JPH0798795B2 - Sulfonamide-substituted unsaturated fatty acid - Google Patents

Description

Detailed Description of the Invention a. Field of the Invention The present invention relates to a compound or an intermediate thereof used in the field of pharmaceuticals for ameliorating the symptoms caused by thromboxane. Specifically, it relates to a compound represented by the general formula (I) and used as an antithrombotic agent, an antivasoconstrictor, an antitracheal constrictor, an intermediate thereof or a salt thereof.

General formula: [In the formula, R ₁ is hydrogen or lower alkyl; X is a C ₁ -C ₄ alkylene which may have a double bond, However, R ₂ is hydrogen, a lower alkyl or an amino protecting group); and m is an integer of 1 to 3] Prior Art Atherosclerosis, which is the main cause of myocardial infarction and cerebral infarction, has an arterial intima. It begins with the accumulation of mucoid substrate in the blood, proliferation of fibroblasts, etc., and then progresses with degeneration and lipid and cholesterol deposition, destruction of intimal tissue, formation of gruel, and gradually progresses to a high degree of localized intimal thickening. It is a common symptom to come. Atherosclerosis has long been attributed to thrombus formation and fibrin deposition in the arterial wall, but recently, Samuelsson et al. Reported that thromboxane A ₂ (TXA ₂ ) Vane
The discovery of prostacyclin (PGI ₂ ) by them et al. Revealed the interaction between platelets and the vascular wall. Platelets are considered to be importantly involved in the development and progression of atherosclerosis, and it is recognized that the administration of antithrombotic drugs, especially drugs having an inhibitory effect on platelet aggregation, is effective in treating atherosclerosis-related diseases. There is.

In addition to conventional antithrombotic agents such as hevalin and coumarin compounds, it is known that certain prostaglandins have a strong platelet aggregation inhibitory action. Focusing on this fact, prostaglandin derivatives have been attracting attention as antithrombotic agents. For example, focusing on the development of agonist analogs for receptors such as prostaglandin E ₁ and prostaglandin I _2, and the fact that thrombosaquine A ₂ has a strong platelet aggregation and vasoconstrictor activity, cyclooxygenase inhibitor Thromboxane A ₂ synthesis inhibitors such as xanthine synthetase inhibitors and thromboxane A ₂ receptor antagonists have also been developed. As a thromboxane A ₂ receptor antagonist, 13-APA [benton (V
enton DL) et al., Journal of Medicinal Chemistry (J.Med.Chem.) Vol. 22, 824 (1979).
)], PTA ₂ [Lefer AM, et al., Proceedings of the National Academy of
Science of you. S. A. (Proc.Natl.Ac
ad.Sci.USA) 76, 2566, (1979)], BM-13
177 [Refer, Drugs of Today (Drugs o
f Today), Volume 21, 283 (1985)], SQ-29548
[Ogletree et al., Journal of Pharmacology and Experimental Therapeutics (J.Pharmacol.Exp.Ther.), Volume 34, Volume 4
35 (1985)] and other compounds.

Problems to be Solved by the Invention Thromboxane A ₂ is a substance in which thrombin acts on platelets,
Cyclooxygenase is activated, and it is enzymatically produced in various cells from arachidonic acid through prostaglandins G ₂ and H ₂ to platelets and blood vessel walls. It has various potent physiological or pathological effects. Particularly strong platelet aggregation and smooth muscle contraction of bronchi, coronary arteries, pulmonary arteries, etc. are thought to be factors that mediate the occurrence and progression of cardiovascular and respiratory diseases such as angina, myocardial infarction, cerebral infarction, and bronchial asthma. Has been. Moreover, its powerful action concentration is 10 ^-10.
It is said to be ~ 10 ^-11 M. Therefore, antithrombotic agents
Thromboxane A ₂ as an anti-vasoconstrictor / anti-bronchoconstrictor
Attention has been focused on the development of antagonists or inhibitors of A. In addition to thromboxane A ₂ , inhibitors have a great influence on prostaglandins that have various important roles, and they cannot control the adverse effects of the accumulated substrate, which is similar to thromboxane. In particular, the development of antagonists is desired.

B. Structure of the Invention Means for Solving Problems The present inventors have synthesized a sulfonamide-substituted unsaturated fatty acid represented by the general formula (I), and the novel compound has a strong potential as a thromboxane A ₂ receptor antagonist. The present invention has been completed by finding out that the compound has an action and is chemically and biochemically stable.

The definitions of various terms used in this specification are as follows.

“Lower alkyl” means C ₁ -C ₇ linear or branched alkyl, for example, methyl, ethyl, n-propyl, isopropyl, diisopropylmethyl, butyl, isobutyl, tert-butyl, pentyl, hexyl or heptyl. And so on.

The "C ₁ -C ₄ alkylene" include methylene, ethylene,
Examples thereof include trimethylene or tetramethylene.

Examples of the "amino protecting group" include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl and the like.

In the general formula (I), more preferable R ₁ is hydrogen or methyl. More preferable X is methylene, ethylene, trimethylene, tetramethylene, propenylene, Or Can be mentioned.

More preferable R ₂ may be hydrogen, methyl or tert-butoxycarbonyl.

Examples of the salt of the general formula (I) include alkali metal salts, for example,
Alkaline earth metal salts such as lithium salt, sodium salt or potassium salt, such as calcium salt, ammonium salt, organic bases such as triethylamine, N-
Methylmorpholine, dicyclohexylamine, pyridine or trimethylamine or amino acid salts, for example
Glycine, valine, alanine, etc. can be mentioned.

The compound of the present invention is represented by the general formula (I) and includes all stereoisomers thereof (diastereomers, epimers, enantiomers, etc.).

The compound of the present invention can be produced according to the outline shown below.

Step-1 (First Step) This step is a step of protecting the amine of the compound 12g and further oxidizing the double bond of the obtained compound 11g to an epoxide to obtain the compound 10g .

The reaction of attaching a protecting group to the amine of the compound 12g is carried out by converting a chloro or fluoro formate or dicarbonate having a desired lower alkyl or aralkyl into a base in the presence of an alcohol solvent such as methanol or ethanol.
It can be carried out by reacting at room temperature for several hours to several tens of hours in a solvent such as ether ether solvent such as ethyl ether, tetrahydrofuran, dioxane, chlorinated hydrocarbon dichloromethane, chloroform, aromatic solvent benzene and the like. . As desired lower alkyl or aralkyl, isobutyl, diisopropylmethyl, te
Examples thereof include rt-butyl and benzyl.
As the base, sodium hydroxide, potassium hydroxide or sodium hydrogen carbonate may be used.

The epoxidation reaction is a combination of hydrogen peroxide and a transition element metal catalyst as an oxidizing agent, performic acid, peracetic acid, perbenzoic acid, monoperphthalic acid, monopermaleic acid, pertrifluoroacetic acid, metachloroperbenzoic acid or Peracids such as paranitroperbenzoic acid or peresters may be used.
Examples of the solvent used include ether solvents such as ethyl ether and tetrahydrofuran, alcohol solvents such as methanol and ethanol, and chlorinated hydrocarbon solvents such as dichloromethane and chloroform. The reaction is accomplished in minutes to tens of hours at 0 ° C. to room temperature.

The epoxide produced in this step may be a mixture of epimers.

(Second Step) This step is a step of additionally cleaving the epoxide of compound 10g to obtain compound 9g .

The reaction can be carried out by reacting the epoxide with a Grignard reagent (alkylmagnesium halide) in anhydrous ether under ice-cooling or at room temperature for several hours according to a conventional method of Grignard reaction.

As the alkyl magnesium halide, allyl magnesium chloride, allyl magnesium bromide, or allyl magnesium iodide may be used.

(Third Step) This step is a step of oxidizing hydroxy of compound 9g to obtain compound 8g .

As the oxidant, chromic acid Jones reagent, Collins reagent, pyridinium chlorochromate, pyridinium dichromate are used, or dimethyl sulfoxide and sulfur trioxide, trifluoroacetic anhydride, methanesulfonic anhydride, thionyl chloride or oxalyl chloride. It is good to use and in combination. When dimethyl sulfoxide is used as an oxidizing agent, it is preferable to use a tertiary amine such as triethylamine or pyridine as a decomposing agent. As a solvent, depending on the nature of the reagent, chlorinated hydrocarbon chloroform, dichloromethane, ether diethyl ether, tetrahydrofuran or dimethylformamide,
Acetone or the like may be used. The reaction can be accomplished in minutes to tens of hours under cooling or at room temperature.

(Step 4) In this step, compound 8g is oxime-converted to give compound 6 ' .

The oximation may be carried out using hydroxyamine hydrochloride, methoxylamine hydrochloride or the like in the presence of a basic substance. As the basic substance, pyridine, potassium hydroxide, sodium carbonate, sodium acetate, or the like is used, and as the solvent, methanol, ethanol, or the like is used alone or mixed with water. The reaction can be carried out under ice cooling or at room temperature for several tens of minutes to several tens of hours.

(Fifth Step) This step is a step of additionally cleaving the epoxide of compound 10e to obtain compound 9e .

This step may be performed according to the second step.

(Sixth step) In this step, the hydroxy of compound 9e is oxidized to give compound 8e.
Is a step of obtaining.

This step may be performed according to the third step.

(Seventh Step) In this step, compound 8e is oxime-converted to give compound 6 ' .

This step may be performed according to the fourth step.

(Eighth Step) This step is a step of introducing allyl into Compound 7 .

As the allylating agent, allyl halide, such as allyl chloride, allyl bromide, and allyl iodide, is used in this step. A relatively strong base such as sodium amide, potassium tert-butoxide, sodium hydride or lithium diisopropylamide may be used as the catalyst. The solvent is preferably an ether type solvent such as tetrahydrofuran, ethyl ether, glyme, diglyme. The reaction is accomplished in a few minutes to a few hours between -78 ° C and 25 ° C.

In this process, a diallyl product may be produced.

(Step 9) In this step, the oxime of compound 6 is reduced to an amine.

This step can be achieved by first reducing oxime 6 to imine, and further reducing it to amine 5 . As a reducing agent for the reaction of reducing oxime 6 to an imine, disulfides such as diphenyl disulfide and cibenzyl disulfide and phosphine such as n-tributylphosphine, trimethoxyphosphine, triethoxyphosphine and triphenylphosphine may be used in combination. As the solvent, ether type diethyl ether, tetrahydrofuran or the like may be used. The reaction can be accomplished in a few hours under cooling. Examples of the reducing agent for the reaction of reducing the imine to the amine 5 include lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride and the like. As the solvent, alcohol-based methanol, ethanol or ether-based diethyl ether,
Tetrahydrofuran etc. can be mentioned.

Also, this step uses metallic sodium, zinc and hydrochloric acid as reducing agents,
It can also be achieved by direct reduction of oxime to amine using stannous chloride and hydrochloric acid or lithium aluminum hydride. As the solvent used in this reaction,
Examples include ether type ethyl ether, tetrahydrofuran, diglyme, alcohol type ethanol, methanol and isopropanol. This reaction is
It is achieved in a few hours at room temperature or under reflux.

The resulting compound 5 may be used in the next step without purification.

(Step 10) This step is a step of reacting compound 5 with a substituted sulfonic acid halide to obtain compound 4 .

The reaction to obtain the sulfonamide derivative is carried out by using, as the substituted sulfonic acid halide, a sulfonic acid derivative having a desired substituent such as benzenesulfonyl chloride or benzenesulfonyl bromide, and using pyridine, triethylamine or an aqueous sodium hydrogen carbonate solution or potassium hydrogen carbonate. Aqueous solution, etc. as a basic substance, in a solvent such as chlorinated hydrocarbon type chloroform, dichloromethane, ether type ethyl ether, tetrahydrofuran, aromatic type benzene or acetone under cooling or at room temperature for tens of minutes to several hours. Can be achieved.

(Step 11) This step is a step of oxidizing the double bond of Compound 4 into an epoxide.

This step may be performed according to the oxidation reaction of the first step.

(Twelfth Step) This step is a step of converting epoxide 3 into aldehyde 2 having one carbon atom less by oxidative cleavage of glycol produced by hydration. As an oxidizer that also functions as a hydration catalyst,
Periodic acid, orthoperiodic acid, or the like may be used. The solvent used is preferably one that is miscible with water,
For example, ether type ethyl ether, tetrahydrofuran, dioxane or alcohol type methanol,
Examples thereof include ethanol. The reaction is completed in several tens of minutes to several hours at room temperature. As another method for carrying out the 11th and 12th steps, compound 4 is oxidized to glycol using an oxidizing agent such as potassium permanganate or osmium tetroxide, and then the produced glycol is sodium periodate, potassium periodate or tetrahydrate. There is also a method of obtaining compound 2 by cleaving with lead acetate. The solvent used is preferably one that is immiscible with water, and is the same as those exemplified above. Alternatively, compound 2 can be obtained all at once by ozone cleavage of compound 4 .

(Step 13) This step is a step of oxidizing compound 22k to obtain compound 2.

This step may be performed according to the third step.

(Step 14) In this step, aldehyde 2 or its equivalent ring-closed compound and ylide are reacted according to the Wittig reaction to give compound I of the present invention.
Is a step of obtaining.

The ylide used can be obtained by subjecting a phosphonium salt obtained by reacting triphenylphosphine and a halogenated fatty acid to a base treatment. As the base used for the base treatment, sodium dimcyl, potassium dimcyl, potassium tert-butoxy, sodium hydride,
Examples thereof include n-butyllithium or lithium diisopropylamide. Examples of the halogenated fatty acid include 3-bromopropanoic acid, 3-chloropropanoic acid, 5-bromopentanoic acid, 5-chloropentanoic acid and the like. This reaction can be carried out in an ether solvent such as ethyl ether, tetrahydrofuran or n-hexane or dimethyl sulfoxide at −10 ° C. to room temperature for several hours. By this reaction, the free carboxylic acid Ib of the compounds of the present invention can be obtained.

In addition, the amino-protecting group of the pyrrolidine derivative Ig-b may be removed to hydrogen as needed, or may be changed to a desired substituent such as lower alkyl.

The removal of the amino protecting group may be performed by a decarboxylation reaction accompanied by hydrogenation under acidic conditions. As the acid, for example, hydrochloric acid, hydrogen bromide, trifluoroacetic acid, aluminum chloride or trimethylsilyl iodide may be used. Anisole or thioanisole may be used as the cation trapping agent.

The N-alkylation may be performed by a reductive alkylation reaction between a carbonyl compound and an amine. As the carbonyl compound, for example, aldehydes such as formaldehyde, acetaldehyde, propionaldehyde, isopropionaldehyde and tert-butyraldehyde are preferable.

The reduction reaction can be carried out by reduction using a metal hydride such as sodium borohydride or sodium cyanoborohydride, or catalytic reduction using a palladium carbon catalyst or Raney nickel catalyst, depending on the nature of the reducing agent used. Alternatively, it may be carried out under acidic conditions such as acetic acid. As the solvent, polar solvents such as alcoholic methanol, ethanol or acetonitrile, and water may be used alone or in combination.

Moreover, you may esterify the carboxy of the obtained compound Ib as needed. The esterification is carried out by reacting a carboxylic acid with an alcohol such as methanol, ethanol, n-propanol, isopropanol, butanol or pentanol together with a catalyst of dry hydrogen chloride or concentrated sulfuric acid, if necessary, the above-mentioned alcohol using carboxylic acid as a halide. Reaction with a base such as dimethylaniline, pyridine, sodium hydroxide, a method using a metal salt of alcohol, a method using diazomethane or a method using dimethylsulfate and diazabicyclononene or diazabicycloundecene is carried out by a conventional method. Good.

By this reaction, the carboxylic acid ester Ia of the compounds of the present invention can be obtained.

The carboxylic acid ester I-a can be hydrolyzed into a free carboxylic acid I-b of the compounds of the present invention by hydrolysis according to a conventional method of ester hydrolysis. For hydrolysis,
Acids such as hydrochloric acid, sulfuric acid or bases such as sodium hydroxide, potassium hydroxide or barium hydroxide are used as catalysts. As a solvent, methanol-water, ethanol-
Water, acetone-water, acetonitrile-water, or the like may be used. If necessary, the carboxylic acid Ib may be sodium methoxide, sodium hydroxide, potassium hydroxide,
The compound of the present invention represented by the general formula (I) by treatment with a base such as calcium hydroxide, ammonium hydroxide, dicyclohexylamine, methylmorpholine, pyridine, triethylamine, glycine, valine, alanine according to a conventional method. Can be converted to the carboxylic acid salt I-c .

Step-2 (Step 15) In this step, compound 18i is hydrolyzed by a base catalyst to give compound 1
This is the step of obtaining 8i ' .

The reaction may be performed according to a conventional method of hydrolysis of an ester with a base catalyst, using sodium hydroxide, potassium hydroxide, barium hydroxide or the like as a base catalyst,
As the solvent, it is preferable to use a mixture of alcohol solvent such as methanol and ethanol with water. This one is
The carboxylic acid salt as it is can be used in the next step.

(Step 16) In this step, carboxy of compound 18i ′ is converted to an acid azide,
In this step, the urethane 17i ' is obtained by rearrangement to isocyanate and then reaction with alcohol.

This step can be achieved by Curtius rearrangement. That is, acid chloride obtained by treating carboxy with thionyl chloride, phosphoryl chloride or phosphorus pentachloride, or carboxy with ethyl chloroformate in the presence of a base catalyst such as triethylamine or 4-dimethylaminopyridine,
An acid azide compound is obtained by reacting sodium azide with an active ester obtained by reacting isobutoxycarbonyl chloride or the like with a solvent such as acetone, dimethylformamide, dimethylsulfoxide, ethyl acetate or tetrahydrofuran under cooling for several minutes to several hours. . Isocyanate can be obtained by refluxing an acid azide compound in benzene, toluene or diphenyl ether for several tens of minutes to several hours. The alcohol reacted with the isocyanate is preferably isobutanol, tert-butanol, diisopropylmethanol, cyclopentanol, cyclohexanol, benzyl alcohol, diphenylmethanol, triphenylmethanol or the like which can easily obtain the primary amine from urethane. This reaction is carried out by triethylamine, 4-dimethylaminopyridine,
This can be achieved by refluxing for several hours in the presence of a base such as 4-pyrrolidinopyridine and the like in a solvent such as aromatic benzene, chlorinated hydrocarbon dichloromethane or chloroform or ethyl acetate, acetone.

(Step 17) This step is a step of converting the tert-butyl ester of compound 17i ′ into a lower alkyl ester having less steric hindrance.

First, in this step, tert-butyl may be removed under acidic conditions by a conventional method to give a free carboxylic acid, and then esterified again.

Examples of the acid catalyst used in the tert-butyl decomposition reaction include hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, and acetic acid. Chlorinated hydrocarbon-based dichloromethane, chloroform, or anisole may be used as the solvent.

The esterification reaction of carboxy may be performed according to the method described in Step 14.

(Step 18) This step is a step of reducing compound 15i to obtain compound 14 .

The reduction reaction is carried out by using a reducing agent such as sodium bis (2-methoxyethoxy) aluminum hydride, diisobutylaluminum hydride, lithium trimethoxyaluminum hydride or lithium tri-tert-butoxyaluminum hydride, and an ethyl ether solvent. The reaction is completed in a solvent such as ether, tetrahydrofuran, an aromatic solvent such as benzene or toluene at room temperature or under cooling for several tens of minutes to several hours. In this reaction, pyrrolidine, piperidine, morpholine, N-, as necessary for controlling the reducing power.
Cyclic amines such as methylpiperidine and N-ethylpiperidine may be added.

(Step 19) This step is a step of leading to urethane 20j in order to protect the amine of compound 21j .

The reaction involves reacting compound 21j with a chloride capable of forming a protecting group,
If necessary, the reaction is completed in the presence of a base in a solvent such as chlorinated hydrocarbon type dichloromethane or chloroform or an ether type solvent such as ethyl ether, tetrahydrofuran or dioxane for several dozen minutes to several hours. Examples of the protective group include tert-butoxycarbonyl of lower alkyloxycarbonyl, diisopropylmethyloxycarbonyl, isobutyloxycarbonyl and the like or benzyloxycarbonyl of aryloxycarbonyl, 4-methoxybenzyloxycarbonyl,
The commonly used ones such as 4-nitrobenzyloxycarbonyl can be mentioned.

(20th step) This step is a step of removing the hydroxy protecting group of compound 20j .

The reaction can be achieved by reacting compound 20j in the presence of an acid catalyst (eg, acetic acid or hydrochloric acid) with heating or at room temperature for several hours. As the solvent, chlorinated hydrocarbon-based dichloromethane, chloroform and the like, ether-based solvent such as ethyl ether and tetrahydrofuran, and alcohol-based solvent such as methanol and ethanol may be used alone or in combination.

(Step 21) This step is a step of oxidizing compound 19j to compound 14 .

This step may be performed according to the third step.

(Step 22) In this step, aldehyde 14 or its equivalent ring-closed compound and ylide are reacted according to the Wittig reaction, and then carboxy is esterified to obtain compound 13 .

This step is preferably performed according to the 14th step.

(Step 23) In this step, the amino protecting group of compound 13 is removed, and then the compound of the present invention is obtained as the sulfonamide derivative Iij .

The reaction for removing the amino protecting group is usually a method used when removing the amino protecting group, for example, hydrolysis using an acid such as hydrochloric acid or sulfuric acid or a base such as sodium hydroxide, potassium hydroxide or barium hydroxide, It may be carried out by decarboxylation with an acid such as trifluoroacetic acid or hydrogenolysis. This product can be used in the next step as an ammonium salt as it is, but if necessary, it can be converted into a free amine form by treating it with an appropriate basic substance such as sodium carbonate or sodium hydrogen carbonate. You can also

The reaction to obtain the sulfonamide derivative may be performed along the 10th step. Through this step, the carboxylic acid ester Ia of the invention compound can be obtained. By the same manner as the first 4 steps of treating the carboxylic acid ester can be obtained free carboxylic acid I-b, or carboxylate I-c of the present compound.

Step-3 (Step 24) This step is a step of, for example, esterifying in order to protect carboxy after adding azide to compound 26 .

The azidation reaction can be carried out by heating compound 26 with sodium azide or lithium azide in a solvent such as hexamethylphosphamide, dimethylformaldehyde, dimethylsulfoxide or diphenyl ether for several tens of minutes to several hours.

The esterification reaction is carried out by reacting the compound obtained above with an alcohol capable of forming a protective group, a chloride, or a diazo derivative, if necessary, with an acid such as hydrochloric acid, sulfuric acid or the like, or a base,
For example, triethylamine or the like may be added and reacted. This reaction is carried out for several tens of minutes using alcohol solvents such as methanol and ethanol, chlorinated hydrocarbons such as dichloromethane and chloroform, ether solvents such as ethyl ether and tetrahydrofuran, or ethyl acetate and dimethylformamide. It can be performed by heating for several hours.

As the carboxy-protecting group, those usually used as a protecting group, for example, substituted or unsubstituted lower alkyl (methyl, methoxymethyl, ethyl, tert-butyl etc.), lower alkenyl (allyl etc.) or substituted or unsubstituted aralkyl (Benzyl, 4-methoxybenzyl, 4-nitrobenzyl, diphenylmethyl, triphenylmethyl, etc.) can be mentioned.

(Step 25) This step is a step of reducing the azide of compound 25 .

Examples of the reducing agent include triphenylphosphine, lithium aluminum hydride, triethylamine-hydrogen sulfide, and triethylamine-mercaptan. Examples of the solvent include alcohol solvents such as methanol and ethanol, and ether solvents such as ethyl ether and tetrahydrofuran. The reaction can be accomplished at room temperature or with heating for several hours. In addition, this step can be performed by catalytic reduction using a catalyst such as platinum or palladium.

(26th step) This step is a compound 24, to give compound compound 231 is reacted with a substituted sulfonic acid halide. This reaction is the first
It is recommended to follow step 0. Further, the compound 231 may be oxidized to the compound 23m or 23n , if necessary. The oxidation reaction may be performed according to the third step.

Those capable of removing the carboxy protecting group under mild conditions prior to the oxidation reaction, for example, lower alkenyl (such as allyl) or aralkyl (benzyl, 4-methoxybenzyl, 4-nitrobenzyl, diphenylmethyl, triphenylmethyl, etc.) ) Is desirable.

(Step 27) In this step, the carboxy protecting group of compound 23 ( 231 , 23m , 23n ) is removed to give compound I of the invention. This reaction can be carried out under hydrolysis or at room temperature for several minutes to several tens of minutes using acid or base hydrolysis or aluminum chloride, trifluoroacetic acid, boron trifluoride ethyl ether complex compound or the like. As the solvent, chlorinated hydrocarbon-based dichloromethane, chloroform and the like, ether-based solvents such as ethyl ether, tetrahydrofuran, anisole and the like, or nitromethane may be used alone or as a mixture depending on the properties of the reagent used.

By this reaction, the free carboxylic acid of the compounds of the present invention
I-b can be obtained. In addition, if necessary, the free carboxylic acid Ib is treated according to the method described in the 14th step to give a carboxylic acid ester of the compound of the present invention.
It can be changed to I-a or carboxylate I-c .

In the reaction scheme, the definitions of R ₁ , R ₂ , X, Y and m are as defined above. R ₃ is substituted or unsubstituted alkyl,
For example, methyl, methoxymethyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, diisopropylmethyl, etc., lower alkenyl, such as allyl, cycloalkyl, such as cyclopentyl, cyclohexyl, etc. or substituted or unsubstituted aralkyl, such as benzyl, 4-methoxy. Represents benzyl, 4-nitrobenzyl, diphenylmethyl, triphenylmethyl and the like.

The salt of the compound represented by formula (I) has the same meaning as described above.

Reference examples, examples and physical constants are shown below to clarify the embodiments of the present invention in more detail, but the scope of the present invention is not limited to these.

In the following Reference Examples and Examples, each compound is represented by one enantiomer in each step.

The wavy line represents the α or β-configuration or a mixture of both.

Reference Example 1 1-allyl-2-hydroxyiminocyclopentane 6ab
Manufacturing of N-Butyllithium (1.5M hexane solution) was added dropwise to a tetrahydrofuran solution (500 ml) of 101 ml (72 mM) diisopropylamine at -10 ° C, and the mixture was stirred at 0 ° C for 30 minutes. This was cooled to −60 ° C., and a solution of starting material cyclopentane oxime 7ab 29.7 g (300 mM) in tetrahydrofuran (50 m
l) is added dropwise. After heating to 0 ° C for 1 hour, 31.2 ml (3
60 mM) solution of allyl bromide in tetrahydrofuran (90 ml)
Is dripped. After stirring at 10 ° C or lower for 1.5 hours, the mixture is poured into an aqueous solution of ammonium chloride, salted out and extracted with ethyl acetate. Then, it is washed with water and dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue is separated and purified by silica gel column chromatography using a mixed solution of n-hexane-ethyl acetate (4: 1) as an elution solvent to obtain 24.01 g of the title compound 6ab as an oily substance. Yield 57.5%. This thing is NMR
And E: Z = 1: 2.1, which can be separated by silica gel-column chromatography.

E form IR: νmax (CHCl ₃ ) 3575,3300,2930,1640,1430,1350,1330,
990,910cm ^-1 . NMR: δ ppm (CDCl ₃ ) 1.17 to 2.82 (m, 9H), 4.87 to 5.17 (m, 2
H), 5.80 (m, 1H). Z form IR: νmax (CHCl ₃ ) 3575,3270,2940,1635,1430,1350,990,9
10 cm ^-1 . NMR: δ ppm (CDCl ₃ ) 1.37 to 2.83 (m, 8H), 3.02 (m, 1H), 4.
88-5.18 (m, 2H), 5.78 (m, 1H). Reference Example 2 Production of 1-allyl-2-aminocyclopentane 5ab Diphenyl disulfide (6.60 g, 30.2 mM) was dissolved in 21 ml of tetrahydrofuran, and 11.3 ml (45.3 mM) of tri-n-butylphosphine was added dropwise under ice-cooling, and the temperature was raised to room temperature.
Stir for minutes. This was ice-cooled again, and 4.20 g (30.2 mM) of a solution of allyl oxime 6ab in tetrahydrofuran (21 ml)
Is dripped. After raising the temperature to 15 ℃ over 1 hour,
Cool to 70 ° C. 14ml acetic acid and 3.80g (60.4mM)
Add sodium cyanoborohydride from above and raise the temperature to 0 ° C. with stirring. Add 50 ml of 5N aqueous sodium hydroxide solution and extract with ether. After extracting with 1N-hydrochloric acid, return to alkaline with 5N-sodium hydroxide aqueous solution,
Extract with ether again. Then, the ether extract was dried over magnesium sulfate and the solvent was distilled off to give allylamine 5a.
b is obtained as an oily crude. This is converted to the next sulfonamide without isolation and purification.

Reference Example 3 Preparation of 1-allyl-2-benzenesulfonamide cyclopentane 4a and 4b The crude product of allylamine 5ab obtained above is dissolved in 17 ml of dichloromethane and 4.64 ml (36.2 mM) of benzenesulfonyl chloride and 5.89 ml (42.3 mM) of triethylamine are added under stirring and ice cooling. After stirring for 40 minutes under ice cooling, the mixture is poured into cold dilute hydrochloric acid water and the dichloromethane solution is separated. The extract is washed with water, an aqueous solution of sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue is separated and purified by silica gel column chromatography using an n-hexane-ethyl acetate (6: 1) mixed solution as an elution solvent to obtain 5.20 g of sulfonamide. Yield 64.9%. This was again separated and purified by silica gel-column chromatography to obtain 3.62 g of trans form 4a and 1.58 g of cis form.
4b is obtained as colorless crystals.

Trans-isomer 4a: mp 40-41 ° C. (ether - recrystallized from petroleum ether mixed solvent) Elemental analysis (C ₁₄ H ₁₉ O ₂ as NS) Calculated (%): C, 63.36; H, 7.22; N, 5.28; S, 12.08; Experimental value (%): C, 63.21; H, 7.21; N, 5.35; S, 12.15.IR: νmax (CHCl ₃ ) 3370,2925,1635,1445,1325,1155,1090,
990,910cm ^-1 . NMR: δ ppm (CDCl ₃ ) 0.93 to 2.37 (m, 9H), 3.18 (m, 1H), 4.
60 ~ 5.03 (m, 3H), 5.63 (m, 1H), 7.33 ~ 8.00 (m, 5H).

Cis isomer 4b: mp 93-96 ° C. (ether - recrystallized from petroleum ether mixed solvent) Elemental analysis (C ₁₄ H ₁₉ O ₂ as NS) Calculated (%): C, 63.36; H, 7.22; N, 5.28; S, 12.08; Experimental value (%): C, 63.19; H, 7.10; N, 5.11; S, 12.24.IR: νmax (CHCl ₃ ) 3370,2925,1640,1445,1340,1325,1155,
1090,990,910 cm ^-1 . NMR: δ ppm (CDCl ₃ ) 1.03 to 2.40 (m, 9H), 3.67 (m, 1H), 4.
62 (d, 1H, J = 9.0Hz), 4.78 to 5.08 (m, 2H), 5.67 (m, 1
H), 7.40 to 8.03 (m, 5H). Reference Example 4 (1α, 2β) -1- (2,3-epoxypropyl) -2-
Production of benzenesulfonamide cyclopentane 3a 16.16 g (60.90 mM) of allylsulfonamide 4a is dissolved in 160 ml of chloroform, 19.7 g (91.35 mM) of 80% metachloroperbenzoic acid is added under ice cooling, and the mixture is stirred at room temperature for 6 hours.
Then, the reaction solution was poured into a cold sodium sulfite aqueous solution,
Separate the organic layer. The organic layer is washed with an aqueous solution of sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and then the solvent is distilled off to obtain 17.14 g of crude epoxide 3a as colorless crystals. This is converted to the next aldehyde without purification.

NMR: δppm (CDCl ₃ ) 1.00 to 2.13 (m, 9H), 2.32 to 3.00 (m, 3
H), 3.20 (m, 1H), 5.14 (m, 1H), 7.35 to 8.10 (m, 5H). Reference Example 5 Production of (1α, 2β) -1-formylmethyl-2-benzenesulfonamide cyclopentane 2a The crude product of epoxide 3a obtained above was dissolved in 450 ml of dioxane-water (10: 3) and 27.8 g (121.8 mM) under ice cooling.
Periodic acid (dihydrate) is added and reacted at room temperature for 3 hours. After the reaction, the mixture is poured into saturated saline and extracted with ethyl acetate. After washing with water and drying over anhydrous sodium sulfate, the solvent is distilled off to obtain aldehyde 2a as an oily crude product.
This product is subjected to the next reaction without isolation and purification.

NMR: δ ppm (CDCl ₃ ) 1.07 to 2.80 (m, 9H), 3.15 (m, 1H), 5.
27 (d, 1H, J = 9.0Hz), 7.35 ~ 8.08 (m, 5H), 9.67 (s, 1
H). Example 1 (1) Preparation of (1α, 2β, 5Z) -7- (2-benzenesulfonamidocyclopentan-1-yl) -5-heptenoic acid methyl ester Ia-a 345 ml of 60% oily sodium hydride 13.15 g (328.9 mM)
In addition to dimethylsulfoxide, the mixture is reacted at 70 ° C for 1 hour. The resulting sodium methylsulfinylmethide solution was kept at 10 to 15 ° C and 81.0 g (182.7mmole) of brominated (4-
A 345 ml solution of carboxybutyl) -triphenylphosphonium in dimethyl sulfoxide is added, and the mixture is reacted at room temperature for 20 minutes. To this solution was added the crude product of aldehyde 2a (6
A solution of 0.90 mM of dimethyl sulfoxide in 345 ml is added, and the mixture is reacted at room temperature for 1 hour. The reaction solution is poured into cold dilute hydrochloric acid water, and salt extraction and ethyl acetate extraction are performed. Then, it is washed with brine, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain an oily crude product. This was dissolved in tetrahydrofuran, esterified with diazomethane, and then separated and purified by silica gel-column chromatography using a mixed solution of benzene-ethyl acetate (10: 1) as an eluent to give 10.51 g of ester Ia-a . Obtained as an oil. Total yield from allylsulfonamide 4a 47.2%.

IR: νmax (CDCl ₃ ) 3360,2925,1720,1440,1325,1155,1090c
m ^-1 . NMR: δppm (CDCl ₃ ) 1.00 to 2.40 (m, 13H), 2.28 (t, 2H, J =
7.0Hz), 3.17 (m, 1H), 3.67 (s, 3H), 4.93 (d, 1H, J = 9.
0Hz), 5.07 to 5.50 (m, 2H), 7.40 to 8.03 (m, 5H). (2) Production of (1α, 2β, 5Z) -7- (2-benzenesulfonamidocyclopentan-1-yl) -5-sodium heptenoate Ia-c 9.71 g (26.6 mM) of ester Ia-a is dissolved in 120 ml of methanol, 53.2 ml of 1N-potassium hydroxide aqueous solution is added under ice-cooling, the temperature is returned to room temperature, and the mixture is left to stand overnight to complete the reaction. The reaction solution is poured into cold dilute hydrochloric acid water, and salt extraction and ethyl acetate extraction are performed. It is dried over anhydrous sodium sulfate and the solvent is distilled off to obtain 9.35 g of carboxylic acid Ia-b as an oily substance. Yield quantitative.

IR: νmax (CHCl ₃ ) 3450,3370,3250,2930,2860,1705,1450,
1325,1155,1090cm ^-1 . NMR: δ ppm (CDCl ₃ ) 1.00 to 2.40 (m, 13H), 2.33 (t, 2H, J =
7.0Hz), 3.19 (m, 1H), 5.07 ~ 5.53 (m, 3H), 7.37 ~ 8.07
(M, 5H), 8.32 (brs, 1H). The carboxylic acid Ia-b is dissolved in methanol and made into a sodium salt using a 1N-sodium hydroxide aqueous solution. The solvent is distilled off, 200 ml of water is added and freeze-dried to give sodium salt Ia-c as a hygroscopic powder.

Elemental analysis (as C ₁₈ H ₂₄ O ₄ NSNa ・ 0.2H ₂ O) Calculated value (%): C, 57.34; H, 6.52; N, 3.71; S, 8.50; Na, 6.10. Experimental value (%): C , 57.14; H, 6.31; N, 3.64; S, 8.44; Na, 6.40.IR: νmax (KBr) 3420,3280,2940,2880,1565,1445,1415,
1325,1310,1155,1095,910,755,720,690cm ^-1 . NMR: δ ppm ext.TMS (D ₂ O) 1.30 to 2.70 (m, 13H), 2.57 (t,
2H, J = 7.0Hz), 3.53 (m, 1H), 5.40 ~ 6.00 (m, 2H), 7.80
~ 8.42 (m, 5H). Reference Example 6 Production of (3aβ-H, 6aβ-H) -2-hydroxy-1-phenylsulfonyl-1-azapa-hydropentalene 2b Allylsulfonamide 4b (469 mg, 1.76 mM) was dissolved in 13 ml of tetrahydrofuran-water (10: 3), and a tetrahydrofuran solution of osmium tetroxide was added in a catalytic amount at room temperature. 5
After stirring for 1 minute, 1.13 g (5.28 mM) of sodium periodate is added little by little and reacted for 1.5 hours. Extract with ether and wash with dilute aqueous sodium sulfite, water. After drying over magnesium sulfate and evaporation of the solvent, the title compound 2b
470 mg are obtained as an oil. This product is subjected to the next reaction without isolation and purification.

NMR: δ ppm (CDCl ₃ ) 1.07 to 2.70 (m, 9H), 3.53 to 4.30 (m, 2
H), 5.37 to 5.67 (m, 1H), 7.33 to 8.07 (m, 5H). Example 2 (1) Preparation of (1α, 2α, 5Z) -7- (2-benzenesulfonamidocyclopentan-1-yl) -5-heptenoic acid methyl ester Ib-a 380 mg (9.50 mM) of 60% oily sodium hydride is added to 10 ml of dimethylsulfoxide and reacted at 70 ° C. for 1 hour. Keep the generated sodium methylsulfinylmethide solution at 10 to 15 ° C, add 2.34 g (5.28 mM) of (4-carboxybutyl) -triphenylphosphonium bromide in 10 ml of dimethyl sulfoxide, and react at room temperature for 10 minutes. Let The crude product of aldehyde 2b (1.76 mM) was added to this solution.
8 ml of dimethyl sulfoxide solution of is added and reacted at room temperature for 1 hour. The reaction solution is poured into cold dilute hydrochloric acid water, and salt extraction and ethyl acetate extraction are performed. Then, it is washed with brine, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain an oily crude product. This was dissolved in tetrahydrofuran, esterified with diazomethane, and then separated and purified by silica gel-column chromatography using a mixed solution of benzene-ethyl acetate (10: 1) as an eluent to give 278 mg of ester Ib-a as an oily substance. Obtained as. Total yield 43.2% from allylsulfonamide 4b.

IR: νmax (CHCl ₃ ) 3370,2940,1725,1445,1345,1325,1160,
1090 cm ^-1 . NMR: δ ppm (CDCl ₃ ) 1.00 to 2.30 (m, 13H), 2.28 (t, 2H, J =
7.0Hz), 3.60 (m, 1H), 3.66 (s, 3H), 4.74 (d, 1H, J = 9.
0Hz), 5.10 to 5.50 (m, 2H), 7.38 to 8.03 (m, 5H). (2) Production of (1α, 2α, 5Z) -7- (2-benzenesulfonamidocyclopentan-1-yl) -5-sodium heptenoate Ib-c 245 mg (0.670 mM) of ester Ib-a is dissolved in 3.0 ml of methanol, 1.34 ml of 1N-potassium hydroxide aqueous solution is added under ice-cooling, the temperature is returned to room temperature, and the reaction is left overnight to complete the reaction. The reaction solution is poured into cold dilute hydrochloric acid water, and salt extraction and ethyl acetate extraction are performed. It is dried over anhydrous sodium sulfate and the solvent is distilled off to obtain 235 mg of carboxylic acid Ib-b as an oily substance. Yield quantitative.

IR: νmax (CHCl ₃ ) 3470,3375,3250,2950,2870,1710,1450,
1345,1325,1155,1090cm ^-1 . NMR: δ ppm (CDCl ₃ ) 1.00 to 2.27 (m, 13H), 2.35 (t, 2H, J =
7.0Hz), 3.67 (m, 1H), 5.12 (d, 1H, J = 9.0Hz), 5.10 ~
5.53 (m, 2H), 7.33 to 8.03 (m, 5H), 8.35 (brs, 1H). This carboxylic acid Ib-b is dissolved in methanol, and the sodium salt Ib-c is obtained using a 1N-sodium hydroxide aqueous solution. After distilling off the solvent, adding 4 ml of water and freeze-drying,
The sodium salt Ib-c is obtained.

Elemental analysis (as C ₁₈ H ₂₄ O ₄ NSNa ・ 0.3H ₂ O) Calculated value (%): C, 56.07; H, 6.55; N, 3.70; S, 8.46; Na, 6.07. Experimental value (%): C , 56.78; H, 6.52; N, 4.01; S, 8.79; Na, 6.29.IR: νmax (KBr) 3430,3280,2950,2880,1565,1445,1415,
1325,1310,1155,1095,930,755,720,690cm ^-1 . NMR: δ ppm ext.TMS (D ₂ O) 1.30 to 2.70 (m, 13H), 2.62 (t,
2H, J = 7.0Hz), 4.10 (m, 1H), 5.50 ~ 6.00 (m, 2H), 7.80
~ 8.43 (m, 5H). Reference Example 7 1-allyl-2-hydroxyiminocyclohexane 6cd
Manufacturing of N-Butyllithium (1.5M hexane solution) was added dropwise at −10 ° C. to a tetrahydrofuran solution (120 ml) of diisopropylamine 20.2 ml (132 mM), and the mixture was stirred at 0 ° C. for 30 minutes. This was cooled to -60 ° C and the starting material cyclohexane oxime 7cd 6.79g (60mM) in tetrahydrofuran (70ml)
Is dripped. After heating to 0 ° C for 1.5 hours, 5.45 ml (63 m
A solution of allyl bromide in M) in tetrahydrofuran (20 ml) is added dropwise. After stirring at 0 ° C. for 1 hour, the mixture is poured into an aqueous solution of ammonium chloride, salt-broken and extracted with ethyl acetate. Then, it is washed with water and dried over anhydrous sodium sulfate, and the solvent is distilled off.
The residue is separated and purified by silica gel column chromatography using a mixed solution of toluene-ethyl acetate (6: 1) as an eluent to give 4.17 g of allyl oxime 6cd as an oily substance. Yield 45.3%. This has an E: Z = 1 by NMR.
It is a 6: 1 mixture and can be separated by silica gel-column chromatography.

E form IR: νmax (CHCl ₃ ) 3570,3250,2925,2850,1640,1440,990,9
10 cm ^-1 . NMR: δ ppm (CDCl ₃ ) 1.20 to 2.67 (m, 10H), 2..83 (m, 1H),
4.83-5.17 (m, 2H), 5.78 (m, 1H), 9.30 (brs, 1H). Z-body IR: νmax (CHCl ₃ ) 3570,3250,2920,2850,1640,1445,1370,
1310,990,950,910,885,860,830 cm ^-1 . NMR: δ ppm (CDCl ₃ ) 1.20 to 2.47 (m, 10H), 3.53 (m, 1H),
4.88-5.18 (m, 2H), 5.78 (m, 1H), 9.28 (brs, 1H). Reference Example 8 Production of 1-allyl-2-aminocyclohexane 5 cd 3.98 g (18.2 mM) of diphenyldisulfide was dissolved in 14 ml of tetrahydrofuran, and 6.80 ml (27.3 mM) of tri-n-butylphosphine was added dropwise under ice-cooling, and then the temperature was raised to room temperature.
Stir for 30 minutes. This is ice-cooled again, 2.79 g (18.2 mM)
Allyl oxime of 6cd in tetrahydrofuran (14m
l) is added dropwise. Allow the temperature to rise to room temperature over 40 minutes and then cool to -70 ° C. Add 9 ml of acetic acid and 2.29 g (36.4
mM) sodium cyanoborohydride and raise the temperature to 0 ° C. with stirring. Add 30 ml of 5N sodium hydroxide solution and extract with ether. After extraction with 1N-hydrochloric acid water, the mixture is made alkaline with 5N-sodium hydroxide aqueous solution and extracted again with ether. Then, the ether extract is dried over magnesium sulfate and the solvent is distilled off to obtain allylamine 5cd as an oily crude product. This is converted to the next sulfonamide without isolation and purification.

Reference Example 9 Production of 1-allyl-2-benzenesulfonamide cyclohexane 4c and 4d The crude product obtained above allylamine 5cd dissolved in dichloromethane 10 ml, stirring ice-cooling, triethylamine are added 2.79 ml (21.8 mm) of benzenesulfonyl chloride and 3.55 ml (25.5 mm). After stirring for 1 hour under ice cooling, the mixture is poured into cold dilute hydrochloric acid water and the dichloromethane solution is separated. The extract is washed with water, an aqueous solution of sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue is toluene-
Silica gel using ethyl acetate (20: 1) as a solvent
By separating and purifying by column chromatography, 3.12 g of sulfonamide is obtained. Yield from 6 cd 6
1.3%. This was again separated and purified by silica gel-column chromatography to obtain 1.30 g of trans form 4c and 1.8 g.
2 g of cis-form 4a is obtained as colorless crystals.

Trans isomer 4c: mp 101 to 104 ° C. (ether - recrystallized from petroleum ether mixed solvent) Elemental analysis (C ₁₅ H ₂₁ O ₂ as NS) Calculated (%): C, 64.48; H, 7.58; N, 5.01; S, 11.48. Experimental value (%): C, 64.46; H, 7.60; N, 4.95; S, 11.30. IR: νmax (CHCl ₃ ) 3375, 2925, 2855, 1640, 1450, 1410, 1330,
1160,1090,995,955,915.NMR: δppm (CDCl ₃ ) 0.87 to 2.00 (m, 10H), 2.37 (m, 1H),
2.90 (m, 1H), 4.69 (d, 1H, J = 9.0Hz), 4.73 to 5.07 (m, 2
H), 5.63 (m, 1H), 7.33 to 8.07 (m, 5H). Cis 4d : melting point 114-116 ° C (recrystallized from dichloromethane-petroleum ether mixed solvent) elemental analysis (as C ₁₅ H ₂₁ O ₂ NS) calculated value (%): C, 64.48; H, 7.58; N, 5.01; S, 11.48. Experimental value (%): C, 64.48; H, 7.58; N, 4.93; S, 11.32.IR: νmax (CHCl ₃ ) 3375, 2925, 2855, 1640, 1450, 1410, 1330,
1155,1090,995,910cm ^-1 . NMR: δ ppm (CDCl ₃ ) 0.90 to 2.20 (m, 11H), 3.48 (m, 1H),
4.72 to 5.07 (m, 2H), 5.21 (d, 1H, J = 9.0Hz), 5.62 (m, 1
H), 7.35 to 8.08 (m, 5H). Reference Example 10 Production of (3aβ-H, 6aα-H) -2-hydroxy-1-phenylsulfonyl-1-azaba-hydroindene 2c Allylsulfonamide 4c (623 mg, 2.23 mM) was dissolved in 14 ml of tetrahydrofuran-water (10: 3), and a tetrahydrofuran solution of osmium tetroxide in a catalytic amount was added at room temperature. 5
After stirring for 1 minute, 1.43 g (6.69 mM) of sodium periodate is added little by little and reacted for 1.5 hours. Extract with ether and wash with dilute aqueous sodium sulfite, water. After drying over magnesium sulfate and evaporating the solvent, the title compound 2c was obtained.
620 mg are obtained as an oil. This product is subjected to the next reaction without isolation and purification.

NMR: δ ppm (CDCl ₃ ) 0.80 to 2.55 (m, 11H), 2.82 (m, 1H),
3.38 (brs, 1H), 5.18 ~ 5.47 (m, 1H), 7.40 ~ 8.00 (m, 5
H). Example 3 (1) Preparation of (1α, 2β, 5Z) -7- (2-benzenesulfonamidocyclohexan-1-yl) -5-heptenoic acid methyl ester Ic-a 482 mg (12.04 mM) of 60% oily sodium hydride is added to 12 ml of dimethyl sulfoxide, and the mixture is reacted at 70 ° C for 1 hour. Keep the generated sodium methylsulfinylmethide solution at 10 to 15 ° C, add 2.97 g (6.69 mM) of (4-carboxybutyl) -triphenylphosphonium bromide in 12 ml of dimethylsulfoxide, and react at room temperature for 10 minutes. Let A solution of the crude product of compound 2c (2.23 mM) in 12 ml of dimethyl sulfoxide is added to this solution, and the mixture is reacted at room temperature for 1.5 hours. The reaction solution is poured into cold dilute hydrochloric acid water, and salt extraction and ethyl acetate extraction are performed. Then, it is washed with brine, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain an oily crude product. This was dissolved in tetrahydrofuran, esterified with diazomethane, and then separated and purified by silica gel-column chromatography using a toluene-ethyl acetate (15: 1) mixed solution as an elution solvent to give an ester Ic. -a 379 mg are obtained as an oil. Total yield 44.8% from allylsulfonamide 4c .

IR: νmax (CHCl ₃ ) 3370,2925,2850,1725,1445,1325,1155,
1090,1065,945,910 cm ^-1 NMR: δppm (CDCl ₃ ) 0.73 to 2.17 (m, 15H), 2.29 (t, 2H, J =
7.0Hz), 2.92 (m, 1H), 3.70 (s, 3H), 4.92 (d, 1H, J = 9.
0Hz), 5.10 to 5.53 (m, 2H), 7.42 to 8.03 (m, 5H). (2) Production of (1α, 2β, 5Z) -7- (2-benzenesulfonamidocyclohexan-1-yl) -5-sodium heptenoate Ic-c 306 mg (0.806 mM) of ester Ic-a is dissolved in 3.6 ml of methanol, 1.61 ml of 1N-potassium hydroxide aqueous solution is added under ice cooling, the temperature is returned to room temperature, and the mixture is left to stand overnight to complete the reaction. The reaction solution is poured into cold dilute hydrochloric acid water, and salt extraction and ethyl acetate extraction are performed. After drying over anhydrous sodium sulfate and distilling off the solvent, 295 mg of carboxylic acid Ic-b is obtained as an oily substance. Yield quantitative.

IR: νmax (CHCl ₃ ) 3450,3370,3250,2925,2845,1705,1445,
1320,1155,1085,910cm ^-1 . NMR: δ ppm (CDCl ₃ ) 0.80 to 2.20 (m, 15H), 2.34 (t, 2H, J =
7.0Hz), 2.88 (m, 1H), 5.10 to 5.53 (m, 2H), 5.24 (d, 1
H, J = 9.0Hz), 7.40 to 8.03 (m, 5H), 9.50 (brs, 1H). This carboxylic acid 1c-b is dissolved in methanol and made into a sodium salt using a 1N-sodium hydroxide aqueous solution. The solvent was distilled off, water was added, and the mixture was lyophilized to give the sodium salt Ic-
c is obtained.

Elemental analysis (as C ₁₉ H ₂₆ O ₄ NSNa ・ 0.2H ₂ O) Calculated value (%): C, 58.35; H, 6.80; N, 3.66; S, 8.20; Na, 5.88. Experimental value (%): C , 58.66; H, 6.99; N, 3.58; S, 8.19; Na, 5.19.IR: νmax (KBr) 3420,3290,2930,2860,1565,1445,1405,
1320,1310,1160,1095,1070,950,915,755,720,690cm ^-1 . NMR: δ ppm ext.TMS (D ₂ O) 1.00 to 2.43 (m, 15H), 2.60 (t,
2H, J = 7.0Hz), 3.22 (m, 1H), 5.50 ~ 5.97 (m, 2H), 7.90
~ 8.42 (m, 5H). Reference Example 11 Production of (3aβ-H, 7aβ-H) -2-hydroxy-1-phenylsulfonyl-1-azaba-hydroindene 2d Allylsulfonamide 4d (500 mg, 1.79 mM) is dissolved in 13 ml of tetrahydrofuran-water (10: 3), and a catalytic solution of osmium tetroxide in tetrahydrofuran is added at room temperature.
After stirring for 5 minutes, 1.15 g (5.37 mM) of sodium periodate is added little by little and reacted for 1.5 hours. Extract with ether and wash with dilute aqueous sodium sulfite, water. After drying over magnesium sulfate and evaporating the solvent, the title compound was obtained.
504 mg of 2d are obtained as an oil. This product is subjected to the next reaction without isolation and purification.

NMR: δ ppm (CDCl ₃ ) 0.80 to 2.83 (m, 11H), 3.48 (m, 1H),
4.11 (brs, 1H), 5.37 to 5.65 (m, 1H), 7.37 to 8.07 (m, 5
H). Example 4 (1) Production of (1α, 2α, 5Z) -7- (2-benzenesulfonamidocyclohexan-1-yl) -5-heptenoic acid methyl ester Id-a 387 mg (9.67 mM) of 60% oily sodium hydride is added to 10 ml of dimethyl sulfoxide, and the mixture is reacted at 65 ° C for 1 hour. Keep the generated sodium methylsulfinylmethide solution at 10 to 15 ° C, add 2.83 g (5.37 mM) of (4-carboxybutyl) -triphenylphosphonium bromide in 10 ml of dimethylsulfoxide, and react at room temperature for 10 minutes. Let A solution of the crude product of compound 2d (1.79 mM) in 10 ml of dimethyl sulfoxide is added to this solution, and the mixture is reacted at room temperature for 1.5 hours. The reaction solution is poured into cold dilute hydrochloric acid water, and salt extraction and ethyl acetate extraction are performed. Then, it is washed with brine, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain an oily crude product. This was dissolved in tetrahydrofuran, esterified with diazomethane, and then separated and purified by silica gel-column chromatography using a toluene-ethyl acetate (15: 1) mixture as an elution solvent to give ester Id. -a 139 mg are obtained as an oil. Total yield 20.5% from allylsulfonamide 4d .

IR: νmax (CHCl ₃ ) 3375,2925,2850,1725,1445,1330,1155,
1090,1000,990, cm ^-1 . NMR: δ ppm (CDCl ₃ ) 1.00 to 2.15 (m, 15H), 2.29 (t, 2H, J =
7.0Hz), 3.47 (m, 1H), 3.67 (s, 3H), 5.03 to 5.50 (m, 2
H), 5.18 (d, 1H, J = 9.0Hz), 7.40 to 8.02 (m, 5H). (2) Production of (1α, 2α, 5Z) -7- (2-benzenesulfonamidocyclohexan-1-yl) -5-sodium heptenoate Id-c 236 mg (0.622 mM) of ester Id-a was dissolved in 2.8 ml of methanol, and 1.24 ml of 1N-potassium hydroxide aqueous solution was added under ice cooling, then returned to room temperature and left overnight to complete the reaction. The reaction solution is poured into cold dilute hydrochloric acid water, and salt extraction and ethyl acetate extraction are performed. After drying over anhydrous sodium sulfate and evaporating the solvent, 227 mg of carboxylic acid Id-b is obtained as an oily substance. Yield quantitative.

IR: νmax (CHCl ₃ ) 3470,3375,3250,2925,2850,1705,1445,
1410,1330,1155,1090,1000,990,910cm ^-1 . NMR: δ ppm (CDCl ₃ ) 1.00 to 2.17 (m, 15H), 2.33 (t, 2H, J =
7.0Hz), 3.47 (m, 1H), 5.03 to 5.50 (m, 2H), 5.50 (d, 1
H, J = 9.0Hz), 7.33 to 8.03 (m, 5H), 9.68 (brs, 1H). This carboxylic acid 1d-b is dissolved in methanol and made into a sodium salt using a 1N-sodium hydroxide aqueous solution. The solvent is distilled off, 4 ml of water is added and freeze-dried to give the sodium salt Id-c .

Elemental analysis (as C ₁₉ H ₂₆ O ₄ NSNa ・ 0.3H ₂ O) Calculated value (%): C, 58.09; H, 6.82; N, 3.57; S, 8.16; Na, 5.85. Experimental value (%): C , 58.16; H, 6.93; N, 3.66; S, 8.27; Na, 5.82.IR: νmax (KBr) 3420,3290,2930,2860,1560,1445,1415,
1330,1305,1290,1160,1090,1070,1005,995,920,805,75
5,720,690 cm ^-1 . NMR: δ ppm ext.TMS (D ₂ O-NaOD, pH 10) 1.50 to 2.53
(M, 15H), 2.61 (t, 2H, J = 7.0Hz), 3.63 (m, 1H), 5.42
~ 6.03 (m, 2H), 7.78 ~ 8.38 (m, 5H). Reference Example 12 Production of (3α, 4β) -3-allyl-4-hydroxytetrahydrofuran 9e Raw Epoxide [EGEHawkins, et al., Journal of the Chemical Society (J.Che
m.Soc.), 1959, p. 248] 10e l.62g (18.8mM)
Under ice cooling, 1.0 M-allyl magnesium bromide ether solution
Drop into 18.8 ml. After stirring for 1 hour, water is added and the mixture is extracted with ethyl acetate. After washing with water and drying over anhydrous sodium sulfate, the solvent is distilled off. The oily residue n- hexane - ethyl acetate (2: 1) silica gel mixture as an elution solvent - allyl alcohol 9e L.91G by separation and purification by column chromatography is obtained as an oil. Yield 7
9.1%.

IR: νmax (CHCl ₃ ) 3575,3400,2920,2850,1635,1575,1070,
985,910 cm ^-1 . NMR: δ ppm (CDCl ₃ ) 1.93 to 2.38 (m, 3H), 2.53 (s.1H), 3.
38-4.20 (m, 5H), 4.90-5.20 (m, 2H), 5.80 (m, 1H). Reference Example 13 Production of 3- allyltetrahydrofuran -4-one 8e Allyl alcohol 9e 1.85g (14.4mM) to 9.32g (43.2mM)
60 ml of pyridinium chlorochromate dichloromethane
Add to suspension and stir overnight at room temperature. 3.11g (14.4m
M) pyridinium chlorochromate is added, and after stirring for 3 hours, ether is added and the solution is decanted. The residue is washed with ether, the combined ether solution is dried over magnesium sulfate, and the solvent is evaporated to give allyl ketone 8e as an oily substance. This is converted to the next allyl oxime without isolation and purification.

NMR: δ ppm (CDCl ₃ ) 1.55 to 2.78 (m, 3H), 3.67 to 4.57 (m, 4
H), 4.97 to 5.27 (m, 2H), 5.28 (m, 1H). Reference Example 14 3-allyl-4-hydroxyiminotetrahydrofuran
6e manufacturing The crude product of the allyl ketone 8e obtained above is dissolved in 20 ml of ethanol and 2.00 g (28.8 mM) of hydroxylamine hydrochloride are added. Under ice-cooling, add 3.49 ml (43.2 mM) pyridine and then return to room temperature and let stand overnight. Dilute hydrochloric acid was added, the mixture was extracted with ethyl acetate, and washed successively with water, aqueous sodium hydrogen carbonate solution and water. The oily residue obtained by drying over anhydrous sodium sulfate and evaporating the solvent was separated and purified by silica gel column chromatography using an n-hexane-ethyl acetate (3: 1) mixture as an elution solvent to give an allyl oxime. 1.71 g of 6e are obtained as an oil. Yield from 9e 83.9%. This is a mixture of E: Z = 5.6: 1 by NMR and can be separated by silica gel-column chromatography.

E form IR: νmax (CHCl ₃ ) 3570,3300,2840,1640,1580,1430,1370,
1335,1170,1060,990,915cm ^-1 . NMR: δ ppm (CDCl ₃ ) 2.10 to 2.67 (m, 2H), 2.89 (m, 1H), 3.
57 ~ 4.22 (m, 2H), 4.48 (s, 2H), 4.92 ~ 5.23 (m, 2H),
5.80 (m, 1H), 9.00 (brs, 1H). Z-body IR: νmax (CHCl ₃ ) 3570,3300,2850,1640,1580,1430,1365,
1170,1070,990,910cm ^-1 . NMR: δ ppm (CDCl ₃ ) 2.07 to 2.85 (m, 2H), 3.23 (m, 1H), 3.
75 ~ 4.47 (m, 4H), 4.92 ~ 5.23 (m, 2H), 5.80 (m, 1H),
8.64 (s, 1H). Reference Example 15 Production of 3-allyl-4-aminotetrahydrofuran 5e Allyl oxime 6e 1.705 mg (12.08 mM) is dissolved in 30 ml of tetrahydrofuran, and 1.375 mg (36.24 mM) lithium aluminum hydride is added under ice cooling. After heating under reflux for 1 hour and cooling, water is added and the precipitate is filtered off to obtain a tetrahydrofuran solution of arylamine 5e . This is converted to the next sulfonamide without isolation and purification.

Reference Example 16 Production of 3-allyl-4-benzenesulfonamide tetrahydrofuran 4e 1.85 ml (14.50 mM) of benzenesulfonyl chloride and 2.36 ml (16.91 mM) of triethylamine are added to the tetrahydrofuran solution of the crude allylamine 5e obtained above under stirring and ice cooling. After stirring for 1 hour under ice cooling, the mixture is poured into cold dilute hydrochloric acid water, salt-broken, and extracted with ethyl acetate. The extract is washed with water, an aqueous solution of sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue is separated and purified by silica gel-column chromatography using a mixed solution of chloroform-ethyl acetate (4: 1) as an elution solvent to obtain 2.465 mg of sulfonamide 4e as an oily substance. 6
76.3% total yield from e . This is a mixture of trans: cis = 5.1: 1 by NMR.

IR: νmax (CHCl ₃ ) 3370,2860,1640,1580,1445,1330,1160,
1090,1060,990,915cm ^-1 . NMR: δ ppm (CDCl ₃ ) 1.80 to 2.50 (m, 3H), 3.27 to 4.10 (m. 5
H), 4.77 to 5.13 (m, 2H), 5.27 to 5.97 (m, 2H), 7.38 to 8.
02 (m, 5H). Reference Example 17 (3α, 4β) -3- (2,3-epoxypropyl) -4-
Production of benzenesulfonamide tetrahydrofuran 3e Allylsulfonamide 4e 1.037 mg (3.88 mM) (trans isomer content 90% or more) is dissolved in 10 ml of dichloromethane, and 1.255 mg (5.82 mM) of 80% metachloroperbenzoic acid is added under ice cooling, and at room temperature, Stir overnight. Aqueous sodium sulfite solution is added and the cyclochloromethane layer is separated. The extract is washed with an aqueous solution of sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and the solvent is distilled off. The oily residue is separated and purified by silica gel column chromatography using an n-hexane-ethyl acetate (1: 1) mixed solution as an elution solvent to obtain 955 mg of epoxide 3e as an oily substance. Yield 86.
9%.

IR: νmax (CHCl ₃ ) 2850,1580,1420,1330,1160,1090,1075,
900 cm ^-1 . NMR: δ ppm (CDCl ₃ ) 1.10 to 2.30 (m, 3H), 2.32 to 3.08 (m, 3
H), 3.22 ~ 4.20 (m, 5H), 5.82 (m, 1H), 7.37 ~ 8.00 (m,
5H). Reference Example 18 Production of (3α, 4β) -3-formylmethyl-4-benzenesulfonamide tetrahydrofuran 2e Epoxide 3e 955 mg (3.37 mM) was dissolved in 28 ml of dioxane-water (3: 1), 1.537 mg (6.74 mM) of periodic acid (dihydrate) was added under ice cooling, and then 1.5 at room temperature. React for hours. The reaction solution is poured into saturated saline and extracted with ethyl acetate. After washing with water and drying over anhydrous sodium sulfate, the solvent is distilled off to obtain aldehyde 2e as an oily crude product. This product is subjected to the next reaction without isolation and purification.

NMR: δ ppm (CDCl ₃ ) 1.83 (m, 1H), 2.54 (m, 2H), 3.18-4.
32 (m, 5H), 5.91 (d, 1H, J = 6.5Hz), 7.37 to 8.00 (m, 5H
H), 9.63 (s, 1H). Example 5 (1) Preparation of (3α, 4β, 5Z) -7- (4-benzenesulfonamidotetrahydrofuran-3-yl) -5-heptenoic acid methyl ester Ie-a 863 mg (21.57 mM) of 60% oily sodium hydride is added to 20 ml of dimethyl sulfoxide, and the mixture is reacted at 65 ° C. for 2 hours. Keep the generated sodium methylsulfinylmethide solution at 10 to 15 ° C, add 5.98 g (13.48 mM) of (4-carboxybutyl) -triphenylphosphonium bromide in 20 ml of dimethyl sulfoxide, and react at room temperature for 20 minutes. Let Aldehyde 2e crude product (3.37 mM) in this solution
15 ml of dimethyl sulfoxide solution of is added and reacted at room temperature for 1 hour. The reaction solution is poured into cold dilute hydrochloric acid water, and salt extraction and ethyl acetate extraction are performed. Then, it is washed with brine, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain an oily crude product. This was dissolved in tetrahydrofuran, esterified with diazomethane, and then separated and purified by silica gel column chromatography using a mixed solution of n-hexane-ethyl acetate (1: 1) as an elution solvent to give ester Ie-c 513 mg. Is obtained as an oily substance.
Total yield from epoxide 3e 41.4%.

IR: νmax (CHCl ₃ ) 3350,2900,1720,1580,1430,1330,1155,
1090,1060,905cm ^-1 . NMR: δ ppm (CDCl ₃ ) 1.42 to 2.27 (m, 7H), 2.27 (t, 2H, J =
7.0Hz), 3.24 ~ 4.07 (m, 5H), 3.66 (s, 3H), 4.97 ~ 5.50
(M, 2H), 5.89 (d, 1H, J = 6.5Hz), 7.37 ~ 8.02 (m, 5
H). (2) Production of (3α, 4β, 5Z) -7- (4-benzenesulfonamidotetrahydrofuran-3-yl) -5-sodium heptenoate Ie-c 473 mg (1.29 mM) of ester Ie-a is dissolved in 5.8 ml of methanol, 2.58 ml of 1N-potassium hydroxide aqueous solution is added under ice-cooling, and the mixture is returned to room temperature and left for 2 days to complete the reaction. The reaction solution is poured into cold dilute hydrochloric acid water, and salt extraction and ethyl acetate extraction are performed. It is dried over anhydrous sodium sulfate and the solvent is distilled off to obtain 456 mg of carboxylic acid Ie-b as an oily substance. Yield quantitative.

IR: νmax (CHCl ₃ ) 3470,3370,3250,2930,2860,1710,1585,
1450,1330,1160,1095,1070,1040,915cm ^-1 . NMR: δ ppm (CDCl ₃ ) 1.43 to 2.27 (m, 7H), 2.31 (t, 2H, J =
7.0Hz), 3.28 ~ 4.13 (m, 5H), 5.00 ~ 5.53 (m, 2H), 5.88
(D, 1H, J = 6.5Hz), 7.38 to ~ 8.27 (m, 5H), 9.40 (brs, 1
H). This carboxylic acid 1e-b is dissolved in methanol and made into a sodium salt using a 1N-sodium hydroxide aqueous solution. The solvent was distilled off, water was added, and the mixture was lyophilized to give the sodium salt Ie-
c is obtained as a hygroscopic powder.

Elemental analysis (as C ₁₇ H ₂₂ O ₅ NSNa ・ 0.4H ₂ O) Calculated value (%): C, 53.36; H, 6.01; N, 3.66; S, 8.38; Na, 6.01. Experimental value (%): C , 53.53; H, 5.99; N, 3.72; S, 8.50; Na, 5.58.IR: νmax (KBr) 3430,3270,2940,2860,1560,1445,1410,
1325,1310,1155,1095,920,755,720,690cm ^-1 . NMR: δ ppm ext.TMS (D ₂ O) 1.72 to 2.60 (m, 7H), 2.57 (t, 2
H, J = 7.0Hz), 3.75 ~ 4.55 (m, 5H), 5.33 ~ 5.93 (m, 2
H), 7.92 to 8.53 (m, 5H). Reference Example 19 1-tert-butyloxycarbonyl-3-pyrroline 11 g
Manufacturing of Raw material 3-pyrroline 12g 3.04ml (30mM) dioxane 69ml
Dissolved in 9.60 g of di-tert-butyl dicarbonate (3
3mM) and stir overnight. The reaction solution is poured into dilute hydrochloric acid water, and salt extraction and ethyl acetate extraction are performed. After washing with water, an aqueous solution of sodium hydrogen carbonate and water, and drying over anhydrous sodium sulfate, the solvent is distilled off to obtain 11 g of urethane as an oily crude product. This product is subjected to the next reaction without purification.

_{NMR: δppm (CDC1 3) 1.49} (s, 9H), 4.14 (s, 4H), 5.80
(S, 2H). Reference Example 20 Production of 10 g of 1-tert-butyloxycarbonyl-3,4-epoxypyrrolidine The crude product of 11 g of the urethane obtained above is dissolved in 80 ml of dichloromethane, 9.75 g (45 mM) of 80% metachloroperbenzoic acid is added under ice cooling, and the mixture is stirred at room temperature overnight. Aqueous sodium sulfite solution is added, and the dichloromethane layer is separated.
The extract is washed with an aqueous solution of sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and the solvent is distilled off. The oily residue is separated and purified by silica gel column chromatography using an n-hexane-ethyl acetate (1: 1) mixed solution as an elution solvent to obtain 10 g of 4.56 g of epoxide as an oily substance. Total yield from 12 g of 3-pyrroline 82.1%.

IR: νmax (CHC1 ₃ ) 2925,2860,1685,1580,1420,1390,136
5,1350,1330,1165,1120,960,855,845cm ^-1 . _{NMR: δppm (CDC1 3) 1.40} (s), 1.44 (s), 3.30 (d, J
= 12.9Hz), 3.66 (s), 3.74 (d, J = 12.9Hz), 3.81 (d,
J = 12.9Hz). Reference Example 21 Production of 9 g of (3α, 4β) -3-allyl-1-tert-butyloxycarbonyl-4-hydroxypyrrolidine Epoxide ( 10 g, 4.56 g, 24.6 mM) was added dropwise to 38.7 ml (27.1 mM) of 0.7M-allyl magnesium bromide ether solution under ice cooling. After stirring for 1 hour, water is added and the mixture is extracted with ethyl acetate. After washing with water and drying over anhydrous sodium sulfate, the solvent is distilled off. 9 g of allyl alcohol was obtained by separating and purifying the oily residue by silica gel-column chromatography using n-hexane-ethyl acetate (1,1) mixed solution as an elution solvent.
4.75 g are obtained as an oil. Yield 84.9%.

IR: νmax (CHC1 ₃ ) 3350,2900,1680,1580,1410,1365,1165,
1115,1060cm ^-1 . _{NMR: δppm (CDC1 3) 1.45} (s, 9H), 1.83~2.40 (m, 3H), 2.
95 ~ 3.77 (m, 5H), 4.06 (m, 1H), 4.92 ~ 5.22 (m, 2H),
5.80 (m, 1H). Reference Example 22 Production of 8 g of 3-allyl-1-tert-butyloxycarbonylpyrrolidin-4-one Allyl alcohol 9g 3.86g (17.0mM), 7.31g (34.0m
M) pyridinium chlorochromate dichloromethane 9
Add to 0 ml suspension and stir at room temperature for 8 hours. 1.83g
Add (8.5 mM) pyridinium chlorochromate,
After stirring overnight, ether is added and the solution decanted. The residue was washed with ether, the combined ether solution was dried over magnesium sulfate, and the solvent was distilled off to give 8 g of allyl ketone.
Is obtained as an oily substance. This is converted to the next methoxyimine without isolation and purification.

_{NMR: δppm (CDC1 3) 1.48} (s, 9H), 1.93~2.90 (m, 3H), 3.
10 to 4.22 (m, 4H), 4.93 to 5.37 (m, 2H), 5.76 (m, 1H). Reference Example 23 3-allyl-1-tert-butyloxycarbonyl-4-
Production of methoxyiminopyrrolidine 6g The crude product of 8 g of the allyl ketone obtained above is dissolved in 22 ml of ethanol and 2.12 g (25.5 mM) of methoxyamine hydrochloride are added. After adding 2.06 ml (25.5 mM) pyridine under ice-cooling, return to room temperature and let stand overnight. Dilute hydrochloric acid was added, the mixture was extracted with ethyl acetate, and washed successively with water, aqueous sodium hydrogen carbonate solution and water. The oily residue obtained by drying over anhydrous sodium sulfate and distilling off the solvent was washed with n-hexane-ethyl acetate (8:
1) By separating and purifying by silica gel-column chromatography using the mixed solution as an elution solvent, methoxyimine 6g 3.14g is obtained as an oily substance. Total yield 72.8% from 9 g of allyl alcohol.

IR: νmax (CHC1 ₃ ) 2925,1685,1580,1405,1365,1160,1115,
1040,890 cm ^-1 . _{NMR: δppm (CDC1 3) 1.45} (s, 9H), 1.85~2.70 (m, 2H), 2.
90 (m, 1H), 3.13 to 3.90 (m, 2H), 3.87 (s, 3H), 4.07
(S, 2H), 4.93 to 5.27 (m, 2H), 5.79 (m, 1H). Reference Example 24 Production of 5 g of 3-allyl-4-amino-1-tert-butyloxycarbonylpyrrolidine Methoxyimine 6g 1.763mg (6.93mM) was dissolved in 15ml isopropanol and stirred at 90-95 ° C under stirring 795mg (34.7mM).
Add the metallic sodium from M) in small pieces. When sodium disappears, cool to room temperature, add water, salt and extract with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent is distilled off to obtain 5 g of allylamine as an oily crude product. This is converted to the next sulfonamide without purification.

_{NMR: δppm (CDC1 3) 1.45} (s, 9H), 1.67~2.40 (m, 5H), 2.
82-3.80 (m, 5H), 4.87-5.22 (m, 2H), 5.80 (m, 1H). Reference Example 25 3-allyl-4-benzenesulfonamide-1-tert-
Production of butyloxycarbonylpyrrolidine 4g 5 g of the crude allylamine obtained above is dissolved in 10 ml of dichloromethane, and 1.15 ml (9.0 mM) of benzenesulfonyl chloride and 1.45 ml (10.4 mM) of triethylamine are added under stirring with ice cooling. After stirring for 30 minutes under ice cooling, the mixture is poured into cold dilute hydrochloric acid water, salt-broken, and extracted with ethyl acetate. After washing with water, an aqueous solution of sodium hydrogen carbonate and water, it is dried over anhydrous sodium sulfate and the solvent is distilled off. The residue is separated and purified by silica gel column chromatography using a mixed solution of n-hexane-ethyl acetate (2: 1) as an elution solvent to give 910 mg of sulfonamide 4g as colorless crystals. Total yield 35.8% from 6 g of methoxyimine.

IR: νmax (CHC1 ₃ ) 3350,2900,1680,1580,1475,1400,1365,
1325,1155,1090,910cm ^-1 . _{NMR: δppm (CDC1 3) 1.42} (s, 9H), 1.67~2.43 (m, 3H), 2.
72 ~ 3.67 (m, 5H), 4.72 ~ 5.13 (m, 2H), 5.62 (m, 1H),
5.82 (d, 1H, J = 7.5Hz), 7.33 to 8.02 (m, 5H). Reference Example 26 (3α, 4β) -3- (2,3-epoxypropyl) -4-
Production of 3 g of benzenesulfonamide-1-tert-butyloxycarbonylpyrrolidine Allylsulfonamide 4 g 1.094 mg (2.99 mM) was dissolved in 20 ml of dichloromethane, and 966 mg (4.49 mM) of 80 was dissolved under ice cooling.
% Metachloroperbenzoic acid is added, and the mixture is stirred at room temperature overnight.
Aqueous sodium sulfite solution is added, and the dichloromethane layer is separated. The extract is washed with an aqueous solution of sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate, and the solvent is distilled off. N-
Separation and purification by silica gel-column chromatography using a mixed solution of hexane-ethyl acetate (1: 1) as an elution solvent gives epoxide ( 3 g, 886 mg) as colorless crystals. Yield 77.4%.

IR: νmax (CHC1 ₃ ) 3350,2900,1680,1575,1465,1445,1400,
1365,1325,1150,1090,900cm ^-1 . _{NMR: δppm (CDC1 3) 1.05~2.28} (m, 3H), 2.28~3.78 (m, 8
H), 5.92 (m, 1H), 7.33 to 8.00 (m, 5H). Reference Example 27 (3α, 4β) -4-benzenesulfonamide-1-tert
-Butyloxycarbonyl-3-formylmethylpyrrolidine 2g Epoxide 3 g 1.091 mg (2.85 mM) in 24 ml of dioxane
Dissolve in water (3: 1), add 1.299 mg (5.70 mM) periodic acid (dihydrate) under ice cooling, and react at room temperature for 2.5 hours. The reaction solution is poured into saturated saline and extracted with ethyl acetate. After washing with water and drying over anhydrous sodium sulfate, the solvent is distilled off to obtain 2 g of an aldehyde as an oily crude product.
This product is subjected to the next reaction without isolation and purification.

_{NMR: δppm (CDC1 3) 1.38} (s, 9H), 2.20~3.87 (m, 8H), 6.
11 (d, 1H, J = 7.5Hz), 7.37 to 8.03 (m, 5H), 9.70 (s, 1
H). Example 6 (1) Preparation of (3α, 4β, 5Z) -7- (4-benzenesulfonamide-1-tert-butyloxycarbonylpyrrolidin-3-yl) -5-heptenoic acid methyl ester 11 913 mg (22.8 mM) of 60% oily sodium hydride is added to 17 ml of dimethyl sulfoxide, and the mixture is reacted at 65 ° C for 1.5 hours. The generated sodium methylsulfinylmethide solution was kept at 10 to 15 ° C, 5.05 g (11.4 mM) of (4-carboxybutyl) -triphenylphosphonium bromide in 17 ml of dimethylsulfoxide was added, and the mixture was kept at room temperature for 30 minutes. React. To this solution, the crude product of 2 g of the above aldehyde (2.85 m
M) in dimethylsulfoxide (13 ml) at room temperature.
Incubate for 4 hours. The reaction solution is poured into cold dilute hydrochloric acid water, and salt extraction and ethyl acetate extraction are performed. Then wash with saline,
After drying over anhydrous sodium sulfate and evaporating the solvent, an oily crude product is obtained. This was dissolved in 7 ml of tetrahydrofuran, esterified with diazomethane, and then n-
By separating and purifying by silica gel-column chromatography using a hexane-ethyl acetate (2: 1) mixed solution as an elution solvent, 780 mg of ester Ig-a is obtained as an oily substance. Total yield 58.7% from 3 g of epoxide.

IR: νmax (CHC1 ₃ ) 3350,2900,1720,1680,1580,1405,1365,
1325,1160,1090cm ^-1 . _{NMR: δppm (CDC1 3) 1.39} (s, 9H), 1.45~2.35 (m, 7H), 2.
29 (t, 2H, J = 7.0Hz), 2.73 to 3.73 (m, 5H) 3.68 (s, 3
H), 4.97 to 5.58 (m, 2H), 5.99 (d, 1H, J = 7.5Hz), 7.32
~ 8.03 (m, 5H). (2) Production of (3α, 4β, 5Z) -7- (4-benzenesulfonamido-1-tert-butyloxycarbonylpyrrolidin-3-yl) -5-heptenoic acid Ig-b 322 mg (0.690 mM) of ester Ig-a was dissolved in 3.1 ml of methanol, and 1.38 ml of 1N-potassium hydroxide aqueous solution was added under ice-cooling, and the mixture was returned to room temperature and left for 1 day to complete the reaction. After adding 3 ml of water and washing with ether, dilute hydrochloric acid water is added, and salt extraction and ethyl acetate extraction are performed. After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain 295 mg of carboxylic acid Ig-b .
Is obtained as an oily substance. Yield 94.6%.

IR: νmax (CHC1 ₃ ) 3460,3230,2925,1710,1680,1580,1475,
1450,1405,1370,1325,1155,1090,910cm ^-1 . _{NMR: δppm (CDC1 3) 1.41} (s, 9H), 1.48~2.30 (m, 7H), 2.
32 (t, 2H, J = 7.0Hz), 2.73 to 3.72 (m, 5H), 5.03 to 5.60
(M, 2H), 5.94 (d, 1H, J = 7.5Hz), 7.34 ~ 8.03 (m, 5H),
8.90 (brs, 1H). This carboxylic acid Ig-b is dissolved in methanol, and the sodium salt Ig-c is obtained using IN-sodium hydroxide aqueous solution. The solvent is distilled off, water is added, and lyophilization is performed to obtain sodium salt Ig-c as a powder.

Elemental analysis (as C ₂₂ H ₃₁ O ₆ N ₂ SNa ・ 0.5H ₂ O) Calculated value (%): C, 54.65; H, 6.67; N, 5.79; S, 6.63; Na, 4.7
5. Experimental value (%): C, 54.64; H, 6.69; N, 5.86; S, 6.73; Na, 5.7
2. IR: νmax (KBr) 3430,2980,2930,1695,1565,1480,1410,
1370,1325,1250,1160,1095,920,885,755,720,690cm ^-1 . NMR: δ ppm ext.TMS (D ₂ O) 1.70 to 2.60 (m, 7H), 1.88 (s, 9
H), 2.60 (t, 2H, J = 7.0Hz), 3.25 ~ 4.15 (m, 5H), 5.45
~ 6.10 (m, 2H), 8.00 ~ 8.52 (m, 5H). Example 7 Preparation of (3α, 4β, 5Z) -7- (4-benzenesulfonamidopyrrolidin-3-yl) -5-butenoic acid If-b Carboxylic acid Ig-b 403 mg (0.890 mM) 0.97 ml (8.9 mM)
And anisole of 3 and 3.43 ml (44.5 mM) of trifluoroacetic acid are stirred at room temperature for 4 hours. The reaction solution is concentrated, the residue is washed with petroleum ether, and the solvent is distilled off to give trifluoroacetic acid salt as an oily substance. This is dissolved in water, passed through ion exchange resin IRA-400 (acetate type), and water is distilled off to obtain 271 mg of amine If-b as an oily substance.

Yield 86.3%.

Elemental analysis _{(C 17 H 24 O 4 N} 2 S · 0.5H 2 O ) Calculated value (%):. C, 56.49 ; H, 6.97; N, 7.75; S, 8.87 Found (%): C, 56.40 ; H, 6.86; N, 7.72; S, 8.56. IR: νmax (KBr) 3420,2930,1550,1445,1400,1325,1155,
1090,915,755,715,685 cm ^-1 . NMR: δ ppm ext.TMS (D ₂ O) 1.73 to 2.87 (m, 9H), 3.25 to 4.2
0 (m, 5H), 5.37 to 6.00 (m, 2H), 7.95 to 8.50 (m, 5H). Example 8 (3α, 4β, 5Z) -7- (4-benzenesulfonamido-1-methylpyrrolidin-3-yl) -5-heptenoic acid
Manufacture of Ih-b Amine If-b 93 mg (0.264 mM) was dissolved in 1.0 ml of acetonitrile, 0.20 ml (2.64 mM) of 37% aqueous formaldehyde solution and 50 mg (0.792 mM) of sodium cyanoborohydride were added, and the mixture was stirred at room temperature. Add a small amount of acetic acid from time to time
After stirring for 1.5 hours while adjusting to 7, IM-phosphoric acid is added to adjust to about pH = 2. Approximately add dipotassium hydrogen phosphate
After adjusting to pH = 5, salt extraction and ethyl acetate extraction are performed. The ethyl acetate layer is extracted with water and the water is distilled off to obtain 35 mg of an oily substance. Column chromatography (HP
-20) and eluting with ethanol-water (1: 4),
The solvent is distilled off, water is added and lyophilized to give methylamine Ih-b as a powder.

IR: νmax (KBr) 3420,2925,1570,1445,1400,125,1160,1
095,755,720,690 cm ^-1 . NMR: δ ppm ext.TMS (D ₂ O) 1.80 to 3.00 (m, 9H), 3.22 to 4.3
0 (m, 5H), 3.35 (s, 3H), 5.32 ~ 6.00 (m, 2H), 7.95 ~ 8.
47 (m, 5H). MS: 366 (M ⁺ ), 349,307,182. Reference Example 28 (1) (d1)-(1β, 2α) -2-tert-butoxycarbonylmethylcyclopropanecarboxylic acid sodium salt 18
Preparation of i ′ (d1)-(1α, 2β) -tert-butyl 2-ethoxycarbonylcyclopropaneacetic acid 18i (Tetrahedron Letters, 26, 1723, 1985) 4.56 g (20 mM) 140 ml
60 ml of an aqueous solution containing 10 ml of 2N sodium hydroxide was added to the methanol solution of, and the mixture was left standing at room temperature for 15 hours. The reaction mixture is dried under reduced pressure to give the crude title compound 18i 'which is used in the next reaction without purification.

(2) Production of (d1)-(1α, 2β) -tert-butyl 2-azidocarbonylcyclopropaneacetic acid 17i The crude product obtained above, 18i ′ , was added to a solution of 10 mM of 50% water-containing acetone in 20 ml of ethyl chlorocarbonate. , 1.243 ml (13 mM) and triethylamine (416 μl, 3 mM) are added, and the mixture is stirred at 0 ° C. for 45 minutes. Add 975 mg of sodium azide (15 m
5 ml of an aqueous solution containing M) is added and reacted at 0 ° C. for 1 hour. The reaction solution is extracted with ethyl acetate. The ethyl acetate layer is washed with water and then dried over magnesium sulfate, and the solvent is distilled off. To the obtained residue, methanol (5 ml) and triethylamine (1 ml) were added under ice cooling, and the mixture was treated at room temperature for 5 minutes. The reaction solution is concentrated under reduced pressure, and ether and saturated brine are added to the residue. The ether layer is washed with water and dried over magnesium sulfate, and the solvent is distilled off. The obtained crude title compound, 17i, is used for the next reaction without purification.

_{NMR: δppm (CDC1 3);} 0.70~1.10 (m, 2H), 1.23~1.65 (m,
1H), 1.45 (s, 9H), 2.10 to 2.65 (m, 3H). IR: νmax (film) 2120, 1718 cm ^-1 . Reference example 29 (1) Production of (d1)-(1α, 2β) -tert-butyl 2-benzyloxycarbonylaminocyclopropaneacetic acid 17i (d1)-(1α, 2β) -tert-butyl 2-azidocarbonylaminocyclonepropaneacetic acid 17i 1.73g (7.68mM)
A solution of anhydrous benzene in 30 ml is refluxed for 1 hour. To the reaction mixture are added benzyl alcohol (1.987 ml, 19.2 mM), triethylamine (1.205 ml, 8.6 mM), and the mixture is further reacted for 3 hours. After cooling, the reaction solution is extracted with ethyl acetate. The ethyl acetate layer is washed with saturated brine and dried over magnesium sulfate, and the solvent is evaporated. The residue is purified by silica gel column chromatography using benzene-ethyl acetate (2: 1) as an elution solvent to obtain 3.13 g of a mixture of the title compound 17i ' and benzyl alcohol.

This product is used for the next reaction of the mixture.

(2) (d1)-(1α, 2β) -2-benzyloxycarbonylaminocyclopropaneacetic acid 16i A mixture of the crude product 17i ′ obtained above and benzyl alcohol, a solution of 3.13 g of dichloromethane in 10 ml of ice-cooled 1 ml of lower anisole and 10 ml of trifluoroacetic acid are added and reacted for 1 hour. The reaction mixture is concentrated under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution are added under ice cooling, the aqueous layer is acidified with 2N-hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried over magnesium sulfate, and the solvent is distilled off. The residue is triturated with ether to give 825 mg (yield 33.1% from compound 18i ) of the title compound, 16i, as a white powder.

_{NMR: δppm (CDC1 3 -CD 3} OD); 0.50~0.98 (m, 2H), 1.00~1.
41 (m, 1H), 2.10 to 2.60 (m, 3H), 5.10 (s, 2H), 7.37
(S, 5H). Reference Example 30 Preparation of (d1)-(1α, 2β) -methyl 2-benzyloxyaminocyclopropaneacetic acid 15i To a solution of 795 mg (3 mM) of 16i (d1)-(1α, 2β) -2-benzyloxycarbonylaminocyclopropaneacetic acid 16i in 20 ml of dichloromethane is added an ether solution of diazomethane under ice cooling. After stirring the reaction solution for 5 minutes, the solvent is distilled off under reduced pressure. The residue was purified by silica gel chromatography using benzene-ethyl acetate (2: 1) mixed solution as an elution solvent to give 790 mg (yield 100%) of the title compound, 15
get i

_{NMR: δppm (CDC1 3);} 0.55~0.95 (m, 2H), 1.03~1.40 (m,
1H), 2.30 (t, J = 7Hz, 2H), 2.27 ~ 2.60 (m, 1H), 3.67
(S, 3H), 4.95 (br.s.1H), 5.08 (s, 2H), 7.33 (s, 5
H). IR: νmax (film) 3320,1715 cm ^-1 . Reference Example 31 Production of (d1)-(1α, 2β) -2-benzyloxycarbonylaminocyclopropaneacetaldehyde 14i (D1)-(1α, 2β) -Methyl 2-benzyloxycarbonylaminocyclopropaneacetic acid 15i 790 mg (3 mM) in anhydrous toluene, 30 ml solution in hexane solution of 1.0 M / L diisobutylaluminum hydride under cooling at −78 ° C. , 5.4 ml
Add (5.4 mM) and incubate for 45 minutes. Under ice cooling to the reaction solution,
A saturated aqueous solution of sodium sulfate is added to separate excess reducing agent, and then the reaction solution is filtered. After the filtrate was concentrated, the obtained residue was purified by silica gel chromatography using a mixed solution of benzene-ethyl acetate (2: 1) as an elution solvent to obtain 700 mg (yield 100%) of the title compound, 14i .

_{NMR: δppm (CDC1 3);} 0.50~1.02 (m, 2H), 1.02~1.40 (m,
1H), 2.23 ~ 2.53 (m, 3H), 4.90 ~ 5.20 (br, 1H), 5.08
(S, 2H), 7.33 (s, 5H), 9.80 (s, 1H). IR: νmax (film); 3300,1700 cm ^-1 . Reference example 32 (1) Preparation of (d1)-(1α, 2β, 5Z) -7- (2-benzyloxycarbonylaminocyclopropyl) -5-heptenoic acid 13i-b 60% oily sodium hydride 864 mg (21.6 mM) 40 ml In addition to the dimethylsulfoxide, the reaction is carried out at 75 ° C for 1.5 hours. The resulting sodium methylsulfinylmethide solution was kept at 12 ° C and 5.32g (12mM) of (-4-carboxybutyl) -triphenylphosphonium bromide was added to the solution at room temperature.
React for minutes. In this reaction solution, the above (d1)-(1α, 2β)
A solution of 700 mg (3 mM) of 2-benzyloxycarbonylaminocyclopropaneacetaldehyde 14i in 3 ml of dimethyl sulfoxide is added, and the mixture is reacted at room temperature for 2 hours. Ethyl acetate and water were added to the reaction solution, the aqueous layer was acidified with 2N-hydrochloric acid, the product was extracted with ethyl acetate, the ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent. Distill off. The residue is benzene-ethyl acetate (4: 1)
Separation by silica gel-column chromatography using the mixed solution as an elution solvent gave 349 mg (yield 36.7%).
%) Of the title compound 13i-b as a crude product.

_{NMR: δppm (CDC1 3);} 0.50~1.10 (m, 3H), 1.50~1.86 (m,
2H), 1.87 ~ 2.20 (m, 4H), 2.20 ~ 2.48 (m, 3H), 4.98 ~
5.20 (br, 1H), 5.07 (s, 2H), 5.12 to 5.60 (m, 2H), 7.31
(S, 5H). (2) (d1)-(1α, 2β, 5Z) -methyl 7- (2-
Benzyloxycarbonylaminocyclopropyl) -5
-Preparation of heptenoic acid 13i-a 349 mg (1.1 mM) of (d1)-(1α, 2β, 5Z) -7- (2
-Benzyloxycarbonylaminocyclopropyl)-
To a solution of 5-heptenoic acid 13i-b in 10 ml of dichloromethane is added an ether solution of diazomethane under ice cooling. After distilling off the solvent, the product was purified by silica gel-column chromatography using ethyl benzene acetate (2: 1) mixed solution as an eluent to obtain 214 mg (yield 59.1%) of the title compound, 13i-
obtain a.

_{NMR: δppm (CDC1 3);} 0.43~1.13 (m, 3H), 1.53~1.87 (m,
2H), 1.87 to 2.18 (m, 4H), 2.20 to 2.48 (m, 3H), 3.66
(S, 3H), 4.90 (br.s.1H), 5.10 (s, 2H), 5.25 ~ 5.60
(M, 2H). IR: νmax (CHC1 ₃ ); 3430,1720 cm ^-1 . Example 9 (1) (d1)-(1α, 2β, 5Z) -methyl 7- (2-
Aminocyclopropyl) -5-heptenoic acid trifluoroacetate salt 13i ' preparation 214 mg (0.65 mM) of (d1)-(1α, 2β, 5Z) -methyl
0.5 ml of anisole and 3 ml of trifluoroacetic acid are added to 13i-a of 7- (2-benzyloxycarbonylaminocyclopropyl) -5-heptenoic acid, and the mixture is heated at 45 ° C for 6.5 hours.
The reaction mixture is concentrated under reduced pressure, 5 ml of anhydrous benzene is further added, and the mixture is concentrated under reduced pressure. The residue is triturated with petroleum ether to give a crude powder of the title compound 13i.

(2) (d1)-(1α, 2β, 5Z) -methyl 7- (2-
Preparation of benzenesulfonamidocyclopropyl) -5-heptenoic acid Ii-a (d1)-(1α, 2β, 5Z) -methyl 7 obtained above.
271 μl (1.95 mM) of triethylamine and 125 μl (0.98 mM) of benzenesulfonyl chloride were added to a solution of trifluoroacetic acid salt 13i ′ of — (2-aminocyclopropyl) -5-heptenoic acid 13i ′ in 4 ml of dichloromethane under ice cooling. After gradually raising the reaction temperature to room temperature and reacting for 30 minutes, the product is extracted with ethyl acetate. The ethyl acetate layer is washed with water, 2N-hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The residue was separated by silica gel-column chromatography using a benzene-ethyl acetate (2: 1) mixture as an elution solvent to give 127 mg (yield from 13i-a
57%) of the title compound Ii-a is obtained.

_{NMR: δppm (CDC1 3);} 0.03~0.57 (m, 1H), 0.60~0.85 (m,
1H), 0.87 to 1.14 (m, 1H), 1.40 to 2.50 (m, 9H), 3.67
(S, 3H), 5.07 (s, 1H), 5.17 to 5.60 (m, 2H), 7.35 to 7.7
5 (m, 3H), 7.80-8.10 (m, 2H). IR: νmax (CHC1 ₃ ); 3360,1725,1320,1160cm ^-1 . Elemental analysis (as C ₁₇ H ₂₃ O ₄ NS) Calculated value (%): C, 60.52; H, 6.87; N, 4.15; S, 9.49, Experimental value (%): C, 60.39; H, 6.81; N, 4.10; S, 9.06. (3) (d1)-(1α, 2β, 5Z) -7- (2-benzenesulfonamidocyclopropyl) -5- heptenoic acid Ii-
b 120 mg (0.36 mM) of (d1)-(1α, 2β, 5Z) -methyl
7- (2-benzenesulfonamidocyclopropyl)-
To a solution of 5-heptenoic acid Ii-a in 3 ml of methanol under ice cooling, 1N
-Sodium hydroxide 0.72 ml (0.72 mM) was added, the reaction temperature was raised to room temperature and reacted for 15 hours. Cool the reaction mixture 1N-
After acidifying with 3 ml of hydrochloric acid, the product was extracted with ethyl acetate, the ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain 107 mg.
(92% yield) of the title compound Ii-b is obtained.

_{NMR: δppm (CDC1 3);} 0.30~1.14 (m, 3H), 1.45~2.18 (m,
7H), 2.30 (t, J = 6.0Hz, 2H), 5.11 (s, 1H), 5.25 to 5.47
(M, 2H), 7.40 to 7.70 (m, 3H), 7.80 to 8.00 (m, 2H). IR: νmax (CHC1 ₃ ); 3330,1700,1310,1150cm ^-1 . (3) (d1)-(1α, 2β, 5Z) -sodium 7-
Preparation of (benzenesulfonamidocyclopropyl) -5-heptenoic acid Ii-c 107 mg (0.33 mM) of (d1)-(1α, 2β, 5Z) -7- (2
-Benzenesulfonamidocyclopropyl) -5-heptenoic acid Ii-b in a solution of 2 ml of methanol under ice-cooling 0.21 M / L sodium metoxide-methanol solution 1.41 ml (0.29
7 mM) is added, the temperature is raised to room temperature, and the reaction is performed for 5 minutes. After the reaction solution was concentrated under reduced pressure, 3 ml of distilled water was added to the obtained residue,
Dissolve and lyophilize to give 109 mg of the title compound, I
i-c is obtained.

Reference Example 33 Preparation of (d1)-(1α, 2β) -2-benzyloxycarbonylcyaminocyclopent-4-enylethanol triphenylmethyl ether 20j 1.85 g (5 mM) of (d1)-(1α, 2β) -2-amino-4
-Ethylethanol triphenyl methyl ether, 21j
20 ml of (compound described in Japanese Patent Application No. 61-273372)
Under ice cooling, 714 μl of carbobenzoxy chloride (5 mM) and 1.045 ml (7.5 mM) of triethylamine are added to the solution and reacted for 1 hour. Add 10 ml of 25% aqueous ammonia to the reaction mixture and stir for 30 minutes. The dichloromethane layer is washed successively with 2N-hydrochloric acid, saturated aqueous sodium hydrogencarbonate and water under ice cooling and then dried over anhydrous magnesium sulfate, and the solvent is distilled off. The obtained title compound, 20j, is used for the next reaction without purification.

_{NMR: δppm (CDC1 3);} 1.50~1.90 (m, 2H), 1.95~2.30 (m,
1H), 2.40 ~ 2.95 (m, 2H), 3.13 (t, J = 6Hz, 2H), 3.70 ~
4.05 (m, 1H), 4.70 ~ 5.05 (m, 1H), 5.07 (s, 2H), 5.57
(S, 2H), 7.35 (s, 5H). Reference Example 34 Production of (d1)-(1α, 2β) -2-benzyloxycarbonylamino-4- enylethanol 19j To the above crude (d1)-(1α, 2β) -2-benzyloxycarbonylaminocyclopent-4-enylethanol triphenylmethyl ether, 20j of tetrahydrofuran 32 ml and methanol 32 ml was added 1N-hydrochloric acid 16 ml.
Heat at 45 ° C for 4 hours. After cooling the reaction solution to room temperature, 2.016 g (24 mM) of sodium hydrogen carbonate is added, and the reaction solution is concentrated under reduced pressure.

The residue is extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline and then dried over magnesium sulfate, and the solvent is distilled off. The residue is separated by silica gel-column chromatography using a mixed solution of benzene-ethyl acetate (1: 1) as an elution solvent to obtain 1.05 g (yield 80.4% from 21j ) of the title compound, 19j .

_{NMR: δppm (CDC1 3);} 1.33~1.80 (m, 2H), 1.90~2.30 (m,
1H), 2.47 ~ 3.05 (m, 2H), 2.97 ~ 3.48 (br, H), 3.50 ~
3.98 (m, 2H), 3.85 to 4.20 (m, 1H), 4.90 to 5.35 (m, 1
H), 5.09 (s, 2H), 5.66 (s, 2H), 7.35 (s, 3H). Reference Example 35 (d1)-(1α, 2β)-(2-benzyloxycarbonylaminocyclopent-4-enyl) acetaldehyde
14j manufacturing 157 μl (1.8 mM) oxalyl chloride in dichloromethane 10
Cool the ml solution to -78 ° C and add dimethyl sulfoxide 255μ.
Add 1 (3.6 mM) and stir for 5 minutes. 392 mg in this solution
(1.5 mM) of (d1)-(1α, 2β) -2-benzyloxycarbonylaminocyclopent-4- enylethanol , 19j of dichloromethane, 2 ml solution was added, and the mixture was added at −60 ° C. for 15
After reacting for 2 minutes, 2.51 ml (18 mM) of triethylamino is added.

After the reaction temperature is gradually raised to room temperature for reaction, the product is extracted with ethyl acetate.

The ethyl acetate layer is washed with water, 2N-hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off.
The obtained title compound, 14j, is used for the next reaction without purification.

_{NMR: δppm (CDC1 3);} 1.90~3.20 (m, 5H), 3.75~4.20 (m,
1H), 4.75 ~ 5.20 (m, 1H), 5.09 (s, 2H), 5.55 ~ 5.83
(M, 2H), 7.34 (s, 5H), 9.80 (s, 1H). IR: νmax (CHC1 ₃ ); 1710 cm ^-1 . Reference Example 36 (d1)-(1α, 2β, 3Z) -methyl 5- (2-benzyloxycarbonylaminocyclopent-4-enyl)
-3-Production of pentenoic acid 13j 324 mg (8.1 mM) of 60% oily sodium hydride is added to 20 ml of dimethylsulfoxide and reacted at 75 ° C for 2 hours.
The resulting sodium methylsulfinylmethide solution was added to
Keeping at ℃, add 1.868g (4.5mM) (2-carboxyethyl) triphenylphosphonium bromide and react at room temperature for 20 minutes.

Into this reaction solution, the above (d1)-(1α, 2β)-(2-benzyloxycarbonylaminocycloppent-4-enyl) acetaldehyde, 14j dimethylsulfoxide, 3
Add ml solution and react at room temperature for 2 hours. Ethyl acetate and water were added to the reaction solution, the aqueous layer was acidified with 2N-hydrochloric acid, the product was extracted with ethyl acetate, the ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent. Distill off.

The product obtained by subjecting the residue to silica gel-column chromatography using a mixed solution of benzene-ethyl acetate (4: 1) as an elution solvent to separate was 10 ml of dichloromethane.
Dissolve in and add an ether solution of diazomethane under ice cooling.
After evaporation of the solvent, the product was benzene-ethyl acetate (2:
1) Purification by silica gel column chromatography using the mixed solution as an elution solvent gave 155 mg (30% from 14j ) of the title compound, 13j .

_{NMR: δppm (CDC1 3);} 1.90~2.37 (m, 3H), 2.40~2.95 (m,
2H), 2.95 to 3.22 (m, 2H), 3.65 (s, 3H), 3.75 to 4.10
(M, 1H), 4.87 to 5.23 (m, 1H), 5.10 (s, 2H), 5.50 to 5.8
0 (m, 4H), 7.33 (s, 5H), IR: νmax; 3425,1710cm ^-1 . Example 10 (1) (d1)-(1α, 2β, 3Z) -methyl 5- (2-
Benzenesulfonamide cyclopent-4-enyl)-
Production of 3-pentenoic acid Ij-a 155 mg (0.47 mM) of (d1)-(1α, 2β, 3Z) -methyl
5- (2-benzyloxycarbonylaminocyclopent-4-enyl) -3-pentenoic acid 13j to anisole 1.2
ml and trifluoroacetic acid 5 ml are added and heated at 45 ° C for 7 hours.
The reaction mixture is concentrated under reduced pressure, and 5 ml of anhydrous benzene is further added to reduce the concentration.

The residue is dissolved in 5 ml of dichloromethane without purification, and 198 μl (1.41 mM) of triethylamine and 90 μl (0.71 mM) of benzenesulfonyl chloride are added under ice-cooling and reacted for 1 hour.

Add 3 ml of 29% aqueous ammonia to the reaction mixture and react at room temperature for 30 minutes. The product is extracted with ethyl acetate, and the ethyl acetate layer is washed successively with 2N-hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated.

71 mg (45% from 13j ) of the title compound, Ij , was obtained by separating the residue by silica gel-column chromatography using a benzene-ethyl acetate (4: 1) mixture as an elution solvent.
-A is obtained.

_{NMR: δppm (CDC1 3);} 1.80~2.27 (m, 3H), 2.30~2.27 (m,
2H), 2.80 to 3.17 (m, 2H), 3.34 to 3.73 (m, 1H), 3.68
(S, 3H), 5.10 to 5.75 (m, 3H), 5.55 (s, 2H), 7.32 to 7.7
0 (m, 3H), 7.73 to 8.05 (m, 2H). IR: νmax (CHC1 ₃ ) 1720,1320,1150cm ^-1 . (2) Preparation of (d1)-(1α, 2β, 3Z) 5- (2-benzenesulfonamidocyclopent-4-enyl) -3-pentenoic acid Ij-b 71 mg (0.21 mM) of (d1)-(1α, 2β, 3Z) -methyl
5- (2-benzenesulfonamide cyclopent-4-
0.63 ml (0.63 mM) of 1N sodium hydroxide was added to a 2 ml solution of methanol of (enyl) -3-pentenoic acid Ij-a under ice-cooling, and the reaction temperature was raised to room temperature and reacted for 15 hours. The reaction solution was acidified by adding 1N-hydrochloric acid under cooling, the product was extracted with ethyl acetate, the ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
67 mg (100%) of the title compound, Ij-b is obtained.

_{NMR: δppm (CDC1 3);} 1.90~2.25 (m, 3H), 2.30~2.70 (m,
2H), 2.80 ~ 3.20 (m, 2H), 3.25 ~ 3.70 (br, 1H), 5.00 ~
5.33 (br, 1H), 5.31 to 5.68 (m, 2H), 5.56 (s, 2H), 7.37
~ 7.65 (m, 3H), 7.70 ~ 8.05 (m, 2H), 8.63 (br, S, 1
H). IR: νmax (CHC1 ₃ ) 3350, (broad), 1703, 1320, 1150 cm ^-1 . (3) (d1)-(1α, 2β, 3Z) -sodium 5-
Preparation of (2-benzenesulfonamidocyclopent-4-enyl) -3-pentenoic acid Ij-c 67 mg (0.21 mM) of (d1)-(1α, 2β, 3Z) 5- (2
-Benzenesulfonamide cyclopent-4-enyl)
To a solution of -3-pentenoic acid IJ-b in 2 ml of methanol was added 2 ml (0.2 mM) of 0.1N sodium hydroxide under ice cooling, the temperature was raised to room temperature, and the reaction was carried out for 5 minutes. The reaction mixture was concentrated under reduced pressure, 1.5 ml of distilled water was added to the obtained residue, and the residue was lyophilized to give 69 mg of the title compound, Ij-c .

Elemental analysis (as C ₁₆ H ₁₈ O ₄ NSNa) Calculated value (%); C, 55.97, H, 5.28, N, 4.08, S, 9.34, Na, 6.7
0 Measured value (%); C, 54.96, H, 5.49, N, 4.01, S, 9.25, Na, 6.5
8 Reference Example 37 Production of (d1)-(1α, 2β)-(2-benzenesulfonamidocyclopent-4-enyl) acetaldehyde 2k 523 μl (6.0 mM) oxalyl chloride in dichloromethane 10
The 0 ml solution was cooled to −78 ° C. and 852 μl of dimethyl sulfoxide was added.
Add (12 mM) and stir for 5 minutes.

1.34 g (5 mM) of (d1)-(1α, 2β)-(2
-Benzenesulfonamide cyclopent-4-enyl)
Ethanol 22k (described in Japanese Patent Application No. 61-273372) A solution of 3 ml of dimethyl sulfoxide was added, and after reacting at -60 ° C for 15 minutes, 8.37 ml (60 mM) of triethylamine was added. After gradually raising the reaction temperature to room temperature for reaction, the product is extracted with ethyl acetate. The ethyl acetate layer is washed with water, 2N-hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off.

The obtained title compound, 2k, is used for the next reaction without purification.

_{NMR: δppm (CDC1 3);} 2.00~2.80 (m, 4H), 2.83~3.20 (m,
1H), 3.48 (quintet, J = 6Hz, 1H), 5.40-5.80 (m, 3H),
7.37 ~ 7.73 (m, 3H), 7.78 ~ 8.05 (m, 2H). IR: νmax (CHC1 ₃ ); 1715,1320,1155 cm ^-1 . Example 11 (1) Preparation of (d1)-(1α, 2β, 5Z) -7- (2-benzenesulfonamidocyclopent-4-enyl) -5-heptenoic acid Ik-b 1.08 g (27 mM) of 60% oily sodium hydride is added to 30 ml of dimethylsulfoxide and reacted at 75 ° C. for 2 hours.
The resulting sodium methylsulfinylmethide solution was added to
Keeping at ℃, add 8.866g (20mM) (4-carboxybutyl) -triphenylphosphonium bromide and react at room temperature for 20 minutes.

(D1)-(1α, 2β) -obtained in the above reaction solution
(2-benzenesulfonamidocyclopent-4-enyl) acetaldehyde 2k dimethyl sulfoxide, 3 ml
Add the solution of and react at room temperature for 24 hours. Ethyl acetate and water were added to the reaction solution, the aqueous layer was acidified with 2N-hydrochloric acid, the product was extracted with ethyl acetate, the ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then used as a solvent. Distill off.

The residue is mixed with benzene-ethyl acetate (4: 1) as an elution solvent. 1.49 g (yield 85.2%) of the title compound, I, was obtained by separation by silica gel-column chromatography.
get k−b.

_{NMR: δppm (CDC1 3);} 1.50~2.75 (m, 11H), 3.35~3.70
(M, 1H), 5.00 to 5.45 (m, 3H), 5.57 (s, 2H), 7.35 to 7.7
0 (m, 3H), 7.80 to 8.00 (m, 2H), 8.50 to 9.40 (br, 1H). IR: νmax (CHC1 ₃ ); 3360,3250,1700,1315,1150cm ^-1 . (2) (d1)-(1α, 2β, 5Z) -methyl 7- (2-
Benzenesulfonamide cyclopent-4-enyl)-
Preparation of 5-heptenoic acid Ik-a 1.49 g (4.26 mM) of (d1)-(1α, 2β, 5Z) -7- (2
-Benzenesulfonamide cyclopent-4-enyl)
To a solution of 5-keptenoic acid Ik-b in 20 ml of dichloromethane is added a solution of diazomethane in ether.

After evaporation of the solvent, the product was benzene-ethyl acetate (4:
1) Purification by silica gel column chromatography using the mixed solution as an elution solvent gives 1.262 g (yield 81.5%) of the title compound Ik-a .

_{NMR: δppm (CDC1 3);} 1.50~2.75 (m, 11H), 3.30~3.78
(M, 1H), 3.68 (s, 3H), 5.05 to 5.45 (m, 3H), 5.58 (s, 2
H), 7.37 to 7.73 (m, 3H), 7.81 to 8.09 (m, 2H). (3) (d1)-(1α, 2β, 5Z) -sodium 7-
Preparation of (2-benzenesulfonamide cyclopent-4-enyl) -5-heptenoic acid Ik-c 295 mg (0.844 mM) of (d1)-(1α, 2β, 5Z) -7-
To a solution of (2-benzenesulfonamide cyclopent-4-enyl) -5-heptenoic acid Ik-b in 3 ml of methanol was added 1N-sodium hydroxide 0.78 ml (0.78 mM) under ice cooling.
React for 10 minutes.

The reaction mixture is concentrated under reduced pressure, 4.5 ml of distilled water is added to the residue, and the mixture is lyophilized to give the title compound, Ik-c .

Elemental analysis (as C ₁₈ H ₂₂ O ₄ NSNa ・ 1 / 4H ₂ O) Calculated value (%): C, 57.51, H, 6.03, N, 3.73, S, 8.53 Measured value (%): C, 57.36, H , 5.98, N, 3.71, S, 8.97 Reference Example 38 (d1)-(1α, 2α, 3α, 4α, 5Z) -7- (1,4-dihydroxy-3-azidocyclopentan-2-yl) -5 −
Production of heptenoic acid diphenyl methyl ester 251 (D1)-(1α, 2α, 3α, 4α, 5Z) -7- (1-hydroxy-3,4-epoxycyclopentan-2-yl) -5
-Heptenoic acid 261 [M. Bee. Floyd (MBFloy
d), Synthetic communication unity (Synth.Commu
n.), Vol. 4, pages 317-323, 1974] 1.13 g (5 mmol) was dissolved in 35 ml of dimethylformamide, 0.975 g (15 mmol) of sodium azide was added, and the mixture was heated to 90 ° C.
Stir for 50 minutes. The solvent is distilled off under reduced pressure, diluted hydrochloric acid is added to the residue to make it weakly acidic, and the mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and the solvent is distilled off to obtain 1.44 g of a brown oily substance. Dissolve this in 30 ml of dichloromethane and add 1.4 g of diphenyldiazomethane.
(7.2 mmol) is added and the solution is heated to reflux for 1 hour. After evaporating the solvent under reduced pressure, the residue was washed with ethyl acetate-
0.592 g of the title compound 251 (yield 27.5%) and its isomer 251 ′ 0.997 g (yield 45%) were obtained by separating and purifying by silica gel column chromatography using an n-hexane (1: 1) mixed solution as an elution solvent. ) Get.

Compound _{251, NMR: δppm (CDC1 3} ); 1.5~2.6 (m, 12H), 2.7~
3.1 (br, 1H), 3.55 (d, d, J = 9 & 4Hz, 1H), 4.0 to 4.3
(M, 2H), 5.43 (m, 2H), 6.87 (s, 1H), 7.33 (br, s, 10
H). IR: νmax (CHC1 ₃ ); 3500,2090,1725 cm ^-1 . Compound 251 ', NMR: δppm (CDC1 3); 1.5~3.0 (m, 13H), 3.8
5 to 4.35 (m, 3H), 5.42 (m, 2H), 6.87 (s, 1H), 7.35 (b
r, s, 10H), IR: νmax (CHC1 ₃ ); 3500,2090,1725cm ^-1 . Reference Example 39 (d1)-(1α, 2α, 3β, 4α, 5Z) -7- (1,4-dihydroxy-3-aminocyclopentan-2-yl) -5-
Production of heptenoic acid diphenyl methyl ester 241 0.725 g (1.66 mmol) of the azide compound 251 obtained above
And 0.873 g (3.33 mmol) of triphenylphosphophin are dissolved in 20 ml of tetrahydrofuran and the solution is left at room temperature for 15 hours. Next, 5 ml of water was added, and the mixture was heated with stirring under reflux for 2 hours, concentrated under reduced pressure and extracted with dichloromethane. The organic layer is dried over anhydrous sodium sulfate and the solvent is distilled off. The residue was dissolved in ethyl acetate, applied to a silica gel column, eluted with ethyl acetate to remove nonpolar substances, and then eluted with a dichloromethane-methanol (5: 1) mixture to give 0.594 g of the title compound 241 (87% yield). obtain.

_{NMR: δppm (CDC1 3);} 1.3~2.6 (m, 11H), 2.75 (br, s, 4
H), 2.96 (d, d, J = 9 & 5Hz, 1H), 3.80 (m, 1H), 4.10
(M, 1H), 5.42 (m, 2H), 6.88 (s, 1H), 7.33 (br, s, 10
H). IR: νmax (CHC1 ₃ ); 3500 (shoulder), 3360,1730 cm ^-1 . Reference Example 40 (d1)-(1α, 2α, 3β, 4α, 5Z) -7- (1,4-dihydroxy-3-phenylsulfonylaminocyclopentan-2-yl) -5-heptenoic acid diphenylmethyl ester Manufacturing 231 0.570 g (1.39 mmol) of the previously obtained amino compound 241
Is dissolved in 10 ml of acetone, and 0.167 g of potassium hydrogen carbonate (1.
67 ml) containing 7 ml of aqueous solution is added. 0.186 ml (1.46 mmol) of benzenesulfonyl chloride was added to this solution under ice cooling.
Is added and the mixture is stirred for 1 hour under ice cooling. After distilling off acetone under reduced pressure, the reaction mixture is extracted with dichloromethane, the organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off. Residue was partitioned between ethyl acetate -n- hexane (2: 1) silica gel mixture as an elution solvent - The title compound separated and purified by column chromatography 231 0.670 g (yield: 88
%).

_{NMR: δ (CDC1 3);} 1.3~2.5 (m, 12H), 3.1~3.5 (m, 2H),
4.08 (m, 2H), 5.26 (m, 2H), 5.70 (d, J = 6Hz, 1H), 6.98
(S, 1H), 7.35 (br, s, 10H), 7.4 to 8.0 (m, 5H). IR: νmax (CHC1 ₃ ); 3524,3375,3290,1725,1330,1165,1100
cm ^-1 . Example 12 of (d1)-(1α, 2α, 3β, 4α, 5Z) -7- (1,4-dihydroxy-3-phenylsulfonylaminocyclopentan-2-yl) -5-heptenoic acid I1-b Manufacturing 0.048 g (0.087 mmol) of the compound 231 obtained above and 47 μl (0.43 mmol) of anisole were added to dichloromethane.
Dissolve in 1.5 ml and add aluminum chloride to this solution at -30 ℃.
0.5 ml of nitromethane solution containing 0.023 g (0.17 mmol)
Add. After stirring the reaction solution at -30 ° C for 30 minutes,
Saturated saline is added, the temperature is returned to room temperature, and the mixture is extracted with ethyl acetate.
The organic layer is extracted with a saturated aqueous solution of sodium hydrogen carbonate, and the aqueous layer is acidified with dilute hydrochloric acid under ice cooling. After adding sodium chloride to the aqueous solution to make it saturated, the mixture is extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and the solvent is distilled off to obtain 0.026 g of an oily substance. Crystallization by adding diisopropyl ether, filtration and washing gave 0.021 g of the title compound I1-b (yield
64%) as a colorless powder with a melting point of 114-119 ° C.

_{NMR: δppm (CDC1 3 -CD 3} OD = 10: 1); 1.4~2.4 (m, 11H),
3.25 (m, 1H), 3.56 (br, s, 4H), 4.06 (m, 2H), 5.30 (m,
2H), 7.4 to 8.0 (m, 5H). IR: νmax (Nujioru); 3510,3325,2625 (broad), 171
0,1330,1160,1100cm ^-1 . Reference Example 41 (d1)-(1α, 2α, 3β, 5Z) -7- (1-hydroxy-3-phenylsulfonylamino-4-oxocyclopentan-2-yl) -5-heptenoic acid diphenylmethyl ester 23m and (d1)-(2α, 3β, 4α, 5Z) -7-
Preparation of (1-oxo-3-phenylsulfonylamino-4-hydroxycyclopentan-2-yl) -5-heptenoic acid diphenylmethyl ester 23n 0.549 g (1 mmol) of the compound 231 obtained above is dissolved in 15 ml of acetone, and 1 ml (8 mmol) of 8N Jyon's reagent is added dropwise to this solution at −20 ° C. over 20 minutes. After the dropping, 1.5 ml of Ihipropyl alcohol is added, and the reaction mixture is returned to room temperature and turns green. The supernatant is applied to a silica gel column and ethyl acetate-n-hexane (1: 1)
Elute with the mixture. The eluate was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 0.500 g of a colorless oily substance. This was separated and purified by silica gel column chromatography using a mixed solution of ethyl acetate-n-hexane (1: 1) as an elution solvent to give 23m of the title compound (0.116g).
(Yield 21%), title compound 23n 0.209 g (Yield 38%) and a mixture of 23m and 23n 0.020 g (Yield 4%).

Compound _{23m, NMR: δppm (CDC1 3} ); 1.5~2.1 (m, 12H), 3.35
(D, d, J = 12 & 8Hz, 1H), 4.32 (m, 1H), 4.98 (d, J = 8Hz,
1H), 5.36 (m, 2H), 6.90 (s, 1H), 7.35 (br, s, 10H) 7.4
~ 8.0 (m, 5H). IR: νmax (CHC1 ₃ ); 3500,3325,1750,1725,1340,1165,1095
cm ^-1 . Compound _{23n, NMR: δppm (CDC1 3} ); 1.5~2.95 (m, 11H), 3.26
(M, 1H), 3.73 (br, s, 1H), 4.30 (q, J = 7.5Hz, 1H), 5.1
5 (m, 2H), 5.70 (d, J = 6Hz, 1H), 6.95 (s, 1H), 7.35 (b
r, s, 10H) 7.4-8.0 (m, 5H). IR: νmax (CHC1 ₃ ); 3500,3360,3260,1745,1730, (shoulde
r), 1310,1160,1095cm ^-1 . Example 13 of (d1)-(1α, 2α, 3β, 5Z) -7- (1-hydroxy-3-phenylsulfonylamino-4-oxocyclopentan-2-yl) -5-heptenoic acid Im-b Manufacturing 0.055 g (0.1 mmol) of 23 m obtained above and 54 μl (0.5 mmol) of anisole are dissolved in 2 ml of dichloromethane, and 0.5 ml of a nitromethane solution containing 0.034 g (0.25 mmol) of aluminum chloride is added at -30 ° C. The reaction solution was stirred at -30 ° C for 30 minutes, saturated saline was added to the mixture, the temperature was raised to 0 ° C, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain 0.064 g of a colorless oily substance. This is applied to a silica gel column and ethyl acetate-n
-Elute with a mixed solution of hexane (1: 2) to remove non-polar substances, and then elute with ethyl acetate to give the title compound Im-b.
0.024 g (yield 63%) is obtained.

_{NMR: δppm (CDC1 3 -CD 3} OD = 30: 1); 1.4~2.5 (m, 11H),
3.7 ~ 4.0 (m, 3H), 4.35 (m, 1H), 5.42 (m, 2H), 5.85 (b
r, d, 0.5H), 7.4 to 8.0 (m, 5H). IR: νmax (CHC1 ₃ ); 3500,3250,2650 (broad), 1755,1715,
1350,1165,1095cm ^-1 . Example 14 (d1)-(2α, 3β, 4α, 5Z) -7- (1-oxo-3
Preparation of In-b -phenylsulfonylamino-4-hydroxycyclopentan-2-yl) -5-heptenoate 0.083 g (0.15 mmol) of the compound 23n obtained above and 83 μl (0.75 mmol) of anisole were added to 4 m of dichloromethane.
1 ml of a nitromethane solution containing 0.052 g (0.4 mmol) of aluminum chloride was added at -30 ° C. This reaction solution is treated in the same manner as in Example 14 to obtain 0.101 g of a crude oily substance. This was similarly separated and purified by silica gel-column chromatography to obtain 0.039 g (yield 67%) of the title compound In-b from the fraction eluted with ethyl acetate.

_{NMR: δppm (CDC1 3);} 1.4~3.0 (m, 11H), 3.27 (m, 1H), 4.
35 (q, J = 7.5Hz, 1H), 4.5 to 5.0 (br, m, 2H), 5.20 (m, 2
H), 6.13 (m, 1H), 7.4-8.0 (m, 5H). IR: νmax (CHC1 ₃ ); 3500,3375,3250,2650 (broad), 1750,
1710,1320,1160,1095cm ^-1 . C. Effect invention compounds of invention act as a potent antagonist against thromboxane A ₂ receptor, thromboxane A ₂
It significantly inhibits platelet aggregation caused by. Therefore, it is a compound that can be a useful antithrombotic agent / antivasoconstrictor. The in vitro platelet aggregation inhibitory action of the representative compounds is shown in the following experimental examples.

[Test material and test method] From the carotid artery of a male rabbit (NIBS-JW, body weight 2.2 to 2.7 kg)
Blood was collected continuously with a plastic syringe containing 0.8 ml of 3.8% sodium citrate (7.2 ml, 8 ml in total). The blood was placed in a plastic test tube, mixed by inverting lightly, and then centrifuged at 20 ° C and 210 g for 10 minutes to collect supernatant platelet-rich plasma [PRP (platelet rich plasma)]. Furthermore, the remaining blood was centrifuged at 20 ° C., 3000 rpm (about 1900 g) for 10 minutes, and the platelet poor plasma [PPP: (Platelet poor plasm
a)] was obtained.

The platelet count of PRP was adjusted with PPP so that the platelet count was 50 to 55 × 10 ⁴ / μl, and the mixture was subjected to aggregation measurement.

The platelet aggregation reaction was measured using an aggregometer (Model AUTO RAM-61, Rika Denki Kogyo) according to the method of Born [Born, GVR, Nature, 194 , 927-929 (1962)]. That is, the platelet count is 50 to 55 × 10 ⁴ / μ
400 μl of PRP adjusted to be 1 is put in a measuring tube and set in an aggregometer and stirred at 37 ° C for 1 minute (1200 rp).
m), after the predicted heating, add the test compound solution (50 μl when dissolved in physiological saline, 2 μl of the solution when dissolved in dimethyl sulfoxide and 48 μl of physiological saline), and 2 minutes after that, arachidone as an aggregation-inducing substance. Acid [sodium salt, Sigma] was added at 500 μM and the change in light transmission caused by aggregation was recorded over time.

Platelet aggregation rate is 0 for PRP and PPP
% And 100%, and the maximum light transmittance of PRP after addition of the aggregation-inducing substance was defined as the maximum aggregation rate.

The 50% platelet aggregation inhibitory concentration (IC ₅₀ ) [μM] was obtained from the aggregation inhibition rate (%) calculated from the ratio of the maximum aggregation rate of the test compound added group to the maximum aggregation rate of the control group (carrier added group).

[Results] The test results are shown in Table 1 below. Prostaglandin (PG) E ₁ was used as a standard substance.

Was used the PGE ₁ as comparative control compounds, the half-life in the PGE ₁ biological very short, there is a point difficult to put into practical use as pharmaceuticals, the goal of the action level of PGE ₁ in order to improve the point Due to the synthesis of a new compound. As a result, the compound of the present invention was able to approach the action level of PGE ₁ considerably.

The compound of the present invention has a strong inhibitory effect on platelet aggregation by arachidonic acid.

The compound of the present invention is a platelet aggregate by thromboxane A _2.
It is a drug that strongly suppresses vasoconstriction and tracheal contraction, and can be used for treatment and amelioration of symptoms such as arteriosclerosis, myocardial infarction, acute myocardial ischemic angina, cardiovascular shock, and sudden death It is a compound that is expected to be applied to its effects.

The compound of the present invention can be administered orally or parenterally. For example, tablets, capsules, pills, granules, fine granules, solutions, emulsions, suppositories, intravenous injections, intramuscular injections or subcutaneous injections can be used. In formulating, an appropriate carrier or excipient that is usually used is used.

The compound of the present invention is orally administered to an adult at about 10 mg to 80 mg per day.
0 mg is administered.

Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location C07C 311/20 C07D 303/36 307/20 307/22 307/33 405/06 207 407/06 303

Claims (1)

[Claims] 1. A formula: [In the formula, R ₁ is hydrogen or lower alkyl; X is a C ₁ -C ₄ alkylene which may have a double bond, R ₂ is hydrogen, lower alkyl or amino protecting group); and m is an integer of 1 to 3] or a salt thereof.