CN108997199B - Synthesis method of tofacitinib intermediate (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine - Google Patents
Synthesis method of tofacitinib intermediate (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine Download PDFInfo
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- CN108997199B CN108997199B CN201810917629.0A CN201810917629A CN108997199B CN 108997199 B CN108997199 B CN 108997199B CN 201810917629 A CN201810917629 A CN 201810917629A CN 108997199 B CN108997199 B CN 108997199B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/07—Optical isomers
Abstract
The invention discloses a synthetic method of a tofacitinib intermediate (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine, which comprises the steps of reacting 3-chlorobutanal (II) serving as a raw material with sodium cyanide, then carrying out Leuckart-Wallach reaction and Thorpe-Ziegler reaction, then reacting with 30% methylamine methanol solution to generate enamine, and carrying out asymmetric catalytic hydrogenation reaction to obtain a final product (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine (I). In the synthesis method, the compound VI is synthesized by adopting a Thorpe-Ziegler reaction, the yield is high, the final product does not need to be subjected to chiral resolution due to asymmetric catalytic hydrogenation, the total yield and the purity are high, and the byproducts are few.
Description
Technical Field
The invention belongs to the technical field of medicine preparation, and relates to a synthetic method of tofacitinib intermediate (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine.
Background
(3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine is an intermediate for preparing tofacitinib citrate (tofacitinib citrate), and the chemical structural formula is as follows:
tofacitinib citrate is 3- [ (3R,4R) -4-methyl-3- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino ] piperidin-1-yl ] -3-oxopropanenitrile citrate, a drug developed by the pharmaceutical company Perey USA for treating rheumatoid arthritis, and is sold under the trade name Xeljanz. Xeljanz can be used as monotherapy or in combination with methotrexate or other abiotic disease modifying antirheumatic drugs (DMARDs). The drug should not be used in combination with a biological DMARD or a strong immunosuppressive agent (e.g., azathioprine and cyclosporine).
On day 11/6 of 2012, the united states Food and Drug Administration (FDA) and the company pfeire declared that tofacitinib citrate is approved for use in adult patients with moderate to severe active Rheumatoid Arthritis (RA) who respond insufficiently or intolerant to methotrexate treatment. Rheumatoid arthritis is a chronic disease with a very long disease course and great pain, causes great harm to physical and psychological health of patients, is a chronic systemic disease mainly comprising inflammatory synovitis with unknown etiology, and is characterized in that multiple joints, symmetrical and invasive arthritides of hands and small joints are often accompanied by positive serum rheumatoid factors of extra-articular organs, can cause joint deformity and function loss, is accompanied by damages of extra-articular organs such as pulmonary interstitial disease, peripheral nerve damage and the like, and is one of the most common rheumatic diseases. Most patients with RA are positive for serum rheumatoid factor and anti-CCP antibody, and RA can cause joint deformation and loss of function.
Unlike most other RA therapeutics that act mainly on extracellular targets, Tofacitinib acts on the core of cytokine networks with intracellular signal transduction pathways as targets. The inhibition strength of Tofacitinib on JAK3 is 5-100 times that of JAK1 and JAK2, and Tofacitinib is an initial drug for developing and treating rheumatoid arthritis.
At present, the synthetic routes of tofacitinib intermediates reported in related documents include the following:
1) the synthetic route reported in patent CN 106831538A is as follows:
1-benzyl-4-methyl-1, 2,3, 6-tetrahydropyridine is used as an initial raw material, alkylene is oxidized into ketone, imine is formed with amine, the imine is asymmetrically reduced to form amine, trans-isomer is removed through recrystallization to obtain cis-isomer, and finally chiral resolution is performed to obtain a final product (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride. The method not only uses the expensive reducing agent lithium tri-sec-butyl borohydride and the raw material, but also reduces the final yield after the reaction is resolved.
2) D.H.Brown et al, org.Proc.Res.Dev.2003,7, page 115-120, disclose the preparation of 3-amino groups by reductive amination of keto C using methylamine as reagent-piperidine structural unit D. The combination of tetrahydropyridine A is subjected to a hydroboration/oxidation process, with the use of an excess of expensive SO3And (3) carrying out pyridine compound, and oxidizing the obtained compound B by using the tosylate of the piperidinol to obtain ketone C. The whole process comprises dangerous reagents such as a hydroboration reagent and a strong oxidant, and brings safety risks to large-scale production.
3) The synthetic route reported in patent WO2010123919a2 is as follows:
according to the patent, 3-amino-4-methylpyridine is used as a raw material, and is subjected to amine ester exchange reaction to form pyridinium salt with benzyl bromide, wherein the pyridinium salt is firstly reduced by sodium borohydride, then reduced into a piperidine ring by platinum oxide, and then reduced by lithium aluminum hydride to obtain a final product. The method not only uses a more expensive metal reducing agent, but also uses lithium aluminum hydride, thereby undoubtedly increasing the safety risk in large-scale industrial production. The method does not mention chiral synthesis, and the final result produces four isomers, so that the optical reaction purity is reduced, and the final reaction yield is also reduced.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a synthetic method of a tofacitinib intermediate (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine, which has the advantages of easily obtained starting raw materials and simple process route, adopts 3-chlorobutanal (II) as a raw material to react with sodium cyanide, then carries out Leuckart-Wallach reaction and Thorpe-Ziegler reaction, then reacts with 30% methylamine methanol solution to generate enamine, and finally obtains the final product (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine (I) through asymmetric catalytic hydrogenation reaction. In the synthesis method, the compound VI is synthesized by adopting a Thorpe-Ziegler reaction, the yield is high, the final product does not need to be subjected to chiral resolution due to asymmetric catalytic hydrogenation, the total yield and the purity are high, and the byproducts are few.
The synthetic route of the invention is as follows:
a synthetic method of tofacitinib intermediate (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine comprises the following steps:
a. 3-chlorobutyraldehyde (II) and sodium cyanide react to synthesize a compound III;
b. the compound III and the compound IV have Leuckart-Wallach reaction under the action of formic acid to synthesize a compound V;
c. carrying out Thorpe-Ziegler reaction on the compound V under a strong alkali condition, and then hydrolyzing and decarboxylating to synthesize a compound VI;
d. reacting the compound VI with 30% methylamine methanol solution to generate a compound VII;
e. carrying out asymmetric catalytic hydrogenation reaction on a compound VII under the conditions of a metal catalyst and a ligand to synthesize (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine (I);
wherein the molar ratio of the 3-chlorobutyraldehyde (II) used in the step a to sodium cyanide is 1: 1-1.1; the reaction solvent is ethanol and water; the reaction temperature is 70-80 ℃; the reaction time is 2-3 h.
The molar ratio of the Leuckart-Wallach reaction compound III, the compound IV and formic acid used in the step b is 1: 1.0-1.1: 1.1-1.5; the reaction solvent is ethanol; the reaction time is 8-12 h.
The strong base used in the step c is sodium ethoxide; the molar ratio of the compound V to the strong base is 1: 1.05-1.5; the reaction solvent is ethanol.
The molar ratio of the compound VI to the 30 percent methylamine methanol solution used in the step d is 1: 1.5; the catalyst is acetic acid, and the pH value is 4-5; the reaction time is 12-16 hours.
The metal catalyst used in step e is bis (acetoxy) ruthenium [ Ru (OAc)2]The ligand is R- (+) -1,1 '-binaphthyl-2, 2' -diphenylphosphine [ (R) -BINAP)](ii) a The molar ratio of the compound VII, the metal catalyst and the ligand is 1: 0.001-0.004: 0.002-0.008; the pressure of the hydrogen is 2.0-3.5 Mpa, and the preferable pressure is 3.0 Mpa; the reaction solvent is N, N-dimethylformamide or isopropanol.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention discloses a method for synthesizing tofacitinib intermediate (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine hydrochloride, wherein 1-benzyl-4-methylpiperidine-3-one is synthesized by utilizing a Thorpe-Ziegler reaction in step c, compared with a synthetic route reported in patent CN 106831538A, the reaction overcomes the defects that expensive initial raw materials are used in the past, and the Thorpe-Ziegler reaction is an effective method for synthesizing cyclic ketone, and has simple operation and high yield.
(2) In the reaction process, the step d is used for synthesizing the 1-benzyl-N, 4-dimethyl-1, 2,5, 6-tetrahydropyridine-3-amine (VII) by controlling the pH value of the reaction and selecting a methylamine solution solvent, so that the resolution of a final product of the reaction is avoided.
(3) In the reaction process, step e adopts an asymmetric catalytic hydrogenation technology, chiral separation is not needed, the reaction route is shortened, and the problem of low total yield of the traditional product in the prior art is solved.
(4) The invention solves the problem of low yield of split products in the prior art, has convenient preparation, no need of splitting in reaction, high total yield and purity of reaction and few byproducts.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited thereto.
Example 1
Synthesis of Compound III
In a 250ml three-necked flask, 10.65g of 3-chlorobutanal (II) and 4.9g of sodium cyanide, 50ml of ethanol and water (V) were added in this orderEthanol:VWater (W)1:1), stirring and heating to 70-80 ℃, reacting for 2-3 h, after the reaction is finished, evaporating solvent ethanol, extracting with ethyl acetate, standing for layering, separating an organic phase, washing with water, drying with anhydrous sodium sulfate, filtering, and evaporating ethyl acetate under reduced pressure to obtain 9.12g of a compound III, wherein the yield is 94.3%, and the HPLC purity is 98.76%.
Example 2
Synthesis of Compound III
3-Chlorobutanal (II) was added to a 250ml three-necked flask in this order)10.65g and sodium cyanide 5.39g, 50ml ethanol and water (V)Ethanol:VWater (W)1:1), stirring and heating to 70-80 ℃, reacting for 2-3 h, after the reaction is finished, evaporating solvent ethanol, extracting with ethyl acetate, standing for layering, separating an organic phase, washing with water, drying with anhydrous sodium sulfate, filtering, and evaporating ethyl acetate under reduced pressure to obtain 9.32g of a compound III, wherein the yield is 96.7%, and the HPLC purity is 98.21%.
Example 3
Synthesis of Compound V
13.9g of 2- (benzylamino) acetonitrile (IV), 9.2g of 2-methyl-4-oxobutyronitrile (III), 4.6g of formic acid and 60ml of ethanol are sequentially added into a 250ml three-neck flask, the mixture is stirred, the temperature is raised to reflux, the mixture reacts for 10 hours, after the reaction is finished, alkali is used for neutralization to weak alkalinity, a solvent is evaporated, chloroform and water are added for extraction, organic phases are combined, anhydrous sodium sulfate is used for drying, filtration is carried out, the solvent chloroform is evaporated, and then a compound V19.37g, the yield is 89.7 percent, and the HPLC purity is 98.33 percent.
Example 4
Synthesis of Compound V
13.2g of 2- (benzylamino) acetonitrile (IV), 9.6g of 2-methyl-4-oxobutyronitrile (III), 6.2g of formic acid and 60ml of ethanol are sequentially added into a 250ml three-necked flask, the mixture is stirred, the temperature is raised to reflux, the mixture reacts for 12 hours, after the reaction is finished, alkali is used for neutralization to weak alkalinity, a solvent is evaporated, chloroform and water are added for extraction, organic phases are combined, dried by anhydrous sodium sulfate, filtered, and the solvent chloroform is evaporated under reduced pressure to obtain 18.51g of a compound V, the yield is 90.5%, and the HPLC purity is 98.88%.
Example 5
Synthesis of Compound V
13.2g of 2- (benzylamino) acetonitrile (IV), 9.6g of 2-methyl-4-oxobutyronitrile (III), 20.7g of formic acid and 60ml of ethanol are sequentially added into a 250ml three-necked flask, the mixture is stirred, the temperature is raised to 100 ℃, the reaction is carried out for 11 hours, after the reaction is finished, alkali is used for neutralization to weak alkalinity, a solvent is evaporated, chloroform and water are added for extraction, organic phases are combined, anhydrous sodium sulfate is used for drying, filtration is carried out, the solvent chloroform is evaporated, and the compound V14.36 g is obtained, the yield is 70.2%, and the HPLC purity is 95.31%.
Example 6
Synthesis of Compound VI
Adding 19.32g of compound V, 6.07g of sodium ethoxide and 60ml of ethanol into a 250ml three-necked flask in sequence, heating to reflux and stirring for reaction for 3h, cooling to room temperature after the reaction is finished, adjusting the pH value to 3-4 with hydrochloric acid, heating to continue reflux and reaction for 4h, evaporating solvent ethanol after the reaction is finished, extracting with ethyl acetate, separating an organic phase, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain 16.5g of colorless liquid, wherein the yield is 95.5% and the HPLC purity is 98.34%.
Example 7
Synthesis of Compound VI
Adding 18.63g of compound V, 8.2g of sodium ethoxide and 60ml of ethanol into a 250ml three-necked flask in sequence, heating to reflux and stirring for reaction for 3 hours, cooling to room temperature, adjusting the pH value to 3-4 with hydrochloric acid, heating to continue reflux and reaction for 3-4 hours, evaporating solvent ethanol after the reaction is finished, extracting with ethyl acetate, separating an organic phase, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain 115.4g of colorless liquid, wherein the yield is 92.1% and the HPLC purity is 97.21%.
Example 8
Synthesis of Compound VI
Adding 18.63g of compound V, 4.64g of sodium methoxide and 60ml of ethanol into a 250ml three-necked flask in sequence, stirring and heating to reflux, reacting for 3 hours, cooling to room temperature after the reaction is finished, adjusting the pH value to 3-4 with hydrochloric acid, heating to continue reflux and reacting for 3-4 hours, evaporating solvent ethanol after the reaction is finished, extracting with ethyl acetate, separating out an organic phase, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain 11.86g of colorless liquid, wherein the yield is 71.2%, and the HPLC purity is 95.37%.
Example 9
Synthesis of Compound VII
Weighing 16.2g of compound VI and 12.4g of 30% methylamine methanol solution, adding into a three-necked flask, adjusting the pH value to 4-5 by using dry glacial acetic acid, reacting at the room temperature of 25-30 ℃ for about 12 hours under the protection of nitrogen, tracking by TLC to complete the reaction, evaporating the solvent to dryness to obtain 16.35g of compound VII, wherein the yield is 94.5%, and the HPLC purity is 97.22%.
Example 10
Synthesis of Compound VII
Weighing 16.2g of compound VI and 12.4g of 30% methylamine methanol solution, adding into a three-necked flask, adjusting the pH value to 2-3 by using dry glacial acetic acid, reacting at the room temperature of 25-30 ℃ for about 16 hours under the protection of nitrogen, tracking by TLC to complete the reaction, evaporating the solvent to dryness to obtain 11.8g of compound VII, wherein the yield is 68.3%, and the HPLC purity is 95.69%.
Example 11
Synthesis of Compound VII
Weighing 16.2g of compound VI and 12.4g of 30% methylamine ethanol solution, adding into a three-necked flask, adjusting the pH value to 4-5 by using dry glacial acetic acid, reacting at the room temperature of 25-30 ℃ for about 14 hours under the protection of nitrogen, tracking by TLC to complete the reaction, evaporating the solvent to dryness to obtain 12.11g of compound VII, wherein the yield is 70.4%, and the HPLC purity is 95.33%.
Example 12
Synthesis of Compound I
In a 250ml three-necked flask, 15.8g of the compound VII, 27.9mg of Ru (OAc) were added2And 0.27g of (R) -BINAP dissolved in 50ml of N, N-dimethylformamide, replacing nitrogen and hydrogen sequentially for three times, introducing hydrogen for three times, stirring and reacting at 20-25 ℃ for 12h, performing suction filtration, evaporating the solvent, and concentrating to obtain 15.3g of a compound I, wherein the yield is 96.1%, the HPLC purity is 98.89%, and the ee value is 98%.
Example 13
Synthesis of Compound I
In a 250ml three-necked flask, 15.1g of the compound VII, 53.4mg of Ru (OAc) were added2And 0.34g of (R) -BINAP, dissolving in 50ml of isopropanol, sequentially replacing nitrogen for three times and hydrogen for three times, introducing hydrogen for 2.5MPa, stirring and reacting at 20-25 ℃ for 12 hours, performing suction filtration, evaporating the solvent, and concentrating to obtain 14.46g of a compound I (0.066mol, molecular weight 218.28), wherein the yield is 94.7%, the HPLC purity is 96.21%, and the ee value is 97%.
Example 14
Synthesis of Compound I
In a 250ml three-necked flask, 15.57g of the compound VII, 27.51mg of Ru (OAc)2And 0.87g of (R) -BINAP dissolved in 50ml of dichloromethane solution, replacing nitrogen and hydrogen sequentially for three times, introducing hydrogen for 2.0MPa, stirring and reacting at 20-25 ℃ for 12 hours, filtering, and evaporating the solventConcentration gave 11.35g of compound I, 73.4% yield, 92.97% HPLC purity, and 90% ee.
Example 15
Synthesis of Compound I
In a 250ml three-necked flask, 15.35g of the compound VII, 81.4mg of Ru (OAc) were added2And 44mg of (R) -BINAP dissolved in 50ml of N, N-dimethylformamide, replacing nitrogen three times and hydrogen three times in sequence, introducing hydrogen 3.0MPa, stirring and reacting at 20-25 ℃ for 12 hours, performing suction filtration, evaporating the solvent, and concentrating to obtain a compound I10.25 g, wherein the yield is 67.3%, the HPLC purity is 91.31%, and the ee value is 84%.
Claims (9)
1. A synthetic method of tofacitinib intermediate (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine is characterized by comprising the following steps:
a. 3-chlorobutyraldehyde (II) and sodium cyanide react to synthesize a compound III;
b. the compound III and the compound IV have Leuckart-Wallach reaction under the action of formic acid to synthesize a compound V;
c. carrying out Thorpe-Ziegler reaction on the compound V under a strong alkali condition, and then hydrolyzing and decarboxylating to synthesize a compound VI;
d. reacting the compound VI with 30% methylamine methanol solution to synthesize a compound VII;
e. carrying out asymmetric catalytic hydrogenation reaction on a compound VII under the conditions of a metal catalyst and a ligand to synthesize (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine (I), wherein the metal catalyst is bis (acetoxy) ruthenium, the ligand is R- (+) -1,1 '-binaphthyl-2, 2' -diphenylphosphine, and the molar ratio of the compound VII, the metal catalyst and the ligand is 1: 0.001-0.004: 0.002-0.008;
the synthetic route is as follows:
2. the method according to claim 1, wherein the molar ratio of the 3-chlorobutyraldehyde (II) to sodium cyanide in the step a is 1: 1-1.1, and the reaction solvent is ethanol and water.
3. The method according to claim 1, wherein the molar ratio of the compound III to the compound IV to the formic acid in the Leuckart-Wallach reaction in the step b is 1:1.0 to 1.1:1.1 to 1.5, and the reaction solvent is ethanol.
4. The method of claim 1, wherein the strong base of step c is sodium ethoxide.
5. The method of claim 1, wherein the molar ratio of the compound V to the strong base in the step c is 1: 1.05-1.5, and the reaction solvent is ethanol.
6. The method of claim 1, wherein the compound VI and 30% methylamine methanol solution in step d are in a molar ratio of 1: 1.5.
7. The process of claim 1, wherein the catalyst used in step d is acetic acid, and the pH is 4-5.
8. The method of claim 1, wherein the pressure of the hydrogen gas in step e is 2.0 to 3.5 Mpa.
9. The process of claim 1, wherein the reaction solvent used in step e is N, N-dimethylformamide or isopropanol.
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