CN113121539A - Preparation method of PF06651600 - Google Patents

Preparation method of PF06651600 Download PDF

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CN113121539A
CN113121539A CN201911417142.7A CN201911417142A CN113121539A CN 113121539 A CN113121539 A CN 113121539A CN 201911417142 A CN201911417142 A CN 201911417142A CN 113121539 A CN113121539 A CN 113121539A
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tetrahydrofuran
reaction
mass
carbonate
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陈磊
吴心宇
陆平波
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Jiangsu Ailikang Pharmaceutical Technology Co ltd
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Priority to PCT/CN2020/142008 priority patent/WO2021136482A1/en
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention provides a preparation method of PF06651600, and specifically relates to a method for preparing a target substance PF06651600 by using a pure enantiomer (3R, 6S) -1-benzyl-6-methylpiperidine-3-amine as a starting material, reacting with 4-chloropyrrolo [2,3-D ] pyrimidine, hydrogenating and debenzylating, and reacting with acryloyl chloride. The invention takes the enantiomer as the raw material, avoids the later expensive chiral chromatographic separation, has mild reaction condition and high controllability, and has good industrial application prospect.

Description

Preparation method of PF06651600
Technical Field
The invention relates to the field of medicines, and particularly relates to a method for preparing PF 06651600.
Background
PF-06651600(1) is a highly selective oral bioavailable Janus kinase 3(JAK3) inhibitor developed by the company Peucedanum and represents a potential immunomodulatory treatment. Due to its good efficacy, safety and ADME properties, this JAk 3-specific covalent inhibitor has been used in the treatment of alopecia areata, rheumatoid arthritis, crohn's disease and ulcerative colitis. Year 2018, month 9, day 5, and with the support of positive results from a phase two study, the FDA awards PF-06651600 the title "breakthrough therapy" for the treatment of alopecia areata. The preparation of this compound is disclosed in patent WO2015/083028, specifically as follows.
Figure RE-RE-GDA0002388459260000011
Figure RE-RE-GDA0002388459260000021
The method has the advantages that the steps of a patent route are long, two times of chiral chromatographic column separation are carried out, the yield is low, the cost is high, and the amplification cannot be carried out; the dry Pd/C catalyst used in catalytic hydrogenation is very dangerous and often cannot be reacted completely, needs two rounds of hydrodechlorination and is obviously not suitable for large-scale production. In view of this, there is an urgent need to develop a new method for synthesizing PF06651600, which uses the raw material of enantiomer prepared by the classical resolution method in the early stage of synthesis, thereby avoiding chiral chromatographic separation; the process flow is optimized, all chromatographic purifications are eliminated, a more efficient catalyst is selected, and the total yield is improved.
Disclosure of Invention
The application provides a preparation method of PF06651600, which comprises the following steps:
(1) nucleophilic substitution reaction of (3R, 6S) -1-benzyl-6-methylpiperidine-3-amine (compound 2) and 4-chloropyrrolo [2,3-D ] pyrimidine (compound 3) to obtain a compound 4;
(2) carrying out catalytic hydrogenation debenzylation on the compound 4 to obtain a compound 5;
(3) carrying out aminolysis reaction on the compound 5 and acryloyl chloride to obtain a compound PF 06651600;
in some embodiments, the reaction solvent in step (1) is alcohols, pyrrolidones, amides, etc., preferably N-butanol, 1-methyl-2-pyrrolidone, N-dimethylformamide. The acid-binding agent is inorganic base or organic base, the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, etc., preferably potassium carbonate; the inorganic base is selected from triethylamine, diisopropylethylamine, pyridine, imidazole and the like, and preferably diisopropylethylamine.
In a specific embodiment, the reaction solvent in the step (1) is 1-methyl-2-pyrrolidone, and the acid-binding agent is potassium carbonate; in another specific embodiment, the reaction solvent in step (1) is n-butanol, and the acid-binding agent is diisopropylethylamine.
The catalyst in the step (2) is palladium carbon and palladium hydroxide carbon, preferably 20 percent wet palladium hydroxide carbon; the mass ratio of the N- ((3R, 6S) -1-benzyl-6-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (compound 4) to the catalyst is 1: 0.1-0.3, preferably 1: 0.2; the reaction temperature is 40-60 ℃, and preferably 45-55 ℃; the hydrogen pressure is 10-60 psi, preferably 15 psi.
The solvent used in the step (2) is one or two mixed solvents of methanol, ethanol, tetrahydrofuran and the like, and preferably methanol.
In a specific embodiment, the solvent in the step (2) is methanol, the catalyst is 20% wet palladium hydroxide carbon, the mass ratio of the compound 4 to the catalyst is 1:0.2, the reaction temperature is 45-55 ℃, and the hydrogen pressure is 15 psi.
The solvent used in the step (3) is a mixed system of tetrahydrofuran and water, and the mass volume ratio of the compound 5 to the tetrahydrofuran is 1: 5-50, wherein the mass-to-volume ratio of the compound 5 to water is 1: 5-50, preferably the mass-to-volume ratio (g: ml: ml) of compound 5, tetrahydrofuran and water is 1:20: 10; the molar ratio of the compound 5 to the acryloyl chloride is 1: 1.0-2.0, preferably 1: 1.2; the acid-binding agent is potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, etc., preferably sodium bicarbonate; the molar ratio of compound 5 to sodium bicarbonate was 1: 1.0-10.0, preferably 1: 5.0; the reaction temperature is 0-30 ℃, preferably 0-5 ℃.
In a specific embodiment, the mass to volume ratio (g: ml: ml) of compound 5, tetrahydrofuran and water in step (3) is 1:20: 10; the molar ratio of the compound 5 to acryloyl chloride and sodium bicarbonate is 1: 1.2: 5.0, and the reaction temperature is 0-5 ℃.
The advantages are that:
the method has shorter steps, and the raw materials of the enantiomers are directly used for synthesis, so that the twice chiral chromatographic column resolution in the patent method is avoided; the method avoids the use of dry palladium carbon, does not need repeated hydrogenation dechlorination and normal-pressure hydrogenation, reduces dangerous operation, has mild reaction and high controllability, and has good industrial application prospect.
The specific implementation mode is as follows:
the present invention is described in detail below by way of examples, and it should be pointed out again that the following examples are only used for further illustration of the present invention and should not be construed as limiting the scope of the present invention.
Synthesis of N- ((3R, 6S) -1-benzyl-6-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (4)
Figure RE-GDA0002388459260000031
To a 5L autoclave were added (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), n-butanol (1700ml) was added, the mixture was warmed to 140 ℃ and stirred overnight, monitored by TLC (dichloromethane/methanol 20:1), the reaction was completed, the heating was stopped, and the mixture was naturally cooled to room temperature. Adding ethyl acetate (3500ml) and water (3500ml), stirring, separating liquid, and concentrating organic phase under reduced pressure to obtain brown semi-oil semi-solid crude product. The crude product was placed in a 3000ml single neck flask and ethyl acetate (510ml) and N-hexane (1530ml) were added, the temperature was raised to 60 ℃ and stirred for 1H, the temperature was naturally lowered to room temperature and stirred overnight, and suction filtration under reduced pressure gave N- ((3R, 6S) -1-benzyl-6-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (195.00g, 72.91%) as a yellow solid, MS: [ M + H ] ═ 322.2.
To a 3L reaction kettle was added (3R, 6S) -1-benzyl-6-methylpiperidine-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), 1-methyl-2-pyrrolidone (600ml) was added, water (300ml) was warmed to 110 ℃ and stirred overnight, monitored by TLC (dichloromethane/methanol ═ 20:1), the reaction was complete, heating was stopped, and the temperature was naturally decreased to room temperature. Adding water (1200ml) to separate out a large amount of solid, continuing stirring for 1h, and carrying out suction filtration under reduced pressure to obtain a yellow solid crude product. The crude product was placed in a 3000ml single neck flask with ethanol (1360ml) added, warmed to 60 ℃ and stirred for 1H, cooled naturally to room temperature and stirred overnight, filtered under reduced pressure to give N- ((3R, 6S) -1-benzyl-6-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine as a pale yellow solid (195.00g, 72.91%). MS [ [ M + H ] ] -322.2.
Synthesis of N- ((3R, 6S) -6-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (5)
Figure RE-GDA0002388459260000041
In a 5L hydrogenation reactor, N- ((3R, 6S) -1-benzyl-6-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (190.00g,591.11mmol) was added under a nitrogen atmosphere, 20% wet palladium carbon hydroxide (38.00g, 20% w/w) was added, methanol (2850ml) was added, hydrogen substitution was performed three times with stirring, the temperature was increased to 55 ℃, the reaction was maintained at 45 to 55 ℃ for 8 hours under a hydrogen atmosphere (15psi), TLC monitoring (dichloromethane/methanol ═ 10:1, 0.5% ammonia) was performed, the reaction was completed, heating was stopped, and the temperature was decreased to room temperature. Replacing nitrogen for three times, performing filter pressing, washing a filter cake by methanol, and concentrating a filtrate under reduced pressure to obtain white solid N- ((3R, 6S) -6-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-amine (130.00g, 95.08%)
Synthesis of (-)1- ((2S, 5R) -5- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) -2-methylpiperidin-1-yl) prop-2-en-1-one (PF06651600)
Figure RE-GDA0002388459260000051
Adding N- ((3R, 6S) -6-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-amine (125.00g, 540.42mmol, 1.0eq), sodium bicarbonate (226.99g,2.70mol, 5.0eq), tetrahydrofuran (2500ml) and water (1250ml) into a 5000ml three-neck flask, stirring to obtain a white turbid liquid, cooling to 0 ℃, dropwise adding acryloyl chloride (58.69g, 648.50mmol) at the inner temperature of 0-5 ℃, slightly turning yellow the system, stirring for 4 hours at the temperature of 0-5 ℃, monitoring by TLC (dichloromethane/methanol 10:1, 0.5% ammonia water) to show that the raw materials are completely reacted, stopping cooling, naturally heating to room temperature, and stirring. Water (2500ml) was added to dilute and extracted with ethyl acetate (2500ml x2), the organic phases were combined and washed once with saturated brine (2000ml), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude product as a white solid.
Adding the crude product, ethyl acetate (500ml) and n-hexane (1000ml) into a 3000ml single-mouth bottle, heating to 60 ℃, stirring for 1h, naturally cooling to room temperature, stirring overnight, carrying out suction filtration under reduced pressure, leaching a filter cake with n-hexane, and carrying out suction drying. And transferring the filter cake to a 2000ml single-neck bottle, adding ethyl acetate (250ml) and n-hexane (500ml), heating to 60 ℃, stirring for 1h, naturally cooling to room temperature, stirring overnight, carrying out suction filtration under reduced pressure, leaching the filter cake with n-hexane, carrying out suction drying, and carrying out forced air drying in a forced air oven at 60 ℃ for 8h to obtain white solid powder (101.50g, 65.82%). MS, 286.1 and 308.1 of [ M + H ] +, Na ] +, respectively; 1H-NMR (400MHz, DMSO-d6) < delta > ppm 11.51(br s,1H), 8.11(d,1H), 7.25-7.29 (m,1H), 7.08-7.10 (m,1H), 6.74-6.85 (m,1H), 6.54-6.56 (m,1H),6.10(dd,1H), 5.67(dd,1H), 4.80(br s,0.5H), 4.56(d,0.5H), 4.37(br s,0.5H), 4.04-4.15 (m,1.5H), 2.96(t, 0.5H), 2.57-2.63 (m,0.5H), 1.67-1.84 (m,4H), 1.16-1.23 (m, 3H).

Claims (5)

1. A method for preparing PF06651600 comprises the following steps
(1) Nucleophilic substitution reaction of (3R, 6S) -1-benzyl-6-methylpiperidine-3-amine (compound 2) and 4-chloropyrrolo [2,3-D ] pyrimidine (compound 3) to obtain a compound 4;
(2) carrying out catalytic hydrogenation debenzylation on the compound 4 to obtain a compound 5;
(3) carrying out aminolysis reaction on the compound 5 and acryloyl chloride to obtain a compound PF 06651600;
Figure RE-FDA0002388459250000011
2. the synthesis method according to claim 1, wherein the reaction solvent in step (1) is alcohols, pyrrolidones, amides, etc., preferably N-butanol, 1-methyl-2-pyrrolidone, N, N-dimethylformamide; the acid-binding agent is inorganic base or organic base, the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, etc., preferably potassium carbonate; the inorganic base is selected from triethylamine, diisopropylethylamine, pyridine, imidazole and the like, and preferably diisopropylethylamine.
3. The synthesis process according to claim 1, wherein the catalyst in step (2) is palladium on carbon, palladium on carbon hydroxide, preferably 20% wet palladium on carbon hydroxide; the mass ratio of the N- ((3R, 6S) -1-benzyl-6-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (compound 4) to the catalyst is 1: 0.1-0.3, preferably 1: 0.2; the reaction temperature is 40-60 ℃, and preferably 45-55 ℃; the hydrogen pressure is 10-60 psi, preferably 15 psi.
4. The synthesis method according to claim 1, wherein the solvent used in step (2) is one or two of methanol, ethanol, tetrahydrofuran, and the like, preferably methanol.
5. The synthesis method according to claim 1, wherein the solvent used in step (3) is a mixed system of tetrahydrofuran and water, and the mass-to-volume ratio of compound 5 to tetrahydrofuran is 1: 5-50, wherein the mass-to-volume ratio of the compound 5 to water is 1: 5-50, preferably the mass-to-volume ratio (g: ml: ml) of the compound 5, tetrahydrofuran and water is 1:20: 10; the molar ratio of the compound 5 to the acryloyl chloride is 1: 1.0-2.0, preferably 1: 1.2; the acid-binding agent is potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, etc., preferably sodium bicarbonate; the molar ratio of compound 5 to sodium bicarbonate was 1: 1.0-10.0, preferably 1: 5.0, and the reaction temperature is 0-30 ℃, preferably 0-5 ℃.
CN201911417142.7A 2019-12-31 2019-12-31 Preparation method of PF06651600 Pending CN113121539A (en)

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JP6944496B2 (en) * 2018-10-22 2021-10-06 ファイザー・インク Pyrrolo [2,3-d] pyrimidintosilate, its crystal form, and its production method and intermediates.

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Non-Patent Citations (2)

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Title
ATLI THORARENSE 等: "DesignofaJanusKinase3(JAK3)SpecificInhibitor1‑((2S,5R)‑5-((7H‑Pyrrolo[2,3‑d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one(PF-06651600)AllowingfortheInterrogationofJAK3SignalinginHumans", 《JOURNAL OF MEDICINAL CHEMISTRY》 *
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Application publication date: 20210716