HU182799B - Process for preparing 5-halo-7-hydroxymethyl-bicyclo-/2,2,1/-hepten-2-ones - Google Patents

Abstract

The present invention relates to a process for the preparation of 5-halo-7-hydroxymethylbicyclo (2,2,1) heptane-2-one of formula (I), wherein X is chloro or bromo, wherein hydroxy-7-hydroxymethyltricyclo (2) is used. , 2,103'5) -heptane is reacted with a triphenylmethyl halide substituted on the unsubstituted or phenyl ring substituted with 1 to 3 carbon atoms or alkoxy in an organic solvent in the presence of a tertiary amine, followed by a compound of formula I optionally substituted with the aforementioned substituents the primary triphenylmethyl ether is oxidized with chromium trioxide and the oxidation product is cleaved with a hydrogen halide to the corresponding compound of formula (I). The process provides simple starting materials for the synthesis of prostaglandins in a simple manner with good yields and readily available starting materials. (I) -1-

Description

The present invention relates to a process for the preparation of 5-halo-7-hydroxymethylbicyclo [2.2.1] heptan-2-one of formula (I) in which X represents a chlorine or bromine atom.

Compounds of formula (I) as defined above are important starting materials for the synthesis of so-called prostaglandins. These compounds are readily and efficiently synthesized. can be used as a key intermediate / 3acx, 4j,

6a. The preparation of 6-N-hexahydro-5-hydroxy-4-hydroxymethyl-2H-cyclopenta [b] furan-2-one derivatives of the above-mentioned compounds (1) is the subject of separate patent applications; all primary prostaglandin derivatives can be readily prepared from said furanone derivatives.

The processes for the preparation of compounds of formula (I) as described previously in the literature are very complex and yield only low yields after several reaction steps (cf. J. Am. Cherni Soc. 95, 7522 (1975)); 5,943,151 Az. U.S. Pat.

The novel process of the present invention overcomes the disadvantages of the prior art processes, and the starting materials of the new process are cheap and readily available in large quantities.

The principle method employed for preparation of the compounds of / 1 / of the formula according to the present invention is based on the 2-hydroxy-7-hydroxymethyl-tricyclo / 2 a / 11/2 _{in the} formula _y l, 0 * »£ 7heptánt an unsubstituted or 1- Reaction of triphenylmethyl halide substituted with 1 to 3 alkylene or alkoxy groups on 3 aromatic rings in an organic solvent in the presence of a tertiary or heteroaromatic amine at 0-50 ° C /, where the reaction component is : 1.0 to 2.5 molar, specifically converted to the corresponding ether (111); in the latter formula, Z is an Ar 1 C group and Ar is substituted in this; or represents a phenyl substituted with a C 1-3 alkyl or alkoxy group. In a subsequent step, the secondary hydroxyl group in the primary triaryl methyl ether of formula (III) is oxidized with chromium trioxide in a heterocyclic amine, preferably pyridine, to give the corresponding ketone of formula (IV) in high yield; Z in this formula is as defined above.

The resulting ketone of formula (IV) is treated with a hydrogen halide at 20-120 ° C, whereby the protecting group Z is cleaved in one step and the CC bond in the tricyclic derivative is cleaved to give the desired 5-halogen of formula (1). 7-Hydroxymethyl-bicyclo / 2 * 2,17-heptan-2-one is formed. This latter operation can be carried out in two reaction flushes; in the first step, the protecting group Z is removed by treatment with concentrated acetic acid in the presence of a hydrogen halide, and in the second step, by treatment with a hydrogen halide at a higher temperature, the C-C bond of the tricyclic system is cleaved. In this two-step cleavage, the corresponding triaryl halomethane is regenerated from the reaction mixture and can be reused without further purification to obtain the ether of formula (III). In the one-step process mentioned above, the protecting group Z is cleaved in the form of the corresponding triaryl methanol, which can then be converted to the corresponding triaryl-halomethane in a known manner, cf. Organic Synthesis Coll. Volume 841 /. However, for industrial applications, the former method is much more advantageous. ·

Practical embodiments of the process of the invention are illustrated by the following examples; it should be noted, however, that the invention is not limited to the specific circumstances set forth in the examples and that these examples are not intended to limit the scope of the invention in any way.

Example 1

2-Hydroxy-7-trityloxymethyltrichloro [2.2.1.0] * 7Heptane (111), Z = (GTHc) ^ C 1.53 g (11) Nuts 40 To a solution of 100 ml of absolute pyridine was added 4.8 g of triphenyl chloromethane in small portions with stirring. After standing at room temperature for 48 hours, water (0 * 5 mL) was added, stirred for half an hour, and then most of the solvent was evaporated in a rotary evaporator. The distillation residue was dissolved in chloroform (100 ml), the chloroform solution was washed with 10% hydrochloric acid (until acidic), then with 1% sodium bicarbonate solution, water, dried over magnesium sulfate and the solvent was distilled off. The resulting 5.9 g of an oily residue is purified by chromatography on a column of 130 g of silica gel using chloroform as the eluent to give 3.3 g of the product (78% of theory) with 1 H NMR and mass spectrum corresponds to the presumed chemical structure.

Example 2

7-trityloxymethyl-tricyclo / 2,2, l, 0 ^{^,} ^ 7heptán-2-one - / IV / Compound I, Z = / ^ II C ^ / C ^

To a solution of 2.44 g of the compound obtained in the preceding example in 35 ml of absolute pyridine is added 3.5 S chromium trioxide in portions over 5 minutes and the reaction mixture is stirred at room temperature for 16 hours. Chloroform (150-200 ml) was added, the mixture was washed with 20% sulfuric acid several times at 0 ° C until the reaction was acidic, and the separated organic layer was partitioned between 1% sodium bicarbonate and water, anhydrous sodium hydroxide. sulfate was dried and the solvents were distilled off. Recrystallization from a syrupy distillation residue (2.18 g / petroleum ether) yields 1.74 g of the title compound, m.p. 114-116 ° C; Rf (on silica gel with 1% methanol in chloroform / = 0.75). Elemental analysis of the product, infrared and mass spectrum consistent with the chemical structure assumed.

3 · Example

7-Hydroxymethyl-5-chlorobicyclo [2.2.1] heptan-2-one - (1), X = Cl

S / 2.63 / µmol / 7-trityloxymethyl-tricyclo / 2,2,1,0,7-heptan-2-one, prepared according to the previous example, in 10 ml of 25% hydrobromic acid in ethyl acetate with slight heating / 35 °. C / sol. The solution immediately precipitates

-3182,799 triphenylbromomethane, filtered off with suction, washed with acetic acid and filtered in a desiccator over solid sodium hydroxide; the resulting material can be reused in the procedure of Example 1. The filtrate obtained above is combined with the acetic acid wash, the mixture is evaporated to dryness, 10 ml of concentrated hydrochloric acid are added and the mixture is refluxed for 30 minutes. The reaction mixture is then evaporated to dryness, the residue is dissolved in chloroform, the chloroform solution is washed with a saturated aqueous sodium bicarbonate solution, then with water, dried over anhydrous magnesium sulfate and evaporated. The resulting crystalline residue is crystallized from benzene; This gives 330 mg of the title compound (72% of theory), m.p. 82-84 ^{° C-} 0-η, with the IR spectrum of the authentic compound.

Example 4

7-Hydroxymethyl-5-bromo-bicyclo _(/ 2.2, l7heptán-2-one - compound / 1 / of the formula X is Bromo

6.8 g (48.7) of 2-hydroxy-7-hydroxymethyl-tricyclo (2.2.1.0%) -5-heptane, 50 ml of pyridine and 21 g / 50.8 (umol) of the mixture of triss-4-methoxyphenyl / bromo mebane was allowed to stand at room temperature for 36 hours. Subsequently, the reaction mixture, which according to TLC as the main product of the formula (III) wherein Z is -CHPOGgH2O / O, is prepared, is mixed with 10 g of a mixture of chromium trioxide and 90 ml of pyridine. After stirring for 10 hours, the reaction mixture was concentrated and the residue was diluted with chloroform (200 mL) and the resulting solution was washed with cold 15% sulfuric acid and water. Evaporation of the organic solvent phase gave a crystalline residue, which was crystallized from 150 mg of heptane to give the analytically pure compound of formula IV, wherein Z is / 4-GH3OG5H4 / 3C-CSO.

To the bulk of the crystalline residue obtained above is added 20% hydrogen bromide, the mixture is cooled, the precipitated tris-methoxyphenylmethanol is filtered off with suction and the filtrate is evaporated to dryness. The residue was recrystallized from water; This gives 6.58 g of the title compound, 62% of the theoretical yield of the starting diol compound (11).

Claims (5)

A process for the preparation of 5-halo-7-hydroxymethylbicyclo [2.2.1] heptan-2-one of formula (I) wherein X represents a chlorine or bromine atom, characterized in that the hydroxy-7-hydroxymethyl -tricyclo / 2,2,1,0,7,7-heptane is reacted with an unsubstituted or phenyl ring on a C 1-3 alkyl or alkoxy substituted triphenylmethyl halide in the presence of a tertiary amine in an organic solvent and then In this case, the resulting triphenyl, methyl ether of the compound substituted with the aforementioned substituents is oxidized with chromium trioxide and the oxidation product is reacted with a hydrogen halide according to -4182,799. 2. The process according to claim 1, wherein the etherification of the triphenylmethyl halide is carried out with the reaction components employed in a molar ratio of 1.0: 1.0 to 2.5, at a temperature between 0 ° C and 50 ° C. juice. 3. The process of claim 1 wherein the organic solvent is a haloalkane having 1 to 3 carbon atoms, preferably chloroform, tetrachloromethane or dichloromethane. The process of claim 1, wherein the cleavage of the oxidation product is carried out with hydrogen chloride or hydrogen bromide at a temperature of 20 to 120 ° C. The process of claim 1, wherein the cleavage is carried out in two steps with hydrogen halide dissolved in acetic acid and then at a temperature of 20120 ° C.