CN104003903B - The synthetic method of sartanbiphenyl - Google Patents

Abstract

The invention discloses a kind of synthetic method of sartanbiphenyl, taking para-totuidine and chlorobenzoyl chloride as raw material, under Louis acid catalysis condition, friedel-crafts acylation occurs; Then natrium nitrosum participate under through diazol and phenyl ring generation closed loop; Then open loop under alkali condition, the accessory substance of the principal product of production VI and formula VII, makes salt by open-loop products and separates; Finally carboxyl is converted into cyano group and makes sartanbiphenyl. Advantage of the present invention: raw material is easy to get, safety, is convenient to production management; Cost is lower, reduces three-waste pollution; Accessory substance recoverable, improves atom utilization.

Description

The synthetic method of sartan biphenyl

technical field

The invention relates to a synthesis method of sartan biphenyl.

Background technique

2-cyano-4'-methylbiphenyl (sartan biphenyl, Ⅰ) is a key intermediate in the synthesis of angiotensin Ⅱ antagonist drugs, such as losartan, telmisartan, valsartan, ibe Shatan et al. This type of drug has the characteristics of high efficiency, safety, good tolerance, and target organ protection, and has a strong development momentum and broad prospects. Therefore, the improvement of the synthesis process of sartan biphenyl is of great significance to the synthesis research and production of the whole beach drugs.

At present, there are many commonly used methods for synthesizing and preparing sartan biphenyl, which mainly contain the following: (1) Meyer o-anisic acid method, using salicylic acid or o-anisic acid as raw material, applying Meyer reaction, and synthesizing sartan biphenyl through oxazoline Tanbiphenyl, but its synthetic route is too long, and the overall reaction yield is low. (2) Suzuki coupling method, 4-methylphenylboronic acid and 2-bromoxynil are coupled under the catalysis of palladium to synthesize sartan biphenyl. Due to the high price of raw materials, this synthetic route can only stay in the laboratory stage , it is not yet possible to carry out industrialized large-scale production. (3) Negishi coupling method, first prepare p-tolyl magnesium halide by Grignard reaction, then react with ZnCl to prepare organozinc reagent, finally cross-coupling with o-bromoxynil to synthesize sartan biphenyl, this synthetic method needs to prepare a large amount of Organic zinc reagents, and anhydrous ZnCl2 is extremely easy to absorb water, which makes the operation more difficult, and the addition of a large amount of metal reagents will also increase the difficulty of separation and purification. (4) Catalytic reduction method, preparing sartan biphenyl by catalytic hydrodebromination of 4'-dibromomethyl-2-cyanobiphenyl or 4'-bromomethyl-2-cyanobiphenyl, the raw material of this method It is synthesized by bromination after the synthesis of sartan biphenyl, and the reverse synthesis is obviously unreasonable.

Contents of the invention

The object of the present invention is to provide a safe, high-yield, high-purity synthetic method of sartan biphenyl.

Technical solution of the present invention is:

The present invention takes p-toluidine (II) as a raw material, undergoes Friedel-Crafts acylation reaction with benzoyl chloride (III) under Lewis acid catalyzed conditions; then undergoes ring closure through diazonium salt and benzene ring under the participation of sodium nitrite; and then Under alkaline conditions, the ring is opened to generate the main product (VI) and by-product (VII), and the ring-opened product is made into a salt for separation; finally, the carboxyl group is converted into a cyano group to obtain sartan biphenyl (I). Its synthetic route is as follows:

In the present invention, the catalyst used in the Friedel-Crafts acylation reaction is a Lewis acid, such as AlCl ₃ , ZnCl ₂ , or FeCl ₃ , and the reaction temperature is 160°C.

In the present invention, the acid used in the diazotization reaction is sulfuric acid, and the solvent used is water.

In the present invention, the catalyst used for ring closure of the diazonium salt is copper powder, copper chloride, or copper sulfate.

In the present invention, the alkali used for alkaline ring opening is sodium hydroxide, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium hydroxide, potassium methylate, potassium ethylate, or potassium tert-butoxide, and potassium tert-butoxide is optimal choose.

In the present invention, the alkali used for separating the ring-opened product into a salt is magnesium hydroxide, barium hydroxide or calcium hydroxide. The discarded ring-opened product after purification can be cyclized back to the starting material in concentrated sulfuric acid.

The dehydrating agent forming cyano group in the present invention is sulfur oxychloride, phosphorus trichloride, or phosphorus pentoxide.

The invention has mild reaction conditions, simple and convenient operation, and is suitable for industrial production.

The invention has the advantages of easy-to-obtain and safe raw materials, and is convenient for production management; the cost is low, and the pollution of three wastes is reduced; by-products can be recycled, and the utilization rate of atoms is improved.

The present invention will be further described below in conjunction with embodiment.

detailed description

Preparation of 2-amino-5-methylbenzophenone (Ⅳ)

Put benzoyl chloride (133.6mL, 1.15mol) in a reaction flask, stir, heat up to 120°C, slowly add p-toluidine (50.00g, 0.46mol), heat up to 140°C after the addition, and add no Water ZnCl2 (79.06 g, 0.58 mol), the temperature was raised to 160 ° C for 3 hours, the temperature was lowered to 100 ° C, 200 mL of water was added, stirred, and the water layer was poured out after cooling. Add 150mL of 70% sulfuric acid to the residue in the reaction bottle, stir at 140°C for 2 hours, pour the reaction solution into a large amount of water after cooling, neutralize the reaction solution with ammonia water, extract with ethyl acetate, and remove the ethyl acetate by rotary evaporation. The solid was recrystallized from 95% ethanol to obtain a yellow solid (79.70 g, yield 82.2%).

1HNMR (400MHz, CDCl3, ppm) δ: 7.64(d,1H),7.54(t,1H),7.47(t,2H),7.23(s,1H),7.13(d,1H),5.91(s,2H ), 2.18(s,3H).

Preparation of 2-Methylfluorenone (Ⅴ)

Put 120mL of water, 120mL of acetic acid and 37.8g of sulfuric acid in a reaction flask, add 2-amino-5-methylbenzophenone (40.00g, 0.19mol), stir to dissolve, then cool to 0°C , 25 mL of sodium nitrite (13.25 g, 0.19 mol) aqueous solution was added dropwise, and 1 hour after the dropwise addition, 4 g of copper powder was added, the temperature was raised to 80° C., and the reaction was carried out for 2 hours. Cool to room temperature, extract with dichloromethane, remove the solvent by rotary evaporation, and recrystallize the solid with 90% ethanol to obtain a yellow solid (30.04 g, 82.4%).

1HNMR(400MHz,DMSO,ppm)δ:7.74(d,1H),7.68(d,1H),7.59(t,2H),7.42(d,2H),7.34(t,1H),2.35(s,3H ).

Preparation of 2-carboxy-4'-methylbiphenyl (Ⅵ)

(1) 2-Methylfluorenone ring-opens under alkaline conditions

(a) 2-Methylfluorenone ring-opening under potassium hydroxide conditions

Put potassium hydroxide (11.71g, 0.21mol) in a reaction flask, add 25mL of toluene, stir and heat to 110°C, dropwise add 2-methylfluorenone (10.00g, 0.051mol) into 40mL of toluene solution , After the dropwise addition, the stirring reaction was continued for 2h. Cool to room temperature, add 50mL of water, stir well, transfer the mixture to a separatory funnel, separate the organic phase, extract the water phase with toluene, adjust the pH of the water phase to 4-6 with hydrochloric acid, filter under reduced pressure, and dry to obtain White solid (6.51 g, 60.2% yield). (The proportion that main product (VI) accounts for is 50%, and the proportion that by-product (VII) accounts for is 50% in the product.)

(b) Ring opening of 2-methylfluorenone under the condition of potassium tert-butoxide

Put potassium tert-butoxide (67.02g, 0.60mol) in the reaction flask, add 800mL tetrahydrofuran, stir to dissolve, add 2-methylfluorenone (29.00g, 0.15mol), continue to stir for 1 hour, then add 400mL of water, stirred to dissolve the solid, and the tetrahydrofuran was removed by rotary evaporation, the aqueous phase was extracted with dichloromethane, the pH of the aqueous phase was adjusted to 4-6 with hydrochloric acid, filtered under reduced pressure, and dried to obtain a white solid (29.21g, yield 91.8% ). (The ratio that main product (VI) accounts for is 60%, and the ratio that by-product (VII) accounts for is 40% in the product.)

(2) Separation of ring-opened products

Put the ring-opened product (21.22g, 0.10mol) and magnesium hydroxide (2.92g, 0.05mol) under the condition of potassium tert-butoxide into a reaction flask, add 200mL of water, heat and stir until it dissolves, and then distill part of the water A small amount of solid precipitated, then cooled to 0°C, filtered, the filter cake was redissolved in water, and the pH was adjusted to 4-6 by adding hydrochloric acid, the solid was precipitated, filtered, and dried to obtain 2-carboxy-4'-methylbiphenyl ( 8.06g, yield 38.0%), the purity reached 99%.

1HNMR (400MHz, CDCl3, ppm) δ: 7.95(d, 1H), 7.57(t, 1H), 7.38-7.45(m, 2H), 7.29(s, 2H), 7.23(d, 2H), 2.42(s ,3H).

(3) By-product (VII) reclaims to obtain 2-methylfluorenone

The filtrate obtained from the above separation was adjusted to pH 4-6 with hydrochloric acid, the old body was precipitated, and dried to obtain a white solid (13.09 g), which was a mixture of main product (VI) and by-product (VII).

Put this mixture (13.09g, 0.062mol) in a reaction flask, add 50mL of concentrated sulfuric acid, stir, raise the temperature to 40°C, add 200mL of water after 6 hours, precipitate a yellow solid, filter, and dry to obtain 2-methylfluorene Ketone (11.86 g, 98.1% yield).

Preparation of 2-cyano-4'-methylbiphenyl (Ⅰ)

2-carboxy-4'-methylbiphenyl (8.48g, 0.040mol) was placed in a reaction flask, 150mL of 1,2-dichloroethane was added, stirred, and then pyridine (3.21g, 0.040mol) and 15mL of chlorine were added Thionyl chloride was heated to reflux, and 1,2-dichloroethane and unreacted thionyl chloride were removed by rotary evaporation after 8 hours. Add 80mL of toluene to the residue, stir to dissolve, add dropwise 50mL of concentrated ammonia water, stir at room temperature for 8 hours, filter, and dry. Put the dried product back into the reaction flask, add 100mL of 1,2-dichloroethane and 25mL of thionyl chloride, heat and stir to reflux, and after 4 hours, rotary evaporate to remove 1,2-dichloroethane and unreacted thionyl chloride, and the residue was recrystallized with 80% ethanol to obtain a white solid (6.48g, yield 83.8%).

1H NMR (400MHz, CDCl3, ppm) δ: 7.75 (d, 1H), 7.63 (t, 1H), 7.40-7.51 (m, 4H), 7.30 (d, 2H), 2.42 (s, 3H).

Claims (1)

1. a synthetic method for sartanbiphenyl, is characterized in that: comprise the following steps:

2 ?An Ji ?the preparation of 5 methyldiphenyl ketones

Chlorobenzoyl chloride 133.6mL is placed in to reaction bulb, stirs, be warming up to 120 DEG C, addPara-totuidine 50.00g, is warming up to 140 DEG C after adding, add anhydrous after 2 hoursZnCl279.06g, temperature rises to 160 DEG C of reactions 3 hours, is cooled to 100 DEG C, adds 200mLWater, stirs, and water layer is poured out after cooling; Toward the sulphur that adds 70% in the residue in reaction bulbAcid 150mL, 140 DEG C are stirred 2 hours, reactant liquor are poured in large water gaging after cooling, use ammoniaWater neutralization reaction liquid, ethyl acetate extraction, revolves to steam and removes ethyl acetate, solid 95% ethanolRecrystallization, obtains yellow solid 79.70g, productive rate 82.2%;

2 ?the preparation of methyl Fluorenone

The sulfuric acid of the acetic acid of the water of 120mL, 120mL and 37.8g is placed in to reaction bulb, addsEnter 2 ?An Ji ?5 ?methyldiphenyl ketone 40.00g, stir and make molten clearly, be cooled to subsequently 0 DEG C, dripAdd natrium nitrosum 13.25g aqueous solution 25mL, drip after 1 hour, add 4g copper powder,Be warming up to 80 DEG C, react 2 hours; Be cooled to room temperature, with dichloromethane extraction, revolve to steam and removeDesolventizing, 90% ethyl alcohol recrystallization for solid, obtains yellow solid 30.04g;

2 ?Suo Ji ?4 ’ ?the preparation of methyl biphenyl

(1 ?a) 2 ?the open loop under potassium hydroxide condition of methyl Fluorenone

Potassium hydroxide 11.71g is placed in to reaction bulb, adds 25mL toluene, be heated with stirring to110 DEG C, be added dropwise to be dissolved with 2 ?in the toluene solution of 40mL of methyl Fluorenone 10.00g, dripComplete rear continuation stirring reaction 2h; Cool to room temperature, adds 50mL water, fully stirs, and will mixCompound is transferred in separatory funnel, divides and goes organic phase, and water extracts with toluene, water hydrochloric acidAdjust pH to 4 ?6, filtration under diminished pressure, dry, obtain white solid 6.51g, productive rate 60.2%; ProduceIn thing, the shared ratio of principal product VI is 50%, and the shared ratio of accessory substance VII is 50%;

(1 ?b) 2 ?the open loop under potassium tert-butoxide condition of methyl Fluorenone

Potassium tert-butoxide 67.02g is placed in to reaction bulb, adds 800mL oxolane, stirMake molten clear, add 2 ?methyl Fluorenone 29.00g, continue stirring reaction after 1 hour, add 400mLWater, stirs and makes dissolution of solid, revolves to steam to remove oxolane, water dichloromethane extraction, waterWith hydrochloric acid adjust pH to 4 ?6, filtration under diminished pressure, dry, obtain white solid 29.21g, productive rate91.8%; In product, the shared ratio of principal product VI is 60%, and the shared ratio of accessory substance VII is40％；

(2) separation of open-loop products

Open-loop products 21.22g under potassium tert-butoxide condition and magnesium hydroxide 2.92g are placed in to reaction bulbIn, adding 200mL water, heating is stirred to molten clear, then part water is distilled and makes to analyseGo out a small amount of solid, be then cooled to 0 DEG C, filter, filter cake is soluble in water again, adds hydrochloric acid and adjusts PHTo 4 ?6, separate out solid, filter, dry, obtain 2 ?Suo Ji ?4 ’ ?methyl biphenyl 8.06g, productive rate38.0%, purity reaches 99%;

(3) accessory substance VII reclaim obtain 2 ?methyl Fluorenone

By above-mentioned separating obtained filtrate with hydrochloric acid adjust pH to 4 ?6, separate out solid, dry, obtainWhite solid 13.09g is the mixture of principal product VI and accessory substance VII;

This mixture 13.09g is placed in to reaction bulb, adds the 50mL concentrated sulfuric acid, stir, riseTemperature, to 40 DEG C, adds 200mL water after 6 hours, separates out yellow solid, filters, dry,Obtain 2 ?methyl Fluorenone 11.86g, productive rate 98.1%;

2 ?Qing Ji ?4 ’ ?the preparation of methyl biphenyl

By 2 ?Suo Ji ?4 ’ ?methyl biphenyl 8.48g be placed in reaction bulb, add 150mL1,2 ?dichloroEthane, stirs, and then adds pyridine 3.21g and 15mL thionyl chloride, adds hot reflux, 8After hour, revolve steam remove 1,2 ?dichloroethanes and unreacted thionyl chloride; 80mL toluene is addedEnter in residue, be stirred to dissolve, drip 50mL concentrated ammonia liquor, stirring at normal temperature 8 hours,Filter, dry; This is dried to thing and be again placed in reaction bulb, add 100mL1,2 ?bis-chloroethenesAlkane and 25mL thionyl chloride, heating be stirred to backflow, after 4 hours, revolve steam remove 1,2 ?dichloroEthane and unreacted thionyl chloride, 80% ethyl alcohol recrystallization for residue, obtains white solidBody 6.48g, productive rate 83.8%.