CN109553513A - A kind of preparation method of metoprolol intermediate - Google Patents

Abstract

The invention belongs to drug organic synthesis fields, and in particular to a kind of preparation method of the intermediate for the drug metoprolol for treating hypertension.Synthetic route provided by the invention are as follows: p bromophenol is reacted in the presence of palladium catalyst, Phosphine ligands with methyl vinyl ether and generates 4- (2- methoxy-ethylene base) phenol；4- (2- methoxy-ethylene base) phenol is hydrogenated in the presence of palladium-carbon catalyst, obtains target product 4- (2- methoxy ethyl) phenol.Reactions steps of this method is shorter, raw material is cheap and easy to get, simple process, easy to operate, does not need special reaction condition, therefore be more suitable for industrialized production.

Description

A kind of preparation method of metoprolol intermediate

Technical field

The invention belongs to drug organic synthesis field, in particular to a kind of drug metoprolol intermediate -- to 4- (2- first Oxygroup ethyl) phenol preparation method.

Background technique

Metoprolol is a kind of beta-blocker, to the selective blocking effect of β1receptor, very to beta 2 receptor blocking effect It is weak, no intrinsic sympathomimetic acitivity and membrane stabilizing action.Antihypertensive effect is played by the excessive activation of antagonism stomodaeal nervous system, Main Hypotensive Mechanism is related to reducing cardiac output, improves the blood pressure adjustment section function of pressoreceptor, and inhibits feritin blood Angiotensin aldosterone system.Metoprolol is orally available or intravenous injection, oral absorption rapidly, completely, take orally rear 1.5~2h blood Concentration reaches peak, bioavilability about 50%, drug and plasma protein binding rate about 12%, and 3~4h of half-life period has lipophilic Property, mainly through liver metabolism, and with metabolite form from kidney excretion.Common side effect includes dyscoimesis, is felt tired, Feel faint and abdominal discomfort.

Entitled 1- [4- (2- methoxy ethyl) phenoxy group] -3- (the isopropylamino) -2- propyl alcohol of metoprolol chemistry, CAS Number 51384-51-1, structural formula such as 1.

Patent (US2005107635, CN101607918A, CN1237958A) is illustrated to prepare the method for metoprolol, be closed As follows at route: compound 3 and epichlorohydrin reaction obtain compound 2, and compound 2 reacts to obtain Mei Tuoluo with isopropylamine You, compound 3 is that 4- (2- methoxy ethyl) phenol is the key intermediate for developing metoprolol.

For 3 synthesis, patent CN107382683 reports a kind of synthetic route: using phenol and chloracetyl chloride three Lower be acylated of aluminium chloride effect obtains chloracetyl phenol, then reacts to obtain 4- (Methoxyacetyl) phenol with sodium methoxide, most Product 3 is obtained by hydrogen reducing under Raney Ni catalysis afterwards.The advantages of reaction be using raw material it is all less expensive, but acyl Glycosylation reaction needs the alchlor using equivalent, and chloracetyl chloride is easy to react with phenolic hydroxyl group and generates a large amount of ester, this by-product Object can further influence the control and post-processing of the material additional amount of second step reaction, especially in technique amplification.Reaction The amount for the Raney Ni that the reduction reaction of final step uses is very big, is unfavorable for industrializing.Document (Synthetic Communication, 1990,20,22,3489) similar synthetic method is disclosed, it is big equally to face alchlor additional amount, The low problem of first step reaction yield.

Patent US5107034 reports a kind of synthetic route: will be to reacting again with sodium methoxide after acetyl phenol bromination To 4- (Methoxyacetyl) phenol, react to obtain product 3 by the hydrogen reducing that target carbon is catalyzed.But reaction has used toxicity Big volatile bromine, it is not easy to operate, or using the metal reagent copper bromide of stoichiometry, three-protection design difficulty is high；Hydrogen is used in reaction Gas reducing carbonyl obtains product 3, and since carbonyl is not easy to restore, condition not easy to control makes carbonyl reduction without restoring phenyl ring, secondary Reaction is difficult to control.

The eighties, the units such as Zhengzhou University, Nanjing pharmaceutical college once carried out research to the synthesis process of metoprolol, closed At route are as follows: benzyl carbinol methyl-etherified is generated methylphenylethyl ether, then nitrifies to obtain 4- (2- methoxy ethyl) nitrobenzene, finally Product 3 is obtained by reduction, diazo-reaction and hydrolysis.Since the starting material benzyl carbinol price of this reaction is higher, nitrified It is easy to generate the product of ortho position substitution in journey, diazo-reaction condition is harsh, and risk is high, therefore is not suitable for industry and generates.

To sum up, there is also use the metal of stoichiometry to try for method of the existing synthesis to 4- (2- methoxy ethyl) phenol Agent, perhaps using toxicity big, high operation requirements, be unfavorable for industrializing and reaction that selectivity of chemical equation is low or to arrive The high initial feed of price, other operating procedure is longer, is unfavorable for reducing cost.

Summary of the invention

To solve the shortcomings of the prior art, metoprolol intermediate compound is prepared it is an object of that present invention to provide a kind of The method of object 3 (4- (2- methoxy ethyl) phenol), the technological reaction condition step is shorter, raw material is cheap and easy to get, reaction condition Mildly, easy to industrialized production.

The technical scheme is that providing a kind of preparation method of metoprolol intermediate, this method includes following work Skill step:

(a) p bromophenol is reacted in the presence of palladium catalyst, Phosphine ligands and alkali with methyl vinyl ether and generates 4- (2- first Ethoxy ethylene base) phenol；

(b) 4- (2- methoxy-ethylene base) phenol is hydrogenated in the presence of palladium-carbon catalyst, obtains 4- (2- methoxyl group second Base) phenol.

The synthetic route of metoprolol intermediate (4- (2- methoxy ethyl) phenol) of the present invention can indicate are as follows:

The present invention provides a kind of completely new 4- (2- methoxy-ethylene base) phenol to prepare thinking, innovatively anti-using coupling The purpose product in high yield with purity should be can be obtained, compared to existing common acylation, to carbonyl with double bond hydrogenation Thinking is hydrogenated, the metal reagent of the invention without using stoichiometry, preparation step is brief, and raw material is cheap, and suitable industry is put Mass production.

Preferably, in the step (a), palladium catalyst uses palladium acetate, palladium chloride, palladium trifluoroacetate, bis- (triphenyls Phosphine) palladium chloride, tetrakis triphenylphosphine palladium, one of two (acetylacetone,2,4-pentanedione) palladiums, preferably palladium acetate.

The palladium catalyst uses catalytic amount；Preferably, palladium catalyst is the 0.5%- of p bromophenol mole 2%；Further preferably 1%.

Preferably, in the step (a), Phosphine ligands are bis- using triphenylphosphine, tri-tert-butylphosphine, tricyclohexyl phosphine, 1,2- One of (diphenylphosphine) ethane, further preferably triphenylphosphine.

Preferably, Phosphine ligands be p bromophenol mole 2%-4%, further preferably 3%.

Preferably, in the step (a), alkali is triethylamine, 4-dimethylaminopyridine, pyridine, sodium carbonate, potassium carbonate, carbon One of sour hydrogen sodium, further preferably triethylamine.

Preferably, alkali is 1.2-2 times of p bromophenol mole；Further preferably 1.5 times.

Preferably, in the step (a), the molar ratio of p bromophenol and methyl vinyl ether is 1:1.1~1.5, Further preferably 1:1.2.

Preferably, the solvent in step (a) be any one of toluene, tetrahydrofuran, dioxane, DMF, acetonitrile or It is mixed, preferably dioxane；P bromophenol (5) and solvent feed ratio are 1:5~30, preferably 1:15.

Preferably, in the step (a), reaction temperature is 60~100 DEG C, preferably 80~90 DEG C.

Preferably, in the step (a), reaction time 10-25h, further preferably 15h.

After step (a) reaction, solvent is removed, without purifying, the double bond hydrogenation of directly progress step (b).

Preferably, solvent in the step (b) selects ethyl acetate, 4- (2- methoxy-ethylene base) phenol (4) with it is molten The feed ratio of agent ethyl acetate is 1:15~30, preferably 1:25.

Preferably, in step (b) target carbon usage amount be 4- (2- methoxy-ethylene base) phenol (4) molal quantity 2%. The hydrogen partial pressure of reaction is 30-50 atmospheric pressure, preferably 40 atmospheric pressure.

Preferably, in the step (b), reaction temperature is 40~70 DEG C, further preferably 50 DEG C.Reaction time is 8- 20h, preferably 16h.

After the completion of hydrogenation, by simply recrystallizing, can in high yield, obtain purpose product to high-purity.

The utility model has the advantages that

This process route is using p bromophenol as starting material, by two-step reaction synthetic intermediate 3, compared with original process, Process route is shorter, the high reagent of risk, and this mild reaction condition is not used, post-processing is simple, is suitable for industrialization Production.Although two-step reaction has all used the higher palladium catalyst of price, usage amount is low, and industrialized production palladium catalyst It can recycle, therefore cost can be reduced.

Specific embodiment:

Embodiment 1

The synthesis of step (a) 4- (2- methoxy-ethylene base) phenol (4)

17.3g (100mmol) p bromophenol (5) is dissolved in 258g dioxane, is added 0.224g palladium acetate (1mmol), 0.787g triphenylphosphine (3mmol), 15.2g triethylamine (150mmol) are eventually adding methyl vinyl ether 7.0g (120mmol), It is heated to 80 DEG C under nitrogen protection, is down to room temperature after reacting 15h, is used after concentrated solvent and ethyl acetate is added, washed with water and salt Active carbon is added after washing drying, filtering solvent evaporated obtains grease, and the HPLC purity that cis and trans alkene is added is 91%, It is direct plungeed into next step without purifying.

The preparation of step (b) 4- (2- methoxy ethyl) phenol (3)

4- (2- methoxy-ethylene base) phenol (4) crude product that back is reacted to be added 375g ethyl acetate in, 2% target carbon (on the basis of 5) is added, and is passed through hydrogen and is forced into 40 atmospheric pressure, is heated to 50 DEG C of reaction 16h, is cooled to room Catalyst, solvent evaporated after washing are filtered off after temperature.Methylene chloride and sodium hydrate aqueous solution is added in obtained grease, quickly stirs After mixing 1h, water phase is removed, pH value acidity is modulated into, then target product is extracted with dichloromethane out, dried, filtered, solvent evaporated. Crude product with n-hexane/ethyl acetate recrystallize 4- (2- methoxy ethyl) phenol (3) 10.0g, HPLC purity be 97%, with right It is 66% that bromophenol (5), which calculates first two steps yield,.

Embodiment 2

The synthesis of step (a) 4- (2- methoxy-ethylene base) phenol (4)

17.3g (100mmol) p bromophenol (5) is dissolved in 258gDMF, is added 0.177g palladium chloride (1mmol), 0.787g Triphenylphosphine (3mmol), 15.2g triethylamine (150mmol) are eventually adding methyl vinyl ether 7.0g (120mmol), and nitrogen is protected It is heated to 90 DEG C under shield, is down to room temperature after reacting 15h, is used after concentrated solvent and ethyl acetate is added, it is dry with water and salt water washing After be added active carbon, filtering solvent evaporated obtains grease, and the HPLC purity that cis and trans alkene is added is 89%, without pure Change direct plunges into next step.

The preparation of step (b) 4- (2- methoxy ethyl) phenol (3)

4- (2- methoxy-ethylene base) phenol (4) crude product that back is reacted to be added 375g ethyl acetate in, 2% target carbon (on the basis of 5) is added, and is passed through hydrogen and is forced into 30 atmospheric pressure, is heated to 50 DEG C of reaction 16h, is cooled to room Catalyst, solvent evaporated after washing are filtered off after temperature.Methylene chloride and sodium hydrate aqueous solution is added in obtained grease, quickly stirs After mixing 1h, water phase is removed, pH value acidity is modulated into, then target product is extracted with dichloromethane out, dried, filtered, solvent evaporated. Crude product with n-hexane/ethyl acetate recrystallize 4- (2- methoxy ethyl) phenol (3) 9.0g, HPLC purity be 95%, with right It is 59% that bromophenol (5), which calculates first two steps yield,.

Claims (10)

1. a kind of method for preparing metoprolol intermediate, which comprises the following steps:

(a) p bromophenol is reacted in the presence of palladium catalyst, Phosphine ligands and alkali with methyl vinyl ether and generates 4- (2- methoxyl group Vinyl) phenol；

(b) 4- (2- methoxy-ethylene base) phenol is hydrogenated in the presence of palladium-carbon catalyst, obtains 4- (2- methoxy ethyl) benzene Phenol.

2. the method as described in claim 1, which is characterized in that in the step (a), palladium catalyst be palladium acetate, palladium chloride, One of palladium trifluoroacetate, bis- (triphenylphosphine) palladium chlorides, tetrakis triphenylphosphine palladium, two (acetylacetone,2,4-pentanedione) palladiums.

3. method according to claim 1 or 2, which is characterized in that palladium catalyst is the 0.5%- of p bromophenol mole 2%.

4. the method as described in claim 1, which is characterized in that in the step (a), Phosphine ligands are triphenylphosphine, three tertiary fourths One of bis- (diphenylphosphine) ethane of base phosphine, tricyclohexyl phosphine, 1,2-.

5. method as described in claim 1 or 4, which is characterized in that Phosphine ligands are the 2%-4% of p bromophenol mole.

6. the method as described in claim 1, which is characterized in that in the step (a), alkali is triethylamine, 4- dimethylamino pyrrole One of pyridine, pyridine, sodium carbonate, potassium carbonate, sodium bicarbonate.

7. method as described in claim 1 or 6, which is characterized in that alkali is 1.2-2 times of p bromophenol mole.

8. the method as described in claim 1, which is characterized in that in the step (a), p bromophenol and methyl vinyl ether Molar ratio is 1 ︰ 1.1~1.5, preferably 1:1.2.

9. the method as described in claim 1, which is characterized in that in the step (a), reaction temperature is 60~100 DEG C, preferably 80~90 DEG C.

10. the method as described in claim 1, which is characterized in that in the step (b), reaction temperature is 40~70 DEG C.