GB2072672A - Process for the preparation of 2- substituted-4-hydroxy-2-cyclopenten- 1-ones - Google Patents

Abstract

Compounds of the general formula:- <IMAGE> (which are valuable intermediates in the production of prostaglandins) are produced from compounds of the general formula:- <IMAGE> in which R represents hydrogen or a lower alkyl radial; A represents a hydrocarbon chain containing 5, 6 or 7 carbon atoms, which chain may contain at least one alkenylene or alkynylene group and may be substituted with one or more lower alkyl groups; and OTrialylBS represents a tri C2-6 alkyl benzene sulphonyl group by reduction with alkali metal borohydride with subsequent hydrolysis and allylic rearrangement. In an example the triisopropyl benzene sulphonate of 2-(6-carbomethoxyhexyl)-4-hydroxy- cyclopenta-1,3-dione is reduced with NaBH4 and hydrolysis and allylic rearrangement, which occurs spontaneously in an acid medium gives 2(6- carbomethoxyhexyl)-4-hydroxy-2- cyclopenten-1-one in high yield.

Description

SPECIFICATION Process for the preparation of 2-substitutedA-hydrnxy-2-cycIopenten-1 -ones This invention relates to an improved process for the preparation of 2-substituted-4-hydroxy-2-cyclo-penten 1-ones.

In U.S. Patent 3969391 there is described a process for the preparation of 2-substituted-4-hydroxy-2cyclopenten-1 -ones of the general formula:

in which R is hydrogen or a lower alkyl radical and m is 5,6 or 7 which process comprises reducing a compound ofthe general formula

in which R' is a lower alkyl radical and R has the above-stated meaning with a hydride reducing agent in a suitably inert solvent and contacting the unisolated enol-ether intermediate with a suitable acidic agent which effects hydrolysis and dehydration (allylic rearrangement) thus forming the corresponding compounds of formula I.

In a preferred embodiment of that process, 1 -methoxy-2(6-carboxyhexyl)-4-hydroxy-1 -cyclopenten-3-one and its lower alkyl esters are reduced with sodium dihydro bis(2-methoxyethoxy) aluminate and then contacted with aqueous hydrochloric acid to yield 2-(6-carboxyhexyl)-4-hydroxy-2-cyclopenten-1-one and its esters respectively.

The compounds of general formula II wherein R is lower alkyl are prepared from compounds of the general formula Ill

in which m has the above-stated meaning by reacting the compound of formula Ill with a lower alkanol under anhydrous acid conditions.

The use of sodium dihydrobis (methoxyethoxy) aluminate, commonly referred to as "Red-Al" has certain disadvantages both from the point of view of the conditions which have to be maintained for its use and from the point of view of the results achieved.

Thus, as regards the conditions which have to be maintained for its used, it is known that a very low temperature has to be used. Thus, as disclosed in Example 1 of the Patent to Pappo mentioned above a temperature of -60 C has to be maintained during the reaction. It is well known to those skilled in the art that the use of "Red-Al" and indeed lithium aluminium hydride (Lith-Al) forthis reaction requires the use of very low temperatures. Other stringent requirements which have to be used include the rigorous drying of all solvents and the necessity of carrying out the reaction under nitrogen or an inert gas.

From the point of view of the results achieved, the use of "Red-Al" has certain disadvantages which arise from the fact that in practice it is very difficult to get "Red-All" in pure form and it is usually contaminated with partially decomposed material, which is positively deleterious to the reduction. Therefore, the tendency is to use the "Red-Al" in excess of that which would theoretically be required, to ensure 1,2-reduction at the C-3, ring carbonyl in formula II. If an excess is used however reduction of the terminal carbomethoxy (CH30CO-) to an hydroxymethyl group ((CH30H) may take place leading to an undesired by-product.

In a U.S. Patent to Sih et al (Patent No.3,968,141) and in a related paper of Sih et al in J.A.C.S. 97:4 February 19,1975 pps 865-874 there is described the reduction of compounds of formula II above in which R' in the above formula represents a bulky group such as for example a benzene sulphonyl or a 2-methyl propyl group.

Sih et al still use "Red-Al" as the preferred reducing agent, which still involves the difficulties as mentioned above.

Amongst the hydride reducing agents disclosed by Pappo in his U.S. Patent there is mentioned sodium borohydride (NaBH4). We have found that if this reagent is used as a reducing agent only a small amount of desired 1,2-reduction takes place at the ring carbonyl. The major reaction is the undesired 1,4-reduction of the five membered ring unsaturated enone system leading to compounds of formula

This is the case not only when R' represents a lower alkyl group as in Pappo but also when R' represents one of the bulky groups, as in Sih.

Therefore the use of sodium borohydride cannot apparently be recommended for production of the compounds of formula I because the yield of the desired product of formula I is low. The use of sodium borohydride however offers certain very definite advantages over the use of "Red-Al" or "Lith-Al" in respect of the conditions required for its use. Thus it may be used at temperatures which are more suitable for large scale operations than those required for "Red-Al" and "Lith-Al". Reduction using sodium borohydride may be effected, for example, preferably within the range of O to +200C and the precautions which one has to take when using Lith-Al and Red-Al do not have to be taken.

The problem, which is solved by the present invention, is how to make compounds of formula I by reduction of a suitable intermediate to give the desired product in high yield using a hydride reducing agent which does not require the stringent conditions of use demanded by Red-Al and Lith-Al. We have found that intermediates of the following formula

OTrialkylBS e 2R tre, HO in which R has the meaning given above, and A represents a hydrocarbon chain containing 5, 6 or 7 carbon atoms which chain may, optionally, contain at least one alkenylene or alkynylene group and may be substituted with one or more lower alkyl groups and Trialkyl BS is a tri2~6 alkyl benzene sulphonyl may be reduced with hydride reducing agents such as alkali metal borohydrides, e.g. sodium borohydride, lithium borohydride, or potassium borohydride, or zinc borohydride to give compounds of the following formula

in which A and R have the meanings given, in high yield.

It will be appreciated that formula V covers compounds of formula I, except that the definition of A is broader than - (CH2)m- in which m is 5, 6 or 7. The process of the present invention also has utility in the production of compounds not described in Pappo as explained later.

In the intermediates of formula IV the group Trialkyl BS preferably represents triisopropyl benzene sulphonyl (TIBS). The group A preferably represents a group -(CH2)m in which m represents 5, 6 or 7 and the group may contain a double or triple bond or may be substituted with one or methyl groups.

The invention therefore provides a process for the preparation of compounds of general formula V above which comprises reducing compounds of formula IV with an alkali metal borohydride and recovering the desired product of formula V by hydrolysis and allylic rearrangement.

It is surprising that the reduction of intermediates of the general formula IV does not lead to some 1,4-reduction of the unsaturated enone system, since this occurs even when the group in the R' position (in formula 11) is a bulky group as in the disclosure of Sih referred to above. The effect of the trialkyl benzene sulphonyl group in preventing reduction at the 1,4-position appears quite specific and was not to be expected.

The fact that by the process of the present invention the compounds of formula V can be prepared in high yields and under non-stringent conditions from the compounds of formula IV is of considerable importance because the compounds offormula V are valuable intermediates in the production of prostaglandins.

Valuable prostaglandins can for example be obtained from 2-(6-carbomethoxy hexyl)-4-hydroxy-2cyclopenten-1 -one as described in Pappo. Valuable prostaglandins which inhibit gastric secretion stimulated by secretogogues can also be obtained from the following 2-cyclopenten-1 -ones, not disclosed in Pappo, but the preparation of which is described herein, namely: 2-(7-carbomethoxy-hept-4,Z-ene)-4-hydroxy-2-cyclopenten-1 -one; 2-(7-carbomethoxy-hept-3,Z-ene)-4-hydroxy-2-cyclopenten-1 -one; 2-(6-carbomethoxy4-dimethyl-hexyl)-4-hydroxy-2-cyclopenten-1 -one; 2-(6-carbomethoxy.hex.3,Z-ene)-4-hydroxy-2-cyclopenten- 1 -one; 2-(6-carbomethoxy-hex-3,Z-yne)-4-hydrnxy.2-cyclopenten1 -one.

The invention can be applied to compounds of formula III which are both optically active or racemic at C4 withoretention of optical activity in the former compounds.

The present invention encompasses a multistage process for the production of the prostaglandins including utilizing as an intermediate a compound of formula IV specified above.

The compounds of formula IV according to the invention may be prepared from compounds of formula Ill by converting this to a lower alkyl ester preferably a C14 alkyl ester for example the methyl ester of the formula:

by reaction with a lower alkanol under ester forming conditions and then reacting this lower alkyl ester to form a compound of formula IV by reaction with a tri C26 alkyl benzene sulphonyl halide in particular a chloride in the presence of an acid binding agent, such as triethylamine. The intermediates of formula IV need not be isolated before reduction according to the process of the invention, although this may in some cases be the preferred method of procedure.

The reduction of the compound of formula IV according to the invention with an alkali metal hydride in particular sodium borohydride can conveniently be effected by addition ofthe solid reducing agent to a solution of the compounds of formula IV in a suitable organic solvent for example a lower alkanol, e.g.

methanol at a temperature of from abientto -100C. Conveniently the solution of the compound offormula IV may be cooled to approximately 5"C and then reduction effected by addition of solid reducing agent, with maintenance of the reaction temperature below 20"C until reduction is complete. The product of the reduction may then be treated with a small quantity of an acid, for example hydrochloric acid or paratoluene sulphonic acid to decompose the borohydride complex. Hydrolysis of the sulphonic ester with loss of sulphonic acid and allylic rearrangement takes place under these acid conditions.

The following Examples illustrate the invention: Example 1 (a) Preparation of 2-(6-carbomethoxyhexyl)-4-hydroxy-cyclopenta-1,3-dione 75 g of 2-(6-carboxylhexyl)-4-hydroxy-cyclopenta-1 ,3-dione were heated with 300 mis of methanol and 3 mls of concentrated hydrochloric acid to reflux with stirring.

The mixture was refluxed for 45 minutes, cooled and 100 mls of water was added.

The mixture was stirred for 11/2 hours and 8 mls of pyridine were then added. The methanol was evaporated off under vacuum. The mixture was then cooled and 300 mls of water followed by 49 g of sodium bicarbonate were added. The reaction mixture was extracted three times with ethyl acetate. The aqueous layer was acidified with 60 mls concentrated hydrochloric acid. This was then extracted three times with chloroform. The extract was then washed twice with water and dried over anhydrous sodium sulphate. The solution was filltered and the chloroform evaporated off under vacuum to give an oil. To this was added 100 mls of diisopropyl ether (DIPE) with stirring. The solution was filtered and dried to give 59 g (76% yield) of the title compound.

(b) Preparation of 2(6-carbomethoxyhexyl)-4-hydroxy-2-cyclopenten-1 -one.

To a solution of 50 g of 2-(6-carbomethoxyhexyl)-4-hydroxy-cyclopenta-1 ,3-dione, and 63 mls of triethylamine in 160 ml tetrahydrofuran (THF) was added a solution of 64 g of triisopropyl benzene sulphonyl chloride (TIBSCI) in 125 mls of THF over 2 hours, the temperature being maintained at 0 C to 20"C. The precipitate was filtered off and washed with THF. The solution was evaporated under vacuum at less than 50"C to give an oil. This oil was dissolved in 220 mls of methanol.To this solution was added 17.5 g of sodium borohydride portionwise over 11/2 hours, with maintenance of the temperature below 30"C. The solution was evaporated under vacuum to a semi-solid dissolved in 300 mls of water, 300 mls of ether and acidified with concentrated hydrochloric acid. The organic layer was separated and washed with brine. It is then dried over anhydrous sodium sulphate and filtered. A few mgs of p-toluene sulphonic acid were then added to the filtrate and it was refluxed for 1 hr. The reaction mixture was then cooled and anhydrous sodium carbonate added until effervescence ceased. The material was then filtered and the filtrate washed 3 times with water and the aqueous was washed five times with ether.The combined organic layers were washed twice with water and dried over sodium sulphate, and then filtered and evaporated to an oil under vacuum. The oil was dissolved in DIPE and allowed to crystallize. The crystals were filtered off and washed with cold DIPE. Yield: 30 g of the title compound (yield 64%) in the form of a crystalline product having m.p.

47"C. The yield of the undesired isomer, that is to say that produced by 1,4 reduction is less than 1%.

Example 2 1 -(2,4,6-triisopropyl benzene sulphonyl)-2(6-carbomethoxyhexyl)-4-hydroxy-1 -cyclopenten-3-one.

To a solution of 5.0 g of 2-(6-carbomethoxy hexyl)-4-hydroxy-cyclopenta-1,3-dione and 6.4 mls of triethylamine in 16.0 mls tetrahydrofuran (THF) was added to a solution of 6.4 g triisopropyl benzene sulphonyl chloride (TIBSCI) in 12.5 mls of THF over 2 hours the temperature being maintained at O" to 20".

The precipitate was filtered off and washed with THF. The solution was evaporated under vacuum at less A than 50"C, to give an oil. This oil was subjected to column chromatography (silica/ethylacetate/hexane) to give pure 1-(2,4,6-triisopropyl benzene sulphonyl)-2(6-carbomethoxyhexyl)-4-hydroxy-1 -cyclopenten-3-one as a pale yellow oil identified from the following NMR spectral data (CDC13)::- Multiplicity Shift (ppm) Protons d 1.3 isopropyl methyls M 3.0 4-isopropyl methine S 3.7 ester methyl M 1.45 C25 (side chain) M 2.3 C1,6 (side chain) M 4.2 2,6-isopropyl methines dofd 4.3 C-4 proton S 7.3 3,5-aromatic protons Example 3 2(6-carbomethoxyhexyl)-4-hydroxy-2-cyclopenten-1 -one To a solution of 500 g of 2-(6-carbomethoxy hexyl)-4-hydroxy-cyclopenta-1 ,3,-dione and triethylamine (630 mls) in 1800 mis of tetrahydrofuran (THF), was added a solution of triisopropyl benzene sulphonyl chloride (TIBSCI) (630 g) in 600 mls THF over 30 minutes at 5-1 00C with stirring. The precipitate was filtered off and washed with THF.Hexane was added to the filtrates and the resultant solution washed with 1400 mls water. It was then washed with a further 400 mls water, 50 mls 5% Na2CO3 solution. 50 mls saturated sodium chloride solution and then dried over an hydros sodium sulphate. Filtration followed by stripping the filtrates to an oil under vacuum gave 1060 grams of 1-(2,4,6-triisopropyl benzene sulphonyl)-2-(6carbomethoxyhexyl)-4-hydroxy-1 -cyclopenten-3-one as an oil (yield 100% of theory).

The 2,4,6-triisopropyl benzene sulphonyl derivative obtained above, in the form of the oil was dissolved in 3100 mls of methanol and cooled to 0 C. To this was added 180 g of sodium borohydride portionwise over one hour with stirring, maintaining the temperature at less than 20"C. The solution was evaporated under vacuum to a semi-solid and dissolved in 150 mls water, 150 mls ether and 200 mls saturated salt solution and separated. The organic layer was washed with salt solution and the organic layer dried over anhydrous sodium sulphate. To this spiution was added 15 g of paratoluene sulphonic acid (PTSA) which decomposed the reduced intermediate. To this was added anhydrous Na2CO3 until effervescence ceased, when 15 g of calcium hydride was added and the suspension stirred for a few hours.

The reaction mixture was filtered and the filtrate washed three times with water. The combined aqueous layer were washed five times with ether. The combined organic layers were dried over anhydrous sodium sulphate filtered and evaporated to an oil under vacuum. The oil was crystallised from di-isopropyl ether to yield 240 grams of 2-(6-carbomethoxyhexyl)-4-hydroxy-2-cyclopenten-1 -one as a crystalline solid (yield 49% of theory).

Example 4 2-(7-carbomethoxy-hept-4,Z-ene)-4-hydroxy-2-cyclopenten-1 -one.

1.3 g of 2-(7-carbomethoxy-hept-4,Z-ene)-4-hydroxycyclopenta-1,3-dione was dissolved in 5 ml of freshly distilled THF containing 1.6 g of triethylamine and stirred under argon at -20 C. Absolution of 1.6 g of triisopropyl benzene sulphonyl chloride in 4 ml THF was added dropwise and the reaction mixture allowed to warm up to room temperature.

It was filtered through Celite and washed with THF and then evaporated on a rotary drier, to yield the triisopropylbenzene sulphonyl derivative as an oil.

The oil was dissolved in 7 ml methyl alcohol and cooled to 0 with stirring. 500 mg of sodium borohydride was added with stirring, over 1/2 hour. It was then evaporated to a partly semi-solid and then treated with a mixture of 20ml 1:1 ether heptane and 10 ml of 1N HCI, and stirred for 5 minutes at room temperature. The organic layer was separated and diluted with more ether/hexane, washed once with 1 N HCI solution and twice with saturated sodium chloride solution. It was then dried over anhydrous sodium sulphate and 1 or 2 mg of paratoluene sulphonic acid was added. It was stripped on the rotary evaporator and allowed to stand at room temperature for several hours.

A'column chromatograph was then set up and the product chromatographed using 50 ethyl acetate/50% hexane as eluting solvent. 290 mg of product were obtained as a brown oil. This product was purified by rechromatographing using the same solvent mixture as above to give a light coloured oil. The constitution of this product was verified by its n.m.r. spectra which was as follows (CDC13) Multiplicity Shift (ppm) Protons side chain M 5.35 C-4+5 S 3.65 Ester methyl M 1.47-2.35 C1--3 + C6.7 ring M 7.21 C3Proton M 4.98 C4Proton d of d 2.83 Csmethylene The yield was 176.9 mg.

Example 5 2-(7-carbomethoxy hept-3,Z-ene)-4hydroxy-2-cyclopenten-1 -one.

2.9 g of 2-(7-carbomethoxy hept-3,Z-ene)-4-hydroxy-cyclopenta-1 ,3-dione were reacted with 3.6 g of triisopropyl benzene sulphonyl chloride in THF in the presence of triethylamine using the procedure described in Example 4 to give the desired product as an oil in a yield of 1.07 g.

Rechromatography using 10% ethyl acetate in hexane gave 80.5 mg of an oil with the following n.m.r.

spectra (in CDCI3): Multiplicity Shift (ppm) Protons side chain S 3.60 Ester methyl M 5.36 C3 + 4 M 1.45-2.38 C1,2 + C57 ring M 7.18 C3 Proton M 4.94 C4 Proton d of d 2.80 C5 Methylene Example 6 2-(6-carbomethoxy-4-dimethyl hexyl)-4-hydroxy-2-cyclopenten-1 -one.

5 g of 2-(6-carbomethoxy-4-dimethyl-hexyl)-4-hydroxy-cyclopenta-1,3-dione in 20 ml I ml ofTHFcontaining 6.3 ml of triethylamine cooled to -20" were treated dropwise with a solution of triisopropylbenzene sulphonyl chloride in 15 ml of THF. The reaction mixture was allowed to come to room temperature.

The solution was filtered to remove triethylamine hydrochloride and the salt washed with THF. The filtrates were combined and stripped to give an oii, which is the triisopropylbenzene sulphonyl derivative.

The oil was dissolved in 20 ml methyl alcohol and cooled to -100 and treated portionwise with 1.5 g of sodium borohydride over 1 hour.

The solution was stripped to a paste, treated with a 50:50 mixture of ether/hexane (30 ml) and 20 ml of 1 N HCI. It was stirred for 5 minutes at room temperature. The organic layer was separated, diluted with more ether/hexane and washed once with 1 N HCI and twice with saturated sodium chloride solution. It was then dried, treated with 5 mg of paratoluene sulphonic acid, stripped to give an oil and left at room temperature overnight. The oil was placed in the refrigerator overnight and then dissolved in 100 ml of 50:50 ether/hexane, and then stirred with powdered Na2CO3 for 1 hour. It was filtered and the filtrate stripped. 9 of material was obtained which on High Performance Liquid Chromatography (HPLC) using 50:50 ethyl acetate/hexane as eluant produced 2 g of 2-(6-carbomethoxy-4-dimethyl-hexyl)-4-hydroxy-2-cyclopenta-1one as a yellow brown oil.THe n.m.r. spectra (CDCl3) was as follows: Multiplicity Shift (ppm) Protons side chain S 3.7 Ester methyl M 2.32 C1,6 M 1.52 C26 S 0.86 6dimethyl M 7.22 C3 Proton M 4.98 C4 Proton d of d 2.82 C6 Methylene Example 7 2-(6-carbomethoxy hex-3,Z-ene)-4-hydroxy-2-cyclopenten-1 -one This was prepared from 2-(6-carbomethoxy-hex-3,Z-ene)-4-hydroxy-cyclopenta-1 ,3-dione by a process similar to that of Example 6. The yield from 2 g of starting material was 0.98 g. It had the following n.m.r.

spectra (CDC13); Multiplicity Shift (ppm) Protons side chain S 3.65 Ester methyl M 5.34 C34 M 1.8-2.84 C7.2.5.6 ring M 7.20 C3 Proton M 4.97 C4 Proton d of d 2.83 C5 Methylene Example 8 2-(6-carbomethoxy hex-3,Z-yne)-4-hydroxy-2-cyclopenten-1 -one.

The compound was prepared from 2-(6-carbomethoxy-hex-3,Z-yne)-4-hydroxy-cyclopenta-1 3-dione, a process similar to that of Example 6. A yield of 1.9 g was obtained from 5.8 g of the starting material, and its structure confirmed by n.m.r.

Claims (12)

1. A process for the preparation of compounds of the general formula V:

in which R represents hydrogen or a lower alkyl radical; and A represents a hydrogen chain containing 5,6 or 7 carbon atoms, which chain may contain at least one alkenylene or alkynylene group and may be substituted with one or more lower alkyl groups; which comprises reducing a compound of the formula IV

OTrialkyl Bs CO2R T(m) HO in which A and R have the meanings given above and OTrialkylBS represents a trip2~6 alkyl benzene sulphonyl group with an alkali metal borohydride, with subsequent hydrolysis and allylic rearrangement.

2. A process as claimed in claim 1 in which A represents a group - (CH2)m in which m represents 5,6 or 7 and the group may contain a double or triple bond or may be substituted with one or methyl groups.

3. A process as claimed in claim 1 or claim 2 in which A represents a group - (CH2)m- in which m represents 5, 6 or 7.

4. A process as claimed in any of claims 1 to 3 in which OTrialkylBS represents triisopropyl benzene sulphonyl.

5. A process as claimed in any of claims 1 to 4 in which R represents an alkyl radical containing from 1 to 4 carbon atoms.

6. A process as claimed in any of claims 1 to 5 in which the alkali metal borohydride is sodium borohydride.

7. A process as claimed in any of claims 1 to 6 in which the product of reduction is decomposed with acid with consequent hydrolysis and allylic rearrangement.

8. A process as claimed in any of claims 1 to 7 in which the compound of formula IV is prepared by treating a compound of the formula

in which A and R have the meanings given in claim 1 with a tri C26 alkyl benzene sulphonyl halide in the presence of an acid binding agent.

9. A process as claimed in claim 8 in which the tri C26 alkyl benzene sulphonyl halide is a chloride.

10. A process as claimed in any of claims 1 to 9 in which the compound of formula IV is formed in situ.

11. A process as claimed in claim 1 substantially as herein described with reference to the Examples.

12. Compounds of formula V defined in claim 1 when prepared by a process as claimed in any of claims 1 to 11.