Method of obtaining heminal dihalogen derivatives of condensed pyrimidin-4-ons,racemates or opticall

专利摘要:
1. A method for the preparation of geminal dihalide derivatives of condensed pyrimidin-4-ones of the general formula I D (SI where X is chlorine, bromine; n is O, 1, 2; R is hydrogen, methyl, ethyl, which can be in positions 6, 7 and 8; Rj is a carboxy,., Carboethoxy group, carbonitrile, bromine, methyl, ethyl, phenyl; R3 is hydrogen, methyl, STIW, racemates, or optically active antipodes, wherein the racemic or optically active compound of the general formula II YY "where Y is hydrogen, chlorine 1-bromine. R, RX and RJ have the indicated meanings to react with the halogenating agent if the Y is chlorine or bromine, the halogenating agent is taken in an equimolar amount, if Y is hydrogen, the galorester is taken in a double equimolar quantity, the process is carried out in an inert organic solvent, the target product is isolated as racemates or optically active antipodes 2. Method POP.1, characterized in that bromine, sd iS chlorine, sulphuryl chloride, N-bromine (chlorine), succinimide, perbromide, pyridium bromide, are used as a halogenating agent. 3. Method POP1, characterized in that chloroform, dichloromethane, glacial acetic acid is used as an inert organic solvent. 4. Method POP1, characterized in that the process is carried out in the presence of a bound acid, an alkali metal acetate agent.
公开号:SU1151210A3
申请号:SU802920002
申请日:1980-05-08
公开日:1985-04-15
发明作者:Хермец Иштван；Брайнинг Тибор；Вашвари Лелле；Хорват Агнеш；Месарош Золтан；Биттер Иштван；Кекеши Иожеф
申请人:Хиноин Дьедьсер Еш Ведьесети Термекек Дьяра Рт (Инопредприятие)；
IPC主号:

专利说明:

The invention relates to a process for the preparation of new compounds — geminal dihalide derivatives of condensed pyrimidin-4-ones, racemates, or optically active antapodes, which can be used as intermediate products in the synthesis of 9-phenylamino or 9-aminopyrido (1,2-a ) pyrimidines, biologically active compounds with anti-allergic, anti-anti-inflammatory activity.  There is a known method for the halogenation of various organic compounds, for example cyclic alkyls, by replacing hydrogen with halogen.  The process is conducted in an organic solvent, for example, chloroform, acetic acid, and halides, N-halo and succinimides, sulfuryl chloride, pyridium bromide, perbromide, GO are used as halogenating agents.  The purpose of the invention is a method of obtaining new geminal dihalide derivatives of condensed pyrimidine A-ones, which are intermediate products in the synthesis of biologically active pyrido (1,2-a) pyrimidines with anti-allergic and anti-asthmatic activity. The goal is achieved by a method for producing geminal dihaloid derivatives condensed pyrimidin-4-ones of general formula I XX V.   About where X is chlorine, bromine; p - O, 1, 2; R, is hydrogen, metnp, ethyl, which may be in positions 6, 7, and 8; R, - carboxy-, carbethoxy group, carbamoyl, carbonitrile, bromine, methyl, ethyl, phenyl, R ,, - hydrogen, methyl, ethyl, racemates or optically active types, concluded that racemic or optically active compounds are common Formula II Y, Yf m, O where Y is hydrogen, chlorine or bromine, n, R, R, and Rj have the indicated meanings, are reacted with a halogenaryl agent, and if Y is chlorine or bromine, the halogenating agent is taken in an equimolar amount If Y is hydrogen, the halogenating agent is taken in two. an equimolar amount, the process is carried out in an inert organic solvent, the target product is isolated in the form of racemates or optically active antipodes.  Bromine, chlorine, sulphuryl chloride, N-bromo- (or chloro) succinimide, and perbromide pyridium bromide are used as a halogenating agent.  Chloroform, dichloromethane, and glacial acetic acid are used as the organic solvent.  The process is carried out in the presence of an alkali metal acetate agent.  Example 1  To a solution of 1.4 g (0.005 mol) of 9-bromo-6-methyl-4-keto6, 7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid in 15 ml of chloroform dried over sodium sulfate, a solution of 0.3 ml (0.005 mol) of bromine in 5 ml of chloroform is added dropwise with stirring at room temperature.  Then the reaction mixture was stirred at room temperature for half an hour and left overnight.  The precipitated crystals are filtered and washed with a small amount of chloroform.  10 ml of water are added to the precipitate and the MP of chloroform is laid, the pH of the aqueous phase is set to 2 with 3 wt. The sodium bicarbonate solution was mixed with stirring, the organic phase was separated, the aqueous phase was treated with chloroform (2 x 10 ml).  The combined organic phases are dried over anhydrous sodium sulphate, waste. put the solvent under reduced pressure.  The residue is recrystallized from methanol.  Obtain 0.3 g (16.4%) of 9 9-dibromo-6-methyl-4-keto, 7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid, t . square  165-16bS  Calculated,%: C 32.81; H 2.75; N 7.65; Br 43.65.  C, OH, K20ZVGg Found,%: C 33.22; H 2.78; N 7.65; Br 43.58.  Example 2  To a solution of 1.5 g (0.005 mol) of 9-bromo-6-methyl-4-keto, 6,7,8,9-tetrahydro-4H-pyrido- (1,2-a) 3 pyrimidine-3-carboxylic Acids in 30 ml of glacial acetic acid solution of 0.3 ml (0.005 mol) of bromine in 2 ml of glacial acetic acid are added dropwise with stirring at room temperature.  The reaction mixture is then stirred at 40-60 for half an hour, after which the hydroxy acid is distilled off under reduced pressure.  10 m of water and 10 ml of chloroform are added to the residue and the pH of the aqueous phase is set to 2 with 10% sodium bicarbonate solution with stirring.  The organic phase is separated. the aqueous phase is treated with chloroform (2x10 ml).  Drying the combined organic phases over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure.  The residue is recrystallized from methanol.  Obtain 0.8 g (53,8%) 9,9-dibromo-6-methyl-4-keto-6, 7,8,9-tetrahydro-4H-pyrido- (1,2-a) -pyrimidine-3 carboxylic acid melting at 164-166 C.  The product does not give any melting point depression when mixed with the product of example 1.  I Example 3.  To a solution of 14 g of crystalline sodium acetate and 10.4 g (0.05 mol) of 6-methyl-4-keto6, 7,8,9-tetrahydro-4H-pyrido (1,2-a pyrimidine-3-carboxylic acid in 100 ml of glacial acetic acid was added dropwise 5.4 ml (0.1 mol) of bromine slowly while stirring at room temperature.  Stirring of the reaction mixture is continued for 2 hours at room temperature, after which the solvent is distilled off under reduced pressure.  50 ml of water and 50 ml of chloroform are added to the residue and the pH of the aqueous phase is adjusted to 2 with 5% sodium bicarbonate solution with stirring.  The organic phase is separated, the aqueous phase is treated with chloroform (2 x 50 ml).  The combined organic phases are dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure. The residue is crystallized from methanol.  9.4 g (51.3%) of 9,9-dibromo-6-methyl-4-keto-6, 7,8,9-tetrahydro-4H-pyrido- (1,2-a) pyrimidine-Zcarboxylic acid are obtained melting at 165-166 C.  The product does not give any melting point depression when mixed with the product of example 1 or 2.  Example 4  The process is carried out under the conditions of example 2, replacing racemic / 1 / -9-bromo-6-methyl-4-keto-6, 7,8,9-tetrahydro-4H-pyrido- (1,2-a) pyrimidine-3 -carboxylic acid on optically active (+) 9-bromo-6methyl-4-keto-6, 7,8,9-tetrahydro-4Npyrido (1, 2-a) pyrimidine-3-carboxylic acid, is obtained ( +) - 9,9-dibromo-6-methyl-4-keto-6, 7,8,9-tetrahydro-4H-pyrido- (1,2-a) pyrimidine-3-carboxylic acid, melting at 157-159 0 .  Yield 49.0% (o).  , 5 ° (, methanol).  Calculated,%: C 32.81; H 2.75; N 7.65; Br 43.66.  MoH, about 20ZVG2 Found,%: C 33.11; H 2.60; N 7.56; Br 43.44.  Example 5  The process is conducted under the conditions of example 3, replacing racemic (1) -6-methyl-4-keto-6,7,8,9 tetrahydro-4H-pyrido- (1,2-a) -pyrimidine-3-carboxylic acid with an optical active (-) - 6-methyl-4-keto-6,7,8,9 tetrahydro-4H-pyrido- (1,2-a) -pyrimidine-3-carboxylic acid, get (+) - 9,9-dibrom -6-methyl-4-keto-6,7, 8, 9-tetrahydro-4H-pyrido- (1,2-a) -pyrimidine-3-carboxylic acid, melting at 157-158 C.  The product does not give any melting point depression when mixed with the product of example 4.  -, Yield 51.2% (ci) +47 ,, methanol).  Example  The process is carried out under the conditions of example 2, replacing racemic (1) -9-bromo-6-metsh-1-4-keto-6, 7,8,9-tetrahydro-4H pyrido- (1,2-a) pyrimidine-3-carbonic acid on the optically active (-) - 9-bromo-6-methyl-4-keto-6, 7,8,9-tetrahydro-4H-pyrido (1,2-a) -pyrimidine-3-carboxylic acid, is obtained ( -) - 9,9-dibromo-6methyl-4-keto-6, 7,8,9-tetrahydro-4Npyrido (1,2-a) -pyrimidine-3-carboxylic acid, melting at 157-159 C.  Yield 49.5% (f. ) ,, methanol).  Calculated,%: C 32.81; H 2.75; N 7.65; Br 43.65.  CioHieN2. 03Brt Found,%: C, 33.21; H 2.72; 7.60; Br 43.62 Example 7, The process is carried out under the conditions of Example 3, replacing the racemic (1) 6-metip-4-keto-6,7,8,9 tetrahydro-4H-pyrido- (1,2-a) -pyrimidine- 3-carboxylic acid on optically active (+) - 6-metsh1-4-keto-6,7, 8,9-tetrahydro-4H-pyrido- (1,2-a) -pyrimidine-3-carboxylic acid, get ( -) - 9,9-dibromo-6-methyl-4-keto6, 7,8,9-tetrahydro-4H-pyrido- (1,2-a) pyrimidine-3-carboxylic acid, get (-) - 9, 9-dibromo-6-metsh1-4-keto-6, 7,8,9-tetrahydro-4H-pyrido (1,2-b) -pyrimidine-3-carboxylic acid, melting at 157-159 C.  Yield 51.5% (0) -47.5 (, methanol).  The product does not give any melting point depression when mixed with the product of Example 6 Examples 8-11.  To a solution of 1.4 g of crystalline sodium acetate and 0.005 mol of the starting compound shown in Table 2.  1, in 10 ml of glacial acetic acid, 0.54 ml (0.01 mol) of bromine was added dropwise, slowly with stirring at room temperature.  The reaction mixture is stirred for 2 hours at room temperature, after which the acetic acid is distilled off under reduced pressure.  10 ml of chloroform was added to the residue and the suspension was stirred for 15 minutes at room temperature.  The crystalline product precipitated into the ocacid is filtered off and washed with chloroform, the filtrate is evaporated, the residue is crystallized from the dissolving solution indicated in table.  one.  Examples 12-17.  To a solution of 1.4 g of crystalline sodium acetate and 0.005 mol of the starting compound shown in Table.  1, in 10 ml of glacial acetic acid, 3.2 g (0.01 mol) of pyridium bromide perbromide was added in portions with stirring at 1 cm at an alternate temperature. The reaction mixture was then stirred at room temperature for 2 hours and distilled with acetic acid at reduced pressure.  10 ml of water was added to the residue and treated with chloroform (3x10 mm).  The combined organic phases are dried over sodium hydroxide sulfate and the solvent is distilled off.  The remainder of the crystal is lysed from methanol.  Examples 18-20.  0.05 mol of the starting compound shown in Table 1 is dissolved (suspended).  1, in 80 ml of dichloromethane and to the resulting suspension solution, a solution of 13.5 mg (0.1 mol) of sulfuryl chloride in 20 ml of dichloromethane is added at room temperature.  The reaction mixture is boiled until gas evolution ceases (3-4 hours), the solvent is distilled off and the residue is recrystallized from ethanol.  Yield 70-80%.  The compounds obtained are presented in Table.  one.  Example 21  To a solution of 2.2 g of crystalline sodium acetate and 0.8 g (0.005 mol) of 6-metsh-6,7,8,9 tetrahydro-4H-pyrido- (1,2-a) -pyrimidin-4-one in 10 ml glacial acetic acid is added dropwise 1.0 ml (0.018 mol) of bromine at room temperature with stirring.  The reaction mixture was stirred at 50-60 ° C for half an hour, after which the acid was distilled off under reduced pressure.  10 ml of chloroform was added to the residue and the suspension was stirred for 10 minutes at room temperature.  The crystals are filtered and washed with chloroform.  The filtrate is evaporated in vacuo.  Upon recrystallization of the residue from methanol, 1.5 g (74.8%) of 3.9, 9 thrombrom-6-methyl-6, 7,8,9-tetrahydro4H-pyrido- (1,2-a) -pyrimidine-4- are obtained she melted at 157-159 C.  Calculated,%: C 26.96; H 2.26; iN 6.98; Br 59.79.  CjHjNjOBrj Found,%: C 26.80; H 2.06; N 7.00; Wg 59.00.  Example 22  The process is carried out under the conditions of Example 8, but starting from 3,6-dimethyl-6,7,8,9-tetrahydro-4N-pyrido- (1,2-a) -pyrimidin-4-one, 9.9-dibromo- E, 6-dimesh1-6,7,8, 9-tetrahydro-4H-pyrido- (1,2-a) -pyrimvdin-4-one, melts at 114,115 ° C.  The output of 30.0%.  Calculated,%: C 35.75; H 3.39; N 8.34; Br 47.56.  С1вН, вНГОВг2 Found,%: С 35.74; H 3.72; N 8.22; Br 47.85.  Example 23  To a solution of 2.1 (0.01 mol) 6-methyl-4-keto-6,7,8,9 tetrahydrr. -4H-pyrido- (1,2-a) -pyrimidium-3-carboxylic acid in 20 ml of chloroform was added in portions of 3.6 g (0.02 mol) of N-bromosuccinimide with stirring.  The reaction mixture was kept under reflux for 5 hours and chloroform was distilled off under reduced pressure.  20 ml of water are added to the residue and the suspension is stirred for 15 minutes at room temperature.  The insoluble crystals are filtered off, dried and recrystallized from methanol.  1.5 g (41.0%) of 9.9 dibromo-6-methyl-4-keto-6,7,8,9 tetrahydro-4H-pyrido- (1,2-b) -pyrimidine-3-carboxylic acid are obtained. melting at 163-164 C.  The product does not give any depression to the point of blending when mixed with the product of example 1.  PRI me 24.  To a solution of 0.4 (0.005 mol) 6-methyl-4-keto-6,7,8,9 tetratidro-4H-pyrido- (1,2-a) -pyrimidine-3-carboxylic acid in 10 ml of chloroform is added portions of 1.33 (0.01 mol) N-chlorosuccinimide with stirring.  The reaction mixture is then heated under reflux for 5 hours, after which the chlorine forms are distilled off under reduced pressure.  10 ml of water was added to the residue and the suspension was stirred under reduced pressure.  To the residue is added 10 m of water and the suspension is stirred at room temperature for 15 minutes.  The crystals are filtered off, dried and recrystallized from methanol.  Get it. 0.7 g (50.5%) of 9,9-dichloro-6-methyl-4-keto-6, 7,8,9-tetrahydro-4Npyrido (1,2-a) -pyrimidine-3-carboxylic acid, melting at 190-191 The product does not give any depression of the melting point when mixed with the product of example 18.  Example 25  The process is carried out under the conditions of Example 8, replacing 6-methyl 4-keto-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyridine-3-carboxylic acid with 3-ethyl-2, 6-dimethyl-6,7,8,9-tetra-tidro-4H-pyrido- (1,2-a) -pyrimidin-4 one, and upon recrystallization of the crude product from 50% aqueous ethanol, 9.9-dibromo -3-ethyl-2,6-dime-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) -pyrimidin-4-one, melting at 90-92 ° C.  Yield 57.2%.  Calculated,%: C 39.59; H 4.43; N 7.69; Br 43.9.  . NjOBrr Found:%: C 39.21; H 4.24: N 7.59; Br 43.76.  Example 26  The process is carried out under the conditions of example 8, replacing 6-methyl 4-keto-6, 7,8,9-tetrahydro-4H-pyrido (1,2-a) -pyrimidine-3-carboxylic acid with 3-phenyl-6-methyl -6,7,8,9 tetrahydro-4H-pyrido- (1,2-a) -pyrimIDIN-4-OH, and by recrystallization of the crude product from ethanol, 9,9-dibromo-3-phenyl-6-methyl-6 , 7,8,9 tetrahydro-4H-pyrido- (1,2-a) -pyruMIDIN-4-OH, melting at 154-156 0.  Yield 70.4%.  Calculated,%: C 45.26; H-3.54; N 7.04; Br 40.14.  C, 5 Found,%: C 45.26; H 3.54; N 7.21; Br 40.25.    Example27.  To a solution of 2.08 g (0.01 mol) of ethyl eLira 4-keto-4,6,7,8-tetrahydropyrrolo (1,2-a) -pyrimidine-3-carboxylic acid in 10 ml of 75% (volume (volume) aqueous acetic acid solution and 2.12 g (0.02 mol) of sodium acetate are added.  Then a solution of 3.2 g (0.02 mol) of bromine in 10 ml of 75% (v / v) aqueous acetic acid is added dropwise.  The reaction mixture is then stirred at 60 ° C for half an hour, diluted with 250 ml of water and shaken with three portions of 4 ml of chloroform.  The combined chloroform phases are dried over sodium sulfate and evaporated.  The yellow oily residue crystallizes on standing.  Upon recrystallization of the crude product from ethanol, 2.2 g (60%) of 8,8-dibromo-4-keto-6,7,8,9-tetrahydropyrrolo (1,2-a) -pyrimidine-3carboxylic acid ethyl ester are obtained, melting at 97-100 ° C.  Calculated,%: C 32.81; H 2.75; N 7.65; Br 43.66.   CioHioN OiBrj Found,%: C 33.28; H 2.62; N 7.52; Br 43.27.  Example 28  The process is carried out under the conditions of example 27, replacing ethyl ester-4-keto-4,6,7,8-tetrahydropyrrole- (1,2-a) -pyrimidine-3-carboxylic acid on ethyl ester 4-keto-5,6 , 7,8,9,10-hexahydro-4Hpyrimido- (1,2-a) azepine-3-carboxylic acid, and carried out the reaction at 90 ° C for one hour, obtain 2.1 g (53%) of ethyl ether 10.10 dibromo-5, 6,7,8,9,10-hexahydro-anpyrido- (1,2-a) -azepin-3-carboxylic acid.  Calculated,%: C, 36.57; H 3.58; N 7.10; Вг 40,35.  Found:%: 36.32; H 3.49; N 7.02; Br 41.02.  Example 29  Carried out under the conditions of example 21, but instead of b-methyl 6, 7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-4-it is used 2-phenyl 6-methyl-6, 7,8 , 9-tetrahydro-4H-pyrido (1,2-a) pyrimkdin-4-one.  3.9, 9-tribromo-2-phenyl-6-metsh-6,7,8,9 tetrahydro-4H-pyrido (1,2-a) pyrimidine-4-OH are obtained, yield 54.5%.  T.  square  164166С.  Calculated,%: C 37.77; H 2.75; N 5.87; Br 50.26.  C, 5H ,, Ngovgz Found,%: C 38.04; H 2.88; N 5.95; Br 49.80.  Example 30  1.0 g (0.005 mol 6-methyl-4-keto-6,7,8,9-tetrahydro-4H pyrido (1,2-a) pyrimidine-3-carboxylic acid, 0.3 g (0.005 mol) hydroxide Potassium and 2.7 g (0.02 mol) of sodium acetate are suspended in 1 ml of anhydrous ethanol.  1.0 ml (0.02 mol) of bromine is added dropwise to the suspension with stirring at room temperature.  The mixture was stirred for another 1 h and evaporated in vacuo.  10 ml of water are added to the residue and shaken three times with a porous capsule, taken in 5 ml portions.  The combined organic phases are dried over sodium sulfate, the solvent is distilled off under reduced pressure.  The residue is recrystallized from methanol.  Obtain 0.4 g (yield 20.0%) 3,9,9-tribromo-6-methyl-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-4ona, t. square  156-157C.  The mixing sample with the compound of Example 21 does not depress the melting point.  Example 31  1.6 g (0.01 mol 6-methyl-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidin-4-one and 2.8 g (0.02 mol) acetate Sodium is dissolved in 20 ml of ice. acetic acid.  While stirring at room temperature, 6.4 g (0.02 mol) of the pyridium bromide complex are added in portions.  The mixture is stirred for 30 minutes at room temperature and the solvent is distilled off under reduced pressure, 10 MP of water are added to the mixture and stirred at RT for 10 minutes for 30 minutes.  The crystals are sucked off and washed with a small amount of water.  0.5 g (yield 15.6%) of 9,9-dibromo-6-methyl-6,7,8,9-tetragilro-4H-pyrido (1,2-a) pyrimidin-4-one is obtained.  T.  square  130-132 C.  Calculated,%: C 33.58; H 3.13; N 8.70; Br 49.63.  CdH, o NjOBrj Found,%: C 33.76; H 3.09; N 8.67; Br 49.49.  Example 32  3.2 g (0.01 mol of 9,9-dibromo-6-methyl-6,7,8,9-totrahydro-4H-pyrido- (1,2-a) pyrimidine-4ona and 1.4 g (0 , 01 mol) sodium acetate is dissolved in 20 ml of acetic acid.  While stirring at room temperature, 54 g (0.01 mol) of bromine is added dropwise.  The mixture is stirred at room temperature for 30 minutes, the solvent is distilled off under reduced pressure.  10 ml of water was added to the residue and the product was extracted with chloroform (3x5 ml).  The combined extracts are dried over sodium sulfate, evaporated in vacuo.  The residue is recrystallized from methanol.  2.2 g (vipsod 55.0%) of 3.9,9-tribromo-6-metsh-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidin-4-one are obtained, t. square  156-159 C.  The mixing sample with the compound of Example 21 does not depress the melting point.  Examples 33-61 show the possibility of obtaining 9-phenylamino- or 9-aminopyrido (1,2-a) pyrimidines biologically active compounds.  having anti-allergic, anti-asthmatic activity, using as starting pyrido derivatives (1,2-a) pyrimidine-4on of general formula I.  Example 33  1.83 g (5 mmol) of 9,9-dibromo-6-methyl-4-keto-6,7,8,9 tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid is dissolved in 5 ml of dimethyl sulfoxide.  To the solution was added 0.5 ml (5.5 mol) of aniline and 1.3 ml (10 mmol) of N, N-dimethylaniline.  The reaction mixture was incubated for 3 days, then poured into 20 ml of water.  The product is dried, washed with a small amount of water, dried and recrystallized from acetonitrile.  Obtain 0.83 g (55.8%) of 9-anshino-6methyl-4-ket6-6, 7-dihydro-4H-pyrido.  (1,2-a) pyrimidine-3-carboxylic acid-ITO C.  lots, t. square  %: C 64.64; H 5.09; 14.13 a ,, H ,, N, 0, C 64.22; H 5.08; Found N, 14.14.  Example 34  In accordance with the procedure of Example 33, but using pyridine instead of H, L-dimethylaniline as a hydrogen halide acceptor, 9-anshino-6-methyl-4-keto-6, 7-dihydro-4H-pyrido (1,2-a) is obtained pyrimidine-carboxylic acid, t. square  170-17GS, yield 47.1%.  Example 35  1.83 g (5 mmol) of 9,9-dibromo-6-methyl-4-oxo-6,7,8,9 tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid is dissolved in 10 ml of chloroform.  To this solution was added 1.5 ml (15 mmol) of n-butylamine.  The reaction mixture is kept for 3 days, after which 5 ml of water is added.  Adjust the pH of the aqueous phase to 2.0 with 5 wt. % hydrochloric acid with stirring.  The organic phase is separated, the aqueous phase is extracted with two portions of 5 ml of chloroform.  The combined organic phases are dried with anhydrous sodium sulfate, after which the solvent is distilled off in vacuo. The residue is recrystallized from methanol.  0.5 G (36.1%) of 9- (n-butylamino) -6-methnl-4-oxo-6,7dihydro-4H-pyrido (1,2-a) -pyrimidine 3 -carboxylic acid is obtained, t. square  135-137 ° C: C 60.63; H Calculated, N 15,15.  .     Found,%: C 60.92; H 7.00; N 15.20.  And p im 36.  1.83 g (5 mmol) of 9.9 dibromo-6-methyl-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido (1,2-a) are suspended in 15 ml of methanol. -pyrimidine-3 carboxylic acid and MP (15 mmol aniline.  The mixture is heated with stirring until a solution is obtained. This solution is cooled to room temperature and stirred for 3 days.  The precipitated crystals from the filter and washed with methanol. Obtain 0.8 g (53,8%) of 9-anilino-6-methyl-4-oxo-6, 7-dihydro-4H-pyrido (1, 2-a) -pyrimidine-3-carbon sour you, t. square  172-173 S.  1 012 Example 37.  3.9 g of ethyl ester (10 mmol) of 9,9-dibromo-6-methyl-4-oxo-6, 7,8,9-tstrahydro-4N-pyrido- (1,2-a) pyrimidine-3 are dissolved in 30 m absolute ethanol. -carboxylic acid.  To this was added 3.3 ml (30 mmol) of N-methylaniline, after which the reaction mixture was heated under reflux for 8 hours.  When the reaction is complete, the solvent is distilled off under reduced pressure.  40 ml of 5% hydrochloric acid are added to the residue, and the product is extracted with two portions of 15 ml of chloroform.  The combined organic phases are dried over anhydrous sodium hydroxide and evaporated in vacuo.  The residue is recrystallized from methanol.  This gives 2.6 g (76.6%) of ethyl 6-methyl-9- (M-methylanilino) -4-OXO-6.7, -dihydro-4H-pyrido (1,2-a) pyrimidine-3- carboxylic acid 141-142C.  lots, t. square  C, 67.24; H 6.23; Calculated N 12.38.  Ci3H2 N30i%: C 67.50; H 6.36; Found 12.41.  Example 38  Following the procedure of Example 37, but using 9,9-dibromo-6-methyl-4oxo-6, 7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid 9, instead of ethyl ester, 9-dibromo-6-methyl-4-oxo-6,7, 8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid is obtained 6-methyl-9- (N-methylanilino ) -4oxo-6, 7-dihydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid, t. square  170-17GS.  Calculated,%: C 65.58; H 5.50; N 13.49.   C, H, NjO Found,%: C 65.22; H 5.62; N 13.37.  Example 39  19.7 g (50 mmol) of 9,9-dibromo-6-methyl-4-oxo-6 ethyl ester, 7,8,9-tetrahydro-4H-pyrido (1,2-a) are dissolved in 40 ml of dimethyl sulfoxide pyrimidine 3-carboxylic acid, followed by the addition of 13.7 ml (150 mmol) of aniline.  This solution is held for 3 cyTi. After aging, the solution is diluted.  100 ml of water and shake in three portions of 30 ml of benzene. . The combined organic phases are dried with anhydrous
sodium sulfate and evaporated in vacuo. Recrystallization of the residue from ethanol gives 9.5 g (58.4%) of ethyl 9-anilino-6-methyl-4-OXO-6, 7-dihydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid ethyl ester m.p. 119-120 0.
Calculated,%: C, 66.45; H 5.89; N 12.91.
Ci, H ,, N, 03
C, 66.28; H 5.81;
Found,%; N 12.82.
Examples 40-51. 3.7 g (10 mol) of 9,9-dibromo-6-methyl-4oxo-6, 7,8,9-tetrahydro-4H-pyrido (1,2-a) are dissolved in 5 ml of dimethyl sulfoxide. pyrimidine-3-carboxylic acid. To this solution, 30 mmol of an aromatic amine is added (Table 2). The reaction mixture was kept at room temperature for 3 days. The precipitated crystals are filtered off (if no crystallisation takes place, the product is precipitated from the reaction mixture by adding 20 ml of water and 25 ml of methiol). The product is recrystallized from the solvent indicated in table. 2
In tab. 2 gives dihalide derivatives of 9-aminopyrido (1,2-a) pyrimIDIN-4-ONOV, obtained using 9-dibromopyrido (1,2-a) pyrimidin-4-ones as starting materials.
Example 52. Following the procedure of example 40, but replacing 9,9-dibromo-methyl-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid by 9.9 -dibromo-4-oxo6, 7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid, get 9- (phenyl-amino) -4-oxo-6,7-digvdro -4H-pyrido (1,2-a) pyrimidine 3-carboxylic acid, m.p. 197198С (acetonitrile). Yield 60.5%.
Calculated,%: C 63.60; H 4.63; N 14.83.
Ct, H ,, N ,, 03
C 63.42; H 4.59;
Found,% i N 14.70.
Examples 53-62. Using the method of Examples 40-51, the compounds listed in Table 2 are obtained. 3 (derivatives of 9-phenylaminopirido (1,2-a) pyrimidin-4-ones).
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权利要求:
Claims (4)
[1]
1. The method of obtaining geminal ^ dihaloid derivatives of condensed pyrimidin-4-ones of general form, where X is chlorine, bromine;
η is 0, 1, 2;
I., - hydrogen, methyl, ethyl, which may be in positions 6, 7 and 8;
R ₂ - carboxy,. carboethoxygroup ~, carbonitrile, bromine, methyl, ethyl, phenyl;
Rj is hydrogen, methyl, ethyl, racemates or optically active antipodes, characterized in that the racemic or optically active compound of the general formula II
Y where Y is hydrogen, chlorine or bromine, n, R ^, and R ₃ have the indicated meanings ^ are reacted with a halogenating agent, and if Y is chlorine or bromine, the halogenating agent is taken in an equimolar amount, if Y is hydrogen, a halogenating agent they are taken in a two-equimolar amount, the process is carried out in an inert organic solvent, the target product is isolated in the form of racemates or optically active antipodes.
[2]
2. The method of Pop. 1, characterized in that bromine, chlorine, sulfuryl chloride, N-bromo (chloro) 'succinimide, and pyridinium bromide perbromide are used as the halogenating agent.
[3]
3. The method of pop. 1, characterized in that as an inert organic solvent using chloroform, dichloromethane, glacial acetic acid.
[4]
4. The method of pop. 1, characterized in that the process is conducted in the presence of an acid-binding agent - alkali metal acetate.

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

AT286990B|1966-11-02|1971-01-11|Chinoin Gyogyszer Es Vegyeszet|Process for the preparation of new homopyrimidazole derivatives and their salts|

---

HU178496B|1977-12-29|1982-05-28|Chinoin Gyogyszer Es Vegyeszet|Process for preparing 6,7,8,9-tetrahydro-4h-pyrido/1,2-a/pyrimidine derivatives with antiallergic activity|HU178453B|1979-05-11|1982-05-28|Chinoin Gyogyszer Es Vegyeszet|Process for producing 9-hydrazino-4-oxo-6,7,8,9-tetrahydro-4h-p-pyrido-square bracket-1,2-a-square bracket closed-pyrimidine derivatives|

---

US4395549A|1981-10-02|1983-07-26|Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt.|6-Hydrazono-pyrido[2,1-b] quinazoline-11 ones|

---

ES524262A0|1982-08-05|1984-11-16|Erba Farmitalia|"PROCEDURE FOR PREPARING QUINAZOLINE DERIVATIVES"|

---

US5158952A|1988-11-07|1992-10-27|Janssen Pharmaceutica N.V.|3-[2-[4--1-piperidinyl]ethyl]-6,7,8,9 tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a]pyrimidin-4-one, compositions and method of use|

---

AP1228A|1997-11-17|2003-11-12|Janssen Pharmaceutica Nv|Aqueous suspensions of submicron 9-hydroxyrisperidone fatty acid esters.|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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HU79CI1932A|HU179443B|1979-05-11|1979-05-11|Process for producing substituted geminal dihalogeno-derivatives of pyrido-square bracket-1,2-a-square closed-pyrimidines,pyrrolo-square bracket-1,2-a-square bracket closed-pyrimidines and pyrimido-square bracket-1,2,-a-square bracket closed-asepines|

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