Process for the Manufacture of a Precursor of Vitamin Bl

The present invention relates to a novel process for the preparation of Grewe diamine (GD; 5-aminomethyl-2-methyl-pyrimidine-4-yl-amine, compound I) of formula

by treating a solution of a 4-amino-2-methyl-5-acylaminomethyl-pyrimidine with an ion exchange resin.

GD is an important precursor for the synthesis of vitamin Bl (see, e.g., Moine, G. and H.- P. Hohmann in Ullmann's Encyclopedia of Industrial Chemistry, VCH, Vol. 27A515- 517 [1996]).

In accordance with methods of the state of the art Grewe diamine can be prepared by expensive reduction processes, e.g., hydrogenation or reductive amination, of corresponding 5-nitrilo- or 5-formyl-pyrimidines, respectively or by reaction of a corresponding 5-alkoxymethyl-pyrimidin with ammonia in the presence of a catalyst at a temperature of at least 230°C (see EP 1 138 675 A and US 6,365,740). DE 35 1 1 273 A describes the hydrolysis of 2-methyl-4-amino-5-formylaminomethyl-pyrimidine with aqueous sodium hydroxide and extraction of the Grewe diamine with methylisobutyl-

carbinol. In order to obtain a pure product (with yields of 58.2 - 65.7%) sublimation at 130 - 220°C/l,5-2 mbar was necessary.

In an attempt to provide an easier but nevertheless very efficient process for the manufacture of Grewe diamine by hydrolysis of a 5-acylaminomethyl-pyrimidine precursor it has been found that this can be achieved by using ion exchange resins.

Therefore, the present invention relates to a process for the manufacture of Grewe diamine of formula

which process is characterized by treating a solution of a 4-amino-2-methyl-5-acylamino- methyl-pyrimidine (compound II) of formula

wherein R is hydrogen or a straight- or branched-chain Ci _-4 -alkyl group,

with an ion exchange resin.

C i- ₄ -alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and tert. -butyl.

The preferred acyl group in compound II is formyl, which corresponds to substituent R being hydrogen. The preferred solvent in which the 4-amino-2-methyl-5-acylamino- methyl-pyrimidine is treated with the ion exchange resin is water. Prior to contacting the solution containing compound II it may be purified by any conventional means, e.g., by filtration or distillation. By the latter impurities resulting from process steps in the synthesis of compound II forming azeotropic mixtures with water can be removed, such as o-chloro aniline. The reaction is preferably carried out using anion exchange resins, most preferably strong basic anion exchange resins such as quaternary ammonium resins.

The essential step of the present process is the hydrolysis of compound II by treatment with a strong basic anion exchange resin. The resin is then separated from the solution by any conventional method and washed with water. The wash-water can be combined with the separated solution. The acylate R - CO - O ^" generated by the hydrolysis of the acyl group R-CO is retained by the strong basic anion exchange resin. The aqueous effluent and/or washings after the hydrolysis containing Grewe diamine and without carboxylate R-CO-O ^" can then be used in solution with or without concentration for further chemical reactions. The GD can be isolated by complete concentration of the solution. If an even higher purity of GD is wanted it can be isolated from the solution by methods well-known in the art, e.g., extraction and/or crystallisation.

The major advantage of the invention is that relatively pure GD can be isolated in a single operation without additional work-up. While by hydrolysis of a compound II, especially a 5-formylaminomethyl-pyrimidine, with bases like NaOH as described in DE 35 1 1 273, no direct separation of the sodium formate by-product from the desired Grewe diamine is achieved, the preferred use of strong basic ion exchange resins provides both: the hydrolysis of compound II and the adsorption of sodium formate at the quarternary ammonium groups of the resin. Thus Grewe diamine is obtained free from sodium formate which is obtained separately by regeneration of the resin. The amount of sodium acylate, particularly sodium formate in the desired end product can thus be easily reduced to <10%, preferably <5%, more preferably <2% and most preferably <1%, calculated as dry GD, depending upon the details of the operating conditions. Furthermore the use of organic solvents can be avoided, thus, providing an environmentally favourable procedure which does not need complex solvent regenerating procedures. Getting an aqueous solution of GD is an additional benefit of the present process since a solution of GD in water is a

suitable starting material for the subsequent synthesis of vitamin Bl . No solvent exchange or complex handling of the compound in solid form is necessary.

The ion exchange resins useful in the present reaction, as a matter of principle, are anion and cation exchange resins, preferably anion exchange resins and particularly strong basic anion exchange resins. The use of anion exchange resins has the advantage that the acylate generated by the hydrolysis of compound II is retained by the resin while the GD is to be found in the eluate and the washings. In case of using a cation exchange resin the acylate is collected in the eluate and the washings as the corresponding carboxylic acid. However, a second step will be necessary, viz. elution of the retained GD from the resin. Therefore, the use of cation exchange resins is less preferred. All known and commercially available ion exchange resins can be used. This includes especially all strong basic anion and all stron acidic cation exchange resins such as Lewatits , Amberlites , Duolite , Dowex and Diaion resins obtainable from the following companies: Bayer AG, Rohm & Haas Comp., Dow Chemical Company and Mitsubishi Chemicals Corp. The resins which can be used for the invention are not limited to the ones mentioned in this paragraph.

The hydrolysis according to the present invention can be carried out at temperatures in the range of 20 - 100°C, preferably 35 - 90°C, more preferably 45 - 80°Cand most preferably 55 - 75°C. The concentration of the aqueous solution of compound II, which is submitted to the process, is in the range of 2 - 30 % (w/w), preferably 4 - 25%, more preferably 6 - 20 and most preferably 8 - 16%. The aqueous solution of compound II is kept in contact with the resin for a reaction time which depends upon the dimensions of the reaction vessel and is normally in the range of 0.25 - 6 hours, preferably 0.5 4 hours, more preferably 0.75 - 3 hours, most preferably 1 - 2 hours.

The amount of resin used is in the range of 1 - 10 equivalents per equivalent of compound II, preferably 1.1 - 6 equivalents, more preferably 1.2 - 4 equivalents and most preferably 1.3 - 3 equivalents.

The process of the present invention can be carried out batch- wise or continuously in accordance with methods well-known to a person skilled in the art. In the case of a batch- wise process the solution of compound II is mixed with the resin in the reactor, e.g. a

stirred tank reactor. Resin and solution are mixed during the respective reaction time and then the resin is removed by filtration and washed with water to obtain the complete amount of GD. For this purpose totally 0.5 - 15 volumes of water per volume of resin are normally used, preferably 1 - 10 volumes, more preferably 1.5 - 8 volumes and most preferably 2 - 5 volumes, in one or several runs. The washing water can be combined with the filtrate or can be recycled completely or partly for the use in an additional experiment. When the resin is nearly completely loaded with acylate, in any case in good time before its capacity is exhausted, it has to be regenerated according to methods well-known in the art, with an aqueous solution of a water-soluble base, preferably sodium hydroxide. The effluent of the regeneration step contains the acylate, in the preferred embodiment sodium acylate, which is suitably collected and worked-up or discarded.

In case of a continuous process the pre-heated solution of compound II is submitted to a fixed-bed reactor, e.g., to a column filled with the resin. The effluent is collected and the resin is washed with water in amounts given above. The washing water containing GD can then be combined with the eluate to give an aqueous solution of GD or can be collected separately. The complete or parts of the eluate or washings can be recycled for the use in an additional experiment. Again, the fixed ion exchanger bed is regenerated with an aqueous solution of a water-soluble base preferably NaOH.

The same procedures apply mutatis mutandis in case acid cation exchange resins are used.

The invention is further illustrated by the following Examples.

Example 1:

Batch Process. Hydrolysis at 6O ⁰ C

9.00 g of N-formyl Grewe diamine (NFGD, 91.44 w/w%; 1.04 w/w% o-Cl-aniline, 1.80 w/w% ethanol) were dissolved in 103.5 g of demineralized water at a temperature of 60°C. The solution was charged with 107.1 g Amberlyst A26 ^® (OH ^" form, 2 eq.). The reaction mixture was stirred for 3 hours at 60°C. The reaction mixture was analyzed at different times. The results are shown in the following table.

Time w/w% GD w/w% NFGD

0.25 h 3,373 0,119

1.25 h 3,520 0,017

2.25 h 3,641 0,009

3.0O h 3,624 0,004

The resin was filtered off and was washed with 14O g of demineralized water. The filtrate (110.13 g) and the washing water (137.07 g) were analyzed separately. GD, NFGD and o- chloroaniline were always analyzed by HPLC; sodium formate was analyzed by ion chromatography.

Filtrate: w/w% g mmol yield GD

GD 3,85 4,23 30,6 61 ,82

NFGD 0,000 0,00 0,00

Na-formate 0,170 0,19 2,75 o-CI-aniline 0,011 0,02 0,09

Washing water: w/w% g mmol yield GD

GD 0,65 0,90 6,5 13,10

NFGD 0,000 0,00 0,00

Na-formate 0,130 0,18 2,62 o-CI-aniline 0,004 0,01 0,04

94.59 g of the filtrate were concentrated to dryness on a rotary evaporator. The solid obtained was dried in a drying cabin and gave 3.95 g of GD with a purity of 90.19 w/w% (HPLC) containing 0.004 w/w % (HPLC) of NFGD and 1.82 w/w % of (ion chromatography) Na-formate. o-Chloro- aniline was not detectable.

The resin was regenerated with 1400 g of aqueous NaOH (4 w/w %) at room temperature. The resin was filtered off and washed neutral with demineralized water and was ready to be used in the next experiment.

The filtrate from the regeneration contained the following compounds:

w/w% g mmol yield GD

GD 0,06 0,77 5,6 11 ,25

NFGD 0,000 0,00 0,00

Na-formate 0,270 3,78 55,6 o-CI-aniline 0,001 0,01 0,11

Example 2:

Batch Process. Hydrolysis at 75°C

230 ml of wet resin IRA 958 ^® (Cl ^" form) was shaken three times with an overall amount of 2000 g aqueous NaOH (4 w/w %). The resin was filtered off and was washed with demineralized water until the wash water remained neutral.

15.00 g of NFGD (93.90 w/w%; 0.35 w/w% o-Cl-aniline) were dissolved in 85.0 g of demineralized water at 75°C. The solution was charged with 230 ml of IRA 958 ^® (OH ^" form, 2 eq.). The reaction mixture was stirred for 3 hours at 75°C. The reaction mixture was analyzed at different times. The results of the analyses are shown in the following table.

Time w/w% GD w/w% NFGD

0.00 h 4,460 2,347

1.00 h 6,511 0,132

2.0O h 6,504 0,000

3.0O h 6,534 0,000

The resin was filtered off and was washed with 230 g of demineralized water. The filtrate (90.62 g) and the washing water (217.20 g) were analyzed separately.

Filtrate: w/w% g mmol yield GD

GD 6,55 5,94 43,0 50,73

NFGD 0,000 0,00 0,00

Na-formate 0,280 0,25 3,73 o-CI-aniline 0,020 0,02 0,14

Washing water:

w/w% g mmol yield GD

GD 1 ,53 3,32 24,0 28,35

NFGD 0,000 0,00 0,00

Na-formate 0,060 0,13 1 ,91 o-CI-aniline 0,007 0,02 0,12

The resin was regenerated with 2036 g of aqueous NaOH (4 w/w %) at room temperature. The resin was filtered off, washed neutral with demineralized water and was ready to be 5 used in the next experiment.

Example 3:

Continuous Process. Fixed bed hydrolysis at 75°C

A column with a heating jacket was charged with 200 ml of wet ion exchange resin IRA 10 958 ^® (Cl-form) at room temperature (0.8 mol ClVl resin). The column was purged with 993.3 g of aqueous NaOH (4 w/w %) over a period of lhour. The resin was washed with 1962.3 g of demineralized water. The jacket of the column was heated to 75°C. Thus the column was prepared with the resin in its OH ^" form.

14.76 g of crude NFGD (89.41 w/w%, 0.62 w/w% o-Cl-aniline) were dissolved in 85.62 g 15 of demineralized water at 75°C. Small quantities of insoluble material were removed by filtration.

The column was loaded with the pre-heated filtrate (75°C, 82.70 g, containing 57 mmol NFGD) at a flow rate of 3.33 ml/min. The eluate of the column was collected in 3 ml fractions. After completion of loading (21 fractions collected), the column was washed 0 with 300 ml of demineralized water (pre-heated to 75°C). Again, the eluate was collected in 3 ml fractions. Starting from fraction 51, fractions of 6 ml each were collected. The elution was stopped at fraction 78.

Analysis of the fractions gave the following results:

GD w/w% NFGD w/w% Na-formate w/w%

NFGD solution 0,092 11 ,369 0,003

Fractions

1 0,000 0,000 0,003

6 0,000 0,000 0,000

12 0,000 0,000 0,000

18 0,000 0,000 0,000

24 2,030 0,000 0,000

30 4,623 0,000 0,005

36 6,113 0,000 0,010

42 6,287 0,000 0,015

48 6,079 0,000 0,050

54 4,860 0,000 0,007

60 2,810 0,000 0,005

66 0,259 0,000 0,003

72 0,051 0,000 0,003

78 0,026 0,000 0,004

Fractions 1 to 78 were combined. The resulting GD solution (324.71 g) was analyzed.

w/w% g mmol yield GD

GD 2,400 7,81 56,5 99,17

NFGD 0,002 0,01 0,04

Na-formate 0,005 0,02 0,29 o-CI-aniline 0,006 0,02 0,02

The column was regenerated with an overall amount of 1500 g of aqueous NaOH (4 w/w %). The eluate from the regeneration was collected in seven fractions which were analysed. The results are shown in the following table.

Fractions Amount GD w/w% NFGD w/w% Na-formate w/w% g Na-formate

1 200,53 0,03 0,000 0,196 0,39

2 204,44 0,01 0,000 2,056 4,20

3 225,57 0,01 0,000 0,493 1 ,11

4 236,69 0,00 0,000 0,029 0,07

5 221 ,16 0,00 0,000 0,011 0,02

6 209,61 0,00 0,000 0,004 0,01

7 172,34 0,00 0,000 0,004 0,01

1470,34 5,82 (85.58 mmol)

The column was washed neutral with demineralized water and was ready for use in the next experiment.

Example 4:

Continuous Process. Fixed bed hydrolysis at 60 ⁰ C

7.40 g of crude NFGD (91.40 w/w%, 0.54 w/w% o-Cl-aniline) were dissolved in 79.89 g of demineralized water at 60°C. Small quantities of insoluble material were removed by filtration.

The column (containing 200 ml of IRA 958 (OH ^" form) was loaded with the pre-heated filtrate (6O ⁰ C) (86.10 g, containing 35 mmol NFGD at a flow rate of 3.33 ml/min. The eluate of the column was collected in fractions. After completion of loading, the column was washed with 300 ml of demineralized water (pre-heated to 75°C). The eluate was collected in fractions which were analysed

The results of analyses are shown in the following table:

Amount [g] GD w/w% NFGD w/w% Na-formate w/w%

NFGD solution 0,000 6,758

Fractions

1 81 ,40 0,014 0,003 0,047

2 97,26 2,850 0,006 0,046

3 100,17 2,304 0,010 0,004

4 101 ,60 0,028 0,002 0,005

Fractions 1 to 4 were combined. The resulting GD solution (380.43 g) was analyzed.

w/w% g mmol yield GD

GD 1 ,346 5,12 37,1 105,87

NFGD 0,001 0,02 0,12

Na-formate 0,011 0,04 0,6 o-CI-aniline 0,005 0,02 0,16

The column was regenerated with an overall amount of 1500 g of aqueous NaOH (4%). The analysis of the eluate is given in the following table.

w/w% g mmol yield GD%

GD 0,002 0,03 0,20 0,57

NFGD 0,002 0,03 0,17

Na-formate 0,252 3,65 53,7

The column was washed neutral with demineralized water and was ready for use in the next experiment.