 0.5h, filter, adjust the pH of the filtrate to 3-4 with concentrated hydrochloric acid, then cool to 0°C, continue stirring until the solid is fully precipitated, filter, wash the filter cake with water, and dry to obtain 101.4g of intermediate 3 (4-methylaminobenzenesulfonic acid) solid with a yield of 84%.

[0115] Example 3

[0116] Preparation of sodium 4-chlorobenzene methanesulfonate:

[0117] Add 96.6 g of p-benzyl chloride, 136.8 g of sodium sulfite, 300 mL of water and 200 mL of tetrahydrofuran to the reactor, heat to 75 ° C for 10 hours, cool to below 30 ° C, filter, wash with water, and dry the obtained solid to obtain 137.6 g of the solid of the oclacitinib intermediate 2 (sodium 4-chlorobenzene methanesulfonate).

[0118] 4-Methylaminobenzene methanesulfonic acid:

[0119] Add 137.6 g of intermediate 2 obtained in the above steps, 6.8 g of CuBr, 6.8 g of N, N'-diethyloxamide, and 300 mL of 25% methylamine aqueous solution into the reactor, heat to 90 ° C and react for 20 h. After the reaction, cool the reaction system to below 50 ° C, then add 200 mL of water to the system, then add 9.2 g of citric acid, stir at room temperature for 1 h, filter, adjust the pH of the filtrate to 3-4 with concentrated hydrochloric acid, then cool to below 10 ° C, continue stirring until the solid is fully precipitated, filter, wash the filter cake with water, and dry to obtain 111.2 g of intermediate 3 (4-methylaminobenzenesulfonic acid) solid with a yield of 92%.

[0120] Example 4

[0121] Preparation of sodium 4-chlorobenzene methanesulfonate:

[0122] Add 96.6 g of p-benzyl chloride, 140.4 g of sodium sulfite and 400 mL of acetone to the reactor, heat to 65 ° C for 20 hours, cool to below 30 ° C, filter, wash with water, and dry the obtained solid to obtain 132.4 g of the solid of the oclacitinib intermediate 2 (sodium 4-chlorobenzene methanesulfonate).

[0123] Preparation of 4-methylaminobenzene methanesulfonic acid:

[0124] Add 132.4 g of intermediate 2 obtained in the above steps, 11.4 g of CuI, 16.0 g of N,N'-dibenzoyl-1,2-ethylenediamine, and 300 mL of 40% methylamine aqueous solution into the reactor, heat to 150°C and react for 25 h. After the reaction, cool the reaction system to below 50°C, then add 200 mL of water to the system, then add 11.4 g of citric acid, stir at room temperature for 2 h, filter, adjust the pH of the filtrate to 3-4 with concentrated hydrochloric acid, then cool to below 10°C, continue stirring until the solid is fully precipitated, filter, wash the filter cake with water, and dry to obtain 102.6 g of intermediate 3 (4-methylaminobenzenesulfonic acid) solid with a yield of 85%.

[0125] Example 5

[0126] Preparation of sodium 4-chlorobenzene methanesulfonate:

[0127] Add 96.6 g of p-benzyl chloride, 113.4 g of sodium sulfite, 400 mL of water and 100 mL of acetonitrile to the reactor, heat to 45 ° C for 5 hours, cool to below 30 ° C, filter, wash with water, and dry the obtained solid to obtain 136.4 g of the solid of the oclacitinib intermediate 2 (sodium 4-chlorobenzene methanesulfonate).

[0128] Preparation of 4-methylaminobenzene methanesulfonic acid:

[0129] 136.4 g of intermediate 2 obtained in the above steps, 3.0 g of CuCl, 4.4 g of N, N'-diacetylethylenediamine, and 300 mL of 20% methylamine aqueous solution were added to the reactor, heated to 100 ° C for reaction for 15 h. After the reaction, the reaction system was cooled to below 50 ° C, and then 200 mL of water was added to the system, and then 5.8 g of citric acid was added. Stirring at room temperature for 2 h, filtered, the filtrate was adjusted to pH 3-4 with concentrated hydrochloric acid, and then cooled to below 10 ° C, and continued to stir until the solid was fully precipitated, filtered, the filter cake was washed with water, and dried to obtain 112.2 g of intermediate 3 (4-methylaminobenzene methanesulfonic acid) solid with a yield of 93%.

[0130] Example 6

[0131] Preparation of Oclacitinib

[0132] A. Add 100g of intermediate 3, 7.5g of 5% palladium carbon and 500mL of water into a reactor, replace with nitrogen, introduce hydrogen, maintain a pressure of 1.0MPa, and keep the temperature of the reaction system at 60°C for hydrogenation reaction. After the hydrogenation reaction is completed, cool the system to room temperature, filter and remove the palladium carbon to obtain a reduction reaction liquid, then distill the reduction reaction liquid until about 80mL of liquid remains, add 800mL of ethanol to the system, heat to 70°C and stir until dissolved, then cool the reaction liquid to below 0°C, and continue stirring until the solid is completely precipitated. Filter, add the filter cake again into a mixture of 50 mL of water and 250 mL of ethanol, heat and stir to dissolve, then cool to about 60 ° C, keep warm for 2 h, and then slowly cool to below 0 ° C in steps. During this process, keep warm for 1 h each time the temperature drops by 10 ° C. Finally, keep warm for 10 h below 0 ° C, filter, wash the filter cake with ice ethanol, and dry to obtain 47.4 g of intermediate 4 (trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid) as a solid, with a yield of 46%.

[0133] B. Add 47.4 g of intermediate 4, 70 g of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, 67.7 g of triethylamine and 550 mL of ethanol into a reactor, raise the temperature to 60°C and stir to react. After the reaction is completed, evaporate the solvent to obtain intermediate 5 ((trans-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid).

[0134] C. Add the intermediate 5 obtained in step B, 660 mL of dichloromethane and 27 g of thionyl chloride into the reactor, control the system to react at 20°C for 60 min, cool the reaction solution to 0°C after the reaction, then add the cooled reaction solution dropwise to 100 mL of 20% methylamine aqueous solution, after the addition is complete, control the system to react at 0-10°C for 3 h, after the reaction is complete, separate the liquids, add 22.5 g of 50% potassium hydroxide aqueous solution to the organic layer, heat to reflux for 5 h, add saturated sodium bicarbonate aqueous solution after the reaction, stir evenly, let stand to separate, separate the liquids, wash the organic layer with water and distill to remove the solvent to obtain 68.7 g of solid product Oclacitinib, with a yield of 89%.

[0135] Example 7

[0136] Preparation of Oclacitinib

[0137] A. Add 100g of intermediate 3, 5g of 10% palladium carbon and 500mL of water into a reactor, replace with nitrogen, introduce hydrogen, maintain a pressure of 0.5MPa, and keep the temperature of the reaction system at 80°C for reaction. After the reaction is completed, cool the system to room temperature, filter and remove the palladium carbon to obtain a reduction reaction liquid, then distill the reduction reaction liquid until about 100mL of liquid remains, add 500mL of ethanol to the system, heat to 90°C and stir until dissolved, then cool the reaction liquid to below 0°C, and continue stirring until the solid is completely precipitated. Filter, add the filter cake again into a mixture of 50 mL of water and 200 mL of ethanol, heat and stir to dissolve, then cool to about 60 ° C, keep warm for 2 h, and then slowly cool to below 0 ° C in steps. During this process, keep warm for 1 h each time the temperature drops by 10 ° C. Finally, keep warm for 5 h below 0 ° C, filter, wash the filter cake with ice ethanol, and dry to obtain 46.4 g of intermediate 4 (trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid) as a solid, with a yield of 45%.

[0138] B. Add 46.4 g of intermediate 4, 81.8 g of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, 57.4 g of diisopropylethylamine and 550 mL of DMF into a reactor, raise the temperature to 100° C. and stir for reaction. After the reaction is completed, evaporate the solvent to obtain intermediate 5 ((trans-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid).

[0139] C. Add the intermediate 5 obtained in step B, 660 mL of tetrahydrofuran and 66.3 g of triphosgene into the reactor, control the system to react at 0°C for 100 min, add the reaction solution dropwise into 100 mL of 30% methylamine aqueous solution after the reaction is completed, control the system to react at 0-10°C for 2 h after the addition is complete, separate the liquids after the reaction is completed, add 44 g of 20% sodium hydroxide aqueous solution to the organic layer, heat to reflux for 10 h, add saturated sodium bicarbonate aqueous solution after the reaction is completed, stir evenly, let stand to separate, separate the liquids, wash the organic layer with water and distill to remove the solvent to obtain 68.7 g of solid product Oclacitinib with a yield of 91%.

[0140] Example 8

[0141] Preparation of Oclacitinib

[0142] A. Add 100g of intermediate 3, 1g of 10% platinum carbon and 500mL of water into a reactor, replace with nitrogen, introduce hydrogen, maintain a pressure of 2.0MPa, and keep the temperature of the reaction system at 120°C for reaction. After the reaction is completed, cool the system to room temperature, filter out the platinum carbon, and obtain a reduction reaction liquid. Then distill the reduction reaction liquid until about 50mL of liquid remains, add 750mL of ethanol to the system, heat to 60°C and stir until dissolved, then cool the reaction liquid to below 0°C and continue stirring until the solid is completely precipitated. Filter, add the filter cake again into a mixture of 50 mL of water and 150 mL of ethanol, heat and stir to dissolve, then cool to about 60 ° C, keep warm for 2 hours, and then slowly cool to below 0 ° C in steps. During this process, keep warm for 1 hour each time the temperature drops by 10 ° C. Finally, keep warm for 2 hours below 0 ° C, filter, wash the filter cake with ice ethanol, and dry to obtain 44.3 g of intermediate 4 (trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid) as a solid, with a yield of 43%.

[0143] B. Add 44.3 g of intermediate 4, 71.7 g of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, 65.4 g of 1,8-diazobispiro[5.4.0]undec-7-ene, 400 mL of water and 200 mL of acetonitrile into a reactor, raise the temperature to 70°C and stir to react. After the reaction is completed, evaporate the solvent to obtain intermediate 5 ((trans-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid).

[0144] C. Add the intermediate 5 obtained in step B, 500 mL of dichloromethane, 100 mL of DMF and 24.3 g of phosphorus oxychloride into the reactor, slowly drop 6.3 g of thionyl chloride, control the system to react at 40°C for 20 min, cool the reaction solution to 20°C after the reaction, then drop the cooled reaction solution into 100 mL of 10% methylamine aqueous solution, after the dropwise addition, control the system to react at 10-20°C for 0.5 h, after the reaction is completed, separate the liquids, add 32 g of 30% potassium hydroxide aqueous solution to the organic layer, heat to reflux for 2 h, add saturated sodium bicarbonate aqueous solution after the reaction, stir evenly and let stand to separate, separate the liquids, wash the organic layer with water and distill to remove the solvent to obtain 67.1 g of solid product Oclacitinib, with a yield of 93%.

[0145] Example 9

[0146] Preparation of Oclacitinib

[0147] A. Add 100g of intermediate 3 and 10g (Ph 3 P) 4 Pd and 500mL water, nitrogen replacement, hydrogen introduction, maintaining 1.5MPa pressure, maintaining the temperature of the reaction system at 30°C for hydrogenation reaction, after the hydrogenation reaction is completed, the system is cooled to room temperature, and the catalyst (Ph 3 P) 4 Pd, obtain the reduction reaction liquid, then distill the reduction reaction liquid until about 50mL of liquid remains, add 400mL of ethanol to the system, heat to 80℃ and stir until dissolved, then cool the reaction liquid to below 0℃, and continue stirring until the solid is completely precipitated. Filter, add the filter cake to a mixed solution of 50mL of water and 250mL of ethanol again, heat and stir until dissolved, then cool to about 60℃, keep warm for 2h, then slowly step-cool to below 0℃, keep warm for 1h every 10℃ in this process, and finally keep warm for 5h below 0℃, filter, wash the filter cake with ice ethanol, and dry to obtain 48.4g of intermediate 4 (trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid) solid, with a yield of 47%.

[0148] B. Add 48.4 g of intermediate 4, 71.4 g of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, 57.6 g of N-methylmorpholine and 550 mL of acetone into a reactor, raise the temperature to 50°C and stir to react. After the reaction is completed, evaporate the solvent to obtain intermediate 5 ((trans-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid).

[0149] C. Add the intermediate 5 obtained in step B, 700 mL DMSO and 14.6 g oxalyl chloride into the reactor, slowly add 17.6 g phosphorus oxychloride, control the system to react at 30°C for 80 min, cool the reaction solution to 10°C after the reaction, then add the cooled reaction solution dropwise to 100 mL of 50% methylamine aqueous solution, after the addition is complete, control the system to react at 20-30°C for 1 h, after the reaction is complete, separate the liquids, add 34.6 g 15% sodium hydroxide aqueous solution to the organic layer, heat to reflux for 8 h, add saturated sodium bicarbonate aqueous solution after the reaction, stir evenly, let stand to separate, separate the liquids, wash the organic layer with water and distill to remove the solvent to obtain 68.6 g of solid product Oclacitinib, with a yield of 87%.

[0150] Example 10

[0151] Preparation of Oclacitinib

[0152] A. Add 100g of intermediate 3 and 5g (Ph 3 P) 4 Pd and 500mL water, nitrogen replacement, hydrogen introduction, maintaining 1MPa pressure, keeping the reaction system temperature at 100℃ for hydrogenation reaction, after the hydrogenation reaction is completed, the system is cooled to room temperature, and the catalyst (Ph 3 P) 4 Pd, obtain the reduction reaction liquid, then distill the reduction reaction liquid until about 50mL of liquid remains, add 500mL of ethanol to the system, heat to 75℃ and stir until dissolved, then cool the reaction liquid to below 0℃, and continue stirring until the solid is completely precipitated. Filter, add the filter cake to a mixture of 50mL of water and 250mL of ethanol again, heat and stir until dissolved, then cool to about 60℃, keep warm for 2h, then slowly step-cool to below 0℃, keep warm for 1h every 10℃ in this process, and finally keep warm for 3h below 0℃, filter, wash the filter cake with ice ethanol, and dry to obtain 47.6g of intermediate 4 (trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid) solid, with a yield of 46%.

[0153] B. Add 47.6 g of intermediate 4, 70.3 g of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, 68 g of 3,5-dimethylpiperidine, 560 mL of water and 100 mL of tetrahydrofuran into a reactor, raise the temperature to 60°C and stir to react. After the reaction is completed, evaporate the solvent to obtain intermediate 5 ((trans-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid).

[0154] C. Add the intermediate 5 obtained in step B, 350 mL of dichloroethane, 350 mL of DMF, 26 g of phosphorus oxychloride and 16.8 g of triphosgene into the reactor, and control the system to react at 10°C for 40 min. After the reaction, cool the reaction solution to 0°C, and then add the cooled reaction solution dropwise to 100 mL of 25% methylamine aqueous solution. After the addition is complete, control the system to react at 0-10°C for 1.5 h. After the reaction is completed, separate the liquids, add 34 g of 45% potassium hydroxide aqueous solution to the organic layer, heat to reflux for 5 h, and then add saturated sodium bicarbonate aqueous solution after stirring evenly, let stand to separate, separate the liquids, wash the organic layer with water and distill to remove the solvent to obtain 71.3 g of solid product Oclacitinib with a yield of 92%.

[0155] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. An oclacitinib intermediate, characterized in that: It has the structure shown in formula 2:

2. The method for preparing the oclacitinib intermediate according to claim 1, characterized in that: The following steps are involved: The p-benzyl chloride, sodium sulfite and the first solvent are mixed and subjected to a sodium sulfite substitution reaction to obtain the oclacitinib intermediate.

3. The preparation method according to claim 2, characterized in that: The molar ratio of the p-benzyl chloride and sodium sulfite is 1:1-2; The sodium sulfite substitution reaction is carried out under heating reflux conditions, and the time of the sodium sulfite substitution reaction is 1 to 20 hours.

4. A method for preparing oclacitinib, characterized in that: The following steps are involved: Using the preparation method according to any one of claims 2 to 3 to carry out a sodium sulfite substitution reaction on p-chlorobenzyl chloride to obtain an oclacitinib intermediate; The oclacitinib intermediate, the first catalyst, the ligand and the first methylamine aqueous solution are mixed to carry out a first methylamine substitution reaction to obtain 4-methylaminobenzene methanesulfonic acid; The 4-methylaminobenzene methanesulfonic acid, the second catalyst and water are mixed, and hydrogenation reaction is carried out under the condition of introducing hydrogen to obtain trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid; The trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid, 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, an organic base and a second solvent are mixed to carry out a condensation reaction to obtain (trans-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid; The (trans-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyridin-4-yl)amino)cyclohexyl)methanesulfonic acid, a chlorinating agent and a third solvent are mixed to carry out a chlorination reaction to obtain a chlorination reaction feed liquid; adding the chlorination reaction feed liquid into a second methylamine aqueous solution, and sequentially performing a second methylamination reaction and liquid separation to obtain an organic layer; The organic layer is mixed with an inorganic base and deprotected to obtain the oclacitinib.

5. The preparation method according to claim 4, characterized in that: After the sodium sulfite substitution reaction, the method further comprises: cooling the obtained liquid to room temperature, filtering, and drying the obtained filter cake to obtain the oclacitinib intermediate.

6. The preparation method according to claim 4, characterized in that: The first catalyst is a cuprous salt, the chemical formula of the cuprous salt is CuX, and X in CuX is a halogen or trifluoromethanesulfonic acid; The ligand is (CONHR)2 or (CH2NHCOR)2, wherein R in (CONHR)2 or (CH2NHCOR)2 is independently aryl, alkyl or hydrogen; The mass fraction of the first methylamine aqueous solution is 10 to 50%; The mass ratio of the oclacitinib intermediate to the first catalyst is 1:0.005-0.2; The mass ratio of the oclacitinib intermediate to the ligand is 1:0.005-0.2; The molar ratio of the oclacitinib intermediate to the methylamine in the first methylamine aqueous solution is 1:1-15; The temperature of the first methylamine substitution reaction is 50-150° C. and the time is 3-48 hours.

7. The preparation method according to claim 4, characterized in that: The second catalyst is palladium carbon, platinum carbon or (Ph3P)4Pd; the mass ratio of the 4-methylaminobenzene methanesulfonic acid to the second catalyst is 1:0.01-0.1; The temperature of the hydrogenation reaction is 30-120° C., the pressure is 0.5-2 MPa, and the time is 12-48 hours.

8. The preparation method according to claim 4, characterized in that: The organic base includes one or more of triethylamine, diisopropylethylamine, 1,8-diazobispiro[5.4.0]undec-7-ene, dimethylaniline, N-methylmorpholine, dimethylpiperidine and triethylenediamine; The molar ratio of the trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid and 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine is 1:0.5-2; The molar ratio of the trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid and the organic base is 1:1-5; The condensation reaction temperature is 50-100° C. and the reaction time is 5-15 hours.

9. The preparation method according to claim 4, characterized in that: The chlorinating agent includes one or more of thionyl chloride, oxalyl chloride, phosphorus oxychloride and triphosgene; The molar ratio of the trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid to the chlorinating agent is 1:0.5-3; The temperature of the chlorination reaction is 0-40° C., and the time is 10-120 min.

10. The preparation method according to claim 4, characterized in that: The molar ratio of the trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid to the methylamine in the second methylamine aqueous solution is 1:1 to 10; The mass fraction of the second methylamine aqueous solution is 10 to 50%; The temperature of the second methylamination reaction is 0 to 30° C. and the time is 0.5 to 3 hours; The inorganic base includes sodium hydroxide and / or potassium hydroxide; The molar ratio of the trans-[4-(methylamino)cyclohexyl]-methanesulfonic acid and the inorganic base is 1:0.5-10; The deprotection is carried out under heating reflux conditions, and the deprotection time is 1 to 10 hours.

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