DE2334275A1 - CYCLIC COMPOUNDS - Google Patents

Description

RAN 4305/1

F. HoiFmann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland

Cyclic compounds

The present invention relates to cyclic turns and processes for their manufacture. The invention relates in particular to aromatic or optically active compounds of the general formula

1 2

wherein R is lower-alkyl and R is hydrogen or represent an easily removable protective group,

According to the invention, the compounds of the formula I are obtained by using a compound of the formula opn / 18.4.73 309884/1468

II

wherein R has the meaning given, a) with a dialkylaluminum nitrile to form a compound of formula

NC

-OR

III

where R has the meaning given,

converts and the nitrile group in the compound of formula III - If desired, after converting the hydroxyl group into a protected hydroxyl group - reduced to the aldehyde group; or

b) with a 1,3-dithiane alkali or alkaline earth metal salt to a compound of the formula

IV

in which R has the meaning given, 'reacts and the compound of the formula IV - if desired after conversion of the hydroxyl group into a protected hydroxyl group - alkylated on at least one sulfur atom and then hydrolyzed; or

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c) with · a compound of the formulas V or VI

= CC-R ⁴

VI

wherein

Hydrogen, O ^ C - ^ - alkyl, O ₅ -C ₇ -CyClo-

alkyl, Cp-C-, _Q- alkenyl, phenyl, lower-alkylphenyl or nitrophenyl, R and R independently of one another hydrogen or _{lower-alkyl or together a C, -C 7} -cycloalkyl ring, RS hydrogen or an easily removable protective group and Me represent an alkali or alkaline earth metal cation, to a compound of the formulas VII or respectively. VIII

H0_

R ⁵ C = GL

VII

_R 5 HO.

Ri-C-CsC.

VIII

14 5

where R, R and R have the given definition

and R is hydrogen or a slightly ' represent removable protecting group is reacted, a compound of the formulas VII obtained in this way or

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VIII

- if desired after conversion of free hydroxyl group (s) in protected hydroxyl group (s) - to a compound of the formulas IX and X, respectively

ITGH = CH

IX

wherein R, R, R, R, R and R "have the aforesaid Have meaning

hydrogenated and the compound of the formulas IZ or X in itself in a known manner either converted into a 1,2-Siykol and this subjects the glycol cleavage., or the ozone separation subject.

The term "lower alkyl" "denotes alkyl groups with up to 6 carbon atoms, especially methyl, ethyl. Propyl and butyl. Examples of Oyclcalcyl residues are jyoiopropyl, Oyclobutyl, Cycloperitjrl and Cyclohexyl. Examples of Alkenyl groups are vinyl, allyl, metal, butenyl, pentenyl, Hexenyl, heptenyl and octenyl. Examples are easily split off

2 β protective groups, symbolized by the radicals R and R. are ethers like lower-alkyl ethers, see 3. tertiary butyl ether and the methoxymethyl ether; as well as the tetrahydropyranyl ether; or esters such as the acetate.

309884 / U86

In the first stage of the reaction according to process variant a), it is expedient to use di-lower-alkylaluminum nitriles such as diethyl- or di-isobutylaluminum nitrile, in an inert organic solvent, e.g. a hydrocarbon such as toluene or an ether such as diethyl ether, Tetrahydrofuran or dioxane. The reaction temperature is not critical for this reaction, you can, for example, at Working temperatures around 0 ° or at an elevated temperature, e.g. the reflux temperature of the solvent.

The conversion of the free hydroxy group into a

protected hydroxyl group, i.e. one of the easily cleavable ones mentioned above Protective groups can be used in a manner known per se, e.g. by reaction with dihydropyran in the presence of catalytic Amounts of acid or by reaction with an alkyl halide be accomplished in the presence of a baso.

The reduction in the second reaction stage of process variant a) can be carried out with complex metal hydrides how di-isobutyl aluminum hydride are carried out. The preferred one The reaction temperature is room temperature. The first stage of implementation according to process variants b) and c) is also carried out in an inert organic solvent, e.g. one of the ethers mentioned above. The reaction temperature is also not critical, preferably but you work at an elevated temperature.

Alkyl halides, for example, can be used as alkylating agents for the second reaction stage of process variant b) such as methyl iodide or triethyloxonium tetrafluoroborate be used. The hydrolysis is expediently in a neutral or slightly acidic medium, for example in acetone, the one Lane Uf-; οser contains carried out. The second stage of the process variant c), i.e. the hydrogenation of a compound of

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Formula YII or VIII can be carried out in a manner known per se with partially poisoned catalysts (Lindlar catalysts). The ozone decomposition may be by ozonization in known manner in a solvent such as an aliphatic hydrocarbon, such as petroleum ether, or an aromatic hydrocarbon such as benzene or toluene; in ethyl acetate, in chlorinated hydrocarbons such as methylene chloride or in alcohols such as methanol. Reductive work-up of the ozonide, e.g. using palladium on calcium carbonate and hydrogen in ethyl acetate then yields the aldehyde I.

Another aspect of the present invention is characterized in that a compound of the formula I with a phosphonate of the formula

YT

wherein R is lower alkyl and the dashed bond can be hydrogenated, or with a phosphonium compound of the formula

where R is hydrogen and R is hydroxy or R and R together are a carbonyl oxygen atom and X ~ is the anion of an acid and the dashed line

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Bond can be hydrogenated,
to a compound of the formula

ff R ¹⁰

XIII

1 2
wherein R and R are given in claim 1 ■

Have meaning, and the dashed bond may be hydrogenated,
reacted in a manner known per se in the presence of a base.

The reaction conditions for this reaction correspond to those generally known for the Herner and Wittig reactions.

If necessary, then in a connection of the formula XIII in which R and R together denote oxygen, the carbonyl group with a complex metal hydride can be reduced to a hydroxyl group. This reduction can e.g. with zinc borohydride or, if R is not hydrogen,

preferably with NaBH ^ in methanol, or with complex boranes be made.

The invention opens up a new, economical access to the pharmacologically interesting class of compounds Prostaglandins. The compounds of formulas I, III, IV, VII, VIII, IX, X and XIII are thus used as intermediates for Making prostaglandins of value.

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The compounds according to the invention of the formulas I, III, -IV, VII, VIII, IX, X and XIII can exist in optically and geometrically different isomers. From these connections those are preferred whose stereo configuration of the formula

corresponds to, in which Z is -GHO or one of those contained in formulas III, IV, VII, VIII, IX, X and XIII Represents carbon side chains.

This compound is obtained when the starting material of the formula II is a compound of the stereoconfiguration

is used.

These isomers can be obtained by using a racemic lactone of the formula

with an optically active amino, such as a-phenethylamine, reacts, the diastereomeric amides separates and the optically active ones saponified lactones. The optically active lactones can then, analogously to the racemates, by epoxidation or reduction of the keto group to the hydroxyl group and etherification of the latter in

309884 / HSS

optically active compounds of Pormel II are converted. The following examples illustrate the invention:

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example 1

To 1.56 g of (2aa, 5aa, 5ba) -hexahydro-4a-methoxy-laaH-oxireno [3,4] cyclopenta- [1,2] furan dissolved in 20 ml of toluene is added dropwise under an argon atmosphere and stirring at 0 ° 10 minutes 16.7 ml of a 1.8 molar diethylaluminum cyanide solution in toluene and stirred at this temperature during another 45 minutes. A mixture of 20 ml of methanol is added dropwise to the almost colorless reaction mixture and 0.5 ml of water, stir the resulting gel at room temperature for 20 minutes, filter through Celite, the is covered with anhydrous sodium sulfate, and washed with methanol. The clear Piltrat is in a water jet vacuum evaporated to a colorless oil, which soon crystallizes through. Recrystallization from methylene chloride / hexane gives 1.0 g of pure (3aa, 6ac:) -hexahydro-4β-hydroxy-2a-methoxy-2H-cyclopenta [b] furan ^ a -carbonitrile, melting point 138-139 °.

By concentrating the mother liquors, a mixture of 4a- and? A-liitrile crystallizes and is finally almost pure (3aa, 6aa) -Hexahydro-5ß-hydroxy-2a-methoxy-2H-cyclopenta [b] furan-4a-carbonitrile, which is obtained by recrystallization from ether / Heptane is obtained analytically pure, melting point 74-75 °.

Example 2

2.4 g of m-dithiane are dissolved in 20 ml of anhydrous tetrahydrofuran dissolved and treated under an argon atmosphere at -30 ° with 9 ml of a 2 molar methyllithium solution in ether. In addition a solution of 1.50 g of (2aa, 5aa, 5ba) -hexahydro-4a-methoxy-laaH-oxireno [3,4] is added dropwise at -30 ° cyclopenta [1,2-b] -furan in 10 ml of tetrahydrofuran is stirred for one hour at this temperature and then for a further 21 hours at room temperature. It is poured into ice water and extracted with

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Ethyl acetate and washes neutral with saline. To Drying the solution over sodium sulfate and removing the solvent on a rotary evaporator gives 4.4 g of a orange-colored, partially crystallized mass, from which most of the excess dithiane in a high vacuum is sublimated at 80-90 °.

The residue (3.7 g) is chromatographed on neutral Alox I on the column. A total of 2.335 g is eluted with ether ($ 84.65) of the two isomers 4a-m-dithian-2-yl- (3aa, 6aa) hexa ~ hydro-2a-methoxy-2H-cyclopenta [b] furan-5β-ol and 5a-ra-dithian-2-yl- (3aa, 6aa) hexahydro-2a-methoxy-2H-cyclopenta] b] furan-4β-ol , 1.2 g of 4β-alcohol crystallize from the first two ether fractions. Recrystallization from methylene chloride / ether / Heptane gives colorless crystals, melting point 121-122 °.

Isolated from the later chromatogram fractions after repeated layer chromatography, the colorless isomeric 5β-alcohol as an oil which can be crystallized, melting point 74-75 °.

Example 3

Under an argon atmosphere and with stirring, 10 ml of a 2m ethereal methyllithius solution are added to 1.92 g of 1-heptyne in 10 ml of tetrahydrofuran at 0-5 °; it is then allowed to warm to room temperature and a solution of 1.56 g of (2aa, 5aa, 5ba) -hexahydro-4ct-methoxy-laaH-oxireno [3,4] cyclopenta- [1,2-b] furan in 10 ml is added dropwise Tetrahydrofuran too. The slightly yellow, clear solution is refluxed for 66 h. It is then poured onto Sis, taken up in ethyl acetate and washed neutral with sodium chloride solution, dried over sodium sulfate and the solvent is removed. The orange residue (2.6 g) is filtered through an Alox column (Akt I, 60 g) _y

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where with benzene / ether 2: 1 and afterwards with ether alone a total of 1930 mg (76.6 $) of a 1: 1 mixture of 4a- (l-heptynyl) - ■ (3act, 6aa) hexahydro-2cc-methoxy-2H-cyclopenta [b] for uran-5β-ol and 5ct- (1-heptynyl) - (3aa, 6aa) hexahydro-2a-methoxy-2H-cyclopenta [b] furan-4β-ol is obtained as a colorless oil. The separation is achieved by column chromatography with diisopropyl ether.

The zone that is more polar in the thin-layer chrociatogram turns out to be 4a- (1-heptynyl) - (3aa, 6aa) hexahydro-2a-methoxy-2H ~ cyclopenta [b] furan-5β-ol.

Example 4

915 mg (3aa, 6aa) -hexahydro-5ß-hydroxy ~ 2cx-methoxy-2H-cyclopenta [b] furan-4a-carbonitrile, dissolved in 10 ml of abs. Tetrahydrofuran are at room temperature with 10.5 BiMoI one Toluene diisobutylaluminum hydride solution is added and the clear solution is stirred for 48 hours under argon. At 0 ° 5 ml of methanol and 1 ml of water are added dropwise and the mixture is stirred for half an hour. Then ethyl acetate is added, dried with sodium sulfate and the solvent removed. 865 mg of (3acc, 6aa) -hexahydro-5β-hydroxy-2amethoxy-2H-cyclopenta [b] furan-4a-carbaldehyde are obtained as a yellowish oil. .

example 5

553 mg of 4a-m-dithian-2 ~ yl- (3aa, 6aa) hexahydro-2a-methoxy-2H-cyclopenta [b] furan-5β-ol dissolved in 5 ml of acetone, in the presence of 0.5 ml of water, 5 ml of methyl iodide and 0.5 g Soda kept at reflux for five hours, after which time no more starting material can be determined. It will be in Aether taken up, washed with water, dried and the solution

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medium away. 270 mg (3aa, 6aa) hexahydro-5β-hydroxy-2a-methoxy-2H-cyclopenta [b] furan-4a-carbaldehyde stay behind.

Example 6

504 mg of 4a- (1-heptynyl) - (3aa, 6aa) hexahydro-2a-ynethoxy-2H-cyclopenta [b] furan-5β-ol are dissolved in 15 ml of methylene chloride and in the presence of 250 mg of Lindlar catalyst and 20 mg of triethylamine hydrogenated. After 2 hours and the uptake of one equivalent of hydrogen, the catalyst is suctioned off Methylene chloride solution washed with water and dried. distance of the solvent gives 500 mg of 40- (l-cis-heptenyl) - (3aa, 6aa) hexahydro-2a-methoxy-2H-cyclopenta [b] furan-5β-ol as a colorless oil.

Example 7

508 mg of 4 <x- (l-cis-heptenyl) - (3aa, 6aa) hexahydro-2a-methoxy-2H-cyclopenta [b] furan-5β-ol _t, dissolved in 10 ml of ethyl acetate, are ozonated at -70 °. After half an hour, nitrogen is blown through instead of the ozone, warmed to -40 ° and 372 mg of trimethylphosph.ite are added. After warming up, the solvent is stripped off at 0 °, taken up in methylene chloride, filtered through 5 g of Alox I and the solvent and the caproaldehyde formed are removed in a high vacuum. 3 ^ 5 mg (3aa, 6aa) -hexahydro-5ß-hydroxy-2a-methoxy-2H-cyclopenta [b] furan-4a-carbaldehyde are obtained as a colorless oil.

Example 8

310 pieces of a 55% suspension of sodium hydride in mineral oil are washed twice with dry pentane and then suspended in> 0 ml of dry ethylene glycol dimethyl ether. 1.7 g of dimethyl 2-oxoheptylphosphonate in 10 ml of the same solvent are then added dropwise with stirring, a white precipitate being formed. In addition one gives

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in the course of 10 minutes 1.15 g of (3aa, 6aoc) -hexahydro-5ß-hydroxy-2a-methoxy-2H-cyclopenta [b] furan-4a-carboxaldehyde in 10 ml of ethylene glycol dimethyl ether and then stirred for a further 1.5 hours . The reaction mixture is adjusted to pH 6-7 with ice-cold 0.1 N hydrochloric acid and extracted with ethyl acetate. 1 * 95 ß of yellow oil is obtained which, after chromatography on silica gel, 975 mg of l - [(3aa, 6aa) -hexahydro-5ß-hydroxy-2a-methoxy-2H-cyclopenta [b] furan- ^J {a.-yl] - l-octen-3> -one yields.

Example 9

564 mg of 1- [(3aa, 6aa) hexahydro-5β-hydroxy-2a-methoxy-2H-cyclopenta [b] furan-4a-yl] -l-octen-3-one are in 7 ml of methylene chloride, 1 ml of pyridine and 0.5 ml of acetic anhydride dissolved and stirred for 6 hours at 50 °, then the solvent and sucked off the excess reagent, the residue in. Benzene, dissolved and sucked dry again, last on High vacuum. The contents of the flask are dissolved in 5 ml of 1,2-Βίώβΐηοχν-ethane dissolved and with 1.3 equivalents of a freshly prepared zinc borohydride solution in ether for two hours stirred at room temperature. It is cooled to 0 °, 2 ml of methanol and 0.5 ml of aqueous potassium carbonate solution are added and stirred for 20 minutes at room temperature, then taken up in ethyl acetate and washed with sodium chloride solution. To Drying and removal of the solvent gives 518 mg (3aa, 6aa) Hexahydro-4a- (3-hydroxy-1-octenyl) -2a-methoxy-2H-cyclopenta [b] furan-5β-oil.

This compound can be converted into prostaglandin F as follows:

980 mg (3aa, 6aa) hexahydro-2a-methoxy-4a [3- (hydroxy-1-oetenyl] 2H-cyelopenta [b] furan-5β-ol are dissolved in 5 ml of acetonitrile and 2 ml of 0.03 normal aqueous hydrochloric acid and stirred for 2 hours at room temperature. It is taken up in ethyl acetate, washed with water, dried and Removed the solvent. The residue is in 3 ml of abs. Dissolved dimethyl sulfoxide and a solution of 5-triphenyl

30988A / .U66 '

ζ = 15 -

Phosphonium valeric acid sodium salt given in dimethyl sulfoxide. The mixture is stirred for four hours at room temperature, poured onto ice water and extracted several times with Perftan. The pentane solution is dried over sodium sulfate, the pentane is removed and the residue is purified on Alox I. 950 mg of cis-7- [3aa, 5cc-dihydroxy-2ß- (3-hydroxy-1-octenyl) -la-cyclopentyl] -5-heptenic acid (CL ^ epimer mixture from rae. Prostaglandin F _? ) Are obtained in the form of a colorless oil.

Example 10

3 »0 g of cis-3,3a, 6,6a-tetrahydro-2H-cyclopenta (b) furan-2-one and 5.0 g (-) - (S) -a-phenylethylamine are heated to 80 for 18 hours under argon ° held. The yellow oil is taken up in ethyl acetate and freed from excess amine by washing with 0.5N hydrochloric acid. The solution is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The desired levorotatory diastereomer (A) crystallizes out from a mixture of dichloromethane, ether and hexane, melting point 99-1OG ⁰ ,

Recrystallization from the same solvent mixture gives optically pure (-) - 5R-hydroxy-N- (alpha- S-methylbenzyl) -2-cyclopentene-IS-acetamide, (A), m.p. 101-102 °, ^ ° -120.5 ° (c = 1, CHCl3).

309884 / U66

The mother liquor is chromatographed on 50 times the amount of silica gel, the diastereomer B being eluted with an ether / methylene chloride mixture of 3: 1. Recrystallization from ethyl acetate / hexane gives cotton-like, colorless crystals, m.p. 72-73, [oc] ^ ⁰ -75.2 ° (c = 1, GHCl) "of (-) - SS-HydroxY-N- (alpha- S-methylbenzyl) -2-cyclopentene-IR-acetamide.

1.0 g of amide A is heated in 10 ml of 20% aqueous sodium hydroxide solution + 2 ml of methanol for 2 1/2 hours in a 100 ° warm oil bath; the starting material disappears completely. The cooled solution is poured onto ice-cold 2Ή hydrochloric acid, extracted twice with ethyl acetate, the organic phase is washed with sodium chloride solution, dried over sodium sulfate and the solvent is removed. The remaining colorless oil crystallizes from ether / hexane and gives (-) - 5R-hydroxy-2-cyclopenteft-IS-acetic acid lactone, m.p. 47.5-48.5 ° [a3 _D -90.0 ° (c = 1, CHCIi).

Analogously, the diastereomer B is obtained (+) - 5S-Hydroxy-2-cyclopentene-1R-acetic acid lactone, m.p. 47-48 °, [a] £ ° + 92.6 ° (c = 1,

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Claims (5)

Claims ι A VI, / Process for the preparation of racemic or optically active compounds of the formula R ² O. OHC. -OR 1 2 wherein R is lower-alkyl and R is hydrogen or represent an easily split off protective group, characterized in that a compound of the formula II wherein R has the meaning given, a) with a dialkylaluminum nitrile to form a compound of formula H (X KO- JMT III 309884/1466 where R has the meaning given ", converts and the kitrile group in the compound of formula III - If desired, after converting the hydroxyl group into a protected hydroxyl group - reduced to the aldehyde group; or b) with a 1,3-dithiane-alkali metal or bradalkali metal salt to give a compound of the formula OR ¹ Cf T 1 reacted and the compound of the formula IV - if desired, after conversion of the hydroxyl group into a protected hydroxyl group, alkylated on at least one sulfur atom and then hydrolyzed; or
c) with a compound of the formulas V or VI = C-CR ⁴ VI \ OR ⁶ where B? Hydrogen, C 1 -C ₄ -alkyl, C ₅ -C 7 -CyClo alkyl, C 1 -C 4 -alkenyl, phenyl, lower-alkyl, phenyl or nitrophenyl, R and R independently of one another are hydrogen or lower-alkyl or together one C _{1 -C 7} -cyeloalkyl ring and R represent hydrogen or an easily cleavable protective group and Me an alkali metal or alkaline earth metal cation 309884 / U66 to a compound of the formulas VII or VIII • R ^ C = VII HO, RC-Oh
R ⁶ C / VIII 14 5 wherein R, R and R have the meaning given have and R represent hydrogen or an easily cleavable protective group, converts a compound of the formulas VII or obtained in this way VIII - if desired after converting free hydroxyl group (s) into protected hydroxyl group (s) - to a compound of the formulas IX or X R ⁵ CH = CH IX : k R ² O. C-CH = CH. 30988A / U66 wherein R ¹ , R ² , R ⁵ , R ⁴ , R ^ and R have the meaning given ", hydrogenated and the compound of the formulas IZ or X in itself in a known manner either transferred to a 1,2-G-lycol and this subject to glycol cleavage, or subject to Oson cleavage; 2. The method according to claim 1, characterized in that one of a compound of formula II of the stereoconfiguration goes out. 309884/1 466 3. Compounds of the formula OHCL 1 2 where R is lower-alkyl and R is hydrogen or an easily removable protective group. 4. Compounds according to claim 3 of the stereo configuration CHO 5. 3aa, 6aa-hexahydro-5β-hydroxy-2a-methoxy-2H-cyclopenta [b] f uranium-4 <* - carbaldehyde. 309884 / U66 ORIGINAL INSPECTED