FI89485B - Foerfarande Foer methylation of xanthers - Google Patents

Abstract

A process in which dimethyl carbonate is used as methylating agent.

Description

! 89485

Method for methylating xanthines - Method for methylation of xanthines

The invention relates to a process for the methylation of xanthines using dimethyl carbonate as a methylation reagent.

Xanthine11a includes compounds of the general formula such as O x3 <n

0 I

X2 also include their alkali and alkaline earth metal salts, in particular the sodium, potassium and calcium salts, wherein X1, X2 and X3 independently of one another denote hydrogen, C1-C6-alkyl, phenyl or benzyl, in which case at least one of the substituents X1, X2 and X3 represents hydrogen.

The compounds prepared according to the method have a physiological effect and / or the compounds are starting materials for the preparation of other physiologically active compounds (e.g. pentiphylline, pentoxyphylline, proteobromine).

It is known to prepare theobromine from xanthine or 3-methyl-xanthine such as caffeine from theophylline by methylation with dimethyl sulfate, methyl chloride or methyl tosylate. These methylation reagents are harmful to health and their reactions form harmful by-products. The yield and the quality of the product are also unsatisfactory, especially for theobromine prepared in this way.

Dimethyl carbonate is known to be a substantially weaker methylation reagent than dimethyl sulfate, dimethyl carbonate is not harmful to health and does not cause harmful by-products. (Chimicaoggi - ottobre 1983, 33 - 34; 2 89485

Chimicaoggi - setembre 1984, 37 - 45; Ing. Chim. Ital., V. 21, N. 1 - 3, Gren. - Mar. 1985, 6 - 12; Liebigs Ann. Chem. 1987, 77 - 79).

In Liebigs Ann. Chem. 1987, 77-79 describes a methylation process for methylating imidazole, substituted imidazole and indole using dimethyl carbonate. According to this description, a suitable catalyst is obtained in satisfactory or good yield of the desired products. It also mentions the methylation of imidazole without the use of a catalyst, however, the reaction time to 90% yield is 72 hours. This method is not suitable for technical use, in particular due to the long reaction time when the use of catalysts is abandoned and because the isolation of the final products when using said catalysts is laborious. Experiments further show that methylation of xanthines by this method gives no or only a very low yield.

According to the last paragraph of the left-hand column of page 78 of the above publication: a) methylation of imidazole gave N-methylimidazole in 36.5% yield, b) methylation of 3-methylxanthine to theophylline and theophylline sodium according to the exact publication did not give the methylated product.

Only after the addition of the solubilizer was the results obtained in c) to e).

c) Methylation of 3-methylxanthine in DMF as a solubilizer (ratio DMC: DMF = 1: 1) gave caffeine in a yield of about 13%.

d) Methylation of theophylline with DMF (ratio DMC: DMF = 1: 1) gave caffeine in about 15% yield.

3 89485 e) Methylation of theophylline sodium in DMF (ratio DMC: DMF = 1: 1) gave caffeine in about 15% yield.

If these results are compared with the data according to the present invention, it can be stated that the methods according to the reference publications: 1. cannot be used unchanged with the starting materials of the process according to the invention;

The task was to develop an improved, technically available method that does not use methylation reagents that are harmful to health. The present invention provides a process for obtaining methyl-substituted xanthines in higher yield and quality. The method is also easily feasible on a technical scale, especially since only a few steps are required to isolate the product. No catalyst or base is used in the process of the invention. It is novel to use dimethyl carbonate for bicyclic heterocyclic compounds having two nitrogen atoms in both fused rings.

According to the invention, xanthines are methylated using dimethyl carbonate. The substances are in each case reacted with xanthine (as defined above) with dimethyl carbonate in a ratio of 1: 3 to 1:50, preferably 1: 7 to 1:10. Dimethyl carbonate also acts as a solvent. The reaction is preferably carried out by adding water or an aqueous buffer (the pH is adjusted from 7.8 to 7.1) or an organic solvent with acidic hydrogen, e.g. an alcohol, in particular a C 1 -C 6 alcohol, preferably methanol.

. 89405 4

The reaction is carried out at 100 to 250 ° C, preferably from 150 (in particular 170) to 200 ° C in an autoclave at a corresponding elevated pressure (1 to 60 bar, mostly 50 to 80 bar). The reaction time is usually between 1 and 10 hours. Due to the different reactivities of the nitrogen atoms contained in the starting materials, the methylation takes place in stages in the process according to the invention. By selecting the reaction conditions and the reaction time within the stated limits, the yield of the individual end products can be optimized. Unwanted methylation products are present as by-products. In the production of theobromine, for example, small amounts of caffeine and 3-methylxanthine (when xanthine is used) are formed as by-products.

The starting compounds are known compounds and / or can be prepared by known methods.

Preferably, xanthine or 3-methylxanthine is used in the process of the invention for the production of theobromine and theophylline, xanthine or 3-methylxanthine for the production of caffeine.

Xanthine is used to prepare theobromine, for example 3-methylxanthine and dimethyl carbonate in a molar ratio of 1: 3 to 1:50, preferably 1: 7 to 1:10. Further, substantially water or aqueous buffer solution (pH 7.8 to 7.1) is added. In this case, equal volumes of water, e.g. buffer, are preferably used as dimethyl carbonate. The reaction temperature is maintained between 170 and 200 ° C; the reaction is usually complete within 2.5 hours, preferably inside the reaction mixture is cooled to about 70 ° C and the autoclave is aerated. The work-up consists of separation of the reaction product (filtration, suction), washing and drying.

For the preparation of caffeine, xanthine, 3-methylxanthine or in particular theophylline or their Na or Ca derivatives with dimethyl carbonate are preferably used in a molar ratio of 1: 3 to 1:50, preferably 1: 7 to 1:10. It is advantageous to use 5 89405 alcohols in the reaction, preferably methanol. In this case, a volume ratio of dimethyl carbonate: methanol between 3.3: 1 and 2: 1 is used. The reaction takes place in an autoclave at a temperature of 100 to 250 ° C, preferably 150 to 200 ° C. After a reaction time of 1 to 10 hours, preferably 3 to 5 hours, the reaction is terminated by cooling to 60 ° C and aerating the autoclave. Work-up of the reaction mixture is followed by separation of the reaction product (filtration, concentration of the filtrate, stirring in an ice bath), washing and drying.

By this method it is possible to prepare e.g. 3- (C 1 -C 10 alkyl) xanthine in a similar manner. From the 3-benzyl-7-methylxanthine thus prepared, 7-methylxanthine can be prepared by suitable methods (e.g., hydrogenation) by cleavage of the benzyl group.

Example 1 o H \ II / H O Hx II, CH3

N \ H

^ NJ ^ N ^ + H3C_0 "C" ° "CH3 -> / LNjLNf + CH3 ° H + C ° 2 OI" </ 7 "ch3 ch3 MG: 166.14 MG: 90.08 MG: 180.17 3- methylxanthine Dimethyl carbonate Theobromine

Place 500 ml of buffer solution pH 7.5 (prepared from 13.65 g of Na2B4C> 7 x 4H2O and 94 ml of 1N HCl, make up to 1 liter volume) in a 2-liter shaking autoclave and make up to 500 ml with dimethyl. carbonate (6 moles). A further 99.6 g (0.6 mol) of 3-methylxanthine are added and the suspension is heated to 170 ° C. The pressure rises to 100 bar during the 2.5 hour reaction. At the end of the reaction time, it is cooled to 70 ° C and the autoclave is aerated. The hot suspension (pH 77.2) is then filtered off with suction through a preheated suction strainer with filter paper, and washed with 6 89405 2 x 100 ml of water. The isolated product is dried at + 50 ° C in a vacuum oven to concentrated weight.

HPLC: 99.8% C, H, N: Theory: c 46.66%, H 4.48%, N 31.10% Found: c 46.62%, H 4.48%, N 31.03 %

Melting point: 352 - 355 ° C Yield: 79.1 g (= 73.23%)

In analogy to this example, theobromine can be prepared from 3-methylxanthine-Na in 79% yield. (Reaction time 2.5 hours).

Example 2

O O

H II / H O Hv II / CH3

Nv H

^ / + H3C-O-C-O-CH3 -> I J [^ ^ + CH3OH + co2 o ^ 1 N o jj ch3 ch3 MG: 166.14 MG: 90.08 MG: 180.17 3-methylxanthine Dimethyl carbonate Theobromine

Place 500 ml of water and 500 ml of dimethyl carbonate in a 2 liter shaking autoclave. A further 99.6 g (0.6 mol) of 3-methylxanthine are added and the suspension is heated to 175 ° C. The pressure rises to 80 bar during the 2.5 hour reaction. At the end of the reaction time, it is cooled to 70 ° C and the autoclave is aerated. The suspension (pH 77.1) is then filtered hot through a preheated suction strainer with filter paper and washed at the end with 100 ml of water. The isolated product is dried at 50 ° C in a vacuum oven to concentrated weight.

HPLC: 98.6% C, H, N: Theory: C 46.66%, H 4.48%, N 31.10% Found: C 46.53%, H 4.47%, N 30.77 %

Melting point: 351 - 355 ° C Yield: 71.17 g (= 65.84%) 7,89435

Example 3

O O

H \ 1, H O H, Il / ch3

«^ V" \ I N ^ V / N

I H Λ + h3c-o-c-o-ch3 -> | Il /) + ch3oh + co2

0 I 0 I

H CH 3 MG: 152.11 MG: 90.08 MG: 180.17

Xanthine Dimethyl carbonate Theobromine

Place 500 ml of buffer solution pH 7.8 (prepared from 6.84 g of Na 2 B 4 O 7 x 4H 2 O and 41 ml of 1N HCl, make up to 500 ml) and 500 ml of dimethyl carbonate in a 2-liter shaking autoclave. A further 91.27 g (0.6 mol) of xanthine are added and the pH 7.8 suspension is heated to 200 ° C. The pressure rises to 160 bar during the 2.5 hour reaction. At the end of the reaction time, it is cooled to 70 ° C and the autoclave is aerated. The suspension (pH 77.6) is then suction filtered through a preheated suction strainer with filter paper, and washed with 2 x 100 ml of water. The isolated product is dried at + 50 ° C in a vacuum oven to constant weight.

HPLC: 98.5% C, H, N: Theory: C 46.66%, H 4.48%, N 31.10% Found: C 46.50%, H 4.59%, N 30.70 %

Melting point: 351 - 354 ° C Yield: 45.61 g (= 42.19%)

Example 4

O O

H3CX II / Na O H3cs H „CH3 N \ Il N v

J 2 + H 3 C-O-C-O-CH 3 -> ^ J Na 2 CO 3 + CH 3 OH

o7 I <> | ch3 ch3 MG: 202.15 MG: 90.08 MG: 194.2

Theophylline-Na Dimethyl carbonate Caffeine 8 8 9 4 G 5

Place 100 ml of methanol, 334 ml of dimethyl carbonate and 90 g (0.4 mol) of 90% theophylline sodium salt in a 1 liter shaking autoclave. The suspension is heated to 200 ° C and stirred at this temperature for 3 hours. In this connection, the pressure rises to about 40 bar. At the end of the reaction time, it is cooled to about 60 [deg.] C., aerated and the suspension is suction filtered hot through a preheated suction filter with filter paper. The precipitate (sodium carbonate) is washed with methanol11a. 400 ml of methanol are distilled off from the combined solutions. The suspension thus obtained is stirred for one hour in an ice bath. The precipitated caffeine is filtered off with suction, washed with cold methanol and dried at 60 [deg.] C. in a vacuum oven to constant weight. To obtain an additional amount of product, methanol is distilled off from the combined solutions to a final volume of 100 ml. The suspension thus formed is stirred for one hour in an ice bath, filtered off with suction, and washed with cold methanol. The secondary teas are dried together with the primary crystals.

HPLC: 99.7% C, H, N: Theory: C 49.48%, H 5.19%, N 28.85% Found: C 49.34%, H 5.20%, N 28.74 %

Melting point: 234-235 ° C Yield: 69.9 g (= 90%)

Example 5

O O

Hs.ll / H O H3C H ^ CH3 N / V ^ Nv H N \ | || ) + 3H3C-O-C-O-CH3 -> | H) + 3CH 3 OH + 3CO 2

AnAn / ° i 0 i H CH 3 MG: 152.11 MG: 90.08 MG: 194.2

Xanthine Dimethylcarbonate Caffeine

Place 55 ml of methanol and 110 ml (1.3 moles) of dimethyl carbonate in a 500 ml shaking autoclave, and then 20 g (0.13 moles) of xanthine. The suspension is heated to 200 ° C. The pressure rises to about 70 bar within a reaction time of 5 hours.

9 39485 At the end of the reaction time, cool to about 70 ° C, aerate, and distill off methanol to a final volume of about 100 ml. The suspension (pH 8 8.3) is cooled in an ice bath. The crystals are filtered off with suction and washed with 2 x 30 ml of cold methanol. The isolated product is dried at 50 ° C in a vacuum oven to constant weight.

HPLC: 99.8%

Melting point: 234-237 ° C Yield: 21.1 g (= 82.6%)

Example 6

O O

HN II / H o h3cs II, ch3 I Γ + h3c-o-c-o-ch3 -> | | [,) + ch3oh + co2 n7 / o I o | ch3 ch3 MG: 166.14 MG: 90.08 MG: 194.2 3-methylxanthine Dimethylcarbonate Caffeine

Place 50 ml of dimethyl carbonate (0.6 mol) and 25 ml of methanol in a 250 ml shaking autoclave. A further 10 g (0.066 mol) of 3-methylxanthine are added and the mixture is heated to 200 ° C. The pressure rises to about 60 bar during the 5 hour reaction. After the reaction time, cool to about 70 ° C, aerate, transfer to an Erlenmeyer flask and further cool to 10 ° C. The precipitated crystals are filtered off with suction and washed with 15 ml of cold methanol. The isolated product is dried at 50 ° C in a vacuum oven to concentrated weight.

HPLC: 99.4%

, Melting point: 234-237 ° C

Yield: 9.3 g (= 79.6%)

Claims (7)

Method for methylating xanthines, characterized in that dimethyl carbonate is used as the methylation reagent, wherein the molar ratio of the starting material to the dimethyl carbonate is 1: 3 - 1:50, the pH of the reaction mixture is adjusted with a water buffer to between 7.8 - 7.1 and the reaction takes place 100 - 250 ° C, under the corresponding elevated pressure. Process according to Claim 1, characterized in that to the reaction mixture is added an organic solvent with an acidic hydrogen atom, preferably methanol. Process according to claim 1, characterized in that xanthine or 3-methylxanthine or their sodium or calcium salt is methylated to theobromine, wherein dimethyl carbonate is used in one mole of the starting material: dimethyl carbonate = 1: 3 - 1:50, preferably 1: 7 - 1:10, and the reaction is carried out in water or a water buffer (pH 7.8 - 7.1) at 100 - 250 ° C, preferably 170 - 200 °, and under the corresponding elevated pressure. 4. A process according to claim 1, characterized in that caffeine is methylated caffeine, xanthine, 3-methylxanthine or theophylline or their sodium or calcium salt, using dimethyl carbonate in a molar ratio of the starting material: dimethylcarbonate = 1: 3 - 1:50, preferably 1 : 7 - 1:10, and the reaction is carried out at 100 - 250 ° C, preferably 170 - 200 ° C, and under the corresponding elevated pressure. Process according to claim 4, characterized in that an acidic solvent is added to the reaction mixture. 6. A process according to claim 5, characterized in that methanol is added to the reaction mixture. 13 89 4 0 5 Process according to claim 6, characterized in that methanol is added in a mole of dimethyl carbonate: methanol off = 3.3: 1 - 2: 1.