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Preparation method of PF-06651600 intermediate

A reaction time and compound technology, applied in the preparation of organic compounds, sulfonate ester preparation, organic chemical methods, etc., can solve problems such as hidden dangers, high price, and violent heat release of resolving agents

Pending Publication Date: 2021-05-07
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the prior art, (R)-N-3,5-dinitrobenzoylphenylglycine is used as a resolving agent, which is expensive, and the literature (Organic Process Research & Development (2019)) records that the resolving agent is violently released when it is used. Thermal phenomenon, poor control during production still poses safety hazards

Method used

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  • Preparation method of PF-06651600 intermediate
  • Preparation method of PF-06651600 intermediate
  • Preparation method of PF-06651600 intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1 Preparation of (R)-2-(N-Boc-amino)-5-carbonyl-hexanoic acid ethyl ester (compound 01-1)

[0063]

[0064] Under the protection of nitrogen, add Boc-D-ethyl pyroglutamate (compound 00-1) 60g (1.0eq, 233.2mmol) and THF 500ml to a 1000ml three-necked flask successively, stir and dissolve at room temperature and then cool down to - At 40°C, slowly add 110ml (1.4eq, 330mmol) of the MeMgBr format reagent dropwise. After the drop, slowly raise the temperature to -20°C, and monitor the reaction by TLC. After the raw materials have reacted, add dropwise 300ml of saturated NH 4 Quench the Cl solution, separate the liquids, extract the aqueous phase with 300ml of ethyl acetate, wash the combined organic phase with 500ml of water once, spin dry under reduced pressure, add 300ml of n-heptane to cool down and crystallize, stir, filter, and dry to obtain (2R)- 63.7 g of off-white solid 2-(N-Boc-amino)-5-carbonyl-hexanoic acid ethyl ester (compound 01-1), yield 93%. analy...

Embodiment 2

[0067] Example 2 Preparation of (2S,5R)-2-(N-Boc-amino)-1,5-hexanediol (compound 02-1)

[0068]

[0069] At room temperature, 10.92g (1.0eq, 40mmol) of compound 01-1 and 40ml of DMF were added to a 100ml two-necked flask, stirred and dissolved, and 13.7ml (6eq, 120mmol) of glacial acetic acid, 13.3ml (2.4eq, 96mmol) of glacial acetic acid were added under nitrogen protection. ) TEA and 0.124g (0.005eq, 0.2mmol) Ru chiral catalyst (CAT01), reacted at 20°C-50°C for 24h, TLC monitored the reaction, the raw materials were completely reacted, after the reaction, neutralized with saturated NaHCO3 solution, Add 80ml of EA for extraction three times, wash once with 160ml of water, dry the organic phase with anhydrous sodium sulfate, spin dry the organic phase under reduced pressure to obtain a colorless oil, add n-heptane for low-temperature crystallization, suction filter, and vacuum-dry the solid to obtain 7.46 g of white solid (2S,5R)-2-(N-Boc-amino)-1,5-hexanediol (compound 02-...

Embodiment 3

[0073] Example 3 Preparation of (2R,5S)-1,5-dimethylsulfonate-2-(N-Boc-amino)hexane (compound 03-1)

[0074]

[0075] Under nitrogen protection, 6g (1.0eq, 25.7mmol) of compound 02-1 and 36ml of DCM were added to a 100ml two-necked flask, stirred and dissolved at room temperature, cooled to 0°C, 6.5g (2.5eq, 64.3mmol) of TEA was added, stirred 0.5h, control until the reaction temperature is less than 0°C, add 6.5g (2.2eq, 56.7mmol) MsCl solution in DCM dropwise, keep warm for reaction after dropping, TLC monitors the reaction, the raw materials react completely (about 1-2h), add 40ml of water Quench the reaction, separate the layers, wash the DCM layer once with 40ml saturated NaHCO3 and aqueous solution, and rotary evaporate to dryness under reduced pressure at room temperature to obtain 9.8g of (2R,5S)-1,5-dimethylsulfonic acid as a yellow oil -2-(N-Boc-amino)hexane (compound 03-1), yield 98%. analyze data:

[0076] LC-MS: m / z (ESI): 412.0 (M+Na + ) + ;

[0077] 1 H...

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Abstract

The invention relates to a preparation method of a PF-06651600 intermediate, and belongs to the field of medicinal chemistry. According to the method, D-Boc-ethyl pyroglutamate is used as a raw material, and a target compound 04 is obtained through Grignard ring opening, metal chiral reduction, hydroxyl sulfonylation and cyclization. According to the method, chiral column resolution or resolving agent resolution is avoided, reaction is mild, reagents are easy to obtain, the product purity is high, the yield is high, the operation is safe, column chromatography purification is avoided, and industrial production is facilitated.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of a PF-06651600 intermediate. Background technique [0002] Alopecia areata is an autoimmune disease characterized by the loss of patches of hair on the head, face and body. Its symptoms are caused by the patient's immune cells attacking the natural hair follicles, and initially it is mostly circular partial hair loss. Alopecia areata occurs on average between the ages of 25 and 35, but can also affect children and adolescents, and occurs in both sexes and all races. [0003] PF-06651600 is a potent and selective JAK3 inhibitor that has previously been granted Breakthrough Therapy designation by the FDA for the treatment of alopecia areata. It is currently in Phase 3 clinical trials for the treatment of moderate to severe alopecia areata and is also continuing trials for the treatment of rheumatoid arthritis (RA), Crohn's disease (CD) and ulcerative coli...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/06C07C271/16C07C271/22C07C303/28C07C309/66C07D211/56
CPCC07C269/06C07C303/28C07D211/56C07B2200/07C07C271/22C07C271/16C07C309/66
Inventor 王仲清卢辉雄许国彬廖守主罗忠华黄芳芳
Owner SUNSHINE LAKE PHARM CO LTD
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