SU498908A3 - The method of producing pyrimidinone derivatives - Google Patents
The method of producing pyrimidinone derivativesInfo
- Publication number
- SU498908A3 SU498908A3 SU1839308A SU1839308A SU498908A3 SU 498908 A3 SU498908 A3 SU 498908A3 SU 1839308 A SU1839308 A SU 1839308A SU 1839308 A SU1839308 A SU 1839308A SU 498908 A3 SU498908 A3 SU 498908A3
- Authority
- SU
- USSR - Soviet Union
- Prior art keywords
- producing
- methyl
- pyrimidinone derivatives
- derivatives
- ethanol
- Prior art date
Links
- 238000000034 method Methods 0.000 title description 7
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical class OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 title description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 150000003839 salts Chemical class 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 5
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 150000001340 alkali metals Chemical class 0.000 description 5
- 239000004202 carbamide Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- WOZVHXUHUFLZGK-UHFFFAOYSA-N dimethyl terephthalate Chemical compound COC(=O)C1=CC=C(C(=O)OC)C=C1 WOZVHXUHUFLZGK-UHFFFAOYSA-N 0.000 description 4
- 150000002431 hydrogen Chemical group 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- -1 tatrate Chemical compound 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- IISGAJPGMKEIAZ-UHFFFAOYSA-N 2,2-diethoxyethoxybenzene Chemical compound CCOC(OCC)COC1=CC=CC=C1 IISGAJPGMKEIAZ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical class C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 1
- YCIPQJTZJGUXND-UHFFFAOYSA-N Aglaia odorata Alkaloid Natural products C1=CC(OC)=CC=C1C1(C(C=2C(=O)N3CCCC3=NC=22)C=3C=CC=CC=3)C2(O)C2=C(OC)C=C(OC)C=C2O1 YCIPQJTZJGUXND-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 240000006240 Linum usitatissimum Species 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- XEAGEWUJVBERFN-UHFFFAOYSA-N [Cl].CC=O Chemical compound [Cl].CC=O XEAGEWUJVBERFN-UHFFFAOYSA-N 0.000 description 1
- UCUJUFDOQOJLBE-UHFFFAOYSA-N [Cl].[Ca] Chemical compound [Cl].[Ca] UCUJUFDOQOJLBE-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- BYNPVFHVZRNRQD-UHFFFAOYSA-N acetic acid;benzene Chemical compound CC(O)=O.C1=CC=CC=C1 BYNPVFHVZRNRQD-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 239000012022 methylating agents Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 150000002913 oxalic acids Chemical class 0.000 description 1
- RKHQZMOCQHXUBC-UHFFFAOYSA-N phenol;potassium Chemical compound [K].OC1=CC=CC=C1 RKHQZMOCQHXUBC-UHFFFAOYSA-N 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000004540 pour-on Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- XQTLDIFVVHJORV-UHFFFAOYSA-N tecnazene Chemical compound [O-][N+](=O)C1=C(Cl)C(Cl)=CC(Cl)=C1Cl XQTLDIFVVHJORV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
- C07D239/56—One oxygen atom and one sulfur atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- 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
- C07D239/52—Two oxygen 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
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
Изобретение относитс к способу получе-« НИ53 новых соединений - производных пири . мидинона, обладающих биологической акти&ностью и превосход щих по своим свойствам ближайшие аналоги. Осноанный на известной реакции образое- i вани пиримидинового кольца при циклиза: дии аминогруппы с карбонильным соединен нием в присутствии спиртового раствора щелочного металла, предлагаемый способ попу чени производных пиримидинона общей формулы R - водород, метил; R - кислог Rg - водород, галоген, i род или сера; К е. водород, хлор, метил, тр№фторметил , или их солей, заключаетс в том, что соединение общей формулы 2 вышеуказан-, ные значени ; R ,., - низший С.| С„-«лкил, обрабатывают мочевиной в присутствии спиртового раствора . щедоч-. ного металла, при необходимости превраща.-. ют полученное соединение в соль щелочЬогб или щелочноземельного металла и метилиг, руют ее до 1 - етилпроизводного и выдел ют целевой продукт в свободном виде или в виде соли известным приемом. Обычно в качестве щелочного металла используют натрий, :. а в качестве метили-, рующего arjBHTa метилйодид. Дл синтеза производных пиримидинона из незал1ей1енного или замещенного фенола.The invention relates to a process for the production of N53 new compounds - pyri derivatives. midinone with biological activity and superior in their properties to the closest analogues. Based on the well-known reaction of forming a pyrimidine ring during cyclisation of the amino group with a carbonyl compound in the presence of an alcoholic solution of an alkali metal, the proposed method for producing pyrimidine derivatives of the general formula R is hydrogen, methyl; R is acid; Rg is hydrogen, halogen, i genus or sulfur; To e. Hydrogen, chlorine, methyl, trfluoromethyl, or their salts, is that the compound of the general formula 2 is as above; R,., - lower S. | With „-“ lkil, treated with urea in the presence of an alcohol solution. generous- if necessary, turning .-. The resulting compound is added to a salt of alkali metal or alkaline earth metal and methyl, rut it to 1-methyl derivative and the desired product is isolated in free form or as a salt by a known technique. Usually sodium is used as alkali metal,:. and methyl-iodide arjBHTa as methyl iodide. For the synthesis of pyrimidinone derivatives from single or substituted phenol.
напримерП - хлорфенола, конденсациейegP - chlorophenol, by condensation
с едким кали получают фенол т кали , конденсируют его-с дизтилацеталем хлор ацетальдегида и получают диэтилацеталь феноксиацетальдегида, который очищаютpotassium hydroxide is used to obtain potassium phenol t, chlorine acetaldehyde is condensed with acetaldehyde with distiyl acetal and get phenoxy acetaldehyde diethylacetal, which is purified
экстракцией или промывкой водным раствог ром едкого натра и .высушивают.extraction or washing with an aqueous solution of caustic soda and drying.
Высушенный продукт постепенно добав л ют к реагенту, -полученному при умеренном нагревании N , N диметилформамида с хлорокисью фосфора, нагревают на па« ровой бане и выдел ю1Т 2т енокси-З диме-тиламиноакролеин , который перекристаллизоБывают из этанола или ацетона.The dried product is gradually added to the reagent, obtained with moderate heating of N, N dimethylformamide with phosphorus oxychloride, heated on a steam bath and the recovery of 1T 2m enoxy-3 dimethylaminoacrolein, which is recrystallized from ethanol or acetone.
Полученное производное акролеина до.-бавл ют к продукту взаимодействи этанола гранулированного металл1гческого натри и мочевины, нагревают 24г-48 час с обратным холодильником, подкисл ют смесь и кристалглизуют )еноксиг 2г-. 1 Н.-.пирпмидинон, например 5( П ХЛорфенокси). пиримидинон из смеси уксусна кислота-, бензол,The resulting acrolein derivative is doped to the product of the interaction of ethanol granulated metal sodium and urea, heated under reflux for 24 g-48 h, the mixture is acidified and crystallized) enoxig 2g-. 1 H.-. Perfmidinone, for example, 5 (P HLorfenoxy). pyrimidinone from acetic acid-, benzene,
Производные пиримидинона, в которых R - метил получают при обработке соответствующ й сопи щелочного или щелочноземельного металла гор чим метилйодвдом и последующей кристаллизации продукта из pacTBopтел , такого, как этанол.Pyrimidinone derivatives in which R is methyl is obtained by treating the corresponding alkali or alkaline earth metal mixture with hot methyl iodide and the subsequent crystallization of the product from pacTBoptel, such as ethanol.
Конденсацией тиофенола и 2-.хлор 3--ди-« метиламиноакролеина получают 2- гиофеног кси-З-диметиламиноакролеин, который очищают кристаллизацией из этиладетата илиBy condensation of thiophenol and 2-chloro 3-di- “methylamino-acrolein, 2-hyopheno-x-3-dimethylamino-acrolein is obtained, which is purified by crystallization from ethylamine or
этанола и добавл ют к продукту взаимодействил этанола, гранулированного металлического натри и мочевины, нагревают 12f-.24 час с обратным холодильником, подкисл ют и. кристаллизуют 5 7Иофенбкси-2 1Н -пирИ мидинон из этанола или этилацетата.ethanol and ethanol, granulated metallic sodium and urea are added to the product, heated under reflux for 12f-.24 hours, acidified and. 5 7 Iofenbxy-2 1N -pyrI midinone is crystallized from ethanol or ethyl acetate.
Дл производных пиримидинона, получе ньгх предлагае мым Способом, возможна ке- то««енолька таутомери .For the pyrimidinone derivatives obtained by the proposed Method, ketomethanol is possible.
из солей производных пиримидинона мо- гуг быть получены гидрохлорид, гидробром МИД; гидройодид, сульфат, бисульфат, фоофат , кислый фосфат, ацетат, малеат, фума« рат, оксалат, лактат, татрат, цитрат, глюконат , сахарат и - голуольсульфонат. На- ибольщее применение наход т растворимые ... соли, например соли лимонной, винной, маг-. леиновой, фумаровой и щавелевой кислоты, а соли аммони и соли с нетоксичными металлами, такими как натрий, кальций и ка.пий.from the salts of pyrimidinone derivatives, hydrochloride and hydrobromic MFA can be obtained; hydroiodide, sulphate, bisulphate, foofate, acid phosphate, acetate, maleate, fumite, oxalate, lactate, tatrate, citrate, gluconate, saharit, and - Gluol sulphonate. The most widely used are soluble ... salts, for example, citric, tartaric, and mag. ammonium and oxalic and oxalic acids, and ammonium salts and salts with non-toxic metals, such as sodium, calcium, and ca.
П р и м е р. 225 мл (3,3 моль) сухо«го перегнанного диметилтерефталата помегщают в высущенную над пламенем трехгор лую колбу на 3 л, снабженную О -Аобразной мешалкой, капельной воронкой сPRI me R. 225 ml (3.3 mol) of dry distilled dimethyl terephthalate are poured into a 3-liter three-necked flask above the flame and equipped with an O-shaped stirrer, with a dropping funnel
компенсированным давлеш1ем над уровнем жидкости в ней, конденсатором и хлоркальциевой трубкой, в течение ЗО-45 мин при охлаждении льдом добавл ют 246,9 мл (2,7 моль) хлорокиси фосфора, нагревают до 25°С и перемешивают 1 час. При работе с очень сухой аппаратурой образуетс белое кристаллическое комплексное соединение, в противном случае раствор превращаетс в в зкую оранжевую массу. Затем в течение 3-5 кпш добавл ют 220,2 г (0,9 моль) диэтилацетал ГЬ-Хлорфеноксиацетальдегида, перемешивают 10 ыпн при комнатной температуре , осторожно нагревают на вод ной бане до перехода окраски в СБетло - ;ерую и по влени пузырьков газа. В течение нескольких минут интенсивно выдел етс хлористый водород и раствор становитс черным . Когда выделение хлористого водорода почти закончитс , соедин ют конденсатор с хлоркальциевой трубкой, нагревают смесь 5-6 час на паровой , охлаждают, постепенно выливают на измельченный лед, перемешивают , добавл ют насыщенный раствор углекислого кали до рН 10 нагревают 2 час на паровой бане с .ным раствот ром этанола в бензоле.246.9 ml (2.7 mol) of phosphorus oxychloride are added during ice cooling with ice cooling over a level of liquid in it, a condenser and a calcium chloride tube, during an MHR of 45 minutes, with ice cooling. The mixture is heated to 25 ° C and stirred for 1 hour. When working with a very dry apparatus, a white crystalline complex is formed, otherwise the solution turns into a viscous orange mass. 220.2 g (0.9 mol) diethyl acetal Gb-Chlorophenoxyacetaldehyde is then added over 3-5 kps, the mixture is stirred at room temperature for 10 sp, heated gently in a water bath until the color turns into bbl; . Within a few minutes, hydrogen chloride was vigorously evolved and the solution turned black. When the release of hydrogen chloride is almost complete, connect the condenser with a calcium chloride tube, heat the mixture for 5-6 hours on steam, cool, gradually pour on crushed ice, stir, add saturated potassium carbonate solution to pH 10 and heat it for 2 hours on a steam bath. ethanol in benzene.
Верхний черный орган1гческий слой л ют, концентрируют в роторном испарителе, наблюда образование кор1тчневых кристаллов, повыашют текшературу бани до 9О°С и пу- тем продолжительного откачивани полно стью удал ют воду и непрореагировавший диметилтерефталат. Кор тчневые кристаллы раствор ют в хлороформе, фильтруют paciv вор, упаривают, нагревают остаток 48 час на паровой бане и высоком вакууме и пО лучают 191,4 г (95%) коричневых кристал.лов 2т-({1-хлорфенокси).-|3«диметиламиноакрор« леина, который по данным ЯМР не содержит примесей.The upper black organic layer is concentrated in a rotary evaporator, the formation of brown crystals is observed, the texture of the bath is increased to 9 ° C and the water and unreacted dimethyl terephthalate are completely removed by continuous pumping. The brown crystals are dissolved in chloroform, the thief is filtered with a paciv, evaporated, the residue is heated for 48 hours on a steam bath and high vacuum, and 191.4 g (95%) of brown crystals of 2 t - ({1-chlorophenoxy) are obtained .- | 3 "dimethylaminoacror" Lein, which according to NMR data does not contain impurities.
В трехгорлую колбу на 2 л, снабженную О -образной мешалкой, конденсатором и хлор кальциевой трубкой, помещают 500 мл а&In a three-necked 2-liter flask equipped with an O-shaped stirrer, a condenser, and a chlorine-calcium tube, 500 ml of a &
солютного этанола, добавл ют 23 г (1,О моль) гранулированного металлического натри и по окончании через воронку дл введени сыпучих веществ быст ро добавл ют 6О,О г (1 мо/гь) мочевины, перемащивают 1О мин, ввод т 112,75 г 2-.( п --хлорфенокси)-Згчдиметиламиноакро- леина, нагревают 24-48 час с обратным холодильником, охлаждают до комнатной тем-пературы и выливают на 6ОО мл лед ной воды. К полученному прозрачному коричне-; ому раствору добавл ют лед ную уксусную, ислоту до рН 5, отдел ют хлопьевидный . оричневый осадок на воронке Бюхнера и олучают 114 г влажного твердого вещесг- ва. После перекристаллизации из смеси уксусна кислота-бензол (1:1) выдел ют 53,9 г светло-коричневого порошка 5-(fi «хлорфенокси)-2« 1Н пиримидинона, т. пл 220-221°С. Вычислено, %: С 53,95; Ч 3,17; N12,58. Найдено, %: С 53,85; Н 3,4О; N12,39. Предмет изобретени Способ получени производных пиримид нона общей формулы R - кисл где R -1 - водород, метил} род или сера; галоген, тил; RH водород, хлор, метил, трифт , 6 етил, или их солей, отл и чающий тем, что соединение общей R5-c CH-N;f INI , R, , R. имеют вышеуказанные где R значени ; R и R низший С.-С алкил, 56J. о обрабатывают мочевиной в присутствии спиртового раствора щелочного металла, при необходимости превращают пол -ченное соединение в соль щелочного или шелочноземель ного металла и метилируют ее до 1-.мети/ь. производного и вьщел ют целевой продукт в свободном виде или в виде соли известным приемом. 2.Способ по п. 1, о т л и ч а ю щ и йс тем, что в качестве щелочного металла используют натрий, 3.Способ по пп. 1 и 2, о т л и ч а -. ю щ и и с тем, что в качестве метилирующего агента используют метилйодид.of ethanol, 23 g (1, O mol) of granulated metallic sodium are added, and at the end, 6O, O g (1 mo / g) of urea are quickly added to introduce granular substances, 112.75 are added g 2 -. (p - chlorophenoxy) -Ggdimethylaminoacrolein, heated for 24-48 hours under reflux, cooled to room temperature and poured onto 6OO ml of ice water. To the resulting clear brown; To the solution, ice-cold acetic acid is added to the acid to pH 5, flaky. brown precipitate on a Buchner funnel and yield 114 g of a wet solid. After recrystallization from acetic acid-benzene (1: 1), 53.9 g of light brown powder of 5- (fi " chlorophenoxy) -2 " 1H pyrimidinone are isolated, mp 220-221 ° C. Calculated,%: C 53.95; H 3.17; N12.58. Found,%: C 53.85; H 3,4O; N12.39. The subject of the invention. A method for producing pyrimide non derivatives of the general formula: R is acid where R -1 is hydrogen, methyl} is a genus or sulfur; halogen, thyl; RH is hydrogen, chlorine, methyl, trift, 6 ethyl, or their salts, in that the compound with total R5-c CH-N; fINI, R,, R. has the above R where; R and R lower C.-C alkyl, 56J. They are treated with urea in the presence of an alcoholic solution of an alkali metal, if necessary, convert the resulting compound to the salt of an alkaline or silk-earth metal and methylate it to 1-methy. the derivative and the desired product in free form or as a salt by a known method. 2. The method according to claim 1, of which is sodium, as the alkali metal, 3. The method according to paragraphs. 1 and 2, about t of l and h and -. This is because methyl iodide is used as the methylating agent.
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SU1839308A SU498908A3 (en) | 1971-10-29 | 1972-10-13 | The method of producing pyrimidinone derivatives |
SU2008490A SU505362A3 (en) | 1971-10-29 | 1974-03-26 | The method of producing oxypyrimidines |
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DE3222914A1 (en) * | 1982-06-18 | 1983-12-22 | Beiersdorf Ag, 2000 Hamburg | SUBSTITUTED 5-PHENYLTHIO-6-AMINO-PYRIMIDINONE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE, AND PREPARATIONS CONTAINING THESE COMPOUNDS |
JPH0655686B2 (en) * | 1988-08-30 | 1994-07-27 | 宇部興産株式会社 | Process for producing p-bromophenoxyacetaldehyde dialkyl acetals |
NZ565955A (en) | 2005-08-22 | 2011-08-26 | Melior Pharmaceuticals I Inc | Methods and formulations for modulating lyn kinase activity and treating related disorders |
US8552184B2 (en) | 2008-07-03 | 2013-10-08 | Melior Pharmaceuticals I, Inc. | Compounds and methods for treating disorders related to glucose metabolism |
WO2011150300A1 (en) | 2010-05-28 | 2011-12-01 | Melior Pharmaceuticals I, Inc. | Prevention of pancreatic beta cell degeneration |
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