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    • 专利摘要:
    Chemical compounds having an effect on the circulatory system have the formulas <IMAGE> (I) or <IMAGE> (II) or a mixture thereof, or a pharmaceutically suitable acid-addition salt or quaternary salt thereof, wherein R is hydrogen or lower alkyl, R1 is lower alkyl, phenyl, carboxyl, lower alkoxycarbonyl, nitrile, carbamoyl or carbohydrazido, R2 is hydrogen or lower alkyl, and wherein the formula I R2 is hydrogen then R1 is other than nitrile, alkoxycarbonyl or propyl.
    公开号:SU1048986A3
    申请号:SU802919651
    申请日:1980-05-08
    公开日:1983-10-15
    发明作者:Кекеши Йожеф；Хермец Иштван；Месарош Золтан；Сас Дьердь；Вашвари Лелле；Хорват Агнеш；Брайнинг Тибор
    申请人:Хиноин Дьедьсер Еш Ведьесети Термекек Дьяра Рт (Инопредприятие)；
    IPC主号:
    专利说明:

    The invention relates to an improved process for the preparation of the known H-substituted tetrahydropyrrolo (1,2-a) pyrimidines, the initial products in the synthesis of biologically active substances, and the process for the preparation of new derivatives of this series.  A known method for the preparation of 3- (1-methylpropyl) -4-oxo-4,6,7,8-tetrahydro-pyrrolo (1,2-a) pyrimidine by the interaction of ethyl ether. 2-amino-4, 5-dimethylthis 1) en-3-carboxylic acid with 2-methoxypnrroline in the presence of phosphorus oxychloride, by desulfurization of the resulting 2,3-dimethyl-4-oxy-5, 6-tetramethylene-4H-but ( 2,3-a) pyrI1L1dina with René nickel in 36.5% fl.  The disadvantage of this method is its two-step process.  The closest to the invention is a method for producing 3-substituted tetrahydropyrrolo (1,2-a) pyrimidines, in particular, 4-oxo-4,6,7 f ethyl ester 8-tetrahydropyrrolo () pyrimidine-3-carboxylic acid, by the reaction 2-methoxy-1-pyrroline, ethoxymethylenemalonic acid ethyl ester and acetate in the fusion process with a yield of 7.1% f 2.  The disadvantage of this method is the low yield of the target product.  The purpose of the invention is to increase the output and target products and to improve the range of products obtained from the product.   This goal is achieved by the fact that according to the method for producing 3-substituted tetrahydropyrrolo (1,2-a pyrimidines common Foomul. four .  where r,.  - hydrogen or C. - hitkil; R - CJ | -alkyl, phenyl, carboxyl, carbamoyl, C 5 -alkoxycarbonyl, cyano or KofbogidrazIdogroup; R is hydrogen or C.  -alkyl,. their acid-positive or quaternary salts as a derivative of 1-pyrroline use 2-amino-g1-pyrrolin of the General formula qi where R has the indicated values, and as the carboxype acid derived is an ester of acrylic acid of the general formula where R has the indicated values; R is C, -alkyl, phenyl, cyano or C-C-alkoxycarbonyl; Yal  is hydrogen or C-alkyl; R -. -alkyl, the process is carried out in an inert solvent, preferably in ethanol, at a temperature from -US to the boiling point of the reaction mixture with after separation of the target product as a mixture of compounds (I) and (P), or isolation of each of the isomers as base or an acid addition salt, or hydrolysis of compounds of formula (I) or SI) where R is said alkoxycarbonyl, to obtain compounds I or II, where R is carboxyl, or by ammonolysis of compounds of formulas (1) or (II), where R is carboxyl , to obtain compounds i or 11, where R is carbamoyl, or g and disruption of compounds I or II ,.  where R is carboxyl, to obtain compounds of for14ul (I) or (II), where R is carbohydrazide, or ashkylation to form quaternary salts, and to isolate the desired product.  The proposed method allows to increase the yield of the target products, in particular, for 4-oxo-4 ethyl ester, 6,7,8-tetrahydropyrrolo (1,2-a-) pyrimidine-3-carboxylic acid up to 48%, and to obtain new -substituted tetrahydropyrrolo (1,2-a) pyrimidines possessing an anti-anginic effect and superior in activity to papaverine, -l -:: Usually, pactaop compounds of the general formula (IV) are added to a solution of a compound of general formula IIII; cases can be worked in reverse order. After removing the solvent by distillation, a mixture of compounds is obtained eny general Formula (I) P (I) Due to the different solubility, basicity or different behaviors when hromatoP afirovanii compounds of general formula () IDN), the resulting mixture of the same. Lania can be divided.  Preferably, salts of hydrochloric, hydrochloric, chloric, and xenoic salts are obtained. , salicylic acids, and quaternary salts are obtained by alkylation, for example, methyl iodide, dialkyl sulfates, such as, for example, dimethyl sulfate, p-toluene sulfonate, and benzosulfonate.  Compounds of general formula (TV) are commercially available compounds, total forg / 1uli 1 (1II) compounds are prepared, for example, by alkylation of 5-alkylpyrrolidin-2-one. Cs, -: example, diethyl sulfate), the resulting 0-alkyl amino ether is reacted with an ammonia-releasing agent, such as ammonium acetate, ammonium chloride, and the like. d. , and receive the compound of General formula (III). .  Example 1  A solution of 50.5 g of 2-amine pyrroline in 600 ml of ethanol is cooled before and while stirring, 3 drops are added dropwise over 3 hours to a solution of 127.8 g of diethyl malone in 200 ml of ethanol.  The reaction mixture is stirred for an additional 1 hour and left at this temperature for 24 hours.  Ethanol is distilled off under reduced pressure and the remaining yellow oil, which contains a mixture of ETIH-4-OXO-4,6,7,8-tetrahydropyrrolo (1,2-a) pyrimidine-3-carboxylate and ETHYL-2-OXO-2 , b, 7,8-tetrahydropyrrolo (1,2-a) pyrimidine-3-carboxylate in the ratio 4: 1, dissolved by melting in 400 ml of benzene.  Benzene | dissolved mortar. The precipitated crystals are filtered off.  Obtain 22 g (P%) of ethyl-2-oxy-2, b, 7,8-tetrahydropyrrolo (1,2-a) pyrimidine-3-carboxylate, which is recrystallized from this Iol, t. square . . .  Calculated,%: C 57.69, H 5.76, -.  Y: 13.1b.  with . 0j.  : Found,%: C 57.34, H 5.61, N 13.10.  The benzene stock solution was shaken twice in succession with 40 MP of 5% (wt. volume) of sodium bicarbonate solution and the combined aqueous phase was shaken c40 with benzene three times.  Combined and dried with anhydrous sodium sulfate benzene solution is concentrated under reduced pressure and the residue is treated with 400 ml of diethyl ether.  The mixture crystallizes upon cooling.  The precipitated crystals are filtered off.  60 g (48%) of ethyl 4-oxo-4,6 / 7,8-tetrahydropyrrolo (1,2-a) pyrimid n-Sgkar of boxyl are obtained, t. square  59-60 S.  Calculated,%: C 57.59, H 5.76, N 13.46.  10 grams with 57.8, H 5.57, Found,%; N 13.48.  If the ethereal mother liquor is saturated with hydrogen chloride, then half of 22 g (13%) of etl-4-oxo-4 6 7,8-tetrahydropyrrol (1,2-a) pyrim is obtained.  din-3-carboxylate-gi. drochloride, which, after recrystallization from ethanol, melts at 182-184s.  Calculated,%: C 49.08, H 5.35, N 11.45; C1 14.48.  AND. ozS1.  Found,%: C 49.23, H 5.61, N 11.36; C1 14.36.  An example.  2  Similar to the burn 1, using 2 instead of a1 "1-pyrroline. no-5-methylpyrroline, after concentrating the ethanolic solution, a yellow oil is obtained, which contains a mixture of ethyl 6-methyl-4-goxo-4,6, 7, 8-tetrahydropyrrolo (1,2-a) pyrimidine-3-carboxylate and . tyl-2-oxo-2,6,7, 8-tetrahydropyrrolo (1, 2-a) pyrimidine-3-carboxylate in a ratio of 2il: This mixture is dissolved in benzene and the benzene solution is shaken with 5% (wt. (volume) sodium bicarbonate solution.  The aqueous phase is again shaken with benzene and chloroform.  The sodium sulfate-dried chloroform extract is concentrated under reduced pressure.  32.3% ethyl 6-methyl-2-oxo-2,6,7,8-tetrahydropyrrolo (1,2-a) pyrch is obtained. chd-3-carboxylate, which, after recrystallization from acetone-petroleum ether, melts at 130 s.  Calculated,%: C 59.45, II 6.35, N 12.61.  С 1Ы% 09 Found,%: C 59.15, and 6.30, N 12.54.  Anhydrous sodium sulfate-dried benzyl extract concentrate; Survive under reduced pressure.  66% ethyl-6-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo (1,2-a) pyrimidine-3-carboxylate is treated as a light yellow, non-crystallizing gum.  Calculated,% g C 59.45, H 6.35, N 12.61,.   H 4NlOib.  Found,%; C 59.80, AND 6.20 G 12.51.  , The oil was dissolved in acetone and then saturated with hydrogen chloride to give white crystals of ethyl 6 - methyl - 4 - oxo - 4.  6,7,8 - tetrahydropyrrolo (1,2-a) piprimidine-3-carboxylate, t. square  1bT 163С.  Calculated,%: C, 51.07; H, 5.84; N, 10.83; Cl, 13.70.  Q WiiaPibCi, Found,%: C 49.65, H 5.77, N 9.76; C1 12.45.   PR I4 meper 3. A solution of 16.8 g of 2-aminopyrroline in 140 ml of ethanol is cooled before and added dropwise with stirring.  solution.  33.8 g of ethyl ethoxymethylene cyanoacetate in 250 ml of ethanol.  Reactionary. the mixture is allowed to warm to room temperature, which is then boiled for 1 h, cooled below, the crista is lysed and filtered.  This gives 13.7 g (42.5%) of 3-cyano-4-oxo-4, b, 7.8-tetra-hydropyrrolo (1,2-a) pyrimidine, which is recrystallized from ethanol t. square  119-121p.  Calculated,%: C 59.62, H 4.38, N 26.07.  CgIi, N50.  Found,% g C 59.49, H 4.24,: -N26.04.  Example 4  Similarly to Example 3, using 2-amino-5-methylpyrroline instead of 2-aminopyrroline, 3-cyano-6-methyl-4-oxo-4 is obtained, §, 7,8 | -tetrahydropyrrolo (1,2-a) pyrimidine (yield 89%), which is recrystallized from ethanol, t. square  .  Calculated,% C 61.70, H 5.18, N 23.98.  . .  Found,%; C 61.65, H 5.04,. N 23.63.  Example 5  8.4 g of 2-amiopyrroline is dissolved in 150 ml of ethanol, to the solution one or two drops of acetic acid and 13.01 g of ethyl 1, -2-formyl propionate are added, the reaction mixture is left for 24 hours at room temperature, then concentrate and the residue containing a mixture of 3-methyl-4-oxo-4, 6,7,8 - tetrahydropyrrolo (1,2a) pyrimidine and 3-methyl-2-oxo-2, b, 7, 8-tetrahydropyrrolo (1 , 2-a) pyrimidine in the A1: 1 ratio, boiled with 200 m of acetone and left to crystallize upon cooling.  The precipitated crystals are filtered.  By concentrating the mother liquor, an additional amount of crystals is obtained, a total of 6.7 g (44.6%) of 3-methyl-2-oxo-2,6, 7 f 8 Tetrahydropyrrolo (1,2-a) pyrimidine, t. square  242C; Calculated,% C 64.01; H 6.66: N 18.64.  ,: Found%: C, 63.85; H, 6.54; N, 18.73; After concentrating the mother acetone, 8.2 g (54.6%) of crystallizing at standing oil, which is 3-methyl-4, are obtained. oxo-4, b, 7, 8-tetrahydropyrrolo (1, 2-a) is pyrimidine and melts at.  Calculated,%: C 64.01, H 6.66, N 18.64.  , NaQ.  Found% {C 63.50, H 6.71, N 18.52.  Example 6  Analogously to example 5, but using 2-amino-5-methylpyrroline instead of 2-aminopyrroline, semi-changg 3,6-dnmethyl-2-oxo-2, 6,7, 8-tet. pghydropyrrolo (1,2-a) pyrimidine (output 36%), which after recrystallization from methyl ethyl ketone melts at 150iS2C, Calculated,%: C 65.83, H 7.37, N 17.06.  CjH a-NaO.  Found,%: C 65.65, H 7.42, N 17.15.  From uterine acetone, 3,6-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo (1, 2-a) pyrimidine is obtained as a yellow oil (yield 42%). Calculated,%: C 65.83, H 7.37, N 17.06.  .  Found,% g C 66.08, H 7.40 N 16.95.  Example 7  8.4 g of 2-aminopyrroline and 19.2 g of ethyl-3-ph6-ml-phenylacetate are boiled in 150 ml of ethanol for 5 hours and the reaction mixture is concentrated.  The residue is treated with petolol ether.  The resulting crystals are filtered.  15.9 g (75%) of a mixture of 3-phenyl-2-oxo-8,6,7,8-tetra-, hydrrpyrrolo (1,2-a1) pyrimidine and 3-fe NIL-4-OXO-4 are obtained, 6,7,8-tetrahydropyrrolo (1,2-a) pyrimidine and 3-phenyl-4-oxo-4; 6,7,8-tetrahydropyrrolo (1,2-a) pyrimidine, t. square  9B-120 ° C (melts slowly).  Calculated,%: C 73.57, H 5.70, N 13.20.  .  Found,%; C, 73.70; H, 5.48; N, 13.11.  Example 8  1 g of a mixture of 3-phenyl-2-oxo-2, 6,7,8-tetrahydropyrrolo (1,2-a) pyrimidine and 3-phenyl-4-oxo-4, 6,7,8-tetrahydropyrrolo (1,2 -a) pyrigidine, prepared according to example 7, is dissolved in benzene and added to a silica gel column (10 g) with a diameter of 1 cm and a particle size of 0.0630, 125 mm and eluted with ethyl acetate. After concentrating the eluate, pure 3-phenyl is obtained -4-oxo-4,6,7,8-tetrahydropyrrolo (1,2-a) pyrimidine, t. square  172-174C.  Credited,%: C 73.57, H 5.70 N 13.20.  .  Found: C: 73.41; H, 5.62; N, 13.28.  After removal of 3-phenyl-4-oxo-4, 6,7,8-tetrahydropyrrolo (1,2-a) pyrimidine, the column was eluted again, but with methanol.  The methanol eluate is concentrated to give pure 3-fennl-2-oxo-2, 6,7,8-tetrahydropyrrolo (1,2-a) pyrimidine, t. square  200-202 C.  Calculated,%: C 73.57, H 5.70, N 13.20.  С -rx iOFound,%: C 73.60, H 5.81, N13.07.  Example 9  10.4 g of ethyl 4-oxo-4, 6,7,8-tetragyropyrrolo (1,2-a) pyrimidine-3-carboxylpto is dissolved in 30 ml of 30% (wt. ) ammonium hydroxide solution.  After 2 h, the precipitated crystals are filtered.  8.7 g (96.6%) of 3-carbamoyl-4-oxo-4, 6,7,8-tetrahydropyrrolo (1,2-a) pyrimidine are obtained, which is recrystallized from dimethylformamide, t. square   Calculated,%: C53.62, H5.06, N 23.45.  CeHjN Oj.  Found: C, 53.47; H, 5.12; N, 23.23.  An example. ten.  In analogy to Example 9, but using 2-ethyl-2-oxo-2,6, 7,8-tetrahydropyrrolo (1,2-a) pyrimidine-3-carboxylate as the starting material, 3-carb & IOIL-2-OXO is obtained. -2 ,, 8-tetrahydropyrrole (1,2-a) pyr1. 4IDin (88% yield), which, after recrystallization from N-butanol, melted at 277-278 seconds.   Calculated,%: C 53.62, H 5.06, N 21.45.  CgHoNjO.  Found,%: C 53.18, H 4.97, N 23. 27.  Example 11  Similar to Example 9, but using ethyl 6-methyl-4-oxo-4,6,7,8 -tetrahydrrpyrrolo (1,2-a) pyrigidid-3 -carboxylate as the starting material, a 3-carbsiluyl 6-methyl-4-oxo-4, 6,7,8-tetrahydrpyrrolo (1,2-a) pyrimidine, yield 81%, tons square  191C. : Calculated,%: C 55.95, H 5.74, N 21.75.   .  Found,%: C 56.03, H 5.84,; N 21.70.  Example 12  Similarly, when used, 9, but using ethyl 6-methyl-2-oxo-2 6,7, 8-tetrahydropyPROlo (1,2-a) dint-3-carboxylate as the starting material, 3-carb-6-methyl-3 2-oxo-2,6,7,8-tetrahydropyrrolo (1,2-a) pyrimidine, yield 76 t. square  223C.  .  Calculated,%: C 55.95, H 5.74, N 21.75.  Co P. .  N.  Odd .  Found,%: C 55.82, H 5.90,.  N 21.76.  .  Example 13  10.5 g of ethyl-4-o-co-4,6,7,8-tetrahydropyrrolo ().  pyrimidine-3-carboxylate is dissolved in 50 ml of 5% (wt. (volume) sodium hydroxide solution, and after 2 hours to add 36% (weight. (volume) hydrochloric acid set the pH of the solution to 2.5.  The precipitated crystals are filtered and rinsed with a small amount of water.  6.0 g (66.7%) of 4-oxo-4,6,7,8-tetrahydropyrrolo (1,2-a) pyrimidine-3-carboxylic acid, are obtained.  . t. square  146-148 C (with decomposition).  Calculated,%: C 53.23, H 4.48, N 15.55.  Cg.  Found: C, 53.23; H, 4.51; N, 15.70.  Example 14  Similarly, use is made of 13, but using ethyl 2-oxo-2,6,7,8 tetrahydropopypropolptl, 2-a) pyrimidine 3-carboxylate as the starting material, 2-oxo-2,6, 8-tetrahydropyrrolo (1,2- a) pyrimyin-3-carboxylic acid, yield 58%,. square  183s (with decomposition).  Calculated,%: C, 53.33; H, 4.48; N, 15.55.  Cgil8N 03.  Found,%: C 53. , 40, H 4.42, N 15.55.  Example 15  Analogously to example 13, but used as starting substance, ethyl-6-methyl-: 4-oxo-4,6, 7,8 tetrahydropyrrolo (1,2-a) pyrimidine 3-carboxylate, get 6-methyl-4oxo-4, 6 , 7,8-tetrahydrdpyrrolo () pyrimidine-3-carboxylic acid, yield 56.5%, t. square   (with decomposition) t Calculated,%: C 55.67, H 5.19, N 14.43.  Cplifo Found: C 55.71; H 5.15; N 14.52.  Example 16  Analogously to example 13, but using as the starting material, methyl-6-methyl-2-ox6-2, 6,7,8-tetrahydropyrrolo (1,2-a) pyrimidine-3-carboxylate, to obtain b-methyl-2-oxo -2, 6,7,8-tetrapyrrolo (1; 2-a) pyrimidine-3-carboxylic acid, yield 43.5%, tons square   (with decomposition).  Calculated,%: C 55.67, H 5.19, N 14.43.  0.11.0,.  Found: C, 55.80; H, 5.19; N, 14.40.  Example 17  2.08 g of ethyl 4-oxo-4, 6,7,8-tetrahydropyrrolo (1,2-a) pyrimidine-3-carboxylate is mixed with 98% (wt. a) hydrazine hydrate and os-, are added at room temperature.  The resulting crystals are filtered and washed with water.  1.5 g (77.5%) of 4-OXO-4,6,7,8-tetrahydropyrrolo (1,2-a) pyrimidine-3 are obtained. - carbohydrazide, t. square  180-181 S.  Calculated,%; C 49.48; H 5.19; N 28.85.   % 02.  Found% C 49.70, H 5.11, N 28.91.  Example 18  Example 17, but using methyl 2-oxo-2,6,7,8-tetrahydropyrrolo (1,2-a) pyrimidine-3-carboxylate as the starting material, 2-oxo-2,6, 7,8 tetrahydropyrrolo (1,2-a) pyrimidine-3-carbohydrazyl, yield 52%, tons. square  204-206 S.  Calculated /%: C 49.48, H 5.19, N 28.85.  .  Found,%: C 49.41, H 5.15, N 28.92.  Example 19  Analogously to example 17, but using ethyl 6-methyl-4-ox-4,6,7,8-tetrahydropyrrolo (1,2-a) pyrimidine-3-carboxylate as the starting material, 6-methyl-4- oxo-4, 6,7,8-tetrahydropyrolol (1, 2-a) pyrimidine-3-carbohydraideg yield 53%, t. square  136-137% calculated: C 51.92, H 5.81, N26.91.  .  Found,%: C 52.15, H 5.90, N. 26.75, Example.  Similar to Example 17, but ethyl-6-methyl-2-hydroxy-2, 6, 7, 8, tetrahydropyrrolo {1,2-a) pyrimidine-3-carboxylate is used as the starting material.  The reaction mixture is left for 2 hours, dissolved in ethanol, hydrogen chloride is added and the precipitated crystals are filtered.  6-methyl-2-oxo-2,6, 7,8-tetrahydropyrrolo (1,2-a) pyrimidine-3-carbohydra-hydrochloride is obtained, yield 66, 7%, t. square  18bs.  Calculated,%: C 51.92, H 5.81, N 26.91,.  ,five. N40a.  Found,%: C, 51.86; H, 5.80; i.  N 27.06,.  Example 21  To a solution of 2.08 Ethyl-4-OXO-4,6,7,8-tetrahydropyrrolo () pyrimidine-3-carboxanate in 5 ml of acetone was added 2.5 ml of methyl iodide.  The crystals which precipitate out after 24 h are filtered and dried with acetone.  2.61 g (74%) of 3-ethoxycarbonyl-1-methyl-4-oxo-4, 6, 8-tetrarolo tetrahydride (1/2-aJ pyrimidine,.   (with decomposition).   numbered.  %: C 37.73, H 4.32, V N 8.00; J 36.24.  WITH . OsJ.  Found,%: C 37.68, H 4.39, N 7.9S, J 35.6.  P Rome p 22.  In a similar manner to the example of 21j, ethyl-2-oxo-2,6,7, 8-tetrahydropyrrolo (1,2-a) sodium is used as the starting material. idin-3-carboxylate and the reaction is carried out in ethanol. 3-ethoxycarbonyl-bmemethyl-2-oxo-2, 6,7,8-tetragyropyrrolo (1,2-a) pyrimidinium iodide, t. square  22 3C (with decomposition).  Charged,%: C 37.73, H 4.32, N 8.00, J 35.24.  QIX fWNa. 03J.  Naide-cho,%: C 38.15, H 4.43, N 7.97, J 36.28.  PR im IM 23.  Similarly to Example 21, but ethyl 6-methyl-4-oxo-4,6,7,8-tetrahydropyrrolo (1,2-a) pyrimidine 3-carboxylate is used as the starting material and the reaction is carried out in ethyl acetate.  Get 3-ztoxycarbonyl-1, 6-dimethyl-4-oxo-4,6,7, 8-tetrahydropyrrolo (1,2-a) pyrimidinium iodide, yield 44%, t. square  186-187 0 (with decomposition).  Calculated,% s With 39.64, And, N 7,71 i.  J 36.03.  . 3  Found: C, 39.65; H, 4.90; N, 1.12; J, 36.18.  Example 24  As in example 21, but using ethyl 6-methyl-2-oxa 2,6,7,8-tetrahydro Dipyrrolo (1,2-a) pyrimidine-3-carboxylate as the starting material, 3-ethoxycarbonyl-5, 6- dimethyl-2-oxo-2,6,7,8-tetrahydropyrrolo (1,2-a) pyrimidinium: iodide, t. square   (with decomposition).  calculated% C 39.64, H 4.68,: N 7.71, J 36.03.  e xH V% 03J Found,%: C 39.70, H 4.52, N 7.80; J 36.30.  P r and measures 25.  To a solution of 5.37 g of 3-carbg1Moyl-4-oxo-4,6,7,8-tetrahydropyrrolo (1,2-a) pyrimidine, in 540 ml of n-butanol was added 3.78 g of dimethyl sulfate, the reaction mixture was stirred in for 3 hours and the solvent is distilled off.  The residue is treated with acetone and the crystals formed are filtered.  This gives 1 g (51%) of a hygroscopic 3-carbs1Moyl-1-methyl-4-oxo-4, 6,7,8-tetrahydropyrrolo (1,2-a) pyrshid-methylsulfate, t. square  190 With fc decomposition).  numbered,% t C 39.34, H 4.95, N 13.76; S 10.50.  .  Found,% s C 39.44, H 5.03, N 13.92; S 10.41.  Example 26.  To a solution of 1.93 g of 3-carbamoyl-6-methyl-4-oxo-4, 6.7, 3-tetrahydropyrrolo (1,2-a) pyimidine in 30 ml of methanol was added 1.26 g of dimethyl sulfate, the reaction mixture t for 1 h and concentrate.  The residue is crystallized from a mixture of acetone and ether.  The resulting crystals are filtered.  2.7 g (87%) of a strongly hygroscopic 3-caramoyl-1, 6-dimethyl-4-oxo-4,6,7,8 tetrahydropyrrolo (1,2-a) pyrimidinymethyl sulfate, t are obtained. square  .  Calculated,%; C 41.37; H 5.37; N. 13.16; S 10.09.  C 4,  Naaceio,%: C 41.45, H 5.41, N 13.15; S 9.86.  With Jd ep 27.  42 g of 2-aminopyroline are dissolved in 400 ml of ethanol and a solution of 108 g of diethyl-toxymethylenenemalonate, in 200 ml of ethanol, is added dropwise to this solution.  At the end of the addition, the mixture is bungled for 1 hour at OS and left for 12 hours at.  Crop tillage filters are filtered.  After concentration of the mother liquor, the residue is boiled with 200 ml of benzene.  The crystals formed after cooling are filtered.  The filtered crystals are combined from and, recrystallized from ethanol.  50.3 g (48.4%) of ethyl 2-oxr-2, 6,7,8-tetrahydropyrrolo 1,2-a) pyrimidine-3-carboxylate are obtained, t. n; r1.   Calculated,% d C 52.63, H 5.26,.  N 12.28.  .  Found,%: C 52.74, H5.31, N 12.21.  The benzene phase is shaken twice with 10 ml of water.  The aqueous phase is alkalized with sodium carbonate to pH 8 and shaken three times with chloroform. The combined organic phase is dried with anhydrous sodium sulphate and the solution is taken oio.  Poi reduced performance.  Newly prepared ETHIL-4-OXO-4, 6, 7,8-tetrahydro pyrrolo (1,2-a) pyrimidine-3-carbox :: yl C40.5 g, 38.9% is crystallized from ether, t. square  59-60 0.  Calculated,%; C 52.63, H 5.26,: N 12.28.  c oW% o Found: C 52.78, H 5.30, N 12.19.  Example 28  0.84 g of 2-aminopyrroline and 1.5 g of 2-ethyl acetoacetate in 10 ml of ethanol are boiled for 5 hours.  Ethanol is distilled off.  The remaining mass is dissolved in 15 ml x orof and shaken twice with 10 x 5% sodium bicarbonate.  Chlorine op.  The dried phase is dried and concentrated under reduced pressure.  The remaining colorless oil is dissolved in acetole and saturated with anhydrous hydrogen chloride.  When adding ether, precipitates are white crystals.  1.2 g (56% of 3-ethyl-2- | methyl-4-oxo-4,6,7,8-tetrahydropyrrolo (1,2-a) pyrimidine hydrochloride, t. square  182C.  Calculated,%: C 55.94, H 7.04, N 13.04; C1 16.51.  C plt -NiOCl Found: C 56.18, H 7.12, N 12.86; C1 16.32.  Example 29  1.96 g of 2-amino-5-methylpyrroline and 3.84 g of methyl-2-.  -formylphenyl acetate in 20 ppm of ethanol is boiled for 5 hours.  The solvent is distilled off.  The remaining oil is treated according to Example 8.  1.08 g (24%) of 3-phenyl-6-methyl-4-oxo-4, 6,7,8-tetrahydropyrrolo (1,2-a) pyrimidine is obtained, which after recrystallization from a mixture of acetone and ether melts at 118 -122 0.  Calculated,%: C 74.14, H 6.22, N 12.35,.  Found  %: C 74. 15.  H 6. 21,  N 12.48.  An additional 1.5 g (33%) of 3-phenyl-6-methyl-2-oxo-2, 6,7,8-tetragndropyrrolo (1,2-a) pyrtilaine is obtained, which after recrystallization from isopropanol melts at 178 ° C.  Calculated,%: C 74.14, H 6.22, N 12.35.  C 44l4N ,, 0.  :.  .  .  : Found,%: C, 73.80; H, 6.15; N, 12.33.  Example 30  1 g of 4-bccc-4,6 ,, 8-tetrahydropyrrolo (1,2-9) pyrimndin-3-carboxylic. the acids are dissolved in 50 ml of ethanol, cooled at.  The mixture is saturated with gaseous hydrogen chloride, after 24 hours the mixture is concentrated, the residue is dissolved in water and neutralized with 5% -lc (weight. (volume) sodium bicarbonate solution.  The neutral solution is extracted three times with 10 l of benzene, the combined benzene solution is dried with anhydrous sodium sulfate, filtered, and evaporated.  Obtain 0.89 g of ethyl 4-oxo-4,6,7,8-tetrahydropyrrolo (1,2-a) pyrimidine-3-carboxylate, which is recrystallized from ethyl acetate, t. square  5960 S.  The test compounds were administered; to rats intravenously in the form of aqueous solutions.  Test data are given in the table.
    ETHIL-4-OXO-4,6,7,8-t 5GrGIDropyrrolo (1,2-a) pyrimidy-3-carboxylate
    ETHIL-2-OXO-2,4,6,8-tetrahydropyrrol (1,2-a) pyrimidine-3-carboxylate
    53.6
    10 10
    40.5
    13, 104898614
    4-OXO-4,6,7,8-tetrahydropyrrolo C1,2-a) pyrimidine-3-carboxylate 10 55.0
    papaverine2 36.9
    Table continuation
    权利要求:
    Claims (1)
    [1]
    The method of obtaining 3-substituted tetrahydropyrrolo (1,2-a) pyrimidines) of the general formulas (I) and. (11) distinctions, 2-amino-1-pyrroline of the general formula (III) q ’· is used as the 1-pyrroline derivative
    To where R has the indicated meanings as the “derivative of a carboxylic acid •” is an ester of acrylic acid of the general formula (IV)
    WWT'nS ” 1
    b. / X with KO COOK o · where R has the indicated meanings;
    R ^ 1 is C-alkyl, .- phenyl, cyano or C 2 _5-alkoxycarbonyl;
    r4 is hydrogen or C-alkyl;
    R 5 -, C And _ 4 -alkyl, and the process is carried out in an inert solvent, preferably in ethanol, at a temperature of from -10 ° C 'to the boiling point of the reaction mixture with the following isolation of the target product as a mixture of compounds of formulas' (I) and (II), or by isolating each of the isomers in the form of a base or an acid addition salt, or by hydrolysis, of compounds of formulas (I) or (II) where R 1 is said alkoxycarbonyl to obtain compounds I or II, where R 1 is carboxyl or ammonolysis of compounds of formulas (I) or (II), wherein R 1 - carboxyl, for the preparation of compounds I or II, rD R 1 - carbamoyl or gidrdzinolizom compounds I or II, wherein R '- carboxy to obtain the compounds of formulas (I) or (II), wherein R 1 - karbogidrazidogruppa or alkylation to obtain quaternary salts and isolation of the desired product.
    >
    where R is hydrogen or alkyl;
    R 1 - -alkyl, phenyl, carboxyl, carbamoyl / C-alkoxycarbonyl. carbamoyl, C-alkoxycarbonyl, cyano- or carbohydrazi g- group;
    R is hydrogen or C ^ -alkyl, ig. acid addition or quaternary salts by the reaction of a derivative of 1-pyrroline and a derivative of a carboxylic acid, characterized in that, in order to increase the yield and expand the range of obtained soyoic acid, an acrylic acid ester of the general formula
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    AU539466B2|1984-09-27|
    PL123709B1|1982-11-30|
    SE437030B|1985-02-04|
    ES491153A0|1981-04-16|
    CS221550B2|1983-04-29|
    DK152501C|1988-08-08|
    IT8067738D0|1980-05-09|
    JPS565479A|1981-01-20|
    BE883215A|1980-09-01|
    CA1149806A|1983-07-12|
    IT1147735B|1986-11-26|
    NL8002682A|1980-11-13|
    DE3017625A1|1980-11-20|
    IL59987A|1984-04-30|
    GB2049694B|1983-05-18|
    YU122080A|1983-02-28|
    US4367229A|1983-01-04|
    AU5827680A|1980-11-13|
    LU82435A1|1980-07-31|
    PL224124A1|1981-02-13|
    DK152501B|1988-03-07|
    SE8003477L|1980-11-12|
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    ES8104293A1|1981-04-16|
    PT71211A|1980-06-01|
    NO155773C|1987-05-27|
    NO155773B|1987-02-16|
    AR225308A1|1982-03-15|
    FI70218C|1986-09-15|
    HU176942B|1981-06-28|
    GB2049694A|1980-12-31|
    NO801376L|1980-11-12|
    FI70218B|1986-02-28|
    FR2456105B1|1984-08-10|
    DD150612A5|1981-09-09|
    IL59987D0|1980-07-31|
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    CH649551A5|1985-05-31|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE1803758U|1959-09-03|1960-01-07|Eugen Haller|SPLASH AND CHIP PROTECTION DEVICE.|
    AT286990B|1966-11-02|1971-01-11|Chinoin Gyogyszer Es Vegyeszet|Process for the preparation of new homopyrimidazole derivatives and their salts|
    DE1803785A1|1968-10-18|1970-06-04|Hoechst Ag|Disubstd-6-oxo-tetrahydro-pyrimidines sedatives|
    BE788601A|1971-09-10|1973-03-08|Takeda Chemical Industries Ltd|PROCESS FOR PREPARING PYRIMIDINE DERIVATIVES|
    HU167676B|1972-11-29|1975-11-28|
    US4209622A|1973-03-30|1980-06-24|Chinoin Gygyszer es Vegyeszeti Termekek Gyara Rt.|3--6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine|
    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|
    JPH07334897A|1994-06-02|1995-12-22|Matsushita Electric Ind Co Ltd|Rotary head drum device|US4482557A|1979-05-11|1984-11-13|Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt.|3-Substituted-2-oxo-tetrahydro-pyrrol[1,2-a]pyrimidines having digitalis-like activity|
    CA1211111A|1982-02-15|1986-09-09|Isao Yanagisawa|Process for preparing novel pyrimidone compounds|
    US5344933A|1991-09-11|1994-09-06|Fuji Photo Film Co., Ltd.|Pyrrole ring-or condensed pyrrole ring-containing azomethine dye|
    ES2181162T3|1997-01-22|2003-02-16|Ciba Sc Holding Ag|PHOTOACTIVE BASES CONTAINING NITROGEN, BASED ON ALFA-AMINO-KETONES.|
    JP2000026465A|1998-07-14|2000-01-25|Fuji Photo Film Co Ltd|Pyrrolo[1,2-a]pyrimidine and thermally sensitive recording material using the same|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU79CI1930A|HU176942B|1979-05-11|1979-05-11|Process for preparing 2,3-disubstituted tetrahydro-pyrrolo!1,2-a!-pyrimidines|
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