JPS5854139B2 - Shinkinaprostan San Luienka Gobutsuno Seihou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Prostaglandins are a group of natural substances isolated from various animal tissues.

These induce various physiological effects in lactating infants.

Natural prostaglandins generally have a carbon composition of 20 carbon atoms, and differ mainly in the content of hydroxyl groups or double bonds in cyclopenta4 (higher or lower). Regarding the structure and action of
'rhe Prostaglandins, Pharmacological and Therapeutic Advances' by Robert Hbert
dins, pharmacological land
Therapeutic advance) J
William Heine
mann )・Medical Books Limited (see 1973 edition).

The synthesis of non-naturally occurring brostanic acid analogs, which differ in many of their pharmacological actions from natural brostanic acid, is becoming increasingly important.

The present invention relates to general formula I (wherein R3 is an alkyl group having 3 to 8 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, or a formula C(R')2-(CH2)n- 0-R", K is hydrogen or an alkyl group having 1 to 3 carbon atoms, n is 0 or 1 and R is 1 to 5
R is an alkyl group having 5 carbon atoms or a phenyl group optionally substituted by fluorine, chlorine or trifluoromethyl, or R is a diphenyl ether in which the terminal phenyl group is substituted by chlorine. Novel non-naturally occurring brostanic acid analogues and their physiologically compatible salts with organic and inorganic bases and their aliphatic, cycloaliphatic or araliphatic alcohols having 1 to 8 carbon atoms. Regarding Esther.

The present invention further encompasses novel, non-naturally occurring brostanic acid 9 analogues having the general formula I, their physiologically compatible salts with organic and inorganic bases, their esters and their active substances. It relates to a method for manufacturing pharmaceutical preparations.

This method has the following: *signs.

That is, (a) an acetal having the formula (CH2- or -〇 group or a single bond) is converted to an acetal of the formula (in which H
(b) the resulting formula ■ (e) The resulting aldehyde ketone having the formula ■ is subjected to acidic or alkaline catalyzed aldol condensation to form the formula ■ (d) the resulting unsaturated ketone having the formula ■ is reacted with cyanide ions under alkaline conditions to yield the cyanoketone having the formula ■; (e) the resulting cyanketone having the formula ■ by using anhydrous alcoholic acid to form an iminoether salt having the formula a (wherein S means an inorganic base and R4 means a lower alkyl residue having 1 to 5 carbon atoms), followed by (f) catalyzing the resulting ester having formula ■ to cleave its benzyl ether group; (g) oxidation of the resulting ester-alcohol of formula X (wherein R4 has the same meaning as in formula 2), (h) the resulting aldehyde having formula or a single bond) in the presence of an acidic catalyst to produce a thioacetal having the formula ■ (wherein R4 has the same meaning as in formula X), (i) obtained A thioacetal having the formula ■ is ketalized under acidic catalyst using a glycol having the formula X■ (in the formula, Y2 has the same meaning as the residue Y1 listed in the formula where Y1 has the same meaning as in formula M, and Y2 has the same meaning as in formula ■, with the proviso that Y, and Y2
may be the same or different and R4 has the same meaning as in formula X); (j) converting the resulting ketal-thioacetal of formula (k) reduce the resulting aldehyde of formula X to an aldehyde of formula XV (wherein Y1 and Y2 have the same meanings as in formula (In the formula, R3 is the formula I
unsaturated ketones of the formula X (in which Y, and Y2 have the same meanings as in formula XIV and R3 has the same meanings as in formula I) (1) The obtained ketone having formula ■ is reduced using a metal hydride complex to obtain an epimer of alcohol having formula X■ (wherein Y1, Y2, and R3 have the same meanings as in formula ■) (e) The resulting alcohol having the formula
Converting dihydropyran into tetrahuman pyranyl ether having the formula XIX (wherein Y1, Y2 and R3 have the same meanings as in formula ■) by acidic addition of dihydropyran, (n) acid bonding the resulting ether having the formula XIX. by heating with 01-C4 alkyl iodide in a polar aprotic solvent in the presence of an agent, (0) is converted into an aldehyde ether having the formula XX The resulting aldehyde ether of formula ) and (p) tetrahylene in the compound with the resulting hole gap*
-Y.

Cleavage of the dropyranyl ether protecting group by acid hydrolysis yields an alcohol of formula X (wherein Y2 and R3 have the same meanings as in formula The groups are removed by mild acid catalyzed hydrolysis or by ketal exchange in the presence of a large excess of ketone.

If desired, the compounds of formula I are converted into physiologically acceptable salts or esters thereof.

The process according to the invention begins with the synthesis of ketones from nitriles having the general formula (1).

Such trills are for example the jhanas 7. ．． Oh...

Organic Chemistry (J, Org, Che
3-(2,5-dioxapentyl)-propyl bromide, which can be prepared by M. M., Vol. 34 (1969), p. It is obtained by converting to

This nitrile or its oxygen analog described by the general formula (X=O) can be reacted directly with a suitable Grignard compound having the general formula
It can be converted to a sulfur analog (X=S) having the general formula (2) by acid-catalyzed ketal exchange using a thiol having the formula (1).

In the next step, a nitrile (X=O or S) of the general formula (2) is reacted with a Grignard compound of the general formula (2), followed by a ketone of the general formula (2) obtained by careful acid hydrolysis.

Grignard compounds having the general formula (1) are obtained by conventional methods from 4-benzyloxybutyl chloride or bromide in conventional solvents such as diethyl ether or tetrahydrofuran.

In principle other organometallic compounds can also be used, such as for example 4-benzyloxybutyllithium.

Components (1) and (2) are allowed to react for 2 to 20 hours in the presence of a protective gas.

A convenient solvent is diethyl ether or tetrahydrofuran, the preferred temperature is between 30 and 70°C, and the reaction time is preferably between 12 and 16 hours.

The reaction product is hydrolyzed under carefully acidic conditions and the ketone having the general formula (1) is isolated in pure form by distillation or column chromatography.

However, it is also possible to use the crude product having the general formula (1) directly in the next step of the synthesis, ie cleavage of the acetal or thioacetal protecting group.

To obtain an aldehyde ketone with the formula ■, the general formula r
In the case of oxygen acecool with v (x=o), the conventional acid ketal decomposition is carried out.

A particularly careful embodiment of the process according to the invention is to prepare a solution of the compound of the general formula (1) (in which X=O is meant) in an ether, for example diisopropyl ether, in the presence of a protective gas at 40 DEG -80 DEG C. The solution consists of vigorous stirring with an aqueous oxalic acid solution for ~6 hours, followed by washing to neutrality, and then distilling off the solvent.

For the cleavage of thioacetals having the general formula (X-8 in the formula), for example, tetrahedron letters (T
etrahedron Lett, ) 1972 No. 1
Methods commonly used in the literature such as those summarized on pages 989-1990 are used.

A preferred embodiment of the method according to the invention is published by the Bulletin of Chemical Society of Japan (Bull,
Cbem, Soc, Japan) Volume 45 (1
972) 5 CuCl reported on page 3724
2 and CuO.

The aldehyde of formula V can be purified by chromatography or distillation; however, it precipitates in high purity, especially when using the CuCl2-CuO method described above, so that it can be used directly in the subsequent reaction without further purification. This is more convenient.

The aldehyde of formula (1) is subsequently subjected to a base-catalyzed aldol condensation to yield an unsaturated ketone of formula (2).

In principle, acidic catalysts can also be used in the aldol condensation.

A particularly preferred embodiment of the mild aldol condensation is to carry out at 40 to 600 °C in a two-phase system with oxygen in place and strong (without agitation), in which one phase is saturated with oxygen, such as diisopropyl ether or benzene. It represents a solution of the aldehyde of the general formula (2) in a water-insoluble solvent that cannot be oxidized, and is separated from the other aqueous solution of caustic soda or caustic potassium.

The unsaturated ketone of formula (2) is purified by chromatography or distillation as described several times.

However, it is also possible to proceed further from the crude product.

A CN- ion is added to the ketone of formula (II) to give the cyanketone of formula (II) in a conventional manner using acetone cyanohydrin in methanolic alkaline solution at room temperature or KCN in methanol/water. is preferable.

In principle, the appearance of cis-trans isomers should be taken into account in this reaction step.

However, the Bretan de la Société Imino de...
France (Bull.

Soc, Chin, ) Volume 6, Page 1622 (196
Based on the research in 5), the more stable trans structure is predominant under alkaline conditions.

The cyanketone of general formula ■ reacts with alcoholic acid, especially ethanolic hydrochloric acid, and iminoether hydrochloride ■a
After that, it becomes an ester of the general formula (■).

The iminoether hydrochloride 1a then precipitates out in oily form after distilling off the excess alcohol and can be purified from the by-product by extraction with a weakly polar solvent such as, for example, pentane or diethyl ether.

A special embodiment of the method of the invention now has the general formulas ■, ■, ■
Each of the compounds is further processed as a crude product, and the precipitated by-products are removed together by extraction in step (a).

The iminoether hydrochloride (1) is then genified to give the ester of the general formula (2) by a conventional method, particularly by layering the ether in an aqueous solution and stirring at room temperature.

The ethereal solution contains an ester of general formula ■,
This is purified by distillation or by chromatography as is customary.

The benzyl ether group from the ester of general formula (1) is decomposed with hydrogen, inter alia, in the presence of a noble metal catalyst such as 10% palladium on animal charcoal to give the ester-alcohol of general formula (1).

The oxidation of the ester-alcohol of general formula IX to the aldehyde of general formula X is carried out using methods customary for the oxidation of primary alcohols to aldehydes.

A preferred method is oxidation using chromic anhydride in the presence of pyridine, optionally using methylene chloride as the solvent, as described in Tetrahedron Letters, page 3363 (1968).

A preferred method is oxidation with chlorine in the presence of thioanisole (The Journal).

of Organic Chemistry Volume 38 (1973
) p. 1233).

Aldehydes of formula X can be prepared pure in conventional manner.

However, it is convenient to react this in crude form with a thiol of the general formula M in an inert solvent in the presence of an acidic catalyst to give a thioacetal of the general formula (2).

A preferred embodiment of the process of the invention comprises precipitating an aldehyde of general formula X with a purity of about 90% in an equimolar amount of a thiol of general formula 15°C to 50°C for 30 minutes to 5 hours in a neutral (aprotic) solvent such as benzene or toluene in the presence of an oxygen-free protective gas such as nitrogen or argon.
The purpose is to carry out the reaction at a temperature of .

In this case, the aldehyde functional group in the compound of general formula (1) is selectively protected.

The remaining keto functionality in the thioacetal of general formula (1) is now protected by ketalization with a glycol of general formula (X) in a neutral solvent in the presence of an acidic catalyst.

Ketal thioacetals having the general formula are thereby obtained.

A particularly preferred method is the ketalization of the general formula (1) using a glycol of the general formula A ketal-thioacetal of the formula Δ■ is obtained.

Compounds 1, X, 2 and XIV can each be prepared in pure form by conventional methods.

However, in the process according to the invention, the compounds of the general formulas 1, Conveniently, purification is carried out by means of graphics.

In the ketal thioacetal of the general formula It is reduced to an aldehyde of general formula X■ by reduction at 80°C.

Furthermore, the aldehyde of general formula
r ), x is reacted with a phosphonic acid ester of general formula X■ by the method of Emmons and Wittig to form an unsaturated ketone of general formula X■.

A preferred embodiment of the reaction is to prepare the sodium salt of the phosphonic ester of general formula X■ with sodium hydride in glycol dimethyl ether, followed by the addition of an aldehyde of general formula The purpose is to react for ~6 hours.

Phosphonate esters of general formula XVI are prepared by methods known in the literature [Journal of the American Chemical Society (J. Am. Chem.
Soc, Vol. 88, p. 5654 (1966)].

The alcohol of the general formula (2) can be obtained in the form of an epimer mixture when the ketone of the general formula (2) is reduced using a metal hydride complex, ganzuku alkali boranate.

Alcohols of the general formula X are particularly suitable for epimer separation, but it is also possible, however, to use epimer mixtures further in the reaction and to carry out epimer separation in the final product stage.

The addition of dihydropyran to the tetrahydropyranyl ether of the general formula x+ is carried out in an ethereal or benzene solution of an alcohol of the general formula X■ in the presence of a customary acidic catalyst, such as, for example, p-)luenesulfonic acid.

It is generally convenient to chromatographically purify the resulting tetrahydropyranyl ether of general formula X with this actor.

The liberation of aldehydes and ketones from thioacetals or thioketals is the subject of much literature because of the production difficulties associated with it (see Tetrahedron Letters, Vol. 19, p. 1989 (1972)).

In particular, the preparation of relatively sensitive aliphatic aldehydes poses increasing difficulties when particularly labile protecting groups are present in the same molecule, such as the tetrahydropyranyl ether group.

Surprisingly, when adding the acid binder inter alia calcium carbonate to a solution of thioacecool of the general formula and 30-70℃ especially 50
After heating for 1 to 5 hours at <RTIgt;C,</RTI> an aldehyde of the general formula V is formed in virtually quantitative yield with the tetrahydropyranyl protecting group retained.

The aldehyde ether of general formula XX thus prepared is reacted without further purification to the carboxylic acid having general formula XM.

A preferred embodiment of the Wittig reaction is described in The Journal
Of Organic Chemistry Volume 28 No. 1128
(1963).

Cleavage of the ether protecting group is carried out inter alia by mild hydrolysis of the tetrahydropyranyl ether group in a 2% aqueous-alcoholic oxalic acid solution at 20-50°C or 60-7
This is carried out by heating in 0% acetic acid at 50 DEG C. for 1-2 hours, giving a carboxylic acid of the general formula X.

The final step in the synthesis according to the invention consists in mild acid hydrolysis of the ketal group of the compound of general formula X■ to give a compound of general formula ■.

Yet another form of ketal decomposition is p-) in the presence of an acidic catalyst such as luenesulfonic acid and in the presence of a large excess of ketones, especially acetone. ) to exchange ketals.

However, a preferred embodiment of the process according to the invention is to cleave both protecting groups in the carboxylic acid of formula has been proven.

A compound having the general formula (2) is then obtained.

If no epimer separation is performed at the stage of the alcohol of general formula ,
15-OH according to Acad, Sci, Vol. 180, p. 14) corresponds to 3-QH according to IUPAC nomenclature].

Furthermore, racemic separation can be carried out by forming a salt with an optically active base in a conventional manner at the acid stage of the general formula XM or at the stage of the general formula (2).

Formula■,■,■,■,■,■,X,■,■,XV,X■,
Compounds having (1), XtX, XX, XXI, xm are valuable intermediates for the synthesis of compounds of formula (1).

The compounds according to the invention are excellent in their general convulsogenic and antispasmodic properties, in particular their bronchodilating and hypotensive properties.

Furthermore, they are effective in the treatment of gastrointestinal disorders and exhibit fertilization-blocking effects.

Compared to the natural prostaglandins E, F and A, they have a significantly greater stability.

They can therefore be used as medicines.

It is surprising that the compounds of the formula (1) with the 15-OH group and the epimer possess the above-mentioned pharmacological properties to the same extent.

The compounds according to the invention can be used as free acids, in their physiologically non-hazardous inorganic or organic salt form Q, or in aliphatic,
They can be used as esters of cycloaliphatic or araliphatic alcohols.

Examples of salts include benzylammonium, triethanolammonium or morpholine salts, especially tris-(
hydroxymethyl)aminomethane salts, and alkali salts such as Na and di salts; esters include, inter alia, esters of lower saturated aliphatic alcohols such as methyl, ethyl, propyl, isopropyl, butyl or pentyl esters, and benzyl esters. can be given.

Acids and salts or esters in the form of their aqueous solutions or suspensions or, for example, monohydric or polyhydric alcohols,
as a solution in a pharmacologically non-hazardous organic solvent such as dimethyl sulfoxide or dimethyl formamide;
It can also be used in the presence of pharmacologically non-hazardous polymeric carriers, such as polyvinylpyrrolidone.

Preparations may include the customary galenic infusion or injection solutions and tablets, but also topical preparations such as creams, emulsions, herbal medicines or aerosols, among others.

These compounds can be used alone or in conjunction with other pharmacological agents, such as diuretics or antidiabetic agents.

Bronchodilator drugs with surprisingly strong effects are 1
Regarding the 5-OH group, the epimeric compound 7-(2,-(
3-Hydroxy-3-pentyl-trans-1-propenyl)-5-oxo-cyclopentylz-4-heptenoic acid in the free form or in the form of its physiologically non-hazardous inorganic or organic salts; They are obtained as esters of aliphatic, cycloaliphatic or araliphatic alcohols when mixed with each other in a weight ratio of 0.75:1 to 1.25:1 and used in aerosol form.

It is surprising that such a mixture exhibits an effect several times higher than that of several isomers.

A particularly advantageous mixture consists of a mixture of isomers in a weight ratio of 1:1.

The isomers can be used in the medicament according to the invention inter alia in the free acid form, in the form of the Na or di salts or in the form of salts with organic bases such as benzylammonium, triethanolammonium or morpholine salts, in particular tris-(hydroxymethyl)aminomethane salts. Alternatively, it is likewise used in the form of esters of lower saturated straight-chain or branched aliphatic alcohols, such as methyl, ethyl, propyl, isopropyl, butyl or pentyl esters, as well as in the form of benzyl esters.

Particularly preferred are the free acids, as well as the methyl of the acids mentioned above,
Ethyl, propyl and isopropyl esters.

The mixtures according to the invention may be made into solutions using customary physiologically non-hazardous, flavored and non-irritating solvents, such as water or ethanol, or may be made into solutions of lower fatty acids such as, for example, myristate isopropyl ester. The alkyl ester is suspended in the alkyl ester, optionally with the addition of surface-active substances such as sorbitan or pentaerythritol fatty acid esters as stabilizers, and placed into use by filling into an aerosol container with a customary inert propellant gas.

The abovementioned preparations can, however, also be applied with conventional atomization equipment using pressurized air.

Possible indications for the species include the following single or daily doses:

Bronchodilatory effect (one dose as an aerosol 0.1-1000 μm, preferably 1-200 μm (77°'-18 amount
.

3, ~ 107Fllip ``Dose 9) Blood pressure lowering effect Single dose 1 to 1000 μm Preferably 1 to 100 μm Parenteral (intravenous) daily dose
1~10■ Oral single dose 0.5~1000! v Preferably 1 to 500 ■ Oral daily dose 1 to IOP The dosage for use in gastrointestinal disorders corresponds to that listed for use as an antihypertensive agent.

Preparation of Starting Materials 3-(2,5-Dioxapentyl)-propyl bromide was prepared according to The Journal of Organic Chemistry, Vol. 34 (1969), p. 1122, according to Chem.

2 molar equivalents of KCN in the presence of a catalytic amount of potassium iodide in a mixture of 60 parts of ethyl alcohol and 40 parts of water and heated under reflux for 3 hours.

The thus obtained 3-(2,5-dioxapentyl)propyl cyanide (boiling point 68-69°C, 10.6 order) was heated under reflux with ethylene thioglycol in the presence of benzene difluoride boron etherate, and then After-treatment boiling point of 12
3-(2,5-dithiapentyl)-furobyl cyanide of 4-126° C./0.5 myb is obtained.

4-Benzyloxybutanol, Journal of the American Chemical Society, Volume 60 (1938)
Retrieved from page 1472 of the Journal of the Chemical Society (J, Chem, Soc.
), Vol. 1927, p. 476, to 4-penzyloxybutyl chloride.

Example 1 7-benzyloxy-1-(2,5-dithiapentyl)
Hebutan-3-one magnesium (0,103 mol) 25i and 4benzyloxybutyl chloride (0,101 mol) 201
The Grignard compound is prepared by heating in 50 ml of diethyl ether for 5 hours.

50rrL of diethyl ether in this Grignard solution
A solution of 3-(2,5-dithiapentyl)-furobyl cyanide 12P (0,076 mol) in 100 mL of chloride was added dropwise and heated under reflux for 18 hours under a stream of argon.

After cooling, add methylene chloride 2007d and ice water and add HCI.
Acidify to pH 1 using water and stir for 15 minutes.

The organic phase is separated, washed with water and concentrated. Dilute the residue with acetone 2
001rLl and methanol 501nl
Stir with 25 ml of N HCl for 4 hours at room temperature.

The solvent was concentrated in vacuo and the residue was taken up in methylene chloride and washed once with 2N sodium carbonate solution and twice with water, and the MgS
Dry over O4 and concentrate.

Distill the residue in vacuo.

Boiling point 205-207℃ 70.3 mm. Example 2 7-Benzyloxy-3-oxyheptanal 7-benzyloxy-1-(2,5-dithiapentyl)-hebutan-3-one 44f (0,135 mol) in acetone 1
The mixture is heated under reflux in a stream of nitrogen for 1 hour with CuCl2.2H2047g (O1275 mol) and CuO 44P (0.57 mol), the copper salts are filtered off and the filtrate is concentrated in vacuo.

The residue is taken up in ether, washed twice with 2N HCl and three times with water, dried and the solvent is removed in vacuo.

Distill the residue in vacuo. Boiling point 185-192℃ 10.5
Close.

Example 3 2-(3-benzyloxyprobyl)-2-cyclobentenone Crude 7-benzyloxy-3-oxoheptanal 30.
Dissolve 8f in 100ml of diisopropyl ether I
Mix well with 500 TrLl of N caustic soda at 50° C. using a vibrating mixer under a nitrogen stream.

The organic phase is separated, the aqueous phase is extracted with 200 ml of ether and the combined ether extracts are washed with water, dried, concentrated and vacuum distilled.

Boiling point: 175-180°C 10.5 Door shame Example 4 2-(3-benzyloxyprobyl)-3-cyano-cyclopentanone 2-(3-benzyloxyprobyl)-2-cyclobentenone 47.8P (0,208 mol) in methanol 20
KCN 41.5 P (0.64 mol) is added and Q glacial acetic acid 15 P (0.25 mol) in 25 TIL methanol is added dropwise with stirring at room temperature for 1 hour.

After stirring for 1 hour, add glacial acetic acid 4@((1066
mol) dropwise and stirred for an additional hour.

After the end of this time no starting material is detected in the thin layer chromatogram.

To this was added 100 ml of 2N NaOH and 900 ml of ice water.
is added and the mixture is extracted three times with diethyl ether 2007711, the combined ether extracts are washed neutral, dried and the solvent is evaporated in vacuo.

Distill the residue.

Boiling point: 210-215°C/Q, 5. Example 5 3-ethoxycarbonyl-2-(3-benzyloxy-
2-(3-benzyloxypropyl)-3-cyanocyclopentanone 5. IP (0.02 mol) is dissolved with anhydrous Veg4F25 (0.022 mol) at 20° C. with stirring, and HCI gas is introduced with a slow gas stream for 4 hours.

Reaction mixture 'I'm 1 Leave at room temperature for 6 hours.

The solvent is then removed in vacuo, the residue is stirred three times with 751 rL each of anhydrous diethyl ether, and the ether extract is discarded.

The oily residue was dissolved in 20 ml of water, layered with 100 ml of diethyl ether, stirred for 30 minutes at room temperature, the organic phase was separated and the aqueous phase was poured with 200 ml of diethyl ether.
Extract with 1.

The combined ethereal extracts are washed with 2N sodium carbonate solution and water, dried and the solvent is removed in vacuo.

oil is obtained. Analytically pure samples were obtained by chromatography on silica gel using cyclohexane/acetate (9:
1).

The spectral data are as follows.

NMR 7.3ppm - heavy line 5 HI3.2 (C
) PI) m4, 4ppm -Double line 2N Single line 2H Example 6 3-Ethoxycarbonyl-2-(3-oxypropyl)
Cyclopentanone 3-ethoxycarbonyl-2-(3-penzyloxy-
propyl)-cyclopentanone 5P in 80% acetic acid 50m
Hydrogenation was carried out using palladium black 11 in 1 at room temperature under a pressure of 50 atm.

Add to this 1001711 of water and 100ml of methylene chloride.
The catalyst is filtered off, an aqueous soda solution is added until the pH is 8-9, the methylene chloride is separated, washed, dried and evaporated in vacuo.

The oily residue is warmed to 50° C. for 1 hour at 0.02 mmHg.

U, R, 3500crrL-1゜Example 7 3-(2-ethoxycarbonyl-5-oxo-cyclopentyl)propionaldehyde 3-ethoxycarbonyl-2-(3-oxypropyl)
-Cyclopentanone 3.07'ft (0,014 mol)
Dissolve in 3ml of methylene chloride and add 300T of methylene chloride.
Cry311.95 in Ll? and pyridine 19.
15f into an oxidizing reagent at 0°C.

After stirring at 0°C for 35 minutes, 61.8 P of sodium hydrogen sulfate monohydrate was added in solid form, and the mixture was stirred at 0°C for an additional 30 minutes.

The mud is filtered through a clear bed filter and the filter residue is washed six times with 50 ml of methylene chloride each.

The combined methylene chloride filtrates are dried over Mg5O and concentrated.

oil is obtained. For U and Ro, no OH absorption band was observed at 3500CrrL'', and 1730-1740cIIL-1
A broad force/1/7 J-''nyl absorption band was present.

Example 8 3-(2-Ethoxycarbonyl-5-oxocyclohentyl)-propionaldehyde-ethylenethioacetal Oily 3-(2-ethoxycarbonyl-5-oxo-cyclopentyl)-propionaldehyde 3f(0,01
4 mol) ethylene thioglycol 1.29P (0,1
37 mol), trifluoride etherate 0.5 + 71
1 and 50 ml of dry benzene at room temperature for 3 hours, diluted with 150 TrL of ether, and cooled on ice.
Wash with NaOH and water.

This is dried over sodium sulfate and the solvent is evaporated in vacuo.

oil is obtained. U, R, ~1740crn' 0 Example 9a 7-C(1,3-dithia-2-cyclopentyl)-ethyl]-3,3-dimethyl-1,5-dioxaspiro-[
5.4)-Desyl-8-yl-carboxylic acid ethyl ester 3-(2-ethoxycarbonyl-5-oxocyclohentyl)-propionaldehyde ethylene thioacetal 3.35 g (0.0116 mol) was added to 2.2 -dimethi/l
/-1,3-propanediol2. IZ (0.02 mol), p-)luenesulfonic acid 0.2P and benzene 5
Heat to reflux on a water separator for 0 ml and 3 hours.

After cooling, dilute with ether, wash with ice-cold 2N soda solution, dry over Na2SO4, and concentrate.

An analytically pure sample is obtained by chromatography of the resulting oil on silica gel, eluting with cyclohexane/acetic acid ester (95:5).

NMR4,2ppm (c)-quartet 2H3,5pp
m - Heavy line 4H 3,2 ppm - Heavy line 4H Example 9b In exactly the same way, 6-C (1
・3-dithia-2-cyclopentyl)ethyl]-1.4
-Dioxaspiro[4.4]nony-7-yl-carboxylic acid ethyl ester is obtained.

NMR3.8~4.5 ppm - heavy line + polyis
7H3,2ppm - Heavy line 4H Example 10 7-[(1,3-dithia-2-cyclopentyl)ethyl]-3,3-dimethyl-1,5-dioxaspiro[5.
4)-Desyl-8-yl-aldehyde 7-((1,3-dithia-2-cyclopentyl)-ethyl]-3,3-dimethyl-1,5-dioxaspiro[5,4)-decy-8
-yl-carboxylic acid ethyl ester 1.3 P (3,
5 mmI, ) mol) was dissolved in 50 ml of anhydrous toluene,
0.777 Il of diisophthyl aluminum hydride in 10 rrtl of anhydrous toluene at -70°C, = 3.85
mmol dropwise within 20 minutes followed by stirring at -70° C. for 2 hours.

followed by methanol ITrLl and 0.5 ml glacial acetic acid
After dropping 20ml of water, add 501r of diethyl ether.
Add ll.

Filter the cloudy solution through a clear bed filter and wash the filtrate with ether.

The ethereal phase is washed with sodium bicarbonate solution, dried and concentrated in vacuo.

The resulting oil has the following spectral properties:

NMR9.35ppm doublet IH 4.4ppm triplet IH 3.5ppm-double 4H 3.2 ppm -double 4H Example 11a 1-[7-((1.3-dithia-2-cyclopentyl)
-ethyl]-3,3-dimethyl-1,5-dioxaspiro[5,4]-desy8-ylcotrans-1-octen-3-one 80% sodium hydride 0.15'(3
, 3 mmol: glycol dimethyl ether 25rr
After stirring for 15 minutes at room temperature, 0.895' (4 mmol) of dimethyl-2-oxo-heptylphosphonate in 5 TL of glycol dimethyl ether is added dropwise.

After stirring for 25 minutes a white emulsion forms.

Add 7-C(1,3-dithia-2-cyclopentyl)-ethyl]-3,3-dimethyl-1,5-dioxaspiro[5,4]-desi-8-yl-aldehyde 1.
A solution of 06P (3.2 mmol) was added dropwise and stirred at room temperature for 2.5 hours.

After this time the solution is still slightly cloudy.

Add a few drops of glacial acetic acid, add 2 tablespoons of charcoal, and filter.

The filtrate is concentrated in vacuo to give a clear oil.

An analytically pure sample is obtained by chromatography on silica gel and elution with cyclohexane/acetate 95:5 and 90:10.

NMR5,8-6.8 ppm multiplet 2H4,4
p triplet 1H 3.5 ppm -double 4H 3,2ppm -double 4H Example 11b 1-[7-[(1.3 -dithia-2-cyclopentyl)-ethyl]-3,3-dimethyl-1,5-dioxaspiro[5,4]-desi-8-ylcotrans-1-decen-3-one is prepared.

Example 11c 1-C by reaction with dimethyl-2-cyclohexyl-2-oxo-ethylphosphonate in a similar manner.
7-C(1,3-dithia-2-cyclopentyl)-ethyl]-3,3-dimethylto5-dioxaspiro[5,4
]-Dezy8yl]-3-cyclohexyl-trans-
1-propen-3-one is prepared.

Example 11d Similarly, 1-47-[(1,3-dithia-2-cyclopentyl)-ethyl ]-3,3-dimethyl-1,5
-Dioxaspiro[5.4]-Desi8-yl]-3-
(i.1-dimethyl-3-*-*v-pentyl)-) lance-1-7'lopen-3-one is prepared.

Example 11e 1-[Nia-
C(1,3-dithia-2-cyclopentyl)-ethyl]
-3,3-dimethyl-1,5-dioxaspiro[5,4
]-Des-8-yl]-3-cycloheptyl-trans-1-propen-3-one is prepared.

NMR5.8-6.8 ppm Multiplet 2H Example 11f 1-C7-(1,3-dithia-2
-cyclopentyl)-ethyl]3,3-dimethyl-1.
5-Dioxaspiro[5,4]-desi-8-ylcotrans-1-hexen-3-one is prepared.

NMR5.8-6.8 ppm Multiplet 2H Example 11g Similarly reacted with dimethyl-2-[1-methyl-1-[p(p-chlorophenoxy)-phenoxy]-methyl]-2-oxo-ethylphosphonate. 1-4 by letting
6-C(1,3-dithia2-cyclopentyl)-ethyl]-1,4-dioxaspiro[4,4]-non-217-yl]-3-[1-methyl-1-Cp-(p- Chlorphenoxy)-phenoxy]-methyl]-trans-1 propen-3-one is prepared.

NMR6.3-7.4 ppm multiplet 10H4,
5ppm (c) Multiplet 1H3, 9ppm
- Heavy line 4H 3,15ppm - Heavy line 4H Example 11h Dimethyl-2-[1,1-dimethyl-1,-
1-C6-C(1,3-dithia-2-cyclopentyl)-ethyl]-4-dioxaspiro by reaction with Cp-(p-chlorophenoxy)-phenoxy]-methyl]-2-oxo-ethylphosphonate. [4.4]
-non2171yl]-3-[1,1-dimethyl-1-[
p(p-chlorophenoxy)-phenoxyiomethyl)
-) Lance-1-propene-3-onca is prepared.

NMR6.8-7.4 ppm multiplet 10H4,
5pP multiplet IH 3,9ppm -multiplet 4H 3,15ppm -multiplet 4H Example 11i 1-[6-[
(1,3-dithia-2-cyclopentyl)-ethyl]-
1,4-dioxaspiro[4,4]-non-7-yl]
-3-phenoxymethyl-trans-1-propene-3
-on is prepared.

NMR6.8-7.5 ppm Multiplet 5H Example 11j 1-C6-C(1.3 -dithia-2-cyclopentyl)-ethyl]-1,4-dioxaspiro[4,4
]-non217-ylni-3-(4-fluorophenoxy)-methyl-trans-1-propen-3-one is prepared.

NMR6.9-7.3 ppm Multiplet 4H Example 11 was similarly reacted with dimethyl-2-(3-chlorophenoxy)methyl-2-oxo-ethylphosphonate to obtain 1-C6-C(1.3- Dithia-2-cyclopentyl)-ethyl]-1,4dioxaspiro[4,4]-nony7-yl]-3-(3-chlorophenoxy)-methyl-trans-1-propen-3-one is prepared. .

NMR6.7-7.5 ppm Multiplet 4H Example 111 Similarly, 1-C6-[1-C6-[ (1,3-dithia-2
-cyclopentyl)-ethyl]-1,4-dioxaspiro[4,4]-no217-yl, :l-3-(3-)lifluoromethylphenoxy)-methyl-1-trans-
1-propen-3-one is prepared.

NMR7.0-7.6 ppm Multiplet 4H Example 11m 1C6-C(1.
3-dithia-2-cyclopentyl)-:r-thyl]-1
・4-dioxaspiro[4-4]-non-7-yl]-
3-isobutyl-trans-1-propene-3-one is prepared.

NMR5,9~7ppm multiplet 2H4,5pp
m Multiplet IH 3,95ppm -Doublet 4H 3,2ppm -Doublet 4H Example 11n Similarly dimethyl-2-(1,1-dimethylpentyl)-
1-C6-CC1.3-dithia 2-cyclopentyl) by reacting with 2-oxo-ethylphosphonate.
-ethyl]-1,4-dioxaspiro[4,4]-non-217-yl]-3-(1,1-dimethylpentyl)-)
Lance-1-propen-3-one is prepared.

Example 12a 1-C7-[(1,3-dithia-2-cyclopentyl)
-Ethyl]-3,3-dimethyl-1,5-dioxaspiro[5,4]-di8-i#)-)-)-lance-1-octen-3-ol NaBH40,12f (3,2 mmol) was added to H2O1a and Dissolved in 101 rLl of CH30H, cooled to 0°C, and dissolved 1- in 151 rLl of methanol.
[7-C(1-3dithia-2-cyclopentyl)-ethyl]-3,3-dimethyl-1,5-dioxaspiro[5
・4]-Digy8-ylcotrans-1-octene-
Add 1.285' (3 mmol) of 3-one dropwise and stir at room temperature for 1 hour.

The solution is made neutral using glacial acetic acid, concentrated in vacuo, and the residue is taken up in diethyl ether and washed with water.

After evaporating the ether in vacuo an oil remains with the following spectral data.

-UR 3500 cm t, no carbonyl absorption band NMR 5,3~5°7p multiplet 2H Example 12
b total (similarly l-[7-[(1,3-dithia-2-cyclopentyl)-ethyl]-3,3-dimethyl-1,5-
Dioxaspiro[5,4]-desi-8-ylcotrans-1-decen-3-one to 1-C7-[(1,3-
dithia-2-cyclopentyl)-ethyl]-3,3--
) mef root 5-dioxaspiro[5.4]-digy8
-yl]trans-1-decen-3-ol is prepared.

UR3500ci' NMR5, 3-5.7ppm multiplet 2H example
12c 1-C7-((1,3-dithia-2-cyclopentyl)
1-[7-4(
1,3-dithia2-cyclopentyl)-ethyl]-3.
3-dimethyl-1,5-dioxaspiro[5,4]-desi-8-yl]-3-cyclohexyl-trans-1-propen-3-ol was obtained.

UR3500crIL-1 NMR5,3-5.7 ppm Multiplet 2H Example 12d 1-C7-C (1,3-dithia-2-cyclopentyl)
-ethyl]-3,3-dimethyl-1,5-dioxaspiro[5,4]-desi-8-yl]3-(1,1-dimethyl-3-oxapentyl)-trans-1-propene-
3-one to 1=[7-[(1,3-dithia-2-cyclopentyl)ethyl]-3,3-dimethyl-1,5-dioxaspiro[5,4]-desy8-yl)-3(1
・1-dimethyl-3-oxapentyl)-) lance-1
-Propen-3-ol was obtained.

UR3500cm ” NMR5.3-5.7 ppm Multiplet 2H Example 12e 1-C7-4 (1,3-dithia-2-cyclopentyl)
-ethyl]-3,3-dimethyl-1,5-dioxaspiro[5,4]-desi-8-yl]3-cycloheptyl-trans-1-70 pen-3-one to 1-[7-(1
・3-dithia-2-cyclopentyl)-ethyl]-3・
3-Dimethyl-1,5-dioxaspiro[5,4]-decy8-yl]-3-cycloheptyl-trans-1=propen-3-ol is prepared.

UR3500cIrL' NMR5.3-5.7 ppm Multiplet 2H Example 12f I-C7-[(1-3-dithia-2-cyclopentyl)-ethyl]-3,3-dimethyl-1 Same as Example 12a・5-dioxaspiro [5.4] desi-8-yl]
trans-1-hexene-3one to 1-[7-[(1
・3-dithia-27clopentyl)-ethyl]-3″-
3-dimethyl=1.5-dioxaspiro[5.4]-desy8-ylcotrans-1-hexen-3-ol is prepared.

UR3500crfL' NMR5.3-5.7 ppm Multiplet 2H Example 12g 1-C6-[1: (1.3 dif
7-2-cyclopentyl)-ethyl]-1,4-dioxaspiro[4,4]-non-217-yl]3-[l-methyl-1-Cp-(p-chlorophenoxy)-phenoxy]-methyl ]-trans l-propen-3-one to 1
-[6-C(1,3-dithia-2-cyclopentyl)-
Ethyl]1,4-dioxaspiro[4,4]-nony7
monoyl]-3-[1-methyl-1-Cp-(p-chlorophenoxy)-phenoxy]-methyl]-trans-
Preparation of 1-propene-3-ol.

UR3500cm' NMR5.3-5.7 ppm Multiplet 2H Example 12h 1-[6-(1,3-dithia-2
-cyclopentyl)-ethyl]-1,4dioxaspiro[4,4]-non217-yl]-3-CI.1-dimethyl-1-Cp-(p-chlorophenoxy)-phenoxy]-methyl]- trans-1-7"Lopen-3-one 1-[6[(1,3-dithia-2-cyclopentyl)
-ethyl]-1,4-dioxaspiro[4,4]-nony-7-yl]-3-[:1,l-dimethyl-1[p-(
p-Chlorphenoxy)-phenoxycomethyl]-)lans-1-propen-3-ol is prepared.

UR3500cfrL' NMR5.3-5.7 ppm Multiplet 2H Example 12i 1-(6-((1,3-dithia 2
-cyclopentyl)-ethyl]-1,4-dioxaspiro[4,4]-non-7-yl]-3 phenoxymethyl-trans-1-propen-3-one to 1-[6-[
(1,3-dithia-27clopentyl)-ethyl]-1
・4-dioxaspiro[4.4]-non-7-yl]-
3-phenoxymethyl-1-trans-propene-3-
oars are prepared.

UN 3500crn ” NMR5.3-5.7 ppm Multiplet 2H Example 12j 1-[6-[(1,3-dithia-
2-cyclopentyl)-ethyl]-1,4-dioxaspiro[4,4]-non217-yl”J3-(4-fluorophenoxy)-methyl-trans-1-propene-3
-one to 1-C6-[(+.3-dithia-2-cyclopentyl)-ethyl]-1.4-dioxaspiro[4.
4]-no=-7-(l,)l-3-(4-fluorophenoxy)-methyl-trans-1-7'loben-3-ol is prepared.

UR3500crfL-1 NMR5.3-5.7 ppm Multiplet 2H Example 12, as in Example 12a, 1-C6-C (1,3-dithia-
2-cyclopentyl)-ethyl"J-1,4-dioxaspiro[4,4]-non-217-yl]3-(3-chlorophenoxy)-methyl]-trans-1-propene-3
-one to i-[6-[(X ・3-dithia-2-cyclopentyl)-ethyl]-1,4-dioxaspiro[4
-4]-non217-yl]-3-(3-chlorophenoxy)methyl)-trans-1-7'lopen-3-ol is prepared.

UR3500 (1771' NMR5, 3-5.7ppm multiplet 2H example
121 l[6-[
(1,3-dithia-2-cyclopentyl)-ethyl-4-dioxaspiro[4,4]-nony7-yl]
-3-(3-)lifluoromethylphenoxy)-methyl-trans-neepropen-3-one to 1-C6-[
(I.3dithia-2-cyclopentyl)-ethyl]-1
-4-dioxaspiro[4.4]-non-217-yl]-
3-(3-)lifluoromethylphenoxy)-methyl-
Trans-1-propen-3-ol is prepared.

UR3500cm' NMR5.3-5.7 ppm Multiplet 2H Example 12m r-C6-[(1,3-dithia-2-cyclopentyl)
1-C6-
(1,3-dithia-2-cyclopentyl)-ethyl]-
1,4-dioxasubilo[4,4]-non-7-yl]
3-isobutyl-trans-1-7''lopen-3ol is prepared.

UR3500cIrL' NMR5.3-5.7 ppm Multiplet 2H Example 12n 1-[6-((1,3-dithia-2-cyclopentyl)-ethyl]-1,4-dioxaspiro[ 4.4]-no21 file]-3-(1.1-
dimethylpentyl)-trans-1-propen-3-one to 1-C6[(1,3-dithia-2-cyclopentyl)-ethyl]-1,4-dioxaspiro[4,4]-
nony-7-yl]-3-(1,1-dimethylpentyl)
-trans-1-propen-3-olka is prepared.

UR3500CrfL-1 NMR5,3-5.7 ppm Multiplet 2H Example 13a 1-C7-C (1,3-dithia-2-cyclopentyl)
)-3,3-dimethyl-1,5-dioxaspiro[5
・4〕-Dizzy8-yl〕-trans-■-octene-
3-ol-tetrahydropyranyl ether 1-47-[(1,3-dithia-2-cyclopentyl)
-Ethyl]-3,3-dimethyl-1,5-dioxaspiro[5,4]-desy8-ylcotrans-1-octen-3-ol 1.11 (2,6 mmol) was dissolved in anhydrous ether. Dissolved in 20 rfLl, processed p-)luenesulfonic acid 20rI19, added dropwise 1.2 ml (13 mmol) of dihydropyran in 10 ml of anhydrous F#, and stirred at room temperature for 4 hours.

Add 0.2rrLl of dihydropyran 51 times.

This adjunct was left overnight, followed by solid Na2 for 30 min.
Stir with COso, 52.

The mud is filtered, the filtrate is concentrated in vacuo and the resulting oil is eluted from the silica gel column using cyclohexane-acetic ester (9:1).

Analytically pure samples are 3500 crfL' in UR
does not show any OH absorption band.

DC (thin layer chromatography) Rf value 0.64 Silica gel, cyclohexane/ether 4:6 NMR 4,5
~4.8 ppm Multiplet 2H The following tetrahydropyranyl ether is prepared from the alcohols 12b-12n described above in a similar manner.

Example 13b 1-C7-C (1,3-dithia-2-cyclopentyl)
-ethyl]-3,3-dimethyl-1,5-dioxaspiro[5,4]-desi-8-yl]-47-1-decen-3-ol-tetrahydropyranyl ether.

NMR4.5-4.8 ppm Multiplet 2H Example 13c 1-C7-[(1,3-dithia-2-cyclopentyl)
-ethyl]-3,3-dimethyl-1,5-dioxaspiro[5,4]-desi-8-yl]3-cyclohexy-trans-1-propen-3-ol-tetrahydropyranyl ether.

NMR4.5-4.8 ppm Multiplet 2H Example 13d 1-C7-C (1-3-dithia-2-cyclopentyl)
-ethyl]-3,3-dimethyl-1,5-dioxaspiro[5,4)-y'cs--yl)-3-(1,1-dimethyl-3-oxapentyl: trans-1-propene-3 -ol-tetrahydropyranyl ether.

NMR4.5-4.8 ppm Multiplet 2H Example 13e 1-47-((1,3-dithia-2-cyclopentyl)
-ethyl]-3,3-dimethyl-1,5-dioxaspiro[5,4)-desi-8-yl]-3-cycloheptyl-trans-1-propen-3-ol-tetrahydropyranyl ether.

NMR4.5-4.8 ppm Multiplet 2H Example 13f 1-c7-c (i.3-dithia-2-cyclopentyl)
-Ethyl]-3,3-dimethyl-1,5-dioxaspiro[5-4,)-desi-8-yl]-)7-1-hexen-3-ol-tetrahydropyranyl ether.

NMR4.5-4.8 ppm Multiplet 2H Example 13g 1-(6-[(1,3-dithia-2-cyclopentyl)
-4thyl]-1,4-dioxaspiro[4,4]-non-217-yl]-3-[l-methyl-1-Cp-(p-chlorophenoxy)-phenoxy]-methyl]-trans- 1-propene-3-ol to l-46-C (1,3-
dithia-2-cyclopentyl)-ethyl]-1,4-dioxaspiro[4,4]-non-217-yl]-3[1-
Methyl-ICp-(p-chlorophenoxy)phenoxy]-methyl]-trans-1-propen-3-ol-
Tetrahydropinyl ether.

NMR4.1~5.0 ppm wide multiplet 4H
Example 13h 1-[6-[(1,3-dithia-2-cyclopentyl)-ethyl]-1,4dioxaspiro[4,4]- from the alcohol of Example 12h analogously to Example 13a
Noni-7-(#]-3-[1,1-dimethyl-1-Cp
-(p-chlorophenoxy)-phenoxy]-methyl]
-trans-1-propen-3-ol-tetrahydropyranyl ether is prepared.

NMR4.5-4.8 ppm Multiplet 2H Example 13i From the alcohol according to Example 12i, 1-J:6-[(1,3-dithia-2-cyclopentyl)-ethyl]- 1.4 Dioxaspiro [4.4
]-non-7-yl]3-phenoxymethyl-trans-1-propene-3-ol-tetrahydropyranyl ether is prepared.

NMR4.5-4.8 ppm Multiplet 2H Example 13j 1-[6-C(1.3-dithia-2-cyclopentyl)-ethyl)-1- from the alcohol according to Example 12j analogously to Example 13a. 4 dioxaspi OC4・4]-
3-(4-fluorophenoxy)-methyl-trans-1-propene-3-ol-tetrahydropyranyl ether is prepared.

NMR4.5-4.8ppm multiplet 2H example
1-[6-C(1,3-dithia-2-cyclopentyl)-ethyl]-1,4dioxaspiro[4,4]- in the same manner as in Example 13a from the alcohol of Example 12k.
No217-yl]3-(3-J'lorphenoxy)-methyl]-)lanth-1-propen-3-ol-tetrahydropyranyl ether is prepared.

NMR4.5-4.8 ppm Multiplet 2H Example 131 1-46-[(1.3-dithia-2-cyclopentyl)-ethyl]-1.4 from the alcohol according to Example 121 in the same manner as in Example 13a. Dioxaspiro [4.4]-
[non-7-yl]3-ynbutyl-trans-1-propen-3ol-tetrahydropyranyl ether is prepared.

NMR4.5-4.8 ppm Multiplet 2H Example 13m Example 12 From the alcohol according to m, 1-[6-C(1,.3-dithia-2-cyclopentyl)-ethyl]- 1.4 Dioxaspiro [4.4
]-non-7-yl]3-inbutyl-trans-1-
Propen-3-ol-tetrahydropyranyl ether is prepared.

NMR4.5-4.8 ppm Multiplet 2H Example 13n Example 12 From alcohol by n l-(:6-[(1-3-dithia-2-cyclopentyl)-ethyl]- 1.4 Dioxaspiro [4.4
]-n-7-yl)3-(1,1-dimethylpentyl)-)lance 1-propen-3-ol-tetrahydropyranyl ether is prepared.

N11i11R4,5-4.8ppm multiplet 2H
Example 14a 3-[3,3-dimethyl-8-[3-pentyl-3-tetrahydropyranyloxy-trans-1-propenyl]-1,5-dioxaspiro[5,4]-desi-7-yl]- Propionaldehyde 1-C7-C (1,3-dithia-2-cyclopentyl)
)-3,3-dimethyl-1,5-dioxaspiro[5.
4]-Dezy8-ylcotrans-1-octene-3
-ol-tetrahydropyranyl ether 1.05?
(2.05 mmol) of methyl iodide in 10 d of DMF
o, 7vtl (10,3 mmol), CaCO3-1
, 49 (14 mmol) and N20 0.4711 for 2 hours at 50°C.

The solution is cooled, 50rrLl of acetone is added, the precipitate is filtered with suction, and the filtrate is evaporated to dryness at 0.1 mrttHg.

The residue was taken up in ether, washed with N20, and the Mg
5O, and the solvent is removed in vacuo.

The oily residue has a strong carbonyl absorption band at 1730 Crrl' in the UR spectrum without further purification;
It exhibits a DCRf value of 0.51 (on silica gel, cyclohexane/ether 4:6).

In a similar manner, the following propionaldehyde having the general formula XX is obtained from the thioacetal 13b=13n.

Example 14b 3-[3,3-dimethyl-8-[3-hebutyl-3-tetrahydropyranyloxy-trans-1-propenyl]
-1,5-dioxaspiro[5,4]--]y'C7-yl]-Fropionaldehyde R1730cIrL-1 Example 14c 3-[3,3-dimethyl-8-[3-cyclohexyl-
3-tetrahydropyranyloxy-trans-1-propenyl]-1,5-dioxaspiro[5,4]-]tcy7-yl]-propionaldehyde RL730crrL' Example 14d 3-[3,3-dimethyl-8 -C3-(1,1-dimethyl-3-oxapentyl-3-tetrahydrohyranyloxy-trans-1-propenyl] = 1,5-dioxaspiro[5,4]-desi7-yl]-propionaldehyde UR1730cm - 1 Example 14e 3-[3.3dimethyl-8-
(3-Cycloheptyl-3-tetrahydropyranyloxy-trans-1-7'penyl)-1,5-dioxaspiro[5,4]desi7-yl]-propionaldehyde is prepared.

URL730cIrL' Example 14f 3-(3,3-dimethyl-8
-(3-tetrahydropyranyloxy)-trans-1
-hexenyl)-1,5dioxaspiro[5,4]-desi-7-yl]propionaldehyde is prepared.

URL730CrrL' Example 14g 3-(7-(3-tetrahydropyranyloxy-3-(1-methyl-1-(p-(p
-chlorophenoxy)phenoxif-methyl, l-trans-1-propenyl]-1,4-dioxaspiro[4
-4]-non-6-yl]-propionaldehyde is prepared.

URL730CIIL-1 Example 14h 3-[7-(3tetrahydropyranyloxy-3-(1,1-dimethyl-1-(p-(p
-chlorophenoxy)phenoxy]-methyl]-trans-1-propenyl]-1,4-dioxaspiro[4.
4]-No216-(/l/)-propionaldehyde is prepared.

URL730crrL' Example 14i 3-(7-(3-tetrahydropyranyloxy-3-phenoxymethyl-trans-
1-propenyl]-1,4-dioxaspiro[4.4]
-Dani-6-yl]propionaldehyde is prepared.

Example 14j 3-[7(3-tetrahydropyranyloxy-3-(4-fluorophenoxy)-methyl-trans-1propenyl]-1. 4-dioxaspiro[4.4]-non-6-yl]-propionaldehyde is prepared.

URL730CrrL ” Example 14 was prepared from 3-(7-(3-tetrahydropyranyloxy-3-(3chlorophenoxy)-methyl-trans-1-flobenyl) from the tetrahydrobicinyl ether according to Example 13k in the same manner as in Example 14a. -1,4-dioxaspiro[4,4]nony-6-yltopropionaldehyde is prepared.

URL730CrIL' Example 141 3-(7-(3-tetrahydropyranyloxy-3-(3trifluoromethylphenoxy)-methyl-trans-1) from the tetrahydropyranyl ether according to Example 131 analogously to Example 14a -propenyl]-1・4
-Dioxaspiro[4,4]-non-6-yl]-propionaldehyde is prepared.

URL730(X'' Example 14m 3-[7(3-tetrahydropyranyloxy-3-inphthyl-trans-1-7'
Lopenyl]-1,4-dioxaspiro[4,4]-non-6-yl]-propionaldehyde is prepared.

UR1730CrrL' Example 14n 3-[7(3-tetrahydropyranyloxy-3-(1,1-dimethylpentyl)-) from the tetrahydropyranyl ether according to Example 13n analogously to Example 14a
) Lance-1-propenyl]-1,4-dioxaspiro[4,4]-non-7-yl]-propionaldehyde is prepared.

UR1730CrrL' Example 15a 7-[3,3-dimethyl-8-(3-pentyl-3-tetrahydroviranyloxy-trans-1-7'ropenyl)-1,5-dioxaspiro[5,4]-desi7- ]-cis-4-heptenoic acid 80% sodium hydride 0.3 f (10 mmol) was dissolved in anhydrous dimethyl sulfoxide 3a for 1 hour under a stream of argon.
4-carboxypropyltriphenylphosphonium bromide 2 in 12 ml of DMS followed by warming to 0-65°C.
．． Add 15f (5 mmol).

Stir the red colored solution for 40 minutes at room temperature followed by DM.
2-[3,3-dimethyl-8-(3
-pentyl-3-tetrahydropyranyloxy-trans-1-70benyl]-15-dioxaspiro[5,4
, l -Qi7-7-i/1/Fropionaldehyde 0.88 f is added dropwise.

Stir the solution for 16 hours at room temperature.

Diluted with 50 ml of ether at 0°C, 5% NaH8
04 solution to pH 1-2, the organic phase is separated and the aqueous phase is extracted three more times with 75 TLl each of diethyl ether.

The combined ether extracts are washed with water, dried over MgSO4 and concentrated in vacuo.

Analytically pure material is obtained by chromatography of the resulting oil on silica gel and elution with 8:2 cyclohexane/acetic acid ester.

NMR8.5ppm Wide Signa/L/IH
5, 3-5.7 ppm wide signal 4H4,
7ppm wide signal In2, 5pp
m doublet 4H Example 15b The following acids are synthesized in a similar manner from aldehydes with general formula XX as obtained by Examples 14b-14n.

7-[3,3-dimethyl-8-[3-heptyl 3-tetrahydropyranyloci-trans-1-propenyl]
-1,5-dioxaspiro[54]-di7-yl]
-cis-4-heptenoic acid.

NMR5.3-5.7 ppm wide signal 4
H Example 15c 7-[3,3-dimethyl-8-[3-cyclohexyl-
3-Tetrahydropyranyloxy-trans-1-propenyl]-1,5-dioxaspiro[5,4]-desi-7-yl]-cis-4-\Nov/1 NMR5.3-5.7 ppm Wide Signal April Example 15d 7-[3,3-dimethyl-8-(3-(1,1-dimethyl-3-oxa-pentyl)-3-5trahydropyranyloxy-trans-1-propenyl]- 1,5-dioxaspiro[5,4desi-7-yl]-cis-4-heptenoic acid Example 15e 7-[3,3-dimethyl-8-( 3-
cycloheptyl-3-tetrahydrohyranyloxy-trans-1-propenyl)-1,5-dioxaspiro [
5.4]-Des-7-yl]-cis-4-heptenoic acid is prepared.

NMR5.3-5.7 ppm wide signal 4
H Example 15f 7-[3,3-dimethyl-8-(3-
Tetrahydropyranyloxy-trans-1-hexenyl)-1,5-dioxaspiro[5,4]-desy7-
yl]-cis-4 heptenoic acid is prepared.

NMR5.3ppm wide signal 4H example
15 g 7-(7-(3-tetrahydrohyranyloxy-3-(1-methyl-(p-(p-chlorophenoxy)-phenoxif-methyl) from fropionaldehyde according to Example 14g analogously to Example 15a -trans-1-propenyl]-1,4-dioxaspiro[4,4,)-
/nee6-A#-cis-4-heptenoic acid is prepared.

NMR5.3-5.7 ppm wide signal 4
H Example 15h Analogously to Example 15a, 7-(7-(3-tetrahydropyranyloxy-3-[1,1-dimethyl-1-(p-(p-
Chlorphenoxy)-fe/xy)-methyl 3-) lance-1-propenylate 4-dioxaspiro [4.4]
-Dani-6yl]-cis-4-heptenoic acid is prepared.

NMR5.3-5.7 ppm wide signal 4
H Example 15i Analogously to Example 15a, from propionaldehyde according to Example 14i, 7-(7-(3-tetrahydropyranyloxy-3-phenoxymethyl-trans-1-propenyl)-l·4-dioxaspiro[4・４〕-Noji-
6-yl]-cis-4-heptenoic acid is prepared.

NMR5.3-5.7 ppm wide signal 4
H Example 15j 7-(7-(3-Tetrahydropyranyloxy-3-(4-fluorophenoxy)-methyl-) from propionaldehyde according to Example 14j analogously to Example 15a.
Trans-1-propenyl]-1,4-dioxaspiro[4,4]-non-6-yl]-cis-4-heptenoic acid is prepared.

NMR5.3-5.7 ppm wide signal 4
H Example 15 was prepared analogously to Example 15a from propionaldehyde according to Example 14k to 7-(7-(3-tetrahydropyranyloxy-3-(3-chlorophenoxy)-methyl-trans-1-7"ropenyl) ]-1,4-dioxaspiro[4,4]-non-6-yl]-cis-4-heptenoic acid is prepared.

NMR5.3-5.7 ppm wide signal 4
H Example 151 7-(7-(3-tetrahydropyranyloxy-3-(3-)IJfluoromethylphenoxy)-methyl-trans-1- from propionaldehyde according to Example 141 analogously to Example 15a propenyl]-1,4-dioxaspiro[4,4]-non-6-yl]-cis-4
- Heptenoic acid is prepared.

NMR5.3-5.7 ppm wide signal 4
H Example 15m 7-(7-(3-tetrahydropyranyloxy-3-inbutyl-trans-l-propenyl)-1,4-dioxaspiro[4. 4]-Non-2-6-yl]-cis-4-heptenoic acid is prepared.

NMR5.3-5.7 ppm wide signal 4
H Example 15n 7-(7-(3-tetrahydropyranyloxy-3-(1·l-dimethylpentyl-trans-1-propenyl)-1· 4-Dioxaspiro [4・4
]-non-7-yl]cis-4-heptenoic acid is prepared.

NMR5.3-5.7 ppm wide signal 4
H Example 16a 7-(2=(3-hydroxy-3-pentyl-trans-1-propenyl)-5-oxo-cycloNext step lucosis-4-heftenoic acid Step 1 7-[3,3-dimethyl-8 -(3-pentyl-3-tetrahydropyranyloxy-trans-1-7"lopenyl)-1,5-dioxaspiro[5,4]-desy7-
yl]-cis-4-heptenoic acid 0.41S' (1217
mol) Dissolved in 25% total ethyl alcohol and stirred with 51 ml of a 2% aqueous oxalic acid solution for 20 hours at room temperature under a nitrogen stream.

Part of the solvent was distilled off in vacuo, and the residue was dissolved in saturated sodium chloride solution 2.
Add 0 ml of the mixture and extract twice with 100 ml of diethyl ether.

The combined ether extracts were purified using H2O201711.
Wash twice, dry and concentrate.

337 ml of clear oil is obtained.

Step 2 337 ml of the clear oil from Step 1 was stirred with 20 .mu. of p-toluenesulfonic acid monohydrate in 30 ml of acetone for 5 hours at 50 DEG C. under a stream of nitrogen and left overnight at room temperature.

It is then concentrated, the residue is taken up in ether, washed with water and concentrated.

The residue is chromatographed on silica gel and analytically pure material is obtained by elution with a solvent mixture consisting of 80 parts of cyclohexane, 20 parts of acetic acid ester and 1 part of glacial acetic acid.

Two isomers are isolated and are distinguished by their Rf value on silica gel (according to Merck) in a solvent consisting of cyclohexane/acetate/glacial acetic acid (80/20/1) as follows.

Isomer B0.41 Isomer A0.36 The NMR spectra of both isomers are virtually identical due to HD exchange.

HD Before replacement 5, 2-6.0 ppm wide signal 6H4,
O5ppm Wide signal Immediately after replacement 5.2~5.4 ppm Wide signal/L'2H5
, 5-5.7 ppm Broad signal 2H4,O
5ppm Broad Signal 1H From compounds with general formula XXI in a similar manner, Examples 15b to 15n
As described in the general formula I (wherein R0 and R
The following carboxylic acids are prepared:

Example 16b 7-(2-(3-hydroxy-3-heptyltrans-
1-propenyl)-5-oxo-cyclopentylcus-4-heftenoic acid NMR 5.2-6.0 ppm Broad signal 6
H Example 16c 7-(2-(3-hydroxy-3-cyclohexyl-trans-1-propenyl)-5-,1-socyclopentyl]-cis-4-heptenoic acid NMR 5,2-6.5 pp
m Broad signal 6H Example 16d 7-(2-(3-hydroxy-3-(1,1-dimethyl-3-oxa-pentyl)-trans-1-propenyl-5-oxo-cyclopentyl)-cis-4- Heptenoic acid NMR5,2-6.Oppm medium wide signal 6
H Example 16e Preparation of 7-(2-(3-hydroxy-3-cycloheptyl-trans-1-propenyl)-5-oxocyclopentylcus-4-heptene from heptenoic acid according to Example 15e analogously to Example 16a) An acid is prepared.

NMR5.2-6.2 ppm Medium wide signal 6
H Example 16f 7-(2-(3-Hydroxy-trans-1-hexenyl)-5-oxocyclopentylcus-4- from heptenoic acid according to Example 15e analogously to Example 16a)
Heptenoic acid is prepared.

NMR5.2-6.5 ppm wide signal 6
H Example 16g 7-[2-(3-hydroxy-3-[1-methyl-(p-(p-chlorophenoxy)-phenoxy]-methyl) from heptenoic acid according to Example 15g analogously to Example 16a -) lance-1-propenyl-5-oxocyclopentyl]-cis 4-heptenoic acid is prepared.

NMR5,2-6. lppm wide signal 6H
Example 16h 7-(2-(3-hydroxy-3-[1,1-dimethyl-1-(p-(p-chlorophenoxy)-phenoxy)] from heptenoic acid according to Example 15h analogously to Example 16a -Methyl]-trans-1-7'ropenyl]-5
-Oxocyclopentylcus-4-heptenoic acid is prepared.

NMR5.2-6.0 ppm wide signal 6
H Example 16i 7-(2-(3-hydroxy-3phenoxymethyl-trans-1-propenyl)5-oxynecyclopentyl]-cis-4-heptene from heptenoic acid according to Example 15i analogously to Example 16a) An acid is prepared.

NMR5.2-6.1 ppm wide signal 6
H Example 16j Preparation of 7-(2-(3-hydroxy-3-(4-fluorophenoxy)-methyl-trans-1-propenyl-5-oxocyclopentyl) from heptenoic acid according to Example 15j analogously to Example 16a. ]-cis-4-heptenoic acid is prepared.

NMR5.2-6.5 ppm wide signal 6
H Example 16 Analogously to Example 16a, 7-[2-[3-hydroxy-3-(3-chlorophenoxy)-methyl-trans-1-7'ropenyl] was prepared from hegetenoic acid according to Example 15k.
-5-oxocyclopentylcus-4-heptenoic acid is prepared.

NMR5.2-6.0 ppm wide signal 6
H Example 161 Preparation of 7-(2-(3-hydroxy-3-(3-)lifluoromethylphenoxy)-methyl-trans-1-propenylcous from hegetenoic acid according to Example 151 analogously to Example 16a) 5-oxocyclopentyl]-cis-4-
Heftenoic acid is prepared.

NMR5.2-6.3 ppm Example 16m 7-(2-(3-hydroxy-3-isobutyl-trans-1-propenyl)-5-oxo Cyclopentylcus-4-heptenoic acid is prepared.

NMR5.2-6.1 ppm wide signal 6
H Example 16n Heptenoic acid according to Example 15n was prepared analogously to Example 16a.
1-dimethylpentyl)-) lance-1-bropenyl]
-5-oxo-cyclohentyltosis-4-heptenoic acid is prepared.

NMR5.2-6.5 ppm Wide Signa/L'
6H Example 17a 7-(2-(3-hydroxy-3-pentyl-trans-1-propenyl)-5-hydroxycyclopentylcus-4-heptenoic acid 7-(2-(3-hydroxy-
3-pentyl-trans-1-propenyl)-5-oxo-cyclopentylcus-4-heptenoic acid 150 ■
Dissolved in 20Tnl of methanol for 1.5 hours or 3 hours.
Add 150 ml of NaBH.

The reaction solution is adjusted to pH 7 using glacial acetic acid, the solvent is distilled off in vacuo and the residue is acidified to pH 1 with 1 2N HCl and extracted three times with 150 rnl of ether.

After washing, the organic layer is concentrated.

UR3500CrrL” and 1720~1700rf
L1 Example 16b from a carboxylic acid having the general formula ■ (in which R1 and R2 jointly represent oxygen) in a similar manner.
~16d as described in formula I (wherein R
1 and R2 each represent hydrogen or a hydroxyl group).

Example 17b -1 and 1 of 7-(2-(3-hydroxy-3-hebutyl-trans-1-propenyl)-5-hydroxy-cyclopentyltosis-4-heftenoic acid UR3500
720-1700α-1 Example 17c 7-[2-(3-hydroxy-3-cyclohexyl-trans-1-7”lopenyl)-5-hydroxy-cyclopentylcus-4-heptenoic acid UR3500CIrL' and 1720-1700Ir
L1 Example 17d 7-[2-(3-hydroxy-3-(1.1 dimethyl-
3-oxa-pentyl)-) lance-1-propenyl]-
5-Hydroxy-cyclopentyl]-cis-4-heptenoic acid UR3500cn' and 1720-1700rrL
-1 Example 17e 7-(2-(3-hydroxy-3-cycloheptyl-trans-1-propenyl)-5-hydroxy-cyclopentyltosis-4-heftenoic acid UR3500crrL' and 1720-1700(1
77L' Example 17f 7-(2-(3-hydroxy-trans-1-hexenyl)-5-hydroxy-cyclopentylcus-4-
heptenoic acid UR3500cIrL” and 1720-1700rr
L-1 Example 17g 7-(2-(3-hydroxy-3-[1-methyl-(p
(p-chlorophenoxy)-phenoxycoumethyl)-
) lance-1-propenyl]5-hydroxy-cyclopentyl]-cis4-heptenoic acid UR3500cfrL" and 1720-1700rf
L-1 Example 17h 7-(2-(3-hydroxy-3-[1.1 dimethyl-
1-(4-(4-chlorophenoxy)phenoxy]-methyl]-trans-1-probeni/L/3-5-hydroxy-cyclopentyl]cis-4-heptenoic acid UR3500CWL' and 1720-1700IrL
-1 Example 17i 7-(2-(3-hydroxy-3-phenoxymethyl-
trans-1-propenyl)-5-hydroxy-cyclopentylcus-4-heptenoic acid UR3500CrfL” and 1720-1700α-
1 Example 17j 7-(2-(3-hydroxy-3-(4-fluorophenoxy)-methyl-trans-1-propenyl]-5-
Hydroxy-cyclopentyl]-cis-4-heptenoic acid UR3500CrfL' and 1720-1700rI
L-1 Example 17 contains 7-(2-(3-hydroxy-3-(3-chlorophenoxy)-methyl-trans-1-propenyl]-5-hydroxyene clohenthyl]-cis-4-heptenoic acid UR3500C1rL-1 and 1720-1700r
n-1 Example 171 7-(2-(3-hydroxy-3-(3-)lifluoromethylphenoxynomethyl-trans-1-propenyl-5-hydroxyenequinethyl)-cis-4 −
Heptenoic acid UR3500CrfL' and 1720-17001r
L-1 Example 17m 7-(2-(3-hydroxy-3-isobutyl-4lans-1-propenyl)-5-hydroxycyclopentylcus-4-heptenoic acid UR3500CrrL' and 1720-1700frL-1 Example 17n 7-(2-(3-hydroxy-3-hydroxy-3-(
1,1-dimethylpentyl)-) lance-1-70benyl]-5-hydroxycyclopentylcus-4-heptenoic acid UR3500crrt-1 1720-17o.

α-1 Example 18 7-(2-(3-hydroxy-3-pentyltrans-
Isomer A and isomer B of 1-propenyl)-5-oxo-cyclopentyl]-cis-4-heftenoic acid (Example 16a) were mixed at a weight ratio of 1:■, dissolved in ethyl alcohol, and diluted with distilled water. Spray in an ultrasonic atomizer with a total volume of 0.02 ml.

Konze was used to test for bronchospasmodic effects.
tt) and Mr. Ressler's (R65sler) method C
Arch, exp, Path, & Pharma
col, 195.71 (1940)].

As a laboratory animal, a male white guinea pig weighs 400~
5001 is used, and Evipan (Evipan) is used.
) Intraperitoneal administration of 9 in 10”9/ and urethane (U
Anesthesia is induced by intraperitoneal administration of 200 μ/kg.

Histamine hydrochloride is an asthmatic factor 1-5 Used at a dosage of μt / kg.

The experimental data is subjected to probit transformation for regression analysis, and the regression line Y=A+B·1y(X) is calculated.

The median inhibitory dose (ED50), as the dosage which inhibits the asthmagenic effect by 50% of the starting value, can also be calculated.

The following table shows the results using 7-(2-(3-hydroxy-3-pentyl-trans-1-propenyl)-5-oxocyclopentyltosis-4-heptenoic acid.

Median amount Blocking amount intraperitoneal aerosol (μr/kg) (μm/animal) Isomer A Isomer B 0.08 0.1 0.01 0.1 mixture A+B (1:1) 0.1 0.002

Claims (1)

[Claims] 1 Formula W (wherein Y2 means -CH2- or -C(CH3)2 group or a single bond, and R3 is an alkyl group having 3 to 8 carbon atoms, 5 to 7 Cycloalkyl group having i carbon atoms or 2〇(R')2-(CH2)
n-0-R", R' is hydrogen or an alkyl group having 1 to 3 carbon atoms, and n is 0 or l
and R〃 is an alkyl group having 1 to 5 carbon atoms or a phenyl group optionally substituted by fluorine, chlorine or trifluoromethyl, or R〃 is a terminal phenyl group substituted by chlorine. The tetrahydropyranyl ether protecting group in the compound having formula The ketal group in the compound of formula A process for the preparation of novel fustanic acid analogues, characterized in that the compound has the same meaning as in formula XXI) and optionally converts the compound of formula I into a physiologically acceptable salt or ester. .