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Preparation method of prostaglandin analogue

A prostaglandin and analogue technology, which is applied in the field of preparation of prostaglandin analogues, can solve the problems of low yield, fewer prostaglandin synthesis methods, and harsh conditions

Inactive Publication Date: 2020-10-16
南京栖云高活医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the synthesis methods of prostaglandin analogues reported so far are less, the conditions are harsh, and the yield is low.

Method used

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  • Preparation method of prostaglandin analogue
  • Preparation method of prostaglandin analogue
  • Preparation method of prostaglandin analogue

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091] (1) Synthesis of compound 2

[0092]

[0093] Compound 1 (5.7g, 30mmol) and TEMPO (470mg, 3mmol) were dissolved in 500mL DMA / DCM (v / v=1:300), at room temperature, PhI(OAc) 2 (10.6g, 33mmol) was slowly added to the above solution. The reaction solution was stirred at room temperature for 6 h. The solvent was distilled off under reduced pressure to obtain a black oily crude product without any residual acetic acid, which was directly put into the next reaction without purification. 1 H NMR (400MHz, Chloroform-d) δ9.44 (d, J = 6.2Hz, 1H), 4.82 (dt, J = 5.1, 4.2Hz, 1H), 3.94 (qd, J = 5.6, 4.6Hz, 1H) ,3.61(d,J=5.3Hz,1H),2.67(q,J=5.9Hz,1H),2.65–2.50(m,3H),2.16(dt,J=14.5,5.4Hz,1H),1.83– 1.75(m,1H).

[0094] (2) Synthesis of compound 3

[0095]

[0096] 0°C, under the protection of nitrogen, the solution of β-dimethoxyheptyl carbonyl phosphate (10g, 45mmol) in THF (50mL) was slowly added dropwise to the suspension of NaH (1.8g, 45mmol) in anhydrous THF (100mL) middl...

Embodiment 2

[0119] (1) Synthesis of compound 2

[0120]

[0121] A solution of DMSO (3ml, 42.2mmol) in DCM (20mL) was added dropwise to a solution of oxalyl chloride (1.5ml, 17.7mmol) in DCM (20mL) at -78°C. After stirring for 30 min, a solution of compound 1 (1.80 g, 10.5 mmol) in DCM (15 mL) was added dropwise to the above solution, and stirred for 2 min. Stirring was maintained at -78°C for 1 h, then TEA (12 mL, 86.0 mmol) was added dropwise to the above reaction solution. After the addition of TEA is complete, add saturated NH 4 Cl solution (10 mL) quenched the reaction. Then, the temperature of the reaction solution was raised to room temperature, washed with saturated brine (3×20mL), and the organic phase was anhydrous Na 2 SO 4 It was dried, filtered, concentrated, and purified by column chromatography to obtain compound 2 (1.7 g, 95%). 1 H NMR (400MHz, Chloroform-d) δ9.44 (d, J = 6.2Hz, 1H), 4.82 (dt, J = 5.1, 4.2Hz, 1H), 3.94 (qd, J = 5.6, 4.6Hz, 1H) ,3.61(d,J=5.3Hz,1H),...

Embodiment 3

[0147] (1) Synthesis of Compound 2

[0148]

[0149] Dess-Martin oxidant (19 g, 45 mmol) was added portionwise to a solution of compound 1 (5.7 g, 30 mmol) in DCM (200 mL) at 0°C. Then, the reaction was transferred to room temperature, and the reaction was stirred for 2h. After the reaction is complete, place it at 0°C, add saturated sodium thiosulfate solution to quench the reaction, filter with suction, and then add saturated NaHCO to the filtrate 3 solution (50mL) and ethyl acetate (100mL), the layers were separated after standing, the aqueous phase was extracted with ethyl acetate (100mL×2), the organic phases were combined, washed with saturated brine (100mL), and the organic phase was anhydrous Na 2 SO 4 It was dried, filtered, concentrated, and purified by column chromatography to obtain compound 2 (3.8 g, 75%). 1 H NMR (400MHz, Chloroform-d) δ9.44 (d, J = 6.2Hz, 1H), 4.82 (dt, J = 5.1, 4.2Hz, 1H), 3.94 (qd, J = 5.6, 4.6Hz, 1H) ,3.61(d,J=5.3Hz,1H),2.67(q,J=5.9Hz,...

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Abstract

The invention discloses a preparation method of a prostaglandin analogue, the prostaglandin analogue is a compound shown as a formula 9, the specific synthetic route is as follows: reagents and raw materials used in the invention are available on the market, and the preparation method has the advantages of mild reaction conditions, simple operation, low energy consumption and cost, and high yield,and is suitable for industrial production.

Description

technical field [0001] The invention specifically relates to a preparation method of prostaglandin analogues. Background technique [0002] Natural prostaglandin F2α widely exists in various tissues and body fluids of the human body. Carprostaglandin is a derivative of natural prostaglandin F2α, which is relatively stable. The 15-position methyl group can delay its dehydrogenation and inactivation in the body, and the effect is longer. Prostaglandin and tromethamine complex form for medicinal use. This drug has the functions of softening and dilating the cervix, increasing the frequency and amplitude of uterine contractions, enhancing the contractility of the uterus, and has strong antifertility effects. Suitable for intramuscular injection. It is used for mid-trimester abortion, late-term pregnancy to promote cervical ripening and induction of labor. Carboprost tromethamine can also stimulate the smooth muscle of the human gastrointestinal tract when carboprost trometham...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C405/00C07C215/10C07C213/08
CPCC07B2200/07C07C213/08C07C405/00C07C2601/08C07C215/10
Inventor 不公告发明人
Owner 南京栖云高活医药科技有限公司
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