CS211526B1 - Process for preparing 5-halo-7-hydroxymethylbicyclo (2,2,1) heptan-2-one - Google Patents

Abstract

The invention relates to a method for the production of 5-halogen-7-hydroxymethylbicyclo/2,2,1/heptan-2-one of the general formula I, xhoA /1/ o where X denotes chlorine or bromine. The substances of the general formula I are referred to as important intermediates in the synthesis of prostadienoic acid derivatives, so-called prostaglandins. From these substances it is possible to easily and effectively prepare key intermediates, i.e. derivatives /3a alpha, 4beta, 5alpha, 6a alpha/hexahydro-5-hydroxy-4-hydroxymethyl~2H-cyclopenta/b/furan-2-one /see author's certificate No. 211527/, which enable the preparation of all primary prostaglandins. The procedures for the preparation of substances of the general formula I described so far in the literature are quite complex and in a number of reaction stages provide low yields £j. Amer. Chem. Soc. 95, 75 22 /1 973/, U.S. Patent No. 3,943,151^J. The production method according to the invention eliminates the disadvantages of the previously known processes. Furthermore, the starting compounds and the reagents required for their synthesis are inexpensive and readily available in large quantities.

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, xhoA (1) o

wherein X is chlorine or bromine.

The compounds of formula (I) are referred to as important intermediates in the synthesis of the prostadienoic acid derivative, the so-called prostaglandins. From these substances it is possible to easily and efficiently prepare key intermediates, ie derivatives (3a alpha, 4beta, 5alpha, 6a alpha) / hexahydro-5-hydroxy-4-hydroxymethyl-2H-cyclopenta (b) furan-2-one / see author's No. 211527], which allow the preparation of all primary s-taglandin. The processes described to date in the literature for the preparation of the compounds of the formula (I) are very complex and yield low yields in a number of reaction steps. Amer. Chem. Soc. 95, 7522 (1997), U.S. Pat. No. 3,943,151.

The process according to the invention eliminates the disadvantages of the hitherto known processes. Further, the starting compounds and reagents required for their synthesis are inexpensive and readily available in large quantities.

The method for producing compounds of the above general formula I according to the invention consists in that the 2-hydroxy-7-hydroxymethyltricyklo / 2,2,1,0 ³ »~ / heptane of the Formula II

HIM

/ 11 /

OH by triphenylmethyl halide unsubstituted or substituted on 1 to 3 aromatic nuclei with alkyl or alkoxy of 1 to 3 carbon atoms in the alkyl chain in an organic solvent in the presence of a tertiary amine or heteroaromatic amine at a molar ratio of reactants of 1.0: 1.0 to 2 5 at 0 to 50 ° C specifically converted to the ether of formula III,

OH wherein Z is an Ar @ 1 C radical and Ar is phenyl unsubstituted or substituted by C1 -C3 alkyl or alkoxy. In the next reaction step, in the primary triaryl methyl ether of formula III, the secondary hydroxyl group is oxidized with chromium trioxide in a heteroaromatic amine, preferably pyridine, in high yield to the corresponding ketone of formula IV,

wherein Z is as defined above. Treatment of the ketone of formula IV at 20 to 120 ° C with a hydrohalic acid cleaves the Z protecting group in one step and cleaves the CC bond in the tricyclic derivative to give the desired 5-halo-7-hydroxymethylbicyclo [2.2.1] heptan-2-one, i.e. the compound of formula I. This operation can also be performed in two steps; in the first step, the protecting group is removed by treatment with concentrated acetic acid and hydrogen halide, and in the second step, by reaction with hydrohalic acid at elevated temperature, the C-C bond in the tricyclic system is cleaved. In the two-step cleavage (second method), the corresponding triaryl halomethane is recovered from the reaction mixture, which can be re-used to prepare the ether of formula III without further purification. In the one-step process (first method), the protecting group Z is cleaved off in the form of the corresponding triarylmethanol which is converted to the triaryl halomethane by a known method (see Organic Synthesis Coll.). Vol. III, 841]. However, from a technical application point of view, the first method is considerably more advantageous.

The invention is not limited to the specific conditions set forth in the following examples, which are illustrative only and do not limit the scope and scope of the invention in any way.

Example 1

2-Hydroxy-7-triyloxymethyltricyclo [2.2.1.0.0 < 2,7 >] heptane of formula III

To a solution of 1.58 g of diol in sample II in 40 ml of abs. pyridine was added with stirring after. Portions of 4.8 g of triphenylchloromethane. After standing at room temperature for 48 hours, 0.5 ml of water was added to the reaction mixture and stirred for 1/2 hour and finally the bulk of the solvents were distilled off on a rotary evaporator. The distillation residue was dissolved in 100 ml of chloroform, the chloroform solution was shaken successively with 10% hydrochloric acid solution (until acidic) with 1% sodium bicarbonate solution, water, dried with magnesium sulfate and the solvents were distilled off. From the oily residue (5.9 g), silica gel column chromatography (130) was used. g, eluent chloroform) yielded 3.38 g (78%) of the product of formula III / Z = whose

NMR and mass spectra were consistent with the proposed structure.

Example 2

7-Triethyloxymethyltricyclo [2.2.1.0 < 5 >] hepan-2-one of formula IV; £ z - (c ^ H ^) ^ c]

To a solution of 2.44 g of the compound of formula III (Z = (6) (5) 3) in 35 ml of abs. Pyridine (3.5 g) was added portionwise over 5 minutes, and the reaction mixture was stirred at room temperature for 16 hours. After addition of 150 to 200 ml of chloroform, the reaction mixture was shaken several times with 202 sulfuric acid (0 ° C, to acidic reaction), 1% sodium bicarbonate, water, and dried over magnesium sulfate, the solvents were distilled off. From the syrupy residue (2.18 g), 1.74 g of the product melting at 114 DEG-116 DEG C. and Rp 0.75 (silica gel) was obtained by crystallization from petroleum ether; eluent of 12 methanol in chloroform). Elemental analysis, IR-aware, ¹ H NMR and mass spectra are consistent with the proposed structure.

Example 3

7-Hydroxymethyl-5-chlorobicyclo [2.2.1] heptan-2-one of formula I, (X = Cl) and 1 g (2.63 millimoles) of the ketone of formula IV (Z = (C 8 H 5) 30) was mild heating (35 ° C) dissolved in 10 ml of acetic acid containing 25% hydrogen bromide. Immediately precipitated triphenylbromomethane, which was aspirated, washed with acetic acid, and after drying in a desiccator over solid NaOH, was again used to prepare the trityl ether of formula III (C 8 H 8 Cl 2). After evaporation to dryness, the residue was dissolved in chloroform, the chloroform solution was washed with saturated sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated.A crystalline residue gave after recrystallization from benzene 330 mg (72%). chloroalcohol of the formula I (X · Cl) mp 82-84 ° C, whose IR spectrum was identical to that of the authentic preparation.

He attaches

7-Hydroxymethyl-5-bromo-bicyclo [2.2.1] heptan-2-one of formula I (X = Br)

A mixture of 6.8 g (48.5 mmol) of the diol of formula II, 50 ml of pyridine and 21 g (50.8 mmol) of (tris-4-methoxyphenyl) -bromomethane was left at room temperature for 36 hours. Then, an oxidizing agent prepared from 10 g of chromium trioxide and 90 ml of pyridine was added to the reaction mixture containing the dominant product of the compound of formula III (Z = (4-CH3OCgH4) 3C) according to thin layer chromatography. After stirring for 10 hours, the reaction mixture was concentrated, diluted with 200 mL of chloroform, and the chloroform solution was shaken with cold 152 sulfuric acid and water. After evaporation, the distillation residue crystallized. An analytically pure preparation of formula IV (Z = (A-CHgOGgH4) 3C) was prepared from a small portion (150 mg) by crystallization from heptane. To the main, the reaction mixture was cooled, the tris-methoxyphenylmethanol was aspirated and the filtrate was evaporated to dryness; its crystallization from water yielded 6.58 g (62%) of the starting diol of formula II (compound of formula I (X 'Br')).

Claims (5)

A process for the preparation of 5-halo-7-hydroxymethylbicyclo [2.2.1] heptan-2-one of formula 1, HO / 1 / O wherein X is chlorine or bromine, characterized in that 2-hydroxy-7-hydroxymethyltricyclo [2.2.1.0] heptane is treated with a triphenylmethyl halide optionally substituted on the phenyl moiety The alkyl triphenylmethyl ether of the compound of formula (I), optionally substituted with the above substituents, is oxidized with chromium trioxide and the oxidation product is cleaved with hydrohalic acid. to the product of formula I. 2. The process according to claim 1, wherein the etherification with triphenylmethyl halide is carried out in a molar ratio of reactants of 1.0: 1.0 to 2.5 at a temperature of 0 to 50 [deg.] C. 3. Process according to claim 1, characterized in that halogenated alkanes having 1 to 3 carbon atoms, preferably chloroform, carbon tetrachloride, dichloromethane, are used as the organic solvent. 4. A process according to claim 1, wherein the oxidation product is cleaved by hydrochloric or hydrobromic acid at a temperature of from 20 to 120 [deg.] C. 5. The process according to claim 1, wherein the cleavage is carried out in two steps by successive treatment with hydrohalic acid in acetic acid and then with hydrohalic acid at a temperature of 20 to 120 ° C.