NO138905B - PROCEDURES FOR THE PREPARATION OF 2- (6-CARBALCOXYHEXYL) -4 (R) -HYDROXYCYCLOPENT-2 ENONES - Google Patents

Description

The present invention relates to a method for the production of 2-(6-carboxyhexyl)-4 (R)-hydroxy-cyclopent-2-en-ones which are key compounds in the production of prostaglandins or prostaglandin-like compounds.

In particular, the invention relates to a process for the production of 2-(6-carbomethoxyhexyl)-4(R)-hydroxy-2-cyclopenten-1-one,

a compound that is a key compound in the production of prostaglandins.

The symbol R as used herein denotes the stereochemical configuration of a compound as defined in the Cahn-Ingold-Prelog nomenclature system.

The prostaglandins, which are cyclic, oxygenated C2Q fatty acids based on the prostanic acid skeleton, are believed to play an important role as therapeutic agents due to the large number of physiological responses they elicit in the cardiovascular system, in the central and peripheral nervous system, in the reproductive system, the endocrine, renal and gastrointestinal system when administered to animals including humans. The supply of these materials is currently very limited, and the proposed methods for producing them involve the use of time-consuming cleavage methods to obtain the desired optically active compounds.

The aim of this invention is to provide a method for the production of chiral compounds which are key compounds in the production of prostaglandins or prostaglandin-like compounds.

The invention thus relates to a process for the production of 2-(6-carbalkoxyhexyl)-4(R)-hydroxy-cyclopent-2-enone of the formula

in which R is an alkyl group with 1-2 carbon atoms, which method is characterized by a) a 2-(6-carbalkoxyhexyl)-4(R)-hydroxycyclopentane-1,3-dione of the formula:

is reacted with an alkyl iodide of the formula:

RIDE

wherein R' is an isoamyl, isopropyl, isobutyl or pivalyl group, forming a C-1 and a C-3 enol ether of the formulas:

or with benzoyl chloride to form a C-1 and C-3 enol ester of the formulas:

where R" is phenyl,

b) the C-1 enol ether or ester is separated from the C-3 enol ether or ester, c) the produced C-1 substituted enol ester or ether is reduced, and d) 2-(6-carbalkoxyhexyl)-4(R)-hydroxycyclopent-2-enone is recovered from the reaction mixture.

Previously, R. Pappo et al. (Annals of the New York Academy of Sciences, Vol. 180, p. 64 (1971)) showed the following method for the preparation of methyleneol ether from 2-(6<1->carbomethoxyhexyl)-4-hydroxy-cyclopentene-1,3- Dion:

This procedure was carried out by refluxing the hydroxydionester (A) with dimethoxypropane under acidic conditions to form the two indicated isomeric enol esters (B and C).

The disadvantages of the one by Pappo et al. described procedure is: (1) it only gives approx. 40% of the desired C-1 enol ether (C), and (2) the asymmetric center at C-4 is destroyed.

The last disadvantage is very serious in prostaglandin preparation using 1,4-addition reactions, as the stereochemistry of the prostanic acid skeleton (the C-8 and C-12 positions in the prostaglandins) is dictated by the stereochemistry at C-4.

The method according to the invention does not entail the disadvantages that Pappo et al. the process is fraught with. The most important thing is that the method according to the invention allows the asymmetric center at C-4 to be retained so that the formed 2-substituted-4-hydroxy-2-cyclopenten-1-one is chiral, an essential feature for how the prostaglandins are to be produced. In addition, the method according to the invention preferentially activates acylation or alkylation of the oxygen atom at the C-1 position in the molecule the molecular configuration that is desired for the subsequent reduction to the desired compound, namely 2-(6-carbalcoxyl)-4(R)-hydr -oxy-cyclopent-2-enone.

Although one does not want to be bound by theoretical considerations, it is assumed that a moderately massive group must be used for acylation so that the acylation by steric hindrance preferably takes place by oxyqenerinq of C-1 stillinq. Likewise, it is assumed that the 0-al-quelation at C-1 is favored under basic conditions, and that the size of the alkylating group is of less importance than in the case of acylation. In all cases, it was found that the above-mentioned conditions allow retention of the asymmetric center at C-4, and that no racemate formation occurs.

The asymmetric reduction of 2-substituted cyclopentane-1,3,4-trione to the corresponding 2-substituted-4(R)-hydroxy-cyclopentane-1,3-dione is carried out by catalytic hydrogenation in the presence of a rhodium complex with a chiral phosphine chain (liqand) as catalyst. (Catalysts of this type are described in Chem. Soc, Chem. Comm., 19, (1972) by W.S. Knowles et al.). The preferred Catalyst in this method can be designated as I^Rl^COD BF^~

(available from Monsanto Co., St.Louis, Mo., under the type designation CP71327), where L indicates o-anisylcyclohexylmethylphosphine, and COD indicates 1,5-cyclooctadiene.

A method for the hydrogenation of 2(6-carbomethoxyhexyl)-cyclopentane-1,3,4-trione using the preferred catalyst is set forth below: Preparation of 2-(6-carbomethoxyhexyl)-4(R)-hydroxy- cyclopentane-1,3-dione 5.0 g of 2(6-carbomethoxyhexyl)-cyclopentane-1,3,4-trione, 95.8 mg of the indicated catalyst and 2.78 ml of triethylamine were dissolved in 35 ml of methanol and subjected to hydrogenation at one atmosphere. After 92.6% of the theoretical amount of hydrogen had been consumed, the reaction was terminated by pouring the hydrogenation reaction mixture into HCl-I^O (approx. pH 2). The resulting mixture was extracted three times with ethyl acetate, the organic layers were separated and washed with sodium bicarbonate solution (5% solution) until no color was visible in the aqueous phase. The combined bicarbonate extracts were extracted with ethyl acetate, the resulting yellow aqueous layer was carefully acidified to pH 2 with hydrochloric acid and extracted with ethyl acetate. The organic layer was separated, dried over Na 2 SO 4 and evaporated to dryness. The dried material was dissolved in ethyl acetate and then crystallized from this, whereby 1.7 g of product was obtained (34% yield with the following characteristics: UV A JJ^°jj 272 nm ( £ 24,000), CDA 281 nm , 6 = -58.3 x.IO<3>, 9 =

+60 x IO<3> at A 262 nm (68% otic purity). The symbol UV stands for ultraviolet, and CD stands for circular dichroism. Another amount (1.6%) showed no optical activity, the filtrate practically no optical activity.

The trione methyl ester used as starting material in the hydrogenation reaction indicated above can be easily obtained from the corresponding trionic acid according to the following method, the trionic acid can be easily obtained according to that of Pappo et al. set method:

A mixture of 1 g of trionic acid, 2 ml of methanol, 0.2 ml of concentrated HCl and 2.5 ml of dimethoxypropane was allowed to stand at room temperature overnight. The solution was then evaporated to dryness (rotary evaporator), and the residue was dissolved in 10 ml of ethyl acetate. The ethyl acetate layer was extracted with a saturated NaHCO 3 solution (2 x 15 mL). The bicarbonate solution was acidified and extracted with ethyl acetate (4 x 25 mL). This extract was washed with a saturated NaCl solution and dried over MgSO 4 . Evaporation of the solvent gave a reddish oil which solidified on standing to form a yellow solid (addition of a crystal of the trione methyl ester facilitated the solidification process).

Alternatively, the dione can be produced microbiologically, as described in Norwegian generally available application 3795/73 with priority from 29 September 1972, by subjecting 2-substituted-cyclo-pentene-1,3,4-trione or 2-substituted-3 -Alkoxy-2-cyclopentene-1,4-dione a fermentative enzymatic action of a microorganism of the class Ascomycetes, or via cleavage with brucine as indicated later. 6 g, 0.022 mol, 2-(6-carbomethoxyhexyl)-4-hydroxy-cyclo-pentane-1,3-dione was mixed with 8.7 g, 0.022 mol, brucine. To this mixture was added 35 ml of acetone and the resulting solution was refluxed under a nitrogen atmosphere for 15 minutes, cooled to room temperature and then allowed to stand at room temperature for 3 hours and then in a refrigerator (4 - 10°C) overnight . The product, a brucine hydroxydione salt is excreted as fine crystals. The crystals were filtered off on a buchner funnel, washed with cold acetone and recrystallized to constant optical rotation from ethyl acetate and Skelly B (five recrystallizations). Skelly B is n-hexane.

Optical rotation of the salt in CHCI3:

2.2 g of the cleaved brucine hydroxydione salt were dissolved in

30 ml of ethyl acetate. To this solution was added 30 ml of 0.25 N HCl and the heterogeneous mixture was stirred very vigorously for 2 minutes. During the reprieve, two teams formed and were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers from the two extractions were combined and washed with water and saturated saline and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 780 mg of 2-(6<1->carbomethoxyhexyl)-4(R)-hydroxy-cyclopentane-1,3-dione as a white crystalline solid.

As previously indicated, the enolization of the 2-substituted dione can be carried out for conversion to the enol ester or enol ether configuration through selective O-acylation or selective O-alkylation according to the following general method.

Enolization with selective O-acylation

In general, this reaction can be carried out according to the following schematic reaction scheme:

where R and R" have the previously stated meanings.

In the indicated O-acylation reaction, it is advantageous

to use only one equivalent of the acylating agent, as the use of excess acylating agents tends to also activate acylation of the hydroxyl group. Likewise, the size of the acylation group is important with regard to the formation of the desired phenolic ester,

a more massive grouping activates the formation of more of the desired enol form, ie 0,acylation of the C-1 position. With acetyl chloride as acylating agent, which is known, and 2(6-carbomethoxyhexyl)-4(R)-hydroxy-2-cyclopentane-1,3-dione as substrate, e.g. two enolacylates

in a ratio of 70 - 75% of A to 30 - 25% of B. However, when a more passive acylating agent such as pivaloyl chloride is used, the ratio between the desired substituted C-1-enol pivaloylate and the substituted C-3-enol pivaloylate is about. 90:10.

Enolization with selective O-alkylation

The O-alkylation reaction can be carried out according to the following reaction scheme:

where R and R<1> have the previously stated meanings.

As noted with respect to the O-acylation, this relative size of the alkylating agent influences the ratio of the enol ethers formed, i.e. the ratio of substituted C-1 enol ether to substituted C-3 enol ether. With e.g. isopropyl iodide as the alkylating agent and 2(6-carbomethoxyhexyl)-4(R)-hydroxy-2-cyclopentane-1,3-dione as the substrate became the two enol ethers

formed in a ratio between A and B of 6:4, while when isoamyl iodide, which is a larger grouping, was used as alkylating agent, the ratio of the desired substituted C-1 enol ether to the substituted C-3 enol ether was approx. 7:3.

The following table indicates the relative amounts of the enol ethers obtained with the indicated alkylating agents:

Reduction of the substituted C-1 enol ester or enol ether can be easily carried out with sodium dihydro-bis-(2-methoxyethoxy)-aluminate (cold Red-Al agent) as shown by Pappo et al., Tetra-hedron Letters, No. 26, p. 2627 (1972), Pergamon Press. Other reducing agents such as e.g. lithium borohydride, diisobutylaluminum hydride and lithium aluminum hydride are also able to reduce the carbonyl function of the substituted C-1-enol ester or ether according to the method according to the invention, forming the desired 2-substituted-4(R)-hydroxy-2-cyclopentene- l-on products.

The following examples illustrate the invention.

Example. 1 Production of di-ertol benzoates

To a solution of 120 mg (0.467 mmol) 2(6-carbometh-oxyhexyl)-4 (R)-hydroxy-cyclopentane-1, 3-dione (II), 0.4 ml (ca. 3 mmol) triethylamine (Et ^N) (distilled over CaH2) in 10 ml of tetrahydrofuran (THF) cooled to -15°C was added 0.5 ml (4.34 mmol) of benzoyl chloride over 5 minutes with stirring. After the reaction mixture was stirred at -15 to 5°C for 3 hours, water was added, and the mixture was extracted three times with diethyl ether. The ether layer was washed respectively with dilute HCl, water, saturated NaHCO-j and NaCl solutions. The ether layer was then dried over Na 2 SO 4 and evaporated to dryness. Proton magnetic resonance (PMR) analysis showed that the dried product contained 90% of the desired substituted C-1-dibenzoate (IIa) which could be easily separated by column chromatography using a silicic acid-Celite (85:15) column (21 x 2.5 cm) with a benzene-ethyl acetate gradient as described in Example 4.

Example 2 Preparation of the monoenol benzoate ester

To a cooled (-11° C) stirred solution of 102.4 mg (0.4 mmol) of the hydroxydione methyl ester (III) and 0.112 ml (ca. 0.84 mmol) of triethylamine (distilled over calcium hydride) in 8 ml of dry tetrahydrofuran ( under (0.046 mL (0.4 mmol) of benzoyl chloride was added over 5 minutes. The resulting solution was stirred at -10°C for 35 minutes. 4 mL of methanol was added and the solution was warmed to room temperature and then poured into 60 mL of water. This solution was extracted four times with 50 mL of ethyl acetate each time and the combined extracts were washed respectively with 0.1N HCl (10 mL), water (10 mL), saturated sodium bicarbonate (10 mL) (sodium The bicarbonate wash was acidified and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over MgSO^. Evaporation of the solvent gave unreacted hydroxydione methyl ester (30 mg) II,) and saturated sodium chloride (10 mL) solutions and dried over MgSO^. Evaporation of the solvent gave a yellow oil of the following character ristika: PMR 63.65 (S, 3H, OCH3, 64.48 (q, 1H, H-C-OH), 87.70 (m, 3H) and 68.18 (m, 2H) aromatic protons, m/e at 360, (cx)q<4> + 35° (C, 2.0 CHCl 3 ), Xjj][£ s 241 nm (e 20,100), (S) 270 nm (e 8,500) which identified the product as Hig. Example 3 Preparation of the isopropylenol ether To 514 mg of the hydroxydionester (II) (2.0 mmol), 546 mg of I^CO-j (4 mmol) and 5 ml (8.5 g, 50 mmol) of isopropyl iodide in 25 ml of dry acetone. The mixture was heated under reflux (N2 atmosphere) for 24 hours. After cooling, the reaction mixture was diluted with Et 2 O and the ether layer was washed respectively with water, NaHCO 3 , water and saturated NaCl. The solvent layer was then dried over Na 2 SO 4 and evaporated to dryness to give 560 mg of an oily residue. The residue was dissolved in isopropyl ether whereby 316 mg (53%) of a product with the following characteristics was obtained: m.p. 60 - 62° C, A*^g 259 nm (e 20,600), PMR (CHC13) 1.35 (d, 6 „„ -""CH3 ), 63.65 (s, COOCH3) , 64.32 (q , 1, CHOH) , 4.67 (s, 1, CH^™3 ), m/e 298, (a)<* >+ 35.1 (C, 1.02 MeOH), which identified 3 it as Illh . Example <4 >Preparation of the isoamylenol ether

To 121 mg of II, 287 mg of K2CC>3 in 15 ml of dry acetone was added 2 ml of isoamyl iodide. After refluxing overnight, the reaction mixture was worked up as described in example 5. 165 mg of residue was obtained. PMR analysis showed an isopropyl doublet (60.95 J = 6HZ), complex region (61.1 - 3.1), methoxyl (63.65), multiplet ( γ^ 64.0 - 4.5, ca. 3H based on methoxyl) and a broad doublet (65.0, J = 6)

(30% 1H, based on methoxyl), approx. 4H total integral from 64.0 to 65.10 indicated inclusion of -OH, -OCH2-CH2-CH2CHMe2 and OH-CH. Thus, the product was calculated to contain approx. 70% of the desired substituted C-1 enol ether Uli, which was easily separated from the substituted C-3 enol ether by column chromatography as described in Example 4.

Example 5 5

Reduction of the mono-enol benzoate ester with "Red-Al"

To a chilled (-78° C), stirred solution of 50 mg (0.147

mmol) of mono-enol benzoate (Hig) in 10 ml of dry tetrahydrofuran under N 2 , "Red-Al" solution (1.5 M in toluene) was added in four 0.38 ml portions over 15 minutes. The resulting solution was stirred at

-78° C for a further 30 minutes. 2 ml of glacial acetic acid was added and the solution was allowed to warm to room temperature. The solution was poured into 40 ml of water and extracted with ethyl acetate (4 x 30 ml). The ethyl acetate layer was washed with 10 ml each of saturated sodium bicarbonate and saturated NaCl solutions and dried over MgSO 4 . Evaporation of an oil. The oil was dissolved in 10 ml of acetic acid-water (75:25) solution. The resulting solution was stirred at room temperature for 24 hours. Acetic water was evaporated from under reduced pressure. The resulting oil was dissolved in ethyl acetate (10 mL) and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and dried over MgSO 4 . Evaporation of the solvent gave a yellow oil (ca. 25 - 30 mg). Crystallization from ethyl acetate-Skelly B gave 20 mg of IV, which was identified by the following characteristics: m.p. 60 - 61° C, (c1)q<4> =

17.82° (C, 0.49 MeOH), PMR (CDCII 3 ) 63.65 (s, 3, COOCH 3 ), 64.93 (m, 1, H-C-OH) , 67.23 (m, 1, vinyl H) , UV xjjj£]j 222 nm (e 8 400) CD 231 nm 9 -9.9° x 10<-3> (MeOH).

Example 6

Reduction of the isopropyl renol ether with Red-Al

The 123 mg of the isopropylenol ether (Illh) (0.412 mmol) i

To 10 ml of THF, stirred under nitrogen at -78°C, four 1.1 ml portions of a solution of Red-Al in benzene (1.5 M) were added dropwise over 7 minutes. The reaction mixture was stirred at -78°C for 45 minutes and 2 ml of acetic acid was then added. The reaction mixture was allowed to warm to room temperature and was evaporated to dryness. 10 ml of 75% acetic acid solution was added and stirred for 24 hours. Acetic acid and water were evaporated from under pressure. The resulting oil was dissolved in 25 ml of ethyl acetate and washed with saturated NaHCO 3 and NaCl solutions and then dried over magnesium sulfate. Crystallization of the residue from ethyl acetate-Skelly B gave 60 mg of IV, which was identified by the following characteristics: m.p. 60 - 61° C, (a)D

+ 17.82° (C, 0.49 MeOH) , UV .xjjjj 222 nm (e 8,400) , CD 231 nm 9.= -9.9° x 10~<3> (MeOH).

The conversion of the compounds prepared according to the method, namely, 2-(6-carbalkoxyhexyl)-4-(R1-hydroxy-cyclopent-2-enones) to prostaglandins or prostaglandin-like compounds can be carried out according to the method described by Charles J. Sih et al .(J.Amer. Chem. Soc, 94' 3643 (May 17th, 1972)) Once the above stereospecific compound is obtained, the conversion to prostaglandins or prostaglandin-like compounds can be easily accomplished while retaining the desired stereochemistry.

In addition to being able to be used as a starting material in the production of prostaglandins, l-isopropoxy-2-(6'-carbo-methoxyhexyl)-4(R)-hydroxy-l-cyclopenten-3-one (isopropylenol ether) was found to have antimicrobial activity as shown in the following example.

Example 7

25 mg of 1-isopropoxy-2-(6'-carbomethoxyhexyl)-4(R)-hydroxy-1-cyclopenten-3-one was dissolved in 1 ml of methyl alcohol. , 0.1 ml of the resulting solution was applied to a filter paper disc (12.7 mmol) and the disc was then dried. Each of the dried slices was then placed in a petri dish containing 10 ml of antibiotica medium II (Difco) to which was added 0.03 ml of an inoculum of the test organism. The Petri dishes were incubated at 25°C for 48 hours and the zone of inhibition was measured with the following results:

Claims (1)

Procedure for the preparation of 2-(6-carbalkoxy- hexyl)-4(R)-hydroxy-cyclopent-2-enone of the formula in which R is an alkyl group with 1-2 carbon atoms, characterized in that a) a 2-(6-carbalkoxyhexyl)-4(R)-hydroxycyclopentane-1,3-dione of the formula: is reacted with an alkyl iodide of the formula: R'I wherein R' is an isoamyl, isopropyl, isobutyl or pivalyl group, forming a C-1 and a C-3 enol ether of the formulas: or with benzoyl chloride to form a C-1 and C-3 enol ester of the formulas: where R" is phenyl, _b) the C-1 enol ether or ester is separated from the C-3 enol ether or ester, c) the produced C-1 substituted enol ester or ether is reduced, and d) 2-(6-carbalkoxyhexyl)-4(R)-hydroxycyclopent-2-enone is recovered from the reaction mixture.