FI68825B - GEMINALA DIHALOGENDERIV AV AVONDENSERADE PYRIMIDIN-4-ONER VILKA AER MELLANPRODUKTER VID FRAMSTAELLNING AV THERAPEUTIC ANAENDBARA 9-AMINOPYRIDO (1,2-A) PYRIMIDIN-OCH 9-HYDRATSONO-6,, 8,9-P-6,9-8,9-T -A) PYRIMIDINDERIVAT - Google Patents

Description

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C (45) Patent Dy ":. N; lty 11 11 1985 <51) κ, Λ.νι. <. Α. · C ° 7 0 471/04, 487/04 i £ | JQ | V || _P | | ^ | _ ^ | ^ Q (21) Patent application - Patentansökning 801512 (22) Application date - Ansökningsdag 09-05.80 (23) Start date - Giltighetsdag 09-05-80 (41) Published public - Blivit offentllg 12 11 80

National Board of Patents and Registration, .... .....,. , u, * # (44) To see the input and hear. publication date— ·} ·. n-ι or

Patent and registration authorities '' Ansökan utlagd och utl.skriften publicerad ^ .u / -OJ

(32) (33) (31) Privilege claimed - Begärd priority 1 1-05-79

Hungary-Hungary (HU) CI -1932 (71) Chinoin Pharmaceuticals and Pharmaceuticals Gyära R.T., 1-5 To utea, 1045

Budapest, Hungary-Hungary (HU) (72) Istvan Hermecz, Budapest, _ Tibor Breining, Budapest, Lei le Vasväri nde Debreczy, Budapest, Agnes Horväth, Budapest, Zoltän Mdszäros, Budapest, Istvän Bitter, Budapest, Jözsef Kökösi, Budaörs,

Hungary-Ungern (HU) (Jk) Oy Kolster Ab (5 * t) Geminal dihalogen derivatives of condensed pyrimidin-4-ones, which are therapeutically useful in the preparation of intermediates for 9-aminopyrido / Ί, 2-a7pyrimidine and 9- hydrazono-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine derivatives and geminal compounds are diluted in the form of condensed pyrimidin-4-one, which is a useful product in the form of a therapeutically active compound 9-aminopyrido / 1, 2-α-pyrimidine and 9-hydrazone, 7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine

The invention relates to geminal dihalogen derivatives of fused pyrimidin-4-one compounds. The compounds are valuable intermediates in the preparation of compounds with antiallergic and / or antiasthmatic properties, * // (C 07 D 471/04, C 07 D 221: 00, C 07 D 239: 00), (C 07 D 487/0 * 1, C 07 D 225: 00, C 07 D 239: 00), (C 07 D 487/04, C 07 D 209: 00, C 07 D 239: 00) 2 63825

It is known that pyrimidine compounds have analgesic and other central nervous system activity (GB Patent No. 1,209,946). A typical representative of these compounds is 3- (ethoxycarbonyl) -1,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidinium methosulfate Probon, Rimazolium), which has very good analgesic potency and is widely used in therapy (Arzneimittel-Forschung 22, 1972, 815).

The present invention relates to geminal dihalogen derivatives of condensed pyrimidin-4-ones which are therapeutically useful in the preparation of intermediates 9-aminopyrido [1,2-a] pyrimidine and 9-hydrazino-6,7,8,9-tetrahydro-4H-pyrido [1 , 2-α / pyrimidine derivatives and having the general formula

XX

V N R

-rYY

II

o wherein R is hydrogen or C 1-4 alkyl, R 1 is C 1-4 alkyl, carboxy, C 1-4 alkoxycarbonyl, carbamoyl, carbonitrile, phenyl or halogen, R is hydrogen, C 1-4 alkyl, N-alkyl or phenyl, X is halogen, n is 0, 1 or 2, and the optically active antipodes and salts of these compounds.

3,60825

The term "halogen" means chlorine, bromine or iodine.

Preferred compounds of the invention are those compounds of formula I wherein R is hydrogen, C 1-6

1 x H

alkyl, preferably methyl, R is carboxy, C 1-4 alkoxycarbonyl, preferably methoxycarbonyl or ethoxycarbonyl, cyano, carbamoyl, phenyl, R is hydrogen, C 1-4 alkyl, preferably methyl, X is chlorine or bromine, and n is 0, 1 or 2.

Also included within the scope of the invention are optical isomers of the compounds of general formula I.

The novel compounds of the general formula I and their pharmaceutically acceptable salts and optically active isomers can be prepared, for example, by the following process alternatives (a) or (b): a) a monohalogen compound of the general formula:

X

rVY '

r — f— I II

O

1 2 wherein R, R, R, X and n are as defined above is reacted with a halogenating agent, or 4 63825 b) a compound of general formula:

Υ ^ γ K Y R2 III

wherein R, R, R and n are as defined above, are reacted with a halogenating agent, and in the obtained compound of general formula I, the group R 1 is optionally converted to another group R, and the resulting racemate of formula I is optionally divided into optically active antipodes.

According to process variant a), a compound of general formula II in which R, R, R, X and n have the same meaning as above is reacted with at least one equivalent of a halogenating agent. The halogenating agent is preferably used in an amount of 1 to 1.5 molar equivalents.

According to process variant b), a compound of the general formula III in which R, R, R and n have the same meaning as above is reacted with at least two molar equivalents of a halogenating agent. The halogenating agent is preferably used in an amount of 2 to 2.5 molar equivalents per mole of the compound of formula III.

As the halogenating agents, ordinary known halogenating agents can be used. Preferably, halogens such as bromine, chlorine or iodine, halogen compounds such as bromochloride, iodine chloride, etc., and other halogen derivatives such as sulfuryl chloride, phosphorus pentachloride, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, , 5-dimethylhydantoin, N-bromocaprolactam, tribromoacetophenone, trichloromethanesulfuryl bromide and chloride, tert-butyl hypochlorite, hypobromite and hypojodite, 1,2,4,6-tetrachloro-68825 riacetan dibromotetrachloroethane, copper (II) bromide and chloride, and halogen complexes such as pyridinium bromide perbromide, phenyltrimethylammonium perbromide, tetramethylammonium tribromide, preferably in the presence of alum bromide, dioxane tribromide, trirolidone-2-hydro-pyrrolidone-2-hydro or in the presence of chloride, phosphorus trichloride, sulfur, calcium oxide or dibenzoyl peroxide or using UV irradiation.

The halogenation is carried out in a conventional manner. Compounds of general formula II or formula III, respectively, are generally reacted with a suitable halogenating agent in an inert solvent, e.g. an alkanecarboxylic acid, a halogenated hydrocarbon, etc., preferably acetic acid or chloroform. Optionally, an acid scavenger such as triethylamine, acetamide, sodium acetate, etc. may also be used in the reaction.

The reactions are carried out at temperatures of 0 to 160 ° C, preferably 20 to 60 ° C. The compounds of formula I or their salts either precipitate from the reaction mixture and can be filtered off, or are separated from the reaction mixture by evaporation of the solvent. The compounds of general formula I can be purified by conventional methods such as crystallization, chromatography, etc.

The compound of general formula I obtained can, if desired, be converted into another compound of general formula I by methods known per se. The change can occur with respect to the group R 1. Thus a compound of general formula I wherein R 1 is carboxy may be decarboxylated in an organic solvent, e.g. lower alkanecarboxylic acid, lower alkanol or the like, or in an inorganic solvent, e.g. water, at a temperature of 0-200 ° C, optionally with a mineral acid such as hydrochloric acid or sulfuric acid. acid. Compounds of general formula I wherein R is hydrogen and R, R, X and n are as defined above are isolated and then reacted with one molar equivalent of Valentine as a halogenating agent. In this way, compounds of general formula I are obtained in which R1 is halogen.

6 68825

Compounds of formula I in which R does not represent hydrogen have a center of asymmetry. Optically active antipodes of the compounds of general formula I can be prepared using optically active compounds of general formulas II or III as starting materials. Alternatively, the racemate of general formula I obtained can be divided into optically active isomers in a manner known per se. Compounds in which Rx represents carbonyl can be resolved by reacting the racemate with a suitable optically active base (e.g. optically active threo-1- (p-nitrophenyl) -2-aminopropane-1,3-diol) and separating the diastereomeric salts formed on the basis of physical properties. , for example by crystallization, and liberating the optically active antipode from the salt, for example by reacting it with a strong base.

1 2

Compounds of general formula III in which R, R, R and n have the same meaning as above are known from the applicant's previous patents (see HU patents 156,119, 158,085, 162,384 and 162,373 and NL 7,212,286) and can be prepared by the methods described in these patents.

The compounds of general formula II are known (Arzneimittel Forschung, 1972, 22, 815) or can be prepared by methods known from the literature.

The advantages of the compounds according to the invention are as follows: A. The reaction of dihalogen derivatives (1) with amino compounds (2) directly gives 9-amino-6,7-dihydro-4H-pyrido [1,2-a] pyrimidines (3): R2 XX '' N ">. N N.

R -4-1 | + HN 1 ->! i I & (1) (2) (3) (FI application 801511 = pat. 67549) 7 68825 while the reaction of monohalogen derivatives (4) with amines (2) in the first step leads to tetrahydro derivatives (5); which are oxidized in the next step: <m ^ r2

X N

J- ..Ν 1 X

r— I + hn „—7- \:

i N 1 N L

^ '' R3 / <- 'R3 a R 5 o 6 (4) (2) (5) ° 2' /

Rv. r2 N

i T J

r ä (3) (FI application 784014 = pat. 65620).

If the latter method is carried out in an inert atmosphere, no oxidation occurs and the tetrahydro derivatives (5) can be separated. In solution, the compounds (5) are oxidized when air is introduced into the solution, which indicates that the oxidation takes place with the oxygen contained in the air.

An example is: 8 68825! j i f [) Y 'o

NH 2 NH

I N In rr i rr i. N I I N.

'^ γ "^ COOH' N ^ '" cooh

R O R O

R = H (6) m.p. 178-180 ° C (7) m.p. 197-198 ° C

R = CH3 (8) m.p. 198-199 ° C (9) m.p. 172-173 ° C

k; j v v

CH3-N 02 CH3_N

! n In C f Ί fr'i N .. N l '^^ COOEt "Y' '" j ^^ COOEt CH3 0 CH3 o

(10) sp. 175-178 ° C (11) m.p. 140-142 ° C

When the amines (2) are reacted with the monohalogen derivatives (4) in a relatively small amount (up to 0.1-0.3 mol) in an open vessel under vigorous stirring, the oxidation takes place automatically. If the amount of the reaction components is increased, the oxidation takes place partially and a mixture of oxidized compounds (3) and non-oxidized compounds (5) is obtained. For example, if the reaction mixture contains 0.5 mol of starting material, then the non-oxidized tetrahydro derivative (5) can be isolated from the crude product as follows: 9 68825 for compound (7) about 15-20% for compound (9) about 20-25% for compound (11) about 50 % in the case of compound (12) about 20-25%

Br ·. '· -> · Λ · \

'-COOH

I il

CH? O

(12)

Separation of tetrahydro compounds (5) and dihydro compounds (3) is possible only with maximum losses. When air is introduced directly into the reaction mixture in the process, the products obtained are highly impure, probably due to the decomposition of unreacted amines. It is well known that amines, especially aromatic amines and aniline derivatives, are very sensitive to oxidizing effects.

B. The reaction between compounds (4) and hydrazine derivatives (13) is a redox event:

R1 R2 I

X N

I N, 1 N, I I + 2NH9N j -> - I + NH .X + HN ~

I N ·, ^ R L / l q R

V 3 R 3 / T T 3 R 0 R 6 (4) (13) (14) 68825 10 in which at least 2 molar equivalents of hydrazine must be used. If less hydrazine is used, the reaction will not proceed completely. In contrast, for the reaction of the dihalogen derivatives (1), 1 mole of hydrazine is sufficient: R1 ^ .R2 * .χ ί> R1 * »·> K -OUV f '^

R —-r— I + NH „N --- - - | I

i N> 2 ^ R ^ acid 1 N II ^ '' vA A A ^ R binding R ^ O substance R & (1) (13) (14) (FI application 801513)

It should be noted that the price or manufacturing cost of some hydrazine derivatives is very high. Thanks to the invention, half the amount of hydrazine can be saved.

In summary, the advantage of dihalogen derivatives (1) over monohalone derivatives is: A. In the reaction with amines (FI application 801511) 1. the reaction takes place in one step 2. no oxidizing tetrahydro derivative is present in the final product, even if large amounts of reaction components are needed in the 3rd reaction oxygen (and even if needed, it is still possible to work in an inert atmosphere) so that the decomposition product of amines does not contaminate the products, so the final product is obtained purer.

B. In the reaction with hydrazines (FI application 801513) it is necessary to use less hydrazine than in the case of monohalogen derivatives (4), so the use of the compounds according to the invention is economical.

il 6 8 8 2 5

The invention is further illustrated by the following examples.

Example 1 9,9-Dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid 1.4 g (0.005 mol) 9 -Bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid is dissolved in 15 ml of chloroform dried over sodium sulfate. 0.3 ml (0.005 mol) of bromine in 5 ml of chloroform are added dropwise to the solution with stirring at room temperature. The reaction mixture is then stirred for 0.5 hours and allowed to stand overnight. The precipitated crystals are filtered and washed with a small amount of chloroform.

10 ml of water and 10 ml of chloroform are added, the pH of the aqueous phase is adjusted to 2 by adding 5% sodium hydrogen carbonate solution with stirring. The organic phase is separated and the aqueous phase is shaken with chloroform (2 x 10 ml). The combined organic phases are dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue is crystallized from methanol to give 0.3 g (16.4%) of 9,9-dibromo-6-methyl-4-oxo-6.7.8.9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylate. acid, m.p. 165-166 ° C.

Analysis for c 10 H 10 N 2 O 3 Br 2

Calculated: C 32.81%, H 2.75%, N 7.65%, Br 43.65%

Found: C 33.22%, H 2.78%, N 7.65%, Br 43.58%.

68825

Example 2 9.9-Dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid 1.4 g (0.005 mol) of 9-bromo Dissolve 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid in 30 ml of glacial acetic acid. 0.3 ml (0.005 mol) of bromine in 2 ml of glacial acetic acid are added dropwise to the solution with stirring at room temperature. The reaction mixture is stirred at 40-60 ° C for 0.5 hours, then the glacial acetic acid is evaporated off under reduced pressure. To the residue are added 10 ml of water and 10 ml of chloroform, and the pH of the aqueous phase is adjusted to 2 by adding, with stirring, 10% sodium hydrogen carbonate solution. The organic phase is separated, the aqueous phase is shaken with chloroform (2 x 10 ml). The combined organic phases are dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue is crystallized from methanol to give 0.8 g (53.8%) of 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid, m.p. 164-166 ° C. When the compound obtained by mixing with the compound prepared in Example 1, the melting point did not decrease.

Example 3 9.9-Dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid 14 g of crystalline sodium acetate and 10.4 g (0.05 moles) 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid is dissolved in 100 ml of glacial acetic acid. 5.4 ml (0.1 mol) of bromine are added dropwise to the solution at room temperature while stirring slowly, then the reaction mixture is stirred at room temperature for 2 hours, after which the solvent is distilled off under reduced pressure. To the residue are added 50 ml of water and 50 ml of chloroform, the pH of the aqueous phase is adjusted to 2 by adding, with stirring, 5% sodium hydrogen carbonate solution. The organic phase is separated, the aqueous phase is shaken with chloroform (2 x 50 ml). The combined organic phases are dried over anhydrous sodium sulfate, and the solvent is evaporated off under reduced pressure. The residue is crystallized from methanol to give 9.4 g (51.3%) of 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid, m.p. 165-166 ° C. It does not cause a decrease in melting point when mixed with the compounds prepared in Examples 1 and 2.

II

13 68825

Example 4 (+) - 9,9-Dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid Following the procedure described in Example 2, but using optically active (+) - instead of racemic (+) - 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid 9-Bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid is obtained in a yield of 49.0% (+ ) -9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid, m.p. 157-159 ° C. [.Alpha.] D @ 20 = + 47.5 DEG (c = 1, methanol).

Analysis for the formula cioH10N2 ° 3Br:

Calculated: C 32.81%, H 2.75%, N 7.65%, Br 43.66%

Found: C 33.11%, H 2.60%, N 7.56%, Br 43.44%

Example 5 (+) - 9,9-Dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [7,2-a] pyrimidine-3-carboxylic acid Following the procedure described in Example 3, but using optically active (-) - 6-methyl-4- instead of racemic (+) - 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid, (+) - 9,9-dibromo-6-methyl-4-oxo-6 is obtained, 7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid, m.p. 157-158 ° C. When mixed with the compound prepared in Example 4, the melting point does not decrease. Yield 51.2%, m.p. = + 47.5 ° (c = 1, methanol).

Example 6 (-) - 9,9-Dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [2,2-a] pyrimidine-3-carboxylic acid Following the procedure described in Example 2, but using the racemic Instead of (+) - 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid, optically active (-) - 9-bromo- 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid is obtained in a yield of 49.5% of (-) - 9,9-dibromoacid. 6-methyl-4-oxo, 6,7,8,9-tetrahydro-4H-pyrido [7,2-a] pyrimidine-3-carboxylic acid, m.p.

157-159 ° C. [.Alpha.] D @ 20 = -47.5 DEG (c = 1, methanol).

Analysis for c 10 H 10 N 2 O 3 Br 2

Calculated: C 32.81%, H 2.75%, N 7.65%, Br 43.65%

Found: C 33.21%, H 2.72%, N 7.60%, Br 43.62% 14 6882 5

Example 7 (-) - 9,9-Dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidinecarboxylic acid

Following the procedure described in Example 3, but replacing racemic (+) - 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid with an optically active (+ ) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H- [1,2-a] pyrimidine-3-carboxylic acid is obtained in 51.5% yield (-) - 9 , 9-di-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid, m.p. 157-159 ° C. λ = -47.5 ° (c = 1, methanol). When mixed with the compound prepared in Example 6, the melting point does not decrease.

Examples 8-11 1.4 g of crystalline sodium acetate and 0.005 mol of the starting material shown in Table 1 are dissolved in 10 ml of glacial acetic acid. 0.54 ml (0.01 mol) of bromine are added dropwise to the solution at room temperature with stirring at low speed. The reaction mixture is then stirred for 2 hours at room temperature, then the acetic acid is distilled off under reduced pressure. 10 ml of chloroform are added to the residue, and the suspension is stirred for 15 minutes at room temperature. The crystals are filtered and washed with chloroform. The filtrate is evaporated and the residue is crystallized from the solvent mentioned in Table I.

Examples 12-17 1.4 g of crystalline sodium acetate and 0.005 mol of the starting material shown in Table II are dissolved in 10 ml of glacial acetic acid. 3.2 g (0.01 mol) of pyridinium bromide perbromate are added portionwise to the solution with stirring at room temperature. The reaction mixture is then stirred at room temperature for 2 hours, and acetic acid is then distilled off under reduced pressure. To the residue is added 10 ml of water and shaken with chloroform (3 x 10 ml). The combined organic phases are dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, and the residue is crystallized from methanol.

Examples 18-20 0.05 moles of the starting material shown in Table III are dissolved (suspended in 80 ml of dichloromethane, and 13.5 g (0.1 moles) of sulfuryl chloride in 20 ml of dichloromethane are added to a solution of 68825 (suspension) at room temperature. until gas evolution ceases (3-4 hours), the solvent is distilled off and the residue is crystallized from ethanol in 70-80% yields, and the compounds obtained are listed in Table III.

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Example 21 3.9.9-Tribromo-6-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one 2.2 g of crystalline sodium acetate and 0.8 g (0 .05 moles) 6-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one is dissolved in 10 ml of glacial acetic acid. 1.0 ml (0.101 mol) of bromine are added dropwise to the solution with stirring at room temperature. The reaction mixture is stirred at 50-60 ° C for 0.5 hours, then the acetic acid is distilled off under reduced pressure. 10 ml of chloroform are added to the residue, and the suspension is stirred at room temperature for 15 minutes. The crystals are filtered and washed with chloroform. The filtrate is evaporated in vacuo. Crystallization of the residue from methanol gives 1.5 g (74.8%) of 3,9,9-tribromo-6-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one, mp. 157-159 ° C.

Analysis for CnH_No0Br ^ y y 2. 3

Calculated: C 26.96%, K 2.26%, N 6.98%, Br 59.79%

Found: C 26.80%, H 2.06%, N 7.00%, Br 59.00%

Example 22 9.9-Dibromo-3,6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one

Following the procedure described in Example 8, but starting from 3,6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one, 9,9-dibromo-3, 6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one, m.p. 114-115 ° C, yield 30.0%.

Analysis for C 18 H 12 N 2 OBr 2

Calculated: C 35.74%, H 3.59%, N 8.34%, Br 47.56%

Found: C 35.74%, H 3.72%, N 8.22%, Br 47.85%

Example 23 9.9-Dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid 6-methyl-4-oxo-6,7 To a solution of 8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid (2.1 g, 0.01 mol) in 20 ml of chloroform is added portionwise with stirring, 3.6 g (0 .02 moles) of N-bromosuccinimide. The reaction mixture is refluxed for 5 hours, then the chloroform is distilled off under reduced pressure. 20 ml of water are added to the residue, and the suspension is stirred at room temperature for 15 minutes. The precipitated crystals are filtered off, dried and recrystallized from methanol to give 1.5 g (41.0%) of 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H- pyrido [1,2-a] pyrimidine-3-carboxylic acid, m.p. 163-164 ° C.

When the product is mixed with the product obtained in Example 1, the melting point does not decrease.

Example 24 9.9-Dichloro-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid 6-methyl-4-oxo-6,7 To a solution of 8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid (1.04 g, 0.005 mol) in 10 ml of chloroform is added, with stirring, 1.33 g (0.01 mol) in small portions. n-chlorosuccinimide. The reaction mixture is then refluxed for 5 hours, and chloroform is distilled off under reduced pressure. 10 ml of water are added to the residue, and the suspension is stirred at room temperature for 15 minutes. The crystals are filtered off, dried and recrystallized from methanol. 0.7 g (50.5%) of 9,9-dichloro-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid are obtained , sp. 190-191 ° C.

By mixing the product obtained with the product prepared in Example 18, the melting point does not decrease.

Example 25 9.9-Dibromo-3-ethyl-2,6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one

Following the procedure described in Example 8, but using 3-ethyl-2,6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid instead of 6-ethyl-2,6 -dimethyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one and crystallization of the crude product from a 50% aqueous-ethanol mixture gives 9,9-dibromo-3-ethyl- 2,6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one, m.p. 90-92 ° C. Yield 57.2%

Analysis of the formula

Calculated: C 39.59%, H 4.43%, N 7.69%, Br 43.9%

Found: C 39.21%, H 4.25%, N 7.59%, Br 43.76% 22,68825

Example 26 9,9-Dibromo-3-phenyl-6-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one

Following the procedure described in Example 8, but using 3-phenyl-6-methyl instead of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid - 6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one and crystallization of the crude product from ethanol gives 9,9-dibromo-3-phenyl-6-methyl-6,7, 8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one, m.p. 154-156 ° C. Yield 70.4%.

Analysis for the formula C ^ H ^ N ^ Br ^

Calculated: C 45.26%, H 3.54%, N 7.04%, Br 40.14%

Found: C 45.26%, H 3.54%, N 7.21%, Br 40.25%

Example 27

Ethyl 8,8-dibromo-4-oxo-6,7,8,9-tetrahydropyrrolo [1,2-a] pyrimidine-3-carboxylate 2.08 g (0.01 mol) of ethyl 4-oxo- 4,6,7,8-Tetrahydro-pyrrolo [1,2-a] pyrimidine-3-carboxylate is dissolved in 10 ml of 75% (v / v) aqueous acetic acid, and 2.72 g are added to the solution. (0.02 moles) of sodium acetate. 3.2 g (0.02 mol) of bromine in 10 ml of 75% (v / v) acetic acid are then added dropwise. The reaction mixture is stirred at 60 ° C for 0.5 h, diluted with 150 mL of water, and shaken with chloroform (3 x 4 mL). The combined chloroform extracts are dried over sodium sulfate and evaporated to dryness. The oily residue obtained crystallizes on standing. Crystallization of the crude product from ethanol gives 2.2 g (60%) of ethyl 8,8-dibromo-4-oxo-6,7,8,9-tetrahydropyrrolo [1,2-a] pyrimidine-3-carboxylate, m.p. 90-100 ° C. Analysis for C 10 H 10 N 2 O 3 Br 2

Calculated: C 32.81%, H 2.75%, N 7.65%, Br 43.66%

Found: C 33.28%, H 2.62%, N 7.52%, Br 43.27%

Example 28

Ethyl 10,10-dibromo-5,6,7,8,9,10-hexahydro-4H-pyrido / 1,2-a / azepine-3-carboxylate

Following the procedure described in Example 27, but using ethyl 4-oxo-5,6,7 instead of ethyl 4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a] pyrimidine-3-carboxylate, 8,9,10-hexahydro-4H-pyrimido [1,2-a] azepine-3-carboxylate and reacting at 90 ° C for 1 hour gives 2.1 g (53%)

II

23 6 8 8 2 5 Ethyl 10,10-dibromo-5,6,7,8,9,10-hexahydro-4H-pyrido [1,2-a] azepine-3-carboxylate. Rf = 0.8 (benzene-methanol 4: 1, silica gel 60 F254)

Analysis for c 12 H 14 N 2 O 3 Br 2

Calculated: C 36.57%, H 3.58%, N 7.10%, Br 40.55% Found: C 36.32%, H 3.49%, N 7.02%, Br 41.02% .

Example 29 3.9.9-Tribromo-2-phenyl-6-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one

Following the procedure described in Example 21 but substituting 6-methyl-6,7,3,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one 2-phenyl-6-methyl-6,7,8 1,9-Tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one gives 3,9,9-tribromo-2-phenyl-6-methyl-6,7,8,9-tetrahydro-4H-pyrido. [1,2-a] pyrimidin-4-one, m.p. 164-166 ° C, yield 54.5%.

Analysis for ci5Hi3N2OBr3

Calculated C 37.77% H 2.75% N 5.87% Br 50.26%

Found C 38.04% H 2.88% N 5.95% BR 49.30% Example 30 3.9.9-Tribromo-6-methyl-6,7,8,9-tetrahydro-4H-pyrido / 1,2 α-pyrimidin-4-one To 10 ml of anhydrous ethanol is added 1.0 g (0.005 mol) of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] / pyrimidine-3-carboxylic acid, 0.3 g (0.005 mol) of potassium hydroxide and 2.7 g (0.02 mol) of sodium acetate. 1.01 ml (0.02 mol) of bromine are then added dropwise to the suspension at room temperature with stirring. Stirring is continued for 1 h, then the reaction mixture is evaporated to dryness in vacuo and 10 ml of water are added to the residue and extracted with three 5 ml portions of chloroform. The combined organic phases are dried over anhydrous sodium sulfate and the solvent is evaporated off. The residue is recrystallized from methanol. 0.4 g (20.0%) of 3,9,9-tribromo-6-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one are obtained, which, when mixed with the product obtained in Example 21, does not lower the melting point. Sp. 156-157 ° C.

24 6 8 8 2 5

Example 31 9.9-Dibromo-6-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one 1.6 g (0.01 mol) are dissolved in 20 ml of glacial acetic acid. 6-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one and 2.8 g (0.02 mol) of sodium acetate. To the solution is added in small portions 6.4 g (0.02 mol) of pyridinium perbromide at room temperature while stirring. The reaction mixture is stirred at room temperature for 30 minutes, after which the solvent is distilled off under reduced pressure. 10 ml of water are added to the residue, and the mixture is stirred at room temperature for 30 minutes. The crystals are collected by filtration and washed with a small amount of water. This gives 0.5 g (15.6%) of 9,9-dibromo-6-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one, m.p. 130-132 ° C.

Analysis for C9H10N2OBr2

Calculated C 33.57% H 3.13% N 8.70% Br 49.63%

Found C 33.76% H 3.09% N 8.67% Br 49.49%

Example 32 3.9.9-Tribromo-6-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one 3.2 g (0.01 mol) of glacial acetic acid are dissolved in 20 ml of glacial acetic acid. , 9-dibromo-6-methyl-6,7,8,9-tetrahydro-4H-pyrido / l, 2-a / -pyrimidin

4-one and 1.4 g (0.01 mol) of sodium acetate. To the resulting solution is added 0.54 g (0.01 mol) of bromine dropwise at room temperature with stirring. Stirring is continued for 30 minutes, after which the solvent is distilled off under reduced pressure. 10 ml of water are added to the residue. The mixture is extracted with three 5 ml portions of chloroform. The combined organic phases are dried over anhydrous sodium sulfate and evaporated to dryness. The residue is recrystallized from methanol to give 2.2 g (55.0%) of 3,9,9-tribromo-6-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a]. / pyrimidin-4-one which, when mixed with the product obtained in Example 21, does not lower the melting point. Sp. 156-159 ° C

Claims (1)

Geminal dihalogen derivatives of condensed pyrimidin-4-ones which are therapeutically useful in the preparation of intermediates for the preparation of 9-aminopyrido [1,2-a] pyramidine and 9-hydrazino-6,7,8,9-tetrahydro- 4H-pyrido [1,2-a] pyrimidine derivatives of the general formula XX ~ I! o wherein R is hydrogen or C 1-4 alkyl, is C 1-4 alkyl, carboxy, C 1-4 alkoxycarbonyl, carbamoyl or carbonitrile, phenyl-X 4 2 or halogen, R is hydrogen, C 1-4 alkyl; alkyl or phenyl, X is halogen and n is 0, 1 or 2, and their optically active antipodes and salts.