CS229083B1 - Method of preparing 7-hydroxymethyltricyclo/2,2,1,-03,5/heptan-2-one - Google Patents

Description

The present invention relates to a process for the preparation of 7-hydroxymethyltricyclo (2,2,1,0 ') hepten-2-one of formula I

(AND),

This is an important intermediate in the production of prostedienic acid derivatives, the so-called prosteglendines. Key intermediates for the synthesis of prostaglendins, namely (3aalpha, βbeta, 5alpha, 6aalpha) hexehydro-5-hydroxy-4-hydroxymethyl-2H-cyclopenta (b) furan-2-one derivatives, can be easily and efficiently prepared from the compound of formula I.

The hitherto known processes for the preparation of the compound of formula (I) are based on 7-hydroxymethyltricyclo (2,2,1,0 ') heptan-2-ol bisformiate, the oxidation of which results in the preparation of 2-oxo-tricyclo (2,2,1,0- and S).

0 ^J ') heptane-7-carboxylic acid, in which the protected carbonyl group PEK as acetélu.

Reduction of the carboxyl group yields the 7-hydroxymethyl derivative which, upon decomposition of the acetal, affords the 7-hydroxymethyltricyclo (2,2,1,0 ', 5) heptan-2-one of Formula I. It can be seen that these are multistep procedures that require the use of relatively expensive reagents, and yields in a number of reaction stages are low.

The process according to the invention eliminates the disadvantages of the hitherto known processes. Further, the starting compounds and reagents required to synthesize the compound of Formula I are inexpensive and readily available in large quantities. The essence of the process for the production of the fly of formula (I) according to the invention is that the readily available 7-hydroxymethyltricyclo (2,2,1,0 ', 5') heptan-2-ol of formula (II)

HO (II)

OH is converted by treatment with arenesulfonyl chloride of formula III,

R 2/2- ^SO 2 ^Cl (III), wherein R is hydrogen, methyl or bromine, to an arensulfonic acid ester of formula IV,

wherein R is as defined above.

This reaction is carried out in an environment of organic solvents, preferably acetone or tert-butyl methyl ketone at a temperature of 0 to 50 ° C. In this reaction, it is preferable to use a small excess of the compound of formula III in a molar ratio of reactants of 1si to 1.2.

In the next step, the compound of formula IV is oxidized to the ketone of formula V,

Z o

wherein R is as defined above.

The oxidation is carried out with a 2.3 to 2.6 M solution of chromium trioxide in 8 M sulfuric acid and acetone at a temperature of the reaction mixture of -5 to +10 ° C or with dilute nitric acid. The crude ester of formula IV can be used for the oxidation. In the next step, the compound of formula (I) is liberated from the ester in the electroreduction of a non-mercury diaphragm cathode under gel-electrostatic conditions (current 0.3 to 1 A, not 15 to 30 V). The reduction is carried out in a C 1 -C 4 alcohol with the addition of tetraalkylammonium salts containing C 1 -C 4 alkyls and a chloride, bromide or iodide anion. In this way, the compound of formula I is obtained in high purity and good yields.

In terms of technical application, this novel process is very advantageous, providing high yields in the individual intermediate steps, carrying out available and safe reagents.

The invention is not limited to the specific examples which are illustrative of the invention.

with simple devices from the use of an example, the conditions specified in the following do not in any way limit the subject of

Example 1

1-tosyloxymethyltricyclo [2.2.1.0 < 2,7 >] heptan-2-ol (Formula IV wherein R = CH3)

21.3 g of the diol of formula II are dissolved in 200 ml of ecetone and 29.6 g of p-toluenesulfonyl chloride in 110 ml of ecetone are added at room temperature (20-25 ° C). The reaction mixture was stirred at room temperature for 12 hours, the acetone was evaporated from vacuum, and the residue was extracted with chloroform. The chloroform fusion was washed with water, dried over MgSO 4, filtered and treated with 50 g of silica gel. The solvents were evaporated from vacuum and the loose mass was overlayed over 100 g of silica gel on a frit and washed with chloroform and traces of bis-tosylethy were isolated. The product was isolated with chloroform-acetone 1: 1 to give 35 g (76%} of a compound of formula IV wherein R = CHy for C ₅ ^H ₈ 0 ₄ 3 (294.4):

calculated:

found:

61.20 # C, 61.34% C,

6.16% H; 6.31% H.

The infrared spectrum comprises bands 960, 1,176, 1,188, 1,370, 1,600, 2,890, 2,955,

070, 3,560, 3,630 cm ^-1 , proton NMR spectra beta signals (ppm) 1.25 (m, 4H), 1.95 (m, 4H), 2.48 (s, 3H), 3.95 ( m, 2H), 7.32.7.42, 7.77, 7.87 (AB system, 4H).

Example 2

TO

7-tosyloxymethylt ricyclo (2,2,1,0 ´) heptan-2-one (general formula V, where R = CH 2)

3.9 of the alcohol of formula IV, wherein R = CH? Was dissolved in 150 ml of ecetone e with 10 ml of a 2.6 M solution of chromium trioxide in 8 M sulfuric acid, vigorously stirred at 0 to 5 ° C. After 30 minutes the excess reagent was removed with 2-propanol and the solvents evaporated to dryness and the residue crystallized from ethanol-water. There were obtained 3.6 g (92) of the compound of formula V wherein R = CH 2 mp 82-84 ° C.

For C ₁₅ H ₁₆ O ₄ S (292.4) calculated: 61.62% C, 5.52% H; found: 61.42 3 »C, 5.56% H.

Infrared spectrum contains bands 947, 975, 1 095, 1 175, 1 188, 1 373, 1 600, 1 770, 2 890, 2 925, 2 955 cm ^-1 , NMR spectrum contains delta signals (ppm) 1.50 ( t, 2H), 2.00 (m, 4H), 2.50 (m, 2H), 2.52 (s, 3H), 4.00 (d, 1H), 7.36 to 7.86 (AB) system, 4H).

Example 3

To a solution of 5.45 g of the diol of formula II in 50 ml of acetone at room temperature, 7.25 g of benzenesulfonyl chloride dissolved in 55 ml of acetone is added dropwise with vigorous stirring of the reaction mixture. After stirring for 12 hours, the organic solvents were evaporated, the distillation residue was extracted with chloroform, the chloroform extract was washed with water and dried over magnesium sulfate, finally 12 g of silica gel were added and evaporated to dryness in vacuo.

The bulk was overlaid on a silica gel column (50 g) and washed with chloroform (eluting with traces of bis-benzenesulfonate), and the product was eluted from the column with acetone-chloroform 1: 1.

Evaporation of the oylox afforded 8.32 g of the product of formula IV wherein R = H.

For C ₁₄ H ₁₆ O ₄ S (280.3) calculated: 59.98% C, 5.75% H;

Found: 60.12 95 c, 5.62 95 H.

Bands 960, 1 176, 1 375, 1 510, 2 890 and 2 955 were found in the infrared spectrum,

060, 3,540.8 3,620 cm -1, proton NMR spectra showing delta (ppm) signals 1.25 (m, 4H), 1.93 (m, 4H), 3.92 (m, 2H), 7.25- 7.70 (m, 5H).

Example 4

7-Hydroxyethyltricyclo (2,2,1,0 ') heptan-2-one (Formula I)

0.6 g of the tosyl derivative of the general formula V, where R = CH3 in 60 ml of ethanol and 2.5 g of tetremethylammonium chloride, were electroplated on a mercury cathode in a diefragm electrolyzer under galvanostatic conditions (0.5 A, 22 V) and after 40 minutes was The reaction mixture was evaporated to dryness, the residue extracted with chloroform, the chloroform phase washed with water, dried over magnesium sulfate and the chloroform evaporated in vacuo. 0.25 g (73 95) of the product of formula I was obtained.

For G ₈ H _{) 0} 0 ₂ (138.2):

calculated: 69.54 95 C, 7.30 95 H;

found: 69.29 95 c, 7.19 95 H.

Proton NMR spectrum contains delta (ppm) signals 1.21 (t, 1H), 1.96 (s, 3H), 2.13 (s, 1H), 2.19 (s, 1H), 2.38 (t 1H, 3.55 (d, J = 7 Hz, 2H), 4.00 (bs, 1H, OH group).

Claims (5)

SUBJECT OF THE INVENTION A process for the preparation of 7-hydroxymethyltricyclo [2.2.1.0] hept-2-one of formula I, 7-hydroxymethyltricyclo (2,2,1,0 ', 5) heptan-2-ol of formula II, (II), OH, characterized in that the compound of formula II is converted by treatment with arensulfonyl chloride of formula III, R SO ₂ Cl (III), wherein R is hydrogen, methyl or bromine, in an organic solvent medium at a molar ratio of reactants of 1: 1 to 1.2 at 0 to 50 ° C to the arenesulfoester of formula IV, R OH (IV), wherein R is as defined above, wherein oxidation of the chromium oxide with nitric acid at a temperature of -5 to +10 ° C yields a ketone of the formula V, 1 — SO ₂ O Λ (V), wherein R is above the meaning from which the desired product of formula I is obtained after electrochemical reduction at the mercury cathode. 2. A process according to claim 1, wherein the organic solvent is aliphatic ketones having 3 to 6 carbon atoms, such as acetone, tert-butyl methyl ketone. 3. The process of claim 1 wherein the oxidation is performed with a 2.3 to 2.6 M chromium trioxide solution in 8 M sulfuric acid. 4. The process of claim 1 wherein the reduction is carried out in an environment of a C1-C4 alcohol, such as ethanol, propanol. 5. The process of claim 1 wherein the reduction is carried out in the presence of quaternary ammonium salts containing C1-C4 alkyls and chloride, bromide or iodide anipine. '