CS226905B1 - Method of preparing hexahydro-5-hydroxy-4-hydroxymethyl-2h-cyclopenta (b)cyclopenta (b)furan-2-one - Google Patents

Description

The invention relates to a process for the preparation of hexahydro-5-hydroxy-4-hydroxymethyl-2H-cyclopenta (bfuran-2-one) derivatives of the general formula I,

wherein Z represents a group RfCeH2CO in which

R @ ¹ denotes hydrogen, methyl, phenyl or nitro.

The compound of formula (I), commonly referred to in the literature as Corey's lactone, is an important intermediate for the preparation of prostaglandins, a substance with multifaceted biological activity derived from prostanoic acid. To date, a number of processes for the preparation of this type of compounds have been described, of which the syn-22905 norbornadiene-based thesis occupies a prominent place. This synthesis has a number of variants, all of which are patented. A common intermediate of some of these variants is 7-hydroxymethyl-5-halobicyclo (2,2,1) heptan-1-one of formula a, wherein A is chlorine, bromine or iodine (see Scheme 1 below), which according to known of the formula I by first protecting the hydroxyl group in the form of acetal, ether or silyl ether to give a compound of formula b wherein A is as defined above and R is tetrahydropyranol-, benzyl-, methyl-, triphenylmethyl- or a trialkylsilyl group (see US Pat. No. 3,943,151, DOS No. 2,704,029, DE Pat. No. 122,817) The compounds of formula (b) are then converted by oxidation with organic peroxyacids to the δ-lactone of formula (c) where A and R have the meaning given above.Transforming the 5-lactone of formula c with alkali metal or mineral acid hydroxide solutions gives the desired χ-lactone of formula d and protecting the hydroxyl the function in the form of the Z derivative of the general formula e, in which Z and R are as defined above, after removal of the protecting group R, the desired β-lactone of the general formula I is obtained.

Sctiéma 1

Compound of Formula I

A disadvantage of the above processes is the fact that most of the intermediates are oily yellow or mild in consistency and chromatographic methods have to be used for their purification. Some reaction steps, in particular the Baeyer-Villiger oxidation and the transformation of 5-lactones to χ-lactones, do not occur unequivocally, which results in low yields. These reactions need to be carried out in dilute solutions, which entails considerable consumption of often readily flammable solvents, which places considerable demands on process equipment, hygiene and occupational safety. Further, in some cases, the protecting group R is difficult to remove, for example, a benzyl group by catalytic hydrogenation. Therefore, this reduces the economic advantageousness of the preparation of the compound of formula (I) by the above known processes. '

These known processes are followed in a positive manner by the process according to the invention, which overcomes the disadvantages of the processes known so far.

Summary of the production method according to the invention consists in that halogenhydroxyketon general 'Formula ¹ II

wherein X is chlorine or bromine or iodine, acylated in an inert solvent or without a solvent with an acylating agent of the general formula

R ² COY, wherein R ² is alkyl containing .. 1-3 carbon atoms and Y represents chlorine, bromine or R ² COO group, where R ² has the abovementioned meaning, in the presence of tertiary amines such as pyridine or triethylamine · for ¹ give the acyl compound of formula III,

wherein R ² and X have the above meanings.

After washing the reaction mixture with sodium bicarbonate solution and evaporating the solvents, a crystalline product is usually obtained which can be oxidized without further purification in acetic acid or chlorinated hydrocarbon solution by organic peroxyacids in a 3- to 5 molar excess of oxidizing agent at 0 to 100 ° C. Excess oxidizing agent is quenched after completion of the reaction with water and sodium sulfite or by boiling the reaction mixture for several hours. The reaction product is extracted with an organic solvent and evaporated to give the crude crystalline δ-lactone of formula IV,

wherein R ² and X have the above meanings. The compound of formula (IV) may be recrystallized from the cyclohexane-dichloroethane mixture prior to the next step or used directly in the crude state. Transformation of the .beta.-lactone of formula IV into the .beta.-lactone of formula V, sodium bicarbonate and dried over magnesium sulfate. After removal of the solvent in vacuo, the crude product is recrystallized from aqueous ethanol or used directly for further processing. From the compound of formula (VI) thus prepared,

(VI)

(V) where R ² is as defined above, is carried out by treating with an equimolar amount of an aqueous solution of an alkali metal hydroxide which is added to a solution of the 5-lactone of formula IV dissolved in a 1: 0.5 to 2, for example tetrahydrofuran hydrogen peroxide, at a temperature of 30 ± 30 ° C. After completion of the reaction, the mixture is diluted with water, acidified to pH = 5-6 with acetic acid and the peroxides present are removed by reduction with solid sodium sulfite. The reaction product is isolated by repeated extraction with an organic solvent, drying the extract with magnesium sulfate and evaporating the solvent under vacuum. The crude product of formula (V) may be treated without further refining in the presence of triethylamine or pyridine, optionally diluted with an inert solvent,

1.1-1.5 molar excess of aroyl chloride of formula

R ¹ —GeHi — COCl, where R ¹ is as previously defined, leave the reaction mixture at 40 ± 20 ° C until completion of the reaction, quench excess reagent by addition of a small amount of water, remove excess base by evaporation under vacuum or wash the reaction mixtures with dilute hydrochloric acid. The residue was dissolved in methylene chloride or dichloroethane, washed repeatedly with a solution hydrokde R ² and Z are as defined above, is selective transesterification of aliphatic ester functions performed at 50 ± 30 ° C treatment; alcohols containing 1 to 3 carbon atoms, for example methanol or ethanol, in the presence of acidic catalysts, for example mineral acids, sulfonic acids or strongly acidic ion exchangers, in the H ⁽⁺⁾ cycle gives the desired product of formula I which is purified by crystallization.

A particular advantage of the process according to the invention is that the bulk of the intermediates are solids which can be readily purified by crystallization, the reactions being carried out in commercially available, mostly chlorinated, non-flammable solvents with relatively concentrated solutions of such reagents. reaction stages of the synthesis.

The invention and its effects are explained in more detail in the following examples, which are illustrative and in no way limit the scope and scope of the invention.

Example 1

To 2.62 g of hydroxyketone II (X = chlorine) was added 1.84 g of freshly distilled acetic anhydride and 1.43 g of dry pyridine. The mixture was self-heating while dissolving the starting material to a homogeneous mixture, which was left overnight at room temperature. The reaction mixture was diluted with 20 mL of dichloroethane, washed with 10 mL of dilute hydrochloric acid (1: 5), 10 mL of saturated sodium bicarbonate solution, and dried over magnesium sulfate. Evaporation of the solvent under vacuum gave 3.23 g (99% of theory) of a colorless oil which crystallized rapidly. Recrystallization from cyclohexane-dichloroethane gave pure acetylderivative of formula III (X 1 -chloro, R ² = CH 3), mp = 70-72 ° C.

Example 2

Analogously to Example 1, a propionyl derivative of general formula (II) was prepared from the hydroxyketone of formula II (X-bromo) by treatment with propionyl chloride and pyridine. of formula III (X = bromo, R ² = CH ³ CH ² -) in 92% of theory.

Example 3

To a solution of 3.04 g of the acetylderivative of formula III '(X = chloro, R ^z = CH 3 -) in 30 ml of acetic acid was added 15 ml of 40% peracetic acid (Persteril) over 10 minutes. The mixture was stirred at room temperature for 8 hours and then left overnight. After dilution with 100 ml of ice-water, the peroxides were decomposed by addition of solid sodium sulphite, the organics were extracted with dichloroethane (8x 25 ml), the extract was washed with saturated sodium bicarbonate solution and dried over magnesium sulfate. Evaporation of the solution in vacuo gave 2.41 g (75% of theory) of crystalline d-lactones of formula IV (X = chlorine, R ² = CH 3 -), mp = 102-104 ° C. Example 4

To a solution of 4.6 g of 5-lactone of formula IV · (X = 'chloro, R ² = CH 3) in a mixture of 100 ml tetrahydrofuran and 50 ml of 30% hydrogen peroxide with stirring at room temperature, is added rapidly 10 ml of 2 N After 2 hours, the reaction mixture was acidified with 10 mL of acetic acid and left overnight. After diluting the mixture with 100 ml of water, the excess hydrogen peroxide was decomposed by addition of solid sodium sulfite with stirring and external cooling so that the temperature did not exceed 30 ° C. After the tetrahydrofuran was evaporated in vacuo, the aqueous solution was extracted with ethyl acetate (5 x 50 mL), the extract was washed with saturated sodium bicarbonate solution and dried over magnesium sulfate. After evaporation of the solvent, 3.85 g of honey-like χ-lactone of formula V (R ² = CH 3 -) was obtained, which was used without further purification.

Example 5

To a solution of 3.80 g χ-lactone of formula V (R ² = CH 3) in 50 ml of dichloroethane were added 5.50 g · p-phenylbenzoyl, and 4 ml of dry triethylamine ·. The reaction mixture, which spontaneously warmed, was left overnight at room temperature and the excess reagent was quenched by addition of 1 mL of water. After 1 hour, the mixture was washed with saturated sodium bicarbonate solution (2 x 50 mL), dried over magnesium sulfate, and filtered through a column of 100 g of carbon monoxide, which was protayed with 250 mL of dichloroethane. Evaporation of the solvent in vacuo yielded 6.90 g of the crude ester of formula VI (R ² = CH 3 -, Z - p - C 6 H 6 -C 6 H 4 - CO), which after recrystallization from aqueous ethanol gave the product tt = 90 to 92 ° C.

Example 6

To a solution of 3.94 g · ester of formula VI (R ² = CHs- Z = P-C6H5-C6H4 - CO--) in 100 mL methanol were added 4.0 g of ion exchanger (Amberlite IR-120) in the H ^{( +)} cycle and the mixture was heated to boiling for 10 hours with stirring. Then the methanol was distilled off, the residue was stirred with 50 ml of dichloroethane, the ion exchanger was filtered off, washed with 20 ml of dichloroethane and the combined filtrates were evaporated in vacuo. From 3.7 g of the crude lactone of formula I (Z = p-C5H5-C6H2-CO-), a product of m.p. = 150-151 ° C was obtained by recrystallization from dichloromethane-cyclohexane.

Example 7

To a solution of 1.72 g of the ester of formula VI ^(R2 = CH3CH2-, Z = CsH5-CO-) in 50 mL of ethanol was .přidáno 0.1 g p-toluenesulfonic acid and the solution was refluxed for 4 hours. The ethanol was evaporated in vacuo, the residue was dissolved in 20 ml of dichloroethane, the solution was washed with 10 ml of saturated sodium bicarbonate solution and dried over magnesium sulfate. After evaporation of the solvent was obtained! 1.34 g of the product of formula I (Z = C6H5-CO-) was practically uniform in chromatography.

Example 8

To a solution of 3.80 g of χ-lactone of formula V (R ² = CH 3 -) in 50 mL of dichloromethane was added 4.9 g of p-toluyl chloride and 4 mL of dry triethylamine. After working up the reaction mixture analogously to Example 5, 5.2 g of the crude diester of general formula VI (R ² = CH 3 -, Z = p - CH 3 - C 6 H 4 - CO -) were obtained.

Example 9

A solution of 2.10 g of an ester of formula VI (R ² = CH 3 -, Z = o - NO 2 - CeH 4 - CO -) and 0.1 g of p-toluenesulfonic acid in 50 ml of methanol was heated to boiling for 8 hours The solution was neutralized hot by the addition of triethylamine and after evaporation of the methanol to a total volume of 10 ml of solution, upon cooling, 1.26 g of crystalline product of formula I (Z = o-NCte-C6H4-CO) was obtained, chromatographically pure.

Claims (4)

OBJECT OF THE INVENTION A process for the preparation of hexahydro-5-hydroxy-4-hydroxymethyl-2H-cyclopenta (b) furan-2-one derivatives of the general formula I, wherein Z is R ¹ -C ⁶ H ⁴ CO- in which R ¹ is hydrogen, methyl, phenyl or nitro, characterized in that to the halohydroxyketone of the formula II, for example with 40% peracetic acid, to the corresponding 5-lactone of the formula IV ^: R ² and X have the above meanings, with the excess oxidant was decomposed; Gd sodium sulfite or the boiling solution and the compound of · the formula IV by the action of alkali metal hydroxides in the system of water-miscible organic solvent - - hydrogen peroxide in a volume ratio of 1: 0.5 to 2 converts at 30 ± 30 ° C to the corresponding χ-lactone of formula V, ni) where X is chlorine, brdm or iodine, acts with an acylating agent of formula R ² C: OY where R ² is C 1 -C 3 alkyl and Y is chloro, bromo or the R ² COO group wherein R ² is as defined above in the presence of tertiary amines such as pyridine or triethylamine, the acylation optionally takes place in the presence of an inert solvent such as dichloromethane or dichloroethane to form an acyl derivative of formula III (V) wherein R ² is as defined above, wherein the 5-position hydroxyl is protected by the Z group as defined above to form a diester of formula VI, (VI) wherein R ² az is as defined above, from which the aliphatic ester function is removed by selective transesterification with an aliphatic alcohol having 1 to 3 carbon atoms in the presence of acidic catalysts, releasing the lactone of formula I above. 2. The process of claim 1 wherein the 5-lactone is transformed into the corresponding .gamma.-lactone by treatment with 0.5 to 2 M lithium or sodium hydroxide solution in the presence of 30-40% hydrogen peroxide, which after ukde ¹ R ² and X are as defined above, which is oxidized in acetic acid, dichloromethane or dichloroethane at a temperature of 0 to 100 ⁰ C. organic peracids, nakončení reaction is removed by reduction with sodium sulfite, and the reaction product of is isolated by repeated extraction with an organic solvent, for example ethyl acetate. 3. A process according to claim 1, wherein the hydroxyl group at position 5 of the compound of formula (V) is protected by treatment with a 1.1-1.5 molar excess of aroyl chloride of formula (I). RI Čehi-COC1, wherein R ¹ is as defined above, in solution or pyridine in the presence of 1.5 to l 8molárního excess of triethylamine in an inert solvent such as dichloromethane or dichloroethane at a temperature of 40 ± 20 ° C. 4. A method according to claim 1, characterized in. That the transesterification is carried out at temperatures of 50 ± 30 ° C for ¹ methanol or ethanol in the presence of mineral acids such as sulfuric acid, aromatic sulfonic acids such as p-toluenesulfonic acid or a strongly acidic ion exchanger in the H ^{( +)} cycle.