CN111471045A - Preparation method of tofacitinib impurity - Google Patents
Preparation method of tofacitinib impurity Download PDFInfo
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- CN111471045A CN111471045A CN202010319099.7A CN202010319099A CN111471045A CN 111471045 A CN111471045 A CN 111471045A CN 202010319099 A CN202010319099 A CN 202010319099A CN 111471045 A CN111471045 A CN 111471045A
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Abstract
The invention provides a preparation method of tofacitinib impurities, and relates to the field of medicine synthesis and medicine quality research. The method comprises the following steps: dissolving N-methyl-N- ((3R, 4R) -4-methylpiperidine-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-amine dihydrochloride in a first organic solvent, catalyzing by an acid-binding agent to react with methyl 3-chloro-3-oxopropanoate to obtain methyl 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoate, dissolving the methyl 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoate in a second organic solvent, adding an alkaline reagent, and adjusting the pH to be acidic to obtain tof; tofacitinib impurity is 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoic acid; the method is simple, and has high yield and purity.
Description
Technical Field
The invention relates to the field of medicine synthesis and medicine quality research, in particular to a preparation method of tofacitinib impurities, and particularly relates to a preparation method of related substances of tofacitinib (chemical name: N-methyl-N- [ (3R, 4R) -1-cyanoacetyl-4-methylpiperidine-3-yl ] -7-H-pyrrolo [2,3-d ] pyrimidine-4-amine).
Background
Tofacitinib (Tofacitinib), with the chemical name of N-methyl-N- [ (3R, 4R) -1-cyanoacetyl-4-methylpiperidin-3-yl ] -7-H-pyrrolo [2,3-d ] pyrimidin-4-amine, is an oral anti-rheumatoid arthritis inhibitor developed by Pfrizer, and Citrate (Tofacitinib Citrate) thereof has passed phase iii clinical trials, is approved by the united states Food and Drug Administration (FDA) to be on the market at 11/6 th of 2012, is approved by the japanese pharmaceutical and medical instruments complex (PMDA) at 3/25 th of 2013/2013, and is approved by the european pharmaceutical quality management office (EDQM) at 22 rd of 3/22 th of 2017.
At present, the preparation process of tofacitinib adopts a strategy that N-methyl-N- ((3R, 4R) -4-methylpiperidine-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-amine dihydrochloride (or free alkali) is prepared firstly, and then N-cyanoacetylation reaction on a pyridine ring is carried out to obtain a finished product.
During the preparation of tofacitinib, acidic or basic reagents are inevitably used, with the risk of hydrolysis of the cyano group to the compound of formula (I). According to the research data of the stability of the raw material medicine, the tofacitinib citrate is slowly degraded in the storage process, so that the content of the compound shown in the formula (I) is gradually increased.
The Chinese patent with the publication number of 109336892A discloses a method for preparing a compound shown in the formula (I) by directly hydrolyzing tofacitinib. However, since the cyano group is hydrolyzed into an amide and an acid during the hydrolysis, and the amide bond is easily hydrolyzed during the reaction, the yield of the compound represented by formula (I) obtained according to the synthesis method thereof is low. How to simply and effectively obtain the compound shown in the formula (I) with high purity is a technical problem to be solved.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a preparation method of tofacitinib impurity.
In order to achieve the above object of the present invention, the present invention provides the following technical solutions: a preparation method of tofacitinib impurities comprises the following steps:
A. dissolving N-methyl-N- ((3R, 4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine dihydrochloride in a first organic solvent, reacting with methyl 3-chloro-3-oxopropanoate in the presence of an acid-binding agent to obtain methyl 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoate, stopping the reaction and purifying;
B. dissolving the obtained methyl 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) piperidine-1-yl) -3-oxopropanoate in a second organic solvent, adding an alkaline reagent for hydrolysis reaction, and adjusting the pH of a reaction solution to acidity to obtain tofacitinib impurities;
the tofacitinib impurity comprises 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoic acid, the structure of which is shown in (I):
the synthetic scheme is shown in figure 1.
The structure of the N-methyl-N- ((3R, 4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-amine dihydrochloride is shown as (II); the structure of the methyl 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) piperidine-1-yl) -3-oxopropanoate is shown in (III).
Preferably, the step a specifically includes the following steps: dissolving N-methyl-N- ((3R, 4R) -4-methylpiperidine-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-amine dihydrochloride into a first organic solvent by stirring, adding an acid-binding agent, cooling to 0-5 ℃, dropwise adding 3-chloro-3-oxopropanoic acid methyl ester, naturally heating to 20-30 ℃ for reaction after dropwise adding, cooling to 0-5 ℃ after the reaction is finished, and adding water to quench the reaction; and the purification comprises the steps of dropwise adding dilute hydrochloric acid to adjust the pH value to 5-6, separating liquid, washing an organic phase with saturated sodium bicarbonate and saturated salt water in sequence, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, and purifying by flash column chromatography to obtain the purified methyl 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropionate.
Preferably, the ratio of the dosage of the first organic solvent in the step A to the dosage of the N-methyl-N- ((3R, 4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine dihydrochloride is 5-20 m L/g, wherein the first organic solvent comprises one or more of tetrahydrofuran, acetonitrile and dichloromethane;
more preferably, the first organic solvent is preferably dichloromethane, and the ratio of the amount of the first organic solvent to the amount of the N-methyl-N- ((3R, 4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine dihydrochloride is 10m L/g.
Preferably, the amount of the acid-binding agent in the step A is 3-7 equivalents; the acid-binding agent comprises one or more of triethylamine, diisopropylethylamine and diethylamine; the equivalent weight of the acid-binding agent is the molar weight of the acid-binding agent divided by the molar weight of N-methyl-N- ((3R, 4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine dihydrochloride in the step A;
more preferably, the acid scavenger is triethylamine, and the amount of the acid scavenger used is preferably 4 equivalents.
Preferably, the addition amount of the methyl 3-chloro-3-oxopropionate is 1.2 to 2.0 equivalents; 3-chloro-3-oxopropanoic acid methyl ester equivalent weight is the molar amount of methyl 3-chloro-3-oxopropanoate divided by the molar amount of N-methyl-N- ((3R, 4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine dihydrochloride in step A
More preferably, the amount of methyl 3-chloro-3-oxopropionate added is 1.5 equivalents.
Preferably, the step B specifically includes the following steps: stirring and dissolving the obtained methyl 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) piperidine-1-yl) -3-oxopropanoate in a second organic solvent, cooling to 0-5 ℃, dropwise adding an alkaline reagent at 0-10 ℃ for reaction, cooling to 0-5 ℃ after the reaction is finished, and adjusting the pH value to 3-7 to obtain the tofacitinib impurity.
More preferably, the pH value of the reaction solution is adjusted to 5-6 in the step B.
Preferably, the ratio of the using amount of the second organic solvent in the step B to the using amount of the methyl 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoate is 5-15 m L/g, and the second organic solvent comprises one or more of methanol, ethanol, dichloromethane, tetrahydrofuran and acetonitrile;
more preferably, the second organic solvent is methanol, and the ratio of the amount of the second organic solvent to the amount of the methyl 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoate is 5m L/g.
Preferably, the alkaline reagent in the step B comprises one of a sodium hydroxide aqueous solution, a lithium hydroxide aqueous solution and a potassium hydroxide aqueous solution, and the concentration of the alkaline reagent is 0.2-1 mol/L;
more preferably, the alkali agent is an aqueous solution of sodium hydroxide having a concentration of 0.5 mol/L.
Preferably, the amount of the alkaline reagent used in the step B is 10 to 20 times of the mass of the methyl 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoate;
more preferably, the alkaline agent is used in an amount of 15 times the mass of the methyl 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoate.
Preferably, step B is followed by a concentration and purification step, wherein the concentration and purification step specifically comprises: the reaction solution of 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoic acid was lyophilized, ethanol and acetonitrile were added, slurried, filtered, and the filtrate was concentrated to dryness.
In summary, compared with the prior art, the invention has the following beneficial effects:
(1) the preparation method provided by the invention has the advantages of simple synthesis process of tofacitinib impurities, easy separation and purification of products, high yield and the like; the compound shown in the formula (I) obtained by the preparation method can be used as an impurity reference substance and applied to the quality research of tofacitinib raw material medicaments and preparations;
(2) the method solves the problems that in the hydrolysis process of the method for preparing the tofacitinib impurity by directly hydrolyzing tofacitinib, cyano can be hydrolyzed into amide and acid, and meanwhile, amide bond is easy to hydrolyze in the reaction process, so that the yield of the tofacitinib impurity is low.
Drawings
Other features, objects and advantages of the invention will become more apparent upon reading of the detailed description of non-limiting embodiments with reference to the following drawings:
FIG. 1 is a scheme showing the synthesis of tofacitinib impurity in example 1;
FIG. 2 is a detection spectrum of HP L C, a compound represented by the formula (III) in example 1;
FIG. 3 is a CMS detection spectrum of compound L represented by formula (III) in example 1;
FIG. 4 is a HNMR detection spectrum of compound 1 represented by formula (III) in example 1;
FIG. 5 is a detection spectrum of HP L C, a compound of formula (I) in example 1;
FIG. 6 is a CMS detection spectrum of compound L of formula (I) in example 1;
FIG. 7 is the HNMR detection spectrum of compound 1 shown in formula (I) in example 1.
Detailed Description
The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention. The present invention will be described in detail with reference to the following specific examples:
first, evaluation and test
As shown in fig. 1:
wherein: m is1Is the weight of the compound of formula (II); m is2Is the weight of the compound of formula (III); 318.28 is the molecular weight of the compound of formula (II); 345.40 is the molecular weight of the compound of formula (III);
wherein: m is2Is the weight of the compound of formula (III); m3Is the weight of the compound of formula (I); 345.40 is the molecular weight of the compound of formula (III); 331.37 is the molecular weight of the compound of formula (I);
example 1:
a method of preparing tofacitinib impurities, said impurities comprising 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoic acid. The synthetic scheme is shown in figure 1; the method comprises the following specific steps:
as shown in fig. 1: the compound shown in the following formula (III) is methyl 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) piperidine-1-yl) -3-oxopropionate; the compound shown in the following formula (II) is N-methyl-N- ((3R, 4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-amine dihydrochloride; the compound shown in the following formula (I) is 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) piperidine-1-yl) -3-oxo propionic acid.
A. Preparing a compound shown as a formula (III);
adding 9.5g (29.8mmol) of a compound shown as a formula (II) into 95m L dichloromethane, adding 12.1g (119.4mmol) of triethylamine, stirring, cooling to 0-5 ℃, dropwise adding 6.5g (47.8mmol) of methyl 3-chloro-3-oxopropionate dichloromethane (10m L) solution, naturally heating to 20-30 ℃, cooling to 0-5 ℃ after the reaction is finished, adding 5m L water to quench the reaction, dropwise adding 2N diluted hydrochloric acid to adjust the pH value to 5-6, separating liquid, washing an organic phase with saturated sodium bicarbonate and saturated salt water in sequence, drying the organic phase with a proper amount of anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, and quickly purifying to obtain 3.9g of a compound shown as a formula (III), wherein the yield is 38%, and the purity of HP L C is 99.1%.
MS-ESI(m/z)：346[M+H]+；
1HNMR(400MHz，DMSO-d6)：11.65(s，1H)、8.11(d，J＝4.0Hz，1H)、7.14-7.15 (m，1H)、6.56(s，1H)、4.87(s，1H)、3.69-3.91(m，2H)，3.60-3.67(m， 3H)、3.46-3.57(m，2H)、3.25-3.32(m，5H)、2.37-2.39(m，1H)、1.79-1.82 (m，1H)、1.57-1.62(m，1H)、1.02(t，J＝8.0Hz，3H)；
B. Preparation of Compounds of formula (I)
Adding 2.2g (6.39mmol) of the compound shown in the formula (III) into 11m L methanol, stirring, cooling to 0-5 ℃, dropwise adding 0.5 mol/L sodium hydroxide aqueous solution 30m L, reacting at 0-10 ℃, cooling to 0-5 ℃ after the reaction is finished, dropwise adding dilute hydrochloric acid to adjust the pH value to 5-6, freeze-drying the reaction solution, adding 20m L ethanol and 20 acetonitrile, pulping, filtering, and concentrating the filtrate to dryness to obtain 1.61g of the compound shown in the formula (I), wherein the yield is 76%, and the purity of HP L C is 98.4%.
MS-ESI(m/z)：332[M+H]+；
1HNMR(400MHz，DMSO-d6)：11.72(s，1H)、8.12(d，J＝8.0Hz，1H)、7.14-7.16 (m，1H)、6.57(s，1H)、4.85(s，1H)、、3.46-3.52(m，3H)、3.24-3.28 (m，5H)、2.37-2.38(m，1H)、1.80-1.81(m，1H)、1.56-1.61(m，1H)、 1.01(t，J＝4.0Hz，3H)。
Example 2:
a method of preparing tofacitinib impurities, said impurities comprising 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoic acid. The synthetic scheme is shown in figure 1; the method comprises the following specific steps:
as shown in fig. 1: the compound shown in the following formula (III) is methyl 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) piperidine-1-yl) -3-oxopropionate; the compound shown in the following formula (II) is N-methyl-N- ((3R, 4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-amine dihydrochloride; the compound shown in the following formula (I) is 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) piperidine-1-yl) -3-oxo propionic acid.
A. Preparing a compound shown as a formula (III);
adding 1g (3.1mmol) of the compound shown in the formula (II) into 5m L dichloromethane, adding 1.11g (11.0mmol) of triethylamine, stirring, cooling to 0-5 ℃, dropwise adding 0.5g (3.8mmol) of methyl 3-chloro-3-oxopropionate solution in 2m L, naturally heating to 20-30 ℃, cooling to 0-5 ℃ after the reaction is finished, adding 2m L water to quench the reaction, dropwise adding dilute hydrochloric acid to adjust the pH value to 5-6, separating liquid, washing the organic phase with saturated sodium bicarbonate and saturated salt water in sequence, drying the organic phase with a proper amount of anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, and purifying to obtain 380mg of the compound shown in the formula (III), wherein the yield is 35%.
B. Preparing a compound shown as a formula (I);
adding 350mg (1.0mmol) of the compound shown in the formula (III) into 2m L methanol, stirring, cooling to 0-5 ℃, dropwise adding 0.5 mol/L aqueous sodium hydroxide solution 3.5m L, reacting at 0-10 ℃, cooling to 0-5 ℃ after reaction, dropwise adding dilute hydrochloric acid to adjust the pH value to 3.0, freeze-drying the reaction solution, adding 5m L ethanol and 5 acetonitrile, pulping, filtering, and concentrating the filtrate to dryness to obtain 238mg of the compound shown in the formula (I), wherein the yield is 71%.
Example 3:
a method of preparing tofacitinib impurities, said impurities comprising 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoic acid. The synthetic scheme is shown in figure 1; the method comprises the following specific steps:
as shown in fig. 1: the compound shown in the following formula (III) is methyl 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) piperidine-1-yl) -3-oxopropionate; the compound shown in the following formula (II) is N-methyl-N- ((3R, 4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-amine dihydrochloride; the compound shown in the following formula (I) is 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) piperidine-1-yl) -3-oxo propionic acid.
A. Preparing a compound shown as a formula (III);
adding 1g (3.1mmol) of the compound shown in the formula (II) into 20m L dichloromethane, adding 2.22g (22.0mmol) of triethylamine, stirring, cooling to 0-5 ℃, dropwise adding 857mg (6.3mmol) of dichloromethane (3m L) solution, naturally heating to 20-30 ℃, cooling to 0-5 ℃ after the reaction is finished, adding 2m L water for quenching reaction, dropwise adding dilute hydrochloric acid to adjust the pH value to 5-6, separating liquid, washing the organic phase with saturated sodium bicarbonate and saturated salt water in sequence, drying the organic phase with a proper amount of anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, and purifying to obtain 346mg of the compound shown in the formula (III), wherein the yield is 32%.
B. Preparing a compound shown as a formula (I);
adding 300mg (0.87mmol) of the compound shown in the formula (III) into 2m L methanol, stirring, cooling to 0-5 ℃, dropwise adding 0.5 mol/L aqueous sodium hydroxide solution 6.0m L, reacting at 0-10 ℃, cooling to 0-5 ℃ after the reaction is finished, dropwise adding dilute hydrochloric acid to adjust the pH value to 5-6, freeze-drying the reaction solution, adding 5m L ethanol and 5 acetonitrile, pulping, filtering, and concentrating the filtrate to dryness to obtain 201mg of the compound shown in the formula (I), wherein the yield is 70%.
Example 4:
a method of preparing tofacitinib impurities, said impurities comprising 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoic acid. The synthetic scheme is shown in figure 1; the method comprises the following specific steps:
as shown in fig. 1: the compound shown in the following formula (III) is methyl 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) piperidine-1-yl) -3-oxopropionate; the compound shown in the following formula (II) is N-methyl-N- ((3R, 4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-amine dihydrochloride; the compound shown in the following formula (I) is 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) piperidine-1-yl) -3-oxo propionic acid.
A. Preparing a compound shown as a formula (III);
adding 1g (3.1mmol) of a compound shown as a formula (II) into 10m L tetrahydrofuran, adding 1.6g (12.6mmol) of diisopropylethylamine, stirring, cooling to 0-5 ℃, dropwise adding 0.63g (4.7mmol) of tetrahydrofuran (3m L) solution of methyl 3-chloro-3-oxopropionate, naturally heating to 20-30 ℃, cooling to 0-5 ℃ after the reaction is finished, adding 2m L water to quench the reaction, dropwise adding 2N diluted hydrochloric acid to adjust the pH value to 5-6, separating liquid, sequentially washing an organic phase with saturated sodium bicarbonate and saturated salt water, drying the organic phase with a proper amount of anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, and quickly performing column chromatography purification to obtain 417mg of the compound shown as a formula (III), wherein the yield is 39%.
B. Preparing a compound shown as a formula (I);
adding 400mg (1.2mmol) of the compound shown in the formula (III) into 2m L methanol, stirring, cooling to 0-5 ℃, dropwise adding 0.5 mol/L lithium hydroxide aqueous solution 6m L, reacting at 0-10 ℃, cooling to 0-5 ℃ after reaction, dropwise adding dilute hydrochloric acid to adjust the pH value to 5-6, freeze-drying the reaction solution, adding 5m L ethanol and 5m L acetonitrile, pulping, filtering, and concentrating the filtrate to dryness to obtain 295mg of the compound shown in the formula (I), wherein the yield is 77%.
Example 5:
a method of preparing tofacitinib impurities, said impurities comprising 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoic acid. The synthetic scheme is shown in figure 1; the method comprises the following specific steps:
as shown in fig. 1: the compound shown in the following formula (III) is methyl 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) piperidine-1-yl) -3-oxopropionate; the compound shown in the following formula (II) is N-methyl-N- ((3R, 4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-amine dihydrochloride; the compound shown in the following formula (I) is 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) piperidine-1-yl) -3-oxo propionic acid.
A. Preparing a compound shown as a formula (III);
adding 1g (3.1mmol) of a compound shown as a formula (II) into 10m L acetonitrile, adding 0.92g (12.5mmol) of diethylamine, stirring, cooling to 0-5 ℃, dropwise adding 0.63g (4.7mmol) of methyl 3-chloro-3-oxopropionate solution of acetonitrile (3m L), naturally heating to 20-30 ℃ after dropwise adding, cooling to 0-5 ℃ after reaction, adding 2m L water for quenching reaction, dropwise adding 2N diluted hydrochloric acid to adjust the pH value to 5-6, separating liquid, washing an organic phase with saturated sodium bicarbonate and saturated salt water in sequence, drying the organic phase with a proper amount of anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, and quickly performing column chromatography purification to obtain 391mg of the compound shown as a formula (III), wherein the yield is 36%.
B. Preparing a compound shown as a formula (I);
adding 380mg (1.1mmol) of the compound shown in the formula (III) into 2m L methanol, stirring, cooling to 0-5 ℃, dropwise adding 0.5 mol/L potassium hydroxide aqueous solution 6m L, reacting at 0-10 ℃, cooling to 0-5 ℃ after reaction, dropwise adding dilute hydrochloric acid to adjust the pH value to 5-6, freeze-drying the reaction solution, adding 5m L ethanol and 5m L acetonitrile, pulping, filtering, and concentrating the filtrate to dryness to obtain 274mg of the compound shown in the formula (I), wherein the yield is 75%.
The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes or modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention. The embodiments and features of the embodiments of the present application may be combined with each other arbitrarily without conflict.
Claims (10)
1. A preparation method of tofacitinib impurities is characterized by comprising the following steps:
A. dissolving N-methyl-N- ((3R, 4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine dihydrochloride in a first organic solvent, reacting with methyl 3-chloro-3-oxopropanoate in the presence of an acid-binding agent to obtain methyl 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoate, stopping the reaction and purifying;
B. dissolving the obtained methyl 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) piperidine-1-yl) -3-oxopropanoate in a second organic solvent, adding an alkaline reagent for hydrolysis reaction, and adjusting the pH of a reaction solution to acidity to obtain tofacitinib impurities;
the tofacitinib impurity comprises 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoic acid, the structure of which is shown in (I):
2. the method for preparing tofacitinib impurity according to claim 1, wherein the step A specifically comprises the following steps: dissolving N-methyl-N- ((3R, 4R) -4-methylpiperidine-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-amine dihydrochloride into a first organic solvent by stirring, adding an acid-binding agent, cooling to 0-5 ℃, dropwise adding 3-chloro-3-oxopropanoic acid methyl ester, naturally heating to 20-30 ℃ for reaction after dropwise adding, cooling to 0-5 ℃ after the reaction is finished, and adding water to quench the reaction; and the purification comprises the steps of dropwise adding dilute hydrochloric acid to adjust the pH value to 5-6, separating liquid, washing an organic phase with saturated sodium bicarbonate and saturated salt water in sequence, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, and purifying by flash column chromatography to obtain the purified methyl 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropionate.
3. The preparation method of tofacitinib impurity as claimed in claim 1 or 2, characterized in that the ratio of the first organic solvent to the N-methyl-N- ((3R, 4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine dihydrochloride in step A is 5-20 m L/g, and the first organic solvent comprises one or more of tetrahydrofuran, acetonitrile and dichloromethane.
4. The method for preparing tofacitinib impurities according to claim 1 or 2, wherein the acid-binding agent is used in an amount of 3-7 equivalents in step A; the acid-binding agent comprises one or more of triethylamine, diisopropylethylamine and diethylamine.
5. The method for preparing tofacitinib impurity as claimed in claim 1 or 2, wherein the amount of methyl 3-chloro-3-oxopropanoate added is 1.2-2.0 equivalents.
6. The method for preparing tofacitinib impurity according to claim 1, wherein the step B comprises the following steps: stirring and dissolving the obtained methyl 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino) piperidine-1-yl) -3-oxopropanoate in a second organic solvent, cooling to 0-5 ℃, dropwise adding an alkaline reagent at 0-10 ℃ for reaction, cooling to 0-5 ℃ after the reaction is finished, and adjusting the pH value to 3-7 to obtain the tofacitinib impurity.
7. The method for preparing tofacitinib impurity according to claim 1 or 6, wherein the ratio of the amount of the second organic solvent to the amount of the methyl 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoate in step B is 5-15 m L/g, and the second organic solvent comprises one or more of methanol, ethanol, dichloromethane, tetrahydrofuran and acetonitrile.
8. The method for preparing tofacitinib impurities as claimed in claim 1 or 6, wherein the alkaline reagent in step B comprises one of sodium hydroxide aqueous solution, lithium hydroxide aqueous solution and potassium hydroxide aqueous solution, and the concentration of the alkaline reagent is 0.2-1 mol/L.
9. The process for preparing tofacitinib impurity according to claim 1 or 6, wherein the amount of the alkaline reagent used in step B is 10 to 20 times the mass of the methyl 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoate.
10. The method for preparing tofacitinib impurity according to claim 1, wherein the step B is followed by a step of concentration and purification, wherein the concentration and purification specifically comprises the following steps: the reaction solution of 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanoic acid was lyophilized, ethanol and acetonitrile were added, slurried, filtered, and the filtrate was concentrated to dryness.
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| CHRISTOPHER L. CIOFFI ET AL.: ""Design, Synthesis, and Evaluation of Nonretinoid Retinol Binding Protein 4 Antagonists for the Potential Treatment of Atrophic Age-Related Macular Degeneration and Stargardt Disease"", 《J. MED. CHEM》 * |
| MARKO JUKIC ET AL.: ""Linker-switch approach towards new ATP binding site inhibitors of DNA gyrase B"", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
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