Preparation method of oxiratinib

Abstract

The invention belongs to the technical field of organic synthesis, and provides a preparation method of olatinib. According to the invention, the compound as shown in the formula 2 is used as an initial raw material for preparing the oxiratinib. According to the invention, first methylamine substitution is carried out on-SO2Cl in the intermediate 4, then dimethylamine substitution is carried out on chlorine in benzyl chloride in the intermediate 5, and the post-treatment process is simplified; the method specifically comprises the following steps: (1) directly carrying out first methylamine substitution reaction on an intermediate 4 obtained by chlorination reaction and methylamine without separation to obtain an intermediate 5; and (2) condensing the intermediate 7 and 4-chloro-7-toluenesulfonyl-7H-pyrrolo [2, 3-d] pyrimidine to obtain an intermediate 8, directly mixing the intermediate 8 with an inorganic base without post-treatment, and carrying out deprotection to obtain the product olatinib. The cuprous salt and the ligand are adopted to carry out the dimethylamine substitution reaction, so that the reaction time is shortened, the efficiency of the dimethylamine substitution reaction is improved, and finally, the yield of the olotinib is improved. # imgabs0 #

Description

Technical Field

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

[0002] Oclacitinib, with the chemical name N-methyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamide and the structural formula shown in Formula 1, 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 for marketing by the US FDA in 2013 for the control of pruritus and atopic dermatitis caused by canine allergic dermatitis.

[0003]

[0004] Related technology reports that oclacitinib is prepared using 4-bromobenzyl bromide as a starting material, and post-treatment is required after each reaction, which makes the operation complicated. Summary of the invention

[0005] In view of this, the object of the present invention is to provide a method for preparing oclacitinib. The preparation method provided by the present invention is simple to operate.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The present invention provides a method for preparing oclacitinib, comprising the following steps:

[0008] The compound represented by Formula 2, sodium sulfite and a first solvent are mixed, and a sodium sulfite substitution reaction is performed to obtain an intermediate 3 represented by Formula 3;

[0009]

[0010] In formula 2, X and Y are independently chlorine or bromine;

[0011] The intermediate 3, the second solvent and the chlorinating agent are mixed to carry out a chlorination reaction to obtain a chlorination reaction liquid; the chlorination reaction liquid contains a system of compounds represented by formula 4;

[0012]

[0013] The chlorination reaction liquid and the methylamine aqueous solution are mixed to carry out a first methylamine substitution reaction to obtain an intermediate 5 shown in Formula 5;

[0014]

[0015] The intermediate 5, the methylamine aqueous solution, the first catalyst and the ligand are mixed, and a second methylamine substitution reaction is performed to obtain the intermediate 6 shown in formula 6;

[0016]

[0017] The first catalyst is a cuprous salt, and the cuprous salt is CuCl, CuBr, CuI or cuprous trifluoromethanesulfonate;

[0018] The ligand is (CONHR)2 or (CH2NHCOR)2, wherein R in (CONHR)2 and (CH2NHCOR)2 is independently an aryl group, an alkyl group or hydrogen, and the carbon number of the alkyl group is 1 to 12;

[0019] The intermediate 6, the second catalyst and the first aqueous organic solvent are mixed, and hydrogenation reduction reaction is performed under the condition of introducing hydrogen to obtain the intermediate 7 shown in formula 7;

[0020]

[0021] The intermediate 7, 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, an organic base and a second aqueous organic solvent are mixed to carry out a condensation reaction to obtain a condensation reaction liquid, wherein the condensation reaction liquid contains the intermediate 8 shown in Formula 8;

[0022]

[0023] The condensation reaction solution is mixed with an inorganic base and deprotected to obtain the oclacitinib.

[0024] Preferably, the first solvent comprises one or more of water and an organic solvent, and the organic solvent comprises one or more of acetonitrile, ethanol, acetone, tetrahydrofuran and N,N-dimethylformamide;

[0025] The molar ratio of the compound represented by formula 2 to sodium sulfite is 1:1-5;

[0026] The temperature of the sodium sulfite substitution reaction is 40 to 90° C.; the time of the sodium sulfite substitution reaction is 4 to 15 hours.

[0027] Preferably, the chlorinating agent includes one or two of thionyl chloride, oxalyl chloride, phosphorus oxychloride and triphosgene; the second solvent includes one or more of dichloromethane, dichloroethane, tetrahydrofuran, N,N-dimethylformamide and dimethyl sulfoxide;

[0028] The molar ratio of the intermediate 3 to the chlorinating agent is 1:1 to 3;

[0029] The temperature of the chlorination reaction is -10 to 40°C.

[0030] Preferably, during the first methylamine substitution reaction, the mass concentration of the methylamine aqueous solution is 10-50%;

[0031] The molar ratio of the intermediate 3 to the methylamine in the methylamine aqueous solution is 1:1-10;

[0032] The temperature of the first methylamine substitution reaction is 0-30° C. and the time is 1-3 hours.

[0033] Preferably, during the second methylamine substitution reaction, the mass concentration of the methylamine aqueous solution is 10-50%;

[0034] The molar ratio of the intermediate 5 to the methylamine in the methylamine aqueous solution is 1:1-20;

[0035] The mass ratio of the intermediate 5 to the first catalyst is 1:0.01-0.1;

[0036] The mass ratio of the intermediate 5 to the ligand is 1:0.01-0.1;

[0037] The temperature of the second methylamine substitution reaction is 50-120° C., and the time is 8-20 hours.

[0038] Preferably, after the second methylamine substitution reaction, the method further comprises: cooling the obtained reaction material to room temperature, adding water and citric acid to carry out a complex reaction, then filtering the obtained complex material, adjusting the pH of the obtained filtrate to acidic, and cooling and crystallizing to obtain the intermediate 6.

[0039] Preferably, the second catalyst is palladium carbon, platinum carbon or (Ph3P)4Pd; the organic solvent in the first aqueous organic solvent includes one or more of methanol, ethanol, acetonitrile, acetone and tetrahydrofuran;

[0040] The mass ratio of the intermediate 6 to the second catalyst is 1:0.01-0.2;

[0041] The pressure of the hydrogenation reduction reaction is 0.5-2 MPa, the temperature is 60-100° C., and the time is 10-20 hours.

[0042] Preferably, the organic base comprises one or more of triethylamine, diisopropylethylamine, 1,8-diazobispiro[5.4.0]undec-7-ene, dimethylaniline, 4-dimethylaminopyridine, N-methylmorpholine, dimethylpiperidine and triethylenediamine;

[0043] The organic solvent in the second aqueous organic solvent includes one or more of acetonitrile, ethanol, acetone, tetrahydrofuran and N,N-dimethylformamide;

[0044] The molar ratio of the intermediate 7 to 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine is 1:1 to 3;

[0045] The molar ratio of the intermediate 7 to the organic base is 1:1-4;

[0046] The condensation reaction is carried out under heating reflux conditions, and the condensation reaction time is 2 to 12 hours.

[0047] Preferably, the inorganic base comprises sodium hydroxide and / or potassium hydroxide;

[0048] The molar ratio of the intermediate 7 to the inorganic base is 1:1 to 3;

[0049] The deprotection is carried out under heating reflux conditions, and the deprotection time is 1 to 5 hours.

[0050] Preferably, after the deprotection, the process further comprises: cooling the obtained feed liquid to room temperature, adding dichloromethane for liquid separation, and sequentially washing the obtained organic layer with a saturated sodium bicarbonate aqueous solution, washing with water and evaporating to dryness to obtain the oclacitinib.

[0051] Beneficial effects of the present invention:

[0052] 1. Compared with the prior art, the method provided by the present invention first replaces the -SO2Cl in the intermediate 4 with a first methylamine, and then immediately replaces the chlorine in the benzyl chloride in the obtained intermediate 5 with a second methylamine, thereby simplifying the post-treatment process; specifically: (1) the intermediate 4 obtained by the chlorination reaction does not need to be separated, but is directly subjected to the first methylamine substitution reaction with methylamine to obtain the intermediate 5; (2) the intermediate 7 is condensed with 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine to obtain the intermediate 8, which does not need to be post-treated, but is directly mixed with an inorganic base for deprotection to obtain the product oclacitinib.

[0053] 2. The present invention uses a cuprous salt and a ligand to carry out a second methylamine substitution reaction, which shortens the reaction time, improves the efficiency of the second methylamine substitution reaction, and ultimately improves the yield of oclacitinib. The data in the examples show that in the preparation method provided by the present invention, the yield of oclacitinib is 21.8-31.2%. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 This is the H NMR spectrum of Oclacitinib obtained in Example 3. DETAILED DESCRIPTION

[0055] The present invention provides a method for preparing oclacitinib, comprising the following steps:

[0056] The compound represented by Formula 2, sodium sulfite and a first solvent are mixed, and a sodium sulfite substitution reaction is performed to obtain an intermediate 3 represented by Formula 3;

[0057]

[0058] In formula 2, X and Y are independently chlorine or bromine;

[0059] The intermediate 3, the second solvent and the chlorinating agent are mixed to carry out a chlorination reaction to obtain a chlorination reaction liquid; the chlorination reaction liquid contains the compound shown in Formula 4;

[0060]

[0061] The chlorination reaction liquid and the methylamine aqueous solution are mixed to carry out a first methylamine substitution reaction to obtain an intermediate 5 shown in Formula 5;

[0062]

[0063] The intermediate 5, the methylamine aqueous solution, the first catalyst and the ligand are mixed, and a second methylamine substitution reaction is performed to obtain the intermediate 6 shown in formula 6;

[0064]

[0065] The first catalyst is a cuprous salt, and the cuprous salt is CuCl, CuBr, CuI or cuprous trifluoromethanesulfonate;

[0066] The ligand is (CONHR)2 or (CH2NHCOR)2, wherein R in (CONHR)2 and (CH2NHCOR)2 is independently an aryl group, an alkyl group or hydrogen, and the carbon number of the alkyl group is 1 to 12;

[0067] The intermediate 6, the second catalyst and the first aqueous organic solvent are mixed, and hydrogenation reduction reaction is performed under the condition of introducing hydrogen to obtain the intermediate 7 shown in formula 7;

[0068]

[0069] The intermediate 7, 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, an organic base and a second aqueous organic solvent are mixed to carry out a condensation reaction to obtain a condensation reaction liquid, wherein the condensation reaction liquid contains the intermediate 8 shown in Formula 8;

[0070]

[0071] The condensation reaction solution is mixed with an inorganic base and deprotected to obtain the oclacitinib.

[0072] In the present invention, unless otherwise specified, the raw materials used in the present invention are preferably commercially available products.

[0073] The present invention mixes the compound shown in Formula 2, sodium sulfite and a first solvent, and performs a sodium sulfite substitution reaction to obtain an intermediate 3 shown in Formula 3;

[0074]

[0075] In formula 2, X and Y are independently chlorine or bromine.

[0076] In a specific embodiment of the present invention, the compound shown in Formula 2 is preferably p-chlorobenzyl chloride or p-bromobenzyl bromide. 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. In a specific embodiment of the present invention, the first solvent is preferably ethanol, acetone, tetrahydrofuran aqueous solution or acetonitrile aqueous solution; the volume concentration of the tetrahydrofuran aqueous solution is preferably 30-40%, and the volume concentration of the acetonitrile aqueous solution is preferably 10-20%.

[0077] In the present invention, the molar ratio of the compound represented by Formula 2 to sodium sulfite is preferably 1:1-5.

[0078] In the present invention, the temperature of the sodium sulfite substitution reaction is preferably 40 to 90° C.; the time of the sodium sulfite substitution reaction is preferably 4 to 15 hours.

[0079] After the sodium sulfite substitution reaction, the present invention preferably further comprises: cooling the obtained liquid to room temperature, filtering, and drying the obtained solid to obtain the intermediate 3.

[0080] After obtaining the intermediate 3 shown in Formula 3, the present invention mixes the intermediate 3, a second solvent and a chlorinating agent to carry out a chlorination reaction to obtain a chlorination reaction liquid; the chlorination reaction liquid contains the compound shown in Formula 4;

[0081]

[0082] In the present invention, the chlorinating agent preferably includes one or two of thionyl chloride, oxalyl chloride, phosphorus oxychloride and triphosgene, and more preferably oxalyl chloride, phosphorus oxychloride, thionyl chloride, triphosgene, thionyl chloride-oxalyl chloride mixture or phosphorus oxychloride-triphosgene mixture. In the present invention, the second solvent preferably includes one or more of dichloromethane, ethylene dichloride, tetrahydrofuran, N,N-dimethylformamide and dimethyl sulfoxide, and more preferably ethylene dichloride or dichloromethane.

[0083] In the present invention, the molar ratio of the intermediate 3 to the chlorinating agent is preferably 1:1-3.

[0084] In the present invention, mixing the intermediate 3, the second solvent and the chlorinating agent preferably comprises: mixing the intermediate 3 and the second solvent to obtain an intermediate 3 solution; and mixing the intermediate 3 solution and the chlorinating agent.

[0085] In the present invention, the temperature of the chlorination reaction is preferably -10 to 40° C. In the present invention, during the chlorination reaction, the content of the intermediate 3 in the system is monitored, and when the intermediate 3 is monitored to react completely, the chlorination reaction is considered to be completed and subsequent operations are performed.

[0086] After the chlorination reaction, the chlorination reaction feed liquid is obtained without any post-treatment.

[0087] After obtaining the chlorination reaction liquid, the present invention mixes the chlorination reaction liquid with a methylamine aqueous solution to perform a first methylamine substitution reaction to obtain an intermediate 5 shown in Formula 5;

[0088]

[0089] In the present invention, the mass concentration of the methylamine aqueous solution is preferably 10 to 50%, more preferably 20 to 40%. In the present invention, the temperature of the methylamine aqueous solution is preferably 0 to 20°C, more preferably 10°C.

[0090] In the present invention, the molar ratio of the intermediate 3 to the methylamine in the methylamine aqueous solution is 1:1-10.

[0091] In the present invention, the temperature of the first methylamine substitution reaction is preferably 0 to 30° C., more preferably 10 to 20° C.; and the time is preferably 1 to 3 hours.

[0092] After the first methylamine substitution reaction, the present invention preferably further comprises: allowing the obtained material to stand for liquid separation, washing the obtained organic layer with water to obtain a washed organic layer; and distilling the washed organic layer to obtain the intermediate 5 represented by formula 5.

[0093] After obtaining the intermediate 5 shown in Formula 5, the present invention mixes the intermediate 5, a methylamine aqueous solution, a first catalyst and a ligand, and performs a second methylamine substitution reaction to obtain the intermediate 6 shown in Formula 6;

[0094]

[0095] The first catalyst is a cuprous salt, and the cuprous salt is CuCl, CuBr, CuI or cuprous trifluoromethanesulfonate; the ligand is (CONHR)2 or (CH2NHCOR)2, and R in (CONHR)2 and (CH2NHCOR)2 is independently an aryl group, an alkyl group or hydrogen, and the carbon number of the alkyl group is 1 to 12.

[0096] In the present invention, during the second methylamine substitution reaction, the mass concentration of the methylamine aqueous solution is 10 to 50%, more preferably 20 to 40%.

[0097] In a specific embodiment of the present invention, the first catalyst is preferably CuCl, CuBr or CuI. In the present invention, the mass ratio of the intermediate 5 to the first catalyst is preferably 1:0.01-0.1.

[0098] In the present invention, the ligand is preferably N,N'-diphenyloxalamide, oxalyl diamine, N1,N2-bis(2,6-dimethoxyphenyl)oxalamide, N,N'-diacetylethylenediamine, N,N'-dibenzyloxalyl diamine or N,N'-dibenzoyl-1,2-ethylenediamine. In the present invention, the mass ratio of the intermediate 5 to the ligand is preferably 1:0.01 to 0.1.

[0099] In the present invention, the molar ratio of the intermediate 5 to the methylamine in the methylamine aqueous solution is preferably 1:1-20.

[0100] In the present invention, the temperature of the second methylamine substitution reaction is preferably 50 to 120° C., more preferably 70 to 100° C.; the time is preferably 8 to 20 hours, more preferably 10 to 15 hours.

[0101] After the second methylamine substitution reaction, the present invention preferably further comprises: cooling the obtained reaction material to room temperature, adding water and citric acid, carrying out a complex reaction, and then filtering the obtained complex material, adjusting the pH of the obtained filtrate to acidic, and cooling and crystallizing to obtain the intermediate 6. The present invention does not specifically limit the amount of citric acid added, as long as it can completely complex the copper in the first catalyst. In the present invention, the temperature of the complex reaction is preferably room temperature, that is, no additional heating or additional cooling is required, the complex time is preferably 1h, and the complex reaction is preferably carried out under stirring. In the present invention, the acidic pH value is preferably 3 to 5; the reagent for adjusting the pH of the obtained filtrate to acidic is preferably concentrated hydrochloric acid.

[0102] After obtaining the intermediate 6 shown in Formula 6, the present invention mixes the intermediate 6, the second catalyst and the first aqueous organic solvent, and conducts a hydrogenation reduction reaction under the condition of introducing hydrogen to obtain the intermediate 7 shown in Formula 7;

[0103]

[0104] In the present invention, the second catalyst is preferably palladium carbon, platinum carbon or (Ph3P)4Pd. In the present invention, the palladium carbon is preferably 10% palladium carbon, and the 10% palladium carbon means that the palladium element accounts for 10% of the total mass of the palladium carbon. In the present invention, the platinum carbon is preferably 10% platinum carbon, and the 10% platinum carbon means that the platinum element accounts for 10% of the total mass of the platinum carbon.

[0105] In the present invention, the organic solvent in the first aqueous organic solvent preferably includes one or more of methanol, ethanol, acetonitrile, acetone and tetrahydrofuran. In a specific embodiment of the present invention, the first aqueous organic solvent is preferably a methanol aqueous solution, an acetonitrile aqueous solution, an acetone aqueous solution, an ethanol aqueous solution or a tetrahydrofuran aqueous solution. In the present invention, the volume concentration of methanol in the methanol aqueous solution is preferably 50%. In the present invention, the volume concentration of acetonitrile in the acetonitrile aqueous solution is preferably 10%. In the present invention, the volume concentration of acetone in the acetone aqueous solution is preferably 30%. In the present invention, the volume concentration of ethanol in the ethanol aqueous solution is preferably 20-30%. In the present invention, the volume concentration of tetrahydrofuran in the tetrahydrofuran aqueous solution is preferably 40%.

[0106] In the present invention, the mass ratio of the intermediate 6 to the second catalyst is preferably 1:0.01-0.2.

[0107] In the present invention, the pressure of the hydrogenation reduction reaction is preferably 0.5 to 2 MPa, more preferably 1 to 1.5 MPa; the temperature is preferably 60 to 100° C., more preferably 70 to 90° C.; and the time is preferably 10 to 20 h.

[0108] After the hydrogenation reduction reaction, the present invention preferably further comprises: filtering the obtained feed liquid, cooling the obtained filtrate to below 0° C., filtering the cooled system, and obtaining the solid as the intermediate 7.

[0109] After obtaining the intermediate 7 shown in Formula 7, the present invention mixes the intermediate 7, 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, an organic base and a second aqueous organic solvent to carry out a condensation reaction to obtain a condensation reaction liquid, wherein the condensation reaction liquid contains the intermediate 8 shown in Formula 8;

[0110]

[0111] 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, 4-dimethylaminopyridine, N-methylmorpholine, dimethylpiperidine and triethylenediamine, and is further preferably triethylamine, 1,8-diazobispiro[5.4.0]undec-7-ene, dimethylaniline, 4-dimethylaminopyridine, N-methylmorpholine or dimethylpiperidine. In the present invention, the dimethylpiperidine is preferably 3,5-dimethylpiperidine.

[0112] In the present invention, the organic solvent in the second aqueous 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 second aqueous organic solvent is preferably an ethanol aqueous solution, a tetrahydrofuran aqueous solution, an acetonitrile aqueous solution, an acetone aqueous solution or a DMF aqueous solution. In the present invention, the volume concentration of ethanol in the ethanol aqueous solution is preferably 80%. In the present invention, the volume concentration of tetrahydrofuran in the tetrahydrofuran aqueous solution is preferably 60%. In the present invention, the volume concentration of acetonitrile in the acetonitrile aqueous solution is preferably 10-25%. In the present invention, the volume concentration of acetone in the acetone aqueous solution is preferably 50%. In the present invention, the volume concentration of DMF in the DMF aqueous solution is preferably 20%.

[0113] In the present invention, the molar ratio of the intermediate 7 to 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine is preferably 1:1-3.

[0114] In the present invention, the molar ratio of the intermediate 7 to the organic base is preferably 1:1-4, and more preferably 1:2-3.

[0115] In the present invention, the condensation reaction is preferably carried out under heating reflux conditions, and the condensation reaction time is preferably 2 to 12 hours.

[0116] After the condensation reaction, the present invention preferably further comprises: cooling the obtained feed liquid to room temperature to obtain the condensation reaction feed liquid.

[0117] After obtaining the condensation reaction liquid, the present invention mixes the condensation reaction liquid with an inorganic base and performs deprotection to obtain the oclacitinib.

[0118] 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 concentration of the inorganic base aqueous solution is 50%. In a specific embodiment of the present invention, the inorganic base aqueous solution is specifically preferably a potassium hydroxide aqueous solution with a mass concentration of 50%.

[0119] In the present invention, the molar ratio of the intermediate 7 and the inorganic base is preferably 1:1 to 3;

[0120] In the present invention, the deprotection is preferably carried out under heating reflux conditions, and the deprotection time is preferably 1 to 5 hours.

[0121] After the deprotection, the present invention preferably further comprises: cooling the obtained feed liquid to room temperature, adding dichloromethane for liquid separation, and washing the obtained organic layer with a saturated sodium bicarbonate aqueous solution, washing with water and evaporating to dryness to obtain the oclacitinib. In the present invention, the number of washings with the saturated sodium bicarbonate aqueous solution is preferably 1 time, and the number of washings with water is preferably 2 times.

[0122] The reaction formula of the preparation method of Oclacitinib provided by the present invention is shown as follows:

[0123]

[0124] The preparation method of oclacitinib provided by the present invention is 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.

[0125] Example 1

[0126] (1) Preparation of Intermediate 3: 30 g of p-benzyl chloride, 25 g of sodium sulfite and 300 mL of ethanol were added to a reactor, heated to 40° C., kept warm for 10 h, cooled, filtered, and the obtained solid was dried to obtain 36.3 g of Intermediate 3.

[0127] (2) Preparation of intermediate 5: 36.3 g of intermediate 3 was added to 200 mL of dichloroethane, and then 39.5 g of oxalyl chloride was added. The system temperature was controlled at 40°C. After the reaction of intermediate 3 was detected to be complete, the reaction solution was cooled to 10°C, and 80 mL of a 10% methylamine aqueous solution precooled to 10°C was added to the reaction system. The reaction was carried out at 10°C for 1 h, and the mixture was allowed to stand for separation. The organic layer was washed with water, and the solvent was removed by distillation to obtain 31.7 g of intermediate 5.

[0128] (3) Preparation of intermediate 6: 31.7 g of intermediate 5, 150 mL of 20% methylamine aqueous solution, 0.75 g of CuCl, and 1.8 g of N,N'-diphenyloxamide were added to a reactor and heated to 50°C for 15 h. After the reaction, the reaction solution was cooled to room temperature, 80 mL of water and 1.5 g of citric acid were added, and stirred at room temperature for 1 h. The residual copper was filtered out, and the pH was adjusted to 4 with concentrated hydrochloric acid. The reaction mixture was cooled and crystallized to obtain 24.2 g of intermediate 6.

[0129] (4) Preparation of intermediate 7: 24.2 g of intermediate 6, 4.3 g of 10% platinum carbon and 100 mL of 50% methanol aqueous solution were added to a reactor, hydrogen was introduced, the pressure was maintained at 0.5-1 MPa, the reaction was heated to 100°C for 20 h, the 10% platinum carbon was removed by filtration, the filtrate was slowly cooled to below 0°C, and filtered to obtain 10.6 g of intermediate 7 solid.

[0130] (5) Preparation of Oclacitinib: 10.6 g of intermediate 7, 15 g of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, 14.5 g of triethylamine and 150 mL of 10% acetonitrile aqueous solution were added to a reactor, and the mixture was heated under reflux for 5 h. Then, 15 mL of 50% potassium hydroxide solution was added to the reaction solution, and the mixture was heated under reflux for 5 h. After the reaction, the reaction solution was cooled to room temperature, 100 mL of dichloromethane was added, and the liquid was separated. The organic layer was washed once with a saturated sodium bicarbonate aqueous solution and twice with water. The solvent was evaporated to dryness to obtain 13.8 g of Oclacitinib with a total yield of 22%.

[0131] Example 2

[0132] (1) Preparation of Intermediate 3: 30 g of p-benzyl chloride, 40 g of sodium sulfite and 300 mL of acetone were added to a reactor, heated to 60° C., kept warm for 15 h, cooled, filtered, and the obtained solid was dried to obtain 34.6 g of Intermediate 3.

[0133] (2) Preparation of Intermediate 5: 34.6 g of Intermediate 3 was added to 180 mL of dichloromethane, and then 46.6 g of phosphorus oxychloride was added. The system temperature was controlled at -10°C. After the reaction of Intermediate 3 was completed, 75 mL of 50% methylamine aqueous solution precooled to 0°C was added to the reaction system. The reaction was carried out at 0°C for 2 h. The mixture was allowed to stand for separation. The organic layer was washed with water and the solvent was distilled off to obtain 28.9 g of Intermediate 5.

[0134] (3) Preparation of intermediate 6: 28.9 g of intermediate 5, 140 mL of 30% methylamine aqueous solution, 0.6 g of CuBr, and 0.4 g of oxalyl diamide were added to a reactor and heated to 80°C for 10 h. After the reaction, the reaction solution was cooled to room temperature, 70 mL of water and 0.8 g of citric acid were added, and stirred at room temperature for 1 h. The residual copper was filtered out, and the pH was adjusted to 5 with concentrated hydrochloric acid. The reaction mixture was cooled and crystallized to obtain 24.5 g of intermediate 6.

[0135] (4) Preparation of intermediate 7: 24.5 g of intermediate 6, 1.3 g of (Ph3P)4Pd and 100 mL of 10% acetonitrile aqueous solution were added to a reactor, hydrogen was introduced, the pressure was maintained at 1.5-2 MPa, the reaction was heated to 70°C for 15 h, (Ph3P)4Pd was removed by filtration, the filtrate was slowly cooled to below 0°C, and filtered to obtain 10.1 g of intermediate 7 solid.

[0136] (5) Preparation of Oclacitinib: 10.1 g of intermediate 7, 14.2 g of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, 20.7 g of 1,8-diazobispiro[5.4.0]undec-7-ene and 150 mL of 80% aqueous ethanol solution were added to a reactor, and the mixture was heated under reflux for 10 h. Then, 14 mL of 50% potassium hydroxide solution was added to the reaction solution, and the mixture was heated under reflux for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature, 100 mL of dichloromethane was added, and the liquid was separated. The organic layer was washed once with a saturated sodium bicarbonate aqueous solution and twice with water. The solvent was evaporated to dryness to obtain 13.7 g of Oclacitinib with a total yield of 21.8%.

[0137] Example 3

[0138] (1) Preparation of Intermediate 3: 30 g of p-benzyl chloride, 38 g of sodium sulfite and 300 mL of 30% aqueous tetrahydrofuran solution were added to a reactor, heated to 80° C., kept warm for 4 h, cooled, filtered, and the obtained solid was dried to obtain 40.6 g of Intermediate 3.

[0139] (2) Preparation of Intermediate 5: 40.6 g of Intermediate 3 was added to 200 mL of dichloromethane, and then 63.5 g of thionyl chloride was added. The system temperature was controlled at 20°C. After the reaction of Intermediate 3 was completed, 90 mL of 20% methylamine aqueous solution precooled to 20°C was added to the reaction system. The reaction was carried out at 20°C for 1 h. The mixture was allowed to stand for separation. The organic layer was washed with water and the solvent was distilled off to obtain 36.7 g of Intermediate 5.

[0140] (3) Preparation of intermediate 6: 36.7 g of intermediate 5, 180 mL of 25% methylamine aqueous solution, 2.1 g of CuBr, and 3.2 g of N1,N2-bis(2,6-dimethoxyphenyl)oxalamide were added to a reactor and heated to 100°C for 20 h. After the reaction, the reaction solution was cooled to room temperature, 90 mL of water and 2.8 g of citric acid were added, and stirred at room temperature for 1 h. The residual copper was filtered out, and the pH was adjusted to 3 with concentrated hydrochloric acid. The reaction mixture was cooled and crystallized to obtain 30.1 g of intermediate 6.

[0141] (4) Preparation of intermediate 7: 30.1 g of intermediate 6, 3 g of 10% palladium carbon and 130 mL of 20% ethanol aqueous solution were added to a reactor, hydrogen was introduced, the pressure was maintained at 1-1.5 MPa, and the reaction was heated to 80°C for 12 h. The palladium carbon was removed by filtration, and the filtrate was slowly cooled to below 0°C and filtered to obtain 14.2 g of intermediate 7 solid.

[0142] (5) Preparation of Oclacitinib: 14.2 g of intermediate 7, 20 g of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, 23.2 g of dimethylaniline and 200 mL of 60% aqueous tetrahydrofuran solution were added to a reactor, and the mixture was heated under reflux for 10 h. Then, 20 mL of 50% potassium hydroxide solution was added to the reaction solution, and the mixture was heated under reflux for 2 h. After the reaction, the reaction solution was cooled to room temperature, 130 mL of dichloromethane was added, and the solution was separated. The organic layer was washed once with a saturated sodium bicarbonate aqueous solution and twice with water. The solvent was evaporated to dryness to obtain 19.6 g of Oclacitinib with a total yield of 31.2%.

[0143] Figure 1 This is the H NMR spectrum of Oclacitinib obtained in Example 3. Figure 1 It can be seen that Oclacitinib was successfully synthesized in the embodiment of the present invention.

[0144] Example 4

[0145] (1) Preparation of Intermediate 3: 30 g of p-benzyl chloride, 35 g of sodium sulfite and 300 mL of 10% acetonitrile aqueous solution were added to a reactor, heated to 90° C., kept warm for 10 h, cooled, filtered, and the obtained solid was dried to obtain 41.9 g of Intermediate 3.

[0146] (2) Preparation of Intermediate 5: 41.9 g of Intermediate 3 was added to 220 mL of dichloromethane, and then 81 g of triphosgene was added. The system temperature was controlled at 0°C. After the reaction of Intermediate 3 was completed, 90 mL of 30% methylamine aqueous solution precooled to 0°C was added to the reaction system. The reaction was carried out at 0°C for 2 h. The mixture was allowed to stand for separation. The organic layer was washed with water and the solvent was distilled off to obtain 37.3 g of Intermediate 5.

[0147] (3) Preparation of intermediate 6: 37.3 g of intermediate 5, 180 mL of 50% methylamine aqueous solution, 0.5 g of CuCl, and 0.9 g of N,N'-diacetylethylenediamine were added to a reactor and heated to 120°C for 12 h. After the reaction, the reaction solution was cooled to room temperature, 90 mL of water and 1.1 g of citric acid were added, and stirred at room temperature for 1 h. The residual copper was filtered out, and the pH was adjusted to 4 with concentrated hydrochloric acid. The reaction mixture was cooled and crystallized to obtain 29 g of intermediate 6.

[0148] (4) Preparation of intermediate 7: 29 g of intermediate 6, 4.3 g of 10% palladium carbon and 130 mL of 30% acetone aqueous solution were added to a reactor, hydrogen was introduced, the pressure was maintained at 1-1.5 MPa, and the reaction was heated to 80°C for 12 h. The palladium carbon was removed by filtration, and the filtrate was slowly cooled to below 0°C and filtered to obtain 13.4 g of intermediate 7 solid.

[0149] (5) Preparation of Oclacitinib: 13.4 g of intermediate 7, 18.9 g of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, 21.9 g of 4-dimethylaminopyridine and 180 mL of 25% aqueous acetonitrile solution were added to a reactor and heated under reflux for 8 h. Then, 18 mL of 50% potassium hydroxide solution was added to the reaction solution and heated under reflux for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature and 120 mL of dichloromethane was added. The organic layer was separated and washed once with a saturated sodium bicarbonate aqueous solution and twice with water. The solvent was evaporated to dryness to obtain 19.3 g of Oclacitinib with a total yield of 30.7%.

[0150] Example 5

[0151] (1) Preparation of Intermediate 3: 46 g of p-bromobenzyl bromide, 32 g of sodium sulfite and 300 mL of 40% aqueous tetrahydrofuran solution were added to a reactor, heated to 75° C., kept warm for 6 h, cooled, filtered, and the resulting solid was dried to obtain 45.1 g of Intermediate 3.

[0152] (2) Preparation of Intermediate 5: 45.1 g of Intermediate 3 was added to 210 mL of dichloromethane, and then 27 g of thionyl chloride and 18 g of oxalyl chloride were added. The system temperature was controlled at 30°C. After the reaction of Intermediate 3 was completed, the reaction solution was cooled to 10°C, and 90 mL of 25% methylamine aqueous solution precooled to 10°C was added to the reaction system. The reaction was carried out at 10°C for 1.5 h, and the mixture was allowed to stand for separation. The organic layer was washed with water and the solvent was distilled off to obtain 42.6 g of Intermediate 5.

[0153] (3) Preparation of intermediate 6: 42.6 g of intermediate 5, 170 mL of 35% methylamine aqueous solution, 1.7 g of cuprous trifluoromethanesulfonate, and 2 g of N,N'-dibenzyl oxalyl diamide were added to a reactor and heated to 70°C for 10 h. After the reaction, the reaction solution was cooled to room temperature, 85 mL of water and 1.5 g of citric acid were added, and stirred at room temperature for 1 h. The residual copper was filtered out, and the pH was adjusted to 4 with concentrated hydrochloric acid. The reaction mixture was cooled and crystallized to obtain 29.5 g of intermediate 6.

[0154] (4) Preparation of intermediate 7: 29.5 g of intermediate 6, 2.6 (Ph3P)4Pd and 130 mL of 30% ethanol aqueous solution were added to a reactor, hydrogen was introduced, the pressure was maintained at 1-1.5 MPa, and the reaction was heated to 90°C for 10 h. The palladium carbon was removed by filtration, and the filtrate was slowly cooled to below 0°C and filtered to obtain 14.1 g of intermediate 7 solid.

[0155] (5) Preparation of Oclacitinib: 14.1 g of intermediate 7, 20 g of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, 12.8 g of N-methylmorpholine and 200 mL of 50% aqueous acetone solution were added to a reactor and heated under reflux for 5 h. Then, 20 mL of 50% potassium hydroxide solution was added to the reaction solution and heated under reflux for 1 h. After the reaction, the reaction solution was cooled to room temperature and 130 mL of dichloromethane was added. The organic layer was separated and washed once with saturated sodium bicarbonate aqueous solution and twice with water. The solvent was evaporated to dryness to obtain 19 g of Oclacitinib with a total yield of 30.6%.

[0156] Example 6

[0157] (1) Preparation of Intermediate 3: 46 g of p-bromobenzyl bromide, 65 g of sodium sulfite and 300 mL of 20% acetonitrile aqueous solution were added to a reactor, heated to 70° C., kept warm for 5 h, cooled, filtered, and the obtained solid was dried to obtain 42.5 g of Intermediate 3.

[0158] (2) Preparation of intermediate 5: 42.5 g of intermediate 3 was added to 200 mL of dichloromethane, and then 34 g of phosphorus oxychloride and 34 g of triphosgene were added. The system temperature was controlled at 10°C. After the reaction of intermediate 3 was completed, 85 mL of 35% methylamine aqueous solution precooled to 10°C was added to the reaction system. The reaction was carried out at 10°C for 3 h. The mixture was allowed to stand for separation. The organic layer was washed with water and the solvent was distilled off to obtain 36.7 g of intermediate 5.

[0159] (3) Preparation of intermediate 6: 36.7 g of intermediate 5, 150 mL of 10% methylamine aqueous solution, 0.5 g of CuI, and 0.7 g of N,N'-dibenzoyl-1,2-ethylenediamine were added to a reactor and heated to 60°C for 8 h. After the reaction, the reaction solution was cooled to room temperature, 80 mL of water and 0.8 g of citric acid were added, and stirred at room temperature for 1 h. The residual copper was filtered out, and the pH was adjusted to 4 with concentrated hydrochloric acid. The reaction mixture was cooled and crystallized to obtain 26.8 g of intermediate 6.

[0160] (4) Preparation of intermediate 7: 26.8 g of intermediate 6, 3 g of 10% platinum carbon and 120 mL of 40% tetrahydrofuran aqueous solution were added to a reactor, hydrogen was introduced, the pressure was maintained at 0.5-1 MPa, and the reaction was heated to 70°C for 20 h. The palladium carbon was removed by filtration, and the reaction was slowly cooled to below 0°C and filtered to obtain 11.5 g of intermediate 7 solid.

[0161] (5) Preparation of Oclacitinib: 11.5 g of intermediate 7, 16.2 g of 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, 17.8 g of 3,5-dimethylpiperidine and 150 mL of 20% DMF aqueous solution were added to a reactor, and the mixture was heated under reflux for 12 h. Then, 16 mL of 50% potassium hydroxide solution was added to the reaction solution, and the mixture was heated under reflux for 3 h. After the reaction, the reaction solution was cooled to room temperature, 100 mL of dichloromethane was added, and the mixture was separated. The organic layer was washed once with a saturated sodium bicarbonate aqueous solution and twice with water. The solvent was evaporated to dryness to obtain 14.4 g of Oclacitinib with a total yield of 23.2%.

[0162] Comparative Example 1

[0163] The difference from Example 1 is that the ligand N,N'-diphenyloxamide in step (3) is omitted, the second methylamine substitution reaction time is 45 hours, and the rest is the same as Example 1. The total yield of oclacitinib obtained is 21.0%.

[0164] Comparative Example 2

[0165] The difference from Example 2 is that the ligand oxalyl diamide in step (3) is omitted, the second methylamine substitution reaction time is 48 hours, and the rest is the same as Example 2. The total yield of oclacitinib obtained is 20.3%.

[0166] Comparative Example 3

[0167] The difference from Example 3 is that the amount of the ligand N1,N2-bis(2,6-dimethoxyphenyl)oxamide added in step (3) is adjusted to 0.1 g, the second methylamine substitution reaction takes 40 hours, and the rest is the same as Example 3. The total yield of oclacitinib obtained is 28.5%.

[0168] Comparative Example 4

[0169] The difference from Example 4 is that the amount of the ligand N,N'-diacetylethylenediamine added in step (3) is adjusted to 0.15 g, the second methylamine substitution reaction takes 30 hours, and the rest is the same as Example 4. The total yield of oclacitinib obtained is 28.8%.

[0170] 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. A method for preparing oclacitinib, characterized in that: The following steps are involved: The compound represented by Formula 2, sodium sulfite and a first solvent are mixed, and a sodium sulfite substitution reaction is performed to obtain an intermediate 3 represented by Formula 3; In formula 2, X and Y are independently chlorine or bromine; The intermediate 3, the second solvent and the chlorinating agent are mixed to carry out a chlorination reaction to obtain a chlorination reaction liquid; the chlorination reaction liquid contains the compound shown in Formula 4; The chlorination reaction liquid and the methylamine aqueous solution are mixed to carry out a first methylamine substitution reaction to obtain an intermediate 5 shown in Formula 5; The intermediate 5, the methylamine aqueous solution, the first catalyst and the ligand are mixed, and a second methylamine substitution reaction is performed to obtain the intermediate 6 shown in formula 6; The first catalyst is a cuprous salt, and the cuprous salt is CuCl, CuBr, CuI or cuprous trifluoromethanesulfonate; The ligand is (CONHR)2 or (CH2NHCOR)2, wherein R in (CONHR)2 and (CH2NHCOR)2 is independently an aryl group, an alkyl group or hydrogen, and the carbon number of the alkyl group is 1 to 12; The intermediate 6, the second catalyst and the first aqueous organic solvent are mixed, and hydrogenation reduction reaction is performed under the condition of introducing hydrogen to obtain the intermediate 7 shown in formula 7; The intermediate 7, 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine, an organic base and a second aqueous organic solvent are mixed to carry out a condensation reaction to obtain a condensation reaction liquid, wherein the condensation reaction liquid contains the intermediate 8 shown in Formula 8; The condensation reaction solution is mixed with an inorganic base and deprotected to obtain the oclacitinib.

2. The preparation method according to claim 1, characterized in that: The first solvent includes one or more of water and an organic solvent, and the organic solvent includes one or more of acetonitrile, ethanol, acetone, tetrahydrofuran and N,N-dimethylformamide; The molar ratio of the compound represented by formula 2 to sodium sulfite is 1:1-5; The temperature of the sodium sulfite substitution reaction is 40 to 90° C.; the time of the sodium sulfite substitution reaction is 4 to 15 hours.

3. The preparation method according to claim 1, characterized in that: The chlorinating agent includes one or two of thionyl chloride, oxalyl chloride, phosphorus oxychloride and triphosgene; the second solvent includes one or more of dichloromethane, dichloroethane, tetrahydrofuran, N,N-dimethylformamide and dimethyl sulfoxide; The molar ratio of the intermediate 3 to the chlorinating agent is 1:1 to 3; The temperature of the chlorination reaction is -10 to 40°C.

4. The preparation method according to claim 1, characterized in that: During the first methylamine substitution reaction, the mass concentration of the methylamine aqueous solution is 10-50%; The molar ratio of the intermediate 3 to the methylamine in the methylamine aqueous solution is 1:1-10; The temperature of the first methylamine substitution reaction is 0-30° C. and the time is 1-3 hours.

5. The preparation method according to claim 1, characterized in that: During the second methylamine substitution reaction, the mass concentration of the methylamine aqueous solution is 10-50%; The molar ratio of the intermediate 5 to the methylamine in the methylamine aqueous solution is 1:1-20; The mass ratio of the intermediate 5 to the first catalyst is 1:0.01-0.1; The mass ratio of the intermediate 5 to the ligand is 1:0.01-0.1; The temperature of the second methylamine substitution reaction is 50-120° C., and the time is 8-20 hours.

6. The preparation method according to claim 1 or 5, characterized in that: After the second methylamine substitution reaction, the method further includes: cooling the obtained reaction material to room temperature, adding water and citric acid to carry out a complex reaction, then filtering the obtained complex material, adjusting the pH of the obtained filtrate to acidic, and cooling and crystallizing to obtain the intermediate 6.

7. The preparation method according to claim 1, characterized in that: The second catalyst is palladium carbon, platinum carbon or (Ph3P)4Pd; the organic solvent in the first aqueous organic solvent includes one or more of methanol, ethanol, acetonitrile, acetone and tetrahydrofuran; The mass ratio of the intermediate 6 to the second catalyst is 1:0.01-0.2; The pressure of the hydrogenation reduction reaction is 0.5-2 MPa, the temperature is 60-100° C., and the time is 10-20 hours.

8. The preparation method according to claim 1, characterized in that: The organic base includes one or more of triethylamine, diisopropylethylamine, 1,8-diazobispiro[5.4.0]undec-7-ene, dimethylaniline, 4-dimethylaminopyridine, N-methylmorpholine, dimethylpiperidine and triethylenediamine; The organic solvent in the second aqueous organic solvent includes one or more of acetonitrile, ethanol, acetone, tetrahydrofuran and N,N-dimethylformamide; The molar ratio of the intermediate 7 to 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine is 1:1 to 3; The molar ratio of the intermediate 7 to the organic base is 1:1-4; The condensation reaction is carried out under heating reflux conditions, and the condensation reaction time is 2 to 12 hours.

9. The preparation method according to claim 1, characterized in that: The inorganic base includes sodium hydroxide and / or potassium hydroxide; The molar ratio of the intermediate 7 to the inorganic base is 1:1 to 3; The deprotection is carried out under heating reflux conditions, and the deprotection time is 1 to 5 hours.

10. The preparation method according to claim 1 or 9, characterized in that: After the deprotection, the method further comprises: cooling the obtained feed liquid to room temperature, adding dichloromethane for liquid separation, and washing the obtained organic layer with a saturated sodium bicarbonate aqueous solution, washing with water and evaporating to dryness to obtain the oclacitinib.

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