CN105348287A - Novel synthesis process of tofacitinib citrate - Google Patents
Novel synthesis process of tofacitinib citrate Download PDFInfo
- Publication number
- CN105348287A CN105348287A CN201510856276.4A CN201510856276A CN105348287A CN 105348287 A CN105348287 A CN 105348287A CN 201510856276 A CN201510856276 A CN 201510856276A CN 105348287 A CN105348287 A CN 105348287A
- Authority
- CN
- China
- Prior art keywords
- tofacitinib citrate
- reaction
- ethanol
- synthesis process
- crude product
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 CC(C)CCN(C**)C(C)=O Chemical compound CC(C)CCN(C**)C(C)=O 0.000 description 1
- LJIXXEMQKBMXRY-UHFFFAOYSA-N CNC(C(C=[I]N1)=C1N=C)=N Chemical compound CNC(C(C=[I]N1)=C1N=C)=N LJIXXEMQKBMXRY-UHFFFAOYSA-N 0.000 description 1
- VJIPQTUCRMUBAN-HTRCEHHLSA-N C[C@H](CC(N1OCCC=N)=O)[C@H]1O Chemical compound C[C@H](CC(N1OCCC=N)=O)[C@H]1O VJIPQTUCRMUBAN-HTRCEHHLSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a novel synthesis process of tofacitinib citrate, which comprises the following steps of 1: mixing the initial raw materials-1, 10% palladium carbon, anhydrous methanol and ammonium formate in a reaction vessel, and reacting to obtain an intermediate-1; step 2, dissolving the intermediate-1 prepared in the step 1 in absolute ethyl alcohol, adding an initial raw material-2, and reacting at a reaction temperature of 20-50 ℃; after the reaction is finished, purifying the reaction solution to obtain an intermediate-2 crude product; refining the intermediate-2 crude product to obtain an intermediate-2 refined product; step 3, heating, refluxing and dissolving the refined intermediate-2 product obtained in the step 2 by using absolute ethyl alcohol, dropwise adding a citric acid aqueous solution, and continuously reacting at 50-90 ℃; then slowly cooling to 20-45 ℃, stirring and crystallizing; filtering the crystals, washing the crystals with ethanol, and drying the crystals at 40-60 ℃ under reduced pressure to obtain a white tofacitinib citrate crude product. The chemical synthesis method has more reasonable route and more mild reaction conditions.
Description
Technical Field
The invention relates to a medicine, in particular to a novel synthesis process of tofacitinib citrate.
Background
Tofacitinib citrate compound patent WO2001/042246, filed 2000.10.23, discloses a synthetic route as follows:
compound patent WO2001/042246, filing date: 2000.10.23
Synthetic route of tofacitinib citrate
The compound has the advantages of stable process, easily obtained raw materials and low reagent price. However, the synthesis of the starting material-1 (the first reaction step) takes a long time and the yield is low. Therefore, a new synthesis process of tofacitinib citrate with high yield and suitable for industrial production needs to be found.
Disclosure of Invention
The invention aims to solve the technical problem of providing a novel synthesis process of tofacitinib citrate. The synthesis process simplifies the operation, improves the yield of the final product, and is a novel synthesis process of tofacitinib citrate suitable for industrial production.
The technical scheme adopted by the invention for solving the technical problems is as follows:
a novel synthesis process of tofacitinib citrate comprises the following steps:
step 1, mixing the following raw materials: mixing the initial raw materials-1, 10% palladium carbon, anhydrous methanol and ammonium formate in a reaction vessel, and reacting to obtain an intermediate-1; the starting material-1 is N-methyl-N- ((3R, 4R) -4-methyl-1-benzyl-3-piperidyl) -7H-pyrrolo [2, 3-d ] pyrimidine-4-amine.
Step 2, dissolving the intermediate-1 prepared in the step 1 in absolute ethyl alcohol, adding an initial raw material-2, and reacting at a reaction temperature of 20-50 ℃; after the reaction is finished, purifying the reaction solution to obtain an intermediate-2 crude product; refining the intermediate-2 crude product to obtain an intermediate-2 refined product; the starting material-2 is cyanoacetic acid N-hydroxysuccinimide ester;
step 3, heating, refluxing and dissolving the refined intermediate-2 product obtained in the step 2 by using absolute ethyl alcohol, dropwise adding a citric acid aqueous solution, and continuously reacting at 50-90 ℃; then slowly cooling to 20-45 ℃, stirring and crystallizing; filtering the crystals, washing the crystals with ethanol, and drying the crystals at 40-60 ℃ under reduced pressure to obtain a white tofacitinib citrate crude product.
Further, in the step 1, the 4 raw materials are added in a certain order. Further, in the step 1, adding the initial raw material-1 and 10% palladium carbon into a reaction vessel, adding anhydrous methanol, stirring and dispersing, and adding ammonium formate; mixing; heating to reflux, reacting for a period of time to obtain an intermediate-1. Further, the reaction time in the step 1 is 1-24 hours. Further, the reaction time in the step 1 is 1-10 hours. Further, the reaction time in the step 1 is 1-5 hours. Further, the reaction time in step 1 is 1, 2, 3, 4, or 5 hours.
Further, in the step 1, the raw materials are added according to a certain feeding ratio. Further, the starting material-1: the feeding mass ratio of the 10% palladium-carbon is 1: 0.1-0.5; the starting material-1: the feeding molar ratio of the ammonium formate is 1: 1 to 5.
Further, the starting material-1: the feeding mass ratio of the 10% palladium-carbon is 1: 0.1-0.3; the starting material-1: the feeding molar ratio of the ammonium formate is 1: 1.
further, the starting material-1: the feeding mass ratio of the 10% palladium-carbon is 1: 0.3-0.5; the starting material-1: the feeding molar ratio of the ammonium formate is 1: 1.
further, the starting material-1: the feeding mass ratio of the 10% palladium-carbon is 1: 0.3; the starting material-1: the feeding molar ratio of the ammonium formate is 1: 4.
further, in the step 2, the reaction temperature is 20-30 ℃, 30-40 ℃ or 40-50 ℃.
Further, in the step 2, the reaction temperature is 20-30 ℃, and specifically can be 20-25 ℃ or 25-30 ℃. Specifically, in the step 2, the reaction temperature may be 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 ℃.
Further, in the step 2, the reaction temperature is 30-40 ℃, and specifically can be 20-25 ℃ or 25-30 ℃. Specifically, in the step 2, the reaction temperature may be 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 ℃.
Further, in the step 2, the reaction temperature is 40-50 ℃, and specifically can be 20-25 ℃ or 25-30 ℃. Specifically, in the step 2, the reaction temperature may be 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 ℃.
Further, in the step 2, the intermediate-1: the feeding molar ratio of the starting material-2 is 1: 1 to 1.3. Further, the intermediate-1: the feeding molar ratio of the starting material-2 is 1: 1 to 1.2. Further, the intermediate-1: the feeding molar ratio of the starting material-2 is 1: 1 to 1.1.
Further, in the step 2, the specific steps of the purification are as follows: and (3) concentrating the reaction liquid after the reaction in the step (2) under reduced pressure until no solvent is evaporated, dissolving the residue with dichloromethane, washing with a sodium hydroxide solution and saturated saline solution in sequence, drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a foamy solid, namely the intermediate-2 crude product.
Further, in the step 2, the purification step of the crude intermediate-2 is as follows: dissolving the intermediate-2 crude product in dichloromethane, loading the column chromatography silica gel into a column, loading a sample on the silica gel column by a wet method, and standing; eluting with ethyl acetate, and detecting by TLC; collecting eluate, and concentrating to obtain refined intermediate-2.
Further, in the step 2, in the step of purifying the crude intermediate-2, the ratio of the intermediate-2: the mass ratio of column chromatography silica gel is 1: 5 to 15. Further, in the purification step of the crude intermediate-2, the intermediate-2: the mass ratio of column chromatography silica gel is 1: 5 to 10. Further, in the purification step of the crude intermediate-2, the intermediate-2: the mass ratio of column chromatography silica gel is 1: 5.
further, in the step 2, the purity of the intermediate-2 in the intermediate-2 refined product obtained by refining the intermediate-2 crude product is 90% -98%.
Further, in the step 3, the concentration of citric acid in the dropwise added citric acid aqueous solution is 0.3-0.5 g/ml. Further, the concentration of citric acid in the dropwise added citric acid aqueous solution is 0.3-0.4 g/ml. Further, the concentration of citric acid in the dropwise added citric acid aqueous solution is 0.4-0.5 g/ml.
In one embodiment, the novel synthesis process of tofacitinib citrate further comprises a step 4, wherein the tofacitinib citrate crude product prepared in the step 3 is heated to 50-90 ℃ by using a solvent to be dissolved and cleared, and is continuously stirred for 1-10 hours at 50-90 ℃; then slowly cooling to 25-50 ℃, stirring and crystallizing for 6-24 hours; filtering the crystal, washing the crystal with ethanol, and drying the crystal at 40-60 ℃ under reduced pressure to obtain a white tofacitinib citrate finished product. And 4, the solvent is at least one of water solutions with the mass concentration of 30-49% and formed by ethanol, isopropanol or n-butanol. Further, the solvent in the step 4 is at least one of water solutions with the mass concentration of 30-35% and formed by ethanol, isopropanol or n-butanol. Further, the solvent in the step 4 is at least one of 35-40% aqueous solution formed by ethanol, isopropanol or n-butanol. Further, the solvent in the step 4 is at least one of water solutions with the mass concentration of 40-49% and formed by ethanol, isopropanol or n-butanol.
Further, the solvent in step 4 is an aqueous solution with a mass concentration of 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, or 49% formed by ethanol.
Further, the solvent in step 4 is an aqueous solution with a mass concentration of 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, or 49% formed by isopropanol.
Further, the solvent in the step 4 is an aqueous solution with a mass concentration of 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, or 49% formed by n-butanol.
Further, the step 4 is that the tofacitinib citrate crude product prepared in the step 3 is heated to 85-90 ℃ by using a solvent to be dissolved and clear, and is continuously stirred for 1-10 hours at 85-90 ℃; then slowly cooling to 25-35 ℃, stirring and crystallizing for 6-24 hours; filtering the crystal, washing the crystal with ethanol, and drying the crystal at 25-35 ℃ under reduced pressure to obtain a white tofacitinib citrate finished product.
Further, the step 4 is that the tofacitinib citrate crude product prepared in the step 3 is heated to 80-90 ℃ by using a solvent to be dissolved and clear, and is continuously stirred for 1-10 hours at 80-90 ℃; then slowly cooling to 36-50 ℃, stirring and crystallizing for 6-24 hours; filtering the crystal, washing the crystal with ethanol, and drying the crystal at 36-50 ℃ under reduced pressure to obtain a white tofacitinib citrate finished product.
Further, the step 4 is that the tofacitinib citrate crude product prepared in the step 3 is heated to 70-79 ℃ by using a solvent to be dissolved and cleared, and is continuously stirred for 1-10 hours at 70-79 ℃; then slowly cooling to 25-35 ℃, stirring and crystallizing for 6-24 hours; filtering the crystal, washing the crystal with ethanol, and drying the crystal at 25-35 ℃ under reduced pressure to obtain a white tofacitinib citrate finished product.
Further, the step 4 is that the tofacitinib citrate crude product prepared in the step 3 is heated to 60-69 ℃ by using a solvent to be dissolved and clear, and is continuously stirred for 1-10 hours at the temperature of 60-69 ℃; then slowly cooling to 25-35 ℃, stirring and crystallizing for 6-24 hours; filtering the crystal, washing the crystal with ethanol, and drying the crystal at 25-35 ℃ under reduced pressure to obtain a white tofacitinib citrate finished product.
Further, the step 4 is that the tofacitinib citrate crude product prepared in the step 3 is heated to 50-59 ℃ by using a solvent to be dissolved and cleared, and is continuously stirred for 1-10 hours at 50-59 ℃; then slowly cooling to 25-35 ℃, stirring and crystallizing for 6-24 hours; filtering the crystal, washing the crystal with ethanol, and drying the crystal at 25-35 ℃ under reduced pressure to obtain a white tofacitinib citrate finished product.
Further, the step 4 is that the tofacitinib citrate crude product prepared in the step 3 is heated to 50-55 ℃ by using a solvent to be dissolved and clear, and is continuously stirred for 1-10 hours at 50-55 ℃; then slowly cooling to 25-35 ℃, stirring and crystallizing for 6-24 hours; filtering the crystal, washing the crystal with ethanol, and drying the crystal at 25-35 ℃ under reduced pressure to obtain a white tofacitinib citrate finished product.
Compared with the prior art, the invention has the following advantages:
(1) the invention finds a novel chemical synthesis method for producing tofacitinib citrate. The chemical synthesis method has more reasonable route and milder reaction conditions.
(2) The synthetic route of the invention simplifies the production operation, thus being more suitable for industrial production.
(3) The preparation method improves the yield of the final product tofacitinib citrate, and has obvious economic benefit.
Detailed Description
For a better understanding of the present invention, reference is made to the following examples. It is to be understood that these examples are for further illustration of the invention and are not intended to limit the scope of the invention. In addition, it should be understood that the invention is not limited to the above-described embodiments, but is capable of various modifications and changes within the scope of the invention.
Example 1 synthesis of intermediate-1:
1g of N-methyl-N- ((3R, 4R) -4-methyl-1-benzyl-3-piperidinyl) -7H-pyrrolo [2, 3-d ] pyrimidin-4-amine (starting material-1) and 0.2g of 10% palladium on charcoal are placed in a three-necked reaction flask, 30ml of absolute methanol are added and stirred for dispersion, and 0.187g of ammonium formate are added. The temperature was raised to reflux and the reaction was monitored by TLC for 2 hours.
Example 2 synthesis of intermediate-1:
1g of N-methyl-N- ((3R, 4R) -4-methyl-1-benzyl-3-piperidinyl) -7H-pyrrolo [2, 3-d ] pyrimidin-4-amine (starting material-1) and 0.2g of 10% palladium on charcoal are placed in a three-necked reaction flask, 30ml of absolute methanol are added and dispersed with stirring, and 0.561g of ammonium formate are added. The temperature was raised to reflux and the reaction was monitored by TLC for 2 hours.
Example 3 synthesis of intermediate-1:
1g of N-methyl-N- ((3R, 4R) -4-methyl-1-benzyl-3-piperidinyl) -7H-pyrrolo [2, 3-d ] pyrimidin-4-amine (starting material-1) and 0.2g of 10% palladium on charcoal are placed in a three-necked reaction flask, 30ml of absolute methanol are added and stirred for dispersion, and 0.748g of ammonium formate are added. The temperature was raised to reflux and the reaction was monitored by TLC for 2 hours.
Example 4 synthesis of intermediate-1:
1g of N-methyl-N- ((3R, 4R) -4-methyl-1-benzyl-3-piperidinyl) -7H-pyrrolo [2, 3-d ] pyrimidin-4-amine (starting material-1) and 0.2g of 10% palladium on charcoal are placed in a three-necked reaction flask, 30ml of absolute methanol are added and dispersed with stirring, and 0.935g of ammonium formate is added. The temperature was raised to reflux and the reaction was monitored by TLC for 2 hours.
The reaction charge ratios (starting material-1: ammonium formate) in examples 1-4 were investigated and are shown in Table 1.
TABLE 1 EXAMPLES 1-4 investigation of deprotection reaction Charge ratio (starting Material-1: ammonium formate)
EXAMPLE 4 Synthesis of intermediate-2
0.5g of intermediate-1 prepared in example 3 was dissolved in 5ml of anhydrous ethanol, 0.5g of cyanoacetic acid N-hydroxysuccinimide ester (starting material-2) was added, and the reaction was carried out at 5 to 10 ℃ for 1 hour with TLC monitoring.
Example 5 Synthesis of intermediate-2:
0.5g of intermediate-1 prepared in example 3 was dissolved in 5ml of anhydrous ethanol, 0.5g of cyanoacetic acid N-hydroxysuccinimide ester (starting material-2) was added, and the reaction was carried out at 5 to 10 ℃ for 2 hours with TLC monitoring.
Example 6 synthesis of intermediate-2:
0.5g of intermediate-1 prepared in example 3 was dissolved in 5ml of anhydrous ethanol, 0.5g of cyanoacetic acid N-hydroxysuccinimide ester (starting material-2) was added, and the reaction was carried out at 5 to 10 ℃ for 3 hours with TLC monitoring.
Example 7 synthesis of intermediate-2:
0.5g of intermediate-1 prepared in example 3 was dissolved in 5ml of anhydrous ethanol, 0.5g of N-hydroxysuccinimide cyanoacetate (starting material-2) was added, and the reaction was carried out at room temperature (25. + -. 5 ℃ C.) for 1 hour with TLC monitoring.
Example 8 synthesis of intermediate-2:
0.5g of intermediate-1 prepared in example 3 was dissolved in 5ml of anhydrous ethanol, 0.5g of cyanoacetic acid N-hydroxysuccinimide ester (starting material-2) was added, and the reaction was carried out at room temperature (25. + -. 5 ℃ C.) for 2 hours with TLC monitoring. After the reaction, the reaction solution was concentrated under reduced pressure until no solvent was distilled off, the residue was dissolved in 20ml of dichloromethane, washed with 1M sodium hydroxide solution and saturated brine in order, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a foamy solid, i.e., intermediate-2, which was weighed to calculate the yield (mass yield). Sampling was detected by liquid chromatography. The intermediate-2 had a mass yield of 122% and a purity of 91.59%.
Example 9 synthesis of intermediate-2:
0.5g of intermediate-1 prepared in example 3 was dissolved in 5ml of anhydrous ethanol, 0.5g of cyanoacetic acid N-hydroxysuccinimide ester (starting material-2) was added, and the reaction was carried out at room temperature (25. + -. 5 ℃ C.) for 3 hours with TLC monitoring. After the reaction, the reaction solution was concentrated under reduced pressure until no solvent was distilled off, the residue was dissolved in 20ml of dichloromethane, washed with 1M sodium hydroxide solution and saturated brine in order, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a foamy solid, i.e., intermediate-2, which was weighed to calculate the yield (mass yield). Sampling was detected by liquid chromatography. The intermediate-2 had a mass yield of 124% and a purity of 87.07%.
Example 10 synthesis of intermediate-2:
0.5g of intermediate-1 prepared in example 3 was dissolved in 5ml of anhydrous ethanol, 0.5g of cyanoacetic acid N-hydroxysuccinimide ester (starting material-2) was added, and the reaction was carried out at 40 to 50 ℃ for 1 hour with TLC monitoring. After the reaction, the reaction solution was concentrated under reduced pressure until no solvent was distilled off, the residue was dissolved in 20ml of dichloromethane, washed with 1M sodium hydroxide solution and saturated brine in order, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure by the organic phase to obtain a foamy solid, intermediate-2, with a yield (mass yield) of 120% by weight. Sampling was detected by liquid chromatography. The purity was 82.58%.
Example 11 Synthesis of intermediate-2:
0.5g of intermediate-1 prepared in example 3 was dissolved in 5ml of anhydrous ethanol, 0.5g of N-hydroxysuccinimide cyanoacetate (starting material-2) was added, and the reaction was carried out at 40 to 50 ℃ for 2 hours with TLC monitoring. After the reaction, the reaction solution was concentrated under reduced pressure until no solvent was distilled off, the residue was dissolved in 20ml of dichloromethane, washed with 1M sodium hydroxide solution and saturated brine in order, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure by the organic phase to obtain a foamy solid, intermediate-2, with a yield (mass yield) of 116% by weight. Sampling was detected by liquid chromatography. The purity was 86.17%.
Example 12 synthesis of intermediate-2:
0.5g of intermediate-1 prepared in example 3 was dissolved in 5ml of anhydrous ethanol, 0.5g of cyanoacetic acid N-hydroxysuccinimide ester (starting material-2) was added, and the reaction was carried out at 40 to 50 ℃ for 3 hours with TLC monitoring. After the reaction, the reaction solution was concentrated under reduced pressure until no solvent was distilled off, the residue was dissolved in 20ml of dichloromethane, washed with 1M sodium hydroxide solution and saturated brine in order, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure by the organic phase to obtain a foamy solid, intermediate-2, with a yield (mass yield) of 112% by weight. Sampling was detected by liquid chromatography. The purity was 84.54%.
Example 13 purification of intermediate-2:
1g of the intermediate-2 prepared in example 8 was dissolved in a small amount of methylene chloride, 5g of 200-300 mesh column chromatography silica gel was packed into a column, and a sample was wet-loaded onto the silica gel column, and allowed to stand for adsorption for 60 minutes. Eluted with 200ml ethyl acetate and checked by TLC. Collecting eluate, and concentrating to obtain refined product. Sampling was detected by liquid chromatography. The yield was found to be 90% and the purity was found to be 92.82%.
Example 14 purification of intermediate-2:
1g of the intermediate-2 prepared in example 8 was dissolved in a small amount of methylene chloride, 10g of 200-300 mesh column chromatography silica gel was packed into a column, and a sample was wet-loaded onto the silica gel column, and allowed to stand for adsorption for 60 minutes. Eluted with 500ml ethyl acetate and checked by TLC. Collecting eluate, and concentrating to obtain refined intermediate-2. Sampling was detected by liquid chromatography. The yield was found to be 85% and the purity was found to be 95.98%.
Example 15 purification of intermediate-2:
1g of the intermediate-2 prepared in example 8 was dissolved in a small amount of methylene chloride, 15g of 200-300 mesh column chromatography silica gel was packed into a column, and a sample was wet-loaded onto the silica gel column, and allowed to stand for adsorption for 60 minutes. Eluted with 1000ml ethyl acetate and checked by TLC. Collecting eluate, and concentrating to obtain refined product. Sampling was detected by liquid chromatography. The yield was found to be 82% and the purity was 97.39%.
Example 16 salification of intermediate-2 with citric acid:
1g of the intermediate-2 prepared in example 14 was heated under reflux with 10ml of absolute ethanol to dissolve it, and a solution of 0.8g of citric acid in 2ml of water was added dropwise thereto, followed by further reaction at 80. + -. 5 ℃ for 2 hours. Then slowly cooling to 30 +/-5 ℃, stirring and crystallizing for 6 hours. Filtering the crystal, washing with a small amount of ethanol, and drying under reduced pressure at 50 +/-5 ℃ to obtain a white tofacitinib citrate crude product. The mass yield was calculated to be 135%.
Example 17 salification of intermediate-2 with citric acid:
1g of the intermediate-2 prepared in example 14 was heated under reflux with 10ml of absolute ethanol to dissolve it, and a solution of 0.8g of citric acid in 2ml of water was added dropwise thereto, followed by further reaction at 80. + -. 5 ℃ for 2 hours. Then slowly cooling to 30 +/-5 ℃, stirring and crystallizing for 12 hours. Filtering the crystal, washing with a small amount of ethanol, and drying under reduced pressure at 50 +/-5 ℃ to obtain a white tofacitinib citrate crude product. The mass yield was calculated by weighing to be 144%.
Example 18 salification of intermediate-2 with citric acid:
1g of the intermediate-2 prepared in example 14 was heated under reflux with 10ml of absolute ethanol to dissolve it, and a solution of 0.8g of citric acid in 2ml of water was added dropwise thereto, followed by further reaction at 80. + -. 5 ℃ for 2 hours. Then slowly cooling to 30 +/-5 ℃, stirring and crystallizing for 18 hours. Filtering the crystal, washing with a small amount of ethanol, and drying under reduced pressure at 50 +/-5 ℃ to obtain a white tofacitinib citrate crude product. The mass yield was calculated by weighing to be 145%.
Example 19 salification of intermediate-2 with citric acid:
1g of the intermediate-2 prepared in example 14 was heated under reflux with 10ml of absolute ethanol to dissolve it, and a solution of 0.8g of citric acid in 2ml of water was added dropwise thereto, followed by further reaction at 80. + -. 5 ℃ for 2 hours. Then slowly cooling to 40 +/-5 ℃, stirring and crystallizing for 6 hours. Filtering the crystal, washing with a small amount of ethanol, and drying under reduced pressure at 50 +/-5 ℃ to obtain a white tofacitinib citrate crude product. The mass yield was calculated to be 120% by weight.
Example 20 salification of intermediate-2 with citric acid:
1g of the intermediate-2 prepared in example 14 was heated under reflux with 10ml of absolute ethanol to dissolve it, and a solution of 0.8g of citric acid in 2ml of water was added dropwise thereto, followed by further reaction at 80. + -. 5 ℃ for 2 hours. Then slowly cooling to 40 +/-5 ℃, stirring and crystallizing for 12 hours. Filtering the crystal, washing with a small amount of ethanol, and drying under reduced pressure at 50 +/-5 ℃ to obtain a white tofacitinib citrate crude product. The mass yield was calculated to be 132% by weight.
Example 21 salification of intermediate-2 with citric acid:
1g of the intermediate-2 prepared in example 14 was heated under reflux with 10ml of absolute ethanol to dissolve it, and a solution of 0.8g of citric acid in 2ml of water was added dropwise thereto, followed by further reaction at 80. + -. 5 ℃ for 2 hours. Then slowly cooling to 40 +/-5 ℃, stirring and crystallizing for 18 hours. Filtering the crystal, washing with a small amount of ethanol, and drying under reduced pressure at 50 +/-5 ℃ to obtain a white tofacitinib citrate crude product. The mass yield was calculated to be 135%.
Example 22 tofacitinib citrate purification:
1g of the tofacitinib citrate crude product prepared in example 17 was heated to 80 + -5 deg.C with an aqueous ethanol solution (the ethanol concentration of the aqueous ethanol solution is 30% by mass) to dissolve and clear, and the stirring was continued at 80 + -5 deg.C for 2 hours. Then slowly cooling to 30 +/-5 ℃, stirring and crystallizing for 6 hours. Filtering the crystal, washing with a small amount of ethanol, and drying under reduced pressure at 50 +/-5 ℃ to obtain a white tofacitinib citrate finished product. The mass yield is calculated by weighing and is 80 percent, and the sampling is detected by liquid chromatography. The purity was 99.921%. The characteristic peaks in an X-ray diffraction powder diffraction pattern of the tofacitinib citrate finished product are 5.76, 14.82, 16.02, 17.43, 18.72, 20.16, 20.48, 21.10, 21.99 and 27.00 +/-0.1 degrees.
Example 23 tofacitinib citrate purification:
1g of the tofacitinib citrate crude product prepared in example 17 was heated to 80 + -5 deg.C with an aqueous ethanol solution (the ethanol concentration of the aqueous ethanol solution is 33% by mass) to dissolve and clear, and the stirring was continued at 80 + -5 deg.C for 2 hours. Then slowly cooling to 30 +/-5 ℃, stirring and crystallizing for 12 hours. Filtering the crystal, washing with a small amount of ethanol, and drying under reduced pressure at 50 +/-5 ℃ to obtain a white tofacitinib citrate finished product. The mass yield is calculated by weighing and is 84%, and the sampling is detected by liquid chromatography. The purity was 99.900%.
Example 24 tofacitinib citrate purification:
1g of the tofacitinib citrate crude product prepared in example 18 is heated to 80 +/-5 ℃ with an aqueous ethanol solution (the ethanol concentration of the aqueous ethanol solution is 35 percent by mass) to be dissolved and cleared, and the stirring is continued for 2 hours at 80 +/-5 ℃. Then slowly cooling to 30 +/-5 ℃, stirring and crystallizing for 18 hours. Filtering the crystal, washing with a small amount of ethanol, and drying under reduced pressure at 50 +/-5 ℃ to obtain a white tofacitinib citrate finished product. The mass yield is 86% by weight calculation, and the sampling is detected by liquid chromatography. The purity was 99.875%.
Example 25 tofacitinib citrate purification:
1g of the tofacitinib citrate crude product prepared in example 17 was heated to 80 + -5 deg.C with an aqueous ethanol solution (the ethanol concentration of the aqueous ethanol solution is 38%) to dissolve, and the mixture was stirred at 80 + -5 deg.C for 2 hours. Then slowly cooling to 40 +/-5 ℃, stirring and crystallizing for 6 hours. Filtering the crystal, washing with a small amount of ethanol, and drying under reduced pressure at 50 +/-5 ℃ to obtain a white tofacitinib citrate finished product. The mass yield is 72% by weight calculation, and the sampling is detected by liquid chromatography. The purity was 99.946%.
Example 26 tofacitinib citrate purification:
1g of the tofacitinib citrate crude product prepared in example 17 was heated to 80 + -5 deg.C with an aqueous ethanol solution (the ethanol concentration of the aqueous ethanol solution is 40% by mass) to dissolve and clear, and the stirring was continued at 80 + -5 deg.C for 2 hours. Then slowly cooling to 40 +/-5 ℃, stirring and crystallizing for 12 hours. Filtering the crystal, washing with a small amount of ethanol, and drying under reduced pressure at 50 +/-5 ℃ to obtain a white tofacitinib citrate finished product. The mass yield is 78% by weight calculation, and the sampling is detected by liquid chromatography. The purity was 99.943%.
Example 27 tofacitinib citrate purification:
1g of the tofacitinib citrate crude product prepared in example 18 is heated to 80 +/-5 ℃ with ethanol water (the ethanol mass concentration of the ethanol water is 49%) to be dissolved and clear, and the stirring is continued for 2 hours at 80 +/-5 ℃. Then slowly cooling to 40 +/-5 ℃, stirring and crystallizing for 18 hours. Filtering the crystal, washing with a small amount of ethanol, and drying under reduced pressure at 50 +/-5 ℃ to obtain a white tofacitinib citrate finished product. The mass yield is 78% by weight calculation, and the sampling is detected by liquid chromatography. The purity was 99.917%.
As above, the present invention can be preferably implemented.
Claims (9)
1. A novel synthesis process of tofacitinib citrate is characterized by comprising the following steps:
step 1, mixing the following raw materials: mixing the initial raw materials-1, 10% palladium carbon, anhydrous methanol and ammonium formate in a reaction vessel, and reacting to obtain an intermediate-1;
step 2, dissolving the intermediate-1 prepared in the step 1 in absolute ethyl alcohol, adding an initial raw material-2, and reacting at a reaction temperature of 20-50 ℃; after the reaction is finished, purifying the reaction solution to obtain an intermediate-2 crude product; refining the intermediate-2 crude product to obtain an intermediate-2 refined product;
step 3, heating, refluxing and dissolving the refined intermediate-2 product obtained in the step 2 by using absolute ethyl alcohol, dropwise adding a citric acid aqueous solution, and continuously reacting at 50-90 ℃; then slowly cooling to 20-45 ℃, stirring and crystallizing; filtering the crystals, washing the crystals with ethanol, and drying the crystals at 40-60 ℃ under reduced pressure to obtain a white tofacitinib citrate crude product.
2. The novel synthesis process of tofacitinib citrate as claimed in claim 1, wherein in the step 2, the purity of the intermediate-2 in the intermediate-2 refined product obtained by refining the intermediate-2 crude product is 90-98%.
3. The novel synthesis process of tofacitinib citrate as claimed in claim 2, wherein in the step 1, the 4 raw materials are added in a certain order: adding 1 percent of initial raw material and 10 percent of palladium-carbon into a reaction vessel, adding anhydrous methanol, stirring and dispersing, and then adding ammonium formate; mixing; heating to reflux, and reacting to obtain an intermediate-1.
4. The novel synthesis process of tofacitinib citrate as claimed in claim 3, wherein in the step 2, the purification comprises the following specific steps: and (3) concentrating the reaction liquid after the reaction in the step (2) under reduced pressure until no solvent is evaporated, dissolving the residue with dichloromethane, washing with a sodium hydroxide solution and saturated saline solution in sequence, drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a foamy solid, namely the intermediate-2 crude product.
5. The novel synthesis process of tofacitinib citrate as claimed in claim 4, wherein in the step 2, the step of refining the crude intermediate-2 comprises the following steps: dissolving the intermediate-2 crude product in dichloromethane, loading the column chromatography silica gel into a column, loading a sample on the silica gel column by a wet method, and standing; eluting with ethyl acetate, and detecting by TLC; collecting eluate, and concentrating to obtain refined intermediate-2.
6. The novel synthesis process of tofacitinib citrate as claimed in claim 5, wherein in the step 3, the concentration of citric acid in the dropwise added citric acid aqueous solution is 0.3-0.5 g/ml.
7. The novel synthesis process of tofacitinib citrate as claimed in claim 1, further comprising a step 4 of heating the crude tofacitinib citrate prepared in the step 3 to 50-90 ℃ with a solvent to dissolve, and continuously stirring at 50-90 ℃ for 1-10 hours; then slowly cooling to 25-50 ℃, stirring and crystallizing for 6-24 hours; filtering the crystal, washing the crystal with ethanol, and drying the crystal at 40-60 ℃ under reduced pressure to obtain a white tofacitinib citrate finished product.
8. The novel synthesis process of tofacitinib citrate as claimed in claim 7, wherein in the step 4, the crude tofacitinib citrate prepared in the step 3 is heated to 50-55 ℃ by using a solvent to be dissolved and cleared, and is continuously stirred for 1-10 hours at 50-55 ℃; then slowly cooling to 25-35 ℃, stirring and crystallizing for 6-24 hours; filtering the crystal, washing the crystal with ethanol, and drying the crystal at 25-35 ℃ under reduced pressure to obtain a white tofacitinib citrate finished product.
9. The novel synthesis process of tofacitinib citrate as claimed in claim 7, wherein the solvent in step 4 is at least one of an aqueous solution with a mass concentration of 30-49% formed by ethanol, isopropanol or n-butanol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510856276.4A CN105348287A (en) | 2015-11-30 | 2015-11-30 | Novel synthesis process of tofacitinib citrate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510856276.4A CN105348287A (en) | 2015-11-30 | 2015-11-30 | Novel synthesis process of tofacitinib citrate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105348287A true CN105348287A (en) | 2016-02-24 |
Family
ID=55324370
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510856276.4A Pending CN105348287A (en) | 2015-11-30 | 2015-11-30 | Novel synthesis process of tofacitinib citrate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105348287A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106967072A (en) * | 2017-04-12 | 2017-07-21 | 山东裕欣药业有限公司 | Tofacitinib citrate crystal form compound and preparation method thereof |
| CN107814802A (en) * | 2016-09-12 | 2018-03-20 | 江苏艾立康药业股份有限公司 | A kind of new method for preparing citric acid tropsch imatinib medicinal crystal-form |
| CN108358929A (en) * | 2017-11-03 | 2018-08-03 | 江苏正大清江制药有限公司 | Refining method of tofacitinib citrate |
| CN108640921A (en) * | 2018-04-03 | 2018-10-12 | 山东科兴生物制品有限公司 | Preparation method of tofacitinib citrate |
| CN108640923A (en) * | 2018-07-09 | 2018-10-12 | 湖南天地恒制药有限公司 | A kind of support method replaces the preparation method of cloth key intermediate |
| CN108948020A (en) * | 2018-07-03 | 2018-12-07 | 南京正大天晴制药有限公司 | Refining method of tofacitinib citrate |
| CN108997355A (en) * | 2018-08-13 | 2018-12-14 | 山东罗欣药业集团恒欣药业有限公司 | A kind of refining methd of citric acid tropsch imatinib compound |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1409712A (en) * | 1999-12-10 | 2003-04-09 | 辉瑞产品公司 | Pyrrolo [2,3-d] pyrimidine compounds |
| CN1596257A (en) * | 2001-12-06 | 2005-03-16 | 辉瑞产品公司 | Novel crystalline compound |
| CN1729192A (en) * | 2001-05-31 | 2006-02-01 | 辉瑞产品公司 | Optical resolution of (1-benzyl-4-methylpiperidin-3-yl) -methylamine and the use thereof for the preparation of pyrrolo 2,3-pyrimidine derivatives as protein kinases inhibitors |
| WO2014102826A1 (en) * | 2012-12-28 | 2014-07-03 | Glenmark Pharmaceuticals Limited; | The present invention relates to process for the preparation of tofacitinib and intermediates thereof. |
| WO2014195978A2 (en) * | 2013-06-05 | 2014-12-11 | Msn Laboratories Limited | PROCESS FOR THE PREPARATION OF (3R,4R)-4-METHYL-3-(METHYL-7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL-AMINO)-ß-OXO-1-PIPERIDINEPROPANENITRILE AND ITS SALTS |
-
2015
- 2015-11-30 CN CN201510856276.4A patent/CN105348287A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1409712A (en) * | 1999-12-10 | 2003-04-09 | 辉瑞产品公司 | Pyrrolo [2,3-d] pyrimidine compounds |
| CN1729192A (en) * | 2001-05-31 | 2006-02-01 | 辉瑞产品公司 | Optical resolution of (1-benzyl-4-methylpiperidin-3-yl) -methylamine and the use thereof for the preparation of pyrrolo 2,3-pyrimidine derivatives as protein kinases inhibitors |
| CN1596257A (en) * | 2001-12-06 | 2005-03-16 | 辉瑞产品公司 | Novel crystalline compound |
| WO2014102826A1 (en) * | 2012-12-28 | 2014-07-03 | Glenmark Pharmaceuticals Limited; | The present invention relates to process for the preparation of tofacitinib and intermediates thereof. |
| WO2014195978A2 (en) * | 2013-06-05 | 2014-12-11 | Msn Laboratories Limited | PROCESS FOR THE PREPARATION OF (3R,4R)-4-METHYL-3-(METHYL-7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL-AMINO)-ß-OXO-1-PIPERIDINEPROPANENITRILE AND ITS SALTS |
Non-Patent Citations (3)
| Title |
|---|
| SHUANG ZHI ET AL.: ""An Efficient Method for Synthesis of Tofacitinib Citrate"", 《J. HETEROCYCLIC CHEM.》 * |
| 胡斯军: ""甲酸铵-Pd/C体系进行胺化反应的研究"", 《中国优秀硕士论文全文数据库 工程科技I辑》 * |
| 赵方露 等: ""枸橼酸托法替尼的合成"", 《中国医药工业杂志》 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107814802A (en) * | 2016-09-12 | 2018-03-20 | 江苏艾立康药业股份有限公司 | A kind of new method for preparing citric acid tropsch imatinib medicinal crystal-form |
| CN106967072A (en) * | 2017-04-12 | 2017-07-21 | 山东裕欣药业有限公司 | Tofacitinib citrate crystal form compound and preparation method thereof |
| CN106967072B (en) * | 2017-04-12 | 2019-05-03 | 山东裕欣药业有限公司 | Tofacitinib citrate crystal form compound and preparation method thereof |
| CN108358929A (en) * | 2017-11-03 | 2018-08-03 | 江苏正大清江制药有限公司 | Refining method of tofacitinib citrate |
| CN108640921A (en) * | 2018-04-03 | 2018-10-12 | 山东科兴生物制品有限公司 | Preparation method of tofacitinib citrate |
| CN108948020A (en) * | 2018-07-03 | 2018-12-07 | 南京正大天晴制药有限公司 | Refining method of tofacitinib citrate |
| CN108640923A (en) * | 2018-07-09 | 2018-10-12 | 湖南天地恒制药有限公司 | A kind of support method replaces the preparation method of cloth key intermediate |
| CN108997355A (en) * | 2018-08-13 | 2018-12-14 | 山东罗欣药业集团恒欣药业有限公司 | A kind of refining methd of citric acid tropsch imatinib compound |
| CN108997355B (en) * | 2018-08-13 | 2020-05-26 | 山东罗欣药业集团恒欣药业有限公司 | Refining method of tofacitinib citrate compound |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105348287A (en) | Novel synthesis process of tofacitinib citrate | |
| CN101792486A (en) | Method for combining caspofungin acetate | |
| CN101812095A (en) | Preparation method of sucralose | |
| CN101863948B (en) | High-purity (2 beta, 3 alpha, 5 alpha, 16 beta, 17 beta)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)-androstane-3,17-diol or composition thereof and preparation method thereof | |
| JPS61275241A (en) | Production of deuterated acrylic acid or methacrylic acid | |
| CN111170892A (en) | Synthesis method of N-methyl (2S) -2-N-fluorenylmethoxycarbonylamino-aspartic acid (4-tert-butyl ester) | |
| CN106946956B (en) | Recrystallization method and application of sucrose-6-acetate | |
| CN102993205A (en) | High-yield purification method for preparation of high-purity sildenafil freebases | |
| JP2023534556A (en) | Method for large-scale synthesis of tetrodotoxin | |
| CN110128385B (en) | Quercetin derivative chemically modified by lauroyl chloride and synthetic method thereof | |
| CN101717346A (en) | Artificial synthesis method of capsaicin homologue | |
| CN107216332A (en) | The synthetic method of (6H) the formic acid base ester of 7 methylol of the tert-butyl group, 7,8 dihydro 4H pyrazolos diazepine 5 | |
| CN102464661A (en) | Preparation method of 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid ethyl ester | |
| CN110437277B (en) | Synthetic method of phosphoalkenyl ester compound | |
| CN101066967B (en) | Synthesis process of dibenzo dioxy octanone compound | |
| CN111320664B (en) | Preparation method of 24-cholenenoic acid ethyl ester | |
| CN104119240A (en) | Preparation method for (S)-(-)-alpha-methylaminopropiophenone | |
| CN106883185B (en) | Preparation method of 4-chloro-2-trifluoromethylpyrimidine | |
| CN109535074A (en) | The preparation method of 2- cyano -5- bromopyridine | |
| CN107298682B (en) | A kind of synthetic method of 4,5,6,7- tetrahydro-pyrazole simultaneously [1,5-A] pyrazine -2- Ethyl formate | |
| JP5645494B2 (en) | Method for producing amine body | |
| CN102731600B (en) | Preparation method of zidovudine and its intermediate | |
| CN111056956A (en) | Method for preparing 2-aminobiphenyl | |
| CN110483360B (en) | Synthesis method of alfaprost alcohol | |
| CN115703806B (en) | Phosphine ligand of pyrazole-amide framework, and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160224 |