CZ286484B6 - 1,3-dioxan derivatives in cis-(4R,6S) form - Google Patents

Abstract

Tetrazole derivs. of formula (XI) in substantially the cis form are new, where R1 and R4 = H, halo, 1-4C alkyl, 1-4C alkoxy or CF3; R2, R3, R5 and R6 = H, halo, 1-4C alkyl or 1-4C alkoxy; R9 and R10 = 1-4C alkyl; or CR9R10 = cyclopentyl, cyclohexyl or cycloheptyl; R12 = H, 1-4C alkyl or metal cation. Specifically R1=R2=R5=R6=H; R3=4-F+ R4=4-F; R)=R10=Me; or CR9R10 = cyclohexyl; R12=H; and cpd. has cis-(4R,6S) form.

Description

Technical field

The invention relates to 1,3-dioxane derivatives in the form of cis- (4R, 6S), which are excellent starting materials for the preparation of other physiologically active substances, in particular antihypercholesterolemic tetrazole derivatives.

BACKGROUND OF THE INVENTION

The starting compounds of formula (II) (see Reaction Scheme) are known when b is zero or 1 or can be readily prepared using known procedures. The starting materials of formula II, wherein n is 1, can also be prepared from compounds of the same type and formula wherein n is zero by using a Wittig reaction with triphenylphosphoranylideneacetaldehyde, or by other methods known in the art. Those skilled in the art will appreciate that the relative configuration at the double bond when n is zero, or at the double bonds when n is 1, can be trans, cis, or mixtures. The relative amount of each geometric isomer (R) or (S) will be influenced by the commercial availability or reaction conditions used in the preparation. In a specific example, as described herein, a mixture containing mostly the trans (5) isomer is used, although a very small percentage of the other isomers may be present in the reaction mixture in a series of reactions, as shown in the scheme, it is clear to those skilled in the art such a relative amount is not critical since the compound is oxidized at the double bond site and removed by ozonolysis.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula I

substantially in the form of cis- (4R, 6S), wherein R ⁷ and R ⁸ are independently from each other hydrogen, C 1 -C 6 alkyl or phenyl, which may be optionally substituted one or two C 1 -C 4 alkyl groups R ⁹ and R ¹⁰ are each independently C 1 -C 4 alkyl, or R ⁹ and R ^{10 are taken} together with the carbon atom to which they are bonded, or halogen, C 1 -C 4 alkoxy or trifluoromethyl; , cyclopentyl, cyclohexyl or cycloheptyl and n is zero or 1.

These compounds are highly preferred for the preparation of antihypercholesterolemic tetrazole derivatives.

Said alkyl groups may be straight or branched, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, amyl, hexyl, etc. Preferably, they are one to four carbon atoms, most preferably one. or two. The term halogen refers to any of these, i.e. fluorine, chlorine, bromine or iodine.

-1 CZ 286484 B6

The compounds of the invention contain two asymmetric carbon atoms per molecule, so that the invention encompasses all four stereoisomers, and particularly relates to optically pure isomers.

The method of preparation of the compounds of formula (I) is clearly understood from the accompanying reaction scheme:

The ketoester of formula III may be reduced to the dihydroxyester of formula IV by any of the known reducing agents. Preferably, this is done by stereospecific two-step stereospecific reduction in order to maximize the formation of the preferred erythro-isomer of the dihydroxyester of formula IV. This is done by trisubstituted alkylboranes, preferably triethylborane or tri-n-butylborane, or by treatment with one of the alkoxydialkylboranes. Preferably, methoxydiethylborane or ethoxydiethylborane, see Tetrahedron Letters 28, 155 (1987), in the temperature range from -70 ° C to room temperature.

The resulting complex is reduced at a temperature of about -50 ° C to about -78 ° C in the presence of sodium borohydride in the middle. an inert organic solvent such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane, preferably using the first. The reduction is then completed by the addition of methanol either with or without further addition of aqueous hydrogen peroxide solution and buffer. Such compounds of formula IV are known and described in US. U.S. Pat. Nos. 4,248,889 (Feb 3, 1981) and 4,650,890 (Mar 17, 1987).

Compounds of formula (V) can be prepared from compounds of formula (IV) by reaction with a ketone such as 2-propanone, 3-pentanone, cyclopentanone and cyclohexanone, in an inert organic solvent such as toluene, benzene or xylene at temperatures from 20 ° C. C to reflux and in the presence of a small amount of an organic, inorganic or resinic acid, such as p-toluenesulfonic acid or sulfuric acid, optionally removing the water formed by treatment with a drying agent such as sodium or magnesium sulfate, further using a molecular sieves or by azeotropic distillation of water using a Dean-Stark trap or other similar apparatus. The reaction of the compound of formula IV with the ketone can be carried out without solvent. Furthermore, the reaction described hereinabove for compounds of formula IV can be carried out using a ketal such as 2,2-dimethoxypropane, 1,1-dimethoxycyclohexane and the like.

Compounds of formula VII wherein R ¹² is a hydrolyzable ester group, i.e. preferably C 1 -C 4 alkyl, can be prepared by the corresponding compounds of formula V by oxidizing an olefinic group to an aldehyde group using conventional reagents. Alternatively, the compound of formula (V) is first hydrolyzed in an alkaline medium to form a compound of formula (VI) and oxidized to a compound of formula (VII) wherein R ¹² is hydrogen. A particularly suitable oxidation process is the reaction of a compound of formula V or VI with ozone in an inert organic solvent such as methanol, ethyl acetate or methylene chloride at a temperature of about -50 ° C to -78 ° C. Once the reaction with ozone is complete, as seen by the color of the reaction mixture, the ozonide intermediate is decomposed by the addition of a mild reducing agent such as dimethylsulfide or triphenylphosphine to give the aldehyde of formula. VII.

A preferred embodiment of the process according to the invention is represented by the compounds of the general formula (VI) in substantially pure cis form, where R ⁷ and R ⁸ are both hydrogen, C 1 -C 6 alkyl or phenyl, in each case independently of one another, R ⁹ and R ¹⁰ represents an alkyl group having one or two carbon atoms, or R ⁹ and R ¹⁰ together with the carbon atom to which they are attached form a cyclohexyl group, wherein n represents zero or 1.

-2GB 286484 B6

Even more preferred embodiment are compounds of formula I in substantially pure cis- (4R.6S) form, wherein R ⁷ and R ⁸ are each independently hydrogen, alkyl of one to six carbon atoms or phenyl group, R ⁹ and R ¹⁰ are an alkyl group having one or two carbon atoms, or R ⁹ and R ¹⁰ together with the carbon atom to which they are attached form a cycloalkyl group and n is zero or 1.

It is also possible to treat the dihydroxy compound of formula IV in substantially erythro form. wherein R ⁷ and R ⁸ are independently from each other hydrogen, C 1 -C 6 alkyl or phenyl optionally substituted by one or two C 1 -C 4 alkyl, halogen, C 1 -C 4 alkoxy, or trifluoromethyl, R ¹¹ is a hydrolyzable ester group and n is zero or 1, in the presence of a small amount of acid, with at least one equivalent of a compound of the general formula

R ⁹ R ¹⁰ R ⁹ R °

In or \ /

II / \ o CH ₃ -O-CH ₃ wherein R ⁹ and R ¹⁰ are as defined above, so that the resulting compound of formula V wherein the general symbols are as an already mentioned meanings, then optionally hydrolyzing the ester of formula V to the compound of formula (VI) and oxidizing the compound of formula (V) or (VI) to a compound of formula (VII), which is obtained essentially in cis form and both R ⁹ and R ¹⁰ have the meanings indicated hereinbefore; R ¹² is hydrogen, methyl or a metal cation especially lithium.

Reaction scheme

oo ₃ / A ^ _z JA _or1 i ------>

R ⁸ OH OO III

ii --------- ►

R ^ J? ¹⁰

R ⁸ tr ^ o 0 - R ^? A ^ <^, A ^ kA _0S1I .____ * (V) r \ j? ^{10 R} 'x ^Rlt>

R ⁸ O o ^ Jt _______ "R ³ O

'VI' (I)

ie

-4GB 286484 B6

DETAILED DESCRIPTION OF THE INVENTION

Example 1

3-Hydroxy-5-oxo-deca-6,8-dienoic acid methyl ester

To a solution of 41.5 g (357 mmol) of methyl acetoacetate in 500 mL of tetrahydrofuran was added, after cooling to -30 ° C, 476 mL of a 1.5 M solution of lithium diisopropylamide in cyclohexane (714 mmol). The resulting solution was stirred at -30 ° C for 15 minutes, cooled to -72 ° C, and after addition of 34.3 g (357 mmol) of 2,4-hexadienal, the reaction mixture was stirred at -78 ° C for 10 minutes. then 16 hours at room temperature. The solution is concentrated under reduced pressure and the syrupy residue is partitioned between 1N hydrochloric acid solution and ethyl acetate. After separation, the organic layer is washed twice with brine, dried over anhydrous sodium sulfate and, after filtration, the filtrate is concentrated. The residue is purified by chromatography on silica gel using diethyl ether / hexane (2: 1) to elute 18.5 g (24.4%) of the title compound as an oil.

1 H-NMR for (E), (E) -isomer, 200 MHz, CDCl ₃ , δ:

6.3 (1H, dd, J = 14.7, 11.9 Hz), 6.02 (1H, dd, J = 14.7, 11.9 Hz), 5.75 (1H, dq, J = 14.7, 6.4 Hz), 5.5 (1H, dd, J = 18.7, 6.4 Hz), 4.74-4.5 (1H, m), 3.73 (3H, s) 3.51 (2H, s), 2.6 (2H, d, J = 5.8 Hz), 1.77 (3H, d, J = 6.4 Hz).

Example 2

3,5-Dihydroxy-deca-6,8-dienoic acid methyl ester

To a cooled solution (-15 ° C) of 18.5 g (86.9 mmol) of 3-hydroxy-5-oxodeka-6,8-dienoic acid methyl ester in 300 mL of tetrahydrofuran was added 113 mL of a 1M solution of triethylborane in tetrahydrofuran (113 mL). The solution thus prepared was stirred for 20 minutes, cooled to -78 ° C and treated with 6g (159 mmol) of sodium borohydride and 37.5 ml of methanol. The reaction mixture was stirred vigorously for 30 minutes at -78 ° C, then for 3 hours at room temperature, then the solvent was distilled off under reduced pressure and the residue was partitioned between 1N hydrochloric acid and ethyl acetate. After drying the organic layer over anhydrous sodium sulfate, the filtrate was concentrated after filtration. The residue was purified by chromatography on silica gel using diethyl ether / hexane (3: 1) to elute.

Thus, 7.95 g (42.7%) of the title compound are obtained as a yellow oil.

1 H NMR for (E), (E) -isomer (360 MHz, CDCl ₃ ), δ:

6.18 (1H, dd, J = 15.1, 10.4 Hz), 6.00 (1H, dd, J = 15.1, 10.4 Hz), 5.69 (1H, dq, J = 15.1, 7.0 Hz), 5.52 (1H, dd, J = 15.1, 6.7 Hz), 4.46-4.37 (1H, m), 4.29-4.22 (1H, m), 3.69 (3H, s), 2.60-2.42 (2H, m), 1.72 (3H, d, J = 7.0 Hz), 1.74-1, 57 (2 H, m).

Example 3

Cis-4- (1,3-Pentadienyl) -1,5-dioxaspiro [5,5] -undecan-2-acetic acid methyl ester

To 10 g (100 mmol) of cyclohexanone was added 7.6 g (35.5 mmol) of 3,5-dihydroxy-deca-6,8-dienoic acid methyl ester and 0.1 g of p-toluenesulfonic acid; the reaction mixture was stirred at room temperature for 16 hours and the resulting yellow solution was directly loaded onto a silica gel column

-5US 286484 Β6 to elute the product with a 1: 4 mixture of diethyl ether and hexane. The appropriate fractions were combined and concentrated to give 3.52 g (33.6%) of the title compound as a colorless oil.

1 H NMR for (E), (E) -isomer (360 MHz, CDCl ₃ ), δ:

6.16 (1H, dd, J = 15.1, 10.6 Hz), 6.00 (1H, dd, J = 15.1, 10.6 Hz), 5.71-5.65 (1H, dd, J = 15.1, 6.5 Hz), 5.47 (1H, dd, J = 15.1, 6.4 Hz), 4.44-4.39 (1H, m), 4.35 Δ 1.30 (1H, m), 3.66 (3H, s), 2.52 (1H, dd, J = 1.54, 7.9 Hz), 2.30 (1H, dd, J = 15) 4, 6.5 Hz), 2.1-1.18 (12H, m), 1.72 (3H, d, J = 6.5 Hz).

Analysis:

calculated for C17H26O4: C 69.36, H 8.90, Found: C 69.59, H 9.16

Example 4

Cis-4- (1,3-pentadienyl) -1,5-dioxaspiro [5,5] undecane-2-acetic acid

3.6 g (12.4 mmol) of 4- (1,3-pentadienyl) -1,5-dioxaspiro [5,5] -undecan-2-acetic acid methyl ester in a mixture of 13 ml of 1N hydroxide solution are heated to reflux. sodium and 26 ml of methanol. After methanol was distilled off under reduced pressure, the remaining aqueous solution was acidified by addition of 1N hydrochloric acid solution followed by extraction into diethyl ether. After concentrating the organic solution, dried over anhydrous sodium sulfate, the solid residue is recrystallized from a mixture of ethyl acetate and hexane. This afforded 2.0 g (55.9%) of the title compound as a colorless solid, m.p. Mp 144-146 ° C.

'H NMR (360 MHz, CDC1 ₃₎ δ:

6.18 (1H, dd, J = 18.0, 12.5 Hz), 5.72 (1H, dq, J = 18.0, 7.7 Hz), 5.99 (1H, dd, J = 18.0, 12.5 Hz), 5.48 (1H, dd, J = 18.0, 7.6 Hz), 4.45 ^ 1.37 (1H, m), 4.37-4.25 (1H, m), 2.56 (1H, dd, J = 18.9, 8.8 Hz), 2.48 (1H, dd, J = 18.9, 6.1 Hz), 2.60- 1.30 (12H, m), 1.73 (3H, d, J = 7.7 Hz).

H, 8.62; Found: C, 68.36; H, 8.59.

Claims (5)

PATENT CLAIMS CLAIMS 1. 1,3-Dioxane derivatives of the general formula I in the form of cis- (4R, 6S), wherein R ⁷ and R ⁸ are each independently hydrogen, C 1 -C 6 alkyl, or phenyl optionally substituted by one or two C 1 -C 4 alkyl, or halogen, C 1 -C 4 alkoxy, or trifluoromethyl, R ⁹ and R ¹⁰ in each case independently represent C 1 -C 4 alkyl, or R ⁹ and R ¹⁰ together with the carbon atom to which they are attached represent a cyclopentyl, cyclohexyl or cycloheptyl group and n is zero or 1. The 1,3-dioxane derivatives of the general formula I according to claim 1, wherein R ⁷ and R ⁸ are independently from each other hydrogen, alkyl of one to six carbon atoms and n is zero, and R ⁹ and R ¹⁰ independently of one another are C 1 -C 4 alkyl, or R ⁹ and R ¹⁰ together with the carbon atom to which they are attached are cyclopentyl, cyclohexyl or cycloheptyl. Compounds of formula (I) according to claim 2, wherein R ⁷ is phenyl, R ⁸ is hydrogen, n is zero and R ⁹ and R ¹⁰ are both methyl. The 1,3-dioxane derivatives of the general formula I according to claim 1, wherein R ⁷ and R ⁸ represent independently of one another an alkyl group of one to four carbon atoms or a phenyl group, n represents zero, and R ⁹ and R ¹⁰ represent an alkyl group of one to four carbon atoms. or R ⁹ and R ¹⁰ together with the carbon atom to which they are attached represent a cyclopentyl, cyclohexyl or cycloheptyl group. Compounds of formula (I) according to claim 4, wherein R ⁷ represents a methyl group, R ⁸ represents hydrogen, n represents 1 and R ⁹ together with R ¹⁰ and the carbon atom to which they are attached together represent a cyclohexyl group .