HU217542B - Process for producing veratrumaldehyde - Google Patents

Abstract

Field of the Invention The present invention relates to a novel process for the preparation of veratric maldehyde of formula (I) by the methylation of vanillin phase transfer catalyst (II) with dimethylfilate in a brine medium, in the form of a heat transfer phase catalyst, avanillin content of 10 to 40% by weight of ethylene glycol (PEG). Veratromaldehyde is a pharmaceutical intermediate, which can be used, for example, in the preparation of an international free-name blood-reducing agent. ŕ

Description

The present invention relates to a new preparation of veratrumaldehyde (3,4-dimethoxybenzaldehyde) of formula I.

Veratrumaldehyde is a valuable pharmaceutical intermediate which can be used, for example, in the manufacture of the international non-hypertensive pharmaceutical agent methyldopa.

Veratrumaldehyde is known to be prepared by methylation of vanillin II (3-methoxy-4-hydroxybenzaldehyde) II with dimethyl sulfate (Org. Synt. Col. Vol. II. 619). The literature reports a yield of 82-87%. The cited publication also describes a modified process which promises a yield of 92-95%. However, the product is referred to as having a relative yield of 10% (Org. Synt. Coll. Vol. II. 621), which is consistent with the low melting point. The gross yield for vanillin is thus 82-87%.

It is known that state-of-the-art alkylation methods improve the yield and the feasibility of the process using a phase transfer catalyst. Alkylation of vanillin under phase transfer conditions is described by S. Nath et al., J. Med. Indian Chem. Soc. 60, 801 (1983). Vanillin is alkylated with dimethyl sulfate in the presence of a quaternary ammonium salt. However, the yield of veratrumaldehyde is only 75%, which is below the yield obtained by the above procedure.

The synthesis of phenol ethers catalyzed by crown ethers has been reported in several places in the literature. The disadvantage of this process is the use of a very expensive catalyst which is difficult to obtain on an industrial scale and is toxic. Although excellent yields of alkyl halides and dimethyl sulfate have been reported in the literature, the process can only be considered for the production of special molecules due to the expensive nature of the catalyst [T. N. Vasilevskaya et al., Sibir. Khim. 21, 1993 (1) 37-40; V. N. Listvan. Zhur. Oscs. Khim 30, 233 (1985)].

It is also known that polyethylene glycols may be used as catalysts. However, in the preparation of phenol ethers, polyethylene glycols showed only sufficient activity in Williamson ether synthesis with alkyl halides. In the case of etherification with alkyl bromides or iodides, polyethylene glycols yield similar yields to those obtained using crown ethers. The disadvantage of this method is that it requires the use of relatively costly, environmentally polluting alkyl halides as the alkylating agent and the use of polyethylene glycol in a molar amount is not catalytic [S. Slaoni et al., Tetrahedron Letters 23, 1681 (1982).

The monograph detailing the use of polyethylene glycol derivatives does not mention the process for preparing phenol ethers by dimethyl sulfate alkylation using polyethylene glycol as a phase transfer catalyst [G. E. Totten and N. a. Clinton: JMS-REV. Macromol. Chem. Phys., C28 (2) 293-337 (1988)].

Since veratrumaldehyde is used as an intermediate in hundreds of tonnes of production (e.g., methyldopa), improving the high yield (82-87%) reported in the literature is very important economically and technically.

It is an object of the present invention to increase the yield of large scale production of veratrumaldehyde while maintaining or improving product quality.

The above object is successfully achieved by the process of the present invention.

The present invention relates to a process for the preparation of veratrumaldehyde of formula I in the presence of a phase transfer catalyst of vanillin II in dimethyl sulfate in a solvent medium, wherein the phase transfer catalyst is polyethylene glycol (10-40% by weight of vanillin).

The present invention is based on the discovery that when using only 3-16 mol% of polyethylene glycol (PEG) as a phase transfer catalyst in the dimethyl sulfate alkylation of vanillin, the yield is significantly increased. In addition, much lower amounts of PEG than those reported in the literature also allow for large scale commercialization of the reaction (reaction components react uniformly, sharp separation of phases during processing, etc.).

This finding is unpredictable and surprising since Williamson ether synthesis of phenols using alkyl halides in the literature (Tetrahedron Letters 23 1681 (1982)) required the use of a molar amount of polyethylene glycol. In contrast, the desired and beneficial effects of polyethylene glycol in the dimethyl sulfate methylation of the present invention are achieved in substantially smaller amounts, a few mol%.

Comparative experiments have shown that quaternary ammonium salt phase transfer catalysts do not substantially improve the yield of methylation of vanillin with dimethyl sulfate. It has also been found that the use of a mixture of toluene and a dipolar aprotic solvent (e.g. toluene and dimethylsulfoxide or a mixture of toluene and dimethylformamide) as a reaction medium instead of toluene does not improve the yield. This suggests that polyethylene glycol exerts its beneficial effects on yield by another, possibly mixed, mechanism.

It is hypothesized that industrially available quaternary ammonium salt catalysts have insufficient potency to substantially influence the distribution of the ions present in the reaction mixture between the aqueous and organic phases, significantly increasing the ionic concentration in the organic phase and providing better yields of St. the mechanism of action of the quaternary ammonium salt lies in improving ion migration). The use of solvent additives seemed to be a promising modification, since the mixture of aprotic (water, alcohol) and dipolar aprotic (dimethylsulfoxide, dimethylformamide) solvents is a well-used reaction medium (Dr. Csaba Szántay: Theoretical Organic Chemistry, pp. 135-140).

In contrast, in the process of the present invention, the properties of the finely miscible aqueous and toluene phases were not favorable.

EN 217 542 Β licking. It is believed that as the amount of aqueous phase increases, the effect of the "auxiliary solvent" used is continuously weakened, thus rendering the auxiliary solvent ineffective in the second third of the reaction and no longer able to increase the yield.

The polyethylene glycols used in the process of the present invention have a dual character. On the one hand, they are phase transfer catalysts and, on the other hand, solvent additives which improve phase contact.

It is believed that the combination of these two effects is required for the reaction to be carried out favorably according to the invention and for the yield increase achieved.

The importance of the excellent yields obtained by the process of the present invention is enhanced by the fact that industrial grade starting materials can be used. The starting materials used in the examples are 98.5-99.2% vanillin, and with this the veratrumaldehyde yield obtained is almost quantitative (98.4-99.1%).

Not only is the process of the present invention carried out in excellent yields, but it is very advantageously convertible to high purity veratrumaldehyde. The veratrumaldehyde of the present invention, prepared by reaction with a few mol% polyethylene glycol-catalyzed reactions, is converted to the next base product of methyl dopa synthesis, 3- (3,4-dimethoxyphenyl) propane (III), by methods known in the art (e.g. -2-one. It has been found that the veratrumaldehyde prepared by the process of the present invention can be converted to the compound of formula III in a better yield than the veratrumaldehyde prepared by the known process.

In the process according to the invention, the polyethylene glycol may be used in an amount of 10-40% by weight, preferably 15-25% by weight, especially 20% by weight, based on the vanillin. Polyethylene glycol having a molecular weight of 400-6000 may be used as the phase transfer catalyst, preferably PEG 400 or PEG 600. The reaction is preferably carried out in an aromatic hydrocarbon. Benzene, toluene or xylene are particularly preferred as the reaction medium; it is convenient to work in a toluene medium.

The reaction may be carried out at 50-65 ° C, preferably 55-60 ° C. The reaction time is 0.5 to 2 hours, preferably 1 hour.

Preferably, the process of the present invention is carried out as follows:

A solution of vanillin and polyethylene glycol and toluene is prepared. The vanillin used as starting material was dissolved by heating and a small amount of toluene was distilled off. Dimethyl sulfate is then added to the mixture cooled to 30-50 ° C. After the addition of the alkylating agent, an alkali metal hydroxide solution (sodium hydroxide or potassium hydroxide) is added at a suitable rate. The addition rate is chosen such that the temperature of the reaction mixture is 50-65 ° C, preferably 55-60 ° C, with slight exotherm. The reaction mixture is stirred for a suitable period of time (0.5-2 hours) at the above temperature.

The toluene and aqueous phases are then warmly separated, the lower aqueous phase is extracted with toluene, and the combined organic phases are washed neutral with warm water and dried. The veratrumaldehyde-containing toluene solution thus obtained can be used directly for the next step of the synthesis, without purification, for the preparation of 3- (3,4-dimethoxyphenyl) -propan-2-one.

The process of the present invention has the following advantages:

- higher yields compared to known methods;

- favorable feasibility under industrial conditions (simple reaction of components, sharp separation during processing);

- a high quality product which can be converted in a favorable way.

The following examples further illustrate the invention without limiting the invention to the examples.

Example 7

Analytical method for the determination of veratrumaldehyde in toluene solution

A) Quantitative test

Principle of definition

The formyl group of veratrumaldehyde reacts with the hydroxylamine hydrochloride reagent to form oxime, liberating the same amount of hydrochloric acid as the aldehyde.

Hydroxylamine hydrochloride acts as a buffer having a pH of 3.5. Back titration with a 0.1 N sodium hydroxide standard solution gives the amount of hydrochloric acid liberated and the aldehyde equivalent.

Reagents'.

96% ethanol;

0.1 N sodium hydroxide standard solution;

3.5% solution of hydroxylamine hydrochloride in ethanol.

Preparation: 35 g of hydroxylamine hydrochloride were dissolved in a 1000 mL standard flask in a mixture of 600 mL of ethanol and 400 mL of water.

Description of the method

Weigh 0.2 g (200 μΐ) of toluene solution into a 100 ml beaker to the nearest 0.1 mg. To the solution was first added 10.00 ml of alcoholic hydroxylamine hydrochloride reagent, and after 20 minutes, 40 ml of ethanol. Blanks are prepared from the reagents, the pH is accurately measured and back-titrated with 0.1 N sodium hydroxide. 1 ml of 0.1 N sodium hydroxide solution contains 0.016617 g of veratrumaldehyde.

(B) Gas chromatographic impurity test

Chromatographic system:

Device: HP 5890

Detector: FID

Column: HP-1 (Methyl Silicone) mx 0.53 mm, film thickness: 2.65

Temperature: Detector 300 ° C

Column: Temperature program 60 ° C to 220 ° C | minutes minutes 10 minutes

Gas flow rates:

Carrier gas (nitrogen) 25 ml / min Hydrogen 35 ml / min

HU 217 542 Β

Air 200 ml / min Purge 5 ml / min

Integrator '. Hewlett Packard Model 3390 A

Zero = 0

Attenuation = 2 Chart Speed = 0.5 Threshold = 0 PeahWidth = 0.04

Time program min Integration = 9 0.5 min Integration = -9

Preparation of calibration solutions:

Weigh 1.00 g of vanillin into a volumetric flask of standard solution, make up to the mark with alcohol and homogenize.

Solution 1: Weigh 2500 μΐ of the stock solution into a 5 ml volumetric flask and make up to the mark with alcohol, homogenize.

Solution 2: Weigh 1000 μ tör of the stock solution into a 5 ml volumetric flask and make up to the mark with alcohol and homogenize.

Solution 3: Weigh 500 μΐ of the stock solution into a 5 ml volumetric flask and make up to the mark with alcohol and homogenize.

Solution 4: Weigh 100 μΐ of the stock solution into a 5 ml volumetric flask and make up to the mark with alcohol, homogenize.

Test procedure:

- Inject the calibration line by injection of the calibration solutions (1 μΐ), based on the measured area.

- Inject μΐ of the solution to be examined. Using the calibration line, the vanillin content is counted based on the area using the calibration line.

Retention time 6.25 minutes for vanillin

6.8 min veratrumaldehyde

C) Identity assay To 10 ml of material add 10 ml of ethyl alcohol and homogenize by shaking. Saturated dinitrophenylhydrazine solution (25-30 mL) was added. An orange precipitate formed which was collected on a filter and washed until the washings were colorless. Dry in an oven at 100 ° C for 4-5 hours and measure its melting point.

Melting point: 258.0-261.0 ° C.

Example 2

In a 500 ml flask with a Marcusson top, a condenser, a middle flask, a dropping funnel, a thermometer and a magnetic stirrer, 75 g (0.49 mol) of vanillin (purity: 98.79% by GC), mp 81.0-81.5 PH 5.22), 15 g of PEG 600 and 157 ml of toluene were weighed. The starting material was dissolved under heating, and about 10 mL of toluene was distilled from the flask.

To the mixture cooled to 40 ° C was added 96 g (71 mL, 0.76 mol) of dimethyl sulfate. After the addition of the alkylating agent, 113 ml (137.5 g) of 20% sodium hydroxide solution is added at 2 drops / second. During the addition, the temperature of the reaction mixture was adjusted to 55-60 ° C and maintained for one hour. The layers were warmly separated and the lower aqueous layer was extracted with toluene (2 x 30 mL). The combined organic layers were washed with warm water to neutral and dried over calcium chloride. The resulting organic phase was used directly for the preparation of 3- (3,4-dimethoxyphenyl) propan-2-one without purification. The veratrumaldehyde content was determined as in Example 1. The toluene phase contained 78.17 g of veratrumaldehyde in 95.4% yield.

Example 3

The flask described in Example 2 was charged with 75.0 g (0.49 mol) of vanillin, 15 g of PEG 400 and 157 ml of toluene. Toluene (10 mL) was distilled off and dimethyl sulfate (96 g, 0.76 mol) was added to the reaction mixture cooled to 40 ° C. It is then made basic with 20% sodium hydroxide as described in Example 2 and the reaction mixture is worked up as described in Example 2 below. The toluene phase contained 79.9 g (97.6%) of veratrumaldehyde as defined in Example 1.

According to the purity test (Example 1), the vanillin impurity of the toluene phase is less than 0.1% per veratrumaldehyde. The PEG 400 used has been shown to catalyze the reaction and to favor the extraction processing.

Using the method of Example 1C, the hydrazone melting at 260.5 ° C is obtained.

Example 4

The procedure of Example 3 was carried out with the exception that 15 g of PEG 400 and PEG 600 in a ratio of 1: 1 were mixed. The reaction mixture was worked up as described in Example 2. The toluene phase contained 78.5 g of veratrumaldehyde as defined in Example 1. Yield: 95.8%.

Example 5 (Comparative Example)

The procedure of Example 3 was performed except that PEG 600 was not added to the starting mixture. The veratrumaldehyde content of the toluene phase was determined as in Example 1. The toluene phase contained 76.5 g of veratrumaldehyde in 93.4% yield.

The phases obtained by working up the reaction mixture were subjected to gas chromatography as described in Example 1.

The toluene phase is contaminated with 1% vanillin, based on the amount of veratrumaldehyde.

The unreacted vanillin can be detected in the aqueous phase after acidification and extraction.

The hydrazone prepared in Example 1C had a melting point of 258.2 ° C.

Example 6 (Comparative Example)

In this example, the effect of the addition of a bipolar aprotic solvent on the yield is investigated.

HU 217 542 Β

A) The procedure described in Example 2 was carried out by changing the solvent to a mixture of toluene (150 ml) and dimethylsulfoxide (20 ml) instead of 157 ml. The veratrumaldehyde content of the toluene phase was determined as in Example 1. Veratrumaldehyde content 75.73 g, 92.9% yield.

B) The procedure described in Example 2 was carried out by changing the solvent to a mixture of toluene (150 ml) and dimethylformamide (20 ml) instead of 157 ml. The veratrumaldehyde content is

76.3 g (93.1%) as obtained in Example 1.

From the above data it can be seen that the yield is practically unaffected by the addition of dipolar aprotic solvent.

Example 7 (Comparative Example)

Use of a quaternary ammonium salt as a phase transfer catalyst.

In a flask fitted with a Marcusson flask, a flask with a condenser, a dropping funnel and a thermometer, 75 g (0.49 mole) of vanillin and 157 ml of toluene are added with magnetic stirring. 10 ml of toluene are then distilled off and 10 ml of a 10% aqueous solution of tetramethylammonium hydroxide are added to the reaction mixture, which is cooled to 40 ° C. The reaction mixture was worked up as described in Example 2. The veratrumaldehyde content of the toluene phase was determined as described in Example 1. The toluene phase contained 75.39 g of veratrumaldehyde in 92.05% yield. Thus, the quaternary ammonium salt phase transfer catalyst does not improve the yield.

Example 8

Conversion of veratrumaldehyde Sodium methylate of 3- (3,4-dimethoxyphenyl) -propan-2-one is suspended in toluene (86.6 g, 100 ml) and cooled to 5 ° C. To the cooled suspension was added a mixture of 63.7 g of veratrumaldehyde prepared in Example 2 and 54 g of 2-chloropropionic acid methyl ester at such a rate that the temperature did not rise above 5-10 ° C. The dosing time is 2-2.5 hours. After the addition was complete, the mixture was reacted for 3 hours while the cooling was stopped and the internal temperature was allowed to rise to 25 ° C. To the resulting thick, well-stirred suspension was added water (165 mL) with stirring, then heated to 50-55 ° C, followed by the addition of 42 g (35 mL) of 20% sodium hydroxide solution and the reaction mixture for 30 minutes. reflux.

The condenser is then distilled and toluene is distilled from the system as an aqueous azeotropic. The distillation is continued until only water is collected in the lid and the internal temperature of the mixture reaches 103-105 ° C. The reaction mixture was diluted with additional 150 mL water and the hydrolysis of the glycid ester was completed by refluxing for 2 hours. At the end of the hydrolysis a yellow emulsion is obtained.

The alkaline reaction mixture was cooled to 50 ° C and acidified by the addition of concentrated hydrochloric acid (about 35 mL to pH 2.0). The mixture is stirred for 10 minutes, the pH is checked, additional hydrochloric acid is added if necessary, and the decarboxylation is carried out under reflux for one hour. The reaction mixture was cooled to 50 ° C, extracted with dichloroethane (75 ml) and the phases were separated. The aqueous phase was stirred with 2 x 40 mL dichloroethane. The combined organic layers were poured into a stirred flask, water (300 mL) was added and concentrated aqueous ammonium hydroxide solution was added to maintain the pH of the aqueous phase at 6.8-7.0 (4-5 mL). The phases are separated after stirring for one hour. The dichloroethane was removed in vacuo to give crude 3- (3,4-dimethoxyphenyl) propan-2-one which was purified by fractionation.

Fine distillation:

boiling point 142 ° C / 346 Pa 118 ° C / 53 Pa

The weight of the distilled product was 69.3 g, 93.1%.

Example 9 (Comparative Example)

The procedure described in Example 8 was performed except that the toluene veratrumaldehyde solution prepared in Example 5 was used as starting material. 68.7 g (92.3%) of purified 3- (3,4-dimethoxyphenyl) propan-2-one are obtained by distillation.

The data of Examples 8 and 9 demonstrate that the veratrumaldehyde obtained by the process of the present invention can be converted to 3- (3,4-dimethoxyphenyl) propan-2-one in better yields than the veratrumaldehyde prepared in the known manner.

Claims (6)

PATENT CLAIMS: A process for the preparation of veratrumaldehyde of formula (I) by methylation with a dimethyl sulfate in a solvent medium in the presence of a vanillin phase transfer catalyst of formula (II), characterized in that the phase transfer catalyst is 10 to 40% by weight of polyethylene (w / w). Process according to claim 1, characterized in that the polyethylene glycol is used in an amount of 15-25% by weight, preferably 20% by weight, based on the vanillin. The process according to claim 1 or 2, wherein the phase transfer catalyst is PEG 400at or PEG 600. 4. Process according to any one of claims 1 to 3, characterized in that the reaction is carried out in an aromatic hydrocarbon. 5. A process according to claim 4 wherein the aromatic hydrocarbon is benzene, toluene or xylene. 6. Process according to any one of claims 1 to 3, characterized in that the reaction is carried out at 50-65 ° C, preferably 55-60 ° C.