CN102372760A

CN102372760A - Synthesis method of progesterone receptor regulating agent ulipristal

Info

Publication number: CN102372760A
Application number: CN201010253176XA
Authority: CN
Inventors: 李航; 何党军
Original assignee: HANGZHOU RONGLI MEDICINE SCIENCE & TECHNOLOGY Co Ltd
Current assignee: HANGZHOU RONGLI MEDICINE SCIENCE & TECHNOLOGY Co Ltd
Priority date: 2010-08-12
Filing date: 2010-08-12
Publication date: 2012-03-14

Abstract

The invention provides a new synthesis method of a progesterone receptor regulating agent ulipristal acetate. The method has simple and short steps and mild conditions and is easy to operate, the obtained product has low cost, high yield and high purity, and the method is easy to amplify and is suitable for industrial production.

Description

The compound method of the excellent Li Site of a kind of synthetic progesterone receptor modulator

Technical field

That the present invention relates to is the excellent Li Site of a kind of progesterone receptor modulator acetic acid (ulipristal acetate), i.e. 17 α-acetoxyl group-11 β-[4-(N, N-dimethylamino)-phenyl]-19-norpregna-4,9-diene-3, the compound method that the 20-diketone is new.

Technical background

The excellent Li Site of acetic acid (ulipristal acetate, formula 5) is a kind of progesterone receptor modulator, tool PgR antagonism and PAA.This medicine obtains EU Committee's approval in May, 2009 by HRA drugmaker exploitation, as the emergency contraception that uses in behind sexual intercourse of women's unprotect or the contraceptive failure 5 days.

PCT patent 2004/065405 discloses the special Preparation Method of the excellent power of acetic acid department, and the impurity (the excellent Li Site N-of acetic acid demethyl) that obtains product is many, is about 0.4%-1%.The excellent Li Site N-of acetic acid demethyl i.e. 17 α-acetoxyl group-11 β-[4-(N-methylamino)-phenyl]-19-norpregna-4,9-diene-3, and the 20-diketone can influence product purity.

Summary of the invention

The present invention provides the synthesis technique of the excellent Li Site of a kind of progesterone receptor modulator acetic acid, is specially:

With 3,3,20, two (ethylenedioxy)-17 of 20-α hydroxy-19-nor pregnant steroid-5 (10), 9 (11)-diene (1) are starting raw material.Synthetic route is following:

(5) are the excellent Li Site of acetic acid among the wherein above-mentioned figure, and preparation process is following:

A. compound (1) is dissolved in the organic solvent, does catalyst reaction with pyridine and hexachloroacetone, drips 30% ydrogen peroxide 50, and temperature of reaction obtains compound (2) at 0～4 ℃;

The B.N.N-dimethylated makes Grignard reagent in the exsiccant THF, 30～35 ℃ of temperature of reaction were reacted 4 hours; Compound (2) is dissolved in the exsiccant THF, drips Grignard reagent reaction, temperature of reaction 15-20 ℃ with cuprous chloride catalysis; Reacted 1 hour, aftertreatment is: filter layer overlay 6～8CM300-400 order silica gel, dense doing with anhydrous methanol making beating, washing; Ethyl acetate backflow making beating crystallization obtains compound (3);

C. compound (3) reacts in aqueous potassium hydrogen sulfate, and wherein temperature of reaction was reacted 4-5 hour at 5 ℃, obtained compound (4);

D. aceticanhydride 316ml and 70% perchloric acid, temperature of reaction add compound (4) below 10 ℃, and preferable reaction temperature was reacted 2-3 hour at-20--30 ℃.Aftertreatment is crossed silica gel and is leant on, and eluent is methylene dichloride/acetone=20/1, and with ethyl acetate/petroleum ether=4/1 crystallization, absolute ethyl alcohol/water=1/1 crystallization 40 ℃ of decompression oven dry, obtains final product (5) again.

The synthetic route step that the present invention adopts is simple and direct; Mild condition, easily operation, the products therefrom cost is low, yield is high, high (single foreign matter content can be controlled in below 0.1% purity; Comprise that the excellent Li Site N-of acetic acid demethyl is also below 0.1%), be easy to amplify, be fit to suitability for industrialized production.

Embodiment

Embodiment 1

The preparation of compound (2):

Two protection compounds (1) 450g is dissolved in the methylene dichloride of 4300ml; Mechanical stirring is dissolved clear, lowers the temperature 0～4 ℃, in this solution, adds the hexachloroacetone of 12ml pyridine and 43ml; The ydrogen peroxide 50 643ml of dropping 30% in the time of 0～4 ℃ adds the back and continued stirring reaction about 18-24 hour at 0～4 ℃.(developping agent: petrol ether/ethyl acetate is PE/EA=3/1 to the raw material primitive reaction fully; Phosphomolybdic acid ethanol solution with 5% is as developer) back adding methylene dichloride 7715ml; Reaction solution is poured in the ice-cold hypo solution (720g Sulfothiorine/water 6000ml), adds back mechanical stirring 30 minutes in the time of 0～10 ℃.Separatory, water layer extracts with methylene dichloride 2140ml, merging organic layer water (2140ml*2) washing, the organic layer anhydrous sodium sulfate drying filters, and concentrating under reduced pressure is done, and oil product pump is drained and is obtained 480g yellow solid (2), weight yield 106.7%.

Embodiment 2

The preparation of compound (3):

N.N-dimethylated 1130g is dissolved among the exsiccant THF 5656ml.Add magnesium 187.5g in the there-necked flask of 10L, tetrahydrofuran solution 460ml and micro iodine (smaller part) add the tetrahydrofuran solution 184ml of above-mentioned N.N-dimethyl-to bromobenzene again.Be heated to 55 ℃～65 ℃, the iodine look takes off, the solvent vigorous reflux, and Ge Shi causes.Temperature is 30～35 ℃ in cooling to, and drips the tetrahydrofuran solution of residue N.N-dimethylated, drips off in about 4 hours, and temperature was 30～35 ℃ in the dropping process kept.Drip off the back at 30～35 ℃ of insulation reaction 1-2 hours, reduce to room temperature, make Grignard reagent.Add epoxy compounds 480g compound (2), cuprous chloride 25.4g, 1450ml exsiccant THF in the there-necked flask of 10L.Solution was 20-25 ℃ of mechanical stirring 15 minutes, and cooling is cooled to 15-20 ℃, grignard reagent solution is added drop-wise in this solution, and in the maintenance warm 15-20 ℃, about 60 minutes of dropping time.Drip the back holding temperature at 20-25 ℃ of stirring reaction 1-2 hour, (developping agent: PE/EA=3/1, the phosphomolybdic acid ethanol solution with 5% is as developer).Reaction solution is poured in the 11000ml saturated ammonium chloride solution of ice-cold (on the rocks), separatory (upper strata THF, lower layer of water), water layer extracts with methylene dichloride (1450ml*3), merges organic layer, water (3625ml*5) washing, organic layer anhydrous sodium sulfate drying.Filter (the 300-400 order silica gel of the about 6-8 cm thick of pad one deck filters the back layer of silica gel and uses the 1450ml dichloromethane rinse), be evaporated to dried.Added 725ml anhydrous methanol mechanical stirring in the resistates 60 minutes after concentrating, floss filters, and solid is with anhydrous methanol (180ml*2) washing, and solid is at 60 ℃ of vacuum dryings.Solid cools to 0-4 ℃ with the making beating of 580ml ethyl acetate backflow, stirs 1 hour.Solid filtering gets white product, and 60 ℃ of vacuum dryings reduce pressure.Get 188.5g white solid compound (3).Weight yield 39.3%.

Embodiment 3

The preparation of compound (4):

Sal enixum 127g is dissolved in the 1410m water, is cooled to 5 ℃, add solid Ge Shi product 188g compound (3) (PH is about 1); Reaction is kept 5 ℃ and was stirred 4-5 hour, after react completely (developping agent: PE/EA=2/1 develops the color with ultraviolet); Add methylene dichloride 1100ml and potassium hydroxide aqueous solution (Pottasium Hydroxide 19.4g/ water 172ml); Stir 15 minutes (PH is about 3), separatory, water layer extracts with methylene dichloride (940ml*3); Organic layer water (1330ml*2) washing is to neutrality, anhydrous sodium sulfate drying.Filter, filtrating is concentrated to about 480ml compound (4), directly is used for next step reaction.

Embodiment 4

The preparation of compound (5):

Add aceticanhydride 316ml in the 3L there-necked flask, mechanical stirring is cooled to-20 ℃, and temperature is no more than 10 ℃ of adding 70% perchloric acid 47ml in the control, after adding solution is cooled to-30 ℃.Temperature drips continued and under this temperature, stirred 2-3 hour at-20--30 ℃ of dichloromethane solution 480ml compound (4) that is added dropwise to the step in the control.React completely after (developping agent: methylene dichloride/acetone=20/1, ultraviolet colour developing), add methylene dichloride 1400ml, mechanical stirring is poured this reaction solution in the aqueous solution (sodium-acetate 45.5g/ water 1730ml) of sodium-acetate into.Separatory, organic layer water (785ml*3) washing, anhydrous sodium sulfate drying.Filter, filtrate decompression concentrates, and adds the dense dried yellow powder of 282g 300-400 order silica gel.Cross silica gel and lean on, 300-400 order silica gel 3760g, the compacting of 20L oil mystery dress post, last appearance (yellow powder), the compacting of oil mystery, an amount of SODIUM SULPHATE ANHYDROUS 99PCT is pushed down yellow powder.With methylene dichloride/acetone=20/1, the flushing wash-out is collected product, concentrates and does, and oil group drains and obtains light solid 118g.Light color solid 118g use the 354ml acetic acid ethyl dissolution, stirs to drip the 1416ml sherwood oil down, separates out solid, stirs half a hour and filters, and solid washs with the mixing solutions (100ml*2) of PE/EA=5/1,40 ℃ of decompressions dry first product 108g.First product 108g is dissolved in the absolute ethyl alcohol of 1080ml, and 60 ℃-70 ℃, add deionized water 1080ml, there is crystal to separate out, to cross and filter crystal, 40 ℃ of decompressions are dried to such an extent that 91.5 digest compound (5).Detect the single impurity of gained final product, all below 0.1%.Weight yield 48.7%.

Claims

1. the compound method of the excellent Li Siteshi of acetic acid (5),

Synthetic route is:

Concrete preparation process is following:

D. aceticanhydride 316ml and 70% perchloric acid, temperature of reaction add compound (4) below 10 ℃, and preferable reaction temperature was reacted 2-3 hour at-20--30 ℃.Aftertreatment is crossed silica gel and is leant on, and eluent is methylene dichloride/acetone=20/1, and with ethyl acetate/petroleum ether=4/1 crystallization, absolute ethyl alcohol/water=1/1 crystallization 40 ℃ of decompression oven dry, obtains final product (5) again.7