HU198062B - Process for producing new pyrimidooxazine derivatives - Google Patents

Abstract

Novel pyrimido-(5,4b)(1,4)oxazine derivs., of formula (I), where R1 = H, 1-4C alkyl gp.; or phenyl gp.; R2: as in this case, a halogen atom, nitro gp., or 1-4C alkyl gp., are prepd. from cpds. of tautomeric formulae (IIa) and (IIb) and sulpho-chloride cpds. of general formula R2-SO2Cl (III), in the presence of a polar solvent and base. - Cpds. (I) are isolated and used as pharmaceutical intermediates.

Description

FIELD OF THE INVENTION This invention relates to novel 4-sulfonyloxy derivatives of the pyrimido [5,4-b] [1,4] oxazine compounds of formula (I). In formula (I)

R 'is C 1-4 alkyl and

R ³ is phenyl optionally substituted with C 1-4 alkyl.

The compounds of formula (I) are valuable intermediates in the preparation of novel pyridinoidoxazine derivatives having a cardiotonic (cardiacotonic (positive inotropic enhancement of myocardial capacity) activity at the 4-position, in particular amino or substituted amino groups. (see Hungarian Patent Application No. 195,822).

Sulfonic acid esters containing a pyrimido [5,4-b] [1,4] oxazine ring system have so far not been reported in the literature, only a few simple sulfonic acid pyrimidinyl esters are disclosed. so e.g. P. K. Bridson et al., Chem. Com 1977, 477, disclose the methanesulfonate of benzoylated guanosine, U.S. Patent No. 854,854. Belgian Patent No. 177,601 discloses pyrimidine III sulfonates containing thiophosphoric acid groups. Hungarian Patent Publication No. 4,198,125 discloses sulfonic acid esters of 2,4-diamino-6-hydroxy-pyrimidine.

According to the present invention, the compounds of formula I are prepared by reacting a pyrimido [5,4-b] [1,4] oxazine derivative of formula 11 wherein R ¹ is as defined above, in the presence of a polar solvent and a base. (III) compounds of formula wherein R ² is as defined above - is reacted with a sulfonic acid chloride, and isolated the compound of formula thus obtained (I).

In carrying out the process of the present invention, the solvent is preferably water, which partially dissolves the compound of formula (II) in the presence of a base. In order to dissolve the sulfonic acid chloride of formula (III), it is desirable to use a solvent which is at least partially miscible with water, preferably a lower aliphatic ketone such as acetone.

The base is preferably an alkali metal hydroxide, such as sodium hydroxide.

In a preferred embodiment of the process according to the invention, a solution of the sulfonic acid chloride in acetone is added dropwise at room temperature to an aqueous solution of the compound of the formula II and the reaction mixture is stirred at room temperature for several hours while the final product precipitates. The resulting crystalline product of formula (I) is isolated by filtration and, if desired, purified by boiling with organic solvent or recrystallization. Acetone is preferably used as the solvent.

Compounds of formula (II) are known (Him. Get. Sed. 1976, 681) or may be prepared by methods known in the art or analogously thereto.

The sulfonic acid chlorides of formula (III) are generally known commercially available compounds.

The sulfonyloxy group at the 4-position of the compound of formula (I) containing a R ² group is a reactive group and therefore has a nucleophilic group such as amines or

It is readily reacted with 57-substituted amines. Thus, the compounds of formula (I) may be widely used in the preparation of derivatives of the ring system containing nucleophilic groups at the 4-position, such as the cardiotonic agents described in the aforementioned Hungarian Patent Application No. 195,822.

The invention is illustrated by the following non-limiting examples.

Example 1 (2-Methyl-7-oxo-6,7-dihydro-4 (8H) -pyrimido [5,4-b] [1.4] oxazinyl) -benzenesulfonate

1.0 g (5.52 mmol) of 4-hydroxy-2-methyl-6,7-dihydro-7 (8H) -pyrimidine [5.4] [1,4] oxazinone is added in 8.85 ml of aqueous sodium hydroxide solution and stirring at room temperature for approx. A solution of benzenesulfonyl chloride (1.07 g, 6.08 mmol) in acetone (5.5 mL) was added dropwise over 1 hour, and the reaction mixture was stirred for an additional 4 hours. The precipitated crystalline product is filtered off, washed with cold water and then boiled with 200 ml of acetone. The insoluble material is filtered off (0.21 g of unreacted starting material), and after cooling, the precipitate is recrystallized from 200 ml of acetone. Yield: 0.73 g (41%), m.p. 211-214 ° C.

Example 2 (2-Methyl-7-oxo-6,7-dihydro-4 (8H) -pyrimido [5,4-b] '[1,4] xazinyl) -4-toluenesulfonate

135.8 g (0.75 mol) of 4-hydroxy-2-methyl-6,7-dihydro-7 (8H) -pyrimido [5,4-b] [1,4] oxazinone and 1205 ml (1.2 A solution of 157.2 g (0.83 mole) of 4-toluenesulfonyl chloride in 450 ml of acetone was added dropwise to a solution of 1N aqueous sodium hydroxide at room temperature over 3 hours, followed by stirring at room temperature for 4 hours. The precipitated crystals are filtered off with ca. Wash with 200 ml water. The crude product obtained was stirred in acetone (2200 ml) at 50 ° C for half an hour and the insoluble unreacted starting material was collected by filtration. The filtrate was evaporated and the precipitated crystals were collected, washed with a little acetone and dried. Yield: 140.8 g (56%), m.p. 184-186 ° C.

Example 3 Conversion of (2-Methyl-7-oxo-6,7-dihydro-4 (8H) -pyrimido [5,4-b] [1.4] oxazinyl) -4-toluenesulfonate to 2-methyl-4- [2 - (4-Morpholinyl) ethylamino] -6,7-dihydro-8H-pyrimido [5,4-b [1,4] oxazin-7-one salt (0.15 mol) prepared according to Example 2 Compound II, 20.73 g (0.15 mol) of anhydrous powdered potassium carbonate and 19.5 g (0.15 mol) of 4- (2-aminoethyl) morpholine in 1250 ml of abs. ethyl acetate was stirred at 20 ° C for 72 hours, then the insoluble material was filtered off and washed with ethyl acetate. The filtrate is extracted with 1N aqueous hydrochloric acid, then the combined aqueous phase is adjusted to pH 4-5 with 1N aqueous sodium hydroxide and extracted with dichloromethane. The pH of the aqueous phase is then adjusted to 9-10 by addition of additional IN sodium hydroxide and extracted with dichloromethane. The combined organic phases from the latter extraction were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue from the evaporation, the crude base of the title compound, was dissolved in acetone and calculated with stirring and cooling. ethanolic hydrogen chloride solution was added

198.062 added. The resulting precipitate was filtered off, washed with acetone and dried to give 27 g (50%) of dihydrochloride, m.p. 233-237 ° C (dec.). 5

The fumarate salt of the title base can be prepared as follows:

To a solution of the crude base (g) in ethanol (9 ml) was added a solution of fumaric acid (0.2 g) in ethanol (5 ml) at 70 ° C, and after cooling, the precipitated mixture was kept at 0 -4 ° C overnight. This gives a nearly quantitative yield of the fumarate of the title base, which contains the base in a molar ratio of 2: 1 to fumaric acid. Mp 215-216 ° C.

Claims (3)

A process for the preparation of pyrlmido [5,4-b] [1,4] oxazine derivatives of the formula I in which R 'is C 1-4 alkyl and R ² is phenyl optionally substituted with C 1 -C 4 alkyl, wherein a compound of formula II, wherein R ¹ is as defined herein, in the presence of a polar solvent and base, is a compound of formula III, wherein R ² is reacted with the sulfonic acid chloride described herein and the resulting compound of formula (I) is isolated. The process of claim 1, wherein the solvent is water and acetone. 3. The process according to claim 1 or 2, wherein the base is an aqueous sodium hydroxide solution.