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Preparation method of PF-06651600 intermediate

A compound and molar ratio technology, applied in the field of preparation of PF-06651600 intermediates, can solve problems such as high price and potential safety hazards

Pending Publication Date: 2021-03-02
DONGGUAN HEC GENERIC DRUG R&D CO LTD +1
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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 document (Organic Process Research & Development (2019), Ahead of Print) records the resolving agent There is a violent exothermic phenomenon during use, and there are still potential safety hazards if the control is not good during production

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

[0043] Example 1 Preparation of (R)-2-(N-Boc-amino)-5-carbonyl-hexanoic acid ethyl ester (compound 01)

[0044]

[0045] Under the protection of nitrogen, 60g (1.0eq, 233.2mmol) of Boc-D-ethyl pyroglutamate and 500ml of THF were successively added to a 1000ml three-necked flask, stirred and dissolved at room temperature, cooled to -40°C, and MeMgBr was slowly added dropwise. Grignard reagent 110ml (1.4eq, 330mmol), after dropping, slowly warm up to -20°C, and control in TLC. After the raw material has reacted, add 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 of ethyl 2-(N-Boc-amino)-5-carbonyl-hexanoate, yield 93%. GC-MS: m / z: 274.1(M+), 1 H NMR (400MHz, CDCl 3 )δ5.16(d,J=6.5Hz,1H),4.15(...

Embodiment 2

[0046] Example 2 Preparation of (R)-2-(N-Boc-amino)-1,5-hexanediol (compound 02)

[0047]

[0048] At room temperature, add compound 01 60g (1.0eq, 219.5mmol), a mixture of absolute ethanol 240ml and THF 240ml into a 1000ml four-neck flask, stir to dissolve, cool to -5°C, add NaBH in batches 4 33.2g (4.0eq, 878mmol), keep stirring for 2h, slowly raise the temperature to room temperature for reaction, TLC control, until the raw material reaction is complete, cool down to -10°C, slowly add 300ml of saturated ammonium chloride solution to quench the reaction, there are a lot of solids Precipitate, filter, extract the filtrate with 300ml EA, spin dry, add 200ml to dissolve, then add 200ml DCM to extract twice, spin dry under reduced pressure, add n-heptane to crystallize at low temperature, filter with suction, and vacuum dry the solid to obtain (2R) - 46.1 g of 2-(N-Boc-amino)-1,5-hexanediol off-white solid, yield 90%. GC: 100%. LC-MS: m / z (ESI): 256.3 (M+Na + ) + . 1 H ...

Embodiment 3

[0049] Example 3 Preparation of (R)-1,5-dimethylsulfonic acid group-2-(N-Boc-amino)hexane (compound 03-Ms)

[0050]

[0051] Under nitrogen protection, 45g (1.0eq, 192.9mmol) of compound 02 and 250ml of DCM were added to a 1000ml four-neck flask, stirred and dissolved at room temperature, cooled to 0°C, 48.8g (2.5eq, 482.2mmol) of TEA was added, and stirred for 0.5 h, control the reaction temperature to be less than 0°C, add 48.6g (2.2eq, 424.4mmol) of MsCl in DCM solution dropwise, keep the temperature for reaction after dropping, TLC monitors until the reaction of raw materials is complete, add 250ml of water to quench, separate liquid, DCM layer Saturate with 250ml NaHCO 3 and aqueous solution were washed once, and evaporated to dryness under reduced pressure at room temperature to obtain (R)-1,5-dimethylsulfonate-2-(N-Boc-amino)hexane yellow oil 72.8g, yield 97%. LC-MS: m / z (ESI): 412.0 (M+Na + ) + . 1 H NMR (400MHz, CDCl 3 )δ4.82(d, J=8.8Hz, 2H), 4.20(dd, J=14.4,...

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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, Grignard ring-opened D-Boc-ethyl pyroglutamate isused as a raw material, a target compound is obtained through reduction, hydroxyl sulfonylation and cyclization, and the target compound can be further subjected to protecting group removal and salification. The method has the characteristics of novel structure intermediate compound, mild condition, easily available reagent, high product purity, high yield and safe operation, and can be used forindustrial production.

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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IPC IPC(8): C07D211/56C07C271/16C07C309/66C07C309/65C07C309/73
CPCC07D211/56C07C271/16C07C309/66C07C309/65C07C309/73C07B2200/07Y02P20/55
Inventor 王仲清卢辉雄孙国栋区锦旺许国彬廖守主罗忠华黄芳芳
Owner DONGGUAN HEC GENERIC DRUG R&D CO LTD
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