JPH0318632B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the formula: (wherein, Z represents a R ¹ C ₆ H ₄ CO group, and R ¹ represents hydrogen, methyl, phenyl or nitro group)
-Hydroxymethyl-2H-cyclopenta[b]
The present invention relates to a method for producing a furan-2-one derivative.

The title compound, commonly referred to in the literature as Corey's lactone, has the formula:
Prostaglandins are important intermediates for the production of compounds with multifaceted biological effects derived from prostanoic acids. A number of preparation methods have been disclosed to date for compounds of this type, among which synthetic methods starting from norbornadiene occupy a predominant position. This synthetic method has several variations, all of which are protected by patents. Typical intermediates of some of these variants are 7-hydroxy-methyl-5- of the formula a, where A represents a chlorine, bromine or iodine atom (see formulas shown below). Halogen bicyclo(2,2,
1) Heptane-2-one, which has the formula b
(wherein A has the meaning defined above and R represents a tetrahydropyranyl, benzyl, methyl, triphenylmethyl or trialkylsilyl group) (U.S. Pat. No. 3,943,151,
(cf. DE 2704029, East German Patent No. 122817), the hydroxy group is first protected in the form of an acetal or silyl ether and converted by known methods into the desired lactone of the general formula. The compound of formula b is then converted to a δ-lactone of formula c by oxidation with an organic peroxoacid, where A and R have the meanings defined above.

The desired γ-lactone represented by the general formula is
obtained by conversion to the δ-lactone of formula c by the action of a solution of an alkali metal hydroxide or mineral acid, optionally containing the required γ-lactone d
is obtained after protection of the hydroxy function in the form of a Z derivative of the formula e, in which Z and R have the meanings defined above, followed by removal of the protecting group R. The disadvantage of the above process lies in the fact that most of the intermediates are in the form of an oily or dense consistency and that for their purification chromatographic treatments have to be used. Some reaction steps, mainly buyer-
Villiger oxidation and conversion of δ-lactone to γ-lactone clearly does not occur, which is responsible for the low yield. These reactions have to be carried out in dilute solutions, which results in a considerable consumption of flammable solvents, which places demands on industrial equipment to ensure operational safety and hygiene. In some cases, protecting groups A, such as benzyl groups, are difficult to further remove by catalytic hydrogenation. These facts therefore reduce the economic benefits of preparing the compounds of the general formula by the above-mentioned known methods.

The production method according to the present invention combines these known methods in a positive sense and aims to eliminate the drawbacks of the known methods up to now.

The main points of the method according to the present invention are the formula: (In the formula, X represents chlorine, bromine or iodine)
R ² COY (in the formula, R ² represents C ₁ to C ₃ alkyl, Y
represents a chlorine, bromine or R ² COO group, in the presence of a tertiary amine such as pyridine or triethylamine, the formula: (wherein R ² and X have the meanings defined above).

The crystalline product is usually obtained by washing the reaction mixture with sodium bicarbonate solution and then evaporating the solvent, and the product is dissolved in acetic acid or chlorinated hydrocarbon solution in a 3-5 molar excess without further purification. Oxidation can be carried out at temperatures of 0 to 100°C due to the action of organic peroxoacids as oxidizing agents. Excess oxidant is
After the reaction is complete, it is decomposed with water and sodium sulfite or by boiling the reaction mixture for several hours. After extracting the reaction product with an organic solvent and evaporating the solvent, the general formula: A crude crystalline δ-lactone of the formula (wherein R ² and X have the meanings defined above) is obtained.

The compound of formula can be recrystallized from a cyclohexane-dichloroethane mixture before proceeding to the next reaction step, or alternatively it can be used directly in pure form. The formula of δ-lactone is expressed by the formula: The conversion to the δ-lactone of the formula (R ² in the formula has the meaning defined above) is carried out at a temperature of 30 ± 30 °C by the action of an aqueous solution of an equimolar amount of alkali metal hydroxide, and this alkali metal hydroxide,
For example, tetrahydrofuran to hydrogen peroxide is 1:
It is added to a solution of a δ-lactone of the formula dissolved in a mixture of a water-miscible organic solvent and hydrogen peroxide in a dosage ratio of 0.5 to 2. After the reaction is complete, the mixture is diluted with water, acidified with acetic acid to PH 5-6 and then reduced and removed with solid sodium sulfite. The reaction product is isolated by successive extractions with organic solvents, the extracts are dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The crude product of the formula can be treated without further purification in the presence of triethylamine or pyridine, optionally giving the formula R ¹ -
diluted with an inert solvent with a _1.1-1.5 molar excess of acyl chloride represented by _C6H4 -COCl (wherein ^R1 has the meaning defined above) and the reaction mixture was stirred for 40 hours until the reaction was complete. Leave it at a temperature of ±20℃,
Excess reagent is destroyed by adding a small amount of water, and excess base is removed by evaporation under vacuum or by washing the reaction mixture with dilute hydrochloric acid. The evaporation residue is dissolved in methylene chloride, washed repeatedly with a solution of sodium bicarbonate and, after drying over magnesium sulfate, the aromatic acid residues are removed by filtration using an alumina oxide column. After evaporating the solvent under vacuum, the crude product is recrystallized from aqueous ethanol or used directly for further processing. The desired product, represented by the formula: (wherein R ² and Z have the meanings defined above) are processed by the action of an alcohol having 1 to 3 carbon atoms, such as methanol or ethanol, to an acid catalyst such as a mineral acid, sulfuric acid or Obtained by selective transesterification of aliphatic ester functional groups at a temperature of 50 ± 30 °C in the presence of a strongly acidic ion exchanger during a H ⁽⁺⁾ cycle, the product is crystallized and purified. be done.

Particular advantages of the production method according to the invention lie in the following facts. That is, the main part of the intermediate is a solid compound, which can be easily purified by crystallization and has high selectivity in all reaction steps of the synthesis in most commonly available chlorinated nonflammable solvents. and that it is carried out using relatively concentrated solutions of the reagents to ensure good yields.

The invention is further illustrated in a non-limiting manner by the following examples.

Example 1 1.84 g of freshly prepared acetanhydride and 1.43 g of dry pyridine
was added to 2.62 g of a hydroxyketone of the formula (where X is chlorine). The mixture heated itself spontaneously while simultaneously dissolving the starting compound into a homogeneous mixture and the mixture was left at room temperature overnight. The reaction mixture was diluted with 20 ml of dichloroethane, washed with 10 ml of dilute hydrochloric acid (1:5), then with 10 ml of a saturated solution of sodium bicarbonate and dried over magnesium sulfate. After evaporation of the solvent under vacuum, 3.23 g (99% of theory) of a colorless oil were obtained which rapidly crystallized. A pure acetyl derivative of the formula (wherein X is chlorine and R ² is methyl) is obtained by recrystallization from a cyclohexane-dichloroethane mixture and has a melting point of 70-72°C.

Example 2 Formula (where X is bromine and R ² is CH ₃ CH ₂ −
A propionyl derivative of the formula (wherein X is bromine) was obtained from a hydroxyketone of the formula (where X is bromine) in a manner analogous to that described in Example 1 by the action of propionyl chloride and pyridine.

Example 3 Add 15 ml of a 40% solution of Persteril to 30 ml of acetic acid.
ml of the formula (where X is chlorine and R ²
was added to a solution of _3.04 g of the acetyl derivative of The mixture was stirred at room temperature for 8 hours and then left overnight. After diluting the contents with 100 ml of ice water, the peroxide was decomposed by adding solid sodium sulfite, the organic fraction was extracted with dichloroethane (8 x 25 ml), and the extract was dissolved in a saturated solution of sodium bicarbonate. and then dried over magnesium sulfate. After evaporating the solution under vacuum, the formula (where X is chlorine and R ² is CH ₃ −)
2.41 g (75% of theory) of crystalline δ-lactone are obtained. Melting point 102-104℃.

Example 4 4.6 ^g of δ _- lactone (wherein It was added quickly to the solution at room temperature and with stirring, and the reaction mixture was acidified after 2 hours with 10 ml of acetic acid and then left overnight. After diluting the mixture with 100 ml of water, the excess hydrogen peroxide was destroyed by adding solid sodium sulfite while stirring and with external cooling such that the temperature did not exceed 30°C. After evaporating the tetrahydrofuran under vacuum, the aqueous solution was extracted with ethyl acetate (5 x 50ml), the extracts were washed with a saturated solution of sodium bicarbonate and dried over magnesium sulphate. Formula (wherein R ² is CH ₃ −)
3.85 g of dense gamma-lactone were obtained after evaporation of the solvent and this lactone was used for further processing without purification.

Example 5 5.50 g of p ^- phenylbenzoyl chloride and 4 ml of dry toethylamine were dissolved in ₅₀ ml of dichloroethane.
- added to a solution of 3.80 g of lactone. The naturally exothermic reaction mixture was allowed to stand overnight at room temperature and the excess reagent was destroyed by adding 1 ml of water.
After 1 hour the mixture was diluted with sodium bicarbonate (2 x 50
ml), dried over magnesium sulfate, then filtered through a column of 100 g alumina oxide and washed with 250 ml dichloroethane. After evaporating the solvent under vacuum, the formula (R ² is
CH ₃ −, Z is p−C ₆ H ₅ −C ₆ H ₄ −CO−)
6.90 g of crude ester was obtained. After recrystallization from aqueous ethanol, a product with a melting point of 90-92°C was obtained.

Example 6 Ion exchange resin (Amberlite) in H ⁺ cycle
4.0 g of IR ^- 120) was dissolved in ₁₀₀ ml _of methanol _.
−C ₆ H ₄ −CO) 3.94
10 g of solution while stirring the mixture.
boiled for an hour. The methanol was then distilled off, the residue was mixed with 50 ml of dichloroethane, the ion exchange resin was filtered off, washed with 20 ml of dichloroethane and the combined filtrates were evaporated under vacuum. Melting point 150
The product with a temperature of ~151°C has the formula (where Z is p-
It was obtained by recrystallizing 3.7 g of the crude lactone represented by _C6H5 - _{C6H4 - CO-} from a dichloromethane-cyclohexane mixture.

Example 7 0.1 g of p-toluene ^- sulfonic _acid was dissolved in 50 ml of ethanol _.
and Z is C ₆ H ₅ −CO−)
1.72g of the solution was added and the solution was then boiled for 4 hours. The ethanol was evaporated under reduced pressure, the residue was dissolved in 20 ml of dichloroethane, the solution was washed with 10 ml of saturated sodium bicarbonate solution and then dried over magnesium sulphate. 1.34 g of a chromatographically substantially homogeneous product of _the formula (wherein Z is _C6H5 -CO-) was obtained after distilling off the solvent.

Example 8 4.9 g of p-tolyl chloride and 4 ml of dry triethylamine are dissolved in 50 ml of dichloromethane to prepare a γ-lactone of the formula (wherein R ² is CH ₃ −).
Added to 3.80g of solution. 5.2 g of the crude diester of _the formula ( ^R2 is _CH3- and Z is p- _CH3 - _C6H4 -CO-) were obtained by similar treatment of the reaction mixture as in Example 5.

Example 9 Formula dissolved in 50 ml of methanol (where R ² is
A solution of 2.10 g of ester ( _CH3- , Z is o- _NO2 - _{C6H4 -} CO-) and 0.1 g of p-toluene-sulfonic acid was boiled for 8 hours. After acidifying the solution by adding triethylamine while heating and evaporating the methanol until the total volume of the solution is 10 ml, a chromatographically substantially pure formula (where Z is o-NO ₂ −C ₆ H ₄ −CO
1.26 g of a crystalline product of - is obtained after cooling.

Claims (1)

[Claims] 1. General formula: ^Hexahydro _{- 5} ^- hydroxy-4 represented by
-Hydroxymethyl-2H-cyclopenta[b]
A method for producing furan-2-one, which has the general formula: (wherein, X represents chlorine, bromine or iodine) A halogenohydroxyketone represented by the formula R ₂ COY (wherein, R ² represents C ₁ to C ₃ alkyl, and Y represents chlorine, bromine or R ₂ The acylation is carried out using an acylating agent of the general formula (representing a COO- group) in the presence of a tertiary amine such as pyridine or triethylamine in an inert solvent such as dichloromethane or dichloroethane, if necessary. (wherein R and
Organic peroxo acids, e.g. 40% at a temperature of 100 °C
Oxidized by the action of peracetic acid, the general formula: The corresponding δ-lactone of the formula (wherein R ² and The expressed compound was added at a temperature of 30±30°C in a volume ratio of 1 to 0.5.
2, due to the action of the alkali metal hydroxide in the water-miscible organic solvent versus the hydrogen peroxide system, the general formula: (wherein R ² has the meaning defined above) into the corresponding γ-lactone, and then protecting the 5-hydroxy group in this lactone with a Z group having the meaning defined above, General formula: (wherein R ² and Z have the meanings defined above) and then by selective transesterification using an aliphatic alcohol having 1 to 3 carbon atoms in the presence of an acidic catalyst. A process as described above, characterized in that the aliphatic ester functionality is removed from the diester and the lactone of the general formula is eliminated. 2. After the reaction is complete, the δ-lactone is converted to the corresponding γ-lactone by the action of a 0.5-2 molar solution of lithium hydroxide or sodium hydroxide in the presence of 30-40% hydrogen peroxide, which is removed by reduction with sodium sulfite. 2. The method of claim 1, wherein the reaction product is isolated by conversion to a lactone and repeated extractions with an organic solvent such as ethyl acetate. 3 The hydroxyl group at the 5-position of the compound represented by the above formula is dissolved in an inert solvent such as dichloromethane or dichloroethane in the presence of 1.5 to 1.8 molar excess of triethylamine, or in a pyridine solution,
1.1 to 1.1 of the acyl chloride represented by the formula R ¹ −C ₆ H ₄ −COCl (R ¹ in the formula has the meaning defined above)
2. A process as claimed in claim 1, in which protection is achieved at a temperature of 40.+-.20.degree. C. by the action of a 1.5 molar excess. 4. The ester conversion reaction is carried out by methanol or ^ethanol for 50±
A method according to claim 1, which is carried out at a temperature of 30°C.