CN107759623B - Intermediate of JAK inhibitor and preparation method thereof - Google Patents
Intermediate of JAK inhibitor and preparation method thereof Download PDFInfo
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- CN107759623B CN107759623B CN201610707558.2A CN201610707558A CN107759623B CN 107759623 B CN107759623 B CN 107759623B CN 201610707558 A CN201610707558 A CN 201610707558A CN 107759623 B CN107759623 B CN 107759623B
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Abstract
The invention relates to a novel key intermediate of a JAK inhibitor ruxolitinib and a preparation method thereof, wherein the chemical name of the intermediate is (R) -3- (4-boric acid-1H-pyrazole-1-yl) -3-cyclopentanepropanitrile. The invention provides a new route for preparing ruxolitinib, and each step of the route has high yield, high total reaction yield, good purity of the obtained product, simple post-treatment of the reaction and no need of column chromatography; by adopting the route, the required raw materials or the used catalyst and other substances are easy to obtain, and compared with the prior art, the method is more economic and more suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of preparation of JAK inhibitor ruxolitinib, and particularly relates to a novel ruxolitinib intermediate, a preparation method of the intermediate and a preparation method of ruxolitinib.
Background
Ruxolitinib (Ruxolitinib) is an orally administrable selective JAK1/JAK2 kinase inhibitor, the first approved by the FDA in the united states for the treatment of intermediate or high-risk myelofibrosis (2011, trade name: Jakafi), including essential myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis (2014). Currently, ruxolitinib Jakavi has been approved worldwide in over 50 countries, including the european union, canada and some asia, latin america and south america. Meanwhile, the research on the aspect that the medicine can be used for treating the bald spots is further carried out as reported abroad recently, so that the research on the medicine has important significance.
The chemical structural formula of ruxolitinib is as follows:
currently, in terms of synthesis, there are several routes for preparing Ruxolitinib (Ruxolitinib):
the patent WO2007070514 (compound patent) reports a route:
the route is a ruxolitinib compound patent, and the greatest defect of the route is that a key intermediate 2 (the Sem-protected ruxolitinib) needs to be prepared by a chiral preparation column, so that the efficiency is low, the cost is too high, and the practical application value is low.
② patent WO2010083283A2 (preparative route patent) reports route 1:
the route takes cyclopentanal as an initial raw material to prepare the 3-cyclopentyl acrolein by a witting reaction, the (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropanal is obtained by asymmetric michael addition reaction with 4-bromopyrazole under the condition of chiral catalyst, then the (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropanal (ee value 85%) is obtained by three steps of reaction with ammonia water and iodine, the (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropanal is obtained by coupling with diboron pinacol ester, and then the obtained product is coupled with 4-chloropyrazolopyrimidine to obtain ruxolitinib. The biggest defects of the route are that the chiral induction reagent has large molecular weight, harsh preparation conditions and high preparation cost, and the asymmetric michael addition method has low selectivity and is not suitable for large-scale production.
③ patent WO2010083283a2 (preparative route patent) reports routes 2, 3:
the two routes mainly obtain the ee value of the related chiral intermediate by the addition of the alkyne intermediate michael and the asymmetric hydrogenation under the condition of the chiral catalyst, and the two routes have the biggest defects that the intermediate raw materials of the two alkynes are difficult to prepare and have high cost; the chiral catalyst used in hydrogenation is difficult to prepare, has quite high cost and is not suitable for industrial production.
Pat. WO2010083283a2 (preparative route patent) reports route 4:
according to the method, racemic (4-boronic acid pinacol ester-1H-pyrazole-1-yl) -3-cyclopentanepropanitrile is obtained through microhale addition, and then the (R) -3- (4-boronic acid pinacol ester-1H-pyrazole-1-yl) -3-cyclopentanepropanitrile is obtained through chiral column preparation, separation and purification.
Document Angew. chem. int. Ed.2015,54, 7149-:
the method takes cyclopentyl allene as a raw material to be added with 4-bromopyrazole under the catalysis of metal rhodium and chiral ligand to obtain a chiral intermediate with an ee value of 91 percent.
In order to overcome the defects of the prior art, a new method is developed, the limitation of the prior patent is broken through, and a new route which is easy to obtain raw materials, simple to operate, low in cost, strong in reaction scalability and suitable for industrial production is developed.
Disclosure of Invention
The invention aims to solve the technical problem of breaking through the existing synthetic method of ruxolitinib and provide a new synthetic route and a new intermediate of ruxolitinib and salt thereof suitable for industrial production.
In order to solve the technical problems, the invention adopts a technical scheme as follows:
a synthetic method of ruxolitinib (compound 12) and salts thereof adopts (R) -3- (4-boric acid-1H-pyrazol-1-yl) -3-cyclopentanepropanitrile (compound 9) and 6-halogen-5- (2-methoxyvinyl) pyrimidin-4-ylamine (in the compound, amine is amine substituted by amino protecting group, such as compound 10) as raw materials, firstly, the two are subjected to Suzuki coupling reaction to generate (3R) -cyclopentyl-3- [4- (5- (2-methoxyvinyl) pyrimidin-4-ylamine) pyrazol-1-yl ] propionitrile (such as compound 11), and then (3R) -cyclopentyl-3- [4- (5- (2-methoxyvinyl) pyrimidin-4-ylamine) pyrazol-1-yl ] propionitrile -yl ] propionitrile (e.g. compound 11) undergoes deprotection and ring closure to form ruxolitinib (compound 12). One reaction equation according to this method is as follows:
in the above compound 10, the Cl substituent may be replaced by other halogens such as Br, I, and the like; the boc group (t-butoxycarbonyl group) as the amino-protecting group may be replaced with other amino-protecting groups such as TMS (trimethylsilyl group), Tr (trityl group), TBS (t-butyldimethylsilyl group), etc.
According to the invention, 6-halo-5- (2-methoxyvinyl) pyrimidin-4-ylamine can be synthesized according to the following scheme (compound 10 is exemplified):
wherein: in the step (1), 4, 6-dihydroxypyrimidine reacts with formamide or substituted formamide (such as DMF) and trihalooxyphosphorus to generate 4, 6-dihalopyrimidine-5-carboxaldehyde, and further, formamide or substituted formamide is added dropwise into trihalooxyphosphorus at a lower temperature of 8 ℃ or below, the mixture is stirred for 0.5 to 2 hours, then 4, 6-dihydroxypyrimidine is added, the mixture is stirred for 0.5 to 1.5 hours, and the mixture is heated to reflux for reaction. In the step (2), 4, 6-dihalopyrimidine-5-carboxaldehyde and NH are reacted3The MeOH reaction produced 4-amino-6-halopyrimidine-5-carboxyformaldehyde. In the step (3), 4-amino-6-chloropyrimidine-5-carboxaldehyde reacts with (methoxymethyl) triphenyl-phosphonium chloride in a solvent to generate 6-halo-5- (2-methoxyvinyl) pyrimidin-4-ylamine; in the step (4), the 6-halo-5- (2-methoxyvinyl) pyrimidin-4-ylamine is subjected to the above-mentioned reactionReaction of the amino protecting group affords 6-halo-5- (2-methoxyvinyl) pyrimidin-4-ylamine. The above steps (1) to (4) can be carried out according to conventional embodiments and conditions known in the art.
Further, the Suzuki coupling reaction is carried out in a solvent in the presence of a base and an organometallic catalyst. Wherein, the base can be inorganic base or organic base, such as potassium carbonate, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, etc.; the solvent can be dioxane, toluene, THF, etc.; the organometallic catalyst can be tetrakis (triphenylphosphine) palladium (Pd (PPh)3)4) [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, and the like. When the conditions are adopted, the conversion rate of the reaction in the step can reach more than 95 percent, and after the reaction is finished, a crude product is obtained through simple post-treatment and can be directly put into the next reaction.
Further, the reaction for preparing ruxolitinib is divided into two processes: firstly, removing amino protecting groups from (3R) -cyclopentyl-3- [4- (5- (2-methoxy vinyl) pyrimidine-4-amine) pyrazol-1-yl ] propionitrile, and then carrying out ring closing reaction to generate ruxolitinib. These two processes can be carried out sequentially in one system. According to a preferred aspect of the invention, the process for the preparation of ruxolitinib is as follows: removing an amino protecting group from (3R) -cyclopentyl-3- [4- (5- (2-methoxyvinyl) pyrimidine-4-amine) pyrazol-1-yl ] propionitrile in a solvent under an acidic condition, heating to 50-100 ℃, and performing a ring closing reaction, wherein the solvent can be tetrahydrofuran, acetonitrile, DMF (dimethyl formamide), methanol, ethanol and the like, the acidic condition can be formed by adding hydrochloric acid and the like, and the reaction conversion rate in the step can reach over 90%.
The invention also provides a preparation method of ruxolitinib phosphate (compound 13), which comprises the following steps of firstly preparing ruxolitinib by the method, and then reacting the ruxolitinib phosphate with phosphoric acid:
further, after the reaction for preparing ruxolitinib is finished, a crude product is obtained through simple post-treatment, and the crude product is directly put into the next step for salt forming reaction. According to a specific and preferred aspect of the present invention, crude ruxolitinib is dissolved in a solvent such as isopropanol, ethanol, etc., then an organic solvent (isopropanol) solution of phosphoric acid is added dropwise thereto, stirred at room temperature, white solid is gradually precipitated, cooled, filtered, and dried to obtain ruxolitinib phosphate with purity higher than 99%.
The invention also provides a key intermediate of the JAK inhibitor, wherein the chemical name of the key intermediate is (R) -3- (4-boric acid-1H-pyrazol-1-yl) -3-cyclopentanepropanitrile, and the structure of the key intermediate is shown as the following formula 9:
preferably, the JAK inhibitor is ruxolitinib.
The present invention also provides a process for producing (R) -3- (4-boronic acid-1H-pyrazol-1-yl) -3-cyclopentanepropionitrile (compound 9), which comprises the step of reacting (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropionitrile (compound 8) with a grignard reagent and a boronic ester to produce (R) -3- (4-boronic acid-1H-pyrazol-1-yl) -3-cyclopentanepropionitrile (compound 9), according to the following reaction equation:
further, in the step of producing the compound 9, the grignard reagent used may be isopropyl magnesium chloride, tert-butyl magnesium chloride, ethyl magnesium chloride or the like, and a borate ester such as triisopropyl borate, trimethyl borate, triethyl borate or the like is usually carried out in a solvent, and here, a suitable solvent such as tetrahydrofuran, toluene or the like is used.
When the reaction is carried out, the compound 8 is dissolved in a solvent, nitrogen is used for protection, the temperature is reduced to a freezing temperature of below-10 ℃, the Grignard reagent is dripped, after the Grignard reagent is added, the temperature is increased to a proper temperature of below-5 to 5 ℃, the mixture is stirred and reacts for a period of time of 0.5 to 2 hours, then the temperature is controlled to be below-5 ℃, the dried boric acid ester is dripped, after the dripping is finished, the mixture reacts for a period of time of 1 to 2 hours at the temperature of between-5 and 5 ℃, and the reaction is finished. Wherein the reaction can be quenched by addition of a saturated ammonium chloride solution.
Further, the preparation method of the compound 9 further comprises the step of reacting (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentylpropionamide (compound 7) in an organic solvent under the action of a dehydrating agent such as phosphorus pentoxide, trichloroacetyl chloride/triethylamine, zinc chloride, ethyl dichlorophosphate/DBU and the like to produce the compound 8, wherein the reaction is preferably carried out at a temperature of 60 to 70 ℃, and the reaction equation is as follows:
further, the process for the preparation of said compound 9 further comprises the step of reacting (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentylpropionic acid (compound 6) with ammonia to give (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentylpropionamide (compound 7). This step of the reaction can be carried out by methods conventional in the art. As a specific and preferred aspect of the present invention, compound 6 is reacted with Carbonyldiimidazole (CDI) in a solvent, which may be, for example, tetrahydrofuran, etc., and then ammonia gas is introduced to carry out the reaction, preferably at room temperature. The reaction equation of this step is as follows:
further, the preparation method of the compound 9 further comprises a step of obtaining (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentylpropionic acid (compound 6) by resolving 3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentylpropionic acid (compound 5) with a chiral amine.
The preparation process can be illustrated by the following equation:
here, any chiral amine that can be used for chiral resolution can be used. In some embodiments, the chiral amine is selected from the optically active forms of the following amines: s-phenylethylamine, D-phenylglycinol, (1R,2S) -2-amino-1, 2-diphenylethanol, (R) -2-isopropylamino-2-phenylethanol, (1S,2R) -1-amino-2-indanol, (S) -1- (2-naphthyl) ethylamine, quinine, cinchonidine, cinchonine, brucine dihydrate, strychnine sulfate pentahydrate, ephedrine, morphine, leucamide, tyrosine hydrazine acetate, and the like. Preferably, the chiral amine is (1S,2R) -1-amino-2-indanol.
The step is implemented in three processes: firstly, different optical isomers of a compound 5 respectively react with chiral amine to generate products with different solubilities, and secondly, the two products are separated by utilizing the solubility difference of the two products; finally, acidolysis is carried out on a product formed by the reaction of (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropionic acid to obtain the (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropionic acid (compound 6). When the chiral amine is (1S,2R) -1-amino-2-indanol, the yield of the compound 6 in the step can reach more than 30%, and the optical purity of the obtained compound 6 is higher than 99%.
Further, the preparation method of the compound 9 also comprises the step of reacting the methyl 3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropionate (the compound 4) under the action of a base to generate the compound 5, wherein the reaction equation of the step is as follows:
specifically, the reaction is carried out in a solvent such as THF, methanol and ethanol, the alkali can be lithium hydroxide monohydrate, potassium hydroxide, sodium hydroxide and the like, and the reaction can be carried out at room temperature of about 20-30 ℃.
Further, the preparation method of the compound 9 further comprises the step of reacting 3-cyclopentyl methyl acrylate (compound 3) with 4-bromopyrazole in the presence of a base to form the compound 4, wherein the reaction equation of the step is as follows:
wherein: the base is preferably 1, 8-diazabicycloundecen-7-ene (DBU), and may also be potassium carbonate, cesium carbonate, and the like.
Further, the preparation method of the compound 9 further comprises a step of reacting cyclopentyl formaldehyde (compound 2), trimethyl phosphorylacetate and a base to prepare methyl 3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentylpropionate, wherein the reaction equation of the step is as follows:
further, the preparation method of the compound 9 further comprises a step of preparing cyclopentyl formaldehyde (compound 2) by taking halogenated cyclopentane and formamide or N-substituted formamide as raw materials. Preferably, the halo-cyclopentane is reacted with magnesium to produce the grignard reagent and then with the formamide or N-substituted formamide.
In the reaction, the halogenated cyclopentane can be iodocyclopentane, bromocyclopentane or chlorocyclopentane. When the halogenated cyclopentane is bromocyclopentane or chlorocyclopentane, it is also preferred to initiate the reaction with elemental iodine. The N-substituted formamide may be Dimethylformamide (DMF), Diethylformamide (DEF), etc.
According to a particular and preferred aspect of the present invention, the process for the preparation of cyclopentyl carbaldehyde (compound 2) is: reacting bromocyclopentane (compound 1) with magnesium in the presence of iodine, then dropping DMF at the temperature of below 10 ℃, stirring at room temperature after dropping, and reacting, wherein the equation is as follows:
according to a particular aspect of the invention, compound 9 is prepared using the following synthetic route:
the method and conditions for carrying out the reactions of the various steps of the scheme can be referred to previously.
Preferably, after the reaction in the previous step is finished, the crude product is obtained through simple post-treatment and then directly put into the next reaction.
The invention also provides a method for resolving 3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropionic acid into (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropionic acid by using a resolving agent, wherein the resolving agent is chiral amine.
Further, the resolution reagent is one or more of S-phenylethylamine, D-phenylglycinol, (1R,2S) -2-amino-1, 2-diphenylethanol, (R) -2-isopropylamino-2-phenylethanol, (1S,2R) -1-amino-2-indanol, (S) -1- (2-naphthyl) ethylamine, quinine, cinchonidine, cinchonine, cinchona alkaloid, brucine dihydrate, brucine sulfate pentahydrate, ephedrine, morphine, leucinamide and tyrosine hydrazine acetate. Preferably, the resolving agent is (1S,2R) -1-amino-2-indanol.
Further, 3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropionic acid is firstly reacted with a resolving agent, then a product system is crystallized, solid crystals are separated, and finally the solid crystals are subjected to acidolysis to obtain the (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropionic acid.
Due to the implementation of the technical scheme, compared with the prior art, the invention has the following advantages:
the invention provides a new route for preparing ruxolitinib, and each step of the route has high yield, high total reaction yield, good purity of the obtained product, simple post-treatment of the reaction and no need of column chromatography; by adopting the route, the required raw materials or the used catalyst and other substances are easy to obtain, and compared with the prior art, the method is more economic and more suitable for industrial production.
Drawings
FIG. 1 shows the NMR spectrum of the product obtained in example 8.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited to the following examples. Conditions not noted in the examples are conventional conditions.
Example 1: preparation of Cyclopentylcarboxaldehyde (Compound 2)
Weighing bromocyclopentane carboxylic acidDrying, dissolving a small amount of the dried product in 5 times of volume of anhydrous THF, adding magnesium chips (1eq), a catalytic amount of iodine simple substance, protecting with nitrogen, heating to about 40 ℃ to initiate reaction, controlling the temperature to be 30-40 ℃, dropwise adding bromocyclopentane, keeping the temperature, stirring for 1-2 h, controlling the temperature to be below 10 ℃, dropwise adding DMF (1.05eq), controlling the temperature to be below 10 ℃, stirring for 1h at room temperature and 30 ℃, adding 3 times of MTBE (methyl tert-butyl ether) in volume into the feed liquid, dropwise adding 3N dilute hydrochloric acid below 0 ℃ to adjust the pH to be 3-4, separating liquid, extracting the water layer twice with MTBE (3 times of volume each time) until the product is basically extracted, combining organic phases, washing twice with saturated saline, washing anhydrous Na twice with2SO4Drying, filtering, and concentrating under reduced pressure to dryness to obtain crude product cyclopentyl formaldehyde with yield of 90% -95%, which is directly used for the next reaction.
Example 2: preparation of methyl 3-cyclopentylacrylate (Compound 3)
Weighing potassium tert-butoxide (1.05eq), dissolving in 10 times volume of anhydrous THF, protecting with nitrogen, adding dropwise trimethyl phosphorylacetate (1.1eq) into the feed liquid at about 0 ℃, keeping the temperature at about 0 ℃, stirring for reaction for 2-3 h, weighing a plurality of cyclopentyl formaldehyde to prepare 2 times volume of anhydrous THF solution, adding dropwise into the feed liquid at about 0 ℃, heating to about 30 ℃ after completing dripping, stirring for reaction for 12-15h, and finishing the reaction. Adding 5 times volume of MTBE into the feed liquid for dilution, adding 10 times volume of water, separating liquid, back-extracting the water layer with 3 times volume of MTBE twice respectively, washing with saturated saline water twice, and adding anhydrous Na2SO4Drying, filtering, and concentrating under reduced pressure to obtain crude 3-cyclopentyl methyl acrylate with yield of 85-90%, which is directly used for the next reaction.
Example 3: preparation of methyl 3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentylpropionate (Compound 4)
Weighing a plurality of 3-cyclopentyl methyl acrylate, dissolving the 3-cyclopentyl methyl acrylate in acetonitrile with 5 times of volume, adding 4-bromopyrazole (1.1eq) and DBU (1.5eq) into the feed liquid, stirring the feed liquid at room temperature of 30 ℃ to react for about 12-16 h, and completely reacting the raw materials. Concentrating under reduced pressure to reduce the volume, adding 5 times of MTBE (methyl tert-butyl ether) volume into the feed liquid for dilution, washing with water, adjusting the pH value to 3-4 with 1N diluted hydrochloric acid, washing with water, washing with saturated saline water and anhydrous Na2SO4Drying, filtering, and concentrating under reduced pressure to obtain crude product of 3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropanoic acid methyl ester, wherein the yield is 90-95 percent and the crude product is directly usedAnd hydrolyzing in the next step.
Example 4: preparation of 3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentylpropionic acid (Compound 5)
Weighing a plurality of methyl 3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentylpropionate, dissolving in THF (tetrahydrofuran) with the volume being 6 times that of the solution, adding lithium hydroxide monohydrate (1.2eq)3 times of the solution in water, stirring the solution at room temperature of 30 ℃ for reaction for 1-2H, and completely reacting the raw materials. Diluting the feed liquid with 5 times of MTBE, adding 1N dilute hydrochloric acid into the feed liquid to adjust the pH of the feed liquid to 3-4, separating liquid, back-extracting a water layer twice with 3 times of MTBE, combining organic phases, washing with water, washing with saturated NaCl solution, and adding anhydrous Na2SO4Drying, filtering, decompressing and concentrating to obtain a crude product of the 3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropanoic acid, wherein the yield is 85-90 percent and the crude product is directly used for next resolution.
Example 5: preparation of (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropanoic acid (Compound 6)
Weighing a plurality of 3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropanoic acid, dissolving in 5 times volume of isopropanol, adding a 3 times volume of isopropanol solution of (1S,2R) -1-amino-2-indanol (0.9eq) into the feed liquid, stirring the feed liquid at room temperature for 12-15H, and filtering the solid. Recrystallizing the solid crude product by using isopropanol with the volume 5 times, slowly cooling and crystallizing feed liquid, filtering solid, drying and detecting that the optical purity is higher than 99%, the chemical purity is higher than 99%, and the yield is 30-35%.
Weighing a plurality of the dried solids, adding 4 times of MTBE, adding 1N diluted hydrochloric acid, adjusting the pH to about 3-4, separating liquid, and back-extracting the water layer with 3 times of MTBE. The organic phases were combined, washed with water, saturated brine and anhydrous Na2SO4Drying, filtering, decompressing and concentrating to obtain crude product (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropanoic acid, wherein the yield is 90-95 percent, and the HPLC purity is higher than 99 percent.
The nuclear magnetic data of the product of this step are as follows:1HNMR(CDCl3,400MHz):1.03～1.12(1H,m),1.16～1.27(1H,m),1.33～1.40(1H,m),1.41～1.70(4H,m),1.83～1.90(1H,m),2.33～2.44(1H,m),2.87(1H,dd,J＝16.0,4.0Hz),3.13(1H,dd,J＝16.0,12.0Hz,),4.21～4.26(1H,m),7.44(1H,s),7.48(1H,s).
example 6: preparation of (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropanoic acid (Compound 6)
Weighing a plurality of 3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropionic acid, dissolving in 5 times of isopropanol, adding 3 times of isopropanol solution of S-phenethylamine (0.9eq) into the feed liquid, stirring the feed liquid at room temperature for 12-15H, and filtering the solid. Recrystallizing the solid crude product by using isopropanol with the volume 5 times, slowly cooling and crystallizing feed liquid, filtering solid, drying and detecting that the optical purity is higher than 99%, the chemical purity is higher than 99%, and the yield is 10-15%.
Weighing a plurality of the dried solids, adding 4 times of MTBE, adding 1N diluted hydrochloric acid, adjusting the pH to about 3-4, separating liquid, and back-extracting the water layer with 3 times of MTBE. The organic phases were combined, washed with water, saturated brine and anhydrous Na2SO4Drying, filtering, decompressing and concentrating to obtain crude product (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropanoic acid, wherein the yield is 90-95 percent, and the HPLC purity is higher than 99 percent.
Example 7: preparation of (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropanoic acid (Compound 6)
Weighing a plurality of 3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentylpropionic acid, dissolving in 5 times of isopropanol, adding 5 times of isopropanol solution of quinine (0.9eq) into the feed liquid, stirring the feed liquid at room temperature for 12-15H, and filtering the solid. Recrystallizing the solid crude product by using 10 times volume of isopropanol, slowly cooling the feed liquid for crystallization, filtering the solid, recrystallizing the solid crude product by using 10 times volume of isopropanol again, slowly cooling the feed liquid for crystallization, filtering the solid, drying and detecting that the optical purity is higher than 99%, the chemical purity is higher than 99%, and the yield is 10-15%.
Weighing a plurality of the dried solids, adding 4 times of MTBE, adding 1N diluted hydrochloric acid, adjusting the pH to about 3-4, separating liquid, and back-extracting the water layer with 3 times of MTBE. The organic phases were combined, washed with water, saturated brine and anhydrous Na2SO4Drying, filtering, and concentrating under reduced pressure to obtain crude product (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropanoic acid, the yield is 90-95%, and the HPLC purity is higher than 99%.
Example 8: preparation of (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropanoic acid (Compound 6)
Weighing a plurality of 3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropionic acid, dissolving in 5-time volume of isopropanol, adding 5-time volume of isopropanol solution of cinchonidine (0.9eq) into the feed liquid, stirring the feed liquid at room temperature for 12-15H, and filtering the solid. Recrystallizing the solid crude product by using 10 times volume of isopropanol, slowly cooling the feed liquid for crystallization, filtering the solid, recrystallizing the solid crude product by using 10 times volume of isopropanol again, slowly cooling the feed liquid for crystallization, filtering the solid, drying and detecting that the optical purity is higher than 99%, the chemical purity is higher than 99%, and the yield is 5-10%.
Weighing a plurality of the dried solids, adding 4 times of MTBE, adding 1N diluted hydrochloric acid, adjusting the pH to about 3-4, separating liquid, and back-extracting the water layer with 3 times of MTBE. The organic phases were combined, washed with water, saturated brine and anhydrous Na2SO4Drying, filtering, decompressing and concentrating to obtain crude product (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropanoic acid, wherein the yield is 90-95 percent, and the HPLC purity is higher than 99 percent.
Example 9: preparation of (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanamide (Compound 7)
Weighing a plurality of (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropanoic acid, dissolving in 4 times of dry tetrahydrofuran, adding carbonyldiimidazole (3eq), reacting at room temperature for 3H under the protection of nitrogen, and completely reacting the raw materials. Introducing ammonia gas into the feed liquid for about 30 minutes, diluting the feed liquid by adding 4 times of MTBE (methyl tert-butyl ether) volume, adding 4 times of MTBE volume into the feed liquid, separating the feed liquid by adding 4 times of MTBE volume, back-extracting the water layer by using 3 times of MTBE volume, combining organic phases, washing by using water, washing by using saturated saline water, and washing by using anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure to obtain a crude product (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropionamide, and pulping with 10 times of volume of n-heptane to obtain a white solid, wherein the yield is 90-95%, and the HPLC (high performance liquid chromatography) is more than 98%.
The nuclear magnetic data of the obtained product are as follows:1HNMR(CDCl3,400MHz):1.03～1.13(1H,m),1.20～1.30(1H,m),1.33～1.41(1H,m),1.43～1.71(4H,m),1.79～1.87(1H,m),2.31～2.43(1H,m),2.68(1H,dd,J＝16.0,4.0Hz),2.94(1H,dd,J＝16.0,8.0Hz),4.26～4.32(1H,m),5.36(1H,brs),5.52(1H,brs),7.43(1H,s),7.74(1H,s)
example 10: preparation of (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanecarbonitrile (Compound 8)
Weighing a plurality of (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropionamide, dissolving in 4 times of dry tetrahydrofuran, adding phosphorus pentoxide (3eq), carrying out nitrogen protection, heating to 60-70 ℃, reacting for 1-2H, and completely reacting the raw materials. Diluting the feed liquid with 4 times volume of MTBE, adding 4 times volume of saturated sodium bicarbonate into the feed liquid, quenching, separating liquid, back extracting water layer with 3 times volume of MTBE, combining organic phase, washing with water, washing with saturated saline, and adding anhydrous Na2SO4Drying, filtering, decompressing and concentrating to obtain crude product (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropanitrile, wherein the yield is 90-95 percent and the crude product is directly used for the next reaction.
The nuclear magnetic data of the product of this step are as follows:1HNMR(CDCl3,400MHz):1.08～1.17(1H,m),1.18～1.27(1H,m),1.44～1.76(5H,m),1.87～194(1H,m),2.42～2.52(1H,m),2.86(1H,dd,J＝16.0,4.0Hz),3.02(1H,dd,J＝16.0,8.0Hz),4.08～4.14(1H,m),7.51(1H,s),7.52(1H,s).
example 11: preparation of (R) -3- (4-boronic acid-1H-pyrazol-1-yl) -3-cyclopentanecarbonitrile (Compound 9)
Weighing a plurality of (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropanonitrile, dissolving the raw materials in 4 times of dry tetrahydrofuran by volume, reducing the temperature of the raw materials to-15 ℃ under the protection of nitrogen, dropwise adding isopropyl magnesium chloride (1.15eq) into the raw materials, stirring the raw materials at-5 ℃ for reaction for 1H, controlling the temperature to be below-5 ℃, dropwise adding dry triisopropyl borate (1.05eq), reacting at-5 ℃ for 1-2H after dropwise adding, completely reacting, diluting the raw materials by adding 4 times of MTBE, adding 4 times of saturated ammonium chloride into the raw materials for quenching, separating, reversely extracting an aqueous layer by using 3 times of MTBE, combining an organic phase, washing by using water, washing by using saturated saline, drying by using anhydrous Na2SO4, filtering, and concentrating under reduced pressure to obtain a crude product (R) -3- (4-boronic acid-1H-pyrazol-1-yl) -3-one-carboxylic acid-one-phase The cyclopropanecarbonitrile and 10 times volume of n-heptane are pulped to obtain a white solid, the yield is 85-90 percent, and the HPLC is more than 98 percent.
The nuclear magnetic data of the product of this step are as follows:1HNMR(DMSO-d6,400MHz):1.02～1.12(1H,m),1.19～1.29(2H,m),1.36～1.61(4H,m),1.72～1.80(1H,m),2.26～2.37(1H,m),3.02～3.15(2H,m),4.36～4.42(1H,m),7.73(1H,s),7.76(2H,brs),7.92(1H,s).
example 12: preparation of 6-chloro-5- (2-methoxyvinyl) pyrimidin-4- (di-tert-butyloxycarbonyl) amine (i.e. compound 10)
The synthetic route is as follows:
the method comprises the following specific steps:
(1) weighing POCl3(4eq) is added into a reaction bottle, the mixture is cooled to about 0 ℃ under the protection of nitrogen, DMF (1.85eq) is added into the feed liquid, the temperature is controlled to be 0-8 ℃ when dropping, the feed liquid is stirred for 1h at 0-10 ℃, 4, 6-dihydroxypyrimidine is added into the feed liquid, the feed liquid is naturally heated to the room temperature after the addition, the stirring is carried out for 1h, then the temperature is raised to reflux, the stirring is carried out for 2h, the feed liquid is cooled, and the stirring is carried out overnight. Distilling the feed liquid under reduced pressure to remove excessive POCl3The residue was slowly added to ice water, the product (2 volumes by volume 3) was extracted with ethyl acetate, the organic phases were combined, washed with water (2 volumes), washed with saturated sodium bicarbonate solution (2 volumes), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give crude 4, 6-dichloropyrimidine-5-carboxaldehyde (yield: 70%) which was used directly in the next reaction.
(2) Weighing a plurality of 4, 6-dichloropyrimidine-5-carboxaldehydes, adding toluene to dissolve the 4, 6-dichloropyrimidine-5-carboxaldehyde (5 times of the volume), adding 7MNH into feed liquid3Heating the feed liquid to 60 ℃ in a MeOH solution (3eq), stirring for reaction for 1h, and adding NH3Stirring was continued for 1h with MeOH (1eq), TLC detection, and the starting material was essentially completely reacted. Cooling the feed liquid to room temperature, concentrating under reduced pressure to remove solvent, adding appropriate amount of H into the residue2O (3 times volume), stirring, extracting with ethyl acetate/n-butanol mixed solvent (V/V-2/1) (4 times volume 2), mixing organic phases, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain crude 4-amino-6-chloropyrimidine-5-carboxaldehyde (yield: 100%) And directly putting into the next reaction.
(3) Weighing (methoxymethyl) triphenyl-phosphonium chloride for a plurality of times (1.05eq), adding THF (30 times volume), stirring, cooling to-5 ℃ under the protection of nitrogen, adding t-BuOK (1.05eq), completely adding, stirring the feed liquid for 1h at 0 ℃. Adding 4-amino-6-chloropyrimidine-5-carboxaldehyde into the feed liquid in batches, naturally heating the feed liquid to room temperature after the addition is finished, stirring for reacting for 30 hours, detecting by TLC, and basically completely reacting the raw materials. Cooling the feed liquid to 0 ℃, adding saturated ammonium chloride liquid to quench reaction, adding concentrated hydrochloric acid into the feed liquid, adjusting the pH value to 1-2, extracting the feed liquid by using ethyl acetate (2 times volume of 2, removing impurities), adjusting the pH value of a water layer to 8-9 by using 6N NaOH liquid, extracting by using ethyl acetate (10 times volume of 3), combining organic phases, drying by using anhydrous sodium sulfate, filtering, decompressing and concentrating to obtain a crude product of 6-chloro-5- (2-methoxyvinyl) pyrimidin-4-ylamine (yield: 60%), and directly using the crude product in the next reaction.
(4) Weighing 6-chloro-5- (2-methoxyvinyl) pyrimidin-4-ylamine, adding ethyl acetate (15 times volume) and DMAP (0.2eq), stirring, and dropwise adding Boc into the feed liquid2And (3) adding O (2.2eq), heating the feed liquid to 45-50 ℃, stirring for reacting for 2 hours, detecting by TLC, and basically completely reacting the raw materials. Cooling the feed liquid to 0-5 ℃, washing with 1N HCl solution (5 times volume), washing with saturated sodium bicarbonate solution (5 times volume), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a crude product (E/Z ═ 5/1) of 6-chloro-5- (2-methoxyvinyl) pyrimidine-4- (di-tert-butyloxycarbonyl) amine, and recrystallizing the crude product with an ethyl acetate/heptane system to obtain 6-chloro-5- (2-methoxyvinyl) pyrimidine-4- (di-tert-butyloxycarbonyl) amine (E formula), namely a compound 10(yield: 60%) and an off-white solid.
Example 13: preparation of (3R) -cyclopentyl-3- [4- (5- (2-methoxyvinyl) pyrimidin-4-ylamine) pyrazol-1-yl ] propionitrile (Compound 11)
Weighing (R) -3- (4-boric acid-1H-pyrazol-1-yl) -3-cyclopentanepropanonitrile (1eq), 6-chloro-5- (2-methoxyvinyl) pyrimidine-4- (di-tert-butyloxycarbonyl) amine (1.03eq), potassium carbonate (3eq) and Pd (PPh3)4 (3% eq), adding into a reaction bottle, adding THF (10 times volume) and H2O (2 times volume) into the bottle, replacing the system with nitrogen for 3-4 times, heating the feed liquid to 50-60 ℃ under the protection of nitrogen, reacting for 12-15H, and basically completely reacting the raw materials. Adding ethyl acetate (10 times volume) and H2O (5 times volume) into the feed liquid, stirring, standing, separating, washing an organic phase H2O (3 times volume), drying the organic phase with anhydrous sodium sulfate, filtering (filling a proper amount of silica gel), concentrating the filtrate under reduced pressure to dryness to obtain a crude product (3R) -cyclopentyl-3- [4- (5- (2-methoxy vinyl) pyrimidin-4-ylamine) pyrazol-1-yl ] propionitrile (yield: 96 percent), and directly using the crude product in the next reaction.
Example 14: preparation of (3R) -cyclopentyl-3- [4- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) pyrazol-1-yl ] propionitrile (Compound 12, ruxolitinib)
Weighing the crude product (3R) -cyclopentyl-3- [4- (5- (2-methoxyvinyl) pyrimidin-4-ylamine) pyrazol-1-yl]Dissolving a plurality of propionitrile in THF (4 times volume), adding concentrated hydrochloric acid (2.2eq) into the THF, stirring the feed liquid at room temperature for 2-3 h, heating to reflux, stirring for reaction for 5h, detecting by TLC (thin layer chromatography), allowing the raw materials to react completely, cooling the feed liquid to room temperature, adding saturated NaHCO3Adjusting the pH of the solution to 8-9, adding ethyl acetate for extraction (10x), washing an organic phase by water (3 times volume), drying by anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain (3R) -cyclopentyl-3- [4- (7H-pyrrolo [2, 3-d ]]Pyrimidin-4-yl) pyrazol-1-yl]Crude propionitrile (yield: 90%).
Example 15: preparation of (3R) -cyclopentyl-3- [4- (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) pyrazol-1-yl ] propionitrile phosphate (i.e., ruxolitinib phosphate)
Weighing a plurality of crude (3R) -cyclopentyl-3- [4- (7H-pyrrolo [2, 3-d ] pyrimidine-4-yl) pyrazol-1-yl ] propionitrile products prepared by the method in the embodiment 10, dissolving the crude products in isopropanol (20 times volume), dropwise adding isopropanol phosphate solution (1.1eq), stirring the feed liquid at room temperature for 3 hours, gradually precipitating a large amount of white solid during the stirring, cooling the feed liquid to 5-10 ℃ in an ice bath, stirring for 0.5 hour, filtering, and drying to obtain white solid (3R) -cyclopentyl-3- [4- (7H-pyrrolo [2, 3-d ] pyrimidine-4-yl) pyrazol-1-yl ] propionitrile phosphate (yield: 90%) with the purity higher than 99%.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (16)
1. A preparation method of ruxolitinib or a salt thereof is characterized in that: the method adopts (R) -3- (4-boric acid-1H-pyrazol-1-yl) -3-cyclopentanepropanitrile as a preparation intermediate;
the preparation method specifically comprises the following steps: the method comprises the following steps of adopting (R) -3- (4-boric acid-1H-pyrazol-1-yl) -3-cyclopentylpropionitrile and 6-halogen-5- (2-methoxy vinyl) pyrimidin-4-ylamine as raw materials, firstly carrying out Suzuki coupling reaction on the raw materials to generate (3R) -cyclopentyl-3- [4- (5- (2-methoxy vinyl) pyrimidin-4-ylamine) pyrazol-1-yl ] propionitrile, and then carrying out deprotection and ring closure reaction on the (3R) -cyclopentyl-3- [4- (5- (2-methoxy vinyl) pyrimidin-4-ylamine) pyrazol-1-yl ] propionitrile to generate ruxolitinib; in the 6-halogen-5- (2-methoxy vinyl) pyrimidine-4-amine, amine is amine substituted by amino protecting group;
wherein the preparation method further comprises the step of reacting the compound 8 with a Grignard reagent and a borate to produce (R) -3- (4-boronic acid-1H-pyrazol-1-yl) -3-cyclopentanepropanitrile represented by the compound 9, which has the following reaction equation:
2. the process for the preparation of ruxolitinib, or salt thereof, of claim 1, wherein: the adopted Grignard reagent is one or more of isopropyl magnesium chloride, tert-butyl magnesium chloride and ethyl magnesium chloride; the borate is one or more of triisopropyl borate, trimethyl borate and triethyl borate.
3. The process for the preparation of ruxolitinib, or salt thereof, of claim 1, wherein: dissolving (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropanitrile in a solvent, reducing the temperature to be below-10 ℃ under the protection of nitrogen, dropwise adding a Grignard reagent, heating to-5 ℃ after adding, stirring for reacting for 0.5-2H, then controlling the temperature to be below-5 ℃, dropwise adding a dried boric acid ester, reacting for 1-2H at the temperature of-5 ℃ after finishing dropping, and finishing the reaction.
4. The process for the preparation of ruxolitinib, or salt thereof, of claim 1, wherein: the preparation method also comprises the step of reacting (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropionamide (compound 7) in an organic solvent under the action of a dehydrating agent to generate (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropanitrile (compound 8), wherein the reaction equation is as follows:
5. the process for the preparation of ruxolitinib, or salt thereof, of claim 4, wherein: in the reaction for generating the (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropanitrile, the dehydrating agent is selected from phosphorus pentoxide, trichloroacetyl chloride/triethylamine, zinc chloride and ethyl dichlorophosphate/DBU, and the reaction is carried out at the temperature of 60-70 ℃.
6. The process for the preparation of ruxolitinib, or salt thereof, of claim 4, wherein: the preparation method also comprises the steps of reacting (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropionic acid (compound 6) with Carbonyldiimidazole (CDI) in a solvent, and then introducing ammonia gas to react to obtain (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropionamide (compound 7), wherein the reaction equation is as follows:
7. the process for the preparation of ruxolitinib, or salt thereof, of claim 6, wherein: the preparation method also comprises the step of obtaining (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropionic acid by resolving 3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropionic acid by using chiral amine.
8. The process for the preparation of ruxolitinib, or salt thereof, of claim 7, wherein: the chiral amine is selected from S-phenylethylamine, D-phenylglycinol, (1R,2S) -2-amino-1, 2-diphenylethanol, (R) -2-isopropylamino-2-phenylethanol, (1S,2R) -1-amino-2-indanol, (S) -1- (2-naphthyl) ethylamine, quinine, cinchonidine, cinchonine, brucine dihydrate, brucine sulfate pentahydrate, ephedrine, morphine, leucamide and tyrosine hydrazine acetate.
9. The process for the preparation of ruxolitinib, or salt thereof, according to claim 7 or 8, characterized in that: firstly, 3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropionic acid reacts with chiral amine, then a product system is crystallized, solid crystals are separated, and finally the solid crystals are subjected to acidolysis to obtain the (R) -3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropionic acid.
10. The process for the preparation of ruxolitinib, or salt thereof, of claim 7, wherein: the preparation method also comprises the step of reacting the methyl 3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropionate (compound 4) under the action of alkali to generate the 3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropionic acid (compound 5), wherein the reaction equation is as follows:
11. the process for the preparation of ruxolitinib, or salt thereof, of claim 10, wherein: in the reaction for preparing 3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentanepropionic acid, the base is selected from lithium hydroxide monohydrate, sodium hydroxide and potassium hydroxide, and the reaction is carried out at room temperature.
12. The process for the preparation of ruxolitinib, or salt thereof, of claim 10, wherein: the preparation method also comprises the step of reacting the methyl 3-cyclopentyl acrylate (compound 3) with 4-bromopyrazole in the presence of a base to generate the methyl 3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentyl propionate (compound 4), wherein the reaction equation is as follows:
13. a process for the preparation of ruxolitinib, or salt thereof, as claimed in claim 12, wherein: the base is selected from 1, 8-diazabicycloundecen-7-ene, potassium carbonate, cesium carbonate.
14. A process for the preparation of ruxolitinib, or salt thereof, as claimed in claim 12, wherein: the preparation method further comprises the step of reacting cyclopentyl formaldehyde (compound 2), trimethyl phosphoryl acetate and base to prepare methyl 3- (4-bromo-1H-pyrazol-1-yl) -3-cyclopentylpropionate (compound 3), wherein the reaction equation is as follows:
15. the process for the preparation of ruxolitinib, or salt thereof, of claim 14, wherein: the preparation method also comprises the step of preparing cyclopentyl formaldehyde (compound 2) by taking halogenated cyclopentane and formamide or N-substituted formamide as raw materials, wherein halogenated cyclopentane and magnesium react to prepare a Grignard reagent, and then the Grignard reagent reacts with formamide or N-substituted formamide.
16. A process for the preparation of ruxolitinib, or salt thereof, as claimed in claim 15, wherein: when preparing the cyclopentyl formaldehyde, the bromocyclopentane (compound 1) reacts with magnesium in the presence of iodine, then Dimethylformamide (DMF) is dripped at the temperature of below 10 ℃, and the reaction is stirred at room temperature after the dripping is finished, wherein the reaction equation is as follows:
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