CH657611A5 - METHOD FOR PRODUCING 2,4-DIAMINO-5-BENZYL-pyrimidine derivatives. - Google Patents

Description

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PATENT CLAIMS 1. Process for the preparation of 2,4-diamino -5-benzyl-pyrimidine derivatives of the formula I.

The invention relates to a process for the preparation of 2,4-diamino-5-benzyl-pyrimidine derivatives of the formula I,

s R,

-VH.,

NH "

wherein

Ri and R3 independently of one another are hydrogen atoms, methyl or methoxy groups,

R2 represents a halogen atom, a Q 4 alkoxy group substituted by halogen atom, a C2 4 alkenyloxy group or a group of the formula R40- (R50) n-, where R4 represents a C 1-4 alkyl group and R5 represents a CI4 alkylene group, and n has a value of 1 or 2, and their pharmaceutically suitable acid addition salts, characterized in that an alpha-benzal-beta-methoxypropionitrile of the formula III,

cn I

ch = c

I.

III,

ch2-och3

wherein Rb R2 and R3 have the above meaning, with a diethylene glycol monoalkyl ether of the formula IV,

ho-ch2ch2-o-ch2ch2-or

(IV),

wherein R is a C, 4 alkyl group, in the presence of a base, the resulting benzyl isomer of formula II

(II),

C H-0-CH2CH2-O-CH2CH2-OR

wherein Rb R2, R3 and R have the above meaning, cyclized with guanidine and, if desired, converted a compound of formula I obtained into an acid addition salt.

2. The method according to claim 1, characterized in that the benzyl isomer of the formula II is cyclized with guanidine without separation.

3. The method according to claim 1 or 2, characterized in that there is used as a compound of formula IV di-ethylene glycol monomethyl ether.

4. The method according to claim 1 or 2, characterized in that an alkali metal alkoxide is used as the base.

5. The method according to claim 1 or 2, characterized in that one carries out the reaction of the benzyl compound with the guanidine in the presence of an alkanol having 4 to 8 carbon atoms.

6. The method according to claim 4, characterized in that isobutanol is used as the alkanol having 4 to 8 carbon atoms.

wherein

15 R] and R3 independently of one another hydrogen atoms, methyl or methoxy groups,

R2 represents a halogen atom, a Q_4 alkoxy group substituted by halogen atom, a C2_4 alkenyloxy group or a group of the formula (R40- (R50) n-, in which R4 20 represents a C 1-4 alkyl group and R5 represents a Q 4 alkylene group, and n has a value of 1 or 2, and their pharmaceutically acceptable acid addition salts.

The 2,4-diamino-5-benzyl-pyrimidine derivatives of For-25 mei I have antibacterial activity and can be used both in human medicine and in veterinary medicine.

According to British Patent No. 1,413,454, 2,4-diamino-5-benzyl-pyrimidine derivatives, in which the benzyl group in position 3 is represented by a methoxy group, in position 4 by an alkoxy-alkoxy group (both of which are alkoxy groups Have 1 to 3 carbon atoms) and in position 5 unsubstituted or substituted by a halogen atom, an alkyl or alkoxy group. According to this process, a suitably substituted hydrocinnamic acid alkyl ester is formylated and the reaction product is cyclized with guanidine. The corresponding 2-amino -4-hydroxy -5-benzyl-pyrimidine obtained is then treated with ammonia.

The above known process consists of numerous 40 reaction stages and is not economical - especially on an industrial scale. The overall yield based on the substituted benzaldehyde is at most 20% of theory.

According to a further process, which is also described in the above-mentioned briti-45 patent, the above compounds can be prepared from the correspondingly substituted al-pha-benzyl-beta-alkoxyacrylonitrile by reaction with guanidine. The benzyl intermediate can only be obtained from the correspondingly substituted benzaldehyde in a yield of 30 to 40% of theory, so the overall yield based on the substituted benzaldehyde is only 20 to 30%.

The same procedure was used to prepare 2,4-diamino-5- (3 ', 5'-dimethoxy-4'-halobenzyl) pyrimidine 55 according to U.S. Patent No. 4,024,145. In this case too, the overall yield based on 3,5-dimethoxy-4-halogenobenzaldehyde is at most about 30% of theory.

The economical synthesis of the 2,4-diamino -5-60 benzyl-pyrimidine derivatives of the formula I is therefore not solved by the known processes.

The object of the invention is to develop an economical process for the preparation of the compounds of the formula I with a purity which corresponds to the pharmaceutical application.

The above object was achieved by a process which is characterized in that an alpha-benzal-beta-methoxypropionitrile of the formula III,

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wherein R], R2 and R3 have the above meaning, with a diethylene glycol monoalkyl ether of the formula IV,

ho-ch2ch2-o-ch2ch2-or

IV

in which R represents a C, 4 alkyl group, in the presence of a base, the benzyl isomer of the formula II obtained,

ClI-O-CltjCH ^ -O-ClLjCH -oll in which Rb R2, R3 and R have the above meaning - advantageously without separation - cyclized with guanidine and, if desired, converts a compound of the formula I obtained into an acid addition salt.

The alpha-benzal-beta-methoxypropionitrile used as the starting compound is prepared in a manner known per se by the reaction of the appropriately substituted benzaldehyde with beta-methoxypropionitrile. The beta-methoxypropionitrile is obtained from acrylonitrile with methanol in an alkaline medium.

The diethylene glycol monoalkyl ether of the formula IV is advantageously diethylene glycol monomethyl ether. The compound of formula IV is generally used in excess. In this case, this reaction component also plays the role of the solvent. At the same time, other solvents can also be present in the reaction of the compounds of the formulas III and IV. In this reaction, an alkali metal alkoxide, e.g. Sodium methoxide, sodium ethoxide, potassium methoxide etc. The reaction is generally carried out at 20 to 200 ° C, advantageously at 60 to 110 ° C.

In the first stage of the process according to the invention, the benzal isomer of the formula IIa

Alkanol with 4 to 8 carbon atoms may be present in the reaction of the benzyl compound with guanidine.

According to a preferred embodiment of the process according to the invention, the compound of the formula II is reacted with guanidine without removal. In this case, the diethylene glycol monoalkyl ether of the formula IV is also present in the cyclization if it was used in excess in the preparation of the benzyl compound. The guanidine is expediently added to the benzyl compound as an acid addition salt, for example hydrochloride, and is released from the salt in the reaction mixture with a base, advantageously an alkali metal alkoxide.

The reaction of the benzyl compound with the guanidine is generally carried out at a temperature of 50 to 1550 ° C., mostly at the boiling point of the reaction mixture.

The compounds of the formula I can be prepared economically by the process according to the invention. The new process enables the desired product to be produced from the compound of the formula III without isolation of the intermediate product formed, and the purity of the product obtained in this way is sufficient for therapeutic use.

The process according to the invention is explained in more detail with reference to the following examples.

II

-0-CH2CH2-0R

formed, wherein Rb R2, R3 and R have the above meaning. Under the reaction conditions used, the benzal isomer is converted into the corresponding benzyl isomer of the formula II in almost theoretical yield, which is of high purity and can also be cyclized with guanidine without separation and purification.

The benzal isomer of formula IIa and the benzyl isomer of formula II are new compounds.

The benzyl isomer of the formula II is advantageously reacted with guanidine in the presence of an alkanol which has 4 to 8 carbon atoms. Sutanol, pentanol, hexanol, heptanol or octanol can be used as the alkanol having 4 to 8 carbon atoms. Tertiary butanol or isobutanol is advantageously used.

Of course, other solvents, for example other alkanols, such as methanol, can also be used in addition to the

example 1

A. 2,4-diamino-5- (4'-bromobenzyl) pyrimidine 2- (4'-bromo-30 benzal) -3-methoxypropionitrile

15 g (0.081 mol) of 4-bromo-benzaldehyde are added to the solution of 8.59 g (0.162 mol) of acrylonitrile in 17 ml of anhydrous methanol, the mixture is stirred at 30 ° C. until the aldehyde has dissolved, then to 60 ° C. heated and 35 of the solution obtained 5.44 g (0.097 mol) of potassium hydroxide, which was dissolved in 49 ml of anhydrous methanol, are added dropwise. The reaction mixture is stirred at 60 to 65 ° C for 5 hours, then cooled to 30 ° C and the solution of 5.18 g (0.092 mol) of potassium hydroxide in 17 ml of methanol 40 is added to the mixture in 1.5 hours. The reaction mixture is stirred at 30 ° C for a further 12 hours. After the completion of the reaction, the excess of the solvent and the acrylonitrile are distilled off. The remaining oil is poured onto ice water and 45 extracted three times with 100 ml of chloroform. After the organic phase has been evaporated, the remaining red-brown oil is fractionated. 9.4 g of 2- (4'-bromobenzal) -3-methoxypropionitrile are obtained, b.p. 130-136 ° C / 0.4 mmHg. Ha The yield is 46% of theory.

50 O'v n g = 1.5543.

Analysis:

calculated for Q jHioNOBr (molecular weight: 252.119): C 52.41%, H 3.99%, N 5.56%, Br 31.69%;

55 found:

C 52.27%. H 4.27%, N 5.45%, Br 31.07%.

IR (KBr):

3090 (= CH), 3060 and 3030 (= CH), 2830 (COCH3), 2210 (CN), 1630 (C = C), 1590 and 1490 (C = C), 1145 and 1100 60 (COC), 1075 ( COC), 1010 (Br), 965 (= CH) cm- '. NMR (DMSO-d6) 5 7.4 (bs, 4H, aromatic protons), 7.2 (bs, 1H, -CH =), 4.05 (s, 2H, CH20), 3.25 (s, 3H) , CH3Ö).

B. 2,4-diamino-5- (4'-bromobenzyl) pyrimidine 3.68 g (0.015 mol) of 2- (4'-bromobenzal) -3-methoxypropionitrile are in 11.92 g (0.099 mol) of anhydrous diethylene glycol monomethyl ether dissolved, 0.92 g (0.017 mol) of sodium methoxide are added to the solution and at 75 to 77 ° C.

65

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Stirred for 6 hours. After cooling, the isomerized product is poured onto 50 ml of ice water and extracted three times with 50 ml of chloroform. The organic phase is evaporated and the red-brown oil obtained (6.17 g) is fractionated. The 2- (4'-bromobenzyl) -3-methoxydiethoxy-acrylonitrile distilled at 63 to 75 TLC under a pressure of 0.06 Hgmm.

n p = 1.6761.

IR (KBr)

2250 (C = N), 1650 (C = C), 1490 (C = C), 1125 and 1110 (COC), 1075 (COC), 1010 (Br), 930 (= CH) cm- '.

NMR (CDC13) 8 7.05 (s, 1H, = CH), 7.1-6.8 (q, 4H, aromatic protons), 3.45 (bs, 8H, (OCH2CH2) 2), 3.22 (s, 3H, CH30), 2.8 (bs, 2H, CH2).

10 g (0.029 mol) of 2- (4'-bromobenzyl) -3-methoxydiethoxy-acrylonitrile are dissolved in the mixture of 15 ml of isobutanol and 5 ml of methanol, and the solution obtained is 9.86 g (0.1 mol) of guanidine hydrochloride and 5.83 g (0.11 mol) of sodium methoxide were added. The reaction mixture is boiled for 8 hours, then cooled to room temperature. The precipitated inorganic salt is filtered and washed with isobutanol. The yellow 2,4-diamino-5- (4'-bromobenzyl) pyrimidine which has precipitated from the cooled filtrate is filtered. The product obtained melts at 225 to 228 ° C. By working up the mother liquor, another product is obtained which melts at 224 to 227 ° C. The overall yield is 93% of theory.

IR (KBr)

3420 (NH,), 3320 and 1630 (NH-,), 1600.1570, 1460.1010 (Br), 800 (NH2) cm-1.

NMR (DMSO-d6) S 7.2-6.9 (q, 4H, aromatic protons), 7.22 (s, 1H, NH), 5.45 and 5.8 (s, 4H, acidic protons), 3.45 (s, 2H, CH2).

Example 2

2,4-diamino-5- (4'-bromobenzyl) pyrimidine

1.1 g (0.004 mol) of 2- (4'-bromobenzal) -3-methoxypropionitrile, which was prepared according to Example 1, paragraph A, are dissolved in 2.5 ml of anhydrous diethylene glycol monomethyl ether, and after the addition of 0.2 g (0.0037 mol) of sodium methoxide, the reaction mixture is stirred at 75 to 76 C for 6 hours. After cooling to 30 ° C, 1 ml of isobutanol, 0.3 ml of methanol, 0.6 g (0.006 mol) of guanidine hydrochloride and 0.35 g (0.004 mol) of sodium methoxide are added, and the reaction mixture is boiled for 8 hours. The product obtained after cooling the mixture is filtered and washed with water. Pale yellow, powdery 2,4-diamino-5- (4'-bromobenzyl) pyrimidine is obtained which melts at 224 ° C to 226 ° C.

Example 3

2,4-diamino-5- (4'-allyloxy-3 ', 5'-dimethoxybenzyl) pyrimidine

A. 3,5-Dimethoxy -4-allyloxybenzaldehyde

40 g of syringaldehyde sodium salt are dissolved in 300 ml of water, and 36.3 g of allyl bromide and 3 ml of TritonR B catalyst (a nonionic surfactant obtained by reacting octylphenol with ethylene oxide) are added to the solution. After five hours of boiling, the mixture is cooled slightly, again 12 g of allyl bromide and 2 g of sodium hydroxide are added to the mixture, which is boiled again for 5 hours. After cooling, the mixture is extracted twice with 50 ml of 1,2-dichloroethane. The dichloroethane phase is washed with 50 ml of 2% aqueous alkali, treated with active carbon and evaporated. The residue is crystallized with cooling. The crystalline product is ground with cold water, filtered and dried at room temperature. The 3,5-dimethoxy -4-allyloxybenzaldehyde obtained melts at 46 to 47: C.

s B. 2- (4'-Allyloxy-3 ', 5'-dimethoxybenzal) -3-methoxypropionitrile

0.09 g (0.001 mol) of potassium hydroxide is dissolved in 6 ml of anhydrous methanol, and 2.3 g (0.04 mol) of acrylonitrile are added dropwise to the resulting solution at 35 to 38 ° C. After the addition has ended, the reaction mixture becomes a Stirred at 40 C for an additional hour, then 3.8 g (0.017 mol) of 4-allyloxy-3,5-dimethoxybenzaldehyde are added to the mixture, which is stirred at 60 to 65 C for 12 hours. After the reaction mixture was cooled to room temperature, the excess of the solvent and the acrylonitrile was distilled off. The oil obtained is poured onto 50 ml of ice water and extracted three times with 50 ml of benzene each. After evaporating the organic phase, 3.46 g of yellow-brown oil are obtained, which corresponds to the title compound. 2o The yield is 70% of theory.

n ^ = 1.5599.

IR (KBr)

3090 and 3010 (= CH), 2850 (CH30), 2210 (CN), 1630 and 25 1590 (C = C), 1510 (C = C), 1465, 1330 and 1130 (CH30), 1190 and 1100 (COC) , 1235 (COC), 985 (COC) cm-1.

NMR (CDC13) S 6.78 (bs, 3H, aromatic protons and CH), 6.5-5.5 (m, 1H, CH =), 5.4-4.8 (m, 2H, CH2 =) , 4.4 (d, 2H, CH2-), 4.0 (s, 2H, so CH2-), 3.7 (s, 6H, CH30-), 3.3 (s, 3H, CH30).

C. 2- (4'-Allyloxy -3 ', 5'-dimethoxybenzyl) -3-methoxydi-ethoxyacrylonitrile

0.55 g (0.01 mol) of sodium methoxide is added to the solution of 2.64 g (0.009 mol) of 2- (4'-allyloxy-3,5-dimethoxybenzal) -3-35 methoxypropionitrile in 7 ml of anhydrous diethylene glycol monomethyl ether, and the reaction mixture is stirred at 80 to 82 C for 6 hours. After the end of the reaction time, the mixture is cooled to room temperature, poured onto 15 ml of ice water and extracted five times with 50 ml of 40 benzene each. After evaporating the organic phase, a red-brown oil remains, which corresponds to the title compound. The yield is 91% of theory.

n p = 1.6720.

45 IR (KBr)

2250 and 2220 (CN), 1248 and 990 (COC), 1465 and 1130 (CH30) cm- '.

NMR (CDC13) Ö 6.2 (m, 1H, = CH), 6.0-5.5 (m, 1H, = CH), 5.3-4.8 (2H, so = CH), 4, 3 (d, 2H, OHUO-), 3.7 (s, 6H, CH30), 3.5 (bs, 8H, (OCH2CH2) 2), 3.27 (s, 3H, CH30), 2.8 ( m, 2H, CH2-).

D. 2,4-diamino-5- (4'-allyloxy-3 ', 5'-dimethoxybenzyl) pyrimidine

1.12 g (0.012 mol) guanidine hydrochloride, 0.66 g (0.013 55 mol) sodium methoxide and then 1.13 g (0.003 mol) 2- (4'-allyloxy -3 ', 5'-dimethoxybenzyl) - 3-methoxydiethoxyacrylonitrile are dissolved in the mixture of 2 ml of isobutanol and 1 ml of methanol. The suspension is stirred at 35 to 40 C for one hour, then heated to 90 to 92 C, and kept at 6o this temperature for 18 hours. When the reaction has ended, the mixture is cooled to room temperature, the sodium chloride which has separated out is filtered off, the filtrate is treated with activated carbon, filtered, and the crystals which separate out with cooling with ice water are filtered and dried. The title compound melts at 188 to 190 C. The yield is 93% of theory.

IR (KBr)

3480,3335 and 3200 (NH2), 1670,1645 and 1610 (NH2 and

C = C), 1470 and 1130 (CH30), 1240 and 1005 (COC) cm- '.

NMR (DMSO-d6)

7.2 (s, 1H, = N), 6.37 (s, 2H, aromatic protons), 5.8, 5.4 (bs, 7H, NH2 and CH2 = CH-), 4.2 (d, 2H, -CH20), 3.68 (s, 6H, ch3o-), 3.4 (s, 2H, -CH2).

Example 4

2,4-diamino-5- (4'-methoxydiethoxy-3 ', 5'-dimethoxybenzyl) pyrimidine

A. 4-methoxydiethoxy -3,5-dimethoxybenzaldehyde 40.80 g (0.2 mol) of syringaldehyde sodium salt are dissolved in 300 ml of water, and 28 g (0.2 mol) of methoxyethoxyethyl chloride are added dropwise to the solution obtained. The reaction mixture is boiled for 20 hours, then cooled to room temperature and extracted three times with 200 ml of benzene. The organic phase is washed twice with 100 ml of 2% aqueous sodium hydroxide solution until the washing liquid becomes very light. After the organic phase has been evaporated, the remaining red oil (16 g) is stirred for one hour at room temperature with the solution of 16 g (0.17 mol) of sodium bisulfite in 100 ml of water. The pH of the solution obtained is brought to 20 % aqueous sodium hydroxide solution with cooling to 10, and the oil formed is extracted three times with 150 ml of benzene, after evaporation of the organic phase, 27.8 g of red oil, which corresponds to the title compound, are obtained. 9% of theory.

25th

D

1.6789.

IR (KBr)

1695 (CO), 1465 (ch3o-), 1130 and 1330 (CH30), 1230 (C = 0) cm - [-

NMR (cdci3) 8 9.46 (s, 1H, -CHO), 6.8 (s, 2H, aromatic protons), 3.75 (s, 6H, ch3o-), 4.1 (t, 2H, - CH20-), 3.8-3.4 (m, 6H, -CH2-), 3.25 (s, 3H, CH30-).

B. 2- (4'-Methoxydiethoxy-3,5-dimethoxybenzal) -3-methoxy propionitrile

4.47 g (0.084 mol) of acrylonitrile are added dropwise to the solution of 0.18 g (0.003 mol) of potassium hydroxide in 18 ml of anhydrous methanol for 1.5 hours at 35 to 40 ° C., and the reaction mixture is stirred at 40 ° for a further hour C stirred. 12.5 g (0.044 mol) of 4-methoxy-diethoxy-3,4-dimethoxybenzaldehyde are added to the mixture and the reaction mixture is boiled at 60 to 65 ° C. for 12 hours, then cooled to room temperature, poured onto 100 ml of ice water and four times extracted with 50 ml of chloroform. After evaporating the organic phase, 14.8 g of red oil are obtained, which corresponds to the title compound. The yield is 95.5% of theory.

25th

D

= 1.6767.

IR (KBr)

2860 (CH30-), 2220 and 2260 (CN), 1625 (C = C), 1590 and 1510 (C = C), 1465 (CH30), 1335 and 1130 (CH30), 1250 (COC), 1100 (COC) cm-'.

NMR (CDC13)

6.75 (s, 3H, aromatic protons), 4.0 (t, 2H, -CH2-), 3.98 (s, 2H, -CH2-), 3.7 (s, 6H, CHsO-), 3.5 (t, 6H, -CH2-), 3.25 (s, 3H, CH30-), 3.22 (s, 3H, CH30-).

C. 2- (4'-methoxydiethoxy-3 ', 5'-dimethoxybenzyl) -3-me-thoxydiethoxyacrylonitrile

10 g (0.028 mol) of 2- (4'-methoxydiethoxy-3 ', 5'-dimethoxybenzal) -3-methoxypropionitrile are dissolved in 23 ml of anhydrous diethylene glycol monomethyl ether, and the solution obtained is 1.76 g (0.033 mol) of sodium methylate admitted. The reaction mixture is kept for 6 hours

5 657 611

stirred at 75 to 77 ° C, then cooled to room temperature, poured onto 100 ml of ice water and extracted three times with 100 ml of chloroform. The combined organic phases are evaporated. The residue also contains diethylene-5 glycol monomethyl ether, which is distilled at 40 to 48 ° C under a pressure of 0.1 mm Hg. The distillation residue corresponds to the title compound. The yield is 95% of theory.

n 5L5 = 1.6772.

10th

IR (KBr)

2250 (CN), 1630 (C = C), 1590 and 1500 (C = C), 1460 (CH3), 1330 and 1120 (CH3), 1240 and 1195 (COC), 1110 and 1040 (COC) cm- '.

15 NMR (CDC13) 8 6.8 (s, 2H, aromatic protons), 6.15 (s, 1 H, = CH-), 4.0 (t, 2H, -CH2-), 3.7 (s , 6H, CH30-), 3.6 (s, 2H, -CH2-), 3.5 (t, 10H, -CH2-), 3.25 (s, 6H, CH30).

D. 2,4-Diamino-5- (4'-methoxydiethoxy-3 ', 5'-dimethoxy-2obenzyl) pyrimidine

A sodium methoxide solution is prepared by adding 1.24 g (0.054 mol) of sodium metal to 20 ml of anhydrous methanol, and 4.87 g (0.051 mol) of guanidine hydrochloride is added to the resulting solution. The reaction mixture is stirred at room temperature for 20 minutes, and the sodium chloride which has separated out (3.12 g) is filtered. 6.5 g (0.015 mol) of 2- (4'-methoxydiethoxy-3 ', 5'-dimethoxybenzyl) -3-methoxydiethoxyacrylonitrile and 8 ml of isobutanol are added to the solution of the guanidine base. The reaction mixture is boiled for 24 hours, then cooled to room temperature and evaporated. The remaining brown oil is taken up in 100 ml of water and extracted three times with 50 ml of ethyl acetate. After evaporation of the organic phase, a somewhat oily product remains, which is filtered and washed with ether. The light, drapy, powdery product obtained corresponds to the title compound and melts at 120 to 123 ° C. The yield is 93% of theory.

IR (KBr)

40 3450 (NH2), 3330 and 3160 (NH2), 1635 (NH2), 1590 and 1560 (NH2), 1450 (CH30), 1325 and 1120 (ch3o), 1230 (COC) cm "1.

NMR (DMSO-d6) 8 7.2 (s, 1H, = N-), 6.25 (s, 2H, aromatic protons), 5.6, 5.4 45 (s, 4H, -NH2), 3 , 56 (s, 6H, CH30-), 3.36 (s, 3H, CH30-), 3.12 (s, 2H, -CH2-).

Example 5

2,4-diamino-5- [4'- (3 "chloropropoxy) -3 ', 5'-dimethoxy-50 benzyl] pyrimidine

A. 3,5-Dimethoxy-4- (3'-chloropropoxy) benzaldehyde

20.4 g (0.1 mol) of syringaldehyde sodium salt are dissolved in 150 ml of water with heating, and the solution is first 15.8 g (0.1 mol) of 1,3-chlorobromopropane and then 2 ml of Triton B catalyst dripped. After boiling for eight hours, 15.8 g (0.1 mol) of 1,3-chlorobromopropane and 1 ml of Triton B are again added dropwise to the reaction mixture and the mixture is refluxed for a further 8 hours. After the reaction has ended, the mixture is cooled to room temperature and extracted three times with 150 ml of 1,2-dichloroethane each time. The organic phase is washed three times with 100 ml of 2% aqueous sodium hydroxide solution, then evaporated. 11.12 g of brown oil are obtained, which corresponds to the title compound. The 65 yield is 43% of theory.

n p = 1.5558.

IR (KBr)

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1695 (C = 0), 1465 (CH30-), 1330 and 1130 (CH30), 1235 (COC), 1020 (COC) cm-1.

NMR (CDC13) 6 9.42 (s, 1H, -CHO), 6.8 (s, 2H, aromatic protons), 4.00 (t, 2H, CH20-), 3.71 (s, 6H, CH30 -), 3.65 (t, 2H, Cl-), 2.01 (m, 2H, CH2 ~).

B. 2- [4'- (3 "Chloropropoxy) -3 ', 5'-dimethoxybenzal] -3-methoxypropionitrile

0.17 g (0.003 mol) of potassium hydroxide is dissolved in 11 ml of anhydrous methanol, and 3.84 g (0.073 mol) of acrylonitrile are added dropwise at 30 to 38 ° C. to the solution obtained. After the addition is complete, the reaction mixture is stirred for a further hour at 40 ° C., then 7.38 g (0.029 mol) of 3,5-dimethoxy-4- (3'-chloropropoxy) benzaldehyde are added to the mixture. The reaction mixture is kept at 60 to 65 ° C for 12 hours, then poured onto 50 ml of ice water and extracted three times with 40 ml of chloroform. After evaporating the organic phase

Obtain 6.7 g of light yellow oil, which corresponds to the title compound. The yield is 72% of theory.

n p = 1.5579.

IR (KBr)

3010 (= CH), 2850 (CH30-), 2220 (CN), 1600 (C = C), 1585 (C = C), 1505 and 1420 (C = C), 1465 (CH3), 1305 and 1130 (CH3 ), 1240 (COC), 1020 (COC), 830 (CH =) cm "1. NMR (CDC13) 5

6.8 (s, 3H, aromatic protons), 4.0 (s, 2H, -CH2-), 3.3 (s, 3H, CH30-), 4.0 (t, 2H, -CH20-), 3, 71 (s, 5H, CH2-, CH30-), 2.1 (m, 2H, -CH2 ~).

C. 2- [4'- (3 "Chloropropoxy) -3 ', 5'-dimethoxybenzyl] -3-methoxydiethoxyacrylonitrile

4 g (0.012 mol) of 2- [4 '- (3 "chloropropoxy) -3', 5'-dimethoxy-benzal] -3-methoxypropionitrile are dissolved in 10 ml of anhydrous diethylene glycol monomethyl ether, and the resulting solution becomes 0.74 g (0.014 mol) of sodium methoxide is added The reaction mixture is stirred for 6 hours at 75 to 77 ° C., then cooled to room temperature, poured onto 50 ml of ice water and extracted three times with 50 ml of chloroform each time, the organic phase is evaporated and evaporated This gives 4.08 g of red oil, which corresponds to the title compound, and the yield is 80% of theory.

n p = 1.5090.

IR (KBr)

2250 (CN), 1585 and 1505 (C = C), 1460 (CH3), 1330 and 1130 (CH3), 1240 (COC), 1030 (COC), 1645 (C = C), 930 (CH =), 850 (CH =) cm_l.

NMR (CDC13) 6 6.8 (s, 2H, aromatic protons), 6.15 (s, 1H, = CH-), 4.0 (t, 2H, -CH.-), 3.75 (s, 6H, CH30-), 3.71 (s, 2H, -CH2-), 3.6 (s, 2H, -CH -, -), 3.5 (t, 8H, -CH2-), 3.3 (s, 3H, CH30), 2.1 (m, 2H, CH2).

D. 2,5-Diamino-5- [4 '- (3 "-chloropropoxy) -3', 5'-dimethoxybenzyl] pyrimidine

The procedure is analogous to Example 4, paragraph D. This gives the title compound which melts at 163 to 164 3C. The yield is 89% of theory.

Example 6

2,4-diamino-5- (4'-methoxyethoxy-3 ', 5'-dimethoxybenzyl) pyrimidine A. Syringaldehyde

1500 ml of concentrated sulfuric acid are added to 300 g of 3,4,5-trimethoxybenzaldehyde with stirring. During the dissolution of the aldehyde, the mixture heats up to a temperature of 35 to 40 ° C and the black solution obtained is stirred at 40 to 42 ° C for 15 hours. In general, the demethylation in position 4 ends within this reaction time. This is assured by thin layer chromatography of a sample of the reaction mixture. (1 ml volume of the reaction mixture 5 is mixed with 3 g ice and 2 ml 1,2-dichloroethane, and 2 to 3 ml of the organic phase are added dropwise on a silica gel plate. The solvent mixture consists of chloroform, acetone and glacial acetic acid in a ratio of 60:30:10). If the reaction mixture still contains starting aldehyde, 10 the reaction is continued. If 3,4,5-trimethoxybenzaldehyde can no longer be detected in the reaction mixture, the latter is cooled to 20 ° C. and the mixture of 4 kg of ice and 2000 ml of 1,2-dichloroethane is mixed. The lower, aqueous phase is separated off and the upper 15 organic phase is washed with 1000 ml of water. Now the two phases will go wrong and the lower organic phase contains the syringaldehyde. This phase is evaporated and 125 g of sodium bisulfite, which was previously dissolved in 2000 ml of water, are added to the residue. The mixture is stirred at 35 to 40 ° C for 2 hours, and after sedimentation, the solution is decanted from the tar, then treated with 20 g of activated carbon and filtered. A 40% sodium hydroxide solution is added dropwise to the filtrate until further precipitation forms. The suspension obtained is cooled below 10 C, filtered and washed with cold water.

The wet salt is dissolved in 10 times the amount of water with stirring, and acidified to pH 2 with concentrated hydrochloric acid. The excreted syringaldehyde 30 is filtered, washed with water and dried. This gives 120 to 140 g of syringaldehyde, which melts at 111-114 C. After the thin-layer chromatography test, the product is uniform.

B. methoxyethyl chloride

35 76 ml of thionyl chloride are added dropwise at about 30 ° C. for 3 hours, 76 g of methoxyethanol and the reaction mixture is stirred at 30 to 35 ° C. for 20 hours. The methoxyethyl chloride formed is distilled through a column 50 cm in length. The main fraction boils at 90 to <to 91 ° C. 68 g of methoxyethyl chloride are obtained.

n ^ = 1.4090.

C. 3,5-Dimethoxy-4-methoxyethoxybenzaldehyde

200 g of syringaldehyde sodium salt are dissolved in 1500 ml of water, 90 g of methoxyethyl chloride are added to the solution obtained, and the reaction mixture is boiled for 16 hours. After the addition of a further 60 g of methoxyethyl chloride and 20 g of sodium hydroxide, the reaction mixture is boiled for a further 16 hours, then cooled to -50 and extracted twice with 500 ml of benzene each. The organic extract is washed twice with 250 ml of 2% aqueous alkali, then treated with activated carbon, filtered and evaporated. The residue consists of about 150 g of oil, which is dissolved in 600 ml of 2% sodium bisulfite solution. The solution obtained is treated with activated carbon, filtered, and the filtrate is adjusted to a pH of 9 to 10 at 0 to 3 ° C. by adding sodium hydroxide solution. The precipitate is filtered cold and dried. This gives 125 g of the title compound which melts at 29 to 33 ° C. and has a purity of 97 to 98% (based on the determination of the aldehyde). After the thin-layer chromatographic test, the product is uniform (the solvent mixture used consists of chloroform, ethyl acetate and gasoline in a ratio of 40:40:20). 65 D. 2,4-diamino-5- (4'-methoxyethoxy-3 ', 5'-dimethoxybenzyl) pyrimidine

1.5 g of potassium hydroxide are dissolved in 100 ml of methanol, and the solution obtained is 45 g of acrylonitrile in 3 hours

the added. The reaction mixture is stirred for a further hour at 40 to 42 ° C. and 100 g of 3,5-dimethoxy-4-methoxyethoxybenzaldehyde are added to the mixture. The reaction mixture is stirred at 60 to 62 C for 8 hours, then the methanol and the excess of the methoxypropionitrile are evaporated off. The residue is dissolved in the mixture of 400 ml of water and 400 ml of benzene and the phases are separated. The organic phase is washed with water and evaporated. The remaining crude product is dissolved in 250 ml of anhydrous diethylene glycol monomethyl ether, and 200 g of powdery sodium methoxide are added to the solution obtained. The reaction mixture is heated to 75 to 76 CC and stirred at this temperature for 6 hours. After the mixture has cooled to 30 ° C., 100 ml of isobutanol, 30 ml of methanol, 60 g of guanidine hydrochloride and 35 g of powdery sodium methoxide are added to the mixture. The reaction mixture is boiled for 8 hours, then about 110 ml of the solvent mixture is distilled off under slightly reduced pressure. The residue is diluted with methanol and cooled. The product crystallizes slowly. It is filtered, washed with a little methanol and recrystallized from five times the amount of hot water. The product corresponding to the title compound melts at 158 to 160 ° C. The yield is 91% of theory.

Example 7

2,4-diamino-5- (4'-methoxyethoxy-3 ', 5'-dimethoxybenzyl) pyrimidine

A. 2- (4-methoxyethoxy-3,5-dimethoxybenzal) -3-methoxypropionitrile

22 g of acrylonitrile are added to the solution of 0.7 g of potassium hydroxide in 50 ml of anhydrous methanol for 3 hours at 35 to 40 ° C. The reaction mixture is stirred for a further hour at 40 ° C., then 49 g of 4-methoxyethoxy-3,5-dimethoxybenzaldehyde, which was prepared according to Example 6, paragraph C, are added to the mixture. The reaction mixture is stirred at 60 to 62 ° C for 8 hours. (The end point of the reaction can be determined by thin layer chromatography. The solvent mixture used consists of chloroform, ethyl acetate and gasoline in a ratio of 40:40:20). After the reaction has ended, the methanol, together with the excess methoxypropionitrile, is distilled off under slightly reduced pressure. The residue is dissolved in the mixture of 200 ml of water and 200 ml of benzene and the phases are separated. The organic phase is washed with water, then evaporated. The remaining crude product is fractionated under a pressure of 0.05 mm Hg. The product distills at 192 to 195 ° C. Light yellow oil is obtained which corresponds to the title compound.

n ?? = 1.5498.

D

B.2- (4'-Methoxyethoxy-3 ', 5'-dimethoxybenzyl) -3-methoxydiethoxyacrylonitrile

The mixture of 50 ml of anhydrous diethylene glycol monomethyl ether, 20 g of 2- (4'-methoxyethoxy-3 ', 5'-dimethoxy-xybenzal) -3-methoxypropionitrile and 4 g of powdery sodium methoxide is heated to 75 to 77 ° C and 6 hours long

7 657 611

kept at this temperature. (The end point of the reaction can be determined by thin layer chromatography. The solvent mixture used consists of xylene and methyl glycol in a ratio of 90:10).

5 After the isomerization has ended, the mixture is cooled and mixed with 200 ml of benzene and 500 ml of water. After separation, the organic phase is washed twice with 200 ml of water, then evaporated. The residue is fractionated under a pressure of 0.02 mm Hg. The main fraction distills at 180 to 185 ° C. This gives a light yellow oil which corresponds to the title compound. The yield is 85% of theory.

20th

n p = 1.5510.

15 C. 2,4-Diamino-5- (4'-methoxyethoxy-3 ', 5'-dimethoxybenzyl) pyrimidine

10 g of 2- (4'-methoxyethoxy-3 ', 5'-dimethoxy-20-benzyl) -3-methoxydiethoxyacrylonitrile are added to the mixture of 15 ml of isobutanol, 4 ml of methanol, 8.5 g of guanidine hydrochloride and 5 g of powdery sodium methoxide , and the reaction mixture is boiled for 7 hours. Then about 15 ml of the solvent mixture are distilled off. The residue consists of a dense oil that crystallizes only slowly. The residue is stirred with 20 ml of methanol, the crystal suspension obtained is filtered, the crystalline product is dissolved in 25 ml of hot water and treated with activated carbon. After the solution has cooled, white, crystalline 2,4-diamino-5- (4'-methoxy-ethoxy-3 ', 5'-dimethoxybenzyl) pyrimidine is obtained, which melts at 158 to 30 ° C. The yield is 89% of theory.

Example 8

2,4-diamino-5- (4'-allyloxy-3 ', 5 / - dimethoxybenzyl) pyrimidine

35 22 g of acrylonitrile are added dropwise to the solution of 0.9 g of potassium hydroxide in 50 ml of methanol at 35 to 38 ° C. The reaction mixture is stirred at 40 ° C for one hour, then 36 g of 4-allyloxy-3,5-dimethoxybenzaldehyde are added to the mixture. The reaction mixture is stirred for 12 hours at 40-65 ° C, then cooled and mixed with the mixture of 300 ml of water and 200 ml of benzene. The organic phase is separated off, washed with water and evaporated. The residue is dissolved in 40 ml of anhydrous diethylene glycol monomethyl ether, 6 g of powdery sodium methoxide are added to the solution obtained, and the reaction mixture is stirred at 80 to 82 ° C. for 6 hours. 60 ml of isobutanol, 15 ml of methanol, 30 g of guanidine hydrochloride and 28 g of powdery sodium methoxide are added to the mixture, which is cooled to 30 ° C., and the reaction mixture is stirred at 35 to 40 ° C. for one hour, then to 90 to Heated 92 ° C and cooked for 18 hours. After the reaction has ended, the isobutanol and the methanol are distilled off under slightly reduced pressure. The residue consists of an oil that slowly crystallizes. The oil is crystallized by adding water in the cold. The crude product obtained is recrystallized from 50% aqueous ethanol. The 2,4-diamino-5- (4'-allyloxy-3 ', 5'-dimethoxybenzyl) pyrimidine obtained melts at 188 to 190 ° C. and corresponds to the product obtained in Example 3 60.

C.