The method of obtaining benzopyrano compounds, intermediate compounds and methods for their production

 

(57) Abstract:

Describes how to obtain substituted benzopyrano derivatives, including at the last stage the cyclization of the corresponding intermediate compounds with an open circuit. 7 C. and 1 C. p. F.-ly.

The invention relates to a new method of preparation of some substituted benzopyrano compounds, to intermediate compounds useful in this method, and the method of production of intermediate compounds.

Substituted benzopyrano compounds known from the prior art. For example, EP 0 173 516-A discloses a class of substituted benzopyrano compounds described as compounds having activity as leukotriene antagonists and are useful in therapy for the treatment of, for example, diseases caused by leukotrienes and 5-reductase.

The invention relates to a new method of obtaining some of benzopyrano compounds described in EP 0 173 516-A, and in particular offers an effective way of obtaining compounds, including much less reaction stages than described so far. Reducing the number of reaction stages in obtaining the desired products results in a much more efficient way than Pte method of obtaining compounds of structure (I):

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where:

R1represents a group of the structure:

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R2represents hydrogen or C1-6alkyl;

R3represents hydrogen;

A represents a single bond; and

X represents oxygen;

or its salt, MES or hydrate, which involves the cyclization of compounds of structure (II):

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or its salt, hydrate or MES, where R1, R2, R3, A and X have the same meaning as described for structure (I), and obtained then, if necessary, its salts, MES or hydrate.

R2represents preferably hydrogen.

The cyclization of compounds of structure (II) is conducted in an appropriate manner in the presence of acid. For example, the cyclization can be carried out in the presence of sulfuric acid, in methanol or in acetic acid as solvent. Preferably, the reaction is carried out in a solvent mixture of methanol/tetrahydrofuran in the presence of hydrochloric acid. Alternative conditions acid/solvent obvious to experts and include, for example, acids such as Hydrobromic or idiscovered acid, perchloric acid or toluensulfonate, ciie as ethanol or methanol, and unsaturated carbocyclic hydrocarbons, such as benzene or toluene.

It should be noted that, although for convenience, the structure (II) is represented as "di-keto-form, the compounds of structure (II) may also exist in keto-enol" form and "the cyclic hydroxypropanoic" form (IIB):

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Have in mind that the structure (II) includes all tautomeric forms of the compounds of structure (II).

In a preferred aspect, therefore, proposes a method of obtaining compounds of structure (IA) or its salt, MES or hydrate:

involving the cyclization of compounds of structure (IIA) or its salt, MES or hydrate:

and after not getting his salt, MES or hydrate. Most preferably, the cyclization is carried out in the presence of hydrochloric acid in methanol/tetrahydrofuran as solvent.

With regard to compounds of structure (II), compounds of structure (IIA) can, of course, exist in the corresponding keto-enol and the cyclic romanovas forms, each of which is assumed to be covered by the structure (IIA).

Compounds of structure (II) (and, in particular, the structure (IIA)) are new and form a further aspect yoroi R1, R2, R3, A and X have the meanings defined for structure (I) in paragraph (1 claims, with the compound of structure (IV) or its salt:

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in which Z represents a group R6O, in particular, C1-C6alkoxy.

Accordingly, the reaction is carried out in an organic solvent, such as, for example, dimethylformamide, ether solvents such as tetrahydrofuran, toluene or benzene, hexane or C1-6the alkanols, such as methanol or ethanol, in the presence of a base, such as alkali metal alkoxide, such as t-piperonyl potassium, sodium methoxide or potassium methoxide, hydrides such as sodium hydride or amide base, such as potassium amide or sodium amide. Preferably, the reaction is carried out in tetrahydrofuran as a solvent in the presence of sodium methoxide as the base.

The method of obtaining compounds of structure (II) is novel and represents another aspect of the invention. In particular, for use in obtaining the compounds of structure (IIA) the method is carried out by reaction of the following compounds of structure (IIIA) and a compound of structure (IVA): or its salt in the presence of sodium methoxide in tetrahydrofuran as RASO standard techniques, as is described below. For example, compounds of structure (III) are described in EP 0173516-A. Compounds of structure (IV), for example, in which Z is R6O, can be obtained from sodium azide and appropriate Olkiluoto ether cyanopyridine acid, such as ethyl ether of cyanopyridine acid by known methods or from disodium salt tetrazol-5-carboxylic acid (commercially available) by reaction with a suitable alkilany, allowin or arylalkyl ether haloalkaline acid, for example, etelcharge.com or isobutylparaben. Obtaining compounds of structure (IV) of the corresponding disodium salt tetrazol-5-carboxylic acid is novel and constitutes another aspect of the invention. It should be noted that the compounds of structure (IV) can be obtained and then allocated before the reaction with the appropriate compounds of structure (III) or can be obtained "in situ" and further described in the interaction with compounds of structure (III) without the prior allocation.

The present invention particularly useful for producing compounds of structure (IA), based on the compounds (IIIA) and (IVA) to obtain the intermediate compounds of structure (IIA), which undergo cyclization in this section the art before the cyclization of compounds of structure (I) or, alternatively, as described in the examples, the reaction between the compounds of structures (III) and (IV) followed by cyclization of compounds of structure (II), formed in this way can be brought to an end "in one pot", so to speak, without the isolation of intermediate compounds formed during this.

The following examples illustrate the invention. Temperatures are given in degrees Celsius (oC).

Examples

1. Obtaining the ethyl ester 1H-tetrazol-5-carboxylic acid

Triperoxonane acid (24,47 g, 0.21 M) is added dropwise over 0.5 h under nitrogen to a stirred suspension of sodium azide (12,59 g 0,19 M) in 2,6-lutidine (100 ml) for 8 of the 12o. After stirring for 7 min add ethyl ether of cyanopyridine acid (20.4 g, 0.20 M) in one portion. The mixture is heated and stirred at 75ofor 6 h and then, after cooling, stirred at 20owithin 16 hours After cooling to 10othe mixture was added to ice (250 g) and II-molar hydrochloric acid (100 ml), keeping the temperature below 20o. The product is extracted into ethyl acetate (1250, 1200, 2100 ml) and the combined extracts dried over magnesium sulfate. After evaporation of the solvent under reduced pressure the oil is ristalliceski ethyl ester 1H-tetrazol-5-carboxylic acid, which is filtered off, washed with cold ether and dried air, 14,12 g (yield 52.6 per cent), so pl. 88 93o.

NMR: (270 MHz, solution in CDCl3): 13,6 13,8 (s, 1H); 4.6 to 4.5 (K, 2N); 1,5 1,4 (t, 3H).

Modification techniques

On a larger scale (84,4 g of sodium azide) the reaction is carried out differently to prevent any allocation of nitric acid.

After stirring at 75oand 20oadd sodium nitrate (63 g) in water (300 ml) for 10 min at 20 30o. The mixture is stirred at 20 to 25ofor 20 min and then add chilled mixture of water (1.5 l) and II-molar hydrochloric acid (690 ml), keeping the temperature between 25 and 30o. Then the product is extracted in ethyl acetate and crystallized as described above.

2. Getting isobutyl ester 1H-tetrazol-5-carboxylic acid

To a stirred suspension of disodium salt tetrazol-5-carboxylic acid (15,8 g, 0.1 mol) in dimethylformamide (100 ml) in a nitrogen atmosphere at 5oadd isobutyl ether of Harborview acid (13,6 g, 13 ml, 0.1 mol) dropwise within 15 minutes the Mixture is stirred at 5 to 10owithin 2 h, then at 20owithin 2 hours the Mixture was added to water (500 ml) and extracted with em (2200 ml). An ethyl acetate extracts washed with water (2200 ml), dried (MgSO4) and evaporated, obtaining the target compound in the form of resin (8.6 g, 50.5 per cent).

1H NMR (CDCl3): d of 0.95 (d, 6N, CH3), 2,08 (TC, 1H, CH), 4,25 (d, 2H, CH2).

3. Obtain methyl ester of 4-(4-phenylmethoxy)benzoic acid

A solution of methyl ester of 4-hydroxybenzoic acid (13,4 kg, 88 mol) in dimethylformamide (52 l) is added dropwise to the mixture aOMe (4.8 kg, 89 mole) and dimethylformamide (50 l) at room temperature under gentle stream of nitrogen. The reaction mixture is heated at 60 70owithin 1 h with stirring and then cooled to room temperature. To this mixture is added dropwise a solution of 4-phenylbutyramide (16,92 kg, 79,4 mol) in dimethylformamide (5 l). The resulting mixture is heated at 60 70ofor 1 h with constant stirring and cooled to room temperature. After adding 1 N. NaOH (110 l) the product is extracted twice with ethyl acetate (50 l 80 l). The extracts are successively washed with 1 N. NAOH (110 l) and saturated brine (20 l) and then concentrated to dryness under vacuum, obtaining the target compound with a quantitative yield.

4. Getting 4-(4-phenylmethoxy)benzoic acid

To a solution of compound of example the MeOH is removed by distillation in vacuum. To the residue is added ice water (120 l) and neutral substances extracted with ether (30 L3). The combined ether extracts are washed with 2 N. NAOH (25 l). The aqueous layers are combined and adjusted to pH 2 to 3 with concentrated HCl (16 l). Precipitated precipitated solids are collected by filtration in a centrifugal field, washed with water and dried by heating at 70 to 80oin air flow, receiving the target product (17,67 kg of 65.4 mol, yield 82% of 4-hydroxybenzoate).

5. Obtaining 3-/4-(4-phenylmethoxy)benzoylamine/-2-hydroxyacetophenone

To a solution of the compound from example 4 (18,1 g, 67 mmol) in CH2Cl2(45 ml) is added a catalytic amount of dimethylformamide (0.45 ml) followed by addition of thionyl chloride (6,26 ml, to 85.8 mmol) at room temperature under nitrogen atmosphere. After boiling under reflux for 2 h the mixture is cooled to room temperature and added to a solution of the hydrochloride of 3'-amino-2'-hydroxyacetophenone (12 g, 64 mmol) and pyridine (15,5 ml, 192 mmol) in CH2Cl2(90 ml), keeping the temperature between 0oand 3o. The mixture is stirred at a temperature of 0 to 3ofor 2 h and poured into 2 N. HCl (200 ml). The aqueous layers are separated. The product in aqueous layers are extracted twice CH2Cl2(150 Ml) and Annam brine (150 ml), dried over MgSO4. The resulting solution was concentrated in vacuo until a precipitate several crystals. To the residue is added ethyl acetate (150 ml) and the solution was concentrated in vacuo until it is removed about half of ethyl acetate. The mixture is cooled to approximately 0o. The precipitated crystals are collected and dried in vacuum, obtaining the target compound (21,6 g, 53.6 mmol, 90% yield).

6. Getting 2-/4-(4-phenylmethoxy)benzoylamine/- 6-/1,3-dioxo-3-(tetrazol-5-yl)propylene

Under nitrogen atmosphere, dissolved under stirring tert.-piperonyl potassium (31,36 g, 0.28 mol) in dry dimethylformamide (160 ml). To the resulting solution was added the compound of hydroxyacetophenone from example 5 (16,12 g, 0.04 mol), and then 5-ethoxycarbonylmethyl example 1 (1.39 g, 0,052 mol, 1.3 EQ.) at room temperature. The reaction temperature rises to 45o. The mixture is stirred for 3 h at 40o(oil bath), then cooled to 30oand poured into cold 1 N. HCl (800 ml). The resulting precipitate is filtered off, washed with water (500 ml) and then dried at 70oin an oven with fan, obtaining the target compound (19,4 g, 97%). Spend cleaning, using any of the following procedures.

Uchenie 2 hours After cooling to room temperature, the mixture is transferred into the fridge and leave for 2 hours, the Product is filtered, washed with cold ethyl acetate (15 ml) and dried at 70oin an oven with fan, receiving the purified product (8.5 g, 85%).

Procedure 2

Stirred suspension of the crude product (5 g) in acetone (50 ml) is heated under reflux for 2 hours After cooling to room temperature, the mixture is transferred into the fridge and leave for 2 hours the Product is then filtered, washed with cold acetone (5 to 10 ml) and dried at 70oin an oven with fan, getting the target product (4.1 g, 82%).

7. Getting 4-oxo-8-/4-(4-phenylmethoxy)benzoylamine/- 2-tetrazol-5-yl-4H-1-benzopyran hemihydrate

To a stirred suspension of purified product from example 6 (7,984 g to 0.016 mol) in methanol (72 ml) is added concentrated sulfuric acid (0.6 ml) and the reaction mixture heated under reflux for 3 hours the Mixture is allowed to cool to room temperature, and then transfer it in the refrigerator for 2 hours the Thick mixture was then filtered, washed with cold methanol (40 ml) and water (90 ml) and then with cold methanol (30 ml). The product is dried at 0oin an oven with fan and then leave to stand for 2 the RA illustrate the method of obtaining the compounds (I) of the intermediate compounds of structures (III) and (IV) "in the same vessel."

8. Getting 4-oxo-8-/4-(4-phenylmethoxy)benzoylamine/- 2-tetrazol-5-yl-4H-1-benzopyran hemihydrate

To a stirred suspension of sodium methoxide (15 g, 0.28 mol) in dry tetrahydrofuran under nitrogen atmosphere add portions of the connection hydroxyacetophenone from example 5 (16 g, 0.04 mol) at approximately 25o. Then add a solution of ethyl ether tetrazol-5-carboxylic acid from example 1 (of 7.3 g, 0.05 mol) in tetrahydrofuran, while maintaining the reaction temperature at approximately 25oC. the Reaction mixture was stirred under conditions of reflux distilled for about 100 min to ensure complete formation of the diketone compounds of example 6. To the reaction mixture is added methanol, and then add concentrated hydrochloric acid (28 ml, 0.34 mol) and subsequent heating of the reaction mixture under reflux for about 2 h leads to the formation of the target compound, which crystallizes from the solution. After cooling to approximately 20othe product is separated by filtration and washed with methanol. The selected solid is purified by conversion into the sodium salt in methanol and re-deposition of target compounds hydrochloric acid. On hydratious at room temperature, receiving the target connection (18,56 g, 94%).

9. Getting 4-oxo-8-/4-(4-phenylmethoxy)benzoylamine/- 2-tetrazol-5-yl-4H-1-benzopyran hemihydrate

To a stirred suspension of sodium methoxide (14,1 kg, 261 mol) in dry tetrahydrofuran under a nitrogen atmosphere are added in several portions connecting hydroxyacetophenone from example 5 (15,0 kg, 37,2 mol) at approximately 25o. Then add a solution of ethyl ether tetrazol-5-carboxylic acid from example 1 (6.8 kg, or 47.9 mol) in tetrahydrofuran, while maintaining the reaction temperature at approximately 25o. The reaction mixture was stirred at reflux distilled for about 100 min to ensure complete formation of the diketone compounds of example 6. To the reaction mixture is added methanol and then concentrated hydrochloric acid (31,4 kg, 314 mol), and subsequent heating of the reaction mixture under reflux for about 2 h leads to the formation of the target compound, which crystallizes from the solution. After cooling to approximately 20oC the product is separated by filtration and washed with methanol. Separated solid is purified by conversion into the sodium salt in methanol and re-translation into the sediment by x the rum methanol, dried and then re-hydratious at room temperature to obtain the target compound (15.5 kg, 85%).

1. The method of obtaining benzopyrano compounds of General formula I

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where R1group

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R2hydrogen or C1WITH6-alkyl;

R3hydrogen;

And single bond;

X is oxygen,

or a salt, hydrate or solvate, characterized in that carry out the cyclization of compounds of General formula II

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where R1, R2, R3And X have the above values,

or its salt, hydrate or MES and, if necessary, the desired product is isolated in the form of a salt, hydrate or MES.

2. The method according to p. 1, wherein the cyclization is carried out in the presence of hydrochloric acid in methanol-tetrahydrofuran as solvent.

3. The compound of General formula II

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where R1, R2, R3And X are specified in paragraph 1 values

or its salt, hydrate or MES.

4. 2-[4-(4-Phenylmethoxy)benzoylamine] -6-[1,3-dioxo-3-(tetrazol-5-yl)propyl]phenol.

5. The method of obtaining compounds of General formula II, wherein conducting the reaction of interaction of the compounds of General formula IV

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where Z C1C6-alkoxygroup,

or its salt.

6. The method of obtaining the compounds of formula IA

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or its salt, hydrate or MES, characterized in that the compounds IIIA

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subjected to interaction with the compound of the formula IVA

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or its salt with subsequent cyclization of the obtained intermediate compound of formula IIA

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or its salt, hydrate or MES.

7. The method of obtaining the compounds of formula IV

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where Z1WITH6-alkoxygroup,

characterized in that the disodium salt of tetrazole-5-carboxylic acid is subjected to interaction with the corresponding alkilany ether haloalkaline acid.

8. The compound of General formula III

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where R1, R2, R3, X and a are specified in paragraph 1 values.

 

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