US3040047A - 2-(pyrazol-1-yl)-pyrimidine derivatives - Google Patents

2-(pyrazol-1-yl)-pyrimidine derivatives Download PDF

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US3040047A
US3040047A US19448A US1944860A US3040047A US 3040047 A US3040047 A US 3040047A US 19448 A US19448 A US 19448A US 1944860 A US1944860 A US 1944860A US 3040047 A US3040047 A US 3040047A
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Sirakawa Kenzo
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Takeda Pharmaceutical Co Ltd
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    • G—PHYSICS
    • G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
    • G03C—PHOTOSENSITIVE MATERIALS FOR PHOTOGRAPHIC PURPOSES; PHOTOGRAPHIC PROCESSES, e.g. CINE, X-RAY, COLOUR, STEREO-PHOTOGRAPHIC PROCESSES; AUXILIARY PROCESSES IN PHOTOGRAPHY
    • G03C1/00—Photosensitive materials
    • G03C1/005—Silver halide emulsions; Preparation thereof; Physical treatment thereof; Incorporation of additives therein
    • G03C1/06—Silver halide emulsions; Preparation thereof; Physical treatment thereof; Incorporation of additives therein with non-macromolecular additives
    • G03C1/34—Fog-inhibitors; Stabilisers; Agents inhibiting latent image regression
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to Z-(pyrazol-l-yl)pyrimidine derivatives which are usable in photographic industries as well as in the apeutic purposes. More particularly, the compounds 01 this invention are representable by the Formula I wherein each of (R) and (X) stands for a combination of three monovalent substituents or of monovalent and bivalent substituents. The respective components of (R) are combined at the 4-, 5- and 6-positions of the pyrimidine nucleus and the respective components of (X) are combined at the 3-, 4- and S-positions of the pyrazole nucleus of the compound I.
  • the monovalent substituents of the compound I may be selected from hydrogen, halogen, cyano, hydroxyl, mercapto, amino, alkyl and atomic groups derivable from them, for instance.
  • the bivalent substituents may be selected, for example, from trimethylene, tetramethylene and lactone groups. But, the compounds representable by the Formula I supra in which (R) 3 is a combination of only hydrogen and alkyl groups have little photographic and therapeutic activities, and therefore such compounds are excluded from the scope of this invention.
  • the compounds t this invention inhibit fogging appearing in the process for preparing or storing the sensitive materials.
  • the compounds may be added to the raw materials or to the intermediate materials or to the final products, e.g. the compounds of this invention may he added when a sensitive emulsion is to be digested or when crystals of silver halide are to be prepared or just before film or paper is to be coated with a sensitive emulsion, or the like.
  • the film thus processed is stored in a vessel for 2 weeks,
  • the film is developed for 10 minutes at 20 C. with a developer having the following components.
  • trimethylenepyrimidinm 0. 3 95 0. 82 0. 07 0. 83 0. 13 2 (4 Oyano 5 aminopyrazol 1 yl) 5 carbethoxy 6 hydroxypy'rimid no 0. 3 0. 83 O. 08 85 0. 2 O. 12 2 (3,5 dimethylpyrazol l yl) 4 formylhydrazino 5 phenylpyrimidine 0.3 90 0. 81 0.07 90 0. 81 0.13 2-(3,5dimethylpyrazol-1-yl)-4-mercapto-6-phenylpyrimitline 0. 03 85 0. 8O 0. 05 80 0. 83 0. 10 2-(3,5-dimethylpyrazol-lyl)-lchloro6-methylpyrimidinc 0- 3 90 0. 80 0. 08 85 0. 82 0. 14 None (control). 0. 0 0. 85 0. 07 85 0. 83 0. 30
  • COO-alkyl COO-alkali metal, all yl, -alkenyl, alkynyl, aryl, aralkyl, alkylene.
  • the compounds of this invention can be conveniently synthesized by condensation between Z-hydrazinopyrirnidine having a desired substituent or substituents at 4-, 5- and/or 6-positions as represented by the Formula II wherein (R) stands for a combination of atoms and/or atomic groups similar to (R) in the desired compound I supra, and an ethylene derivative representable by the Formula III IV or its isomer V Then, in the second step, further condensation occurs between the imino group (marked with asterisk) of-IV or V and the group A to form the compound I.
  • the intermediate'IV or V can rarely be taken out, but the formation'of the intermediate can not always be perceptible during the course of the reaction.
  • the compound III if R is hydrogen atom, the compound can become a keto-form compound, since it has a hydroxyl group adjacent double bond. And, the reaction of this invention may proceed when the compound II-I becomes either of keto or enol form.
  • the reaction may be conducted in the presence or absence of a solvent such a water, an aliphatic lower alcohol, e.g. methyl, ethyl or butyl alcohol, dioxane, benzene, toluene, ligroin and their mixtures.
  • a solvent such as a water, an aliphatic lower alcohol, e.g. methyl, ethyl or butyl alcohol, dioxane, benzene, toluene, ligroin and their mixtures.
  • the reaction is, in general, effected at a mild condition. In most cases, the reaction proceeds smoothly at around the boiling point of the solvent employed, which is generally around 100 C. Of course, the reaction may be carried out without using any solvent, if desired. In such a case too, the reac tion conditions are not necessarily so drastic.
  • the reaction generally requires rather short time, e.g. ranging from several minutes to one hour.
  • the products automatically separate out from the reaction system when such a solvent is employed. If the compounds I do not separate completely, water may be added in a large portion to the reaction mixture or the solvent may be removed by distillation to secure the separation.
  • the substituent or substituents of the compounds I thus obtained can, if desired, be converted into other substituent or substituents in the per se known manner or manners.
  • a carboxyl group can be converted into its ester or amide or alkali or alkaline earth metal salt
  • an alkoxycarbonyl group can be hydrolyzed into a carboxyl group by the use of an alkali or acid
  • a hydroxyl group can be converted into halogen atom by the action of e.g. phosphorous oxyhalide, halogen atom into thiouronium salt by thiourea, thiouronium salt into mercapto group by hydrolysis, halogen atom into a substituted amino group by the reaction with secondary or primary amines.
  • the compounds I may be purified by recrystallization from eg water, alcohols, benzene or ligroin. Or, the purification may be effected by distillation under reduced pressure, in case the compounds I have considerably low boiling point.
  • Example '1 To 300 parts by volume of water are added 5 parts of 2- hydrazino-4-amino-5-cyanopyrimidine and 7 parts of ethyl ethoxymethylenecyanoacetate. After boiling for 30 minutes, the mixture is cooled. The separated 2-(4-carbethoxy-S-amino-pyrazol-4-yl)-4-arnino-5 cyanopyrimidine is collected. Recrystallation of the product from diluted acetic acid gives 5 parts of colourless needles, decomposing at 284 C.
  • Example 2 To 300 parts by volume of Water are added 3 parts of 3-hydrazino-4-amino-S-cyanopyrimidine and 4.2 parts of ethyl a-acety-l-fi-ethoxyacrylate. The mixture is boiled for 5 minutes, whereupon 2-(4-carbethoxy-5-methylpyrazoll-yl)-4-amino-S-cyanopyrimidine is produced. After being recrystallized from diluted acetic acid, the product occurs as colourless needles which color and sinter from about 230 C. and change into a dark red liquid at a temperature over 248 C. The yield is 4.6 parts.
  • Example 3 Three parts of 2-hydrazino-4-amino-S-cyanoPyrimidine is heated together with parts by volume of 50% (volume) ethyl alcohol. To the mixture is added 5.2 parts of ethyl a-benzoyl-fl-ethoxyacrylate, and boiled for 15 minutes. After adding 100 parts by volume of water, the hot mixture is cooled to separate 2-(4-carbethoxy-5-phenylpyrazol-l-yl)-4-amino-S cyanopyrimidine. Recrystallizations of the product first from diluted ethyl alcohol, then from ethylene chloride give 6 parts of colourless needless, M.P. 20l-202 C.
  • Example 4 A mixture composed of 0.7 part of 2-hydrazin0-4-arnino- S-cyanopyrimidine, 0.7 part of ethoxymethylenemalononitrile and 30 parts by volume of water is boiled for one hour. After being cooled, the product separated is recrystallized from 70% formic acid to give 0.6 part of 2-(4- cyano-S-arninopyrazol-l-yl)-4-amino-5 cyanao yrimidine as colourless fine crystals, M.P. 360 C.
  • Example 5 To a mixture of 6 parts of 2-hydrazino-4-amino-5- cyanopyn'midine and 6 parts of acetylacetone is added 150 parts by volume of water. After boiling the mixture for minutes, the separated product, is filtered. Recrystallization of -the product from 70% acetic acid gives 6 parts of 2-(3,5-dimethylpyrazol-1-yl)-4-amiuo-5 cyanopyrimidine, as colourless plates which decompose at 262 C.
  • Example 6 To a hot solution of 3 parts of 2-hydrazino-4-amino-5- carbethoxypyrimidine in 50 parts by volume of 50% (volume) ethyl alcohol is added 2.7 parts of ethyl ethoxymethylenecyanoacetate. The mixture is boiled for 10 min utes, whereupon 2-(4-carbethoxy-S-aminopyrazol-1-yl)-4- amino-S-carbethoxypyrimidine is produced. Recrystallization from diluted acetic acid of the product gives 3.4 parts of colourless crystals which decompose at 245-247 C.
  • 2-hydrazino-4-amino-S-carbethoxypyrimidine employed in thi example was obtained by reacting 2-nitroamino-4- amino-S-carbethoxypyrimidine with hydrazine hydrate (Journal of the Pharmaceutical Society of Japan, vol. 79 (1959), pp. 1174-1182).
  • Example 7 Three parts of 2-hydrazino-4-amino-5-carbe1;hox pyrimi dine is dissolved in 50 parts by volume of 50% (volume) ethyl alcohol, then 1.7 parts of acetylacetone is further added. The mixture is boiled for 20 minutes to give 2- (3,5-dimethyl-pyrazol-1-yl) -4-amino-5 carbethcxypyrimidine. Recrystallization of the product from monoethyl ether of ethyleneglycol gives 3.4 parts of colourless fine needles, M.P. 220-221 C.
  • Example 8 In diluted ethyl alcohol are boiled for 5 minutes 3 parts of 2-hydrazino-4-hydroxy-5-carbethoxypyrimidine and 3 parts of ethyl ethoxymethylcneacetoacetate to give 2-(4- carbethoxy 5 methylpyrazol l yl) 4 hydroxy -5 carbethoxypyrirnidine. Recrystmlization of the product from diluted ethyl alcohol gives colourless scales, M.P. 207-209 C. The yield is 3.3 parts.
  • 2-hydrazino-4-hydroxy-S-carbethoxypyrimidine one of the starting materials, was obtained by reacting Z-nitroamino-4-hydroxy-5-carbethoxypyrimidine with hydrazine hydrate, see e.g. Journal of the Pharmaceutical Society of Japan, vol. 79 (1959), pp. 1477-1482.
  • Example 9 To a hot solution of 7 parts of 2-hydrazino-4-hydroxy- S-carbethoxypyrimidine in 150 parts by volume of water is added 6 parts of ethyl ethoxymethylenecyanoacetate, and the mixture is boiled for 2 minutes to produce 2-(4- carbethoxy-S-aminopyrazol-1-yl)-4-hydroxy-5 carbethoxypyrimidine. Recrystallization of the product from diluted acetic acid gives 6 parts of colourless crystals, M.P. 226-227 C.
  • Example 10 A mixture composed of 3.3 parts of 2-hydrazino-4- hydroxy-S-carbethoxypyrimidine, 2.2 parts of ethoxymethylenemalononitrile and 50 parts by volume of water is boiled for a while. The separated product is recrystallized from diluted acetic acid to give 2.4 parts of 2-(4- cyano 5 -aminopyrazol 1 yl) 4 hydroxy 5 car-
  • Example 12 To a mixture composed of parts by volume of water and 10 parts by volume of alcohol are added 3 parts of 2-hydrazino-4-methyl-5-carbethoxypyrimidine and 3 parts of ethyl a-acetyl-B-ethoxyacrylate.
  • 2-hydrazino-4-methyl-5-carbethoxypyrimidine one of the starting materials, was obtained through a reaction between 2-nitroamino-4-methyl-5-carbethoxypyrimidine and hydrazine hydrate as shown in Journal of the Pharmaceutical Society of Japan, vol. 79 (1959), pp. 1477-1482.
  • Example 13 To a solution of 2 parts of 2-hydrazino-4-methyl-S-carbethoxypyrimidine in 30 parts by volume of ethyl alcohol is added 2.6 parts of ethyl a-benzoyl-B-ethoxyacrylate. The mixture is boiled for 15 minutes and water is added to separate 2-(4-carbethoxy-S-phenylpyrazol-l-yl)-4-methyl- S-carbethoxypyrimidine. The product occurs as colourless plates, M.P. 91.5 C., after recrystallization from a mixture of ligroin and benzene. The yield is 3.8 parts.
  • Example 14 A mixture composed of 3 parts of Z-hydrazino-4- methyl-S-carbethoxypyrimidine, 2 parts of ethoxymethylenemalononitrile and 80 parts by volume of water is boiled for 15 minutes to give 2-(4-cyano-S-aminopyrazol-l-yl)- 4-methyl-S-carbethoxypyrimidine. The product is recrystallized from diluted ethyl alcohol to give 3.2 parts of colourless plates, M.P. 218-220 C.
  • Example 15 A mixture composed of 3 parts of 2-hydrazino-4- methyI-S -carbethoxypyrimidine, 1.8 parts of acetylacetone and 80 parts by volume of water is boiled for a while. After cooling the mixture, the separated 2-(3,5-dimethylpyrazol-l-yl)-4-methyl-5-carbethoxypyrimidine is collected. The product is recrystallized from diluted ethyl alcohol to give 4 parts of colourless needles containing 2 moles of water of crystallization. The crystals sinter from about 70 C. and melt at about 84 C.
  • Example 16 To a mixture of 90 parts by volume of an aqueous solution of potassium hydroxide (l-normal) and 30 parts by Volume of ethyl alcohol is added 8 parts of 2-(3,5- dimethylpyrazol 1 yl) 4 hydroxy 5 carbethoxypyrimidine. After being boiled for 30 minutes, the mixture is concentrated under reduced pressure to obtain the potassium salt of 2-(3,S-dimethylpyrazol-l-yl)-4-hydroxy- S-carboxypyrimidine as colourless needles, M.P. 300 C.
  • a hot aqueous solution of the product is acidified with hydrochloric acid to separate 2-(3,5-dimethylpyrazol-1- yl)-4-hydroxy-5-carboxypyrimidine, as colourless needles, M.P. 255 C. (decomposition).
  • the yield is 2.3 parts.
  • Example 17 To a mixture of 30 parts by volume of sodium hydroxide solution (1 N) and 10 parts by volume of ethyl alcohol is added 2.6 parts of 2-(4,5-dimethylpyrazol-1-yl)- 4-methyl-S-carbethoxypyrimidine. The mixture is boiled for minutes, then is concentrated to separate the sodium salt of 2-(4,5-dimethylpyrazol-l-yl)-4-methyl-5-carboxypyrimidine as colourless fine crystals, M.P. 300 C. A hot aqueous solution of the sodium salt is acidified with hydrochloric acid to obtain 2-(4,5-dimethylpyrazol-l-yl)- 4-rnethyl-5-carboxypyrimidine. Recrystallization of the product from diluted ethyl alcohol gives 1.8 parts of colourless needles, M.P. 282 C. (decomposition).
  • Example 18 To a mixture of 14 parts of 2-hydrazino-4-methyl-6- hydroxypyrimidine and 18 parts of ethyl ethoxymethylenecyanoacetate is added 200 parts by volume of water. The mixture is boiled for minutes, then allowed to stand for cooling. Crystals separated are recrystallized from diluted ethyl alcohol to give 22 parts of 2-(4-carbethoxy 5 aminopyrazol l yl) 4 methyl 6 hydroxypyrimidine, as colourless needles, M.P. 199.5- 200.5 C.
  • Example 21 To 100 parts by volume of water are added 7 parts of 2-hydrazino-4-methyl-6-hydroxypyrimidine and 8 parts of ethoxymethylenemalononitrile. The mixture is boiled for 10 minutes. After cooling the mixture, the product separated is collected. The product is recrystallized from diluted ethyl alcohol to give 8 parts of 2-(4-cyano-5-aminopyrazol-l-yl)-4-niethyl-6-hydroxypyrirnidine, as colourless long plates, M.P. 26026l C.
  • Example 22 To a hot solution of 1.4 parts of 2-hydrazino-4-methyl- 6-hydroxypyrimidine in parts by volume of water is added a mixture of 1.3 parts of v2-formylcyclohexanone and 5 parts of ethyl alcohol. The mixture is boiled for 15 minutes to separate 2-(4,S-tetramethylenepyrazol-l-yl)- 4-methyl-6-hydroxypyrimidine. The product is recrystallized from diluted acetic acid to give 1 part of colourless long plates, M.P. l7818l C.
  • Example 23 Sevenparts of 2-(4-carbethoxy-S-aminopyrazol-l-yl)- 4-rnethyl-6-hydroxypyrimidine is boiled for 30 minutes with a mixture of 80 parts by volume of an aqueous solution of sodium hydroxide (1 N) and 80 parts by volume of ethyl alcohol. The reaction mixture is concentrated to obtain the sodium salt of 2-(4-carboxy-5-aminopyrazol-1-' yl)-4-methyl-6-hydroxypyrimidine (M.P. 300 C., colourless fine crystals).
  • Example 25 To 100 parts by volume of Water are added 6 parts eachof Z-hydrazino-4-phenyl-6-hydroxypyrimidine and ethyl ethoxymethylenecyanoacetate. The mixture is boiled for 10 minutes to produce 2-(4-carbethoxy-S-aminopyrazoll-yl)-4-phenyl-6-hydroxypyrimidine. Recrystallization of the product from acetic acid gives 8 parts of colourless scales, M.P. 236-238 C.
  • 2-hydrazino-4-phenyl-6- hydroxypyrimidine is obtained by reacting 2-nitroamino- 4-phenyl-6-hydroxypyrimidine with hydrazine hydrate as described in Journal of the Pharmaceutical Society of Japan, vol. 79 (1959),pp. 14774482.
  • Example 26 To a hot solution of 2 parts of 2-hydrazino-4-phenyl-6- hydroxypyrimidine in 60 parts by volume of 50% (volume) alochol is added 2.1 parts of ethyl a-acetyLB-ethoxyacrylate. The mixture is boiled for 10 minutes, then 40 parts by volume of Water is added thereto. After cooling, the separated crystals are collected. Recrystallization of the crystals from diluted ethyl alcohol gives 3 parts of 2 (4 carbethoxy 5 methylpyrazol-l-yl) 4 phenyl- 6-hydroxypyrimidine as colourless needles, M.P. 197 199 C.
  • Example 27 To a hot solution of 3.2 parts of 2-hydrazino-4-phenyl- -hydroxypyrimidine in 100 parts by volume of 50% (volume) ethyl alcohol is added 4.1 parts of ethyl a-benzoyl-fi-ethoxyacrylate. The mixture is boiled for 15 minutes, whereupon 2-(4-carbethoxy-S-phenylpyrazol-l-yl)-4- phenyl-6-hydroxypyrimidine is produced. After recrystallization from benzene the product melts at 196-198" C. The yield is 5 parts.
  • Example 28 To 100 parts by volume of Water are added 6 parts of Z-hydrazino-4-phenyl-6-hydroxypyrimidine and 4 parts of ethoxymethylenemalononitrile. The mixture is boiled for 10 minutes to separate 2-(4-cyano-5-aminopyrazol-1-y1)- 4-phenyl-6-hydroxypyrimidine. The product is recrystallized from acetic acid to give 7 parts of colourless needles, M.P. 273275 C.
  • Example 29 To a mixture of 70 parts by volume of an aqueous solution of sodium hydroxide (1 N) and 70 parts by volume of ethyl alcohol is added 8 parts of 2-(4-carbethoxy-5- methylpyrazol-l-yl) 4 phenyl 6 hydroxypyrimidine. After being boiled for 30 minutes, the mixture is concentrated to obtain the sodium salt of 2-(4-carboxy-5-methylpyrazol-l-yl)-4-phenyl-6-hydroxypyrimidine, as colourless fine crystals, M.P. 300 C. An aqueous solution of this product is acidified with hydrochloric acid to separate 2-(4-carboxy-S-methylpyrazol-l-yl)-4-phenyl-6 hydroxypyrimidine. Recrystallization of the product from ethylene glycol monoet'nyl ether gives 4.4 parts of colourless fine crystals, M.P. 325 C. (decomposition).
  • Example 30 To 70 parts by volume of 30% (volume) ethyl alcohol are added 6 parts of 2-hydrazino-4-phenyl-6-hydroxypyrimidine and 4 parts of acetylacetone. The mixture is boiled for 30 minutes, and is cooled. The separated substance is recrystallized from diluted ethyl alcohol to give 8 parts of 2-(3,5-dimethylpyrazol-1-yl)-4 phenyl 6 hydroxypyrimidine, as colourless needles, M.P. 150-151 C.
  • Example 31 (a) A mixture composed of 10.1 parts of Z-hydrazino- 4-phenyl-6-hydroxypyrimidine, 8.1 parts of benzoylacetone and 200 parts by volume of 50% (volume) alcohol is boiled for 30 minutes. To the mixture is added water, whereupon (4-phenyl-6-hydroxypyrimidine-2-yl) hydrazone of benzoylacetone is produced. From diluted monoethyl ether of ethyleneglycol, the product is recrystallized to give 14.2 parts of colourless needles, M.P. 184-186 C.
  • Example 32 Five parts of 2-hydrazino-4-phenyl-6-hydroxypyrimidine is admixed with 4 parts of ethyl acetoacetate, and the mixture is heated at about 140-150 C. for 5' minutes, further at about 205-210 C. for 5 minutes to produce 2-(3-methyl-S-hydroxypyrazol-l-yl)-4 phenyl 6 hydroxypyrim idine. When recrystallized from acetic acid, the product is obtained as colourless scales decomposing at 271 C. The yield is 3.9 parts.
  • Example 33 To a hot solution of 2.8 parts of 2-hydrazino-4-amino- G-hydroxypyrirnidine in 150 parts by volume of Water is added 2.2 parts of acetylacetone. After the mixture is boiled for a while, the separated product is recrystallized from diluted acetic acid to give 3.1 parts of 2-(3,5-dimethylpyrazol-1-yl)-4-amino 6 hydroxypyrimidine, as colourless plates, M.P. 266268 C.
  • 2-hydrazino-4-amino-G-hydroxypyrimidine employed in this example is obtained by the reaction between hydrazine hydrate and 2-nitroamino-4-amino-6-hydroxypyrimidine synthesized by the condensation of nitroguanidine and ethyl cyanoacetate.
  • This material is a novel compound.
  • Example 34 To a solution of 3 parts of 2-(3-methyl-5-phenylpyrazol-l-yl)-4-phenyl-6-hydroxypyrimidine in 40 parts by volume of chloroform is added 4 parts of bromine at room temperature. After being left standing overnight, the mixture is concentrated. To the residue, water is added and the matter separated is filtered. The product is recrystallized from diluted ethyl alcohol, then from toluene to obtain 3.5 parts of 2-(3-methyl-4-bromo-5-phenylpyrazol-l-yl)-4-phenyl 5 bromo 6 hydroxypyrimidine as colourless prisms, M.P. 229-231 C.
  • Example 35 A mixture composed of 7 parts of 2-hydrazino-4,5-trimethylene-6-hydroxypyrimidine, 8 parts of ethyl ethoxymethylenecyanoacetate and 100 parts by volume of Water is boiled for 10 minutes. After cooling the mixture, the separated substance is recrystallized from 90% (volume) 10 ethyl alcohol to give 11 parts of 2-(4-carbethoxy-5-aminopyrazol-l-yl)-4,5-trimethylene 6 hydroxypyrimidine as colourless needles, M.P. 183.5185.5 C.
  • Example 36 To a hot solution of 16.6 parts of 2-1ydrazino-4,5-trimethylene-6-hydroxypyrimidine in 500 parts by volume of water is added 20.5 parts of ethyl a-acetyl-fi-ethoxyacrylate. The mixture is boiled for a While to produce 2-(4- canbethoxy-S-methylpyrazol-l-yl) 4,5 trimethylene 6- hydroxypyrimidine. Recrystallization of the product from diluted ethyl alcohol gives 22.2 parts of colourless scales, M.P. C.
  • Example 3 7 To a boiling solution of 3 parts of 2-hydrazino-4,5-trimethylene-6-hydroxypyrimidine in 100 parts by volume of Water is added a solution of 4.7 parts of ethyl ethoxymethylenebenzoylacetate in 20 parts by volume of ethyl alcohol. The mixture is boiled for 20 minutes. After cooling, the separated 2-(4-carbethoxy-S-phenylpyrazol-lyl)-4,5-trimethylene-6-hydroxypyrimidine is recrystallized from diluted ethyl alcohol to give 3.6 parts of colourless prisms, M.P. 173-174 C.
  • Example 38 A mixture com-posed of 7 parts of 2-hydrazino-4,5-trimethylene-6-hydroxypyrimidine, 7 parts of ethoxymethylenemalononitrile and 100 parts by volume of Water is boiled for 10 minutes, and is cooled. The separated crystals are recrystallized from normal butanol to obtain 6 parts of 2-(4-cyano-5-aminopyrazol-l-yl)-4,5-trimethylene-6-hydroxypyrimidine, as colourless needles, M.P. 277 C.
  • Example 39 To a hot solution of 1.6 parts of 2-hydrazino-4,5-trimethylene-6-hydroxypyrimidine in 50 parts by volume of 20% (volume) ethyl alcohol is added a mixture of 1.3 parts of 2-formylcycl0hexanone and 5 parts by volume of ethyl alcohol. After boiling the mixture for a while, the separated 2-(4,5-teuamethylenepyrazol-l-yl)-4,5-trlmethylene 6 hydroxypyrimidine is collected. Recrystallization of the product from diluted ethyl alcohol gives 1.7
  • Example 40 To 50 parts by volume of water are added 8 parts of 2- hydrazino-4,5-t1imethylene 6 hydroxypyrirnidine and 5 parts of acetylacetone. The mixture is boiled for 5 minutes and cooled. The product is filtered and recrystallized from diluted ethyl alcohol to give 9 parts of 2-(3,5 dimethylpyrazol-l-yl)-4,5-trimethylene-6 hydroxypyrimidine, as colourless prisms, M.P. -196 C.
  • Example 41 To 100 parts by volume of water are added 9 parts each of Z-hydrazino -4,5-tetramethylene-6 hydroxypyrimidine and ethyl ethoxymethylenecyanoacetate. The mixture is boiled for 15 minutes to produce 2-(4-carbethoxy-5-aminopyrazol-l-yl) -4,5-tetramethylene-6- hydroxypyrimidine.
  • Example 43 To a hot solution of 6 parts of 2-hydrazino-4,5-tetramethylene-6-hydroxypyrimidine in 200 parts by volume of Water is added 6.5 parts of ethyl a-acetyl-fi-ethoxyacrylate. The mixture is boiled for 1 minutes, whereupon 2-(4-carbethoxy S-rnethylpyrazol-l-yl) 4,5-tetramethylene-G-hydroxypyrimidine is produced. The product occurs as colourless needles, M.P. 164166 C., after recrystallization from diluted ethyl alcohol. The yield is 7.2 parts.
  • Example 44 To a hot solution of 3 parts of 2-hydrazino-4,5-tetramethylene-6-hydroxypyrimidine in 80 parts by volume of 50% (volume) of ethyl alcohol is added 4.2 parts of ethyl a-benzoyl-B-ethoxyacrylate. The mixture is boiled for minutes. After addition of 80 parts by volume of water, the mixture is allowed to stand to separate crystals. The product is recrystallized from a mixture of benzene and ligroin to obtain 4.2 parts of 2-(4-carbethoxy-5-phenylpyrazol-l-yl)-4,5-tetrarnethylene-6-hydroxypyrimidine, as colourless needles, M.P. ISO-152 C.
  • Example 45 To a mixture of parts by volume of an aqueous solution of sodium hydroxide (1 N) and 20 parts by volume of ethyl alcohol is added 2 parts of 2-(4-carbethoxy-5- arriinopyrazol-l-yl)-4,5 tetramethylene-6-hydroxypyrimidine. After being boiled for minutes, the mixture is concentrated to a little quantity, whereupon the sodium salt of 2-(4-cmboxy-5 aminopyrazol-l-yl)-4,5-tetramethylene-6-hydroxypyrirnidine is obtained as colourless fine crystals, M.P. 300 C.
  • a hot aqueous solution of the product is acidified With hydrochloric acid to separate 2-(4-carboxy-5 aminopyrazol-l-yl) 4,5-tetramethylene- 6-hydroxypyrimidine. Recrystallization of the product from diluted ethylene glycol monethyl ether gives 1 part of colourless needles, M.P. 248 C. (decomposition).
  • Example 46 A mixture composed of 9 parts of 2-hydrazino- 4,5-tetramethylene-fi-hydroxypyrimidine, 7 parts of ethoxymethylenemalononitrile and 100 parts by volume of water is boiled for 20 minutes to seperate 2-(4-cyano-5-amino pyrazol-1-yl)-4,5 tetrarnethylene-6 hydroxypyrimidine.
  • Example 47 In 30 parts by volume of water 1.8 parts of Z-hydrazino- 4,5-tetramethylene-6-hydroxypyrimidine is heated, and a mixture of 1.3 parts of 2-formylcyclohexanone and 5 parts by volume of ethyl alcohol is added. The mixture is boiled for. 15 minutes, and the separated crystals are recrystallized from diluted ethyl alcohol to give 2-(4,5-tetramethylenepyrazol 1-yl)-4,5-tetrametl1ylene 6-hydroxypyrimidine, as colourless prisms, M.P. 17ll72 C. The yield is 1.3 parts.
  • Example 48 To 50 parts by volume of water are added 8 parts of Z-hydrazino-4,5-tetramethylene-6-hydroxypyrimidine and 6 parts of acetylacetone. The mixture is boiled for 10 minutes to separate 2-(3,5-dirnethylpyrazol-1-yl)-4,5-tetramethylene-6-hydroxypyrimidine. The product is recrystallized from a diluted ethyl alcohol to give 8.2 parts of colourless needles, M.P. l63165 C.
  • Example 49 In 200 parts by volume of 50% (t olume) ethyl alcohol, 9 parts of 2-hydrazino-4,5-tetramethylene-G-hydroxypyrirnidine is reacted with 8.1 parts of benzoylacetone for 1 hour under boiling. The crystals obtained through evaporation of the reaction mixture under reduced pressure are recrystallized from ethylene chloride to obtain 8.8 parts I of 2- 3-methyl-5-phenylpyrazol- 1 -yl -4,5 -tetramethylene-6-hydroxypyrimidine. The product occurs as colourless needles, M.P. 1971'99 C.
  • Example 50 A mixture or" 84 parts of 2-(3,5-dimethylpyrazol-1-yl)- 4-methyl-6-hydroxypyrimidine and 191) parts of phosphorus oxychloride is boiled for 2 hours. Under reduced pressure, the mixture is concentrated. The residue is poured into ice-water. After a while, the solution is neutralized with an aqueous ammonia to produce 2-(3,5- dimethylpyrazol-1-yl)-4 rnethyl-o-chloropyrimidine. An alcoholic solution of the product is filtered, then Water is added thereto, whereupon 50 parts of colourless needles, M.P. 57 C. is obtained. The yield is 50 parts.
  • Example 51 A mixture of 48parts of 2-(3,5-dimethylpyraz0l-1-yl)- 4,5-trimethylene 6-hydroxyprimidine and parts of phosphorus oxychloride is boiled for one hour. After the concentration of the solution under reduced pressure, ice pieces are added to the residue. The mixture is kept standing for a while to obtain .2-(3,5-dimethylpyrazol-lyl)-4,S-trimethylene-G-chloropyrimidine. The product is recrystallized from a mixture of benzene and ligroin,
  • Example 53 A mixture of'85 parts of 2-(3,5-dimethylpyrazold-yl)- 4,5-tetramethylene-6-hydroxypyrimidine and 160 parts of phosphorus oxychloride is boiled for 2 hours, and the excess of the phosphorus oxychloride is removed by distilllation under reduced pressure. Thewresidue is poured into ice-water. After a While, the mixture is extracted With benzene. The concentration of the benzene solution gives 53 parts of 2-(3,5-dimethylpyrazol-1-yl)-4,5-tetramethylene-S-chloropyrimidine, as colourless needles, M.P. 132 C.
  • Example 54 A mixture composed of 5 parts of 2-(3,5-dirnethylpyrazol-l-yl)-4,5-trimethylene-6-chloropyrirnidine, 1.8 parts of thiourea and 40 parts by volume of ethyl alcohol is boiled for 1 hour. After cooling, the separated S-[2-(3,5- dimethylpyrazol l-yl)-4,5-trimethylenepyrimidin 6-yl1- thiouronium hydrochloride is collected. Recrystallization of the product gives 1.6 parts of pale yellow needles which decompose at 207-208 C.
  • Example 55 To 50 parts by volume of ethyl alcohol are added 5 parts of 2-(3,S-dimethylpyrazol-l-yl)-4,5-tetramethylene- 6-chloropyrimidine and 1.7 parts of thiourea. After boiling for 20 minutes, the mixture is allowed to stand to cool. The separated crystals are recrystallized from acetic 13 acid to obtain S-[2-(3,5-dimethylpyrazol-l-yl)-4,5-tetramethylenepyrirnidin '6 yl] thiouronium hydrochloride which occurs as pale yellow needles, M.P. 205 C. (decomposition). The yield is 2.7 parts.
  • Example 56 To 50 parts by volume of ethyl alcohol are added 10 parts of 2-(3.5-dimethylpyrazol-l-yl)-4-methyl-6-chloropyrimidine and 4.2 parts of thiourea. The mixture is boiled for 4 hours, then allowed to stand to separate pale yellow crystals showing M.P. 196197 C. after recrystallization from normal butanol). The product is boiled together with 60 parts by volume of an aqueous solution of potassium hydroxide (1 N), then is acidified with acetic acid to separate 2-(3,5-dimethylpyrazol-l-yl) 4-methyl-6- mercaptopyrimidine. Recrystallization of the product from 90% acetic acid gives yellow needles, M.P. 174- 175 C. The yield is 1.3 parts.
  • Example 57 A mixture composed of 10 parts of 2-(3,5-dimethylpyrazol-l-yl)-4-phenyl-6-chloropyrimidine, 3.2 parts of thiourea and 50 parts by volume of ethyl alcohol is boiled for 6 hours. The mixture is concentrated until its volume becomes about a half, then a large quantity of Water is added. After being left standing for a while, the separated product is collected. Recrystallization of the product from pyridine, then from normal butanol gives 2 parts of 2-(3,5 dimethylpyrazol l-yl)-4- phenyl-6 mercaptopyrimidine, as yellow needles, M.P. 174-175 C.
  • Example 58 To 18 parts by volume of an aqueous solution of potassium hydroxide (1 N) is added 1.5 parts of S-[2-(3,5- dimethylpyrazol-l-yl) 4,5 tetramethylenepyrimidin-6- yl]-thiouronium hydrochloride. After boiling for 1.5 hours, the mixture is acidified with acetic acid to separate 2-(3,5-dimethylpyrazol-l-yl)-4,5-trimethylene 6 mercaptopyrimidine. Recrystallization of the product from acetic acid gives 0.25 part of pale yellow needles which decompose at 217 C.
  • Example 59 To a mixture of 13 parts by volume of 80% hydrazine hydrate and 20 parts by volume of ethyl alcohol is added 20 parts of 2-(3,5-dimethylpyrazol-1-yl)-4-phenyl-6- chloropyrimidine. As soon as the mixture is heated, it gives 2-(3,5-dimethylpyrazol-l-yl)-4-phenyl-6-hydrazinopyrimidine. Recrystallization of the product from normal butyl alcohol gives 13 parts of colourless needles, M.P. 206207 C.
  • Example 61 To a mixture of 12 parts by volume of 80% hydrazine hydrate and 12 parts by volume of ethyl alcohol is added 10 parts of 2-(3,5-dimethylpyrazol-1-yl)-4,5-trimethylene-6-chloropyrimidine. After boiling the mixture for 30 minutes, 50 parts by volume of water is added. The product separated is recrystallized from diluted ethyl alcohol to give 7.8 parts of 2-(3,5-dimethylpyrazol-1-yl)- The crystals separated are recrystallized from 14 4,5 trimethylene 6 hydrazinopyrimidine, as colourless long plates, M.P. 185187 C.
  • Example 62 To a hot solution of 25 parts of 2-(3,5-dimethylpyrazol-l-yl)-4,S-tetramethylene-6-chloropyrimidine in a little quantity of ethyl alcohol is added 15 parts by volume of hydrazine hydrate. After boiling for 5 minutes, the mixture is cooled to separate 2-(3,5-dimethylpyrazol-l-yl)-4,5-tetramethylene 6 hydrazinepyrimidine. The product is recrystallized from diluted ethyl alcohol to give 20 parts of colourless needles, M.P. 182-183" C.
  • Example 63 A mixture of 5 parts of 2-(3,S-dimethylpyrazol-l-yl)- 4-phenyl-6-hydrazinopyrimidine and 35 parts by volume of 80% formic acid is boiled for 22 hours and then concentrated. The residue is recrystallized from diluted acetic acid to give 1.7 parts of 2-(3,5-dimethylpyrazol-1- yl)-4-phenyl-6-formylhydrazinopyrimidine which occurs as colourless needles, M.P. 245-246" C.
  • Example 64 In an autoclave, a mixture of 10 parts of 2-(3,5-di met'hylpyrazol-l-yl)-4-methyl-6-chloropy1imidine and 33 parts by volume of 33% aqueous solution of dimethylamine is heated for 1 hour at 98 to 102 C. After being cooled, the mixture is extracted with ether. The ethereal solution is concentrated to obtain 2-(3,5-dimethylpyrazol-l-yl)-4-methyl 6 dimethylaminopyrimidine. The product is recrystallized from ligroin to give 7.2 parts of needle-like crystals, M.P. 87-88 C.
  • Example 65 A mixture composed of 10 parts of 2-(3,5-dimethylpyrazol-l-yl)-4-methy1-6-chloropyrimidine, 6.1 parts of diethanolamine and 6.2 parts by volume of anhydrous potassium carbonate is heated at about 190 C. for 20 minutes. After cooling the mixture, 60 parts by volume of water is added to separate 2-(3,5-dimethylpyrazol-l-yl) 4 methyl-6-bis-(fi-hydroxyethyl) -,aminopyrimidine. The product is recrystallized from water to give 4 parts of colourless needles, M.P. 75-77 C.
  • Example 66 A mixture composed of 10 parts of 2-(3,5-dimethylpyrazol-l-yl) -4-methyl-6-chloropyrimidine, 19.1 parts of piperidine and 45 parts by volume of water is boiled for 1 hour. After cooling, the mixture is extracted with ether, and from the ethereal layer, the solvent is removed. The residue is distilled under reduced pressure to obtain 2-(3,5-dimethylpyrazol-1-yl)-4-methyl 6 piperidinopyrimidine, B.P. 200-205 C. (0.3 millimeter Hg). The yield is 7.4 parts.

Description

United States Patent 3,040,047 Z-(PYRAZOL-l-YD-PYRIMIDINE DERIVATIVES Kenzo Sirakawa, Nishinomiya, Japan, assignor to Takeda Pharmaceutical Industries, Ltd., Osaka, Japan N0 Drawing. Filed Apr. 4, 1960, Ser. No. 19,448 8 Claims. (Cl. 260256.4)
This invention relates to Z-(pyrazol-l-yl)pyrimidine derivatives which are usable in photographic industries as well as in the apeutic purposes. More particularly, the compounds 01 this invention are representable by the Formula I wherein each of (R) and (X) stands for a combination of three monovalent substituents or of monovalent and bivalent substituents. The respective components of (R) are combined at the 4-, 5- and 6-positions of the pyrimidine nucleus and the respective components of (X) are combined at the 3-, 4- and S-positions of the pyrazole nucleus of the compound I. And, the monovalent substituents of the compound I may be selected from hydrogen, halogen, cyano, hydroxyl, mercapto, amino, alkyl and atomic groups derivable from them, for instance. The bivalent substituents may be selected, for example, from trimethylene, tetramethylene and lactone groups. But, the compounds representable by the Formula I supra in which (R) 3 is a combination of only hydrogen and alkyl groups have little photographic and therapeutic activities, and therefore such compounds are excluded from the scope of this invention.
3,040,047 Patented June 19, 1962 anti-fogging activity against sensitive materials used in photographic industries. That is to say, the compounds t this invention inhibit fogging appearing in the process for preparing or storing the sensitive materials. To make the compounds display their activities they may be added to the raw materials or to the intermediate materials or to the final products, e.g. the compounds of this invention may he added when a sensitive emulsion is to be digested or when crystals of silver halide are to be prepared or just before film or paper is to be coated with a sensitive emulsion, or the like.
An example of the use of the compounds of this invention as anti-foggant is shown in the following:
To a negative gelatino silver bromoiodide emulsion (silver halide concentration: 0.25 gram-mole per kilogram) which was subjected to the second digestion are added several kinds of compounds of this invention in optional quantities, and a film-base is coated with the mixture and then dried.
The film thus processed is stored in a vessel for 2 weeks,
keeping the relative humidity at around 80%. Then the film is developed for 10 minutes at 20 C. with a developer having the following components.
DEVELOPER Gramme N-methyl-p-aminophenol sulfate 1.5 Hydroquinone 2.5 Sodium sulfite 100.0 Sodium metaborate 2.0 Potassium bromide 0.5
Water (enough to make the whole volume 1 litre).
The results (relative speed, gamma and fog) are shown 1n the following table.
Fresh test Incubation for 2 weeks Gramme at 40 0. per tnole Compounds of silver halide Rela- Relative Gamma Fog tive Gamma Fog speed speed 2 4 Carbetho 5 henyl yrazol l yl) 5 carbethoxy 6 niethylpyrimid izie p p 0. 4 95 0. 0. 07 90 0. 81 0. 14 2-(4Cyano-5-aminopyrazol-1-yl) 4-hydroxy-fi-phenylpyrimidinec 0. 3 90 O. 83 0. G6 85 0. 80 O. 11 2 (4 Carbethoxy 5 methylpyrazol 1 yl) 4 hydroxy 5,6
trimethylenepyrimidinm. 0. 3 95 0. 82 0. 07 0. 83 0. 13 2 (4 Oyano 5 aminopyrazol 1 yl) 5 carbethoxy 6 hydroxypy'rimid no 0. 3 0. 83 O. 08 85 0. 2 O. 12 2 (3,5 dimethylpyrazol l yl) 4 formylhydrazino 5 phenylpyrimidine 0.3 90 0. 81 0.07 90 0. 81 0.13 2-(3,5dimethylpyrazol-1-yl)-4-mercapto-6-phenylpyrimitline 0. 03 85 0. 8O 0. 05 80 0. 83 0. 10 2-(3,5-dimethylpyrazol-lyl)-lchloro6-methylpyrimidinc 0- 3 90 0. 80 0. 08 85 0. 82 0. 14 None (control). 0. 0 0. 85 0. 07 85 0. 83 0. 30
COO-alkyl, COO-alkali metal, all yl, -alkenyl, alkynyl, aryl, aralkyl, alkylene.
The compounds of this invention have remarkable In this experiment, relative speed is given in the centuple value of the ratio of the speed of the control emulsion to that of the sample emulsion, Where the speed is estimated in 10/E (E is the light quantity required to produce a density of 0.10 above fog).
Moreover, the compounds of this invention have remarktble anti-tubercle activity in vivo as Well as in vitro. Their minimum concentration for complete inhibition of the growth of Mycobacterium tuberculosis H37Rv strain is about 0.5 to 10 rnicrogramme per millilitre or less on Kirchners medium. The efiectiveness of the compounds of this invention bears comparison with that of streptomycin. And, the acute toxicity of the compounds of this invention to rats is as low as LD =5O0l000 milligrammes per kilogramme (intraperitoneally), which is far less than that of isonicotinoyl hydrazine. Thus the compounds of this invention can also he therapeutically usable for the treatment of tubercule diseases of human beings by oral administration.
The compounds of this invention can be conveniently synthesized by condensation between Z-hydrazinopyrirnidine having a desired substituent or substituents at 4-, 5- and/or 6-positions as represented by the Formula II wherein (R) stands for a combination of atoms and/or atomic groups similar to (R) in the desired compound I supra, and an ethylene derivative representable by the Formula III IV or its isomer V Then, in the second step, further condensation occurs between the imino group (marked with asterisk) of-IV or V and the group A to form the compound I. The intermediate'IV or V can rarely be taken out, but the formation'of the intermediate can not always be perceptible during the course of the reaction. In this reaction, in case A is an acyl group, the substituent at the 5-position of the pyrazole nucleus of the compound I becomes hydrocarbon radical; e.g. a methyl group is formed from an acetyl group, 'a propyl group from a butyryl group, a phenyl group from a benzoyl group, a tolyl group from a toluoyl group. In case A is a formyl group, it is, of course, converted into hydrogen atom. And, in case A is a carbalkoxy group, the substituent at the 5-position of pyrazol'e nucleus becomes a hydroxyl group, and a cyano group changes into an amino group.
In the compound III, if R is hydrogen atom, the compound can become a keto-form compound, since it has a hydroxyl group adjacent double bond. And, the reaction of this invention may proceed when the compound II-I becomes either of keto or enol form.
The reaction may be conducted in the presence or absence of a solvent such a water, an aliphatic lower alcohol, e.g. methyl, ethyl or butyl alcohol, dioxane, benzene, toluene, ligroin and their mixtures. The reaction is, in general, effected at a mild condition. In most cases, the reaction proceeds smoothly at around the boiling point of the solvent employed, which is generally around 100 C. Of course, the reaction may be carried out without using any solvent, if desired. In such a case too, the reac tion conditions are not necessarily so drastic. The reaction generally requires rather short time, e.g. ranging from several minutes to one hour.
As most of the compounds I are hardly soluble in water,
alcohol, or the solvent generally employed in the above process, the products automatically separate out from the reaction system when such a solvent is employed. If the compounds I do not separate completely, water may be added in a large portion to the reaction mixture or the solvent may be removed by distillation to secure the separation.
The substituent or substituents of the compounds I thus obtained can, if desired, be converted into other substituent or substituents in the per se known manner or manners. For example, a carboxyl group can be converted into its ester or amide or alkali or alkaline earth metal salt, an alkoxycarbonyl group can be hydrolyzed into a carboxyl group by the use of an alkali or acid, a hydroxyl group can be converted into halogen atom by the action of e.g. phosphorous oxyhalide, halogen atom into thiouronium salt by thiourea, thiouronium salt into mercapto group by hydrolysis, halogen atom into a substituted amino group by the reaction with secondary or primary amines.
The compounds I may be purified by recrystallization from eg water, alcohols, benzene or ligroin. Or, the purification may be effected by distillation under reduced pressure, in case the compounds I have considerably low boiling point.
Most of the purified compounds I are colourless or pale coloured crystals, and some of the purified compounds I occur as liquid. And, the detailed description on each compound is given in the examples described later.
The following examples set forth presently-preferred representative embodiments of the invention. In these examples, parts and percents are given by weight unless otherwise specified. The relationship between parts by Weight and parts by volume is the same as that between grammes and millilitres. And, the temperatures are all uncorrected. All of the products were confirmed by elementary analysis on carbon-, hydrogen-and nitrogen-contents, etc.
Example '1 To 300 parts by volume of water are added 5 parts of 2- hydrazino-4-amino-5-cyanopyrimidine and 7 parts of ethyl ethoxymethylenecyanoacetate. After boiling for 30 minutes, the mixture is cooled. The separated 2-(4-carbethoxy-S-amino-pyrazol-4-yl)-4-arnino-5 cyanopyrimidine is collected. Recrystallation of the product from diluted acetic acid gives 5 parts of colourless needles, decomposing at 284 C.
One of the starting materials of this example, 2-hydrazino-4-amino-S-cyanopyrimidine, was synthesized by the reaction between 2-methylmercapto-4-amino-5-cyanopyrimidine and hydrazine hydrate. This material is a novel compound.
Example 2 To 300 parts by volume of Water are added 3 parts of 3-hydrazino-4-amino-S-cyanopyrimidine and 4.2 parts of ethyl a-acety-l-fi-ethoxyacrylate. The mixture is boiled for 5 minutes, whereupon 2-(4-carbethoxy-5-methylpyrazoll-yl)-4-amino-S-cyanopyrimidine is produced. After being recrystallized from diluted acetic acid, the product occurs as colourless needles which color and sinter from about 230 C. and change into a dark red liquid at a temperature over 248 C. The yield is 4.6 parts.
Example 3 Three parts of 2-hydrazino-4-amino-S-cyanoPyrimidine is heated together with parts by volume of 50% (volume) ethyl alcohol. To the mixture is added 5.2 parts of ethyl a-benzoyl-fl-ethoxyacrylate, and boiled for 15 minutes. After adding 100 parts by volume of water, the hot mixture is cooled to separate 2-(4-carbethoxy-5-phenylpyrazol-l-yl)-4-amino-S cyanopyrimidine. Recrystallizations of the product first from diluted ethyl alcohol, then from ethylene chloride give 6 parts of colourless needless, M.P. 20l-202 C.
Example 4 A mixture composed of 0.7 part of 2-hydrazin0-4-arnino- S-cyanopyrimidine, 0.7 part of ethoxymethylenemalononitrile and 30 parts by volume of water is boiled for one hour. After being cooled, the product separated is recrystallized from 70% formic acid to give 0.6 part of 2-(4- cyano-S-arninopyrazol-l-yl)-4-amino-5 cyanao yrimidine as colourless fine crystals, M.P. 360 C.
Example 5 To a mixture of 6 parts of 2-hydrazino-4-amino-5- cyanopyn'midine and 6 parts of acetylacetone is added 150 parts by volume of water. After boiling the mixture for minutes, the separated product, is filtered. Recrystallization of -the product from 70% acetic acid gives 6 parts of 2-(3,5-dimethylpyrazol-1-yl)-4-amiuo-5 cyanopyrimidine, as colourless plates which decompose at 262 C.
Example 6 To a hot solution of 3 parts of 2-hydrazino-4-amino-5- carbethoxypyrimidine in 50 parts by volume of 50% (volume) ethyl alcohol is added 2.7 parts of ethyl ethoxymethylenecyanoacetate. The mixture is boiled for 10 min utes, whereupon 2-(4-carbethoxy-S-aminopyrazol-1-yl)-4- amino-S-carbethoxypyrimidine is produced. Recrystallization from diluted acetic acid of the product gives 3.4 parts of colourless crystals which decompose at 245-247 C.
2-hydrazino-4-amino-S-carbethoxypyrimidine employed in thi example was obtained by reacting 2-nitroamino-4- amino-S-carbethoxypyrimidine with hydrazine hydrate (Journal of the Pharmaceutical Society of Japan, vol. 79 (1959), pp. 1174-1182).
Example 7 Three parts of 2-hydrazino-4-amino-5-carbe1;hox pyrimi dine is dissolved in 50 parts by volume of 50% (volume) ethyl alcohol, then 1.7 parts of acetylacetone is further added. The mixture is boiled for 20 minutes to give 2- (3,5-dimethyl-pyrazol-1-yl) -4-amino-5 carbethcxypyrimidine. Recrystallization of the product from monoethyl ether of ethyleneglycol gives 3.4 parts of colourless fine needles, M.P. 220-221 C.
Example 8 In diluted ethyl alcohol are boiled for 5 minutes 3 parts of 2-hydrazino-4-hydroxy-5-carbethoxypyrimidine and 3 parts of ethyl ethoxymethylcneacetoacetate to give 2-(4- carbethoxy 5 methylpyrazol l yl) 4 hydroxy -5 carbethoxypyrirnidine. Recrystmlization of the product from diluted ethyl alcohol gives colourless scales, M.P. 207-209 C. The yield is 3.3 parts.
2-hydrazino-4-hydroxy-S-carbethoxypyrimidine, one of the starting materials, was obtained by reacting Z-nitroamino-4-hydroxy-5-carbethoxypyrimidine with hydrazine hydrate, see e.g. Journal of the Pharmaceutical Society of Japan, vol. 79 (1959), pp. 1477-1482.
Example 9 To a hot solution of 7 parts of 2-hydrazino-4-hydroxy- S-carbethoxypyrimidine in 150 parts by volume of water is added 6 parts of ethyl ethoxymethylenecyanoacetate, and the mixture is boiled for 2 minutes to produce 2-(4- carbethoxy-S-aminopyrazol-1-yl)-4-hydroxy-5 carbethoxypyrimidine. Recrystallization of the product from diluted acetic acid gives 6 parts of colourless crystals, M.P. 226-227 C.
Example 10 A mixture composed of 3.3 parts of 2-hydrazino-4- hydroxy-S-carbethoxypyrimidine, 2.2 parts of ethoxymethylenemalononitrile and 50 parts by volume of water is boiled for a while. The separated product is recrystallized from diluted acetic acid to give 2.4 parts of 2-(4- cyano 5 -aminopyrazol 1 yl) 4 hydroxy 5 car- Example 12 To a mixture composed of parts by volume of water and 10 parts by volume of alcohol are added 3 parts of 2-hydrazino-4-methyl-5-carbethoxypyrimidine and 3 parts of ethyl a-acetyl-B-ethoxyacrylate. The mixture is boiled for 1-5 minutes to separate 2-(4-carbethoxy-5-methylpyrazol-l-yl)-4-methyl-5-carbethoxypyrimidine whose recrystallization from ligroin gives 4.3 parts of colourless needles, M.P. 82-83 C.
2-hydrazino-4-methyl-5-carbethoxypyrimidine, one of the starting materials, was obtained through a reaction between 2-nitroamino-4-methyl-5-carbethoxypyrimidine and hydrazine hydrate as shown in Journal of the Pharmaceutical Society of Japan, vol. 79 (1959), pp. 1477-1482.
Example 13 To a solution of 2 parts of 2-hydrazino-4-methyl-S-carbethoxypyrimidine in 30 parts by volume of ethyl alcohol is added 2.6 parts of ethyl a-benzoyl-B-ethoxyacrylate. The mixture is boiled for 15 minutes and water is added to separate 2-(4-carbethoxy-S-phenylpyrazol-l-yl)-4-methyl- S-carbethoxypyrimidine. The product occurs as colourless plates, M.P. 91.5 C., after recrystallization from a mixture of ligroin and benzene. The yield is 3.8 parts.
Example 14 A mixture composed of 3 parts of Z-hydrazino-4- methyl-S-carbethoxypyrimidine, 2 parts of ethoxymethylenemalononitrile and 80 parts by volume of water is boiled for 15 minutes to give 2-(4-cyano-S-aminopyrazol-l-yl)- 4-methyl-S-carbethoxypyrimidine. The product is recrystallized from diluted ethyl alcohol to give 3.2 parts of colourless plates, M.P. 218-220 C.
Example 15 A mixture composed of 3 parts of 2-hydrazino-4- methyI-S -carbethoxypyrimidine, 1.8 parts of acetylacetone and 80 parts by volume of water is boiled for a while. After cooling the mixture, the separated 2-(3,5-dimethylpyrazol-l-yl)-4-methyl-5-carbethoxypyrimidine is collected. The product is recrystallized from diluted ethyl alcohol to give 4 parts of colourless needles containing 2 moles of water of crystallization. The crystals sinter from about 70 C. and melt at about 84 C.
Example 16 To a mixture of 90 parts by volume of an aqueous solution of potassium hydroxide (l-normal) and 30 parts by Volume of ethyl alcohol is added 8 parts of 2-(3,5- dimethylpyrazol 1 yl) 4 hydroxy 5 carbethoxypyrimidine. After being boiled for 30 minutes, the mixture is concentrated under reduced pressure to obtain the potassium salt of 2-(3,S-dimethylpyrazol-l-yl)-4-hydroxy- S-carboxypyrimidine as colourless needles, M.P. 300 C. A hot aqueous solution of the product is acidified with hydrochloric acid to separate 2-(3,5-dimethylpyrazol-1- yl)-4-hydroxy-5-carboxypyrimidine, as colourless needles, M.P. 255 C. (decomposition). The yield is 2.3 parts.
Example 17 To a mixture of 30 parts by volume of sodium hydroxide solution (1 N) and 10 parts by volume of ethyl alcohol is added 2.6 parts of 2-(4,5-dimethylpyrazol-1-yl)- 4-methyl-S-carbethoxypyrimidine. The mixture is boiled for minutes, then is concentrated to separate the sodium salt of 2-(4,5-dimethylpyrazol-l-yl)-4-methyl-5-carboxypyrimidine as colourless fine crystals, M.P. 300 C. A hot aqueous solution of the sodium salt is acidified with hydrochloric acid to obtain 2-(4,5-dimethylpyrazol-l-yl)- 4-rnethyl-5-carboxypyrimidine. Recrystallization of the product from diluted ethyl alcohol gives 1.8 parts of colourless needles, M.P. 282 C. (decomposition).
Example 18 To a mixture of 14 parts of 2-hydrazino-4-methyl-6- hydroxypyrimidine and 18 parts of ethyl ethoxymethylenecyanoacetate is added 200 parts by volume of water. The mixture is boiled for minutes, then allowed to stand for cooling. Crystals separated are recrystallized from diluted ethyl alcohol to give 22 parts of 2-(4-carbethoxy 5 aminopyrazol l yl) 4 methyl 6 hydroxypyrimidine, as colourless needles, M.P. 199.5- 200.5 C.
One of the starting materials, 2-hydrazino-5-methyl-6- hydrazinopyrimidine, was obtained by reacting 2-nitroamino4-hydroxypyrimidine with hydrazine hydrate in a similar manner as described in Journal of the Pharmaceutical Society of Japan, vol. 79 (1959), pp. 14771482.
Example 19 To a hot solution of 3 :5 parts of 2-hydrazino-4-methyl- 6-hydroxypyrimidine in 90 parts by volume of water is added 3.9 parts of ethyl a-acetylfi-ethoxyacrylate. The mixture is boiled for five minutes. When the mixture is cooled, =2-(4-carbethoxy-5-methylpyrazol-l-yl)-4-methyl- 6-1ydroxypyrimidine'is separated. The product is recrystalized from diluted ethyl alcohol to give 5.5 parts of colourless needles, M.P. 156.5158 C.
Example 20 Example 21 To 100 parts by volume of water are added 7 parts of 2-hydrazino-4-methyl-6-hydroxypyrimidine and 8 parts of ethoxymethylenemalononitrile. The mixture is boiled for 10 minutes. After cooling the mixture, the product separated is collected. The product is recrystallized from diluted ethyl alcohol to give 8 parts of 2-(4-cyano-5-aminopyrazol-l-yl)-4-niethyl-6-hydroxypyrirnidine, as colourless long plates, M.P. 26026l C.
Example 22 To a hot solution of 1.4 parts of 2-hydrazino-4-methyl- 6-hydroxypyrimidine in parts by volume of water is added a mixture of 1.3 parts of v2-formylcyclohexanone and 5 parts of ethyl alcohol. The mixture is boiled for 15 minutes to separate 2-(4,S-tetramethylenepyrazol-l-yl)- 4-methyl-6-hydroxypyrimidine. The product is recrystallized from diluted acetic acid to give 1 part of colourless long plates, M.P. l7818l C.
Example 23 Sevenparts of 2-(4-carbethoxy-S-aminopyrazol-l-yl)- 4-rnethyl-6-hydroxypyrimidine is boiled for 30 minutes with a mixture of 80 parts by volume of an aqueous solution of sodium hydroxide (1 N) and 80 parts by volume of ethyl alcohol. The reaction mixture is concentrated to obtain the sodium salt of 2-(4-carboxy-5-aminopyrazol-1-' yl)-4-methyl-6-hydroxypyrimidine (M.P. 300 C., colourless fine crystals). An aqueous solution of the product is acidified with hydrochloric acid to obtain 2-(4-carboxy- S-aminopyrazol-l-yl) -4-methyl-6-hydroxypyrimidine. This product occurs as colourless fine needles, M.P. 217 C., after recrystallization from diluted acetic acid. The yield is 5.6 parts.
Example 24 A mixture composed of 6 parts of 2-hydrazino-4- methyl-6-hydroxypyrimidine, 5 parts of acetylacetone and parts by volume of water is boiled for 10 minutes to separate a product. Recrystallization of the product from diluted ethyl alcohol gives 7.1 parts of 2-(3,5-dimethyl pyrazol-l-yl) -4-me-thyl-6=hydroxypyrimidine, as colourless crystals, M.P. l35l37 C.
Example 25 To 100 parts by volume of Water are added 6 parts eachof Z-hydrazino-4-phenyl-6-hydroxypyrimidine and ethyl ethoxymethylenecyanoacetate. The mixture is boiled for 10 minutes to produce 2-(4-carbethoxy-S-aminopyrazoll-yl)-4-phenyl-6-hydroxypyrimidine. Recrystallization of the product from acetic acid gives 8 parts of colourless scales, M.P. 236-238 C.
One of the starting materials, 2-hydrazino-4-phenyl-6- hydroxypyrimidine, is obtained by reacting 2-nitroamino- 4-phenyl-6-hydroxypyrimidine with hydrazine hydrate as described in Journal of the Pharmaceutical Society of Japan, vol. 79 (1959),pp. 14774482.
Example 26 To a hot solution of 2 parts of 2-hydrazino-4-phenyl-6- hydroxypyrimidine in 60 parts by volume of 50% (volume) alochol is added 2.1 parts of ethyl a-acetyLB-ethoxyacrylate. The mixture is boiled for 10 minutes, then 40 parts by volume of Water is added thereto. After cooling, the separated crystals are collected. Recrystallization of the crystals from diluted ethyl alcohol gives 3 parts of 2 (4 carbethoxy 5 methylpyrazol-l-yl) 4 phenyl- 6-hydroxypyrimidine as colourless needles, M.P. 197 199 C.
Example 27 To a hot solution of 3.2 parts of 2-hydrazino-4-phenyl- -hydroxypyrimidine in 100 parts by volume of 50% (volume) ethyl alcohol is added 4.1 parts of ethyl a-benzoyl-fi-ethoxyacrylate. The mixture is boiled for 15 minutes, whereupon 2-(4-carbethoxy-S-phenylpyrazol-l-yl)-4- phenyl-6-hydroxypyrimidine is produced. After recrystallization from benzene the product melts at 196-198" C. The yield is 5 parts.
Example 28 To 100 parts by volume of Water are added 6 parts of Z-hydrazino-4-phenyl-6-hydroxypyrimidine and 4 parts of ethoxymethylenemalononitrile. The mixture is boiled for 10 minutes to separate 2-(4-cyano-5-aminopyrazol-1-y1)- 4-phenyl-6-hydroxypyrimidine. The product is recrystallized from acetic acid to give 7 parts of colourless needles, M.P. 273275 C.
Example 29 To a mixture of 70 parts by volume of an aqueous solution of sodium hydroxide (1 N) and 70 parts by volume of ethyl alcohol is added 8 parts of 2-(4-carbethoxy-5- methylpyrazol-l-yl) 4 phenyl 6 hydroxypyrimidine. After being boiled for 30 minutes, the mixture is concentrated to obtain the sodium salt of 2-(4-carboxy-5-methylpyrazol-l-yl)-4-phenyl-6-hydroxypyrimidine, as colourless fine crystals, M.P. 300 C. An aqueous solution of this product is acidified with hydrochloric acid to separate 2-(4-carboxy-S-methylpyrazol-l-yl)-4-phenyl-6 hydroxypyrimidine. Recrystallization of the product from ethylene glycol monoet'nyl ether gives 4.4 parts of colourless fine crystals, M.P. 325 C. (decomposition).
Example 30 To 70 parts by volume of 30% (volume) ethyl alcohol are added 6 parts of 2-hydrazino-4-phenyl-6-hydroxypyrimidine and 4 parts of acetylacetone. The mixture is boiled for 30 minutes, and is cooled. The separated substance is recrystallized from diluted ethyl alcohol to give 8 parts of 2-(3,5-dimethylpyrazol-1-yl)-4 phenyl 6 hydroxypyrimidine, as colourless needles, M.P. 150-151 C.
Example 31 (a) A mixture composed of 10.1 parts of Z-hydrazino- 4-phenyl-6-hydroxypyrimidine, 8.1 parts of benzoylacetone and 200 parts by volume of 50% (volume) alcohol is boiled for 30 minutes. To the mixture is added water, whereupon (4-phenyl-6-hydroxypyrimidine-2-yl) hydrazone of benzoylacetone is produced. From diluted monoethyl ether of ethyleneglycol, the product is recrystallized to give 14.2 parts of colourless needles, M.P. 184-186 C.
Four parts of this product is heated in a bath of 200 to 205 C. to obtain 2-(3-methyl-5-phenylpyrazol-1-y1)-4- phenyl 6 -hydroxypyrimidine. Recrystallization of the product from alcohol gives colourless plates which melt at 178-180 C.
(b) A mixture composed of 20.2 parts of Z-hydrazino- 4-phenyl-6-hydroxypyrimidine and 19.4 parts of benzoylacetone is heated at about 140 to 150 C. for minutes, then at about 200 to 210 C. for 15 minutes. The product is recrystallized from ethylene chloride, then from ethyl alcohol to give 25 parts of 2-(3-methyl-5-phenylpyrazol-l-yl)-4-phenyl-6-hydroxypyrimidine. This product occurs as colourless plates, M.P. 178-180 C.
Example 32 Five parts of 2-hydrazino-4-phenyl-6-hydroxypyrimidine is admixed with 4 parts of ethyl acetoacetate, and the mixture is heated at about 140-150 C. for 5' minutes, further at about 205-210 C. for 5 minutes to produce 2-(3-methyl-S-hydroxypyrazol-l-yl)-4 phenyl 6 hydroxypyrim idine. When recrystallized from acetic acid, the product is obtained as colourless scales decomposing at 271 C. The yield is 3.9 parts.
Example 33 To a hot solution of 2.8 parts of 2-hydrazino-4-amino- G-hydroxypyrirnidine in 150 parts by volume of Water is added 2.2 parts of acetylacetone. After the mixture is boiled for a while, the separated product is recrystallized from diluted acetic acid to give 3.1 parts of 2-(3,5-dimethylpyrazol-1-yl)-4-amino 6 hydroxypyrimidine, as colourless plates, M.P. 266268 C.
2-hydrazino-4-amino-G-hydroxypyrimidine employed in this example is obtained by the reaction between hydrazine hydrate and 2-nitroamino-4-amino-6-hydroxypyrimidine synthesized by the condensation of nitroguanidine and ethyl cyanoacetate. This material is a novel compound.
Example 34 To a solution of 3 parts of 2-(3-methyl-5-phenylpyrazol-l-yl)-4-phenyl-6-hydroxypyrimidine in 40 parts by volume of chloroform is added 4 parts of bromine at room temperature. After being left standing overnight, the mixture is concentrated. To the residue, water is added and the matter separated is filtered. The product is recrystallized from diluted ethyl alcohol, then from toluene to obtain 3.5 parts of 2-(3-methyl-4-bromo-5-phenylpyrazol-l-yl)-4-phenyl 5 bromo 6 hydroxypyrimidine as colourless prisms, M.P. 229-231 C.
Example 35 A mixture composed of 7 parts of 2-hydrazino-4,5-trimethylene-6-hydroxypyrimidine, 8 parts of ethyl ethoxymethylenecyanoacetate and 100 parts by volume of Water is boiled for 10 minutes. After cooling the mixture, the separated substance is recrystallized from 90% (volume) 10 ethyl alcohol to give 11 parts of 2-(4-carbethoxy-5-aminopyrazol-l-yl)-4,5-trimethylene 6 hydroxypyrimidine as colourless needles, M.P. 183.5185.5 C.
One of the starting materials, 2-hydrazino-4,5-trimethylene-G-hydroxypyrimidine, was synthesized from 2-nitroamino-4,5-trimethylene-6-hydroxypyrimidine and hydrazine hydrate (Journal of the Pharmaceutical Society of Japan, vol. 79 (1959), pp. 1477-1482).
Example 36 To a hot solution of 16.6 parts of 2-1ydrazino-4,5-trimethylene-6-hydroxypyrimidine in 500 parts by volume of water is added 20.5 parts of ethyl a-acetyl-fi-ethoxyacrylate. The mixture is boiled for a While to produce 2-(4- canbethoxy-S-methylpyrazol-l-yl) 4,5 trimethylene 6- hydroxypyrimidine. Recrystallization of the product from diluted ethyl alcohol gives 22.2 parts of colourless scales, M.P. C.
Example 3 7 To a boiling solution of 3 parts of 2-hydrazino-4,5-trimethylene-6-hydroxypyrimidine in 100 parts by volume of Water is added a solution of 4.7 parts of ethyl ethoxymethylenebenzoylacetate in 20 parts by volume of ethyl alcohol. The mixture is boiled for 20 minutes. After cooling, the separated 2-(4-carbethoxy-S-phenylpyrazol-lyl)-4,5-trimethylene-6-hydroxypyrimidine is recrystallized from diluted ethyl alcohol to give 3.6 parts of colourless prisms, M.P. 173-174 C.
Example 38 A mixture com-posed of 7 parts of 2-hydrazino-4,5-trimethylene-6-hydroxypyrimidine, 7 parts of ethoxymethylenemalononitrile and 100 parts by volume of Water is boiled for 10 minutes, and is cooled. The separated crystals are recrystallized from normal butanol to obtain 6 parts of 2-(4-cyano-5-aminopyrazol-l-yl)-4,5-trimethylene-6-hydroxypyrimidine, as colourless needles, M.P. 277 C.
Example 39 To a hot solution of 1.6 parts of 2-hydrazino-4,5-trimethylene-6-hydroxypyrimidine in 50 parts by volume of 20% (volume) ethyl alcohol is added a mixture of 1.3 parts of 2-formylcycl0hexanone and 5 parts by volume of ethyl alcohol. After boiling the mixture for a while, the separated 2-(4,5-teuamethylenepyrazol-l-yl)-4,5-trlmethylene 6 hydroxypyrimidine is collected. Recrystallization of the product from diluted ethyl alcohol gives 1.7
parts of needle-like crystals, M.P. l70-173 C.
Example 40 To 50 parts by volume of water are added 8 parts of 2- hydrazino-4,5-t1imethylene 6 hydroxypyrirnidine and 5 parts of acetylacetone. The mixture is boiled for 5 minutes and cooled. The product is filtered and recrystallized from diluted ethyl alcohol to give 9 parts of 2-(3,5 dimethylpyrazol-l-yl)-4,5-trimethylene-6 hydroxypyrimidine, as colourless prisms, M.P. -196 C.
Example 41 To 100 parts by volume of water are added 9 parts each of Z-hydrazino -4,5-tetramethylene-6 hydroxypyrimidine and ethyl ethoxymethylenecyanoacetate. The mixture is boiled for 15 minutes to produce 2-(4-carbethoxy-5-aminopyrazol-l-yl) -4,5-tetramethylene-6- hydroxypyrimidine.
Recrystallization of the product from diluted ethyl alcohol gives 12 parts of colourless needles, M.P. 169171 C.
One of the starting materials, 2-hydrazino-4,5-tetramethylene-6-hydroxypyrimidine, was synthesized from 2- nitroamino-4,5 tetramethylene-6-hydroxypyrimidine and hydrazine hydrate (Journal of the Pharmaceutical Society of Japan, vol. 79 1959), pp. 14774482).
Example 43 To a hot solution of 6 parts of 2-hydrazino-4,5-tetramethylene-6-hydroxypyrimidine in 200 parts by volume of Water is added 6.5 parts of ethyl a-acetyl-fi-ethoxyacrylate. The mixture is boiled for 1 minutes, whereupon 2-(4-carbethoxy S-rnethylpyrazol-l-yl) 4,5-tetramethylene-G-hydroxypyrimidine is produced. The product occurs as colourless needles, M.P. 164166 C., after recrystallization from diluted ethyl alcohol. The yield is 7.2 parts.
Example 44 To a hot solution of 3 parts of 2-hydrazino-4,5-tetramethylene-6-hydroxypyrimidine in 80 parts by volume of 50% (volume) of ethyl alcohol is added 4.2 parts of ethyl a-benzoyl-B-ethoxyacrylate. The mixture is boiled for minutes. After addition of 80 parts by volume of water, the mixture is allowed to stand to separate crystals. The product is recrystallized from a mixture of benzene and ligroin to obtain 4.2 parts of 2-(4-carbethoxy-5-phenylpyrazol-l-yl)-4,5-tetrarnethylene-6-hydroxypyrimidine, as colourless needles, M.P. ISO-152 C.
Example 45 To a mixture of parts by volume of an aqueous solution of sodium hydroxide (1 N) and 20 parts by volume of ethyl alcohol is added 2 parts of 2-(4-carbethoxy-5- arriinopyrazol-l-yl)-4,5 tetramethylene-6-hydroxypyrimidine. After being boiled for minutes, the mixture is concentrated to a little quantity, whereupon the sodium salt of 2-(4-cmboxy-5 aminopyrazol-l-yl)-4,5-tetramethylene-6-hydroxypyrirnidine is obtained as colourless fine crystals, M.P. 300 C. A hot aqueous solution of the product is acidified With hydrochloric acid to separate 2-(4-carboxy-5 aminopyrazol-l-yl) 4,5-tetramethylene- 6-hydroxypyrimidine. Recrystallization of the product from diluted ethylene glycol monethyl ether gives 1 part of colourless needles, M.P. 248 C. (decomposition).
Example 46 A mixture composed of 9 parts of 2-hydrazino- 4,5-tetramethylene-fi-hydroxypyrimidine, 7 parts of ethoxymethylenemalononitrile and 100 parts by volume of water is boiled for 20 minutes to seperate 2-(4-cyano-5-amino pyrazol-1-yl)-4,5 tetrarnethylene-6 hydroxypyrimidine.
Recrystallization of the product from normal butanol gives 7.5 parts of colourless needles, M.P. 2615-2635 C.
Example 47 In 30 parts by volume of water 1.8 parts of Z-hydrazino- 4,5-tetramethylene-6-hydroxypyrimidine is heated, and a mixture of 1.3 parts of 2-formylcyclohexanone and 5 parts by volume of ethyl alcohol is added. The mixture is boiled for. 15 minutes, and the separated crystals are recrystallized from diluted ethyl alcohol to give 2-(4,5-tetramethylenepyrazol 1-yl)-4,5-tetrametl1ylene 6-hydroxypyrimidine, as colourless prisms, M.P. 17ll72 C. The yield is 1.3 parts.
Example 48 To 50 parts by volume of water are added 8 parts of Z-hydrazino-4,5-tetramethylene-6-hydroxypyrimidine and 6 parts of acetylacetone. The mixture is boiled for 10 minutes to separate 2-(3,5-dirnethylpyrazol-1-yl)-4,5-tetramethylene-6-hydroxypyrimidine. The product is recrystallized from a diluted ethyl alcohol to give 8.2 parts of colourless needles, M.P. l63165 C.
poured into ice-water.
12 Example 49 In 200 parts by volume of 50% (t olume) ethyl alcohol, 9 parts of 2-hydrazino-4,5-tetramethylene-G-hydroxypyrirnidine is reacted with 8.1 parts of benzoylacetone for 1 hour under boiling. The crystals obtained through evaporation of the reaction mixture under reduced pressure are recrystallized from ethylene chloride to obtain 8.8 parts I of 2- 3-methyl-5-phenylpyrazol- 1 -yl -4,5 -tetramethylene-6-hydroxypyrimidine. The product occurs as colourless needles, M.P. 1971'99 C.
Example 50 A mixture or" 84 parts of 2-(3,5-dimethylpyrazol-1-yl)- 4-methyl-6-hydroxypyrimidine and 191) parts of phosphorus oxychloride is boiled for 2 hours. Under reduced pressure, the mixture is concentrated. The residue is poured into ice-water. After a while, the solution is neutralized with an aqueous ammonia to produce 2-(3,5- dimethylpyrazol-1-yl)-4 rnethyl-o-chloropyrimidine. An alcoholic solution of the product is filtered, then Water is added thereto, whereupon 50 parts of colourless needles, M.P. 57 C. is obtained. The yield is 50 parts.
Example 51 Example 52 A mixture of 48parts of 2-(3,5-dimethylpyraz0l-1-yl)- 4,5-trimethylene 6-hydroxyprimidine and parts of phosphorus oxychloride is boiled for one hour. After the concentration of the solution under reduced pressure, ice pieces are added to the residue. The mixture is kept standing for a while to obtain .2-(3,5-dimethylpyrazol-lyl)-4,S-trimethylene-G-chloropyrimidine. The product is recrystallized from a mixture of benzene and ligroin,
' whereupon 49.5 pants of colourless needles, M.P. 131- 132 C., are obtained.
Example 53 A mixture of'85 parts of 2-(3,5-dimethylpyrazold-yl)- 4,5-tetramethylene-6-hydroxypyrimidine and 160 parts of phosphorus oxychloride is boiled for 2 hours, and the excess of the phosphorus oxychloride is removed by distilllation under reduced pressure. Thewresidue is poured into ice-water. After a While, the mixture is extracted With benzene. The concentration of the benzene solution gives 53 parts of 2-(3,5-dimethylpyrazol-1-yl)-4,5-tetramethylene-S-chloropyrimidine, as colourless needles, M.P. 132 C.
Example 54 A mixture composed of 5 parts of 2-(3,5-dirnethylpyrazol-l-yl)-4,5-trimethylene-6-chloropyrirnidine, 1.8 parts of thiourea and 40 parts by volume of ethyl alcohol is boiled for 1 hour. After cooling, the separated S-[2-(3,5- dimethylpyrazol l-yl)-4,5-trimethylenepyrimidin 6-yl1- thiouronium hydrochloride is collected. Recrystallization of the product gives 1.6 parts of pale yellow needles which decompose at 207-208 C.
Example 55 To 50 parts by volume of ethyl alcohol are added 5 parts of 2-(3,S-dimethylpyrazol-l-yl)-4,5-tetramethylene- 6-chloropyrimidine and 1.7 parts of thiourea. After boiling for 20 minutes, the mixture is allowed to stand to cool. The separated crystals are recrystallized from acetic 13 acid to obtain S-[2-(3,5-dimethylpyrazol-l-yl)-4,5-tetramethylenepyrirnidin '6 yl] thiouronium hydrochloride which occurs as pale yellow needles, M.P. 205 C. (decomposition). The yield is 2.7 parts.
Example 56 To 50 parts by volume of ethyl alcohol are added 10 parts of 2-(3.5-dimethylpyrazol-l-yl)-4-methyl-6-chloropyrimidine and 4.2 parts of thiourea. The mixture is boiled for 4 hours, then allowed to stand to separate pale yellow crystals showing M.P. 196197 C. after recrystallization from normal butanol). The product is boiled together with 60 parts by volume of an aqueous solution of potassium hydroxide (1 N), then is acidified with acetic acid to separate 2-(3,5-dimethylpyrazol-l-yl) 4-methyl-6- mercaptopyrimidine. Recrystallization of the product from 90% acetic acid gives yellow needles, M.P. 174- 175 C. The yield is 1.3 parts.
Example 57 A mixture composed of 10 parts of 2-(3,5-dimethylpyrazol-l-yl)-4-phenyl-6-chloropyrimidine, 3.2 parts of thiourea and 50 parts by volume of ethyl alcohol is boiled for 6 hours. The mixture is concentrated until its volume becomes about a half, then a large quantity of Water is added. After being left standing for a while, the separated product is collected. Recrystallization of the product from pyridine, then from normal butanol gives 2 parts of 2-(3,5 dimethylpyrazol l-yl)-4- phenyl-6 mercaptopyrimidine, as yellow needles, M.P. 174-175 C.
Example 58 To 18 parts by volume of an aqueous solution of potassium hydroxide (1 N) is added 1.5 parts of S-[2-(3,5- dimethylpyrazol-l-yl) 4,5 tetramethylenepyrimidin-6- yl]-thiouronium hydrochloride. After boiling for 1.5 hours, the mixture is acidified with acetic acid to separate 2-(3,5-dimethylpyrazol-l-yl)-4,5-trimethylene 6 mercaptopyrimidine. Recrystallization of the product from acetic acid gives 0.25 part of pale yellow needles which decompose at 217 C.
Example 59 Example 60 To a mixture of 13 parts by volume of 80% hydrazine hydrate and 20 parts by volume of ethyl alcohol is added 20 parts of 2-(3,5-dimethylpyrazol-1-yl)-4-phenyl-6- chloropyrimidine. As soon as the mixture is heated, it gives 2-(3,5-dimethylpyrazol-l-yl)-4-phenyl-6-hydrazinopyrimidine. Recrystallization of the product from normal butyl alcohol gives 13 parts of colourless needles, M.P. 206207 C.
Example 61 To a mixture of 12 parts by volume of 80% hydrazine hydrate and 12 parts by volume of ethyl alcohol is added 10 parts of 2-(3,5-dimethylpyrazol-1-yl)-4,5-trimethylene-6-chloropyrimidine. After boiling the mixture for 30 minutes, 50 parts by volume of water is added. The product separated is recrystallized from diluted ethyl alcohol to give 7.8 parts of 2-(3,5-dimethylpyrazol-1-yl)- The crystals separated are recrystallized from 14 4,5 trimethylene 6 hydrazinopyrimidine, as colourless long plates, M.P. 185187 C.
Example 62 To a hot solution of 25 parts of 2-(3,5-dimethylpyrazol-l-yl)-4,S-tetramethylene-6-chloropyrimidine in a little quantity of ethyl alcohol is added 15 parts by volume of hydrazine hydrate. After boiling for 5 minutes, the mixture is cooled to separate 2-(3,5-dimethylpyrazol-l-yl)-4,5-tetramethylene 6 hydrazinepyrimidine. The product is recrystallized from diluted ethyl alcohol to give 20 parts of colourless needles, M.P. 182-183" C.
Example 63 A mixture of 5 parts of 2-(3,S-dimethylpyrazol-l-yl)- 4-phenyl-6-hydrazinopyrimidine and 35 parts by volume of 80% formic acid is boiled for 22 hours and then concentrated. The residue is recrystallized from diluted acetic acid to give 1.7 parts of 2-(3,5-dimethylpyrazol-1- yl)-4-phenyl-6-formylhydrazinopyrimidine which occurs as colourless needles, M.P. 245-246" C.
Example 64 In an autoclave, a mixture of 10 parts of 2-(3,5-di met'hylpyrazol-l-yl)-4-methyl-6-chloropy1imidine and 33 parts by volume of 33% aqueous solution of dimethylamine is heated for 1 hour at 98 to 102 C. After being cooled, the mixture is extracted with ether. The ethereal solution is concentrated to obtain 2-(3,5-dimethylpyrazol-l-yl)-4-methyl 6 dimethylaminopyrimidine. The product is recrystallized from ligroin to give 7.2 parts of needle-like crystals, M.P. 87-88 C.
Example 65 A mixture composed of 10 parts of 2-(3,5-dimethylpyrazol-l-yl)-4-methy1-6-chloropyrimidine, 6.1 parts of diethanolamine and 6.2 parts by volume of anhydrous potassium carbonate is heated at about 190 C. for 20 minutes. After cooling the mixture, 60 parts by volume of water is added to separate 2-(3,5-dimethylpyrazol-l-yl) 4 methyl-6-bis-(fi-hydroxyethyl) -,aminopyrimidine. The product is recrystallized from water to give 4 parts of colourless needles, M.P. 75-77 C.
Example 66 A mixture composed of 10 parts of 2-(3,5-dimethylpyrazol-l-yl) -4-methyl-6-chloropyrimidine, 19.1 parts of piperidine and 45 parts by volume of water is boiled for 1 hour. After cooling, the mixture is extracted with ether, and from the ethereal layer, the solvent is removed. The residue is distilled under reduced pressure to obtain 2-(3,5-dimethylpyrazol-1-yl)-4-methyl 6 piperidinopyrimidine, B.P. 200-205 C. (0.3 millimeter Hg). The yield is 7.4 parts.
Having thus disclosed the invention what is claimed is:
1. 2-(4-carbethoxy-5-aminopyrazol-l-yl) 4 methyl- 6-hydroxypyrimidine.
2. 2-(4-carbethoxy-S-methylpyrazol-1-yl) 4 methyl- 6-hydroxypyrimidine.
3. 2-(4-carbethoxy-S-phenylpyrazol-l-yl) 4 methyl- 6-hydroxypyrimidine.
4. 2-(4-cyano-5-aminopyrazol-l-yl) -4-methyl 6 hydroxypyrimidine.
5. 2-(4,5-tetramethylenepyrazol-l-yl) 4 methyl-6- hydroxypyrimidine.
6. 2-(4-carboxy-5-aminopyrazol-l-yl) 4 methyl-6- hydroxypyrimidine.
7. 2-(3,5-dimethylpyrazol 1 yl) 4 methyl 6 hydroxypyrimidine.
8. A sodium salt of the compound claimed in claim 6.
No references cited.
UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,040,047 June 19 1962 Kenzo Sirakawa i It is hereby certified that error appeazce in the above numbered pat.- ent requiring correction and that the said Letters Patent should read as corrected below.
Column 1, line 10, for "the apeutic" read therapeutic column 4, line 46, for "Recrystallation" read Recrystallization line 56, for "3hydrazino" read 2-hydrazinocolumn 5, line 7, for "-cyanoapyrimidine" read -cyanopyrimidine column 7, line 29 for "3:5" read 3.5 column 8 line 36 for "alochol" read alcohol Signed and sealed this 20th day of November 1962.
(SEAL) meat:
DAVID L. LADD Commissioner of Patents ERNEST W. SWIDER testing Officer

Claims (1)

1. 2-(4-CARBETHOXY-5-AMINOPYRAZOL-1-YL) -4-METHYL6-HYDROXYPYRIMIDINE.
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Cited By (15)

* Cited by examiner, † Cited by third party
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US3106467A (en) * 1960-10-19 1963-10-08 Eastman Kodak Co Bis-pyrazoles as antifoggants for photographic silver halide emulsions
US3161515A (en) * 1962-12-18 1964-12-15 Gen Aniline & Film Corp Stabilized light-sensitive silver halide emulsions
US3426023A (en) * 1965-04-23 1969-02-04 Daiichi Seiyaku Co 1-(4'-methyl-6'-methoxy-2'-pyrimidinyl) 3-methyl-5-methoxypyrazole
US4201582A (en) * 1974-05-02 1980-05-06 Eastman Kodak Company Photothermographic and thermographic element, composition and process
US4268627A (en) * 1979-06-15 1981-05-19 Fuji Photo Film Co., Ltd. Photographic light-sensitive material
US4405743A (en) * 1979-08-31 1983-09-20 Hokko Chemical Industry Co., Ltd. Pyrazolylpyrimidine derivatives
EP0293743A1 (en) * 1987-06-03 1988-12-07 BASF Aktiengesellschaft Substituted 5-amino-pyrazoles and fungicides containing them
US4849424A (en) * 1986-08-05 1989-07-18 Nissin Shokuhin Kabushiki Kaisha Pyrimidine derivatives
WO1992019615A2 (en) * 1991-04-24 1992-11-12 E.I. Du Pont De Nemours And Company Fungicidal pyrazoles, pyrazolines and tetrahydropyridazines
US5292744A (en) * 1990-07-24 1994-03-08 Bayer Aktiengesellschaft 1-[pyri(mi)dyl-(2)]-5-hydroxy-pyrazole microbicides
WO2000042025A1 (en) * 1999-01-14 2000-07-20 Meiji Seika Kaisha, Ltd. Poly(adp-ribose) polymerase inhibitors consisting of pyrimidine derivatives
WO2005003099A2 (en) * 2003-07-02 2005-01-13 Vertex Pharmaceuticals Incorporated Pyrimidines useful as modulators of voltage-gated ion channels
US20080255147A1 (en) * 2005-05-31 2008-10-16 Dean Wilson Heterocycles useful as modulators of ion channels
US20110183978A1 (en) * 2009-10-09 2011-07-28 Bayer Cropscience Ag Phenylpyri(mi)dinylazoles
US9963462B2 (en) 2015-09-30 2018-05-08 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Sepiapterin reductase inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
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Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3106467A (en) * 1960-10-19 1963-10-08 Eastman Kodak Co Bis-pyrazoles as antifoggants for photographic silver halide emulsions
US3161515A (en) * 1962-12-18 1964-12-15 Gen Aniline & Film Corp Stabilized light-sensitive silver halide emulsions
US3426023A (en) * 1965-04-23 1969-02-04 Daiichi Seiyaku Co 1-(4'-methyl-6'-methoxy-2'-pyrimidinyl) 3-methyl-5-methoxypyrazole
US4201582A (en) * 1974-05-02 1980-05-06 Eastman Kodak Company Photothermographic and thermographic element, composition and process
US4268627A (en) * 1979-06-15 1981-05-19 Fuji Photo Film Co., Ltd. Photographic light-sensitive material
US4405743A (en) * 1979-08-31 1983-09-20 Hokko Chemical Industry Co., Ltd. Pyrazolylpyrimidine derivatives
US4849424A (en) * 1986-08-05 1989-07-18 Nissin Shokuhin Kabushiki Kaisha Pyrimidine derivatives
EP0293743A1 (en) * 1987-06-03 1988-12-07 BASF Aktiengesellschaft Substituted 5-amino-pyrazoles and fungicides containing them
US5292744A (en) * 1990-07-24 1994-03-08 Bayer Aktiengesellschaft 1-[pyri(mi)dyl-(2)]-5-hydroxy-pyrazole microbicides
WO1992019615A2 (en) * 1991-04-24 1992-11-12 E.I. Du Pont De Nemours And Company Fungicidal pyrazoles, pyrazolines and tetrahydropyridazines
EP0515041A2 (en) * 1991-04-24 1992-11-25 E.I. Du Pont De Nemours And Company Fungicidal pyrazoles, pyrazolines and tetrahydropyridazines
WO1992019615A3 (en) * 1991-04-24 1993-01-21 Du Pont Fungicidal pyrazoles, pyrazolines and tetrahydropyridazines
EP0515041A3 (en) * 1991-04-24 1993-04-28 E.I. Du Pont De Nemours And Company Fungicidal pyrazoles, pyrazolines and tetrahydropyridazines
WO2000042025A1 (en) * 1999-01-14 2000-07-20 Meiji Seika Kaisha, Ltd. Poly(adp-ribose) polymerase inhibitors consisting of pyrimidine derivatives
WO2005003099A2 (en) * 2003-07-02 2005-01-13 Vertex Pharmaceuticals Incorporated Pyrimidines useful as modulators of voltage-gated ion channels
US8324220B2 (en) 2003-07-02 2012-12-04 Vertex Pharmaceuticals Incorporated Pyrimidines useful as modulators of voltage-gated ion channels
WO2005003099A3 (en) * 2003-07-02 2005-05-12 Vertex Pharma Pyrimidines useful as modulators of voltage-gated ion channels
US20050049247A1 (en) * 2003-07-02 2005-03-03 Wilson Dean Mitchell Pyrimidines useful as modulators of voltage-gated ion channels
US7816529B2 (en) 2003-07-02 2010-10-19 Vertex Pharmaceuticals Incorporated Pyrimidines useful as modulators of voltage-gated ion channels
US20110003814A1 (en) * 2003-07-02 2011-01-06 Vertex Pharmaceuticals Incorporated Pyrimidines useful as modulators of voltage-gated ion channels
US7880008B2 (en) 2005-05-31 2011-02-01 Vertex Pharmaceuticals Incorporated Heterocycles useful as modulators of ion channels
US20110059984A1 (en) * 2005-05-31 2011-03-10 Vertex Pharmaceuticals Incorporated Heterocycles useful as modulators of ion channels
US20080255147A1 (en) * 2005-05-31 2008-10-16 Dean Wilson Heterocycles useful as modulators of ion channels
US8329702B2 (en) 2005-05-31 2012-12-11 Vertex Pharmaceuticals Incorporated Heterocycles useful as modulators of ion channels
US20110183978A1 (en) * 2009-10-09 2011-07-28 Bayer Cropscience Ag Phenylpyri(mi)dinylazoles
WO2011042389A3 (en) * 2009-10-09 2012-08-16 Bayer Cropscience Ag Phenylpyri(mi)dinylazoles and their use as fungicides
JP2013507334A (en) * 2009-10-09 2013-03-04 バイエル・クロップサイエンス・アーゲー Phenylpyri (mi) dinirazoles
EP2784073A1 (en) * 2009-10-09 2014-10-01 Bayer CropScience AG 3-phenyl-4-pyri(mi)dinyl-1h-pyrazoles and their use as fungicides
US9963462B2 (en) 2015-09-30 2018-05-08 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Sepiapterin reductase inhibitors

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