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A kind of preparation method of carfilzomib intermediate compound

A carfilzomib and compound technology, which is applied in the preparation of organic compounds, chemical instruments and methods, and the preparation of carbamic acid derivatives, can solve the problems of high process requirements, high cost, and low yield, and achieve simple experimental operation Easy to control, mild conditions, simple operation effect

Active Publication Date: 2017-09-29
SHANGHAI INST OF TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] Aiming at the above-mentioned technical problems in the prior art, the invention provides a kind of preparation method of carfilzomib intermediate compound, the preparation method of described this kind of carfilzomib intermediate compound solves the preparation method in the prior art Technical problems of high method cost, high process requirements and low yield

Method used

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  • A kind of preparation method of carfilzomib intermediate compound
  • A kind of preparation method of carfilzomib intermediate compound
  • A kind of preparation method of carfilzomib intermediate compound

Examples

Experimental program
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Embodiment 1

[0055] Example 1 Preparation of Compound IV

[0056]

[0057] In a 50mL three-necked flask equipped with a thermometer, a constant pressure titration funnel, and a glass stopper, add compound L-leucine Ⅴ (5.0g, 0.038mol), add NaOH (3.0g, 0.075mol) and 15mL of water, and vigorously Stir for 5 minutes to dissolve the material completely. Slowly add (Boc) dropwise at room temperature water bath temperature control 25~30℃ 2 O (10.8 g, 0.50 mol) in THF (5 mL) was slowly heated to 50-55°C after the dropwise addition. After 0.5h, a solution of NaOH (1.5g, 0.038mol) in water (5mL) was added to the system, and the reaction was incubated for 3h. After the reaction was complete by TLC, ethyl acetate (20mL) was added to the system. Under an ice-water bath, adjust the pH value to 2-3 with 6N dilute hydrochloric acid, filter the ethyl acetate phase, wash the water phase with ethyl acetate (20 mL), combine the ethyl acetate phases, and successively wash with saturated NaHCO 3 , saturat...

Embodiment 2

[0058] Example 2 Preparation of Compound III

[0059]

[0060] In a 100mL three-neck flask equipped with a thermometer, a constant pressure dropping funnel and a drying tube, add L-Boc-leucine Ⅳ (5.0g, 0.022mol) and dichloromethane (25mL), and stir vigorously for 5min to dissolve the material completely . CDI (5.6 g, 0.035 mol) was slowly added in batches under stirring in a room temperature water bath controlled at 25-30° C., and kept for 3 h. After no raw materials were detected by TLC, N,O-dimethylhydroxylamine hydrochloride (3.4 g, 0.035 mol) was slowly added in batches at 20-25° C., and reacted for 1 h. TLC detects that the intermediate state reaction is complete, and the organic phase is washed twice with 25mL water, once with 25mL 1N dilute hydrochloric acid, twice with 25mL saturated sodium bicarbonate solution, once with 50mL saturated saline, and then washed with Na 2 SO 4 After drying, the system solvent was distilled off under reduced pressure to obtain 6.42 ...

Embodiment 3

[0061] Example 3 Preparation of Compound II

[0062]

[0063] Add III (8.2g, 0.030mol) and 40mL THF to a 250mL three-neck flask equipped with a thermometer, constant pressure dropping funnel and nitrogen protection, and stir vigorously for 5min to dissolve the material completely. Under the condition of room temperature controlled by water bath at 20-25°C, slowly add THF solution of ethylmagnesium chloride (45mL, 0.090mol) dropwise, then maintain the temperature in the range of 25-30°C for 3-4h, TLC detection until the end of the reaction. Slowly add 100mL of 1N dilute hydrochloric acid to the system to quench the system at room temperature, and add 100mL of ethyl acetate to extract the product. The ethyl acetate phase is washed twice with 50mL of saturated sodium bicarbonate solution, and then washed with 50mL of saturated brine. 2 SO 4 After drying, the solvent in the system was evaporated under reduced pressure, and the crude product was subjected to column chromatograp...

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Abstract

The preparation method of a compound of a carfilzomib intermediate of the present invention uses L-leucine V as a raw material, and undergoes amidation reaction with di-tert-butyl dicarbonate under alkaline conditions to generate compound IV; ,N'-carbonyldiimidazole reacts with N,O-dimethylhydroxylamine hydrochloride under the action of Weinreb amidation reaction to generate compound Ⅲ, compound Ⅲ reacts with ethylmagnesium halide solution to generate compound Ⅱ, compound Ⅱ reacts with formaldehyde Or paraformaldehyde undergoes aldol condensation reaction to generate carfilzomib intermediate compound Ⅰ ((S)-4-(tert-butoxycarbonylamino)-2,6-dimethyl-1-hepten-3-one) . The invention avoids the use of expensive reagent 2-bromopropene and uses ethylmagnesium chloride, which conforms to the design principles of easy-to-obtain raw materials and simple operation. The synthesis route of the invention has mild conditions, excellent or good synthesis yield in each step, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to organic chemistry, in particular to a pharmaceutical intermediate, especially a preparation method of a carfilzomib intermediate compound. Background technique [0002] Carfilzomib (Carfilzomib) is the latest second-generation epoxy ketone proteasome inhibitor approved by the US FDA. This drug is usually used in the clinical treatment of relapsed and refractory multiple myeloma. Prior treatment with two drugs including bortezomib and immunomodulators was required. As a drug for treating multiple myeloma, carfilzomib has the advantages of being safe to take and not prone to drug resistance. According to the latest clinical data, carfilzomib has a significant therapeutic effect on the treatment of relapsed and refractory multiple myeloma. [0003] Carfilzomib (Carfilzomib), the chemical name is (S)-2-((S)-2-(2-(2H-1,4-oxazin-4(3H)-yl)acetamido)-4- Phenylbutyramide)-4-methyl-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxirane-2-yl) ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C271/18C07C269/06
Inventor 刘烽陈元鹏潘仙华王琨史尧于翠郭磊李勤勤王亚萍陈彦宇
Owner SHANGHAI INST OF TECH
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