CN1300079C - New technology of synthesizing 4-[2-(cyclo propyl methoxy] ethyl] phenol - Google Patents

Abstract

The invention discloses that the target product 4-[2-(cyclopropylmethoxy)ethyl] can be obtained by using p-chlorophenol as a starting material through reactions such as phenolic hydroxyl protection, Grignard reaction, etherification and hydrolysis deprotection. Phenol process. The raw materials used in the process are easy to obtain and low in price, and the whole reaction process has the characteristics of short steps, mild conditions, high yield, easy operation, etc., and is easy for industrialized production. The structure of the compound 4-[2-(cyclopropylmethoxy)ethyl]phenol is represented by the following formula.

Description

A new process for the synthesis of 4-[2-(cyclopropylmethoxy)ethyl]phenol

technical field

The present invention relates to a new method for preparing 4-[2-(cyclopropylmethoxy)ethyl]phenol, in particular, it belongs to the category of organic synthesis.

Background technique

Betaxolol hydrochloride is a cardioselective β-adrenergic receptor blocker with endogenous sympathomimetic effect and strong effect. The pharmacological effect of human oral administration is 4 times that of propranolol and 5 times that of atenolol. The selectivity to the receptor is higher than that of metoprolol, the oral absorption rate is higher than that of atenolol, and the first pass effect is lower than that of metoprolol, so the bioavailability is higher than both of them, reaching 90%, and its half-life is as long as 20 Hour. In addition to treating high blood pressure and angina pectoris, the drug can also be used in the treatment of glaucoma with its 0.5% eye drops, and is a very promising drug.

4-[2-(cyclopropylmethoxy) ethyl] phenol is an important intermediate for the synthesis of betaxolol hydrochloride, and its synthesis has the following methods: 1. take p-bromophenol as raw material, group protection, Grignard reaction, esterification, reduction, chlorination, cyano replacement, hydrolysis, ester formation, reduction and other reactions; 3. Using p-hydroxyphenylethanol as raw material, it is prepared by reacting directly with cyclopropyl chloride under the action of alkali (see US patent US 5731463) . All there are deficiencies in the above methods, method 1 synthetic route is longer, and total yield is not high; Method 2 route is also longer, and cost is also very high; Although method 3 synthetic route is short, the price of starting material p-hydroxyphenethyl alcohol is high , while the yield of the reaction is low and the selectivity is not very good.

In summary, the current methods for synthesizing 4-[2-(cyclopropylmethoxy)ethyl]phenol have disadvantages such as high raw material prices and long synthetic routes, or low product yields and high costs. , difficult to industrialize.

Contents of the invention

The purpose of the present invention is to provide a method for preparing 4-[2-(cyclopropylmethoxy)ethyl]phenol with simple operation, high yield, easy industrialization and low cost. That is, p-chlorophenol is reacted with isobutylene under acid catalysis to obtain p-chlorophenyl tert-butyl ether; p-chlorophenyl tert-butyl ether is reacted with magnesium and ethylene oxide to obtain 4-tert-butoxyphenethyl alcohol; 4-tert-butoxyphenethyl alcohol reacts with cyclopropylhalomethane at a certain temperature and under the action of alkali to obtain 1-tert-butoxy-4-[(2-cyclopropylmethoxy)ethyl]benzene; 1- tert-butoxy-4-[(2-cyclopropylmethoxy)ethyl]benzene is decomposed by acid to obtain 4-[2-(cyclopropylmethoxy)ethyl]phenol. The raw materials of the method are easy to obtain and the price is low, the steps of the whole reaction process are short and the yield is high. The reaction formula is as follows:

The present invention is achieved through the following scheme, using p-chlorophenol as a starting material, in organic solvents such as benzene, toluene, chlorobenzene, or dichloromethane, at a temperature of 15-50 ° C, in p-toluenesulfonic acid, In the presence of acids such as methanesulfonic acid, dilute sulfuric acid or strongly acidic ion-exchange resin, pass through isobutylene for reaction to synthesize p-chlorophenyl tert-butyl ether. Wherein the molar ratio of p-chlorophenol and isobutene is 1:1-3; the ventilation time is 0.5-50 hours.

Slowly add p-chlorophenyl tert-butyl ether into the solution containing magnesium and tetrahydrofuran in anhydrous tetrahydrofuran at a temperature of 40°C to reflux temperature to make a Grignard reagent, and drop ethylene oxide into the above Grignard reagent 4-tert-butoxyphenethyl alcohol was obtained in . The molar ratio of p-chlorophenyl tert-butyl ether to magnesium is 1:1-2; the molar ratio of p-chlorophenyl tert-butyl ether to ethylene oxide is 1:1-3.

Adopt the method of the present invention, the base used when synthesizing 1-tert-butoxy-4-[(2-cyclopropylmethoxy) ethyl] benzene by 4-tert-butoxyphenethyl alcohol is sodium hydride, tert-butyl Potassium or sodium alkoxide, the alkylating agent used is cyclopropylhalomethane. The molar ratio of 4-tert-butoxyphenethyl alcohol to the base is 1:1-5, and the molar ratio of 4-tert-butoxyphenethyl alcohol to cyclopropylhalomethane is 1:1-3.

In the method of the present invention, use a known inorganic acid to detach tert-butyl methods, usually with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid or their aqueous solutions at room temperature to 100 ° C with 4-tert-butoxyphenethyl alkyl ether The final product is obtained after reacting for 0.5-5 hours. The molar ratio of 4-tert-butoxyphenethyl alkyl ether to inorganic acid is 1:1-100. The use of higher amounts of mineral acid also has no effect on the reaction.

The following examples are helpful for understanding the present invention, but not limiting the content of the present invention.

Detailed ways

Embodiment 1: add 128.0 grams (1 mole) p-chlorophenol, 200 milliliters of toluene and a few drops of methanesulfonic acid in four-necked bottle, pass into isobutylene at 35 ℃, keep certain ventilation rate, ventilate at constant temperature for 10 After 1 hour, the amount of isobutene was controlled at 1.30 moles, reacted at 45° C. for another 15 hours, and weighed. Add a small amount of water, heat to drive off excess isobutylene, weigh after liquid separation, add alkali to wash twice to remove unreacted phenol, and weigh after washing. Then washed with water for 3-4 times, evaporated the solvent to obtain 153.0 g of crude product, and rectified under reduced pressure to obtain 141.0 g of p-chlorophenyl tert-butyl ether. The yield was 76.4%, and the content was 99.5% (GC).

IR(KBr): 2980, 1890, 1590, 1480, 1390, 1360, 1240, 1080, 1155, 1055, 890, 850

¹ H-NMR (CDCl ₃ /TMS): δ1.34 (9H, s), 6.90 (2H, d), 7.20 (2H, d)

Embodiment 2: Add 128.0 grams (1 mole) p-chlorophenol, 200 milliliters of chlorobenzene and a few drops of dilute sulfuric acid in a four-necked bottle, feed isobutylene at 15 ° C, keep a certain ventilation rate, and ventilate at a constant temperature for 10 After 1 hour, the amount of isobutene was controlled at 1.30 mol, reacted at 25° C. for another 15 hours, and weighed. All the other operations are the same as in Example 1, the yield of p-chlorophenyl tert-butyl ether is 68.8%, and the content is 99.5% (GC).

Example 3: Add 128.0 grams (1 mole) of p-chlorophenol, 200 milliliters of dichloromethane and a few drops of dilute sulfuric acid in a four-necked bottle, feed isobutylene at 25° C., keep a certain rate of ventilation, and ventilate at a constant temperature After 10 hours, the amount of isobutylene was controlled at 1.30 mol, and the reaction was carried out at 30° C. for another 15 hours, and the mixture was weighed. All the other operations are the same as in Example 1, the yield of p-chlorophenyl tert-butyl ether is 69.5%, and the content is 99.2% (GC).

Embodiment 4: add 0.2 gram of p-toluenesulfonic acid 0.2 gram of 128.0 grams (1 mole) p-chlorophenol, 200 milliliters of toluene and 30% in four-necked bottle, pass into isobutylene at 20 ℃, keep certain aeration rate, at constant After airing for 10 hours at high temperature, the amount of isobutene was controlled at 1.30 moles, reacted at 25° C. for another 15 hours, and weighed. All the other operations are the same as in Example 1, the yield of p-chlorophenyl tert-butyl ether is 72.2%, and the content is 99.2% (GC).

Embodiment 5: Add 30.0 grams of magnesium strips and 80 milliliters of anhydrous tetrahydrofuran into a 1000 milliliter four-necked bottle, add 2-3 milliliters of bromoethane under stirring, slowly heat to initiate the reaction, add dropwise at reflux temperature The mixed solution of 184.6 grams (1 mole) of p-chlorophenyl tert-butyl ether and 500 milliliters of tetrahydrofuran was added in about 2 hours. After the dropwise addition, it was continued to reflux for 6 hours, cooled, and 60 milliliters of ethylene oxide was added dropwise. Control the rate of addition, so that the temperature is controlled at about 10°C. After the dropwise addition is complete, the reaction is continued for 2 hours.

Pour the above solution into 500 ml of saturated ammonium chloride aqueous solution, stir, add 500 ml of toluene at the same time, separate the organic phase, wash the organic phase with saturated brine several times, dry, and remove the solvent by rotary evaporation to obtain 196.0 g of crude product. Pressure distillation yielded 176.0 grams of product 4-tert-butoxyphenethyl alcohol (II). The yield was 90.7%, and the content was 99.5% (GC).

IR (KBr): 3350, 2980, 1890, 1595, 1486, 1392, 1365, 1100, 1055

¹ H-NMR (CDCl ₃ /TMS): δ1.30 (9H, s), 2.74 (2H, t), 3.10 (1H, s), 3.68 (2H, t), 6.88 (2H, d), 7.18 ( 2H, d)

Embodiment 6: In a 500 ml four-necked bottle, add 40 ml of N, N-dimethylformamide and 5.2 grams of sodium hydride, and add 4-tert-butoxyphenylethanol under stirring N, N-dimethyl Formamide solution (a solution obtained by dissolving 19.4 g (0.1 mol) of 4-tert-butoxyphenethyl alcohol in 60 ml of N,N-dimethylformamide), heated to 70°C, and added N,N-dimethylformamide 140 ml of imine, cooled to 30 ° C, dropwise added cyclopropyl bromide in N, N-dimethylformamide solution (wherein 17.5 g of cyclopropyl bromide was dissolved in 40 ml of N, N-dimethylformamide) After the dropwise addition was completed, the temperature was raised to 60° C., and the reaction was continued at this temperature for 8 hours. After the reaction is complete, cool, add water to dilute under ice-water cooling, extract with ether, dry, and remove the solvent to obtain 25.6 grams of crude product, which is distilled under reduced pressure to obtain the product 1-tert-butoxy-4-[(2-cyclopropylmethyl Oxygen) ethyl] benzene (III) 21.8 grams. The yield was 87.9%, and the content was 99.5% (GC).

IR(KBr): 2930, 2980, 1890, 1595, 1486, 1360, 1230, 1160, 1110, 895

¹ H-NMR (CDCl ₃ /TMS): δ0.22 (2H, m), 0.55 (2H, m), 1.03 (1H, m), 1.35 (9H, s), 2.88 (2H, t), 3.34 ( 2H,d), 3.66(2H,t), 6.92(2H,d), 7.20(2H,d)

Embodiment 7: In a 500 milliliter four-neck bottle, add 40 milliliters of dimethyl sulfoxide and 8.7 grams of sodium methylate, add the dimethyl sulfoxide solution of 4-tert-butoxyphenethyl alcohol under stirring (wherein 4-tert-butoxy 19.4 g (0.05 moles) of phenylethyl alcohol dissolved in 60 ml of dimethyl sulfoxide obtained solution), heated to 70 ° C, added 140 ml of dimethyl sulfoxide, cooled to 30 ° C, dropwise added cyclopropylchloromethane di Methyl sulfoxide solution (wherein 11.9 g of cyclopropyl chloride was dissolved in 40 ml of dimethyl sulfoxide), after the dropwise addition was completed, the temperature was raised to 60° C., and the reaction was continued at this temperature for 8 hours. Other operations were the same as in Example 6. The yield of 1-tert-butoxy-4-[(2-cyclopropylmethoxy)ethyl]benzene was 72.5%, and the content was 99.5% (GC).

Example 8: Add 24.8 grams (0.1 mol) of 1-tert-butoxy-4-[(2-cyclopropylmethoxy)ethyl]benzene into the reaction flask, and add dropwise at about 25-30°C while stirring 25 ml of concentrated hydrochloric acid, after adding, continue to react at this temperature for 2 hours, cool, add saturated sodium bicarbonate solution to neutralize, extract with ethyl acetate three times, wash the organic phase with saturated brine, dry, and remove under reduced pressure solvent to obtain 22.5 grams of crude product, and vacuum distillation to obtain 17.7 grams of product 4-[2-(cyclopropylmethoxy)ethyl]phenol (IV). The yield was 92.2%, and the content was 99.5% (GC).

IR(KBr): 3300, 2900, 1890, 1595, 1440, 1392, 1220, 1100, 1095, 890, 850

¹ H-NMR (CDCl ₃ /TMS): δ0.24 (2H, m), 0.56 (2H, m), 1.08 (1H, m), 2.88 (2H, t), 3.34 (2H, d), 3.66 ( 2H,t), 5.35(1H,s), 6.92(2H,d), 7.20(2H,d)

Claims (8)

1. One kind to adopt para-chlorophenol be raw material, make and obtain 4-[2-(cyclo propyl methoxy) ethyl] novel process of phenol; It is characterized in that with the para-chlorophenol being raw material, under acid catalysis, obtain the rubigan tertbutyl ether with isobutene reaction; Rubigan tertbutyl ether and magnesium and oxyethane carry out grignard reaction and obtain 4-tert.-butoxy phenylethyl alcohol; 4-tert.-butoxy phenylethyl alcohol obtains 1-tert.-butoxy-4-[(2-cyclo propyl methoxy with the reaction of cyclopropyl halomethane under the alkali effect) ethyl] benzene; 1-tert.-butoxy-4-[(2-cyclo propyl methoxy) ethyl] benzene frees the tertiary butyl through mineral acid and obtains 4-[2-(cyclo propyl methoxy) ethyl] phenol.
2. 2. as right 1 described synthetic 4-[2-(cyclo propyl methoxy) ethyl] method of phenol, in synthetic rubigan tertbutyl ether, the mol ratio that it is characterized in that para-chlorophenol and iso-butylene is 1: 1-3, used catalyzer is dilute sulphuric acid, tosic acid, methylsulfonic acid or strong-acid ion exchange resin, used solvent is benzene, toluene, chlorobenzene or methylene dichloride, temperature of reaction is at 15-50 ℃, and aeration time is 0.5-50 hour.
3. 3. as right 1 described synthetic 4-[2-(cyclo propyl methoxy) ethyl] method of phenol, at synthetic 1-tert.-butoxy-4-[(2-cyclo propyl methoxy) ethyl] in the benzene, it is characterized in that alkali is sodium hydride, potassium tert.-butoxide or sodium alkoxide.
4. 4. as right 1 described synthetic 4-[2-(cyclo propyl methoxy) ethyl] method of phenol, at synthetic 1-tert.-butoxy-4-[(2-cyclo propyl methoxy) ethyl] in the benzene, the mol ratio that it is characterized in that described 4-tert.-butoxy phenylethyl alcohol and alkali is 1: 1-5.
5. 5. as right 1 described synthetic 4-[2-(cyclo propyl methoxy) ethyl] method of phenol, at synthetic 1-tert.-butoxy-4-[(2-cyclo propyl methoxy) ethyl] in the benzene, it is characterized in that solvent is methyl-sulphoxide or N, dinethylformamide.
6. 6. as right 1 described synthetic 4-[2-(cyclo propyl methoxy) ethyl] method of phenol, at synthetic 1-tert.-butoxy-4-[(2-cyclo propyl methoxy) ethyl] in the benzene, it is characterized in that used cyclopropyl halomethane is Cyclopropylmetyl bromide or cyclopropyl methyl chloride.
7. 7. as right 1 described synthetic 4-[2-(cyclo propyl methoxy) ethyl] method of phenol, at synthetic 1-tert.-butoxy-4-[(2-cyclo propyl methoxy) ethyl] in the benzene, the mol ratio that it is characterized in that 4-tert.-butoxy phenylethyl alcohol and cyclopropyl halomethane is 1: 1-3.
8. 8. as right 1 described synthetic 4-[2-(cyclo propyl methoxy) ethyl] method of phenol, at 1-tert.-butoxy-4-[(2-cyclo propyl methoxy) ethyl] benzene frees the tertiary butyl through mineral acid and obtains 4-[2-(cyclo propyl methoxy) ethyl] and in the phenol, 1-tert.-butoxy-4-[(2-cyclo propyl methoxy) ethyl] mol ratio of benzene and mineral acid is 1: reaction is 0.5-5 hour when 1-100 and room temperature to 100 ℃.