Synthesis process of ruxolitinib

Abstract

The present application falls within the field of drug synthesis, and in particular, the present application relates to a method for preparing ruxolitinib, and a method for preparing the intermediate and relevant intermediates used. The method comprises reacting a compound of formula II with a compound of formula IV or a salt thereof to obtain a compound of formula III, and then subjecting the compound of formula III to an acyl halogenation reaction, an amidation reaction, and a reaction dehydrating an amide to form a cyano group or removing the protecting group to prepare ruxolitinib. The method has the characteristics of brief steps, a high stereoselectivity, a high utilization ratio of atoms, mild reaction conditions and convenient post treatment. The method avoids using expensive asymmetric reaction catalysts, and is suitable for industrial production. ##STR00001##

Claims

1. A process for preparing ruxolitinib, a compound of Formula I, comprising the following steps: Step 3: reacting a compound of Formula II with a compound of Formula IV or a salt thereof to obtain a compound of Formula III, ##STR00039## Step 4: converting the compound of Formula III into a compound of Formula XI, and then converting the compound of Formula XI into a compound of Formula XII in the presence of an aminating agent, ##STR00040## wherein, R is selected from H and an amino-protecting group, and X is selected from Cl and Br; and Step 5-1: where R is H, converting the acylamino group in Formula XII into a cyano group in the presence of a dehydrating agent to obtain ruxolitinib, the compound of Formula I; or Step 5-2: where R is an amino-protecting group, converting the acylamino group in Formula XII into a cyano group in the presence of a dehydrating agent and removing the amino-protecting group R to obtain ruxolitinib, the compound of Formula I; ##STR00041## wherein, R is selected from H and an amino-protecting group, wherein, the reagent used in the reaction of converting the compound of Formula III into the compound of Formula XI in Step 4 is selected from one or more of phosphorus trichloride, phosphorus pentachloride, thionyl chloride and oxalyl chloride; and wherein, the aminating agent used in the reaction of converting the compound of Formula XI into the compound of Formula XII in Step 4 is selected from one or more of aqueous ammonia, liquid ammonia, and ammonia gas.

2. The process according to claim 1, further comprising Step 2: converting a compound of Formula VI into the compound of Formula II in the presence of DMF and a chlorinating agent, ##STR00042## wherein, R is selected from H and an amino-protecting group; and wherein, the chlorinating agent in Step 2 is selected from oxalyl chloride, phosphorus oxychloride, thionyl chloride, and a mixture of any two or more of the above agents.

3. The process according to claim 1, wherein the process for preparing the compound of Formula IV or a chiral salt thereof in Step 3 comprises the following steps: ##STR00043## Step C-1: reacting a compound of Formula X with a chiral acid in the presence of a solvent to form a chiral salt of the compound of Formula IV, ##STR00044## Step C-2: separating the chiral salt of the compound of Formula IV; and Step C-3: optionally, treating the chiral salt of the compound of Formula IV with a base to obtain the compound of Formula IV.

4. The process according to claim 3, wherein the process for preparing the compound of Formula IV or a chiral salt thereof in Step 3 further comprises the following steps: Step A: reacting a compound of Formula VII with malonic acid in the presence of a base to obtain a compound of Formula VIII, ##STR00045## and Step B: reacting the compound of Formula VIII with hydrazine hydrate to obtain the compound of Formula X, ##STR00046##

5. A process for preparing ruxolitinib, a compound of Formula I, comprising the following steps: Step (1): reacting a compound of Formula II with a compound of Formula IV or a salt thereof in the presence of NH.sub.3 to obtain a compound of Formula XII, ##STR00047## wherein, R is selected from H and an amino-protecting group; and Step (2-1): where R is H, converting the acylamino group in Formula XII into a cyano group in the presence of a dehydrating agent to obtain ruxolitinib, the compound of Formula I, or Step (2-2): where R is an amino-protecting group, converting the acylamino group in Formula XII into a cyano group in the presence of a dehydrating agent and removing the amino-protecting group R to obtain ruxolitinib, the compound of Formula I; ##STR00048## wherein, R is selected from H and an amino-protecting group.

6. The process according to claim 1, wherein the amino-protecting group is selected from benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(4-trifluoromethylphenylsulfonyl)ethoxycarbonyl, tert-butoxycarbonyl, 1-adamantyloxycarbonyl, 2-adamantylcarbonyl, 2,4-dimethylpent-3-yloxycarbonyl, cyclohexyloxycarbonyl, 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl, vinyl, 2-chloroethyl, 2-phenylsulfonylethyl, p-nitrophenylsulfonyl, p-toluenesulfonyl, phenyl sulfonyl, methanesulfonyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl, N,N-dimethylhydrazino, methoxymethyl, tert-butoxymethyl, benzyloxymethyl, 2-tetrahydropyranyl, tri(C.sub.1-4alkyl)silyl, 1,1-diethoxymethyl, 2-(trimethylsilyl)ethoxymethyl and N-pivaloyloxymethyl.

7. The process according to claim 5, wherein the amino-protecting group is selected from benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethyl silyl)ethoxycarbonyl, 2-(4-trifluoromethylphenylsulfonyl)ethoxycarbonyl, tert-butoxycarbonyl, 1-adamantyloxycarbonyl, 2-adamantylcarbonyl, 2,4-dimethylpent-3-yloxycarbonyl, cyclohexyloxycarbonyl, 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl, vinyl, 2-chloroethyl, 2-phenylsulfonylethyl, p-nitrophenylsulfonyl, p-toluenesulfonyl, phenyl sulfonyl, methanesulfonyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl, N,N-dimethylhydrazino, methoxymethyl, tert-butoxymethyl, benzyloxymethyl, 2-tetrahydropyranyl, tri(C.sub.1-4alkyl)silyl, 1,1-diethoxymethyl, 2-(trimethylsilyl)ethoxymethyl and N-pivaloyloxymethyl.

8. The process according to claim 1, wherein Step 3 is carried out under an acidic, basic or neutral condition.

9. The process according to 8, wherein the acidic condition is provided by adding an acidic reagent selected from citric acid, fumaric acid, tartaric acid, maleic acid, malic acid, succinic acid, acetic acid, ascorbic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, and a mixture thereof; and, wherein the basic condition is provided by adding an alkaline reagent selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, DBU, and a mixture thereof.

10. The process according to claim 1, wherein the molar ratio of the compound of Formula II to the compound of Formula IV is 1.0:1.05.0.

11. The process according to claim 2, wherein the chlorinating agent in Step 2 is phosphorus oxychloride.

12. The process according to claim 6, wherein the amino-protecting group is selected from 2-(trimethylsilyl)ethoxymethyl, N-pivaloyloxymethyl, p-nitrophenyl sulfonyl, p-toluenesulfonyl, phenyl sulfonyl, methanesulfonyl or benzyl.

13. The process according to claim 12, wherein the amino-protecting group is 2-(trimethylsilyl)ethoxymethyl.

14. The process according to claim 7, wherein the amino-protecting group is selected from 2-(trimethylsilyl)ethoxymethyl, N-pivaloyloxymethyl, p-nitrophenyl sulfonyl, p-toluenesulfonyl, phenyl sulfonyl, methanesulfonyl or benzyl.

15. The process according to claim 14, wherein the amino-protecting group is 2-(trimethylsilyl)ethoxymethyl.

16. The process according to 10, wherein the acidic condition is provided by adding an acidic reagent selected from tartaric acid, acetic acid or hydrochloric acid.

17. The process according to 9, wherein the basic condition is provided by adding an alkaline reagent selected from triethylamine, sodium hydroxide or potassium hydroxide.

18. The process according to claim 10, wherein the molar ratio of the compound of Formula II to the compound of Formula IV is 1.0:1.03.0.

19. The process according to claim 18, wherein the molar ratio of the compound of Formula II to the compound of Formula IV is 1.0:1.01.5.

20. The process according to claim 19, wherein the molar ratio of the compound of Formula II to the compound of Formula IV is 1.0:1.01.2.

Description

SPECIFIC EMBODIMENTS

(1) The following examples are provided as further detailed non-limiting illustrations of the technical solutions of the present application. They should not be construed as limiting the scope of the present application, but as merely illustrations and typical representatives of the present application. The solvents, reagents and raw materials used in the present application are all commercially available, chemically pure or analytically pure products.

Example 1: (R)-5-cyclopentylpyrazolidin-3-one D-tartrate

(2) ##STR00031##

Step 1: 3-cyclopentyl Acrylic Acid

(3) 660 mL of cyclopentanecarbaldehyde and 500 g of malonic acid were added to 1 L of pyridine, and 13.4 mL of piperidine was added dropwise thereto and the resulting mixture was stirred at room temperature to react for 1 hour. Then the temperature was raised to 80 C. and the stirring was continued for 5 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to distill off the pyridine, and then 2.6 L of purified water was added thereto and the pH was adjusted to 25 with concentrated hydrochloric acid. Then, the resulting mixture was extracted with ethyl acetate (1.7 L3), and the organic layers were combined, and washed sequentially with 1 L of water and 1 L of saturated brine. To the combined organic layer was added 4 L of 9% sodium hydroxide (1.3 L3) and stirred, and the aqueous layers were combined and cooled down to 05 C., and then concentrated hydrochloric acid was added dropwise thereto to adjust the pH to 25 and the resulting mixture was extracted by adding 2.6 L of ethyl acetate. The aqueous layer was washed with ethyl acetate (1.3 L2), and the organic layers were combined, washed with 2.6 L of purified water and then with 2.6 L of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3-cyclopentyl acrylic acid (650 g, 96.6%).

(4) .sup.1H-NMR (500 MHz, CDCl.sub.3): =11.24 (bs, 1H), 7.08 (dd, J=15.6, 8.0 Hz, 1H), 5.81 (dd, J=15.5, 1.2 Hz, 1H), 2.64 (dd, J=8.1, 7.6 Hz, 1H), 1.921.81 (m, 2H), 1.71 (ddq, J=12.5, 6.5, 2.9 Hz, 2H), 1.681.58 (m, 2H), 1.481.37 (m, 2H);

(5) MS (ES): 141.09 (M+H.sup.+).

Step 2: 5-cyclopentylpyrazolidin-3-one

(6) 586 g of hydrazine hydrate was cooled down to 05 C., and 600 g of 3-cyclopentyl acrylic acid was added thereto under stirring. After the addition was completed, the resulting mixture was heated to 7075 C. to react for 0.5 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure into an oil, and 1.2 L of purified water was added to dissolve the oil under stirring, and then the resulting mixture was cooled down to 05 C., stirred and crystallized overnight. The resulting mixture was suction-filtered and the filter cake was rinsed with 1.5 L of isopropyl ether and dried at 45 C. to obtain 5-cyclopentylpyrazolidin-3-one (508 g, 77.0%).

(7) .sup.1H-NMR (500 MHz, DMSO-d6): =8.92 (bs, 1H), 5.17 (bs, 1H), 3.13 (q, J=8.3 Hz, 1H), 2.32 (dd, J=15.8, 7.3 Hz, 1H), 2.03 (dd, J=15.9, 8.4 Hz, 1H), 1.89 (d, J=8.2 Hz, 1H), 1.751.62 (m, 2H), 1.601.42 (m, 4H), 1.26 (dq, J=12.4, 7.6 Hz, 1H), 1.201.06 (m, 1H);

(8) MS (ES): 155.21 (M+H.sup.+).

Step 3: (R)-5-cyclopentylpyrazolidin-3-one D-tartrate

(9) 406 g of the racemic 5-cyclopentylpyrazolidin-3-one was added to 4.1 L of acetone, stirred and dissolved to obtain a clear solution, and then 198 g of D-tartaric acid was added thereto. After the resulting mixture was stirred for 30 minutes, the temperature was lowered to 05 C. to crystallize. After filtration, the filter cake was rinsed with 1.5 L of acetone and then dried at 45 C. to obtain (R)-5-cyclopentylpyrazolidin-3-one D-tartrate (326 g, 40.7%) with an ee value of 99.4%.

Step 4: (R)-5-cyclopentylpyrazolidin-3-one

(10) 220 mL of sodium hydroxide solution (3M) was slowly dropped into (R)-5-cyclopentylpyrazolidin-3-one D-tartrate (64 g) and cooled in an ice bath to 05 C., and then concentrated hydrochloric acid was slowly added dropwise thereto under stirring until the solution became cloudy. Then, the pH of the solution was adjusted to neutral with 30 mL of 3M hydrochloric acid, and the resulting mixture was extracted three times with in total 500 mL of dichloromethane. The organic layers were combined, dried over anhydrous magnesium sulfate and filtered, and the filtrate was collected and concentrated under reduced pressure to obtain the product (24.71 g, 76.2%).

(11) .sup.1H-NMR (500 MHz, DMSO-d6): =8.93 (bs, 1H), 5.15 (bs, 1H), 3.17 (q, J=7.9 Hz, 1H), 2.30 (dd, J=16.0, 7.3 Hz, 1H), 2.01 (dd, J=16.0, 8.4 Hz, 1H), 1.89 (m, 1H), 1.741.60 (m, 2H), 1.55 (m, 2H), 1.47 (m, 2H), 1.26 (m, 1H), 1.14 (m, 1H);

(12) MS (ES): 155.12 (M+H.sup.+).

Example 2: (R)-3-cyclopentyl-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile

(13) ##STR00032## ##STR00033##

Step 1: 4-methyl-7H-pyrrolo[2,3-d]pyrimidine

(14) 150 g of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and 5.72 g of Pd(bppf)Cl.sub.2 were added to 1.5 L of tetrahydrofuran, stirred at room temperature for 0.5 hour, and then cooled down to below 0 C. To the resulting mixture was slowly added dropwise 850 mL of methylmagnesium bromide (3M dissolved in ether). After the addition was completed, the temperature was raised to 6065 C., and the resulting mixture reacted under reflux for 2 hours. Then, the temperature was lowered to below 0 C., and the reaction was quenched by slowly adding dropwise concentrated hydrochloric acid. After the addition was completed, 650 mL of purified water was added to the resulting mixture and stirred for 15 minutes, the phases were separated and the organic phase was discarded. The aqueous phase was adjusted to pH 6 with NaHCO.sub.3 and then suction-filtered, the filter cake was washed with 455 mL of purified water, and the filtrate was collected and extracted three times with 1.05 L of ethyl acetate, and then the organic phase was concentrated to obtain 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (109.5 g, 84.2%).

(15) .sup.1H-NMR (500 MHz, DMSO-d6): =12.00 (bs, 1H), 8.61 (s, 1H), 7.47 (d, J=3.6 Hz, 1H), 6.62 (d, J=3.5 Hz, 1H), 2.64 (d, J=1.6 Hz, 3H);

(16) MS (ES): 134.07 (M+H.sup.+).

Step 2: 3-hydroxy-2-(7H-pyrrolo[2,3-d]ipyrimidin-4-yl)acrylaldehyde

(17) 91.6 g of 4-methyl-7H-pyrrolo[2,3-d]pyrimidine was added to a mixed solvent of 230 mL of DMF and 460 mL of dioxane and cooled down to below 0 C., and then 190 mL of phosphorus oxychloride was added dropwise thereto under stirring, and the temperature of the solution was kept to be lower than 20 C. After the addition was completed, the resulting mixture was heated to 80 C. and stirred to react for 3 hours, and then concentrated under reduced pressure to remove dioxane and DMF. To the residue was added 920 mL of tetrahydrofuran, and the pH was adjusted to 1012 with 25% aqueous NaOH solution. After the addition was completed, the resulting mixture was heated to 60 C. and stirred to react for 2 hours. Then, the mixture was adjusted to pH 6-7 with concentrated hydrochloric acid, cooled, stirred and crystallized for 2 hours, and then suction-filtered to obtain a filter cake. The filter cake was dried at 60 C. to obtain 3-hydroxy-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acrylaldehyde (78.3 g, 60.2%).

(18) .sup.1H-NMR (500 MHz, DMSO-d6): =13.51 (bs, 1H), 12.04 (bs, 1H), 9.49 (s, 2H), 8.72 (s, 1H), 7.47 (dd, J=46.2, 3.7 Hz, 2H);

(19) MS (ES): 190.06 (M+H.sup.+).

Step 3: (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionic acid

(20) Method I: 54 g of 3-hydroxy-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) acrylaldehyde was added to a mixed solvent of 648 mL of acetic acid and 324 mL of purified water, and then 87 g of (R)-5-cyclopentylpyrazolidin-3-one D-tartrate was added thereto. The resulting mixture was heated to reflux to react for 8 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and to the residue was added 500 mL of water, the pH was adjusted to 6.57, and then the resulting solution was washed twice with 300 mL of ethyl acetate. The aqueous phase was further adjusted to pH 55.5 with 3M HCl and suction-filtered to obtain (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionic acid (55.8 g, 60.0%).

(21) Method 5 g of 3-hydroxy-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acrylaldehyde was added to 100 mL of water, and then 1.3 g of sodium hydroxide and 4.1 g of (R)-5-cyclopentylpyrazolidin-3-one were added thereto. The resulting mixture was heated to reflux to react for 8 hours. After the reaction was completed, the resulting mixture was adjusted to pH 12 with hydrochloric acid, concentrated under reduced pressure, and then dissolved in 100 mL of methanol. Then 1.4 g of sodium methoxide was added to the resulting mixture, heated to reflux for 0.5 h and concentrated to dryness, and the residue was refined with ethyl acetate for 2 h and then suction-filtered to obtain sodium (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionate (6.7 g, 73.0%).

(22) Method III: 10.1 g of 3-hydroxy-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) acrylaldehyde was added into 200 mL of anhydrous ethanol, and then 8.23 g of (R)-5-cyclopentylpyrazolidin-3-one was added thereto. The resulting mixture was heated to reflux to react for 36 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to distill off the solvent, and then 120 g of 2M NaOH solution was added to the residue and stirred at room temperature for 5 h, and the pH was adjusted to 67 with 3M HCl. Then, 200 mL of ethyl acetate was added to wash the resulting mixture three times, and the aqueous phase was further adjusted to pH 55.5 with 3M HCl and then extracted three times with 400 mL of ethyl acetate. The organic layers were combined and concentrated to dryness to obtain (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionic acid (11.3 g, 65.7%).

(23) .sup.1H-NMR (500 MHz, DMSO-d6): =12.12 (bs, 1H), 8.66 (s, 2H), 8.28 (s, 1H), 7.56 (s, 1H), 6.98 (s, 1H), 4.684.39 (m, 1H), 2.99 (t, J=13.0 Hz, 1H), 2.84 (d, J=16.6 Hz, 1H), 2.430.89 (m, 10H);

(24) MS (ES): 326.16 (M+H.sup.+).

Step 4: (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionamide

(25) 48 g of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionic acid was added to a mixed solvent of 48 mL of dichloromethane and 80 mL of NMP, and then 48 mL of oxalyl chloride was added dropwise thereto, and the temperature during this process was kept not higher than 5 C. After the addition was completed, the resulting mixture reacted for 2.5 hours at a temperature maintained at 2025 C. The above reaction solution was then dropped into an appropriate amount of aqueous ammonia and reacted for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to remove the dichloromethane, the aqueous phase was extracted with ethyl acetate (800 mL3), and the resulting organic phase was concentrated under reduced pressure to remove the ethyl acetate to obtain (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionamide (29.8 g, 62%).

(26) .sup.1H-NMR (500 MHz, DMSO-d6): =12.06 (bs, 1H), 8.67 (s, 1H), 8.58 (s, 1H), 8.28 (s, 1H), 7.56 (d, J=3.6 Hz, 1H), 7.35 (d, J=3.1 Hz, 1H), 6.98 (d, J=3.6 Hz, 1H), 6.79 (d, J=3.1 Hz, 1H), 4.59 (td, J=9.7, 3.9 Hz, 1H), 2.90 (dd, J=15.3, 10.0 Hz, 1H), 2.732.62 (m, 2H), 1.84 (dddd, J=40.6, 13.1, 8.0, 4.6 Hz, 2H), 1.561.24 (m, 6H);

(27) MS (ES): 325.18 (M+H.sup.+).

Step 5: (R)-3-cyclopentyl-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile

(28) 14.6 g of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionamide was added to a mixed solvent of 480 mL of dichloromethane and 40 mL of NMP, and then 28 mL of phosphorus oxychloride was added dropwise thereto. The reaction was performed at room temperature, the temperature during this process was kept not higher than 30 C., and the reaction was carried out for 3 hours. After the reaction was completed, to the reaction solution was added 600 mL of purified water, and then a saturated sodium bicarbonate solution was added dropwise until the pH of the mixture solution was 7. The mixture solution was layered, and the organic phase was concentrated under reduced pressure to obtain (R)-3-cyclopentyl-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile (10.6 g, 77.3%).

(29) .sup.1H-NMR (500 MHz, DMSO-d6): =12.13 (bs, 1H), 8.84 (d, J=0.4 Hz, 1H), 8.69 (s, 1H), 8.37 (s, 1H), 7.63 (dd, J=2.3, 3.5 Hz, 1H), 7.01 (dd, J=1.4, 3.4 Hz, 1H), 4.56 (td, J=19.5, 4.6 Hz, 1H), 3.26 (dd, J=17.3, 9.9 Hz, 1H), 3.17 (dd, J=17.4, 4.3 Hz, 1H), 2.43 (m, 1H), 1.83 (m, 1H), 1.641.09 (m, 7H);

(30) MS (ES): 307.17 (M+H.sup.+).

Example 3: 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

(31) ##STR00034##

(32) 450 g of 4-chloropyrrolo[2,3-d]pyrimidine was added to 3.6 L of DMF, and the temperature was lowered to 10 C.20 C., and then 144 g of sodium hydride (60%) was added in batches. 586.0 g of 2-(trimethylsilyl)ethoxymethyl chloride was slowly added dropwise to the resulting mixture and stirred to react for 2 hours. After the reaction was completed, the reaction was quenched by dropwise adding 36 g of glacial acetic acid under stirring. Then, the reaction solution was poured into 14.4 L of purified water, and extracted with ethyl acetate, and then the organic layer was washed with saturated brine. The organic layer was concentrated under reduced pressure to remove the solvent, and the residue was purified by using 200300 mesh silica gel column chromatography to obtain 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (808.2 g, 97.2%).

(33) .sup.1H-NMR (500 MHz, DMSO-d6): =8.69 (s, 1H), 7.85 (d, J=3.8 Hz, 1H), 6.70 (d, J=3.6 Hz, 1H), 5.62 (s, 2H), 3.53 (t, J=7.9 Hz, 2H), 0.81 (t, J=8.1 Hz, 2H), 0.23 (s, 9H);

(34) MS (ES): 284.10 (M+H.sup.+).

Example 4: (R)-3-cyclopentyl-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile

(35) ##STR00035## ##STR00036##

Step 1: 4-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

(36) 103.6 g of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine and 2.96 g of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium were added to 1.13 L of tetrahydrofuran, and cooled down to 155 C., and then 200 mL of methylmagnesium bromide (3M dissolved in ether) was slowly added dropwise thereto. After the addition was completed, the resulting mixture was heated to 6065 C. and reacted under reflux for 2 hours. After the reaction was completed, the temperature was lowered to 155 C., and then the reaction was quenched by slowly dropwise adding 455 mL of a saturated ammonium chloride solution. The resulting mixture was filtered, the filter cake was rinsed with 455 mL of tetrahydrofuran, and then the filter cake was discarded, and the filtrate was concentrated under reduced pressure. To the residue was added 455 mL of purified water, and 1.13 L of ethyl acetate was added to extract the resulting mixture twice. The organic phases were combined and washed with 150 g of saturated brine. Then, the organic phase was concentrated under reduced pressure to distill off the solvent to obtain 103.2 g 4-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine.

(37) .sup.1H-NMR (500 MHz, DMSO-d6): =8.67 (s, 1H), 7.63 (d, J=3.7 Hz, 1H), 6.70 (d, J=3.6 Hz, 1H), 5.60 (s, 2H), 3.543.45 (m, 2H), 2.64 (s, 3H), 0.81 (t, J=8.0 Hz, 2H), 0.12 (s, 9H);

(38) MS (ES): 264.15 (M+H.sup.+).

Step 2: 3-hydroxy-2-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)acrylaldehyde

(39) 103.2 g of 4-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine was added into 453 mL of DMF and cooled down to 155 C., and then 184.2 g of phosphorus oxychloride was added dropwise thereto under stirring, and the temperature was kept at 55 C. After the addition was completed, the resulting mixture was heated to 80 C. and stirred to react for 3 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to distill off the DMF, to the residue was added 1.13 L of tetrahydrofuran, and the temperature was lowered to 05 C. NaOH solution was slowly added dropwise to the resulting mixture, and the temperature of the solution was kept below 20 C. After the addition was completed, the resulting mixture was heated to 60 C. and stirred to react for 2 hours. The reaction solution was concentrated under reduced pressure, adjusted to pH 4 with 3M hydrochloric acid, and then extracted twice with 1.13 L of ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then decolorized by activated carbon. Then, the resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a black sticky residue. 453 mL of anhydrous ether was added to the black sticky residue, and the temperature was raised until a clear solution was obtained, and then the resulting solution was slowly cooled down to 05 C., and crystallized under stirring for 4 hours. The resulting mixture was filtered, and the filter cake was rinsed twice with in total 113 mL of ether and then dried under reduced pressure to obtain 3-hydroxy-2-((4(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) acrylaldehyde (53.2 g, 41.9%).

(40) .sup.1H-NMR (500 MHz, DMSO-d6): =15.77 (s, 1H), 9.51 (s, 2H), 8.80 (s, 1H), 7.70 (d, J=3.7 Hz, 1H), 7.58 (d, J=3.7 Hz, 1H), 5.63 (s, 2H), 3.553.48 (m, 2H), 0.83 (t, J=8.0 Hz, 2H), 0.10 (s, 9H);

(41) MS (ES): 320.14 (M+H.sup.+).

Step 3: (R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionic acid

(42) 51.2 g of 3-hydroxy-2-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)acrylaldehyde was added to 2.05 L of anhydrous ethanol. After the solution was clear, 53.7 g of (R)-5-cyclopentylpyrazolidin-3-one D-tartrate was added thereto, and the resulting mixture was heated to 8085 C. and reacted under reflux for 9 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to distill off the solvent, and to the residue was added 640 g of 2M NaOH solution. The resulting mixture was stirred at room temperature for 1.0 hour, adjusted to pH 34 with 3M HCl, and then extracted twice by adding 256 mL of ethyl acetate. The organic layers were combined and washed with saturated brine. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by using 200-300 mesh silica gel column chromatography to obtain (R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) propionic acid (58.4 g, 79.6%).

(43) .sup.1H-NMR (500 MHz, DMSO-d6): =12.22 (s, 1H), 8.74 (s, 1H), 8.70 (s, 1H), 8.31 (s, 1H), 7.74 (d, J=3.7 Hz, 1H), 7.09 (d, J=3.7 Hz, 1H), 5.63 (s, 2H), 4.55 (td, J=9.9, 3.7 Hz, 1H), 3.52 (t, J=8.0 Hz, 2H), 3.04 (dd, J=16.5, 10.3 Hz, 1H), 2.89 (dd, J=16.4, 3.7 Hz, 1H), 2.35 (d, J=8.5 Hz, 1H), 1.81 (dtd, J=11.0, 6.9, 3.7 Hz, 1H), 1.621.47 (m, 3H), 1.311.21 (m, 3H), 0.83 (t, J=8.0 Hz, 2H), 0.10 (s, 9H);

(44) MS (ES): 456.24 (M+H.sup.+).

Step 4: (R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionamide

(45) 49.2 g of (R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionic acid was added to 480 mL of dichloromethane, and then 16.59 mL of oxalyl chloride was added dropwise thereto. After the addition was completed, 0.1 mL of DMF was added to the resulting mixture and reacted at 2025 C. for 3 hours. The reaction solution was then dropped into 480 mL of aqueous ammonia and reacted for 1 hour. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to remove the dichloromethane. The aqueous phase was extracted three times with ethyl acetate (450 mL3) and the resulting organic phase was concentrated under reduced pressure to remove the ethyl acetate to obtain (R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionamide (48 g, 97.5%).

(46) .sup.1H-NMR (500 MHz, DMSO-d6): =8.73 (s, 1H), 8.61 (s, 1H), 8.29 (s, 1H), 7.74 (d, J=3.7 Hz, 1H), 7.34 (d, J=2.6 Hz, 1H), 7.08 (d, J=3.6 Hz, 1H), 6.76 (d, J=2.5 Hz, 1H), 5.63 (s, 2H), 4.59 (td, J=9.7, 3.9 Hz, 1H), 3.53 (t, J=8.0 Hz, 2H), 2.89 (dd, J=15.3, 10.0 Hz, 1H), 2.66 (dd, J=15.3, 3.9 Hz, 1H), 2.36 (q, J=8.4 Hz, 1H), 1.81 (dtd, J=11.6, 7.1, 3.7 Hz, 1H), 1.621.48 (m, 3H), 1.461.37 (m, 1H), 1.26 (td, J=14.9, 13.6, 7.9 Hz, 3H), 0.83 (t, J=8.0 Hz, 2H), 0.10 (d, J=1.7 Hz, 9H);

(47) MS (ES): 455.26 (M+H.sup.+).

Step 5: (R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile

(48) 200 mL of dichloromethane was added to 42.6 g of (R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) propionamide, and then 57 mL of phosphorus oxychloride was added dropwise thereto and the resulting mixture reacted at room temperature for 24 hours. After the reaction was completed, to the resulting mixture was added 300 mL of purified water, and a saturated sodium bicarbonate solution was added dropwise until the pH of the mixture solution was 7. The mixture solution was layered, and the organic phase was concentrated under reduced pressure to obtain (R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile (38.4 g, 93.8%).

(49) .sup.1H-NMR (500 MHz, DMSO-d6): =8.83 (s, 1H), 8.75 (s, 1H), 8.39 (s, 1H), 7.77 (d, J=3.7 Hz, 1H), 7.09 (d, J=3.7 Hz, 1H), 5.63 (s, 2H), 4.53 (td, J=9.4, 4.0 Hz, 1H), 3.51 (t, J=8.1 Hz, 2H), 3.23 (dq, J=9.3, 4.3 Hz, 2H), 2.41 (m, 1H), 1.79 (m, 1H), 1.661.13 (m, 7H), 0.81 (t, J=8.2 Hz, 2H), 0.124 (s, 9H);

(50) MS (ES): 437.25 (M+H.sup.+).

Step 6: (R)-3-cyclopentyl-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile

(51) 35 g of (R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionitrile was added to 700 mL of acetonitrile, and then 31.5 mL of boron trifluoride ethyl ether was added dropwise thereto. After the addition was completed, the resulting mixture was heated to 6070 C. and reacted for 5 hours, and then 270 mL of aqueous ammonia and 540 mL of purified water were added thereto and stirred at room temperature for 12 hours. After the reaction was completed, to the reaction solution were added 200 mL of ethyl acetate and 200 mL of saturated ammonium chloride, the aqueous phase was extracted three times with ethyl acetate (300 mL3), and the organic phase was concentrated under reduced pressure to obtain (R)-3-cyclopentyl-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl) propionitrile (22.61 g, 92.1%).

(52) .sup.1H-NMR (500 MHz, DMSO-d6): =12.10 (bs, 1H), 8.80 (d, J=0.4 Hz, 1H), 8.68 (s, 1H), 8.37 (s, 1H), 7.60 (dd, J=2.3, 3.5 Hz, 1H), 6.99 (dd, J=1.4, 3.4 Hz, 1H), 4.53 (td, J=9.5, 4.3 Hz, 1H), 3.26 (dd, J=17.3, 9.9 Hz, 1H), 3.19 (dd, J=17.4, 4.3 Hz, 1H), 2.39 (m, 1H), 1.82 (m, 1H), 1.601.08 (m, 7H);

(53) MS (ES): 307.17 (M+H.sup.+).

Example 5: (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionamide

(54) ##STR00037##

(55) 6.0 g of (R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propionamide was added to 120 mL of acetonitrile, and then 6 mL of boron trifluoride ethyl ether was added dropwise thereto. After the addition was completed, the resulting mixture was heated to 6070 C. and reacted for 7 hours, and then 60 mL of aqueous ammonia and 54 mL of purified water were added thereto and stirred at room temperature for 6 hours. After the reaction was completed, to the reaction solution were added 60 mL of ethyl acetate and 50 mL of saturated sodium chloride, the aqueous phase was extracted three times with ethyl acetate (60 mL3), and the organic phase was concentrated under reduced pressure to obtain (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionamide (4.08 g, 95.3%).

(56) .sup.1H-NMR (500 MHz, DMSO-d6): =12.06 (bs, 1H), 8.66 (s, 1H), 8.58 (s, 1H), 8.29 (s, 1H), 7.56 (d, J=3.6 Hz, 1H), 7.33 (d, J=3.1 Hz, 1H), 6.97 (d, J=3.6 Hz, 1H), 6.79 (d, J=3.1 Hz, 1H), 4.55 (td, J=9.7, 3.9 Hz, 1H), 2.90 (dd, J=15.3, 10.0 Hz, 1H), 2.722.62 (m, 2H), 1.84 (dddd, J=40.6, 13.1, 8.0, 4.6 Hz, 2H), 1.551.24 (m, 6H);

(57) MS (ES): 325.11 (M+H.sup.+).

Example 6: (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionamide

(58) ##STR00038##

(59) 3-hydroxy-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)acrylaldehyde (30.1 g) was added to a mixed solvent of 180 mL of tetrahydrofuran and 180 mL of aqueous ammonia to obtain a clear solution, and then 29.4 g (R)-5-cyclopentylpyrazolidin-3-one was added thereto. After the addition was completed, the resulting mixture was reacted for 10 hours at a temperature maintained at 6070 C., and then water (1.2 L) was added thereto and the resulting mixture was extracted with ethyl acetate (1.8 L3). Then, the ethyl acetate was removed by concentrating under reduced pressure to obtain a concentrate (50.4 g). The concentrate was heated under reflux and refined for 1 h in acetonitrile, slowly cooled down, and stirred at 05 C. for 1 h. The resulting mixture was suction-filtered to obtain a red-brown solid, and a crude product (33.2 g) was obtained by collecting with a yield of 64.4%. The crude product was heated in 300 mL of isopropanol and dissolved to obtain a clear solution. Then, the resulting solution was cooled, stirred and crystallized, and then suction-filtered to obtain (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionamide (15.3 g, 46.1%, purity>99.4%).

(60) .sup.1H-NMR (500 MHz, DMSO-d6): =12.04 (bs, 1H), 8.67 (s, 1H), 8.56 (s, 1H), 8.26 (s, 1H), 7.54 (d, J=3.6 Hz, 1H), 7.33 (d, J=3.1 Hz, 1H), 6.96 (d, J=3.6 Hz, 1H), 6.77 (d, J=3.1 Hz, 1H), 4.57 (td, J=9.7, 3.9 Hz, 1H), 2.90 (dd, J=15.3, 10.0 Hz, 1H), 2.712.63 (m, 2H), 1.82 (dddd, J=40.6, 13.1, 8.0, 4.6 Hz, 2H), 1.541.22 (m, 6H);

(61) MS (ES): 325.18 (M+H.sup.+).