MXPA01002714A - 3-(hydroxymethyl)chromen-4-ones and process for preparing - Google Patents

Abstract

3-(Hydroxymethyl)chromen-4-ones of formula (I) are described and a process for preparing said compounds. The process consists in reacting the compounds of general formula (II) wherein R is hydrogen, halogen, alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms optionally substituted by phenyl or halogen, with formaldehyde and a basic catalyst followed by dehydration in an acid medium to form 3-(hydroxymethyl)chromen-4-ones of general formula (I), wherein R is as defined for (II).

Description

PROCESS TO PREPARE THE 3- (HYDROXYMETHYL) CROMEN-4- ONAS DESCRIPTION The present invention relates to a new process for preparing the 3- (hydroxymethyl) chromen-4-ones, of the general formula (I): wherein R is hydrogen, halogen, alkyl having 1 to 4 carbon atoms or alkoxy with 1 to 4 carbon atoms, optionally substituted by phenyl or halogen. The compounds of the present invention are useful as intermediates in the preparation of pharmaceutical products, such as those disclosed in WO 96/32389. The processes in use for preparing the compounds of the general formula (I) consist of: a) The reduction of the corresponding 3-formylchromen-4-ones with NaBH4 and A1C13. { Tetrahedron Letters, 1973, 1995; Tetrahedron, 1974, 22, 2959). These reactions have the inconvenience of resulting in poor performance. b) The condensation of the corresponding 2-sulfinyl-acetophenones with two moles of HCHO and the subsequent pyrolysis of the sulfoxide (J. "Het Chem., 1974, 11, 183) Unfortunately, there is the danger of an explosion when they are prepared sulfinylacetophenones with an industrial scale The process of the present invention is to treat compounds of the general formula (II), in which R is as defined for (I), with formaldehyde and catalytic amounts of basic compounds, such as for example, sodium acetate, followed by dehydration in an acidic medium.The common mineral acids, such as hydrochloric acid, can be used as acidifying agents.The compounds of the general formula (II) are in balance with their open tautomeric forms (II ') and (II "). {Tetrahedron Letters, 1984, 25, 5813.) In both II' and II", R is defined as for the preceding structures. fF: In contrast to the processes, previously described, the process of the present invention provides high yields and, moreover, the industrial preparation of the precursors is easily produced. 5 EXAMPLE 1; 2- (hydroxy) chromen-4-ones (II) 3.25 g (60 mmol) of sodium methoxide, under a nitrogen atmosphere, were suspended in 60 ml of ethyl formate, cooled to 0 ° C. The mixture of let reach the At room temperature, a solution of the corresponding o-hydroxyacetophenone (III) (20 mmoles) was added dropwise, in which R is defined as for the preceding structures, in a minimum amount of tetrahydrofuran. The mixture was stirred for 30 minutes, and a rigid paste formed. 100 ml of water and 4.5 ml of acetic acid were added and stirred for 10 minutes, and the precipitate dissolved. The organic phase was decanted and the aqueous phase was stirred with an additional 40 ml of ethyl formate. The collected organic extracts were washed with two 40 ml portions of a saturated solution g of sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was suspended in 40 ml of diisopropyl ether, filtered and dried in vacuo to give the compounds of the general formula (II): - IIIr R (II) Yield (%) PF ° C (DSC) H 88.30 6-CH3 100 136.03 7-OH3 85 139.44 6-OCH3 92 146.61 6-C1 93 160.62 7-OCH2Ph 92 172.63 7-0 (CH2) 3Cl 80 118.23 7.0 (CH2) 3Br 69 104.95 EXAMPLE 2; 3 - (hydroxymethyl) chromen-4-ones (I) To a solution of 10 mmol of (II) in 40 ml of acetone, 40 mg (0.5 mmol) of sodium acetate and 1 ml of 37% formaldehyde were added ( 12 mmol) and stirred at room temperature for 2 hours. To this solution, 1 ml of concentrated hydrochloric acid was added and stirred at room temperature overnight. The solution was neutralized with an aqueous solution of sodium acetate and evaporated to dryness in vacuo. 50 ml of water were added and then they were removed with two 50 ml portions of ethyl acetate. The organic extracts were dried over anhydrous sodium sulfate and concentrated to a volume of about 15 ml. The product obtained was allowed to stand in a refrigerator overnight, and then crystallized and collected by filtration. The filtrate was washed with ethyl acetate and dried under vacuum to give the compounds of the general formula (I): R (I) Yield (%) PF ° C (DSC) H 82 109.3 6-CH 3 70 143.7 7-OH 3 78 119.98 6-OCH 3 80 151.8 6-C1 71 164.27 7-OCH 2 Ph 70 135.9 7-0 (CH 2) 3 Cl 75 101.77 7-0 (CH2) 3Br 75 105.38 »-? _,

Claims (4)

1. CLAIMS 1. A process for preparing the (hydroxymethyl) chromen-4-ones, of the general formula (I): wherein R is hydrogen, halogen, alkyl having 1 to 4 carbon atoms or alkoxy with 1 to 4 carbon atoms, optionally substituted by phenyl or halogen, characterized in that the compounds of the general formula II: where R has the above definitions, it is treated with formaldehyde and a basic catalyst, followed by dehydration in an acid medium.
2. 2. A process, as claimed in claim 1, in which sodium acetate is used as a basic catalyst.
3. 3. A process, as claimed in claim 1 or claim 2, wherein a mineral acid is used as an acidifying agent.
4. 4. A process, as claimed in claims 1 to 3, wherein the hydrochloric acid is used as an acidifying agent. ^^^^^? j ^^ fe ^^^^^?