GB2125044A - Pyrimidine derivatives - Google Patents

Pyrimidine derivatives Download PDF

Info

Publication number
GB2125044A
GB2125044A GB08321618A GB8321618A GB2125044A GB 2125044 A GB2125044 A GB 2125044A GB 08321618 A GB08321618 A GB 08321618A GB 8321618 A GB8321618 A GB 8321618A GB 2125044 A GB2125044 A GB 2125044A
Authority
GB
United Kingdom
Prior art keywords
formula
group
benzyl
mixture
mole
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
GB08321618A
Other versions
GB8321618D0 (en
GB2125044B (en
Inventor
Ivan Beck
Janos Egri
Elemer Jakfalvi
Gyorgyi Kovanyi
Eva Furdyga
Istvan Simonyi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Egyt Gyogyszervegyeszeti Gyar
Original Assignee
Egyt Gyogyszervegyeszeti Gyar
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Egyt Gyogyszervegyeszeti Gyar filed Critical Egyt Gyogyszervegyeszeti Gyar
Publication of GB8321618D0 publication Critical patent/GB8321618D0/en
Publication of GB2125044A publication Critical patent/GB2125044A/en
Application granted granted Critical
Publication of GB2125044B publication Critical patent/GB2125044B/en
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/04—Saturated ethers
    • C07C43/12—Saturated ethers containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Oncology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Liquid Crystal Substances (AREA)

Abstract

2,4-Diamino-5-benzyl-pyrimidine derivatives (antibacterials) of the formula <IMAGE> (R1 and R3 represent hydrogen, a methyl group or a methoxy group; R2 is a halogen, a C1-4 alkoxy group substituted with a halogen, a C2-4 alkenyloxy group or an R4O(R5O)n group; R4 is a C1-4 alkyl group; R5 a C1-4 alkylene group; n is 1 or 2), and their acid addition salts are prepared by reacting an alpha - benzal- beta -methoxypropionitrile of the formula <IMAGE> with a diethylene glycol monoalkyl ether in the presence of a base, cyclising the thus-obtained benzyl isomer of the formula <IMAGE> (preferably without separation) with quanidine and, if desired, converting the product to a salt.

Description

SPECIFICATION A process for the preparation of 2,Sdiamino-5-benzylpyrimidine derivatives The invention relates to a process for the preparation of 2,4-diamino-5-benzyl-pyrimidine derivatives of the formula I,
wherein R1 and R3 represent, independently, hydrogen, a methyl group or a methoxy group, R2 is a halogen, a C14 alkoxy group substituted with a halogen, a C24 alkenyloxy group or an R40(RsO)n group (wherein R4 and R5 stand, independently, for a C14 alkyl group and n is 1 or 2), and the pharmaceutically acceptable acid addition salts thereof.
The compounds of the formula I have antibacterial activity and can be employed both in the human and veterinary therapy.
According to British patent specification No. 1,413,454, 2,4-diamino-5-[3'-methoxy-4'AC13 alkoxy)-(C13 alkoxy)-5'-unsubstituted or halogen, alkyl or alkoxy substitutedj-pyrimidines are prepared from the corresponding hydrocinnamic alkyl ester through formylation followed by cyclization with guanidine. The thus-obtained 2-amino-4-hydroxy-5-substituted benzyl-pyrimidine is then treated with ammonia. This known process consists of several reaction steps and is not economical, especially on an industrial scale, the overali yield being lower than 20%.
In accordance with a further process described in the above-cited British patent specification, the above compounds can be prepared from the suitably substituted alpha-benzyl-beta-alkoxy-acrylonitrile with guanidine. However, the latter benzyl intermediate can be prepared from the corresponding substituted benzaldehyde only with a yield of 30 to 40%. Thus, the total yield of the end-product calculated for the substituted benzaldehyde is not more than 20 to 30%.
The same process is employed for the preparation of 2,4-diamino-5-(3,5-dimethoxy-4halobenzyl)-pyrimidine as described in United States patent specification No. 4,024,145. The overall yield of the end-product, calculated for 3,5-dimethoxy-4-halobenzaidehyde, is not more than about 30%.
Thus, the known processes fail to provide the economical synthesis of the 2,4-diamino-5-benzylpyrimidine derivatives of the formula I.
The object of the invention is to provide an economical process for the preparation of the 2,4diamino-5-benzyl-pyrimidine derivatives of the formula I in a purity suitable for pharmaceutical purposes.
This object is achieved by a process comprising reacting an alpha-benzal-betamethoxypropionitrile of the formula Ill,
wherein R1, R2 and R3 are as stated above, with a diethylene glycol monoalkyl ether of the formula IV, HO-CH2CH2-O-CH2CH2-OR IV wherein R is a C14 alkyl group, in the presence of a base, cyclizing the thus-obtained benzyl isomer of the formula II
wherein R1, R2, R3 and R are as stated above, preferably without separation, with guanidine and, if desired, converting the obtained compound of formula I to its acid addition salt.
The alpha-benzal-beta-methoxypropionitrile of the formula Ill used as the starting compound is prepared by the reaction of the suitably substituted benzaldehyde with beta-methoxy-propionitrile in a manner known in itself. The beta-methoxy-propionitrile is obtained by reacting acrylonitrile with methanol in alkaline medium.
Diethylene glycol monomethyl ether is preferred as diethylene glycol monoalkyl ether of the formula IV. In general, this reagent is used in an excess. In this case, the compound of the formula IV functions as a solvent, too. However, also further one or more solvents can be employed in the reaction of the compounds of the formulae lli and IV. In this reaction, the base is preferably an alkali alkoxide, e.g. sodium methoxide, sodium ethoxide, potassium methoxide etc. The reaction is performed at 20 to 2000C, preferably at 60 to 1 1 OOC.
In the reaction of the compounds of the formulae Ill and IV, the first step consists in the formation of the benzal isomer of the formula Ila,
wherein R1, R2, R3 and Rare as stated above. Under the reaction conditions of the invention, the benzal isomer of the formula Ila is converted to the benzyl isomer of the formula II within a short time, with nearly theoretical yield. The purity of the benzyl isomer thus obtained allows also a direct reaction with guanidine, without separation purification of the benzyl isomer.
The benzal isomer of formula Ila and the benzyl isomer of formula II are novel compounds of which only the benzyl isomer can be cyclized with guanidine to form a 2,4-diamino-5-benzylpyrimidine derivative with a good yield.
In the formulae II, Ila and IV, R stands for an alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl or tert.-butyl group. Preferably, R is a methyl group.
The benzyl isomer of the formula II is cyclized with guanidine preferably in the presence of an alkanol having 4 to 8 carbon atoms, such as butanol, pentanol, hexanol, heptanol or octanol. Preferred C48 alkanols are those having branched chain, such as tertiary butanol or isobutanol.
Of course, in the cyclization reaction an additional organic solvent can be present, too, e.g.
another alkanol, such as methanol.
If. according to a preferred embodiment of the process of the invention, the benzyl isomer of the formula II is cyclized without separation with guanidine, the diethylene glycol monomethyl ether of the formula IV is also present when it was employed in excess for the preparation of the benzyl isomer.
Preferably, guanidine is added in the form of its acid addition salt, such as hydrochloride, to the benzyl compound. In this case, it is liberated from its salt with a base, preferably sodium methoxide, in the reaction mixture.
The cyclization reaction is performed, in general, at 50 to 1500 C, usually at the boiling.point of the reaction mixture.
The process of the invention allows the economical production of the compounds of formula I.
The purity of the end-products is suitable for pharmaceutical purposes. It is also possible to prepare the 2,4diamino-5-benzyl-pyrimidine derivatives of formula I from the compound of formula Ill in a single step.
The invention is further illustrated by the following Examples, without limiting its scope to the exemplified embodiments.
Example 1 2,4-Diamino-5-(4-bromobenzyl)-pyrimidine A. 2-(4-Bromobenzylidene)-3-methoxypropionitrile To a solution of 8.59 g (0.1 62 mole) of acrylonitrile in 17 ml of anhydrous methanol, 1 5 g (0,081 mole) of 4-bromobenzaldehyde are added, the mixture is stirred at 300C to obtain a solution, then warmed to 600C and a solution of 5.44 g (0.097 mole) of potassium hydroxide in 49 ml of anhydrous methanol are added, drop by drop. The reaction is continued at 60 to 650C for 5 hours, then the mixture is cooled to 300 C, 5.18 g (0.092 mole) of potassium hydroxide dissolved in 17 ml of methanol are added in 1.5 hours and the mixture is stirred for further 12 hours at 300C. When the reaction is completed, any excess of solvent and acrylonitrile is distilled off. The oil obtained is poured into 1 50 ml of ice water, extracted three times with chloroform using 100 ml of solvent for each extraction, the solvent is evaporated and the residual red brown oil is distilled in vacuo.
9.4 g of the aimed compound are obtained; b.p.; 130-1 360C/0.4 mm Hg. nD5=1.5543. Yield: 46%.
Analysis: calculated for C1,H10NOBr (M.W. 252.119): C 52.41 %, H 3.99%, N 5,56%, Br 31.69%; found: C 52.27%, H 4.27%, N 5.45%, Br 31.07%.
IR (KBr): 3090 (=CH), 3060 (=CH), 3030 (=CH), 2830 (-COCH3), 2210 (CN), 1630 (C=C), 1590 and 1490 (aromatic C=C), 1145 and 1100 (COC), 1075 (COC), 1010 (Br), 965 (=CH) cm-l.
NMR (DMSO-d6: S 7.4 (bs, 4H, aromatic protons), 7.2 (bs, 1 H, CH=), 4.05 (s, 2H, CH2O), 3.25 (s, 3H, CH3O).
B. 2.4-Diamino-5-(4-bromobenzyl)-pyrimidine 3.68 g (0.01 5 mole) of 2-(4-bromobenzylidene)-3-methoxy-propionitrile are dissolved in 11.92 g (0.099 mole) of anhydrous diethylene glycol monomethyl ether, 0.92 g (0.017 moie) of sodium methoxide are added and the reaction is carried out for 6 hours at 75 to 770C. After cooling, the isomerized product is poured into 50 ml of ice water and extracted three times with chloroform using 50 ml of solvent each time. The organic solvent is evaporated and the residual red brown oil (6.17 g) is fractionated in vacuo. 2-(4-Bromobenzyl)-3-(methoxydiethoxy)-acrylonitrile boils at 63 to 750C/0.06 mm Hg.
nD5=1.6761.
IR (KBr): 2250 (CN), 1650 (C=C), 1490 (aromatic C=C), 1125 and 1110 (COC), 1075 (COC), 1010 (Br), 930 (=CH) cm-1.
NMR (CDCl3): S 7.05 (s, 1 H, =CH), 7.1-6.8 (q, 4H, aromatic protons), 3.45 (bs, 8H, -(OCH2CH2)2-), 3.22 (s, 3H, -OCH3), 2.8 (bs, 2H, CH2).
10 g (0.029 mole) of 2-(4-bromobenzyl)-3-(methoxydiethoxy)-acrylonitrile are dissolved in a mixture of 1 5 ml of isobutanol and 5 ml of methanol. To the solution obtained, 9.86 g (0.1 mole) of guanidine hydrochloride and 5.83 g (0.11 mole) of sodium methoxide are added, the mixture is boiled for 8 hours, then cooled to room temperature. The inorganic salt is filtered and washed with isobutanol.
On cooling, yellow 2,4-diamino-5-(4-bromobenzyl)-pyrimidine separates, m.p.: 225-2280C. From the mother liquor a further amount of product is obtained, m.p.: 224-2270C. Total yield: 93%.
Example 2 2,4-Diamino-5-(4-bromobenzyl)-pyrimidine 1.1 g (0.004 mole) of 2-(4-bromobenzylidene)-3-methoxy-propionitrile prepared according to section A of Example 1 are dissolved in 2.5 ml of anhydrous diethylene glycol monomethyl ether. After the addition of 0.2 g (0.0037 mole) of sodium methoxide, the mixture is stirred for 6 hours at 75 to 760C, then cooled to 300C and 1 ml of isobutanol, 0.3 ml of methanol, 0.6 g (0.006 mole) of guanidine hydrochloride and 0.35 g (0.004 mole) of sodium methoxide are added, then boiled under reflux for 8 hours. The mixture is cooled and the product precipitated is filtered and washed with water.
The aimed compound obtained as a light yellow powder melts at 224-2260C. Yield: 95%.
IR (KBr): 3420 (NH2), 3320 (NH2), 1 630 (NH2), 1 600, 1 570 and 1460 (aromatic protons), 1010 (Br), 800 (NH2) cm-1.
NMR (DMSO-d6); S 7.2-6.9 (q, 4H, aromatic protons), 7.22 (s, 1 H, N), 5.45-5.8 (s, 4H), 3.45 (s, 2H, CH2).
Example 3 2,4-Diamino-5-(4-allyloxy-3,5-dimethoxybenzyl)-pyrimidine A. 3,5-Di methoxy-4-allyloxybenzaldehyde 40 g of syringaldehyde sodium salt are dissolved in 300 ml of water. 36.3 g of allyl bromide and 3 ml of Triton B catalyst (non-ionic tenside; reaction product of octylphenol and ethylene oxide) are added and the mixture is boiled under reflux for 5 hours. 1 2 g of allyl bromide and 2 g of sodium hydroxide are added to the somewhat cooled mixture, then boiling is continued for further 5 hours.
After cooling, the mixture is extracted twice with 1,2-dichloroethane using 50 ml of solvent each time.
The organic phase is washed with 50 ml of 2% alkaline water, treated with active carbon, filtered and evaporated. On cooling, the residue becomes crystalline. The crystalline mass is rubbed with water, filtered and dried at room temperature. The aimed compound melts at 46-470C.
B. 2-(4-AI Iyloxy-3,5-dimethoxybenzylidene)-3-methoxypropionitrile To 0.09 g (0.001 mole) of potassium hydroxide dissolved in 6 ml of anhydrous methanol, 2.3 g (0.04 mole) of acrylonitrile are added, drop by drop, at 35 to 380 C. The reaction is continued for a further hour at 40"C, then 3.8 g (0.01 7 mole) of 4-allyloxy-3,5-dimethoxybenzaldehyde are added. The mixture is stirred for 12 hours at 60 to 650C, then cooled to room temperature. Any excess of the solvent and the acrylonitrile is removed by distiilation, the residual oil is poured into 50 ml of ice water, extracted with 3x50 ml of benzene and evaporated, 3.46 g of a yellowish brown oil corresponding to the aimed compound are obtained. Yield: 70%.
nD25=1.5599.
IR (KBr): 3090 and 3010 (=CH), 2850 (OCH3), 2210 (CN), 1630 and 1590 (C=C), 1510 (C=C of the aromatic ring), 1465, 1 330 and 1130 (OH3), 1235 and 985 (COC) cm-'.
NMR (CDCI3): S 6.78 (bs, 3H, aromatic protons), 6.5-5.5 (m, 1 H, =CH), 5.4-4.8 (m, 2H, CH2=CH),4.4 (d, 2H, CH2=CH-CH2O), 4.0 (s, 2H, -CH2), 3.7 (s, 6H, CH2O-), 3.3 (s, 3H, CH3O).
C. 2-(4-Allyloxy-3,5-dimethoxybenzyl)-3-( methoxydiethoxy)-acrylonitrile 2.64 g (0.009 mole) of 2-(4-allyloxy-3,5-dimethoxybenzylidene)-3-methoxypropionitrile are dissolved in 7 ml of anhydrous diethylene glycol monomethyl ether, 0.55 g (0.01 mole) of sodium methoxide are added and the mixture is stirred for 6 hours at 80 to 820C, then cooled to room temperature, poured into 15 ml of ice water and extracted with 5x50 ml of benzene. The solvent is evaporated, and the residual red brown oil corresponds to the aimed compound; nD5=1.6720.
Yield=91 %.
IR (KBr): 2250 and 2220 (CN), 1 465 and 1130 (CH3O), 1248 and 990 (COC) cm-'.
NMR (CDCl3: S 6.2 (m, 1 H =CHO-), 6.0-5.5 (m, 1 H, =CH-), 4.8 (m, 2H, CH2=), 4.3 (d, 2H, CH2O-). 3.7 (s, 6H, CH3), 3.5 (bs, 8H, (OCH2CH2)2), 3.27 (s, 3H, CH3O), 2.8 (m, 2H, CH2).
D. 2,4-Diamino-5-(4-allyloxy-3,5-dimethoxybenzyl)-pyrimidin 1.12 g (0.012 mole) of guanidine hydrochloride, 0.66 g (0.013 mole) of sodium methoxide,then 1.13 g (0.003 mole) of 2-(4-allyloxy-3,5-dimethoxybenzyl)-3-(methoxydiethoxy)-acrylonitrile are dissolved in a mixture of 2 ml of isobutanol and 1 ml of methanol. The mixture is stirred for 1 hour at 35 to 400 C, then warmed to 90-920C and kept at this temperature for 1 8 hours. When the reaction is completed, the mixture is cooled to room temperature, the sodium chloride precipitated is filtered, the filtrate treated with active carbon, filtered and cooled in ice water. The aimed compound precipitating in crystalline form is filtered. Yield: 93%. M.p.: 188-1 900 C.
IR (KBr): 3480 (NH2), 3335 (NH2), 3200 (NH2), 1670, 1645 and 1610 (NH2 and C=C), 1470 and1 130 (CH3O), 1240 and 1005 (COC) cm-'.
NMR (DMSO-d6): S 7.2 (s, 1 H, =N), 6.37 (s, 2H, aromatic protons), 5.8 5.4 (bs, 7H, NH2 and CH2=CH), 4.2 (d, 2H, CH2O), 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 mole) of syringaldehyde sodium salt are dissolved in 300 ml of water, 28 g (0.2 mole) of methoxyethoxyethyl chloride are added, drop by drop, the mixture is heated under reflux for 20 hours, then cooled to room temperature and extracted with 3 x200 ml of benzene. The organic phase is washed with 2 xl 00 ml of 2% aqueous sodium hydroxide solution until the washing liquor becomes quite light. The benzene is evaporated, and the residual red oil (16 g) is stirred with a solution of 16 g (0.1 7 mole) of sodium bisulfite in 100 ml of water for one hour.The solution obtained is adjusted to pH 10 with 20% aqueous sodium hydroxide under cooling, and the oil separated is extracted with 3x 1 50 ml of benzene. Upon evaporation, 27.79 g of red oil are obtained that corresponds to the aimed compound. Yield: 49%.
nD5=1.6789.
IR (KBr): 1695 (CO), 1465 (CH3O), 1130 (CH3O), 1330 (CH3O), 1230 (C=O) cm-1.
NMR (CDCI3): S 9.46 (s, 1 H, -CHO), 6.8 (s, 2H, aromatic protons),3.75 (s, 6H, CH3O), 4.1 (t, 2H, CH2CH2O),-3.8-3.4 (m, 6H, OCH2C H2-O-CH2CH2), 3.25 (s, 3H, CH3O).
B.2-(4-Methoxydiethoxy-3,5-dimethoxybenzylidene)-3-methoxypropio nitrile To a solution of 0.18 g (0.003 mole) of potassium hydroxide in 18 ml of anhydrous methanol 4.47 g (0.084 mole) of acrylonitrile are added, drop by drop, in 1.5 hours at 35 to 400 C. The reaction mixture is stirred for a further hour at 400 C. Then 12.5 g (0.044 mole) of 4-methoxydiethoxy-3,4- dimethoxybenzaldehyde are added, the mixture is heated under reflux at 60 to 65 C for 12 hours, then cooled to room temperature, poured into 100 ml of ice water and extracted with 4x50 ml of chloroform. After evaporation, 14.78 g of red oil are obtained that corresponds to the title compound.
Yield: 95,5%.
nD5=1 .6767 IR (KBr): 2860(CH30), 2220 (CN), 2260 (CN), 1625 (C=C), 1590 and 1510 (aromatic C=C), 1465 (CH3O), 1335 and 1130 (CH3O), 1250 (COC), 1 100 (COC) cm-1.
NMR (CDCI3):S 6.75 (s 3H, aromatic protons, CH=), 4.0 (t, 2H, CH2O), 3.98 (s, 2H, =0-OH2- OCH3), 3.7 (s, 6H, CH3O), 3.5 (t, 6H, CH2CH2OCH2), 3.25 (s, 3H, CH3O-CH2OH2), 3.22 (s, 3H, CH3OCH2C=).
C. 2-(4-Methoxydiethoxy-3,5-di methoxybenzyl)-3-( methoxydiethoxy)-acrylonitrile 10 g (0.028 mole) of 2-(4-methoxydiethoxy-3,5-dimethoxybenzylidene)-3-methoxypropionitrile are dissolved in 23 ml of anhydrous diethylene glycol monomethyl ether and to the solution obtained 1.76 g (0.033 mole) of sodium methoxide are added. The reaction mixture is stirred for 6 hours at 75 to 770C, then cooled to room temperature, poured into 100 ml of ice water and extracted with 3 x 100 ml of chloroform. After evaporation the residue contains some diethylene glycol monomethyl ether that is removed at 40 to 48 C in vacuo (0.1 mm Hg). The residual oil corresponds to the aimed compound.
Yield: 95%.
n D25=1 .6772.
IR (KBr): 2250 (CN), 1630 (C=C), 1590 and 1500 (aromatic C=C), 1460 (OH3), 1330 and 1120 (OH3), 1 240 and 1195 (COC), 1110 and 1040 (COC) cm-1.
NMR (CDCI3): S 6.8 (s, 2H, aromatic protons), 6.15 (s, 1 H, C=CHO), 4.0 (t, 2H, CH2O), 3.7 (s, 6H, CH3O), 3.6 (s, 2H, OH2-O), 3.5 (t, 1 OH, CH2CH2OCH2 and CH2CH2OCH3, 3.25 (s, 6H, OCH3).
D. 2,4-Diami no-5-(4-methoxydiethoxy-3,5-di methoxybenzyl)-pyrimidine 4.87 g (0.051 mole) of guanidine hydrochloride are added to a solution of 1.24 g (0.054 atom) of sodium methoxide in 20 ml of anhydrous methanol. The reaction mixture is stirred for 20 minutes at room temperature and the sodium chloride precipitated is filtered. (Thus, 3.12 g of sodium chloride are removed). To the solution of guanidine, 6.5 g (0.015 mole) of 2-(4-methoxydiethoxy-3,5dimethoxybenzyl)-3-(methoxydiethoxy)-acrylonitrile and 8 ml of isobutanol are added. The reaction mixture is heated under reflux for 24 hours, then cooled to room temperature and evaporated. The residual brown oil is taken into 100 ml of water, extracted with 3x50 ml of ethyl acetate and evaporated. A slightly oily, drab product remains which is filtered and washed with diethyl ether.The light drab, powdery product corresponds to the aimed compound, m.p.: 120--1230C. Yield: 93%.
IR (KBr): 3450 (NH2), 3330 and 3160 (NH2), 1635 (NH2), 1590 and 1560 (NH2), 1450 (CH3O), 1325 and 11 20 (CH3O), 1230 (COC) cm-'.
NMR (DMSO-d6): a 7.2 (s, 1 H, =N), 6.25 (s, 2H, aromatic protons), 5.6 and 5.4 (s, 4H, NH2), 3.56 (s, 6H, CH3O), 3.36 (s, 3H, CH3O), 3.1 2 (s, 2H, OH2).
Example 5 2,4-Damino-5-(4-chloropropoxy-3,5-dimethoxybenzyl)-pyrimidine A. 3,5-Dimethoxy-4-(3-chloropropoxy)-benzaldehyde 20.4 g (0.1 mole) of syringaldehyde sodium salt are dissolved in 150 ml water under heating, and to the solution obtained 15.8 g (0.1 mole) of 1 ,3-chlorobromopropane, then 2 ml on Triton B catalyst are added. The reaction mixture is heated under reflux for 8 hours, then again 15.8 g (0.1 mole) of 1,3chlorobromopropane are added, drop by drop, 1 ml of Triton B is added, and the reflux is continued for further 8 hours. The mixture is cooled to room temperature and extracted with 3 xl 50 ml of 1,2dichloroethane. The organic phase is washed with 3x 100 ml of 2% aqueous sodium hydroxide, then evaporated. 1 1.12 g of aimed compound are obtained as a brown oil. Yield: 43%.
nD5=1 .5558.
iR (KBr): 1695 (C=O), 1465 (CH30), 1330 and 1130 (OH3O), 1235 and 1020 (COC) cm-'.
NMR (0D0l3): a 9.42 (S, 1 H, CHO), 6.8 (s, 2H, aromatic proton), 4.0 (t, 2H, CH2O), 3.71 (s, 6H, CH3O), 3.65 (t, 2H, Cl-OH2), 2.01 (m, 2H, OH2).
B. 2-(4-Chloropropoxy-3,5-dimethoxybenzylidene)-3-methoxypropionitrile 3.849 (0.073 mole) of acrylonitrile are added, drop by drop, to a solution of 0.17 g (0.003 mole) of potassium hydroxide in 11 ml of anhydrous methanol at 30 to 380C. The reaction mixture is stirred for a further hour at 400C, then 7.38 g (0.029 mole) of 3,5-dimethoxy-4-chloropropoxy-benzaldehyde are added. The reaction mixture is kept at 60 to 65 C for 12 hours, then evaporated, poured into 50 ml of ice water and extracted with 3x40 ml of chloroform. The solvent is removed and 6.7 g of the aimed compound are obtained as a light yellow oil. Yield: 72%.
nD5=1 .5579.
IR (KBr): 3010 (=OH), 2850 (CH3O), 2220 (CN), 1600 (C=C), 1585, 1505 and 1420 (aromatic protons), 1465, 1305 and 1130 (CH3), 1240 (COC), 1020 (COC), 830 (CH) cm-1* NMR (CDCI3): a 6.8 (s, 3H, aromatic protons), 4.0 (s, 2H, CH2OCH3),3.71 5H, Cl-OH2 and OH3O), 3.3 (s, 3H, CH30),2.1 (m,2H, OH2).
C.2-(4-Chloropropoxy-3,5-dimethoxybenzyl)-3-(methoxydiethoxy)-acrylonitrile 4 g (0.012 mole) of 2-(4-chloropropoxy-3,5-dimethoxybenzyiidene)-3-methoxypropionitrile are dissolved in 10 ml of an hydros diethylene glycol monomethyl ether, and 0.74 g (0.014 mole) of sodium methoxide are added to the solution obtained. The reaction mixture is stirred for 6 hours at 75 to 77 C, then cooled to room temperature, poured into 50 ml of ice water and extracted with 3x50 ml of chloroform. The organic solvent is distilled off, whereby 4.08 g of the aimed compound are obtained as a red oil. Yield: 80%.
nD5=1.5090.
IR (KBr): 2250 (CN),1585 and 1505 (aromatic C=C), 1460 (CH3),1330 and 1130 (CH3),1240 (COC), 1030 (COC),1645 (C=C), 930 (=CH), 850 (=CH) cm-'.
NMR (CDCI3): S 6.8 (s, 2H, aromatic protons), 6.15 (s, 1 H, C=CH--O), 4.0 (t, 2H, CH2O),3.75 (s, 6H, CH3O), 3.71(s, 2H, CICH2),3.6 (s, 2H, CH2),3.5 (t, 8H, OOH2OH2-O-OH2OH2), 3.3 (s, 3H, OH3O), 2.1 (m, 2H, OH2).
D. 2,4Diamino-5-[4"-(3-chloropropoxy)-3,5-dimethoxybenzyl]-pyrimidine 2-(4-Chloropropoxy-3,5-dimethoxybenzyl)-3-(methoxydiethoxy)-acrylonitrile is reacted with guanidine in a similar way as described in section D of Example 4. The aimed compound is obtained with a yield of 89%; m.p.: 1 63-1 640 C.
Example 6 2,4-Diamino-5-(4-methoxyethoxy-3,5-dimethoxybenzyl)-pyrimidine A. Syringaldehyde 300 g of 3,4,5-trimethoxybenzaldehyde are added to 1500 ml of concentrated sulfuric acid under stirring. During dissolution the mixture warms to 35 40 C and a black, homogeneous solution is formed that is stirred for 15 hours at 40 to 420 C. Then, in general, demethylation at position 4 is complete. This is confirmed by the thin layer chromatographic analysis of a sample of the mixture (1 ml of the reaction mixture is admixed to 3.9 of ice and 2 ml of 1,2-dichloroethane and a portion of the organic phase is transferred to a Kieselgel plate. The solvent mixture is a mixture of chloroform, acetone and glacial acetic acid in a ratio of 60:30:10).If the reaction mixture contains 3,4,5trimethoxybenzaldehyde, the reaction is carried on. If the starting aldehyde is consumed, the mixture is cooled to 200C and admixed to 4 kg of ice and 2 litres of 1 2-dichloroethane. The lower aqueous phase is removed, the upper organic phase is washed with 1 litre of water. On washing, the organic phase becomes the lower one comprising syringaldehyde. The solvent is removed, and to the residue 125 g of sodium bisulfite dissolved in 2 litres of water are added. The mixture is stirred for 2 hours at 35 to 400 C, then sedimented. The solution is decanted from the tar, treated with active carbon and filtered.
The filtrate is made alkaline with 40% aqueous sodium hydroxide solution under stirring until further precipitation of the product is observed when adding a further portion of alkali. The suspension formed is cooled under 1 ooh, filtered and washed with cold water.
The wet salt is dissolved in water, acidified with concentrated hydrochloric acid to pH 2, the syringaldehyde separated is filtered, washed with water and dried. 1 20 to 140 g of syringaldehyde are obtained, m.p.: 1 1 1--1 140C. No foreign spot is indicated by thin layer chromatography.
B. Methoxyethylchloride 76 ml of thionyl chloride are added, drop by drop, to 76 g of methoxyethanol at 300C during 3 hours, and the reaction mixture is stirred for 20 hours at 30 to 350C. The methoxyethyl chloride formed is distilled through a column of 50 cm length. 68 g of the aimed compound are obtained; b.p.: 90--91"C n0=1.4090.
C. 3,4-Dimethoxy-4-methoxyethoxy-benzaldehyde 90 g of methoxyethyl chloride are added to 200 g of syringaldehyde sodium salt dissolved in 1500 ml of water. The reaction mixture is heated under reflux for 1 6 hours, then 60 g of methoxyethyl chloride and 20 g of sodium hydroxide are added and reflux is continued for further 16 hours. The mixture is cooled, extracted with 2x500 ml of benzene, the organic liquid is washed with 2x250 ml of 2% alkaline water, treated with active carbon, filtered and evaporated. The residual oil (about 150 g) is dissolved in 600 ml of 20% sodium bisulfite solution, treated with active carbon, filtered and made alkaline by adding an aqueous sodium hydroxide solution to pH 9-10 at 0--3 0 C. The product precipitated is filtered after cooling and dried.
125 g of the aimed compound are obtained; m.p.: 29--330C.
D. 2,4-Diamino-5-(3,5-dimethoxy-4-methoxyethoxybenzyl)-pyrimidine 45 g acrylonitrile are added to a solution of 1.5 g of potassium hydroxide in 100 ml of methanol at 35 to 400C during 3 hours. The mixture is stirred for a further hour at 40 to 420 C, then 100 g of 4 methoxyethoxy-3,5-dimethoxy-benzaldehyde are added, and the reaction mixture is stirred for 8 hours at 60 to 620C. The methanol and any excess of methoxypropionitrile are removed under slightly reduced pressure, the residue is dissolved in a mixture of 400 ml of water and 400 ml of benzene. The phases are separated, the organic one is washed with water and evaporated. The residual crude product is dissolved in 250 ml of anhydrous diethylene glycol monomethyl ether.To the solution obtained 200 g of powdered sodium methoxide are added, and the reaction mixture is heated for 6 hours at 75 to 760C. The mixture is cooled to 300C, 100 ml of isobutanol, 30 ml of methanol, 60 g of guanidine hydrochloride and 35 g of powdered sodium methoxide are added. The reaction mixture is heated under reflux for 8 hours, then about 110 ml of solvent mixture is distilled off under slightly reduced pressure. The residue is diluted with methanol and cooled. The crystalline product is filtered and washed with methanol.2,4-Diamino-5-(4-methoxyethoxybenzyl-3,5-dimethoxy)-pyrimidine is obtained; m.p.: 158--1600C (water). Yield: 91%.
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 a solution of 0.7 g of potassium hydroxide in 50 ml of anhydrous methanol at 35 to 400C during 3 hours. The mixture is stirred for a further hour at 400C, then 49 g of 4-methoxyethoxy-3,5-dimethoxy-benzaldehyde prepared according to section C of Example 6 are added. The reaction mixture is stirred for 8 hours at 60 to 620 C. (The end-point of the reaction can be determined by thin layer chromatography using a mixture of chloroform, ethyl acetate and gasoline at a ratio of 40:40:20).The methanol and any excess of methoxypropionitrile are removed under slightly reduced pressure, the residue is dissolved in a mixture of 200 ml of water and 200 ml of benzene, and the phases are separated. The organic phase is washed with water and evaporated. The residual crude product is distilled in vacuo at 0.05 mm Hg. The aimed compound is obtained as a light yellow oil; b.p.: 192--1950C/0.05 mm Hg.
20 nD=1.5498 B 2-(4-Methoxyethoxy-3,5-dimethoxy-benzyl)-3-( methoxydiethoxy)-acrylonitrile A mixture of 50 ml of anhydrous diethylene glycol monomethyl ether, 20 g of 2-(4 methoxyethoxy-3,5-dimethoxybenzal)-3-methoxypropionitrile and 4 g of powdered sodium methoxide is heated for 6 hours at 75 to 770C. (The end-point of the reaction can be determined by thin layer chromatography using a mixture of xylene and methyl glycol at a ratio of 90:10.) The isomerized reaction mixture is cooled, admixed to 200 ml of benzene and 500 ml of water. The phases are separated, the organic one is washed with 2 x200 ml of water, and the organic solvent is removed. The residue is distilled in vacuo.The aimed compound is obtained as a light yellow oil; b.p.: 1 80- 185 C/0.02 mm Hg. Yield: 85%.
20 nD =1.5510.
C.2,4-Diamino-5-(4-methoxyethoxy-3,5-dimethoxybenzyi)-pyrimidine 10 g of 2-(4-methoxyethoxy-3,5-dimethoxybenzyl)-3-(methoxydiethoxy)-acrylonitrile are added to a mixture of 15 ml of isobutanol, 4 ml of methanol, 8.5 g of guanidine hydrochloride and 5 g of powdered sodium methoxide. The reaction mixture is heated under reflux for 7 hours, then 1 5 ml of solvent mixture is removed by distillation. The residue is a thick oil becoming slowly crystalline. The product is admixed to 20 ml of methanol, and the crystal suspension being formed is filtered. The crystalline product is dissolved in 25 ml of hot water, treated with active carbon, filtered and cooled to obtain the aimed compound; m.p.: 158--1600C. Yield: 89%.
Example 8 2,4-Diamino-5-(4-allyloxy-3,5-dimethoxybenzyl)-pyrimidine 22 g of acrylonitrile are added, drop by drop, to a solution of 0.9 g of potassium hydroxide in 50 ml of methanol at 35 to 380C. The mixture is stirred for a further hour at 400C, then 36 g of 4-allyloxy3,5-dimethoxybenzaldehyde are added. The reaction mixture is stirred for 12 hours at 60 to 650C, then cooled and admixed to a mixture of 300 ml of water and 200 ml of benzene. The organic phase is separated, washed with water and the organic solvent is removed under reduced pressure. The residue is dissolved in 40 ml of anhydrous diethylene glycol monomethyl ether, and 6 g of powdered sodium methoxide are added. The reaction mixture is stirred for 6 hours at 80 to 820C, then cooled to 300C.
60 ml isobutanol, 1 5 ml of methanol, 30 g of guanidine hydrochloride and 28 g of powdered sodium methoxide are added to the mixture. The reaction mixture is stirred for 1 hour at 35 to 400C, then heated under reflux for 18 hours at 90 to 920C. At the end of the reaction the isobutanol and methanol are removed under slightly reduced pressure. The residual oil becomes slowly crystalline. Cold water is added to accelerate crystallization. The crude product is recrystallized from 50% aqueous ethanoi, m.p.: 188--1 900C. The product obtained corresponds to the product of section C of Example 3.

Claims (9)

Claims
1. A process for the preparation of 2,4-diamino-5-benzyl-pyrimidine derivatives of the formula I,
wherein R, and R3 represent, independently, hydrogen, a methyl group or a methoxy group, R2 is a halogen, a C,~4 alkoxy group substituted with a halogen, a C2~4 alkenyloxy group or an R40(R5O)n group (wherein R4 and R5 stand, independently, for a Ct~4 alkyl group, and n is 1 or 2), and the pharmaceutically acceptable acid addition salts thereof, comprising reacting an alpha-benzalbeta-methoxy-propionitrile of the formula III,
wherein R1, R2 and R3 are as stated above, with a diethylene glycol monoalkyl ether of the formula IV, HO-0H20H2-O-OH2OH2-OR IV wherein R is a C,~4 alkyl group, in the presence of a base, cyclizing the thus-obtained benzyl isomer of the formula II,
wherein R1, R2, R3 and R are as stated above, preferably without separation, with guanidine and, if desired, converting the obtained compound of the formula I to its acid addition salt.
2. A process as claimed in Claim 1, in which diethylene glycol monomethyl ether is used as diethylene glycol monoalkyl ether.
3. A process as claimed in Claim 1, in which the base is an alkali metal alkoxide.
4. A process as claimed in Claim 3, in which the alkali metal alkoxide is sodium methoxide.
5. A process as claimed in Claim 1, in which the benzyl isomer is cyclized in the presence of an alkanol having from 4 to 8 carbon atoms.
6. A process as claimed in Claim 5, in which the alkanol is isobutanol.
7. A process according to any one of claims 1 to 6 substantially as hereinbefore described in any one of Examples 1 to 8.
8. A 2,4-diamino-5-benzyl-pyrimidine derivative when produced by a process as claimed in any one of claims 1 to 7.
9. A benzyl/benzal isomer of the formula II and Ila
wherein R, R1, R2, R3 and R4 are as defined in claim 1.
GB08321618A 1982-08-13 1983-08-11 Pyrimidine derivatives Expired GB2125044B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
HU822604A HU188588B (en) 1982-08-13 1982-08-13 Process for the production of 2,4-diamino-5-benzyl-pyrimidine-derivatives

Publications (3)

Publication Number Publication Date
GB8321618D0 GB8321618D0 (en) 1983-09-14
GB2125044A true GB2125044A (en) 1984-02-29
GB2125044B GB2125044B (en) 1985-09-18

Family

ID=10960229

Family Applications (1)

Application Number Title Priority Date Filing Date
GB08321618A Expired GB2125044B (en) 1982-08-13 1983-08-11 Pyrimidine derivatives

Country Status (8)

Country Link
JP (1) JPS5993061A (en)
AT (1) AT387216B (en)
CH (1) CH657611A5 (en)
DE (1) DE3329226A1 (en)
GB (1) GB2125044B (en)
HU (1) HU188588B (en)
IT (1) IT1194372B (en)
SU (1) SU1222194A3 (en)

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR94837E (en) * 1966-02-19 1969-11-28 Wellcome Found Process for the preparation of pyrimidine derivatives.
CH598231A5 (en) * 1973-07-27 1978-04-28 Hoffmann La Roche
JPS6119628B2 (en) * 1973-11-08 1986-05-17 Efu Hofuman Ra Roshu Unto Co Ag
AR207671A1 (en) * 1975-01-03 1976-10-22 Prayon PROCEDURE FOR OBTAINING A BASIC PIGMENT OF IRON OXIDE IN ALPHA-FE2O3 FORM
DE2559752C3 (en) * 1975-10-17 1978-12-07 Ludwig Heumann & Co Gmbh, 8500 Nuernberg 2,4-diamino-5- (3-methoxy-4-hydroxy-5-methyl-benzyl) -pyrimidine, process for its preparation and medicament containing this compound
DE2546667C3 (en) * 1975-10-17 1978-10-12 Ludwig Heumann & Co Gmbh, 8500 Nuernberg 2,4-DiamuH »-5- (3-methoxy-4-hydroxy-5-halobenzyl) -pyrimidines, and medicinal products containing these compounds
DE2617967C3 (en) * 1976-04-24 1978-11-02 Nordmark-Werke Gmbh, 2000 Hamburg Process for the preparation of 2,4-diamino-5-benzylpyrimidines
DE2635765C3 (en) * 1976-08-09 1979-02-08 Ludwig Heumann & Co Gmbh, 8500 Nuernberg Process for the preparation of 2,4-EMamino-5- (3 ', 4'r5'-trimethoxybenzyl) -pyrimidine
IL57375A0 (en) * 1978-05-24 1979-09-30 Wellcome Found Benzylpyrimidines, their preparation and pharmaceutical compositions containing them

Also Published As

Publication number Publication date
IT8322540A0 (en) 1983-08-12
GB8321618D0 (en) 1983-09-14
ATA290583A (en) 1988-05-15
DE3329226A1 (en) 1984-02-23
CH657611A5 (en) 1986-09-15
SU1222194A3 (en) 1986-03-30
HU188588B (en) 1986-04-28
AT387216B (en) 1988-12-27
GB2125044B (en) 1985-09-18
JPS5993061A (en) 1984-05-29
IT8322540A1 (en) 1985-02-12
IT1194372B (en) 1988-09-22

Similar Documents

Publication Publication Date Title
US3697512A (en) 5-benzyl pyrimidines intermediates
US3855265A (en) 5-benzyl pyrimidines intermediates therefore, and method
US4216319A (en) Synthesis of 2,4-diamino-5-benzylpyrimidines using benzyl cyanoacetal intermediates
GB2125044A (en) Pyrimidine derivatives
US3852276A (en) 5-benzyl pyrimidines intermediate therefore, and method
US4143227A (en) Process for substituted 5-benzyl-2,4-diamino-pyrimidines
US4255574A (en) Process for preparing 2,4-diamino-pyrimidines
US3991050A (en) Preparation of β-Amino-α-benzylacrylonitriles
US4125721A (en) Process for the production of 2,4-diamino-5-(3&#39;,4&#39;,5&#39;-trimethoxybenzyl)-pyrimidine
US4052553A (en) 5-benzyl pyrimidines intermediates therefore, and method
US3956327A (en) Method of preparing 2,4-diamino-5-benzyl pyrimidines
US3878252A (en) Ring substituted beta-hydroxy-phenyethylmethyl sulphone or sulphoxide
US3850927A (en) 5-benzyl pyrimidines intermediates therefore,and method
US3849407A (en) 5-benzyl pyrimidines intermediates
US3998814A (en) Process for preparing β-amino-α-benzylacrylonitriles
CA1176265A (en) Process for the manufacture of dibenzoxepinones
IE62321B1 (en) New process for the synthesis of the alpha-(1-methylethyl)-3,4-dimethoxybenzeneacetonitrile
SU1147252A3 (en) Method of obtaining 2,4-diamino-5-(3&#39;,4&#39;,5&#39;-trimethoxybenzil)-pyrimidine
US3634500A (en) 2-(18-dimethoxy-4-methyl-2-naphthoil)-3 5-dialkoxyterephthalamic acids
US3950378A (en) Preparation of β-anilino-α-benzylacrylonitriles
US3426023A (en) 1-(4&#39;-methyl-6&#39;-methoxy-2&#39;-pyrimidinyl) 3-methyl-5-methoxypyrazole
CA1186319A (en) Alphasulfonyloxyketone acetals
US4775756A (en) 5-(4-amino-3,5-dimethoxyphenyl)-5-hydroxy-barbituric acid
KR840000945B1 (en) Process for the preparation of phenyl ethanol amine
FR2511246A1 (en) NOVEL CYCLIC ALPHA-AMINODERIVATES OF 1- (3 &#39;, 4&#39;-METHYLENE-DIOXYPHENYL) ETHANOL AND PROCESS FOR PRODUCING THE SAME

Legal Events

Date Code Title Description
PCNP Patent ceased through non-payment of renewal fee

Effective date: 19930811