GB2133001A - A process for producing hexahydro- 5-hydroxy-4-hydroxymethyl- 2H-cyclopenta[B]furan-2-one derivatives - Google Patents
A process for producing hexahydro- 5-hydroxy-4-hydroxymethyl- 2H-cyclopenta[B]furan-2-one derivatives Download PDFInfo
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- GB2133001A GB2133001A GB08228827A GB8228827A GB2133001A GB 2133001 A GB2133001 A GB 2133001A GB 08228827 A GB08228827 A GB 08228827A GB 8228827 A GB8228827 A GB 8228827A GB 2133001 A GB2133001 A GB 2133001A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
- C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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Abstract
A process for producing the title compounds of general formula I <IMAGE> wherein Z stands for the group R<1>- C6H4CO-, and R<1> stands for H, Me, Ph or NO2, wherein a halogen hydroxy ketone of general formula II <IMAGE> where X is Cl, Br or I, is reacted with an acylating agent of general formula R<2>COY, wherein R<2> stands for C1-3 alkyl and Y stands for Cl, Br or a R<2>COO- group in the presence of tertiary amines to give an acyl derivative of general formula III <IMAGE> wherein R<2> and X have the above- mentioned meaning. The acyl derivative is oxidized with a peroxo-acid to the corresponding ???-lactone which is converted to the corresponding ???-lactone of general formula V <IMAGE> wherein R<2> has the above-mentioned meaning, by the effect of alkali metal hydroxides. The hydroxyl group of the compound of general formula V is protected by the Z group, which has the above-mentioned meaning, to give a diester, from which Corey's lactone of general formula I is released by selective transesterification. This synthesis is applicable to the production of prostaglandines.
Description
SPECIFICATION
A process for producing hexahydro-5-hydroxy-4-hydroxymethyl-2H-cyclopenta(b)furan-2- one derivatives
The invention relates to a process for producing hexahydro-5-hydroxy-4-hydroxymethyl-2 Hcyclopenta(b)furan-2-one derivatives of general formula 1
wherein Z stands for a R1C6H4CO group and R' stands for hydrogen, or a methyl, phenyl or nytro group.
The title compound of general formula 1, ususally denominated as Corey's lactone in the literature, is an important intermediate for the preparation of prostaglendines, compounds with a wide range of biological activity derived from prostanoic acid. A lot of processes for the preparation of compounds of this type have been described, of which processes the foremost place is occupied by a synthesis starting from norbornadiene. This synthesis has several variants all of which are protected by patents.A common intermediate of some of these variants is 7hvdroxy-methyl-5-halogenebicyclo(2,2, 1) heptane-2-one of general formula a wherein A stands for a chlorine, bromine or iodine atom (see below) which is converted according to known processes to the desired lactone of general formula I in such a way that the hydroxy group is protected at first in the form of an acetal, ether or silylether to obtain a compound of general formula b wherein A has the above meaning and R stands for a tetrahydropyranyl-, benzyl-, methyl-, triphenylmethyl- or trialkylsilyl- group (see US Patent No. 3 943 151, DOS No. 2 704 029, DDR Patent No. 122 817). The compounds of general formula b are then converted to a lactone of general formula c by oxidation with organic peroxo-acids, wherein A and R have the above meaning.The desired y-lactone of general formula I
Compound of Formula I is obtained by transformation of the 6lactone of general formula c by the effect of solutions of alkali metal hydroxides or of mineral acids. The required y-lactone d is obtained, after protecting the hydroxyl function in the form of the Z derivative of general formula e, wherein Z and R have the above meaning, and after removing the protecting group R. The drawback of the abovementioned processes is the fact that most of the intermediates are of oily or honey-like consistency and for their purification chromatographic methods have to be used. Also, some reaction stages, mainly the Bayer-Villiger's oxidation and transformation of 6-lactones to ylactones do not proceed in a straight forward fashion which is the cause of low yields.These reactions have to be carried out in dilute solutions and this brings about a considerable consumption of easily inflammable solvents and consequently demanding requirements for production equipment, occupational hygiene and safety of operation. In some cases the protecting group A is also removed with difficulty, for example a benzyl group by catalytic hydrogenation. These facts therefore suppress the economic advantage of the preparation of the compound of general formula I by the above-mentioned known processes.
The processes of the present invention are linked with these known processes in a positive sense, except that the drawbacks of the previously known processes have been eliminated.
The subject matter of the process according to the invention consists in that a halogen hydroxy ketone of general formula II
wherein X stands for chlorine or bromine or iodine, is acylated in an inert solvent or without solvent by an acylating agent of general formula R2COY, wherein R2 stands for an aikyl group containing 1 to 3 carbon atoms and Y stands for chlorine, bromine or a R2COO- group, in the presence of tertiary amines, for example pyridine or triethylamine, to obtain an acyl derivative of general formula Ill,
wherein R2 and X have the above-mentioned meanings.
A crystalline product is usually obtained after washing the reaction mixture with a solution of sodium hydrogen carbonate and evaporation of solvents, which product can be oxidized without further purification in a solution of acetic acid or chlorinated hydrocarbons by the action of organic peroxo-acids in 3 to 5 molar excess of oxidation agent at a temperature of O to 1 00 C.
The excess of oxidizing agent is decomposed by water and sodium sulphite or by several hours boiling of the reaction mixture after the reaction has ended. The reaction product is extracted by an organic solvent and after its evaporation crude crystalline lactone of general formula IV is obtained
wherein R2 and X have the above-mentioned meanings.
The compound of general formula IV can be recrystallized before further reaction from the mixture cyclohexane-dichloroethane or it can be used directly in the pure state. The transformation of lactone of general formula IV to y-lactone of general formula V
wherein R2 has the above-mentioned meaning, is carried out by the action of an equimolar amount of an aqueous solution of alkali metal hydroxide which is added to a solution of 6lactone of general formula IV dissolved in a mixture of water-miscible organic solvent - hydrogen peroxide in a volume ratio of 1:0.5 to 2, for example tetrahydrofuran - hydrogen peroxide at a temperature of 30 + 30"C.After the reaction has ended the mixture is diluted with water, acidified with acetic acid to a pH = 5 to 6 and the peroxides present are removed by reduction with solid sodium sulphite. The reaction product is isolated by repeated extraction with an organic solvent, by drying the extract with magnesium sulphate and by evaporation of the solvent under vacuum.The crude product of general formula V can, without further refining be treated in the presence of triethylamine or pyridine and with diluted inert solvents, with a 1.1 to 1.5 molar excess of an acyl chloride of general formula R1-C6H4-COCl, wherein R1 has the above-mentioned meaning, the reaction mixture is allowed to stand at a temperature of 40 + 20"C until the reaction has ended, the excess of agent is decomposed by the addition of a small amount of water, excessive 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, repeatedly washed with a solution of sodium hydrogen carbonate and after drying with magnesium sulphate the residues of aromatic acids are removed by filtration over an aluminium oxide column. After evaporation of the solvent under vacuum the crude product is recrystallized from aqueous ethanol or it is directly used for further treatment.The required product of general formula I is obtained from the thus prepared compound of general formula VI
wherein R2 and Z have the above-mentioned meanings, by selective transesterification of the aliphatic ester function carried out at a temperature of 50 + 30"C by the effect of alcohols containing 1 to 3 carbon atoms, for example methanol or ethanol, in the presence of acidic catalysts, for example mineral acids, sulphonic acids or strongly acidic ion exchange resins (H/+ cycle), which proset is purified-by crystallization.
A special advantage of the process of the present invention is the fact that, the majority of intermediates are solid compounds which can be easily purified by crystallization, and the reactions are carried out in commonly accessible mostly chlorinated incombustible solvents, with relatively concentrated solutions of such agents which ensure high selectivity and excellent yields in all the reaction stages of the synthesis.
The invention and effect thereof are more thoroughly elucidated by the following examples which are provided for illustration and are not to be construed as limiting the scope of the invention in any way.
Example 1
1.84 g of freshly distilled acetanhydride and 1.43 g of dry pyridine was added to 2.62 g of hydroxy ketone of general formula II /X = chlorine/. Dissolution of the starting compound occurred exothermically to give a homogeneous mixture which 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/, 10 ml of a saturated solution of sodium hydrogen carbonate and dried with magnesium sulphate. After evaporation of solvent under vacuum 3.23 g /99% of theoretical/ of a colourless oil was obtained which quickly crystallized. Pure acetyl derivative of general formula 111 /X = chlorine, R2 = CH3/ was obtained by recrystallization from a mixture of cyclohexane-dichloroethane. The derivative had a m.p. of 70 to 72"C.
Example 2
The propionyl derivative of general formula II /X = bromine, R2 = CH3CH2-/ theoretical yield 92% was prepared by the action of propionyl chloride and pyridine from a hydroxyketone of general formula II /X = bromine/ in an analogous manner to that of Example I.
Example 3 1 5 ml of a 40% solution of peracetic said /Persteril/ was added to a solution of 3.04 g of acetyl derivative of general formula Ill /X = chlorine, R2 = CH3-/ in 30 ml of acetic acid within 10 minutes. The mixture was stirred at room temperature for 8 hours and then left to stand overnight. After dilution of the contents with 100 ml of iced water the peroxides were decomposed by the addition of solid sodium sulphite, and organic fractions were extracted with dichloroethane /8 X 25 ml/, the extracts were washed with a saturated solution of sodium hydrogen carbonate and dried with magnesium sulphate. After evaporation of the solution under vacuum 2.41 g /75% of theoretical/ of crystalline 8lactone of general formula IV /X = chlorine, R2 = CH3-/ having a m.p. of 102 to 1 04 C were obtained.
Example 4
10 ml of a 2N solution of lithium hydroxide was quickly added at room temperature and under mixing to a solution of 4.6 g of 6-lactone IV /X = chlorine, R2 = CH3-/ in a mixture of 100 ml of tetrahydrofuran and 50 ml of 30% hydrogen peroxide, the reaction mixture was acidified with 10 ml of acetic acid after 2 hours and was left overnight.After dilution of the mixture with 100 ml of water the excess of hydrogen peroxide was decomposed by the addition of solid sodium sulphite under mixing and external cooling in such a way that the temperature did not exceed 30"C. After evaporation of the tetrahydrofuran under vacuum the aqueous solution was extracted with ethyl acetate /5 x 50 ml/, the extract was washed with a saturated solution of sodium hydrogen carbonate and dried with magnesium sulphate. 3.85 g of honeylike y-lactone of general formula V /R2 = CH3-/ was obtained after evaporation of the solvent, which lactone could be used for further synthesis without purification.
Example 5
5.50 g of p-phenylbenzoyl chloride and 4 ml of dry triethylamine were added to a solution of 3.80 g of lactone of general formula V /R2 = CH3-/ in 50 ml of dichloroethane. The exothermic reaction mixture was left at room temperature overnight and the excess of agent was decomposed by the addition of 1 ml of water. After 1 hour the mixture was washed with a saturated solution of sodium hydrogen carbonate /2 x 50 ml/, dried with magnesium sulphate and filtered over a column of 100 g of aluminium oxide which was washed with 250 ml of dichloroethane.After evaporation of the solvent under vacuum 6.90 g of crude ester of general formula VI /R2 = CH3-, Z = p-C6H5-C6H4-CO-/ was obtained, which ester yielded a product having a m.p. of 90 to 92"C after recrystallization from aqueous ethanol.
Example 6
4.0 g of ion exchange resin /Amberlite (RTM) IR-120/ (H+ cycle) was added to a solution of 3.94 g of ester of general formula VI /R2 = CH3-, Z = p-C6H5-C6H4-CO-/ in 100 ml of methanol and the mixture heated to boiling while mixing for 10 hours. Methanol was then distilled off, the residue was mixed with 50 ml of dichloroethane, the ion exchange resin was filtered off, the solution washed with 20 ml of dichloroethane and the united filtrates were evaporated under vacuum. A product having a m.p. of 150 to 151 C was obtained from 3.7 g of crude lactone of general formul I /Z = p-C6H5-C6H4-C0-/ by recrystallization from a mixture of dichloromethane-cyclohexane.
Example 7
0.1 g of p-toluene-sulphonic acid was added to a solution of 1.72 g of ester of general formula VI /R2 = CH3CH2-, Z = C6H5-C0-/ in 50 ml of ethanol and the solution heated to boiling for 4 hours. Ethanol was evaporated under vacuum, the residue was dissolved in 20 ml of dichloroethane, and the solution was washed with 10 ml of a saturated solution of sodium hydrogen carbonate and dried with magnesium sulphate. 1.34 g of a product of general formula
I /Z = C6H5-CO-/ which was chromatographically substantially uniform was obtained after evaporation of the solvent.
Example 8
4.9 g of p-toluyl chloride and 4 ml of dry triethylamine were added to a solution of 3.80 g of y-lactone of general formula V /R2 = CH3-/ in 50 ml of dichloromethane. 5.2 g of crude diester of general formula VI /R2 = CH3-, Z = p-CH3-C6H4-CO-/ was obtained after analogous treatment of the reaction mixture to that described in Example 5.
Example 9
A solution of 2.10 g of ester of general formula IV /R2 = CH3-, Z = o-N02-C6H4-CO-/ and 0.1 g of p-toluene-sulphonic acid in 50 ml of methanol was heated to boiling for 8 hours. The solution was neutralized while heating by the addition of triethylamine and after the evaporation of methanol to a total volume of 10 ml of solution 1.26 g of a crystalline product of general formula I /Z = o-NO2-C8H4-CO-/ which was chromatographically substantially pure was obtained after cooling.
Claims (6)
1. A process for producing hexahydro-5-hydroxy-4-hydroxymethyl-2H-cyclopenta/b/furan-2one derivatives of general formula I
wherein Z stands for a R'-C6H4CO-group, and R' stands for hydrogen, or a methyl, phenyl or nitro group in which a halogen hydroxy ketone of general formula II
wherein X stands for chlorine, bromine or iodine, is reacted with an acylation agent of general formula R2COY, wherein R2 stands for an alkyl group containing 1 to 3 carbon atoms and Y stands for chlorine, bromine or a R2COO- group in the presence of a tertiary amine, acylation being carried out in the presence of an inert solvent to obtain an acyl derivative of general formula Ill
wherein R2 and X have the meaning mentioned above, which is oxidized by the action of an organic peroxoacid, to the corresponding 6-lactone of general formula IV
wherein R2 and X have the above-mentioned meaning, the excess of oxidizing agent being decomposed and a compound of general formula IV is converted to the corresponding y-lactone of general formula V
wherein R2 has the above-mentioned meaning, at a temperature of 30 + 30"C by the effect of an alkali metal hydroxide in a system of water-miscibleorganic solvent - hydrogen peroxide in a volume ratio of 1::0.5 to 2, in which lactone the hydroxyl group in 5-position is protected by the
Z-group which has the above-mentioned meaning, to obtain a diester of general formula VI
wherein R2 and Z have the above-mentioned meaning, from which diester the aliphatic ester function is eliminated in the presence of acidic catalysts by selective transesterification with an aliphatic alcohol containing 1 to 3 carbon atoms, lactone of the above-mentioned general formula I being released.
2. A process according to Claim 1 in which lactone is converted to the corresponding y- lactone by the effect of an 0.5 to 2 M solution of lithium or sodium hydroxide in the presence of 30 to 40% hydrogen peroxide which is removed by reduction with sodium sulphite after the reaction has ended and the reaction product is isolated by repeated extraction with an organic solvent.
3. A process according to Claim 1 or Claim 2 in which the hydroxyl group in the 5-position of the compound of general formula V is protected by the action of a 1.1 to 1.5 molar excess of acyl chloride of general formula R1-C6H4-COC1, wherein R1 has the above-mentioned meaning, in a pyridine solution or in the presence of a 1.5 to 1.8 molar excess of triethylamine in an inert solvent at a temperature of 40 + 20"C.
4. A process according to any one of Claims 1 to 3 in which the transesterification is carried out at a temperature of 50 i 30"C with methanol or ethanol in the presence of mineral acids or a strongly acidic ion-exchange resin (H/+/ cycle).
5. A process for producing hexahydro-5-hydroxy-4-hydroxymethyl-2H-cyclopenta(b)furan-2one derivatives of general formula I wherein Z stands for a R-C6H4CO- group and R' stands for hydrogen or a methyl, phenyl or mitro group substantially as hereinbefore described with reference to any one of the Examples 1 to 9.
6. Hexahydro-5-hydroxy-4-hydroxymethyl-2 Hcyclopenta(b)furan-2-one derivatives of general formula I when produced by any one of the processes claimed in Claims 1 to 5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08228827A GB2133001B (en) | 1982-10-08 | 1982-10-08 | A process for producing hexahydro-5-hydroxy-4-hydroxymethyl-2h-cyclopenta(b)furan2-one derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08228827A GB2133001B (en) | 1982-10-08 | 1982-10-08 | A process for producing hexahydro-5-hydroxy-4-hydroxymethyl-2h-cyclopenta(b)furan2-one derivatives |
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| Publication Number | Publication Date |
|---|---|
| GB2133001A true GB2133001A (en) | 1984-07-18 |
| GB2133001B GB2133001B (en) | 1986-01-29 |
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| GB08228827A Expired GB2133001B (en) | 1982-10-08 | 1982-10-08 | A process for producing hexahydro-5-hydroxy-4-hydroxymethyl-2h-cyclopenta(b)furan2-one derivatives |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102190642A (en) * | 2010-03-05 | 2011-09-21 | 上海天伟生物制药有限公司 | Preparation method and purification technique of dicyclic compound |
| CN104513186A (en) * | 2015-01-13 | 2015-04-15 | 宁波第二激素厂 | Preparation method of optically pure dextro cloprostenol sodium |
-
1982
- 1982-10-08 GB GB08228827A patent/GB2133001B/en not_active Expired
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102190642A (en) * | 2010-03-05 | 2011-09-21 | 上海天伟生物制药有限公司 | Preparation method and purification technique of dicyclic compound |
| CN102190642B (en) * | 2010-03-05 | 2014-11-05 | 上海天伟生物制药有限公司 | Preparation method and purification technique of dicyclic compound |
| CN104513186A (en) * | 2015-01-13 | 2015-04-15 | 宁波第二激素厂 | Preparation method of optically pure dextro cloprostenol sodium |
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| Publication number | Publication date |
|---|---|
| GB2133001B (en) | 1986-01-29 |
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| PCNP | Patent ceased through non-payment of renewal fee |