WO2021136482A1

WO2021136482A1 - Method for preparing pf06651600 and intermediate used therein

Info

Publication number: WO2021136482A1
Application number: PCT/CN2020/142008
Authority: WO
Inventors: 陈磊; 吴心宇; 陆平波
Original assignee: 江苏艾立康医药科技有限公司
Priority date: 2019-12-31
Filing date: 2020-12-31
Publication date: 2021-07-08
Also published as: CN113121539A

Abstract

Disclosed are a method for preparing PF06651600 and an intermediate used therein. The method for preparing PF06651600 comprises the following processes: compound 5 and acryloyl chloride undergo an aminolysis reaction to obtain compound PF06651600; compound 4 is subjected to debenzylation by means of catalytic hydrogenation to obtain compound 5; furthermore, compound 2 and compound 3 undergo a nucleophilic substitution reaction to obtain compound 4.

Description

Preparation method of PF06651600 and its intermediates

Technical field

The present invention relates to the field of medicine, in particular to a method for preparing PF06651600 and intermediate compounds used in the method.

Background technique

PF-06651600(1) is a highly selective oral bioavailable Janus kinase 3 (JAK3) inhibitor researched and developed by Pfizer, representing a potential immunomodulatory treatment. Due to its good efficacy, safety and ADME properties, this JAk3 specific covalent inhibitor has been used in the treatment of alopecia areata, rheumatoid arthritis, Crohn's disease and ulcerative colitis. On September 5, 2018, with the support of the positive results of a Phase II study, the FDA awarded PF-06651600 the title of "Breakthrough Therapy" for the treatment of alopecia areata.

The preparation method of the compound is disclosed in WO2015/083028, which is specifically as follows.

The synthesis route of the above method is tedious, and the two chiral chromatographic column separations are not only low in yield, high in cost, and unable to be scaled up; the dry Pd/C catalyst used in catalytic hydrogenation is very dangerous and often fails to complete the reaction, requiring two rounds Hydrodechlorination is obviously not suitable for large-scale production.

In view of this, there is an urgent need to develop a new method of synthesizing PF06651600.

Summary of the invention

An object of the present invention is to provide a new method for preparing compound PF06651600.

Another object of the present invention is to provide an intermediate compound for preparing compound PF06651600.

Another object of the present invention is to provide a method for preparing the intermediate compound.

In one aspect, the present invention provides a method for preparing compound PF06651600, which comprises the following steps:

Aminolysis reaction between compound 5 and acryloyl chloride to obtain compound PF06651600:

According to a specific embodiment of the present invention, the method for preparing compound PF06651600 in the present invention further includes a process of preparing compound 5 by catalytic hydrogenation debenzylation:

The method for preparing compound PF06651600 provided by the present invention can take the compound 4 as a raw material, undergo debenzylation by catalytic hydrogenation, and undergo aminated reaction with acryloyl chloride to obtain compound PF06651600.

According to a specific embodiment of the present invention, the method for preparing compound PF06651600 in the present invention further includes a process of preparing compound 4 by performing a nucleophilic substitution reaction between compound 2 and compound 3:

According to a specific embodiment of the present invention, in the present invention, when compound 5 and acryloyl chloride are subjected to amination reaction, the molar ratio of compound 5 to acryloyl chloride is 1:1.0 to 2.0, preferably 1:1.2.

According to a specific embodiment of the present invention, in the present invention, the amidolysis reaction between compound 5 and acryloyl chloride is carried out in a solvent, the solvent used is a mixed system of tetrahydrofuran and water, and the mass-volume ratio of compound 5 to tetrahydrofuran is 1:5 ～50, the mass volume ratio of compound 5 to water is 1:5～50;

According to a specific embodiment of the present invention, in the present invention, preferably, the mass-volume ratio (g:mL:mL) of compound 5, tetrahydrofuran and water is 1:20:10.

According to a specific embodiment of the present invention, in the present invention, the reaction system for the aminated reaction between compound 5 and acryloyl chloride also contains an acid binding agent, and the acid binding agent is selected from potassium carbonate, sodium carbonate, cesium carbonate, and potassium bicarbonate. One or more of sodium bicarbonate; the molar ratio of compound 5 to acid binding agent is 1:1.0 to 10.0, preferably 1:5.0.

According to a specific embodiment of the present invention, in the present invention, the reaction temperature of the amination reaction is 0-30°C, preferably 0-5°C.

According to a specific embodiment of the present invention, in the present invention, in the process of preparing compound 5 by catalytic hydrogenation debenzylation, palladium on carbon or palladium hydroxide on carbon is used as the catalyst; preferably, the catalyst is wet palladium on carbon or hydrogen. Palladium oxide on carbon. In some more specific embodiments of the present invention, the catalyst is wet 20% palladium hydroxide on carbon (20% palladium hydroxide on carbon refers to a dry basis of palladium hydroxide on carbon, containing 20% palladium hydroxide).

According to specific embodiments of the present invention, in the present invention, preferably, the mass ratio of compound 4 to the catalyst is 1:0.1 to 0.3, preferably 1:0.2.

According to a specific embodiment of the present invention, in the present invention, compound 4 undergoes catalytic hydrogenation debenzylation reaction in a solvent selected from one or more mixed solvents of methanol, ethanol, and tetrahydrofuran.

According to a specific embodiment of the present invention, in the present invention, the reaction temperature of catalytic hydrogenation debenzylation is 40-60°C, preferably 45-55°C; the hydrogen pressure is 10-60 psi, preferably 15 psi.

According to a specific embodiment of the present invention, in the present invention, the nucleophilic substitution reaction of compound 2 and compound 3 is carried out in a solvent, and the reaction solvent is selected from one or more of alcohols, pyrrolidones, and amides , Preferably n-butanol, 1-methyl-2-pyrrolidone or N,N-dimethylformamide.

According to a specific embodiment of the present invention, in the present invention, the reaction system for the nucleophilic substitution reaction of compound 2 and compound 3 further includes an acid binding agent; the acid binding agent is an inorganic base or an organic base; and the inorganic base is selected from One or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, and sodium bicarbonate; the inorganic base is selected from one or more of triethylamine, diisopropylethylamine, pyridine, and imidazole Kind.

In addition, the present invention also provides an intermediate for preparing compound PF06651600, which is compound 4 or compound 5 having the following structure:

The present invention also provides a preparation method of intermediate compound 4, which comprises:

Compound 4 is prepared by nucleophilic substitution reaction between compound 2 and compound 3:

The present invention also provides a preparation method of intermediate compound 5, which comprises:

Compound 5 is prepared by catalytic hydrogenation debenzylation of compound 4:

According to a specific embodiment of the present invention, the preparation method of the intermediate compound 5 of the present invention preferably further includes a process of preparing compound 4 by performing a nucleophilic substitution reaction between compound 2 and compound 3.

In summary, the present invention provides a new method for preparing compound PF06651600. The reaction route and steps of the method are relatively short. The raw materials of enantiomers are directly used for synthesis, which avoids the two steps in the prior art method. Chiral chromatographic column resolution; avoids the use of dry palladium on carbon, and does not require repeated hydrogenation and dechlorination. It can be hydrogenated under normal pressure, reducing dangerous operations, and has a mild reaction and high controllability. It has a good industrial application prospect.

Description of the drawings

Figure 1 is the hydrogen spectrum of compound 4 prepared by the present invention.

Figure 2 is the hydrogen spectrum of the compound PF06651600 prepared by the present invention.

Detailed ways

In order to have a clearer understanding of the technical features, purposes and beneficial effects of the present invention, the following detailed descriptions are now made with reference to specific embodiments and the technical solutions of the present invention. It should be understood that these examples are only used to illustrate the present invention and not to limit the present invention. range. In the examples, the experimental methods without specifying specific conditions are conventional methods and conventional conditions well-known in the art, or according to the conditions recommended by the instrument manufacturer.

Example 1

Synthesis of N-((3R,6S)-1-benzyl-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Compound 4)

In a 5L autoclave, add (3R, 6S)-1-benzyl-6-methylpiperidin-3-amine (170.00g, 832.04mmol, 1.0eq), 4-chloropyrrolo[2,3- D] pyrimidine (140.55g, 915.24mmol, 1.0eq), diisopropylethylamine (287.60g, 2.50mol, 3.0eq), add n-butanol (1700mL), raise the temperature to 140°C and stir overnight, TLC monitoring (dichloro Methane/methanol=20:1), the reaction is complete, the heating is stopped, and the temperature is naturally cooled to room temperature. Add ethyl acetate (3500 mL) and water (3500 mL), stir and separate the layers, and concentrate the organic phase under reduced pressure to obtain a brown semi-oil semi-solid crude product. The crude product was placed in a 3000mL single-necked flask and added ethyl acetate (510mL) and n-hexane (1530mL), heated to 60°C and stirred for 1h, naturally cooled to room temperature and stirred overnight, and filtered under reduced pressure to obtain a yellow solid N-((3R, 6S)-1-benzyl-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4amine (195.00 g, 72.91%).

MS: [M+H] ⁺ = 322.2; ¹ H-NMR (400MHz, DMSO-d6) δppm 11.45 (s, 1H), 8.03 (s, 1H), 7.38～7.15 (m, 5H), 7.05 (dd, 1H), 6.93(d,1H), 6.54(s,1H), 4.24(s,1H), 3.63(d,1H), 3.53(d,1H), 2.83(q,1H), 2.55(dd,1H) ), 2.48～2.41(m,1H), 1.82～1.47(m,4H), 1.06(d,3H).

In a 3L reactor, add (3R, 6S)-1-benzyl-6-methylpiperidin-3-amine (170.00g, 832.04mmol, 1.0eq), 4-chloropyrrolo[2,3- D] Pyrimidine (140.55g, 915.24mmol, 1.0eq), potassium carbonate (126.49g, 915.24mmol, 1.10eq), add 1-methyl-2-pyrrolidone (600mL), water (300mL), warm to 110°C and stir overnight , TLC monitoring (dichloromethane/methanol=20:1), the reaction was complete, the heating was stopped, and the temperature was naturally cooled to room temperature. Water (1200 mL) was added, a large amount of solids precipitated, stirring was continued for 1 h, and suction filtration was performed under reduced pressure to obtain a crude yellow solid. The crude product was placed in a 3000mL single-neck flask and ethanol (1360mL) was added. The temperature was raised to 60°C and stirred for 1 hour. The temperature was naturally cooled to room temperature and stirred overnight. The product was filtered under reduced pressure to obtain a light yellow solid N((3R, 6S)-1-benzyl -6-Methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (195.00 g, 72.91%). MS: [M+H] ⁺ =322.2.

The hydrogen spectrum of compound 4 prepared in this example is shown in FIG. 1.

Synthesis of N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Compound 5)

Add N-((3R,6S)-1-benzyl-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine in a 5L hydrogenation reactor under nitrogen atmosphere -4-amine (190.00g, 591.11mmol), add 20% wet palladium hydroxide on carbon (38.00g, 20% w/w), add methanol (2850mL), replace with hydrogen three times under stirring, heat up to 55℃, Under a hydrogen environment (15 psi), the reaction was kept at 45-55°C for 8 hours, monitored by TLC (dichloromethane/methanol=10:1, 0.5% ammonia water), the reaction was complete, the heating was stopped, and the temperature was lowered to room temperature. Replace with nitrogen three times, filter by pressing, wash the filter cake with methanol, and concentrate the filtrate under reduced pressure to obtain a white solid N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d ] Pyrimidine-4-amine (130.00 g, 95.08%).

(-)1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)propan-2 Synthesis of En-1-one (Compound PF06651600)

In a 5000mL three-necked flask, add N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (125.00g, 540.42) mmol, 1.0eq), sodium bicarbonate (226.99g, 2.70mol, 5.0eq), add tetrahydrofuran (2500mL), water (1250mL), stir the system into a white turbid liquid, cool to 0℃, control the internal temperature 0～5 Add acryloyl chloride (58.69g, 648.50mmol) dropwise at ℃, the system turns slightly yellow, keep it at 0～5℃ and stir for 4h, TLC monitoring (dichloromethane/methanol=10:1, 0.5% ammonia water) shows that the raw material reaction is complete, stop Cool down, naturally warm up to room temperature and stir. Add water (2500 mL) to dilute, and extract with ethyl acetate (2500 mL×2), combine the organic phases, wash once with saturated brine (2000 mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude white solid.

In a 3000mL single-neck flask, add the crude product, ethyl acetate (500mL) and n-hexane (1000mL), raise the temperature to 60℃ and stir for 1h, naturally cool to room temperature and stir overnight, filter under reduced pressure, rinse the filter cake with n-hexane, and pump dry. The filter cake was transferred to a 2000 mL single-necked flask, ethyl acetate (250 mL) and n-hexane (500 mL) were added, the temperature was raised to 60°C and stirred for 1 h, the temperature was naturally cooled to room temperature, and the cake was stirred overnight, filtered under reduced pressure, and the filter cake was rinsed with n-hexane. It was drained and dried in a blast oven at 60° C. for 8 hours to obtain a white solid powder (101.50 g, 65.82%).

MS: [M+H] ⁺ =286.1, [M+Na] ⁺ =308.1; 1H-NMR(400MHz,DMSO-d6)δppm 11.51(s, 1H), 8.11(d,1H), 7.34～7.18(m ,1H), 7.09(dd,1H), 6.79(q,1H), 6.54(dd,1H), 6.09(dd,1H), 5.67(dd,1H), 4.80(s,0.5H), 4.55(d ,0.5H), 4.37(s,0.5H), 4.00～4.14(m,1.5H), 2.95(t,0.5H), 2.59(t,0.5H), 1.55～1.89(m,4H), 1.16～ 1.26 (m, 3H).

Refer to Figure 2 for the hydrogen spectrum of the compound PF06651600 prepared in this example.

Claims

A method for preparing compound PF06651600, which includes the following steps:

Aminolysis reaction between compound 5 and acryloyl chloride to obtain compound PF06651600:
The method according to claim 1, which further comprises a process of preparing compound 5 by using compound 4 through catalytic hydrogenation debenzylation:
The method according to claim 2, further comprising a process of preparing compound 4 by performing a nucleophilic substitution reaction between compound 2 and compound 3:
The method according to any one of claims 1 to 3, wherein the molar ratio of compound 5 to acryloyl chloride is 1:1.0 to 2.0, preferably 1:1.2 when compound 5 is subjected to amination reaction with acryloyl chloride.
The method according to any one of claims 1 to 4, wherein the amidation reaction of compound 5 and acryloyl chloride is carried out in a solvent, the solvent used is a mixed system of tetrahydrofuran and water, and the mass-volume ratio of compound 5 to tetrahydrofuran It is 1:5-50, and the mass-volume ratio of compound 5 to water is 1:5-50;

Preferably, the mass-volume ratio (g:mL:mL) of compound 5, tetrahydrofuran and water is 1:20:10.
The method according to any one of claims 1 to 5, wherein the reaction system for the aminated reaction between compound 5 and acryloyl chloride further contains an acid binding agent, and the acid binding agent is selected from the group consisting of potassium carbonate, sodium carbonate, and cesium carbonate. One or more of potassium bicarbonate and sodium bicarbonate; the molar ratio of compound 5 to the acid binding agent is 1:1.0 to 10.0, preferably 1:5.0.
The method according to any one of claims 1 to 3, wherein the reaction temperature of the amination reaction is 0 to 30°C, preferably 0 to 5°C.
The method according to claim 2, wherein in the process of preparing compound 5 from compound 4 through catalytic hydrogenation debenzylation, palladium on carbon or palladium hydroxide on carbon is used as a catalyst; preferably, the catalyst is wet 20% palladium hydroxide carbon;

Preferably, the mass ratio of compound 4 to the catalyst is 1:0.1 to 0.3, preferably 1:0.2.
The synthesis method according to claim 2 or 8, wherein the compound 4 undergoes catalytic hydrogenation debenzylation reaction in a solvent, and the solvent is selected from one or more mixed solvents of methanol, ethanol, and tetrahydrofuran.
The method according to claim 2 or 8 or 9, wherein the reaction temperature of catalytic hydrogenation debenzylation is 40-60°C, preferably 45-55°C; hydrogen pressure is 10-60 psi, preferably 15 psi.
The method according to claim 3, wherein the nucleophilic substitution reaction of compound 2 and compound 3 is carried out in a solvent, and the reaction solvent is selected from one or more of alcohols, pyrrolidones, and amides, Preferably, it is n-butanol, 1-methyl-2-pyrrolidone or N,N-dimethylformamide.
The method according to claim 11, wherein the reaction system for the nucleophilic substitution reaction of compound 2 and compound 3 further comprises an acid binding agent; the acid binding agent is an inorganic base or an organic base; and the inorganic base is selected from carbonic acid One or more of potassium, sodium carbonate, cesium carbonate, potassium bicarbonate, and sodium bicarbonate; the inorganic base is selected from one or more of triethylamine, diisopropylethylamine, pyridine, and imidazole .
An intermediate for the preparation of compound PF06651600, which is compound 4 or compound 5 with the following structure:
A preparation method of intermediate compound 4, which comprises:

Compound 4 is prepared by nucleophilic substitution reaction between compound 2 and compound 3:
A preparation method of intermediate compound 5, which comprises:

Compound 5 is prepared by catalytic hydrogenation debenzylation of compound 4:

Preferably, the method further includes a process of preparing compound 4 by performing a nucleophilic substitution reaction between compound 2 and compound 3.