CN111909156B - Preparation method of olatinib maleate - Google Patents
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Abstract
The invention discloses a preparation method of olatinib maleate. Trans-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid and 4-chloro-7-tosyl-7H-pyrrolo [2,3-d ] pyrimidine are used as initial raw materials, and are subjected to reduction, condensation, esterification, sulfonation, deprotection, chlorination, methylamination and salt formation reaction to obtain the olatinib maleate. The synthetic route is optimized through processes of mesylate, sulfonation, methylamination, salification and the like, so that the post-treatment times are reduced, and the production efficiency and yield are improved; the operation is more simple and convenient, and the method is suitable for domestic industrial production. The total yield reaches more than 65 percent, and the product purity reaches more than 99 percent.
Description
Technical Field
The invention belongs to the field of chemistry or pharmaceutical chemistry, and particularly relates to a preparation method of olatinib maleate.
Background
Olatinib obtained FDA approval in 2013 in the united states and was used to control itching and atopic dermatitis caused by allergic dermatitis in dogs. Olatinib is a very potent inhibitor of JAK1, and also inhibits the function of JAK 1-dependentchystatins in some anti-allergic, inflammatory and pruritic reactions. The drug has little influence on cytokines which do not participate in JAK1 activation, and in the beginning of 2019, Olatinib maleate produced by Shuotang company in America is examined and approved to be registered in China, and the drug is published as imported veterinary drug registration certificate, and after Shuotang comes into the market in 2013 and is like Pocke, millions of dogs suffering from pruritus diseases are benefited, and like Bork (A), (B), (
The common name is: olatinib maleate tablets) has become the largest single product in the world.
The currently reported synthetic routes of olatinib mainly include the following four routes:
route 1:
patent WO2010/020905 reports that trans-4-tert-butoxycarbonyl-cyclohexanecarboxylic acid is used as an initial raw material, is reduced by red aluminum to obtain trans-4- (methylamino) -cyclohexyl ] methanol, is condensed with 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine under the catalysis of triethylamine, protects hydroxyl and amino by p-toluenesulfonyl chloride, substitutes by potassium thioacetate, oxidizes by hydrogen peroxide/formic acid, chlorinates by thionyl chloride, performs methylamine tetrahydrofuran for methylamine amination, deprotects by lithium hydroxide to obtain olatinib, and finally forms salt with maleic acid to obtain the olatinib maleate.
The synthetic route has various steps, and explosive chemical hydrogen peroxide is needed when preparing the [ trans-4- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclohexyl ] methanesulfonic acid, so that the safety risk exists. The intermediate is isolated in each step by work-up, in particular by the preparation of [ trans-4- (methyl {7- [ (4-tolyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclohexyl ] methanesulfonyl chloride which requires crystallization from ethyl acetate and hexane, storage under nitrogen and difficult handling. And methylamine tetrahydrofuran solution is needed to be used during the methylamine amination, the raw material is high in price, and the wastewater contains tetrahydrofuran, so that the wastewater is difficult to treat.
Route 2:
patent WO2010/020905 also reports another preparation method, substitution with sodium sulphate instead of hydrogen peroxide/formic acid oxidation at the time of sulfonation, other steps being in line with scheme 1:
the synthetic route is as many as the first route, and each intermediate is separated by post-treatment, particularly [ trans-4- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclohexyl ] methyl sulfinate is prepared by pulping twice with a mixed solvent of methyl tert-butyl ether and heptane, the post-treatment is troublesome, and the yield is only 58.28%. When [ trans-4- (methyl {7- [ (4-tolyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclohexyl ] methanesulfonic acid is produced using sodium sulfate or sodium sulfite, side reactions such as deprotection or hydrolysis of a methanesulfonate easily occur under basic conditions, resulting in low intermediate purity in this step. And methylamine tetrahydrofuran solution is needed to be used during the methylamine amination, the raw material is high in price, and the wastewater contains tetrahydrofuran, so that the wastewater is difficult to treat. 1-butanol/water (8:1) with the volume ratio of 17 times is used as a solvent during salt formation, and the 1-butanol with half volume needs to be distilled in vacuum during post-treatment, so that the post-treatment is troublesome.
Route 3:
patent CN107365312 reports that the final product is obtained by using N-benzyl-N-methylmethanesulfonamide and 1,4 cyclohexanedione monoethylene ketal as starting materials through condensation, chlorination, elimination, catalytic hydrogenation, hydrolysis, reduction-amination, condensation, debenzylation and salification. The synthetic route is as follows:
although the reaction steps are shorter than the route of the prior art, ultralow temperature reaction (-below 30 ℃) is required during the first condensation step, a dangerous reagent n-butyllithium is used, the industrial production is not easy to operate, and meanwhile, pressure catalytic reaction is required during hydrogenation reduction, so that the potential safety hazard is large.
Route 4:
patent US2017/0233397 reports that p-bromobenzyl bromide is used as a starting material, and sodium sulfite substitution, methylamine substitution, palladium-carbon catalytic hydrogenation reduction of benzene ring, condensation with 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine, chlorination, methanization and salt formation are carried out to obtain the olatinib maleate:
although the steps of the route are few, the (4- (methylamino) phenyl) methanesulfonic acid is subjected to Pd/C catalytic hydrogenation to generate a mixture of cis-form products and trans-form products, about 30% of the cis-form products cannot be isomerized after recrystallization separation, the utilization rate of raw materials is low, and the generated solid waste is large.
In view of the above disadvantages of the synthesis process of olatinib maleate, the development of a synthetic method of olatinib maleate, which is simple and convenient to operate, mild in reaction conditions, high in yield, high in purity, green and environment-friendly, and suitable for production, is yet to be further explored and researched.
Disclosure of Invention
Aiming at various defects of the above route, the invention aims to provide a synthesis method of the olatinib maleate, which has the advantages of mild reaction conditions, few steps, simple and convenient operation, high yield, environmental protection and suitability for production, and the specific technical scheme is as follows:
a preparation method of olatinib maleate, which is prepared by the following chemical reaction equation:
wherein X is NH4、Li
The reaction equation is prepared by the following steps:
(1) reduction, condensation and esterification: adding trans-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid into toluene, dropwise adding a sodium dihydrobis (2-methoxyethoxy) sodium aluminate toluene solution, heating to a certain temperature, and carrying out reduction and heat preservation reaction for a period of time; adding 5-10% sodium hydroxide solution to quench reaction, separating a water layer, concentrating a toluene layer to be dry, adding a certain amount of acetonitrile, 4-chloro-7-tosyl-7H-pyrrolo [2,3-d ] pyrimidine, an acid-binding agent and a catalyst potassium iodide, starting stirring, heating to a certain temperature, and carrying out condensation and heat preservation reaction for a period of time; cooling to 5-25 ℃, dropwise adding a certain amount of methylsulfonyl chloride, and after dropwise adding, keeping the temperature of the esterification reaction for a period of time; then adding a certain amount of water into the reaction liquid, stirring and crystallizing for 1-2 hours, carrying out suction filtration, washing a filter cake with a certain amount of acetonitrile to obtain a white solid, and drying at 60-85 ℃ to obtain trans-4- (methyl {7- [ (4-tolyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclohexyl ] methyl sulfinate;
(2) sulfonation and deprotection: adding the trans-4- (methyl {7- [ (4-tolyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclohexyl ] methyl sulfinate obtained in the step (1) into a mixed solution of a certain amount of alcohol solvent and water, adding sulfite, sulfonating, and carrying out heat preservation reaction for a period of time; cooling to 20-25 deg.C, adding deprotection reagent, performing deprotection and heat preservation reaction for a period of time, adjusting pH to 7-8 with acid, cooling to 0-5 deg.C, vacuum filtering, and drying filter cake at 60-85 deg.C to obtain trans-4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonic acid;
(3) chlorination and methylamine: adding the trans-4- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) cyclohexyl) methanesulfonic acid prepared in the step (2) into an acetonitrile solvent, cooling to 0-5 ℃ under the catalysis of organic base, dropwise adding oxalyl chloride, and carrying out chlorination and heat preservation reaction for a period of time; dropwise adding 35-40% methylamine water solution, after dropwise adding, carrying out methylamine reaction, keeping warm and stirring for 0.5-1H, adding drinking water, keeping warm and stirring for 1H, carrying out suction filtration, and drying a filter cake at 60-85 ℃ to obtain N-methyl-1- { trans-4- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclohexyl } methanesulfonamide;
(4) salifying: adding N-methyl-1- { trans-4- [ methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino ] cyclohexyl } methanesulfonamide and maleic acid into 95% ethanol, heating up, reacting for 1-2 hours under heat preservation for salification, filtering, cooling the filtrate to 5-10 ℃, stirring for 1-2 hours, filtering, leaching the filter cake with 95% ethanol, and drying the filter cake at 50-60 ℃ in vacuum to dryness to obtain the orlatinib maleate.
In the reaction step (1), the dosage of the toluene is 6-8 times of the weight of the trans-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid; the content of the sodium dihydrobis (2-methoxyethoxy) aluminate toluene solution is 65-70%; the feeding molar ratio of the sodium dihydrobis (2-methoxyethoxy) aluminate to the trans-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid is 3.0-5.5: 1; the feeding molar ratio of 5-10% of sodium hydroxide solution used for the quenching reaction to trans-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid is 2.0-5.0: 1; the reduction heat-preservation reaction temperature is 105-110 ℃, and the reaction time is 3-6 hours.
In the reaction step (1), the feeding amount of the acetonitrile is 4-6 times of the weight of the trans-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid; the feeding molar ratio of the 4-chloro-7-tosyl-7H-pyrrolo [2,3-d ] pyrimidine to the trans-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid is 0.7-1.1: 1; the acid-binding agent is at least one of potassium hydroxide, sodium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, lithium hydroxide, pyridine, N-diisopropylethylamine, tetramethylethylenediamine, tripropylamine, 4-dimethylaminopyridine, triethylenediamine, hexamethylenetetramine, tetrabutylammonium hydroxide, gamma-chloropropylmethyldimethoxysilane, N-methylmorpholine or 2,4, 6-trimethylpyridine, and the feeding molar ratio of the acid-binding agent to trans-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid is 1.5-2.1: 1; the feeding molar ratio of the catalyst potassium iodide to the trans-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid is 0.02-0.2: 1; the condensation heat-preservation reaction temperature is 65-82 ℃, and the reaction time is 24-30 hours.
In the reaction step (1), the feeding molar ratio of the methylsulfonyl chloride to the trans-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid is 1.5-2.1: 1; the esterification heat preservation reaction temperature is 20-25 ℃, and the reaction time is 16-24 hours; the water addition amount is 1.2-2 times of the weight of the acetonitrile feeding material, and the crystallization temperature is 10-25 ℃. The washing amount of the acetonitrile is 0.8 to 2 times of the feeding weight of the trans-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid.
In the reaction step (2), the alcohol is at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol and 2-butanol; the feeding volume ratio of the alcohol to the water is 1-5: 1; the dosage of the alcohol is 3-6 times of the dosage weight of trans-4- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidine-4-yl } amino) cyclohexyl ] methylsulfinate; the sulfite is at least one of ammonium sulfite and lithium sulfite, and the feeding molar ratio of the sulfite to trans-4- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclohexyl ] methyl sulfinate is 1.5-3.5: 1; the sulfonation heat preservation reaction temperature is 70-85 ℃, and the reaction time is 24-30 hours.
In the reaction step (2), the deprotection reagent is at least one of tetrabutylammonium fluoride, sodium hydroxide, potassium tert-butoxide, potassium hydroxide, strontium hydroxide and sodium methoxide; the molar ratio of the de-protecting group reagent to trans-4- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclohexyl ] methyl sulfinate is 1.2-5: 1; the deprotection reaction temperature is 20-60 ℃, and the reaction time is 5-16 hours; the acid for adjusting pH and neutralizing is at least one of acetic acid, formic acid, phosphoric acid, hydrochloric acid, sulfuric acid and oxalic acid. In the reaction step (3), the feeding amount of the acetonitrile is 3-5 times of the weight of the trans-4- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) cyclohexyl) methanesulfonic acid; the organic base is at least one of pyridine, N-diisopropylethylamine, tetramethylethylenediamine, tripropylamine and 4-dimethylaminopyridine; the feeding molar ratio of the organic base to the trans-4- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) cyclohexyl) methanesulfonic acid is 0.1-0.3: 1; the feeding molar ratio of oxalyl chloride to trans-4- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) cyclohexyl) methanesulfonic acid is 1.1-1.5: 1; the chlorination reaction temperature is 0-10 ℃, and the reaction time is at least 3 hours; the feeding molar ratio of the methylamine water solution to the trans-4- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) cyclohexyl) methanesulfonic acid is 8-11: 1; the temperature of the methylamine dropping and the heat preservation reaction is 0-10 ℃; the water addition amount is 3-5 times of the weight of the acetonitrile feeding material, and the crystallization temperature is 0-10 ℃.
In the reaction step (4), the dosage of the 95 percent ethanol is 4 to 8 times of the weight of the N-methyl-1- { trans-4- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclohexyl } methanesulfonamide; the feeding molar ratio of the maleic acid to the N-methyl-1- { trans-4- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclohexyl } methanesulfonamide is 0.9-1.1: 1; the dosage of the active carbon is 3-5% of the weight of N-methyl-1- { trans-4- [ methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino ] cyclohexyl } methanesulfonamide; the temperature of the salt forming reaction is 78-82 ℃.
The invention has the beneficial effects that:
1) the invention provides a preparation method of olatinib maleate, which simplifies post-treatment, does not need to carry out separation and purification by each step of reaction, and adopts a one-pot method for reduction, condensation and esterification procedures, sulfonation and deprotection procedures, chlorination and methylamine procedures, thereby reducing the post-treatment times and improving the production efficiency;
2) according to the preparation method of olatinib maleate, the step of preparing S- { [ trans-4- (methyl {7- [ (4-tolyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclohexyl ] methyl sulfoacetate is omitted during preparation of trans-4- (methyl {7- [ (4-tolyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclohexyl ] methyl sulfinate, the conversion rate is improved, only acetonitrile is needed for washing a filter cake during aftertreatment, and the purity of the product reaches over 99.0%.
3) According to the preparation method of olatinib maleate, sodium sulfite is replaced by ammonium sulfite or lithium sulfite with weak basicity during sulfonation, ester hydrolysis of trans-4- (methyl {7- [ (4-tolyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclohexyl ] methyl sulfinate is reduced, and the yield is improved to over 86.0%.
4) According to the preparation method of the olatinib maleate, provided by the invention, a methylamine tetrahydrofuran solution is replaced by a methylamine aqueous solution during methylamine amination, so that the raw material cost is reduced, and the treatment of tetrahydrofuran-containing wastewater is avoided.
5) According to the preparation method of the olatinib maleate, provided by the invention, 95% ethanol is used as a solvent instead of 1-butanol/water (8:1) during salification, so that the use amount of the 1-butanol is reduced, the vacuum distillation of the butanol during post-treatment is avoided, and the operation is simplified.
6) According to the preparation method of the maleic acid olaratinib, the total yield is more than 65%, the product purity is more than 99.5%, the maleic acid + olaratinib content is more than or equal to 99.5%, the impurity A is less than or equal to 0.4%, the impurity B is less than or equal to 0.1%, and the impurity C is less than or equal to 0.1%.
Drawings
FIG. 1 is a mass spectrum of trans-4- (methyl {7- [ (4-tolyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclohexyl ] methanesulfonate
FIG. 2 shows a mass spectrum of trans-4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonic acid
FIG. 3 shows a mass spectrum of N-methyl-1- { trans-4- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclohexyl } methanesulfonamide
FIG. 4 shows the nuclear magnetic hydrogen spectrum of N-methyl-1- { trans-4- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclohexyl } methanesulfonamide
FIG. 5 Oratinib maleate X-ray diffraction spectrum
FIG. 6 Olatinib maleate HPLC chromatogram
Detailed Description
The present invention is described in detail by the following specific examples, which are provided for the purpose of illustration and are not to be construed as limiting the invention.
Example 1
Preparation of trans-4- (methyl {7- [ (4-tolyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclohexyl ] methanesulfonate:
350g of toluene and 48.7g (0.2mol) of trans-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid were charged in a 1L four-necked flask, and 202.2g (0.7mol) of a 70% sodium dihydrobis (2-methoxyethoxy) aluminate toluene solution was added dropwise thereto, and the mixture was heated to 110 ℃ and reacted for 6 hours while maintaining the temperature. The reaction was quenched by the addition of 320g (0.4mol) of 5% sodium hydroxide solution, the aqueous layer was separated and the toluene layer was concentrated to dryness. Acetonitrile 200g, 4-chloro-7-tosyl-7H-pyrrolo [2,3-d ] pyrimidine 58.5g (0.19mol), N, N-diisopropylethylamine 54.3g (0.42mol) and potassium iodide 3.7g (0.022mol) were added, and the mixture was stirred and heated to 65 ℃ and then allowed to react for 28 hours while maintaining the temperature. Cooling to 5-10 deg.c, dropping methanesulfonyl chloride in 34.4g (0.3mol), maintaining at 20-25 deg.c and stirring for 16 hr. 240g of water was added thereto, followed by crystallization with stirring for 1 to 2 hours, suction filtration was conducted, the filter cake was washed with 95g of acetonitrile and dried at 80 to 85 ℃ to obtain 87.2g of trans-4- (methyl {7- [ (4-tolyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclohexyl ] methylsulfinate as a white solid in 88.5% yield. Purity by HPLC 99.3%.
[ M +1] ═ 493.1 (see FIG. 1 for details)
Example 2
Preparation of trans-4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonic acid:
440g of ethanol and 296g of water were put into a 1L four-necked flask, 73.9g (0.15mol) of trans-4- (methyl {7- [ (4-tolyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclohexyl ] methylsulfinate was added, 52.3g (0.45mol) of ammonium sulfite was added, the temperature was raised to 75 to 85 ℃ and the reaction was carried out for 24 to 30 hours while maintaining the temperature. Cooling to 20-25 ℃, adding 47.1g (0.18mol) of tetrabutylammonium fluoride, keeping the temperature at 25 ℃ for reaction for 16 hours, adjusting the pH value to 7-8 by using phosphoric acid, cooling to 0-5 ℃, carrying out suction filtration, and drying a filter cake at 80-85 ℃ to obtain 42.1g of trans-4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonic acid; the yield thereof was found to be 86.5%. HPLC purity 98.2%.
[ M-1] ═ 323.1 (see FIG. 2 for details)
Example 3
Preparation of N-methyl-1- { trans-4- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclohexyl } methanesulfonamide:
adding 130g of acetonitrile into a 1L four-neck flask, adding 32.4g (0.1mol) of trans-4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonic acid and 3.5g (0.03mol) of tetramethylethylenediamine, cooling to 5 ℃, dropwise adding 15.3g (0.12mol) of oxalyl chloride, stirring at 5-10 ℃ for at least 3 hours under heat preservation, dropwise adding 70g (0.9mol) of 35-40% methylamine water solution, controlling the temperature to be 0-10 ℃, dropwise adding, stirring at 0-10 ℃ for at least 0.5-1 hour under heat preservation, adding 400g of drinking water, stirring for 1 hour under heat preservation, performing suction filtration, and drying at 75-85 ℃ to obtain 30.5g of N-methyl-1- { trans-4- [ methyl (7H-pyrrolo [23-d ] pyrimidin-4-yl) amino ] cyclohexyl } methanesulfonamide, yield 90.5% HPLC purity 99.1%.
WNMR-I-500MHz type nuclear magnetic resonance instrument nuclear magnetic hydrogen spectrum detection, the data is as follows:
1H NMR(DMSO-d6,500MHz)δ:11.553(s,1H)，8.083(s,1H),7.100-7.107(t,1H),6.827-6.864(d,1H)，6.522(d,1H)，4.646-4.668(d,1H)，3.158(s,3H)，2.938-2.953(m,2H)，2.500-2.591(s,3H)，2.029-2.062(m,2H)，1.833-1.863(m,1H)，1.687-1.707(m,4H)，1.238-1.341(m,2H)。
[ M +1] ═ 338.1 (see fig. 3 for details).
Example 4
Preparation of orlatinib maleate:
adding 150ml of 95-ethanol, 24.0g (0.071mol) of N-methyl-1- { trans-4- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclohexyl } methanesulfonamide, 8.2g (0.071mol) of maleic acid and 1.2g of activated carbon into a 500ml reaction bottle, heating to 78-80 ℃, preserving heat for reaction for 1-2 hours, carrying out suction filtration, cooling the filtrate to 5-10 ℃, stirring for 1-2 hours, carrying out suction filtration, leaching a filter cake by using 95% ethanol, drying the filter cake at 50-60 ℃ in vacuum to dryness to obtain 30.5g of orlatinib maleate, wherein the yield is 95.5%.
The total yield is as follows: 88.5% × 86.5% × 90.5% × 95.5% ═ 66.1%
The related substances are detected as follows:
example 5
Preparation of trans-4- (methyl {7- [ (4-tolyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclohexyl ] methanesulfonate:
295g of toluene and 48.7g (0.2mol) of trans-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid were put into a 1L four-necked flask, 288.9g (1.0mol) of a 70% sodium dihydrobis (2-methoxyethoxy) aluminate toluene solution was added dropwise, the temperature was raised to 110 ℃ and the reaction was maintained for 3 hours. The reaction was quenched by the addition of 160g (0.4mol) of 10% sodium hydroxide solution, the aqueous layer was separated and the toluene layer was concentrated to dryness. Acetonitrile 250g, 4-chloro-7-tosyl-7H-pyrrolo [2,3-d ] pyrimidine 61.6g (0.2mol), potassium carbonate 41.5g (0.3mol) and potassium iodide 3.7g (0.022mol) were added, and the mixture was stirred and heated to 80 ℃ to carry out the reaction for 24 hours while maintaining the temperature. Cooling to 15-20 ℃, dropwise adding 45.9g (0.4mol) of methylsulfonyl chloride, and keeping the temperature at 20-25 ℃ and stirring for 18 hours after the dropwise adding is finished. 500g of water was added and the mixture was stirred for crystallization for 1 to 2 hours, followed by suction filtration, washing the filter cake with 50g of acetonitrile and drying at 70 to 75 ℃ to obtain 87.5g of trans-4- (methyl {7- [ (4-tolyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclohexyl ] methyl sulfinate as a white solid in 88.8% yield. Purity by HPLC 99.3%.
Example 6
Preparation of trans-4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonic acid:
350g of ethanol and 350g of water were charged into a 1L four-necked flask, 73.9g (0.15mol) of trans-4- (methyl {7- [ (4-tolyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclohexyl ] methanesulfinate was added, 49.3g (0.53mol) of lithium sulfite was further added, the temperature was raised to 75 to 85 ℃ and the reaction was allowed to proceed for 24 to 30 hours while maintaining the temperature. Cooling to 20-25 ℃, adding 80g (0.6mol) of 30% sodium hydroxide aqueous solution, keeping the temperature at 60 ℃ for reaction for 5 hours, adjusting the pH value to 7-8 by formic acid, cooling to 0-5 ℃, carrying out suction filtration, and drying a filter cake at 70-75 ℃ to obtain 42.6g of trans-4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonic acid; the yield thereof was found to be 87.6%. HPLC purity 98.2%.
Example 7
Preparation of N-methyl-1- { trans-4- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclohexyl } methanesulfonamide:
adding 160g of acetonitrile into a 1L four-neck flask, adding 32.4g (0.1mol) of trans-4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonic acid and 1.2g (0.01mol) of 4-dimethylaminopyridine, cooling to 0 ℃, adding 19.1g (0.15mol) of oxalyl chloride dropwise, stirring at 0-10 ℃ for at least 3 hours under heat preservation, adding 85.6g (1.1mol) of 35-40% methylamine water solution dropwise, controlling the temperature to 0-10 ℃, stirring at 0-10 ℃ for at least 0.5-1 hour under heat preservation, adding 550g of drinking water, stirring at 1 hour under heat preservation, filtering, drying a filter cake at 60-70 ℃ to obtain 30.4g of N-methyl-1- { trans-4- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclohexyl } methanesulfonamide, yield 90.2% HPLC purity 99.2%.
Example 8
Preparation of orlatinib maleate:
adding 180ml of 95-ethanol, 24.0g (0.071mol) of N-methyl-1- { trans-4- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclohexyl } methanesulfonamide, 8.0g (0.07mol) of maleic acid and 1.0g of activated carbon into a 500ml reaction bottle, heating to 78-80 ℃, preserving heat for reaction for 1-2 hours, carrying out suction filtration, cooling the filtrate to 5-10 ℃, stirring for 1-2 hours, carrying out suction filtration, leaching the filter cake with 95% ethanol, and drying the filter cake at 50-60 ℃ in vacuum to dryness to obtain 30.4g of orlatinib maleate with the yield of 95.0%. The total yield is as follows: the assay of the relevant substances was found to be 88.8% × 87.6% × 90.2% × 95.0% >, 66.7%:
the X-ray diffraction data are as follows:
the present invention is not limited to the above-described embodiments, and any simple, equivalent changes or modifications made to the above-described embodiments in accordance with the technical spirit of the present invention fall within the technical scope of the present invention.
Claims (8)
1. A preparation method of olatinib maleate is characterized by comprising the following chemical reaction equations:
wherein X is NH4、Li
The reaction equation is prepared by the following steps:
(1) reduction, condensation and esterification: adding trans-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid into toluene, dropwise adding a sodium dihydrobis (2-methoxyethoxy) sodium aluminate toluene solution, heating to a certain temperature, and carrying out reduction and heat preservation reaction for a period of time; adding 5-10% sodium hydroxide solution to quench reaction, separating a water layer, concentrating a toluene layer to be dry, adding a certain amount of acetonitrile, 4-chloro-7-tosyl-7H-pyrrolo [2,3-d ] pyrimidine, an acid-binding agent and a catalyst potassium iodide, starting stirring, heating to a certain temperature, and carrying out condensation and heat preservation reaction for a period of time; cooling to 5-25 ℃, dropwise adding a certain amount of methylsulfonyl chloride, and after dropwise adding, keeping the temperature of the esterification reaction for a period of time; then adding a certain amount of water into the reaction liquid, stirring and crystallizing for 1-2 hours, carrying out suction filtration, washing a filter cake with a certain amount of acetonitrile to obtain a white solid, and drying at 60-85 ℃ to obtain trans-4- (methyl {7- [ (4-tolyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclohexyl ] methyl sulfinate;
(2) sulfonation and deprotection: adding the trans-4- (methyl {7- [ (4-tolyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclohexyl ] methyl sulfinate obtained in the step (1) into a mixed solution of a certain amount of alcohol solvent and water, adding sulfite, sulfonating, and carrying out heat preservation reaction for a period of time; cooling to 20-25 deg.C, adding deprotection reagent, performing deprotection and heat preservation reaction for a period of time, adjusting pH to 7-8 with acid, cooling to 0-5 deg.C, vacuum filtering, and drying filter cake at 60-85 deg.C to obtain trans-4- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) cyclohexyl) methanesulfonic acid;
(3) chlorination and methylamine: adding the trans-4- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) cyclohexyl) methanesulfonic acid prepared in the step (2) into an acetonitrile solvent, cooling to 0-5 ℃ under the catalysis of organic base, dropwise adding oxalyl chloride, and carrying out chlorination and heat preservation reaction for a period of time; dropwise adding 35-40% methylamine water solution, after dropwise adding, carrying out methylamine reaction, keeping warm and stirring for 0.5-1H, adding drinking water, keeping warm and stirring for 1H, carrying out suction filtration, and drying a filter cake at 60-85 ℃ to obtain N-methyl-1- { trans-4- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclohexyl } methanesulfonamide;
(4) salifying: adding N-methyl-1- { trans-4- [ methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino ] cyclohexyl } methanesulfonamide and maleic acid into 95% ethanol, heating up, reacting for 1-2 hours under heat preservation for salification, filtering, cooling the filtrate to 5-10 ℃, stirring for 1-2 hours, filtering, leaching the filter cake with 95% ethanol, and drying the filter cake at 50-60 ℃ in vacuum to dryness to obtain the orlatinib maleate.
2. The method for preparing olatinib maleate according to claim 1, characterized in that: in the reaction step (1), the dosage of the toluene is 6-8 times of the weight of the trans-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid; the content of the sodium dihydrobis (2-methoxyethoxy) aluminate toluene solution is 65-70%; the feeding molar ratio of the sodium dihydrobis (2-methoxyethoxy) aluminate to the trans-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid is 3.0-5.5: 1; the feeding molar ratio of 5-10% of sodium hydroxide solution used for the quenching reaction to trans-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid is 2.0-5.0: 1; the reduction heat-preservation reaction temperature is 105-110 ℃, and the reaction time is 3-6 hours.
3. The method for preparing olatinib maleate according to claim 1, characterized in that: in the reaction step (1), the feeding amount of the acetonitrile is 4-6 times of the weight of the trans-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid; the feeding molar ratio of the 4-chloro-7-tosyl-7H-pyrrolo [2,3-d ] pyrimidine to the trans-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid is 0.7-1.1: 1; the acid-binding agent is at least one of potassium hydroxide, sodium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, lithium hydroxide, pyridine, N-diisopropylethylamine, tetramethylethylenediamine, tripropylamine, 4-dimethylaminopyridine, triethylenediamine, hexamethylenetetramine, tetrabutylammonium hydroxide, gamma-chloropropylmethyldimethoxysilane, N-methylmorpholine or 2,4, 6-trimethylpyridine, and the feeding molar ratio of the acid-binding agent to trans-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid is 1.5-2.1: 1; the feeding molar ratio of the catalyst potassium iodide to the trans-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid is 0.02-0.2: 1; the condensation heat-preservation reaction temperature is 65-82 ℃, and the reaction time is 24-30 hours.
4. The method for preparing olatinib maleate according to claim 1, characterized in that: in the reaction step (1), the feeding molar ratio of the methylsulfonyl chloride to the trans-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid is 1.5-2.1: 1; the esterification heat preservation reaction temperature is 20-25 ℃, and the reaction time is 16-24 hours; the water adding amount is 1.2-2 times of the weight of the acetonitrile feeding material, and the crystallization temperature is 10-25 ℃; the washing amount of the acetonitrile is 0.8 to 2 times of the feeding weight of the trans-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid.
5. The method for preparing olatinib maleate according to claim 1, characterized in that: in the reaction step (2), the alcohol is at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol and 2-butanol; the feeding volume ratio of the alcohol to the water is 1-5: 1; the dosage of the alcohol is 3-6 times of the dosage weight of trans-4- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidine-4-yl } amino) cyclohexyl ] methylsulfinate; the sulfite is at least one of ammonium sulfite and lithium sulfite, and the feeding molar ratio of the sulfite to trans-4- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclohexyl ] methyl sulfinate is 1.5-3.5: 1; the sulfonation heat preservation reaction temperature is 70-85 ℃, and the reaction time is 24-30 hours.
6. The method for preparing olatinib maleate according to claim 1, characterized in that: in the reaction step (2), the deprotection reagent is at least one of tetrabutylammonium fluoride, sodium hydroxide, potassium tert-butoxide, potassium hydroxide, strontium hydroxide and sodium methoxide; the molar ratio of the de-protecting group reagent to trans-4- (methyl {7- [ (4-methylphenyl) sulfonyl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-yl } amino) cyclohexyl ] methyl sulfinate is 1.2-5: 1; the deprotection reaction temperature is 20-60 ℃, and the reaction time is 5-16 hours; the acid for adjusting pH and neutralizing is at least one of acetic acid, formic acid, phosphoric acid, hydrochloric acid, sulfuric acid and oxalic acid.
7. The method for preparing olatinib maleate according to claim 1, characterized in that: in the reaction step (3), the feeding amount of the acetonitrile is 3-5 times of the weight of the trans-4- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) cyclohexyl) methanesulfonic acid; the organic base is at least one of pyridine, N-diisopropylethylamine, tetramethylethylenediamine, tripropylamine and 4-dimethylaminopyridine; the feeding molar ratio of the organic base to the trans-4- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) cyclohexyl) methanesulfonic acid is 0.1-0.3: 1; the feeding molar ratio of oxalyl chloride to trans-4- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) cyclohexyl) methanesulfonic acid is 1.1-1.5: 1; the chlorination reaction temperature is 0-10 ℃, and the reaction time is at least 3 hours; the feeding molar ratio of the methylamine water solution to the trans-4- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) cyclohexyl) methanesulfonic acid is 8-11: 1; the temperature of the methylamine dropping and the heat preservation reaction is 0-10 ℃; the water addition amount is 3-5 times of the weight of the acetonitrile feeding material, and the crystallization temperature is 0-10 ℃.
8. The method for preparing olatinib maleate according to claim 1, characterized in that: in the reaction step (4), the dosage of the 95 percent ethanol is 4 to 8 times of the weight of the N-methyl-1- { trans-4- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclohexyl } methanesulfonamide; the feeding molar ratio of the maleic acid to the N-methyl-1- { trans-4- [ methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] cyclohexyl } methanesulfonamide is 0.9-1.1: 1; the dosage of the active carbon is 3-5% of the weight of N-methyl-1- { trans-4- [ methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino ] cyclohexyl } methanesulfonamide; the temperature of the salt forming reaction is 78-82 ℃.
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