CN103755617A - Method for preparing key impurity of ezetimibe - Google Patents

Abstract

The invention belongs to the field of medicinal chemistry and relates to preparation of 1-phenyl-(3R)-(3-(4-fluorophenyl)-(3S)-hydroxypropyl)-(4S)-(4-hydroxyphenyl)-2-propyllactam. The 1-phenyl-(3R)-(3-(4-fluorophenyl)-(3S)-hydroxypropyl)-(4S)-(4-hydroxyphenyl)-2-propyllactam is a medicine for inhibiting the cholesterol absorbing agent, i.e., key impurity in ezetimibe; different from the ezetimibe, one nitrogen-atom substituent group is phenyl group instead of 4-hydroxyphenyl, and 1-phenyl-(3R)-(3-(4-fluorophenyl)-(3S)-hydroxypropyl)-(4S)-(4-hydroxyphenyl)-2-propyllactam is obtained by adopting 1-(5-methoxyl-1, 5-dioxoamyl)-4-(S)-phenyl-2-oxazolidinone as materials, adopting proper materials and catalyst and carrying out seven-step synthesis.

Description

A kind of method of preparing Ezetimibe critical impurities

Technical field

The invention belongs to pharmaceutical chemistry field, relate to a kind of 1-phenyl-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxy phenyl)-2-azetidinone preparation method.

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Background technology

Ezetimibe again translated name is according to ezetimibe, Zetia etc., being applicable to treat primary hypercholesterolemia, homozygote familial hypercholesterolemia, homozygote Sitosterolemia (or plant sterol mass formed by blood stasis), is the assisting therapy medicine beyond a kind of dietary control.By itself and statins combined utilization, can be used as other by the adjuvant therapy of lipid therapy, there is good result for the treatment of.This medicine is developed by Schering-Plough, in the 2002 Nian U.S. and Germany's listing, within 2008, enters Chinese market, the advantages such as consumption is few, toxic side effect is little, determined curative effect that it has.

At present, for Ezetimibe, there is very stable synthesis technique.Patent US5767115, with simple material, prepare the Ezetimibe that optical purity is higher, but its operation is comparatively complicated through seven step reactions, and product exists the problem of bad purifying.Patent US19980206931 provides the method for the synthetic Ezetimibe of a kind of improved simple use neutrallty condition high productivity, only needs 5 step reactions, and yield can reach 50% left and right.Below be all early, and the synthesis technique of more ripe Ezetimibe.

For target compound of the present invention, itself and Ezetimibe be very close structurally, but its pharmaceutical activity has with it larger difference, research finds that it has different results for the treatment of from Ezetimibe, affect activity and the stability of medicine, in the detection of medicine, having consequence, is the key impurity of Ezetimibe.But the bibliographical information that does not relate to synthesising target compound at present, we are by complete synthesis this impurity of preparing, and the method raw material is easy to get, simple to operate, exploitativeness is strong, and for the pharmaceutical analysis research of Ezetimibe, and active constituents of medicine research has great importance.

Summary of the invention

The invention provides a kind of 1-phenyl-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxy phenyl)-2-azetidinone preparation method, its step is, with 1-(5-methoxyl group-1,5-dioxo amyl group)-4 (S)-phenyl-2-oxazolidone is raw material, adopt suitable raw material and catalyzer, through seven steps are synthetic, obtain.The method has simple to operate, and reaction conditions is gentle, the features such as stable configuration.

The TBAF being adopted by compound 2 synthetic compounds 3 described in it is tetrahydrofuran solution, and its concentration is 0.5 ~ 1.5 mol/L, and this step temperature of reaction is 40 ~ 60 ℃; The alkali being adopted by compound 3 synthetic compounds 4 is highly basic alkene solution, comprises NaOH solution, KOH solution, wherein preferred NaOH solution; The acylating reagent being adopted by compound 4 synthetic compounds 5 is oxalyl chloride; Compound 5 Yu Geshi reagent react synthetic compounds 6, and added ZnCl ₂active to reduce Grignard reagent, and four triphenyl phosphorus palladium catalyzed reactions are carried out; Compound 6 is compound 7 by Borohydride reduction, adopts R-CBS as chiral catalyst, and temperature of reaction is 0 ~-25 ℃, preferably-15 ℃; Compound 7 obtains target product by Pd/C catalysis debenzylation, and hydroborating reagent is wherein hydrogen, ammonium formiate, wherein preferable formic acid ammonium.

Embodiment

Further illustrate by the following examples the present invention, but not as limitation of the present invention.

embodiment:

Step 1: add 100 mL methylene dichloride and 3.3 mL titanium tetrachlorides, nitrogen protection in 250 mL there-necked flasks.Stirring is cooled to 0 ℃, drip 2.97 mL titanium tetraisopropylates, stir after 15 min, add 8.8 g 1-(5-methoxyl group-1,5-dioxo amyl group) 20 mL dichloromethane solutions of-4 (S)-phenyl-2-oxazolidone, then slowly drip diisopropylethylamine (DIPEA) 11.7mL, keep 0 ℃ to stir 1 h.Be cooled to-20 ℃, add compound 1-01 20.7 g, keep-20 ℃ of reaction 4 h.Question response finishes to drip 8.8 mL Glacial acetic acid and 18 mL dichloromethane solutions.Reaction solution is warming up to 0 ℃, adds 36 mL 2 mol/L sulfuric acid, keeps 0 ~ 5 ℃ of reaction 1 h.Suction filtration, filtrate separatory, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains yellow solid.Crude product adds hot breakdown with 100 mL Virahols, and cooling suction filtration, obtains white solid, and vacuum-drying obtains compound 2 desciccate 13.5 g, yield 74.7%.

Step 2: to the tetrahydrofuran solution that adds the TBAF of 10.0 g compounds 2 and 115 mL toluene, 0.4 mL 1 mol/L in 250 mL there-necked flasks, nitrogen protection, 30 ℃ of temperature controls.Measure 10 mL BSA and drip as reaction system, after dripping off, be warming up to 50 ℃.TLC point plate, question response finishes, and stops heating, drips 28 mL methyl alcohol, and reaction solution is used 50 mL 1N hydrochloric acid, 70 mL saturated sodium bicarbonates, 70 mL deionized water wash successively, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains tawny oily matter.Oily matter is dissolved in to 40 mL methyl alcohol, adds ice bath crystallization, suction filtration, obtains white solid, vacuum-drying.Obtain the dry compound 3 of 6.1 g, yield 84.9%.

Step 3: add 6.0 g compounds 3 and 10 mL acetone, 20 ℃ of water-bath temperature controls in 100 mL there-necked flasks.Slowly drip the NaOH solution of 20 mL 0.83 mol/L, in 20 ℃ of reaction 2 h.The monitoring of TLC point plate, after reaction finishes, adds 20 mL deionized waters and 35 mL ethyl acetate, stirs 0.5 h.40 mL ethyl acetate extracting twice for water, water intaking drips with 12 mL 1mol/L salt slow acids mutually, has a large amount of white solids to separate out, and is acidified to pH=3, with 50 mL ethyl acetate extracting twice, anhydrous sodium sulfate drying.Suction filtration, filtrate decompression is concentrated into dry, obtains oily product 5.8 g, and cooling curing obtains 5.6 g compounds 4, yield 96.5%.

Step 4: with 5.6 g compounds 4 in 30 mL methylene dichloride dissolving steps three, add 100 mL there-necked flasks, stir nitrogen protection, 20 ℃ of temperature controls.Get 2 mL oxalyl chlorides and be dissolved in 14 mL methylene dichloride, be added dropwise to reaction system, and drip 3 DMFs.React 6 h, TLC point plate, question response finishes, and reaction solution is concentrated into dry, obtains oily matter 5.8 g, is compound 5, product coarse yield 99.0%.

Step 5: in 100 mL there-necked flasks, add 0.5 g magnesium chips, several iodine and 30 mL anhydrous tetrahydro furans, nitrogen protection, stirs, and is warming up to 40 ℃.2.4 mL p-Fluoro bromo benzenes are slowly dripped as reaction system, and reaction 2 h, treat that magnesium chips disappears, and are cooled to 0 ℃, weigh the anhydrous ZnCl of 2.9 g ₂add reaction system, stir 0.5 h, get 0.5 g Pd (PPh ₃) ₄add system.With 5.8 g compounds 5 in the molten step 4 of 20 mL anhydrous tetrahydro furan, slowly drip as reaction system, in 0 ℃ of reaction 1 h.TLC point plate, question response finishes substantially, is warming up to 20 ℃ of reaction 1 h, suction filtration, filtrate decompression is concentrated, obtains sorrel oily matter 7.5 g, and TLC shows impure, containing two impure points, obtains the crude product of compound 6.

Step 6: add 100 mL methylene dichloride in 250 mL there-necked flasks, add 2 mL borine dimethyl sulphides and 2.2 mLR-CBS under 0 ℃ of stirring, reaction 1 h.The crude product of compound 6 in 7.5 g step 5 is dissolved in 15 mL methylene dichloride, slowly drips as reaction system, 0 ℃ of reaction 10 h.Question response finishes, and the hydrogen peroxide of 18 mL concentration 5% is dripped as reaction system to separatory, hydrochloric acid and 75 each washed twice of mL saturated aqueous common salt of 75 mL 1mol/L for organic phase, anhydrous sodium sulfate drying.Suction filtration, filtrate decompression is concentrated into dry, obtains brown oil 5.2 g, and TLC, containing four impure points, by column chromatography for separation, obtains the compound 7 of TLC single-point, and quality is 3.6 g.

Step 7: add 3.6 g compounds 7 and 35 mL methyl alcohol in 100 mL there-necked flasks, stirring and dissolving, adds respectively 5.7 g ammonium formiates, 18 mL formic acid and 0.4 g Pd/C in reaction system, stirring reaction 2 h.Point plate, question response finishes, by reaction solution suction filtration, it is dry that filtrate decompression is concentrated into, white solid 4.6 g, TLC shows containing two small impurities points.By column chromatography for separation, obtain the compound 8 of TCL single-point, i.e. ultimate aim compound, quality is 2.4 g.

¹HNMR（DMSO,400MHz）δ:1.720-1.828?(4H,m),?2.506(1H,d),?4.799(1H,d),?5.309(1H,d),?6.737-7.354(13H,m),?9.537(1H,s)。

Claims (8)

1. a method of preparing Ezetimibe impurity, with 1-(5-methoxyl group-1,5-dioxo amyl group)-4 (S)-phenyl-2-oxazolidone is raw material, through following steps, prepares 1-phenyl-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxy phenyl)-2-azetidinone

。

2. according to the method for claim 1, it is characterized in that, the TBAF being adopted by compound 2 synthetic compounds 3 is tetrahydrofuran solution, and its concentration is 0.5 ~ 1.5 mol/L, and this step temperature of reaction is 40 ~ 60 ℃.

3. according to the method for claim 1, it is characterized in that, the alkali being adopted by compound 3 synthetic compounds 4 is highly basic dilute solution.

4. according to the method for claim 3, it is characterized in that, the alkali adopting is the NaOH solution of 1 mol/L or the KOH solution of 0.5 mol/L.

5. according to the method for claim 1, it is characterized in that, the acylating reagent being adopted by compound 4 synthetic compounds 5 is oxalyl chloride.

6. according to the method for claim 1, it is characterized in that, in the process of compound 5 Yu Geshi reagent react synthetic compounds 6, add ZnCl ₂, catalyzer is four triphenyl phosphorus palladiums.

7. according to claim 1 method, it is characterized in that, compound 6 is compound 7 by Borohydride reduction, adopts R-CBS as chiral catalyst, and temperature of reaction is 0 ~-25 ℃.

8. according to claim 1 method, it is characterized in that, in the step of compound 7 synthetic compounds 8, catalyzer is Pd/C, and hydroborating reagent is hydrogen or ammonium formiate.