KR950001024B1 - Process for preparing bicyclic sulfonamide derivatives - Google Patents

Abstract

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Description

Method for preparing bicyclo cyclic sulfonamide derivative

Compounds of the present invention are used in the field of medicaments to ameliorate symptoms caused by thromboxane. Specifically, it relates to a method for producing a compound represented by the following general formula (II) or an salt thereof used as an antithrombogenic agent, an antivascular contraction agent, or an anti-organ contractile agent.

General formula:

(Wherein R 'is hydrogen or lower alkyl or salt forming group; R2 is substituted or unsubstituted phenyl;

Moreover, it is related with the manufacturing method I and manufacturing method II of the novel compound specifically represented by said general formula (I).

Recipe Ⅰ

General formula:

(Wherein R ^{1 ′} is hydrogen, lower alkyl;

To the compound represented by

Formula: Hal-SO₂-R₂

Wherein R2 represents substituted or unsubstituted phenyl; Hal represents halogen. A general formula characterized by deprotection reaction and / or salt formation reaction, if necessary:

는 상기 내용과 같은 뜻이다.)로서 표시되는 술폰아미드 유도체 또는 그 염의 제조법.Wherein R 'represents hydrogen, lower alkyl, or a salt forming group, and R2 and

Is the same meaning as described above.) A method for producing a sulfonamide derivative or salt thereof.

Preparation Method II

General formula

을 나타낸다.)로서 표시되는 화합물과

And a compound represented by

Wherein R 'is hydrogen, lower alkyl; Ar represents an aromatic hydrocarbon group, and the esterification reaction and / or salt formation reaction are carried out as necessary.

는 상기 내용과 같은 뜻이다.)로서 표시되는 술폰아미드 유도체 또는 그 염의 제조법.Wherein R 'represents hydrogen, lower alkyl or salt forming group, R2 and

Is the same meaning as described above.) A method for producing a sulfonamide derivative or salt thereof.

Atherosclerosis, which is the main cause of myocardial infarction or cerebral infarction, begins with the accumulation of mucoid substrates in the artery lining, proliferation of fibroblasts, and then degeneration and lipid, cholesterol deposition, destruction of endometrial tissue, and formation of atherosclerotic bodies. It is a common symptom to progress and gradually bring about high endometrial thickening. Atherosclerosis has long been known to be caused by thrombus formation and sedimentation of fibrin in the artery wall, but recently, protoncycline was induced by thromboxane A₂ (TXA₂) and vane (Vane) by Samuelsson. As PGI₂ was discovered, the interaction between platelets and blood vessel walls became clear. Platelets are known to have an important relationship in the development and progression of atherosclerosis, and it has been recognized that administration of antithrombotic drugs, particularly drugs with platelet aggregation inhibitory effects, is effective for the treatment of atherosclerosis related diseases.

It is known that certain types of prostaglandins have a strong platelet aggregation inhibitory activity, including heparin, coumarin-based compounds, and the like, which are anti-thrombotic drugs. In light of this fact, he began developing agonists for the receptors such as prostaglandin E₁ and prostaglandin I2, and he noted that thromboxane A2 has strong platelet coagulation and vasoconstriction. Thromboxane A₂ synthesis inhibitors such as thromboxane synthetase inhibitors, thromboxane A₂ receptors, and antagonists are also being developed. For thromboxane A2 receptors and antagonists, 13-APA (Venton DL et al., And J. Med. Chem., Vol. 22, p. 824 (1979), PTA2 [Lefer] (AM), et al., Proc. Natl. Acad. Sci. USA, Vol. 76, p. 2566 (1979)], BM-13177 [Lipper, Drugs] Journals of Today, Vol. 21, p. 283 (1985), SQ-29548 [Ogletree et al., Journal of Pharmacologue and Experiential Ceraputis (J. Pharmacol.Exp) Ther., Vol. 34, p. 435 (1985)].

Thromboxane A2 is activated by cyclooxygenase when thrombin acts on platelets, and is produced enzymatically in various cells by arachidonic acid through prostaglandin C₂ and H₂ and platelets and blood vessel walls. It has a variety of powerful physiological or pathological actions. In particular, strong platelet aggregation and smooth muscle contraction of the bronchus, coronary artery, and pulmonary artery are thought to be a mediator of the development and progression of circulatory respiratory diseases such as angina pectoris, myocardial infarction, cerebral infarction, and bronchial asthma. Moreover, the potent action concentration is known to be 10 ⁻¹⁰ to 10 ⁻¹¹ M. Therefore, the development of antagonists or inhibitors of thromboxane A₂ as an antithrombogenic agent, an antivascular contraction agent, and an antibronchial contractor has attracted attention. Inhibitors have problems such as prostaglandins, which have various important roles other than thromboxane A2, and inability to control the bad action of thromboxane-like accumulation of substrates, especially the development of antagonists. It is becoming.

The present inventors synthesize bicyclo cyclic sulfonamide derivatives represented by the general formula (1), and find out that this novel compound has a strong action as a thromboxane A 2 receptor and antagonist, and is also a chemically and biochemically stable compound. The invention was completed.

Definitions of various phrases in the present specification are as follows.

"Lower alkyl" and the like C₁ ~ C ₅ straight-chain or stands on the alkyl side chain of, for example, a methyl, ethyl, n- propyl, isopropyl, butyl, pentyl.

Examples of the phenyl substituents include methoxy, nitro, hydroxy, carboxyl, cyano, lower alkyl, amino, lower alkylamino, unsubstituted lower alkylamino, alkanoylamino, halogen, and the like. The substituent may be substituted one or more in all possible positions.

"Alkanoyl" means formyl, acetyl, or propionyl of C₁-C₃.

"Halogen" means fluorine, chlorine, bromine or iodine.

"Aromatic hydrocarbon group" means such as phenyl.

Salts of the general formula (I) are, for example, alkali metal salts such as lithium salts, sodium salts and potassium salts, alkaline earth metal salts such as calcium salts, ammonium salts, triethylamine, dicyclohexylamine, N-methylmorpholine, And salts with organic bases such as pyridine or amino acids such as glycine, valine, and alanine.

The compound of the present invention represented by general formula (I) can be prepared as follows using amide (II) or aldehyde (III) as a starting material.

[Production Method I]

This production method is a method for obtaining compound sulfonamide derivative I of the present invention by reacting compound II with a substituted sulfonic acid halide in the presence of a base.

Reactions with sulfonamide derivatives are substituted sulfonic acid halides, namely methanesulfonyl chloride, ethanesulfonyl chloride, propanesulfonyl chloride, butanesulfonyl chloride, pentanesulfonyl chloride, hexanesulfonyl chloride, heptanesulfonyl chloride, octane chloride Sulfonyl, benzenesulfonyl chloride, methoxybenzenesulfonyl chloride, nitrobenzenesulfonyl chloride, acetoxybenzenesulfonyl chloride, toluenesulfonyl chloride, ethylbenzenesulfonyl chloride, aminobenzenesulfonyl chloride, acetylaminobenzenesulphate Chlorinated hydrocarbon-based chloroform, dichloromethane, ether-based ethyl ether, tetrahydrofuran or aromatics, using a sulfonic acid derivative having a desired substituent such as vinyl or dimethylaminobenzenesulfonyl as a base material In solvents, such as benzene of the system, it can be achieved within tens of minutes at room temperature. According to the present invention, the carboxylic acid ester I-a in the compound of the present invention can be obtained. Carboxylic acid ester I-a can be hydrolyzed by the general method of hydrolysis of ester, and can be converted into the free carboxylic acid 1-b in the compound of this invention. Hydrolysis, hydrochloric acid, sulfuric acid, sodium hydroxide, potassium hydroxide or barium hydroxide is used as a catalyst. It is preferable to use methanol water, ethanol water, acetone water or acetonitrile water as the solvent. If necessary, carboxylic acid I-b uses bases such as sodium methoxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, dicyclohexylamine, methylmorpholine, pyridine, triethylamine, glycine, valine and alanine. Thus, by treating according to a general method, the carboxylic acid I-c in the compound of the present invention represented by the general formula (I) can be replaced.

[Production Method II]

This production process is a step of obtaining compound (I) of the present invention by reacting an alkylide (III) with an illide. The reaction between the aldehyde body and the ilide (reaction to generate a double bond) may be performed according to the general method of the witig reaction. Ilide used in the reaction is obtained by reacting a base with a phosphonium salt obtained from triphenylphosphine and an alkanoic acid having a carboxyl group on ω. Examples of the halogenated alkanoic acid to be used include 5-bromopentanoic acid or 5-chloropentanoic acid. Examples of the base include sodium hydride, dimsil sodium, dimsil potassium, n-butyllithium, tert-butoxy potassium or lithium diisopropylamide. The reaction is completed under cooling or at room temperature for several hours using, for example, ether-based ethyl ether, tetrahydrofuran or n-hexane, toluene, dimethyl sulfoxide or the like as a solvent. By this reaction, free carboxylic acid I-b in the compound of this invention can be obtained. In this reaction, only Z-form or a mixture of N-form and E-form is produced depending on the reaction conditions. As needed, you may esterify carboxylic acid I-b. The esterification reaction is a method in which a carboxylic acid and an alcohol such as methanol, ethanol, n-propanol, isopropanol, butanol or pentanol are reacted with a catalyst of dry hydrogen chloride and concentrated sulfuric acid as necessary, and the carboxylic acid is halogenated with the alcohol. Reaction with base such as dimethylaniline, pyridine, sodium hydroxide, method using alcohol metal salt, method by diazomethane or method by dimethyl sulfate and diazabicyclononene or diazabicyclo undecene It is good to perform according to. By this esterification reaction, the carboxylic acid ester I-a in the compound of this invention can be obtained. Moreover, the free carboxylic acid I-b can also be changed to carboxylsin I-c in the compound of this invention by processing according to the method of the manufacturing method I.

More specifically, the compound of the present invention represented by the general formula (Ia) among the compounds of the present invention represented by the general formula (I) may be represented by exo-hexahydro-4,7-epoxyisobenzofuran-1,3-dione [ TA Eggelte et al., Tetrahedron, Vol. 29, p. 2445, 1973], exo-hexahydro-4,7-epoxyisobenzofunnan-1-one (USP 4,143,053) or 5 (2) -7 -[Endo-3- (hydroxymethyl) -7oxabicyclo [2,2,1] hept-endo-2-yl] -5-heptenate methyl ester [pwSprague), etc. J. Med. Chem., Vol. 28, p. 1580, 1985], the compound of the present invention represented by the general formula (Ib) as a starting material and is represented by 5 (2) -7 -[(1S, 2S3S, 5R) -3- (amino-6,6-dimethylbicyclo [3,3,1] hept-2-yl] -5-heptenic acid methyl ester [examine 58-13551], (1S, 2S, 3S, 5R) -2-formylmethyl-3-benzenesulfonamido-6,6-dimethylbicyclo [3.1.1] heptane, or (1S, 2R, 5R) -6,6- Dimethyl-3-keto-2- [2- (tetrahydro What can be each prepared by a 2-yloxy) ethyl] bicyclo [3,1,1] heptane [Patent places 58-13551] as a starting material.

All of the products of the present invention represented by the general formula (Ia) in the reaction fixed formula are racemates and are represented as only one active substance for convenience. The product of the present invention represented by general formula (Ib) is an optically active substance having an absolute configuration represented by the structural formula. In addition, the dashed line in a process formula shows S or R-batch or a mixture thereof.

[Process Formula Ia-1]

[Step 1]

This step is a step of derivatizing the acid anhydride 1 with an alcohol and inducing it to Compound 2. The esterification reaction is achieved by refluxing an acid anhydride, for example, in alcohols such as methanol, ethanol, propanol, isopropanol, butanol or tert-butanol or in phenols for several tens of minutes to several hours.

[Second process]

This step is a step of azating the second carboxyl group of compound 2, transposing it to isocyanane, and reacting with alcohol to lead to urethane 3. This step can be achieved by the clease dislocation. That is, the acid chloride or carboxyl group obtained by treating the carboxyl group with thionyl chloride, phosphoryl chloride or phosphorus pentachloride is present in the presence of a base catalyst such as triethylamine, 4-dimethylaminopyridine, ethyl chloroformate, isobutoxycarbonyl chloride, and the like. An azide compound is obtained by reacting sodium azide with an acid anhydride obtained by reaction between water and paper receiving under cooling in a solvent such as acetone, dimethylformamide, dimethyl sulfoxide, ethyl acetate or tetrahydrofuran. Isocyanate is obtained by refluxing an azide compound in benzene, toluene, diphenyl ether for several tens of minutes to several hours. The alcohol reacted with isocyanate easily obtains primary amines from urethanes obtained such as isobutanol, tert-butanol, diisopropylmethanol, cyclopentanol, cyclohexanol, benzyl alcohol, diphenylmethanol or triphenylmethanol. It is desirable to be able to. This reaction can be achieved by refluxing for several hours in a solvent such as benzene, dichloromethane, chloroform or ethyl acetate in the presence of a base such as triethylamine, 4-dimethylaminopyridine, 4-pyrrolidinopyridine or the like as necessary.

[Third process]

This step is a step wherein aldehyde 4 is obtained by reducing the ester of compound 3. The reduction reaction was carried out using a reducing agent such as sodium bis (2-methoxyethoxy) aluminum sodium, diisobutylaluminum hydride, lithium trihydride aluminum hydride, or lithium trihydride-butoxyaluminum hydride. In solvents such as ethyl ether, tetrahydrofuran, aromatic benzene, toluene and the like, the reaction is completed in several tens of minutes to several hours under room temperature or cooling. In this reaction, cyclic amines such as pyrrolidine, piperidine, morpholine, N-methylpiperidine, and N-ethylpiperidine may be added as necessary to control the reducing power. In this process, aldehyde 4 may be reduced again to produce alcohol 5.

[4th process]

This step is a step of oxidizing alcohol 5 to obtain aldehyde 4. Oxidation reaction uses chromic acid-based Jones reagent, Collins reagent, pyridinium, chlorochromate, pyridinium, dichromate, etc., and dimethylformamide, dimethyl sulfoxide, chlorinated hydrocarbon-based chloroform, dichloromethane, ether It can be achieved for several hours under cooling in a solvent such as ethyl ether, tetrahydrofuran or acetone or at room temperature.

[5th process]

This step is a step of obtaining enoether 6 by reacting lide with aldehyde 4. This reaction may be performed according to the general method of the Wittig reaction. Ilide is synthesized by applying a base to a phosphonium salt formed from triphenylphosphine and chloromethyl ether or bromomethyl ether. As the base, sodium hydride, n-butyllidium, potassium tert-butoxide, lithium diisopropylamine, dimsil sodium, dimsil potassium and the like are used. The reaction is completed in a few hours under cooling or at room temperature using ether-based ethyl ether, tetrahydrofuran or n-hexane, toluene, dimethyl sulfoxide and the like.

[Sixth Step]

This step is an acid hydrolysis of enol ether 6 to produce aldehyde 7. Formic acid, acetic acid, hydrochloric acid, sulfuric acid, perchloric acid and the like are used as the acid catalyst. As the solvent, alcohol-based methanol, ethanol, ether-based ethyl ether, tetrahydrofuran or acetonitrile and the like are used. The reaction is achieved in tens of minutes to hours under room temperature or warming.

[7th process]

This step is a step wherein aldehyde 7 is reacted with lide to obtain starting material IIa of the compound of the present invention. The reaction of the aldehyde body and the illi (reaction to generate a double bond) may be carried out in accordance with the general method of the Wittich reaction. Ilide used for the reaction is synthesized by applying a base to a phosphonium salt obtained from triphenylphosphine and a halide of alkanoic acid having a carboxyl group on ω. As the halogenated alkanoic acid used in this reaction, for example, 5-bromopentanoic acid or 5-chloropentanoic acid and the like. Examples of the base include sodium hydride, dimsil sodium, dimsil potassium, n-butyllithium, tert-butoxy potassium or lithium diisopropylamide. This reaction is completed in several hours under cooling or at room temperature using, for example, ether-based ethyl ether, tetrahydrofuran or n-hexane, toluene, dimethyl sulfoxide and the like as a solvent. This reaction produces a carcass only or a mixture of carcasses and carcasses, depending on the reaction conditions. It is then esterified to protect the carboxylic acid in subsequent reactions. The esterification is a method of reacting a carboxylic acid with an alcohol such as methanol, ethanol, n-propanol, isopropanol, butanol or pentanol as necessary with a catalyst of dry hydrogen chloride and concentrated sulfuric acid, the carboxylic acid as a halide and the alcohol and dimethyl Reaction with bases such as aniline, pyridine, sodium hydroxide, a method using an alcohol metal salt, a method by diazo methane, or a method by dimethyl sulfate and diazabicycloene or diazabicyclo undecene You can do it accordingly.

[Step 8]

This step is a step wherein the starting material IIa of the compound of the present invention is reacted according to Preparation I to obtain the compound of the present invention.

In the case where the amino group is protected prior to the reaction, a method usually used when removing the amino protecting group, for example, hydrolysis using acid such as hydrochloric acid and sulfuric acid or base such as sodium hydroxide, potassium hydroxide, barium hydroxide, and trifluorine What is necessary is just to carry out by acid decomposition or hydrogenolysis by roacetic acid, etc. Although it can be used for the next reaction as it is, even if it is an ammonium salt, it can also be set as a free amine body by processing with a suitable basic substance, ie, sodium carbonate, sodium hydrogencarbonate, etc. as needed.

Carboxylic acid esters Ia-a (2R ^* -t), carboxylates Ia-c (2R ^* -t) and 2R ^* -cis- of 2S ^* -trans-sulfonamide derivatives in the compounds of the present invention by this process Carboxylic acid esters Ia-a (2R ^* -t) of sulfonamide derivatives Ia (2R ^* -t), free carboxylic acids Ia-b (2R ^* -t), carboxylates Ia-c (2R ^* - t) can be obtained.

[Process Formula I a-2]

[Process Formula I a-2]

[Step 1]

This step is a step of ring-opening by cyanating lactone 8 to lead to carboxylic acid 9. This process is accomplished by heating in a solvent such as dimethyl sulfoxide or dimethylformamide using a metal cyanide, for example potassium cyanide, sodium cyanide, copper cyanide, or the like as a cyanating agent.

Second Process

This step is a step of esterifying the carboxyl group of compound 9 to promote isomerization in the next step. What is necessary is just to perform esterification according to the general method of esterification of a carboxyl group. For example, a method using alcohols such as methanol, ethanol, propanol, isopropanol, benzyl alcohol, a method using diazomethane, diphenyl diazomethane, or the like or triphenylmethyl chloride, phthalamidomethyl chloride, 4 chloride According to the method using picolyl. As needed, you may use acid, such as hydrochloric acid, a sulfuric acid, and p-toluenesulfonic acid, or bases, such as sodium hydroxide, potassium hydroxide, barium hydroxide, triethylamine. The reaction is carried out in several tens of minutes to several hours at room temperature or under heating using methanol, ethanol, ether ethyl ether, tetrahydrofuran, chlorohydrocarbon dichloromethane, chloroform or methyl acetate, dimethylformamide as a solvent. Is achieved.

[Third process]

This step is a step of isomerizing compound 10, which is a cis body, into a thermodynamically stable trans body 11. This process is carried out in a few hours at room temperature in a solvent such as methanol methanol, ethanol, ether ethyl ether, tetrahydrofuran and the like. If necessary, bases such as sodium hydroxide, potassium hydroxide and barium hydroxide may be added. In the case of adding a base, the ester is hydrolyzed to give carboxylic acid.

[4th process]

This step is a step of azide the carboxyl group of compound 11 to displace it into isocyanate, and then react with alcohol to lead to urethane 12. This process can be accomplished by the clease potential. It is preferable to make this process react according to the 2nd process of process formula Ia-1.

[5th process]

This step is a step of reducing the cyan group of Compound 12 to aldehyde 13. In this step, diisobutylaluminum hydride is used as the reducing agent. The reaction is completed in a few hours under cooling in a solvent such as ether ether, ether ether, tetrahydrofuran, aromatic toluene or hexane.

[Sixth Step]

This step is a step of reacting aldehyde 13 with illi to obtain starting material IIa (2R ^* -t) of the compound of the present invention. The reaction of the aldehyde body and the illi (reaction to generate a double bond) may be carried out in accordance with the general method of the Wittich reaction. What is necessary is just to react this process according to the Wittich reaction of the 7th process base material of process formula Ia-1.

[7th process]

This step is a step wherein the starting material IIa (2R ^* -t) of the compound of the present invention is reacted according to the step Ia-1 8th step to obtain the compound of the present invention. Carboxylic acid ester Ia-a (2S ^* -6) of 2R ^* -trans-sulfonamide derivative Ia (2R ^* -t) in the compound of this invention by this process, free carboxylic acid Ia-b (2R ^*) -t), carboxylate Ia-c (2R ^* -t) can be obtained.

[Process Formula Ia-3]

Process Ia-3

[Step 1]

This step is a step of oxidizing hydroxy of compound 20 to carboxy. The oxidation reaction is carried out in a solvent such as chlorinated hydrocarbons such as dimethylformamide, dimethyl sulfoxide, chloroform or acetone using chromic acid-based oxidizing agents such as Jones reagent, Collins reagent, pyridinium, chromium chromate or pyridinium and dichromate. It can be achieved in a few hours under cooling or at room temperature.

Second Process

This step is a step of converting the carboxy of compound 21 into urethane IIa (2S ^* -c) by agitating the carboxyl compound, transposing it to isocyanate and reacting with alcohol. This step may be performed according to the methods of Step Ia-1 and Second Step.

[Third process]

This step is a step wherein compound IIa (2S ^* -c) is reacted according to step Ia-1, step 8 to obtain a compound of the present invention. In the present process, 2S ^* - cis-acid ester Ia-a (2S ^* -c) of the sulfonamide derivatives, Ia-b-carboxylic acid of the glass (2S ^* -c) or the carboxylate Ia-c ( 2S ^* -c)

[Process Formula Ib-1]

[Process Formula Ib-1]

[Manufacturing Method A]

[Step 1]

This step is a step of obtaining the compound of the present invention by reacting according to the starting material IIb (2R * -t) step Ia-1 8th step of the compound of the present invention. Carboxylic acid Ib-b (2R * -t) of 2S-trans-sulfonamide derivative Ib (2R * -t) carboxylic acid ester Ib-a (2R * -t) glass in the compound of this invention by this process. Cap acid salt Ib-c (2R * -t) can be obtained.

[Manufacturing Method B]

[Step 1]

This step is a step wherein the compound of the present invention is obtained by reacting according to Production Method IIIb (2R * -t) Production Method II of the compound of the present invention. Carboxylic acid Ib-b (2R * -t) of 2S-trans-sulfonamide derivative Ib- (2R * -t) carboxylic acid ester Ib-a (2R * -t) glass in this compound by this process. ) Carboxylic acid salt Ib-c (2R * -t) can be obtained.

[Process Formula Ib-2]

[Process Formula Ib-2]

[Step 1]

This step is a step of azating the hydroxy group of the compound 14. First, hydroxy 14 is treated with thionyl chloride to make a chloride, or hydroxy 14 is converted to p-toluenesulfonyl chloride, methanesulfonyl chloride, in the presence of a base catalyst such as triethylamine, 4-dimethylaminopyridine, Trifluoromethane sulfonic anhydride and the like chlorinated hydrocarbon-based chloroform, dichloromethane, ether-based ethyl ether, tetrahydrofuran or acetone, dimethylformamide, dimethyl sulfoxide, ethyl acetate and the like to react for a few minutes to several hours under cooling Obtain an intermediate. The azide compound 15 can be obtained by heating the obtained intermediate and sodium azide in hexamethylphosphamide, dimethylformamide, dimethyl sulfoxide or diphenyl ether for several tens of minutes to several hours.

Second Process

This step is a step wherein amide 16 is obtained by reducing azide compound 15. The reaction is achieved at room temperature or under heating for several hours in a solvent such as ethyl ether, tetrahydrofuran or the like based on ether by using a metal hydride compound such as lithium aluminum hydride as a reducing agent or by using triphenylphosphine.

[Third process]

This step is a step of introducing an amino protecting group into amine 16. Amine, i.e., trifluoroacetic anhydride, trifluoroacetyl, benzyloxycarbonyl chloride, triphenylmethyl chloride and the like, in a solvent such as chloroform, dichloromethane, aromatic benzene, toluene, etc. Just react with pyridine, sodium hydrogen carbonate and the like. The reaction is achieved in tens of minutes to several hours at room temperature or under heating.

[4th process]

This step is a step of removing the hydroxy protecting group by acid hydrolysis. The reaction is carried out using acetic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, or the like as an acid catalyst according to a general method of hydrolysis, such as alcohol-based methanol, ethanol, ether-based ethyl ether, tetrahydrofuran, and the like. In a solvent.

[5th process]

This step is a step of oxidizing alcohol 18 to form an aldehyde. The reaction may be performed by using a combination of dimethyl sulfoxide and trifluoroacetic acid, thionyl chloride or oxalyl chloride, or using a chromic acid-based oxidizing agent such as Jones reagent, Collins reagent, pyridinium, chlorochromate or pyridinium, dichromate, and the like. Do it according to the method. As the solvent, chloroform, dichloromethane or the like of chlorinated hydrocarbon can be used. This aldehyde body is easily closed and exists as hemiacetal body 19.

[Sixth Step]

This step is a step wherein hemiacetal 19 is reacted with illi to obtain starting material IIb (2S-c) of the compound of the present invention. This step is carried out according to the Wittwig reaction of Step 7a-1, Step 7.

[7th process]

This step is a step wherein the compound of the present invention is obtained by reacting the starting material IIb (2S-c) of the compound of the present invention according to the step 8a-1. Carboxylic acid ester Ib-a (2S-c) of 2S-trans-sulfonamide derivative Ib (2S-c) in the compound of this invention in accordance with this process, free carboxylic acid Ib-b (2S-c), Carboxylic acid salt Ib-c (2S-c) can be obtained.

[Process Formula Ib-3]

[Step Ib-3]

[Step 1]

This step is a step of isomerizing Compound 22 '(2R ^* ) to Compound 22' (2R ^* ). The reaction is carried out in a solvent such as alcohols, for example methanol or ethanol, ethers such as diethyl ether or tetrahydrofuran, aromatics such as toluene or xylene or dimethyl sulfoxide or dimethylformamide. It can be achieved in hours to tens of hours at room temperature or under heating. A catalytic amount of basic material such as diazabicyclononene, diazabicycloundecene, pyrrolidine-acetic acid, piperidine-acetic acid, sodium methoxide, potassium tert-butoxide, lithium isopropylamide, Triethylamine etc. may be added.

Second Process

This step is a step of reducing ketone 22 '(2R ^* -t) alcohol to 22' (2R ^* -t). Examples of the reducing agent include metal hydrides such as lithium aluminum hydride, hydride 21, methoxyaluminum lithium, trihydride tert-butoxyaluminum lithium, lithium borohydride or sodium borohydride. As the solvent, for example, alcohol-based methanol or ethanol or ether-based diethyl ether or tetrahydrofuran may be used in anhydrous state. The reaction can be performed for several hours under cooling or heating.

The compound of the present invention can be obtained by reacting the alcohol 22 (2R ^* -t) obtained in this step by the method up to the seventh step in the step Ib-2 and the first step. 2R ^* - cis-sulfonamide derivatives, the carboxylic acid ester Ib-a (2R ^* -c) or the carboxylate Ib-c (2R ^* -c) is obtained.

[Third process]

This step is a step of converting the hydroxy of compound 22 (2R ^* -t) into an azide having a hydroxy-like configuration. First, compound 22 (2R ^* -t) is reacted with a nucleophilic reagent under Mitsunobu conditions, i.e., in the presence of azodicarboxylic acid ethyl ester and triphenylphosphine to obtain an intermediate for azide formation. Examples of nucleophilic reagents include methyl bromide, methyl iodide, p-toluenesulfonic acid methyl ester, benzenesulfonic acid methyl ester, methanesulfonic acid methyl ester, zinc p-toluenesulfonic acid, zinc benzene sulfonate, zinc methane sulfonate, and lithium P-toluene sulfonate. And lithium methane sulfonate or lithium methane sulfonate. As a solvent, it can carry out in ether diethyl ether, tetrahydrofuran, or room temperature in several hours. This reaction allows compound 22 (2R ^* -t) to be converted to the corresponding sulfonic acid esters or halides, each having an inverted configuration.

Azide 22 (2R ^* -t) can be obtained by reacting an intermediate in a solvent such as sodium azide, hexamethylphosphamide, dimethylformamide, dimethyl sulfoxide or diphenyl ether for several tens of minutes. The compound of this invention can be obtained by making the azide 23 (2R ^* -t) obtained by this process react with the method of process Ib-2, 2nd process-7th process. Carboxylic acid Ib-a (2R ^* -t), free carboxylic acid Ib-b (2R ^* -t) or carboxylic acid Ib-c (2R ^* -) to the carboxylic acid of the 2R ^* -trans-sulfonamide derivative t) can be obtained.

In the formula, R ', R' and R2 are as described above, respectively. R3 represents hydrogen, linear or branched alkyl, for example methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl and the like or benzyl. R 'represents diisopropylmethyl, isobutyl, tert-butyl, cyclopentyl, benzyl, diphenylmethyl or triphenylmethyl. Prot-N usually refers to those used as amino protecting groups, for example trifluoroacetyl, benzyloxycarbonyl, tert-butoxycarbonyl or triphenylmethyl and the like. Prot-C represents a carboxy protecting group such as methyl, ethyl, propyl, isopropyl, tert-butyl, benzyl, diphenylmethyl, triphenylmethyl, phthalimidemethyl or 4-picolyl. Dashed lines indicate the R or S- configuration or a mixture of both.

The salt of the compound represented by general formula (I) is as above-mentioned.

Hereinafter, the present invention will be described in detail by showing reference examples, examples, and physical constants, but the scope of the present invention is not limited thereto.

In the following Reference Examples and Examples, each compound is represented as one enantiomer in each step. The coordination of the optically active substance is indicated by the R and S notation of the compound name or compound number.

Reference Example 1

Cis-exo-7-oxabicyclo [2.2.1] heptane-2,3-ticarboxylic acid monomethyl ester 2a

A mixture of 24.3 g of exo-hexahydro-4,7-epoxyisobenzofuran-1,3-dione 1 and 200 ml of anhydrous methanol is heated under reflux for 18 hours. After concentration under reduced pressure, the crystalline residue was recrystallized with ethyl acetate to give 27.5 g of the title compound 2a (yield 95.1%).

Melting Point 144 ~ 146 ℃

IR (nusol): υmax 1737, 1697㎝ ^-1

NMR (DMSO-d ₆ ): δ ppm 1.52 (4H, s), 2.98 (2H, s), 3.50 (3H, s), 4.66 (2H, s).

Elemental Analysis (C ₉ H ₁₂ O ₅ )

Calculated Value: C; 54.00, H; 6.04

Found: C; 54.04, H; 5.93

Reference Example 2

Cis-exo-3-benzyloxycarbonylamino-7-oxabicyclo [2,2,1] heptane-exo-2-carboxylic acid methyl ester 3a

Acetone is added until a mixture of 46.8 g of carboxylic acid 2a obtained in Reference Example 1 and 42 ml of water is a homogeneous solution. Under ice-cooling, a 490 mL solution of 27.8 g of acetone of triethylamine is added, followed by a 30 minute solution of 120 mL of acetone of 34.1 g of ethyl chloroformate. After stirring the mixture at 3 ° C. for 30 minutes, an aqueous solution of 23.2 g of sodium azide is added in 30 minutes under ice cooling. The mixture is stirred at 3 ° C. for 1 h, then poured into ice water and extracted with ether. The organic layer is washed with saturated brine, dried over magnesium sulfate, and the solvent is removed under reduced pressure to obtain an oily substance.

IR (Film): υmax 213cm ^-1

The TKS azide described above is dissolved in 200 ml of benzene and heated to reflux for 2 hours. A small amount is removed and the solvent is removed under reduced pressure to obtain an oily substance.

IR (Film): υmax 2230cm ^-1

To the remaining solution was added 12 ml of triethylaALS and 25 ml of benzyl alcohol and heated under reflux for 4 hours. Distillable material under reduced pressure is distilled off and the residue is crystallized in ether to give colorless crystals 3a (47.2 g, 66.1% yield in carboxylic acid).

Melting point 108 ℃

IR (nusol): υmax 3350, 1728, 1716 cm ^-1

NMR (CDCl ₃ ): δppm 1.3 ~ 2.0 (4H, m), 2.95 (1H, d, J = 10㎐), 3.55 (3H, s), 4.2 ~ 4.5 (2H, m), 4.79 (1H, d, J = 3 Hz), 5.09 (2H, s), 5.50 (1H, d, J = 10 Hz), 7.36 (5H, s).

Elemental Analysis (C ₁₆ H ₁₉ NO ₅ )

Calculated Value: C; 62.94, H; 6.27, N; 4.59

Found: C; 62.74, H; 6.09, N; 4.37

Reference Example 3

[Exo-3-benzyloxycarbonylamino-7-oxybicyclo [2,2,1] hept-2-yl] formaldehyde 4a and [exo-3-benzyloxycarbonylamino-7-oxabicyclo [ 2,2,1] hept-exo-2-yl] methanol 5a

A 14 mL solution of 5.5 mL of N-methylpiperazine benzene is added to 26 mL of a benzene solution of 35% bis (2-methoxyethoxy) aluminum sodium in ice stream under nitrogen cooling. The mixture was stirred at 0 ° C. for 10 minutes, and then added to a benzene suspension of 12.3 g of ester 3a obtained in Reference Example 2 under ice cooling, and the reaction solution was stirred at room temperature for 2.5 hours. Water and then dilute hydrochloric acid are added dropwise under ice-cooling, then separated into two layers, and the aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with saturated brine, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue was subjected to silica gel (150 g) column chromatography using hexane-ethyl acetate (1: 1) as the eluent to obtain 0.622 g of raw material 3a (yield 5.1%). Elution with ethyl acetate again yields 4.4 g of an epimer mixture 4a (yield 43.8%) and an alcohol derivative 5a of an about 1: 1 aldehyde derivative containing about 10% of the aldehyde derivative. This alcohol derivative is purified by crystallization with ether (0.222 g, 2.0% yield).

Physical Constants of Aldehyde Derivatives 4a:

NMR (CDCl ₃ ): δppm 1.2 ~ 2.0 (4H, m), 2.7 ~ 3.0 (1H, m), 4.0 ~ 4.5 (2H, m), 4.7 ~ 4.9 (1H, m), 5.06 (2H, s), 5.5 to 5.9 (1H, m), 7.30 (5H, s), 9.50 (0.5H, d, J = 2 Hz), 9.73 (0.5H, s).

Physical constants of alcohol derivative 5a:

Melting Point 174 ~ 175 ℃

IR (nusol): υmax 3330, 1685㎝ ^-1

NMR (CDCl ₃ ): δppm 1.48 (4H, s), 1.95 (1H, m), 3.19 (1H, d, J = 4Hz), 3.79 (1H, t, J = 10Hz), 4.20 (1H, s), 4.39 (1H, s), 4.50 (1H, t, J = 2 Hz), 5.01 (2H, s), 7.11 (1H, d, J = 10 Hz). 7.35 (5H, s).

Elemental Analysis (C ₁₅ H ₁₉ NO ₄ )

Calculated Value: C; 64.97, H; 6.91, N; 5.05

Found: C; 64.73, H; 6.70, N; 5.06

190.5 mg of alcohol derivative 5a are added to a suspension of 301 mg of pyridinium chlorochromate at one time. After stirring for 2 hours at room temperature, ether is added. The mixture is eluted with ether and subjected to Florisil chromatography and crystallized with benzene to give 138 mg (73%) of cis-exo.

Melting point 117 ~ 119 ℃

IR (nusol): υmax 3300, 1706 cm ^-1

NMR (CDCl ₃ ): δppm 1.2 ~ 2.0 (4H, m), 2.90 (1H, d, J = 9Hz), 4.3 ~ 4.6 (2H, m), 4.93 (1H, m), 5.07 (2H, s), 5.30 (2H, m), 7.36 (1H, s). 9.56 (1H, doublet, J = 2 Hz).

Elemental Analysis (C ₁₅ H ₁₇ NO ₄ )

Calculated Value: C; 65.44, H; 6.22, N; 5.09

Found: C; 65.55, H; 6.17, N; 4.96

Reference Example 4

2- (2-methoxyethenyl) -exo-3-benzyloxycarbonylamino-7-oxabicyclo [2,2,1] heptane 6a

36.6 g of methoxymethyltriphenylphosphonium chloride is suspended in 100 ml of toluene and dried by distilling off a small amount of toluene. Separately, lithium diisopropylamide synthesized in a nitrogen stream at 0 ° C. in 70 ml of a 1.6 M n-butyllithium hexane solution, 11.0 g of diisopropylamine and 40 ml of anhydrous tetrahydrofuran was added to the suspension at 0 ° C. for 30 minutes. Drop over. After the mixture was stirred at 0 ° C. for 2 hours, a solution of 20 ml of anhydrous tetrahydrofuran and 20 ml of anhydrous toluene obtained in Reference Example 3 was added dropwise at 0 ° C. The mixture is stirred at 0 ° C. for 2.5 hours and then poured into poor water. The mixture is separated into two layers, and the aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with saturated brine, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was chromatographed on silica gel (160 g) using hexane-ethyl acetate (1: 1) as eluent to give 6.5 g of Table 3 compound 6a and 0.9 g of ester 3a incorporated in Reference 3.

Reference Example 5

2- [exo-3-benzyloxycarbonylamino-7-oxabicyclo [2,2,1] hept-2-yl] acetaldehyde 7a

3.07 g of ether 6a obtained in Reference Example 4 is dissolved in 90% formic acid (10 ml) and left to stand at room temperature for 2 hours. Careful addition to aqueous sodium carbonate solution is followed by extraction with trichloromethane. The extract was washed with saturated brine and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 2.8 g of an oily substance 7a.

IR (Film): υmax 1720cm ^-1

Reference Example 6

5 (Z) -7- [exo-3-tert-butoxycarbonylamino-7-oxabicyclo [2,2,1] hept-2-yl] -5-heptenic acid methyl ester IIa-b

In a stream of nitrogen, 13.9 g of potassium tert-butoxide at room temperature are added to a 50 ml anhydrous tetrahydrofuran suspension of 27.5 g of 4-carboxybutyltriphenylphosphonium bromide at once. After the mixture was stirred for 30 minutes at room temperature, 6.0 g of anhydrous tetrahydrofuran (20 ml) solution of aldehyde 7a obtained in Reference Example 5 was added dropwise at room temperature. The mixture is stirred at room temperature for 1 hour, and then poured into an aqueous solution of hydroxide. The organic layer is separated, and the aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with saturated brine and dried over sodium sulfate. The solvent is distilled off under reduced pressure. The residue was chromatographed on silica gel (200 g) using hexane-ethyl acetate (1: 1) as the eluent.

3.2 g of the obtained crude carboxylic acid is dissolved in 10 ml of ether and treated with an excess ether solution of diazomethane. The residue was chromatographed on silica gel (90 g) with hexane-ethyl acetate (2: 1) as eluent, and tert-butoxycarbonyl derivative (hereinafter abbreviated as BOC derivative) II5-b 0.95 g (aldehyde yield 13) %) And benzyloxy carbonyl derivative IIa-a1.25 g (15.6% yield from aldehyde).

Physical constants of BOC derivatives:

NMR (CDCl ₃ ): δppm 1.45 (9H, s), 1.5 ~ 1.9 (6H, m), 1.9 ~ 2.4 (7H, m), 3.25 (1H, dd, J = 10,3Hz), 3.69 (3H, s ), 4.29 (1H, d, J = 5 Hz), 4.43 (1H, t, J = 5 Hz), 4.75 (1H, m), 5.3-5.5 (2H, m).

Physical constants of benzyloxycarbonyl derivative IIa-a:

NMR (CDCl ₃ ): δppm 1.3 ~ 1.9 (7H, m), 1.9 ~ 2.5 (6H, m), 3.30 (1H, dd, J = 9,4Hz), 3.62 (3H, s), 4.26 (1H, d , J = 4 Hz, 4.41 (1H, t, J = 4 Hz), 5.06 (2H, s), 4.9-5.2 (1H, m), 5.31 (2H, m), 7.31 (5H, s).

Example 1

5 (Z) -7- [exo-3-benzenesulfonamide-7-oxabicyclo [2,2,1] hept-endo-2-yl] -5-heptenic acid methyl ester Ia-aa (2S ^* - t)

To 0.675 g of the BOC derivative IIa-b obtained in Reference Example 6, 3 ml of trifluoroacetic acid was added and left to stand at room temperature for 1 hour. Concentrate under reduced pressure and add hexane. Repeat this procedure to remove excess trifluoroacetic acid. 0.7 g of triethylamine and 0.35 g of benzenesulfonyl chloride are added to a 10 ml solution of dichloromethane of the salt described above, and left to stand at room temperature for 1 hour. After adding hydrochloric acid under ice-cooling, the organic layer is separated. The aqueous layer is extracted with dichloromethane. The organic layers are combined and washed with sodium bicarbonate aqueous solution followed by saturated saline solution. The solvent is distilled off under reduced pressure. The residue was subjected to silica gel (25 g) chromatography using hexane-ethyl acetate (2: 1) as eluent to afford 0.417 g (yield 55.5%) of trans derivative Ia-aa (2R ^* -t).

IR (Film): υmax 3270, 1735, 1162 cm ^-1

NMR (CDCl ₃ ): δppm 1.1 ~ 2.4 (13H, m), 2.92 (1H, dd, J = 9,3Hz), 3.69 (3H, s), 4.12 (1H, d, J = 6Hz), 4.40 (1H , t, J = 6 Hz), 5.0-5.4 (3H, m), 7.60 (2H, m), 7.90 (2H, m).

Example 2

5 (Z) -7- [exo-3-benzenesulfonamide-7-oxabicyclo [2,2,1] hept-exo-2-yl] -5-heptenic acid methyl ester Ia-aa (2S ^* - t)

The BOC derivative IIa-b obtained in Reference Example 6 was treated as in Example 1, and the initial eluted portion was crystallized with benzene-hexane to obtain 15 mg of cis derivative Ia-aa (2R ^* -c) (2% yield). .

Melting Point 93 ~ 94 ℃

Physical constant of cis derivative Ia-aa (2R * -c):

IR (KBr): υmax 3420, 3195, 1734, 1165cm ^-1

NMR (CDCl ₃ ): δppm 1.2 ~ 2.4 (13H, m), 3.60 (1H, m), 3.70 (3H, s), 3.93 (1H, t, J = 2Hz), 4.16 (1H, t, J = 2Hz ), 4.89 (1H, d, J = 10 Hz), 5.48 (2H, m), 7.58 (3H, m), 7.89 (2H, m).

Example 3

5 (Z) -7- [exo-3-benzenesulfonamide-7-oxabicyclo [2,2,1] hept-endo-2-yl] -5-heptenic acid Ia-ba (2R ^* -t) And salts Ia-ca (2R ^* -t)

To 0.366 g of methanol (7.2 ml) solution of ester Ia-aa (2R ^* -t) obtained in Example 1, 7.2 ml of 10% sodium hydroxide solution was added and left overnight. Acidic with dilute hydrochloric acid, and the mixture is extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure to obtain 348 mg of oily substance Ia-ba (2R ^* -t) (yield 98.6%).

IR (Film): υmax 3220, 1708, 1162 cm ^-1

NMR (CDCl ₃ ): δppm 1.1 ~ 2.5 (13H, m), 2.93 (1H, dd, J = 10,2Hz), 4.13 (1H, d, J = 3Hz), 4.43 (1H, t, J = 2Hz) , 5.20 (1H, m), 5.45 (1H, d, J = 10 Hz), 7.56 (3H, m), 7.90 (2H, m), 9.00 (1H, s).

311 mg of the obtained carboxylic acid Ia-ba (2R ^* -t) was dissolved in methanol, 2.80 ml of 0.263 M sodium methoxide methanol solution was added, and the residue obtained by distilling off the solvent under reduced pressure was dissolved in water, Activated charcoal is added and filtered. The obtained aqueous solution is freeze-dried to obtain sodium salt Ia-ca (2R ^* -t) having the following physical constants.

IR (KBr): υmax 3420, 3260, 1565, 1324, 1159 cm ^-1

Example 4

5 (Z) -7- [exo-3-benzenesulfonamide-7-oxabicyclo [2,2,1] hept-endo-2-yl] -5-heptenic acid Ia-ba (2R ^* -t) And salts thereof Ia-ca (2S ^* -c)

The ester obtained in Example 2 was treated in the same manner as in Example 3 to obtain the title compound Ia-ba (2R ^* -c).

NMR (CDCl ₃ ): δppm 1.2 ~ 2.5 (13H, m), 3.60 (1H, m), 3.99 (1H, d, J = 2Hz), 4.19 (1H, ∂, J = 2Hz), 5.36 (2H, m ), 5.48 (1H, m), 7.58 (3H, m), 7.90 (2H, m).

The resulting carboxylic acid Ia-ba (2S ^* -c) is treated in the same manner as in Example 3 to obtain sodium salt Ia-Ca (2S ^* -c) having the following physical constant.

IR (KBr): υmax 3415,3270,1563,1317,1157㎝ ^-1

Reference Example 7

Exo-2-cyanomethyl-7-oxabicyclo [2,2,1] -exo-3-carboxylic acid 9

A mixture of 4.3 g of exo-hexahydro-4,7-epoxyisobenzofuran-1 (3H) -one 8, 2.0 g of potassium cyanide and 30 ml of dimethylsulfoxide is heated at 180 ° C. under stirring for 2 hours. Water, then dilute hydrochloric acid, is carefully added to make it acidic. The mixture is extracted with ethyl acetate. The extract is washed with water and dried over sodium sulfate, and then the solvent is distilled off under reduced pressure. The residue is crystallized with ether to give 2.1 g (yield 41.6%) of the title compound 9 having the following physical terms.

Melting point 124 ~ 126 ℃

IR (Nusol): υmax 2325,1710,1693㎝ ^-1

NMR (CDCl ₃ ): δppm 1.6 ~ 2.2 (4H, m), 2.47 (2H, s), 2.5 ~ 3.0 (2H, m), 4.55 (1H, d, J = 4Hz), 4.86 (1H, d, J = 3 Hz), 8.09 (1 H, s).

Elemental Analysis (C ₉ H ₁₁ NO ₃ )

Calculated Value: C; 59.66, H; 6.12, N; 7.73

Found: C; 59.50, H; 6.13, N; 7.76

Reference Example 8

(1) exo-2-cyanomethyl-7-oxabicyclo [2,2,1] heptane-exo-3-carboxylic acid methyl ester 10a

383 mg of the carboxylic acid 9 is added in small portions to an excess ether solution of diazomethane. Concentrated under reduced pressure, and the residue was purified by silica gel (10 g) column chromatography using hexane-ethyl acetate (1: 1) as the elution solvent, and then recrystallized from benzene hexane to give the title compound 10a having the following physical constants. 330 mg (80.4% yield) are obtained.

Melting Point 88 ~ 89 ℃

IR (Nusol): υmax 2319,1724㎝ ^-1

NMR (CDCl ₃ ): δppm 1.3 ~ 2.1 (4H, m), 2.42 (2H, s), 2.4 ~ 2,8 (1H, m), 2.83 (1H, d, J = 8Hz), 3.71 (3H, s ), 4.50 (1H, d, J-5 Hz), 4.85 (1H, d, J = 3 Hz).

Elemental Analysis (C ₁₀ H ₁₃ NO ₃ )

Calculated Value: C; 61.84, H; 6.23, N; 7.21

Found: C; 61.35, H; 6.67, N; 7.23

(2) exo-2-cyanomethyl-7-oxabicyclo [2,2,1] heptane-endo-3-carboxylic acid 11

5.5 g of the ester 10a is dissolved in 50 ml of 10% potassium hydroxide methanol solution and stirred at room temperature for 1 hour. It is made acidic with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate and the solvent was distilled off under reduced pressure. The crystalline residue is recrystallized from benzene and then ether to give 3.95 g (yield 77.0%) of the title compound 11 having the following physical constants.

Melting point 103 ℃

IR (Nusol): υmax 2240,1702㎝ ^-1

NMR (CDCl ₃ ): δppm 1.4 ~ 2.1 (4H, m), 2.2 ~ 2.8 (4H, m), 4.41 (1H, d, J = 3Hz), 4.85 (1H, d, J = 5Hz), 10.29 (1H , s).

Elemental Analysis (C ₉ H ₁₁ NO ₃ )

Calculated Value: C; 59.66, H; 6.12, N; 7.73

Found: C; 59.62, H; 6.11, N; 7.77

Reference Example 9

Exo-2-cyanomethyl-endo-3- (tert-butoxycarbonylamino) -7-oxabicyclo [2,2,1] heptane 12a

4.6 g of the carboxylic acid 11, using tert-butanol instead of benzyl alcohol in the method of Reference Example 2 to obtain 3.45 g (yield 53.9%) of the title compound 12a having the following physical constant.

IR (Film): υmax 3345,2250,1703cm ^-1

NMR (CDCl ₃ ): δppm 1.43 (9H, s), 1.5 ~ 20 (5H, m), 2.4 ~ 2.8 (2H, m), 3.50 (1H, m), 4.37 (1H, d, J = 5Hz), 4.63 (1H, t, J-4 Hz), 4.80 (1H, s).

Reference Example 10

Exo-2-formylmethyl-endo-3- (tert-butoxycarbonylamino) -7-oxabicyclo [2,2,1] heptane 13a

Under a stream of nitrogen, 13 ml of a 1 M-hexane solution of protected diisobutylaluminum is added dropwise to 50 ml of a dry toluene solution of 2.94 g of the above cyano derivative 12a at -20 ° C. The mixture is stirred at -20 [deg.] C. for 6 hours, then saturated ammonium chloride water is added to stop the reaction. The solid is dissolved in dilute hydrochloric acid and then separated into two layers. The aqueous layer is extracted with ethyl acetate, the organic layers are combined, washed with water, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. In 2.05 g of residue, incorporation of raw materials is recognized from thin layer chromatography and NMR. A small amount of oily residue was purified by silica gel column chromatography using hexane-ethyl acetate (2: 1) as the eluent to afford the title compound 13a having the following physical constants.

IR (Film): υmax 3330,1705,1515 cm ^-1

NMR (CDCl ₃ ): δppm 1.40 (9H, s), 1.5 ~ 2.0 (5H, m), 2.71 (2H, d, J = 7Hz), 3.46 (1H, m), 4.10 (1H, d, J = 4Hz ), 4.63 (1H, t, J = 4 Hz), 4.96 (1H, s), 9.76 (1H, s).

The remaining part is used for the next reaction without purification.

Reference Example 11

5 (z) -7- [endo-3- (tert-butoxycarbonylamino) -7-oxabicyclo [2,2,1] hept-exo-2-yl] -5-heptene methylester IIa -ab (2R ^* -t)

813 mg of the crude aldehyde 13a was treated by the method of Reference Example 6 to obtain 300 mg of the carboxylic acid IIa-ab (2R ^* -t) having the following physical constant.

NMR (CDCl ₃ ): δppm 1.45 (9H, s), 1.2 ~ 1.9 (7H, m), 1.9 ~ 2.5 (6H, m), 3.49 (1H, m), 4.14 (1H, d, J = 5Hz), 4.61 (1H, t, J-3 Hz), 5.39 (2H, m), 8.35 (1H, s).

1.05 g of this carboxylic acid IIa-bb (2R ^* -t) is esterified by the method of Reference Example 6 to obtain 0.95 g of the title compound IIa-ab (2R ^* -t) having the following physical constant.

IR: υmax film 3340,1740,1713,1170cm ^-1

NMR (CDCl ₃ ): δppm 1.42 (9H, s), 1.1 ~ 1.9 (6H, m), 1.9 ~ 2.47 (H, m), 3.47 (1H, m), 4.11 (1H, d, J = 5Hz), 4.61 (1H, t, J = 3 Hz), 4.82 (1H, d, J = 6 Hz), 5.37 (2H, m).

Example 5

5 (Z) -7- [endo-3-benzenesulfonamide-7-oxabicyclo [2,2,1] hept-enso-2-yl] -5-heptenic acid methyl ester Ia-aa (2R ^* − t)

0.09 g of the above BOC derivative IIa-ab (2R ^* -t) was treated by the method of Example 2 to obtain quantitatively trifluoroacetic acid. 601 mg of its salt is taken to give 361 mg (67.9% of BOC derivatives) of the title compound 1a-aa (2R ^* -t) having the following physical constants by the method of Example 2.

IR (Film): υmax 3270,1735,1160 cm ^-1

NMR (CDCl ₃ ): δppm 1.0 ~ 2.4 (13H, m), 3.02 (1H, m), 3.69 (3H, s), 4.09 (1H, d, J = 4Hz), 4.46 (1H, t, J = 3Hz ), 5.17 (2H, m), 5.64 (1H, d, J = 5 Hz), 7.60 (3H, m) 7.93 (2H, m).

Example 6

5 (Z) -7- [endo-3-benzenesulfonamide-7-oxabicyclo [2,2,1] hept-enso-2-yl] -5-heptenic acid Ia-ba (2R ^* -t) And its naturium salt Ia-ca (2R ^* -t)

(1) carboxylic acid Ia-ba (2R ^* -t)

335 mg of the ester Ia-aa (2R ^* -t) was treated by the method of Example 3 to obtain 310 mg of the title compound Ia-ba (2R ^* -t) having the following physical constants.

IR (Film): υmax 3260,1706,1157 cm ^-1

NMR (CDCl ₃ ): δppm 1.2 ~ 2.4 (13H, m), 3.01 (1H, m), 4.07 (1H, d, J = 4Hz), 4.41 (1H, t, J = 5Hz), 5.16 (2H, m ), 5.64 (1H, d, J = 6 Hz), 7.55 (3H, m), 7.88 (2H, m).

(2) sodium salt Ia-ca (2R ^* -t)

3.0 ml of methanol solution of 0.21 M sodium methoxide is added to a 2 ml solution of 225 mg of carboxylic acid Ia-ba (2R ^* -t). The solvent is distilled off under reduced pressure, and the residue is dissolved in water, and activated carbon is added followed by filtration. The filtrate was lyophilized to give 240 mg of the title compound Ia-ca (2R ^* -t) having the following physical constants.

IR (KBr): υmax 3410,3260,1560,1320,1155㎝ ^-1

Example 7

Methyl Ester Ib-aa (2S-t-5Z)

5 (2) -7-[(1S, 2S, 3S, 5R) -3-amino-6,6-dimethylbicyclo [3,1,1] hept-2-yl] -5-heptenic acid methylester IIb 107 mg of -aa (2S-t-5Z) is dissolved in 10 ml of dichloromethane, 1 ml of triethylamine is added, and then 126 mg of benzenesulfonyl chloride is added and stirred at room temperature for 1 hour. The reaction solution was washed sequentially with 5 ml of 10% hydrochloric acid, 10 ml of 5% aqueous sodium carbonate solution, and 10 ml of saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography using a mixed solvent of n-hexane-ethyl acetate (10: 14: 1) as the eluent to give the titled compound Ib- having the following physical properties: 85 mg of aa (2S-t-5Z) is obtained.

[α] _D −10.5 (21 ° C., C = 1.609, methanol)

CD (CH₃OH): λnm (△ ε) 268.5 (-0.061), 260 (-. 0115) 225 (-4.48)

NMR (CDCL₃: δppm 0.78 (1H, d, J = 9Hz), 0.93 (3H, s), 1,15 (3H, s), 1.43 ~ 2.50 (14H), 3.57 (1H, m), 3.67 (3H, s), 4.82 (1H, d, J = 8 Hz), 5.26 (2H, m), 7.36-7.63 (3H, m), 7.86-7.97 (2H, m).

IR (Film): υmax 3280,1737,1330,1159㎝ ^-1

MS: m / z 419 (M ⁺ )

Example 8

5 (2) -7- [1S, 1S, 2S, 5R) -3-benzenesulfonamide-6,6-dimethylbicyclo [3,1,1] hept-2-yl] -5-heptenic acid Ia- ba (2S-t-5Z) and salts thereof b-ca (2S-t-5Z), Ib-da (2S-t-5Z)

Ia-ba (2S-t-5Z) R₁ = H

Ia-ca (2S-t-5Z) R₁ = Na

Ia-da (2S-t-5Z) R₁ = NH₂ (C ₆ H ₁₀ ) ₂

(1) carboxylic acid Ib-ba (2S-t-5Z)

120 mg of methyl ester Ib-Aa (2S-t-5Z) obtained in Example 7 was dissolved in 15 ml of methanol, and 7 ml of 5% aqueous potassium hydroxide solution was added and stirred at room temperature for 20 hours. 10% hydrochloric acid is added to the reaction mixture, which is made acidic and extracted twice with 25 ml of ethyl acetate. The extract is washed twice with 5 ml of saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography using a mixed solution of n-hexane-ethyl acetate (2: 1) as the eluent to obtain the title carboxylic acid Ib- having the following physical constant. 109 mg of ba (2S-t-5Z) are obtained.

[α] _D −9.4 (21 ° C., C = 1.928, methanol)

NMR (CDC1₃): δppm 0.79 (1H, d, J = 10Hz), 0.92 (3H, s), 1,14 (3H, s), 1.40 ~ 2.53 (14H), 3.60 (1H, m), 5.10 ~ 5.50 (3H), 7.37-7.70 (3H, m), 7.89-8.00 (2H, m), 8.86 (1H, br, s).

IR (Film): υmax 3270,1709,1325,1156 cm ^-1

MS: m / z 406 (MH)

(2) sodium salt Ib-ca (2S-t-5Z)

90 mg of the obtained carboxylic acid Ib-ba (2S-t-5Z) was dissolved in 6 ml of methanol, 1 ml of 0.21 M sodium methylate methanol solution was added, and the residue obtained by distilling off the solvent under reduced pressure was dissolved in 5 ml of water. Activated charcoal is added and filtered. The resulting aqueous solution was lyophilized to obtain 86 mg of sodium salt Ib-da (2S-t-5Z) having the following physical constants.

IR (KBr): υmax 3420,3275,1565,1324,1157㎝ ^-1

Elemental Analysis (C ₂₃ H ₃₀ NO ₄ SN _a )

Calculated Value: C; 61.81, H; 7.07, N; 3.28 S; 7.50

Found: C; 61.52, H; 7.04, N; 3.31 S; 7.43

(3) dicyclohexyl ammonium salt Ib-da (2S-t-5Z)

6.83 g of carboxylic acid Ib-ba (2S-t-5Z) is dissolved in 180 ml of ether and a 20 ml solution of 3.06 g of dicyclohexylamine is added dropwise with stirring. The resulting colorless crystals are filtered to obtain 9.8 g of salt Ib-da (2S-t-5Z) having the following physical constants.

Melting Point 129 ~ 131 ℃

NMR (CDCl ₃ ): δ ppm 0.83 (1H, d, J = 6Hz), 0.90 (3H, s), 1.13 (3H, s), 1.00 ~ 2.60 (34H), 2.92 (2H, m), 3.47 (1H, m), 5.10-5.50 (2H), 7.18 (1H, br, s), 7.35-7.62 (3H), 7.85-8.11 (2H), 8.71 (2H, br, s).

IR (KBr): υmax3435,1618,1555,1324,1165,1155cm ^-1

Elemental Analysis (C ₃₄ H ₅₄ N₂O₄)

Calculated Value: C; 69.58, H; 9.27, N; 4.77, S; 5.46

Found: C; 69.40 H; 9.34, N; 4.66, S; 5.53

Example 9

5 (Z) -7-[(1S, 2S, 3S, 5R) -3-benzenesulfonamide-6,6-dimethylbicyclo [3,1,1] hept-2-yl] -5-heptenic acid

Ib-ba (2S-t-5Z) and its sodium salt Ib-ca (2S-t-5Z), and 5 (E) -7-[(1S, 2S, 3S, 5R) -3-benzenesulfonamide- 6,6-dimethylbicyclo [3,1,1] hept-2-yl] -5-heptenic acid

Ib-ba (2S-t-5E) and its sodium salt Ib-ca (2S-t-5E)

IIIb-a (2R * -t) is (1S, 2S, 3S, 5R) -2-formylmethyl-3-benzelsulfonamide-6,6-dimethylbicyclo [3,1,1]-as a raw material. It can be synthesized as follows using heptene [compound based on Patent Application 58-13551]. That is, the amine which is a starting material of the starting material is first sulfonylated using benzenesulfonyl chloride as in Example 7 to obtain a sulfonamide derivative. Next, the tetrahydropyranyl at the 2nd position is removed to form a hydroxy compound, and the hydroxy body is oxidized again using dimethyl sulfoxide-oxalyl chloride or the like as an oxidizing agent, thereby aldehyde IIIb-a (2R *) of the starting material. -t) The title compound Ib-ba (2S-t) can be synthesized below than the above-mentioned aldehyde IIIb-a (2S-t).

Under a nitrogen atmosphere, 36 g of 4-carboxybutyl triphenylphosphonium bromide is suspended in 250 ml of tetrahydrofuran, and 22 g of potassium tert-butoxide is added thereto at room temperature and stirred for 1 hour. To this was added dropwise 130 ml of tetrahydrofuran (9.76 g of aldehyde IIIb-a (2R * -t)) at room temperature and stirred for 1 hour. 300 ml of water was added to the reaction solution, and the mixture was washed with 200 ml of ether. The aqueous layer is made acidic with 10% hydrochloric acid and extracted with ether. The extract was washed with saturated brine, dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography using a mixed solvent of ethyl acetate-n-hexane (1: 2) as the elution solvent. Purification yields 8.46 g of highly polar 5Z-olefin Ib-ba (2S-t-5Z) and 1.91 g of the title 5E-olefin Ib-ba (2S-t-5E) having the following physical constants.

[α] _D −5.0 (26 ° C., C = 1.562, methanol)

_{[α] 365 -43.7 (26 ℃} , C = 1.562, methanol)

IR (Film): υmax 3275,1709,1328,1155,970cm ^-1

NMR (CDCl ₃ ): δ ppm 0.81 (1H, d, J = 10Hz), 0.88 (3H, s), 1.13 (3H, s), 1.41 ~ 2.53 (14H), 3.55 (1H, m), 5.02 ~ 5.44 ( 3H), 7.35-7.70 (3H), 7.86-7.96 (2H), 9.20 (2H, br, s).

600 mg of the carboxylic acid Ib-ba (2S-t-5E) was treated by the method of Example 3 to obtain 600 mg of sodium salt Ib-ca (2S-t-5E) having the following physical constant.

IR (KBr): υmax 3420,3280,1562,1326,1153,968 cm ^-1

Reference Example 12

(1) (2S, 2S, 3S, 5R) -2- [2- (tetrahydropyran-2-yloxy) ethyl] -3- (methanesulfonyloxy) -6,6-dimethylbicyclo [3, 1,2] heptane 14a

(1S, 2S, 3S, 5R) -3-hydroxy-6,6-dimethyl-2- [2- (tetrahydropyran-2-yloxy) ethyl] -ratio dissolved in 130 ml of dichloromethane under nitrogen atmosphere After adding 9.9 ml of triethylamine to 13 g of cyclo [3,1,1] heptane 14, 6.16 g of methanesulfonyl chloride is added dropwise at -20 ° C, and stirred for 15 minutes at the same temperature. The reaction solution is diluted with ether, washed with water, saturated ammonium chloride solution and saturated brine in that order, dried over sodium sulfate, and concentrated under reduced pressure to obtain 16 g of the title compound 14a having the following physical constants.

NMR (CDCl ₃ ): δppm 0.92 (3H, s), 1.12 (1H, d, J = 10Hz), 1.22 (3H, s), 1.36 ~ 2.86 (14H), 3.03 (3H, s), 3.30 ~ 3.63 (2H, m), (1S, 2S, 3R, 5R) -2- [2- (tetrahydropyran-2-yloxy) ethyl] -3-azide-6,6-dimethylbicyclo [3,1 , 1] heptane 15

3.67-3.83 (2H, m), 4.57 (1H, m), 5.06 (1H, m).

4.73 g of sodium azide is added to 16 g of the above methanesulfonyl compound 14a dissolved in 60 ml of hexamethylphosphamide under nitrogen atmosphere, and stirred at 50 ° C for 2 hours. 200 ml of ether was added to the reaction mixture, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using n-hexane-ethyl acetate (20: 1) as the eluent to obtain 8.64 g, of the title compound 15 having the following physical constants.

NMR (CDCl ₃ ): δ ppm 0.96 (3H, s), 1.12 (1H, d, J = 10Hz), 1.16 (3H, s), 1.36 ~ 2.68 (11H), 3.21 ~ 3.97 (4H), 4.22 (1H, td, J = 10,6 Hz), 4.54 (1H, m).

(1S, 2S, 3R, 5R) -2- [2- (tetrahydropyran-2-yloxy) ethyl] -3-amino-6,6-dimethyl bicyclo [3,1,1] heptane 16

To 8.64 g of the above azide compound 15 dissolved in 300 ml of ether under nitrogen atmosphere, 1.2 g of lithium aluminum hydride was added in small portions at 0 ° C. and heated to reflux for 1 hour. Add 10 g of ice and 300 ml of 10% aqueous sodium hydroxide solution, shake well to separate the ether layer. The aqueous layer is extracted again with ether. The combined ether layers were washed with water, dried over sodium sulfate and concentrated under reduced pressure to obtain 7.56 g of the title compound 16 having the following physical constants.

NMR (CDCl ₃ ): δ ppm 0.93 (3H, s), 1.16 (3H, s), 1.28 (1H, d, J = 9Hz), 1.30-2.47 (16H), 3.16-3.97 (5H), 4.56 (1H, m).

Reference Example 13

(1) (+)-(1S, 2S, 3R, 5R) -2- [2- (tetrahydropyran-2-yloxy) ethyl] -3- (trifluoroacetylamino) -6,6-dimethyl Bicyclo [3,1,1] heptane 17a

To 7.56 g of the amino compound 16 dissolved in 200 ml of dichloromethane under a nitrogen atmosphere, 23 ml of pyridine was added at 0 ° C, and 7.44 g of trifluoroacetic anhydride was slowly added dropwise, followed by stirring for 15 minutes. Ether was added, washed with water and brine, dried over sodium and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using n-hexane-ethyl acetate (9: 1) as an eluting solvent to give 9.9 g of the title compound 17a having the following physical constants.

[α] _D ⁺ 63.8 (25 ° C., C = 2.241, methanol)

NMR (CDCl ₃ ): δ ppm 0.97 (3H, s), 1.21 (3H, s), 1.38 (1H, d, J = 9Hz), 1.40 ~ 2.78 (14H)

3.13-4.00 (4H), 4.45-4.93 (2H), 6.62 (1H, br.s).

IR (Film): υmax 3310,1697,1554 cm ^-1

MS: m / z 364 (MH)

Elemental Analysis (C ₁₈ H ₂₈ NO₃F₃)

Calculated Value: C; 59.49, H; 7.77, B; 3.85, F; 15.68

Found: C; 59.30, H; 7.84, N; 3.60, F; 15.59

(2) 18a (+)-(1S, 2S, 3R, 5R) -2- (2-hydroxy) ethyl-3- (trifluoroacetyl amino) -6,6-dimethylbicyclo [3,1, 1] heptane 18a

115 mg of p-toluenesulfonic acid was added to 9.7 g of said tetrahydropyran-2-yloxy compound 17a dissolved in 270 ml of methanol in a nitrogen atmosphere, and stirred at room temperature for 2 hours. 0.5 ml of triethylamine is added, and the residue obtained by concentration under reduced pressure is dissolved in chloroform, washed with water and saturated brine, dried over sodium sulfate, and the solvent is concentrated under reduced pressure. The residue is crystallized from chloroform-hexane to give needle crystals. 6.62 g of the title compound 18a having the following physical constants is obtained.

Melting Point 143 ~ 144 ℃

[α] _{D +} 69.3 (25 ° C., C = 2.639, methanol)

NMR (CDCl ₃ ): δppm 1.95 (3H, s), 2.21 (3H, s), 1.38 (1H, d, J = 10Hz), 1.50 ~ 2.85 (9H), 3.61 (2H, m), 4.67 (1H, m), 6.25 (1 H, br, s).

IR (KBr): υmax 3450,3220,3080,1695,1566 cm ^-1

MS m / z: 280 (MH)

Elemental Analysis (C ₁₃ H ₂₀ NO₂F₃)

Calculated Value: C; 55.90, H; 7.22, N; 5.02, F; 20.41

Found: C; 56.22, H; 7.29, N; 4.99, F; 20.34

Reference Example 14

(-)-(2RS, 3aS, 4S, 6R, 7aR) -2-hydroxy-5,5-dimethyl-1-trifluoroacetyl-4,6-methaneoctahydroindole 19a

3.4 ml of dimethyl sulfoxide dissolved in 5 ml of dichloromethane under nitrogen atmosphere were slowly added dropwise at -50 ° C to 2 ml of oxalyl chloride dissolved in 25 ml of dichloromethane, and stirred at the same temperature for 2 minutes. 2.79 g of the alcohol 18a dissolved in a mixed solvent of 20 ml of dichloromethane and 2 ml of dimethyl sulfoxide was added at -50 ° C, and stirred at -15 ° C for 20 minutes.

The reaction solution was cooled to -50 ° C again, 10 ml of triethylamine was added thereto, stirred for 5 minutes, 50 ml of water was added to the reaction mixture at room temperature, and extracted as a mixed solvent of ether-ethyl acetate (1: 1).

5 : 1)의 용매를 사용하여 실리카겔 칼럼 크로마토그래피로 정제하고, 디클로로메탄-헥산에서 재결정시켜 다음의 물리항수를 갖는 표제 화합물 19a 1.9g을 얻는다.The extract was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in eluent as n-hexane-ethyl acetate (10: 1).

Purification by silica gel column chromatography using a solvent of 5: 1) and recrystallization from dichloromethane-hexane to obtain 1.9 g of the title compound 19a having the following physical constants.

Melting Point 90 ~ 91 ℃

[α] _D -63.8 (25 ° C., C = 1.208, methanol) (with photoresin, value after dissolution 1 hour)

NMR (CDCl ₃ ): δppm 0.89 (3H, s), 1.15 (1H, d, J = 10Hz), 1.21 (3H, s), 1.60 ~ 3.60 (9H), 4.23 ~ 4.80 (1H, m), 5.75 ~ 6.10 (1 H, m).

IR (KBr): υmax 3520,1672cm ^-1

MS m / z: 277 (M ⁺ )

Elemental Analysis (C ₁₃ H ₁₈ NO₂F₃)

Calculated Value: C; 56.31, H; 6.54, N; 5.05, F; 20.55

Found: C; 56.25, H; 6.53, N; 5.14, F; 20.73

Reference Example 15

(1) (+)-7-[(1S, 2S, 3R, 5R) -3- (trifluoroacetylamino) -6,6-dimethylbicyclo [3,1,1] hept-2-yl] -5-heptenic acid

IIb-b (2S-c)

[Manufacturing Method A]

To 6.785 g of brominated 4-carboxybutyltriphenylphosphonium suspended in 60 ml of tetrahydrofuran under argon atmosphere, 4.117 g of potassium tert-butoxide is added at room temperature and stirred for 30 minutes. 1.697 g of the aldehyde equivalent 19a dissolved in 50 ml of tetrahydrofuran was added dropwise thereto at room temperature, followed by stirring at the same temperature for 1 hour. 100 ml of water are added and washed with ether. The ether layer is extracted with 10% aqueous sodium carbonate solution and the aqueous layers are combined to make acidic with 10% hydrochloric acid. Extract with ether, washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using n-hexane-ethyl acetate (4: 1 → 2: 1) as the elution solvent, and a mixture of Forms Z and E in the title compound having the following physical constants IIb Obtain 2.045 g of -b (2S-c).

[α] _D- 92.0 (25 ° C., C = 1.876, methanol)

NMR (CDCl ₃ ): δ ppm 0.97 (3H, s), 1.20 (3H, s), 1.32 (1H, d, J = 10Hz), 1.47 ~ 2.80 (14H), 4.72 (1H, m), 5.33 (2H, m), 6.38 (1H, broad doublet, J = 9 Hz), 9.67 (1H broad).

IR (Film): υmax 3300,3100,1705,1558 cm ^-1

MS: m / z: 361 (M ⁺ )

[Manufacturing Method B]

2.4 g of sodium hydride (content 50%) suspended in 50 ml of dimethyl sulfoxide under a nitrogen atmosphere is stirred at 70 ° C. for 1 hour and a half. 11.08 g of 4-carboxybutyl triphenylphosphonium bromide dissolved in 25 ml of dimethyl sulfoxide was added dropwise at room temperature, followed by stirring at the same temperature for 15 minutes. Subsequently, 1.664 g of an aldehyde equivalent 19a dissolved in 20 ml of dimethyl sulfoxide was added dropwise and stirred at room temperature for 1 hour and a half. 10 g of ice is added to the reaction solution, and 100 ml of water is added thereto, followed by washing with 50 ml of ether. 10% hydrochloric acid is added to the aqueous layer to make it acidic, extracted twice with 50 ml of ether, and the extract is washed with saturated brine and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography using a mixed solution of n-hexane-ethyl acetate (4: 1) as the elution solvent. 2.107 g of -b (2S-c-5Z) are obtained.

[α] _{D +} 94.0 (25 ° C., C = 0.957, Methanol)

NMR (CDCl ₃ ): δ ppm 0.97 (3H, s), 1.20 (3H, s), 1.32 (1H, d, J = 10Hz), 1.46 ~ 2.75 (14H), 4.70 (1H, m), 5.30 (2H, m), 6.31 (1H, broad doublet, J = 7 Hz), 7.20 (1H broad).

IR (Film): υmax 3300,3100,1705,1558 cm ^-1

(2) (+)-7-[(1S, 2S, 3R.5R) -3-amino-6,6-dimethylbicyclo [3,1,1] hept-2-yl] -5-heptenate methyl ester

(1) IIb-b (2S-c)

To 1.995 g of carboxylic acid IIb-b (2S-c) obtained by Production Method A, a 10% aqueous potassium hydroxide solution was added and heated to reflux for 2 hours. The reaction solution is cooled to room temperature, neutralized with acetic acid and the solvent is distilled off under reduced pressure. The residue is dissolved in 40 ml of methanol, the insolubles are filtered and concentrated again under reduced pressure. And again dissolved in 40ml of methanol to filter the insolubles. To the filtrate is added an ether solution of excess diazomethane at 0 ° C. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography using chloroform methanol (10: 1) as the elution solvent. 1.06 g of b (2S-c) is obtained.

NMR (CDCl ₃ ): δ ppm 0.96 (3 / 2H, s), 1.0 (3 / 2H, s), 1.15 (3H, s), 1.23 (1H, d, J = 10Hz), 1.40 ~ 2.62 (16H), 3.66 (3H, s), 3.40-3.90 (1H, m), 5.38 (2H, m)

Compound IIb-b (2S-c-5Z) can be treated in the same manner to obtain IIb-a (2S-c-5Z) of the Z form of the title compound.

NMR (CDCl ₃ ): δ ppm 0.99 (3H, s), 1.16 (3H, s), 1.22 (1H, d, J = 10Hz), 1.40 ~ 2.65 (16H), 3.5 ~ 3.9 (1H), 3.66 (3H, s), 5.36 (2H, m).

Example 10

(+)-7-[(1S, 2S, 3R, 5R) -3-benzenesulfonamide-6,6-dimethylbicyclo [3,1,1] hept-2-yl] -5-heptenic acid methyl ester

Ib-aa (2S-c)

1.06 g of amino compound IIb-a (2S-c) was treated by the method of Example 7 to obtain 1.36 g of the title compound Ib-aa (2S-c) of a mixture of Z and E having the following physical constants.

Get

[α] _D- 52.0 (25 ° C., C = 2.521, Methanol)

NMR (CDCl ₃ ): δ ppm 0.90 (3 / 2H, s), 0.92 (3 / 2H, s), 1.12 (3H, s), 1.15 (1H, d, J = 10Hz), 1.45 ~ 2.53 (14H), 3.67 (3H, s), 4.05 (1H, m), 4.08 (1H, m), 5.27 (2H, m), 7.40-7.70 (3H, m) 7.87-7.97 (2H, m).

IR (Film): υmax 3285,1737,1322 cm ^-1

MS: m / z: 419 (M ⁺ )

CD (methanol) λ nm (Δε) 269 (+0.300), 262 (+0.390), 257 (+0.358), 221 (+4.63).

Elemental Analysis (C ₂₃ H ₃₃ NO₄S)

Calculated Value: C; 65.84, H; 7.93, N; 3.34, S; 7.64

Found: C; 65.42, H; 7.91, N; 3.36, S; 7.52

Compound IIb-a (2S-c-5Z) can be treated in the same manner to obtain the title compound Ib-aa (2S-c-5Z) in the Z form.

[α] _{D +} 48.2 (25 ° C., C = 1.826, methanol)

NMR (CDCl ₃ ): δ ppm 0.93 (3H, s), 1.13 (3H, s), 1.15 (1H, d, J = 10Hz), 1.43 ~ 2.53 (14H), 3.66 (3H, s), 4.02 (1H, m), 4.92 (1Hd, J = 9 Hz), 5.26 (2H, m), 7.39-77.6 (3H), 7.85-7.96 (2H).

Example 11

(+)-7-[(1S, 2S, 3R, 5R) -3-benzenesulfonamide-6,6-dimethylbicyclo [3,1,1] hept-2-yl] -5-heptenic acid

Ib-ba (2S-c) and its sodium Ib-ca (2S-c)

1.237 g of methyl ester Ib-aa (2S-c) was treated by the method of Example 8 to obtain 1.244 g of the title carboxylic acid Ib-ba (2S-c) of a mixture of Z and E having the following physical constants. Get

[α] _D -51.0 (25 ° C., C = 2.524, Methanol)

NMR (CDCl ₃ ): δ ppm 0.92 (3H, s), 1.12 (3H, s), 1.15 (1H, d, J = 10Hz), 1.45 ~ 2.57 (14H), 4.02 (1H, m), 5.00 ~ 5.40 ( 3H, m), 7.34-7.96 (3H, m), 7.84-7.95 (2H, m), 8.36 (1H, br.s).

IR (Film): υmax 3285,1708,1320,1160cm ^-1

Compound Ib-aa (2S-c-5Z) can be treated in the same manner to obtain Z form Ib-ba (2S-c-5Z) of the title compound.

[α] _{D +} 46.0 (25 ° C., C = 1.620, methanol)

NMR (CDCl ₃ ): δ ppm 0.92 (3H, s), 1.11 (3H, s), 1.15 (1H, d, J = 10Hz), 1.43 ~ 2.53 (14H), 4.03 (1H, m), 5.06 ~ 5.48 ( 3H, m), 7.35-7.76 (3H), 7.84-7.96 (2H, m), 8.50 (1H, br.s).

MS: m / z 405 (M +)

IR (Film): υmax 3285,1708,1320,1160cm ^-1

The carboxylic acid Ib-ba (2S-c) or Ib-ba (2S-c-5Z) was treated by the method of Example 8 to give sodium salt Ib-ca (2S-c) or sodium having the following physical constants. Salt Ib-ca (2S-c-5Z) can be obtained, respectively.

IR (KBr): υmax 3420,3280,1560,1320,1160㎝ ^-1

Elemental Analysis (C ₂₂ H ₃₀ NO₄SNa)

Calculated Value: C; 61.81, H; 7.07, N; 3.28, S; 7.50

Found: C; 61.17, H; 6.89, N; 3.33, S; 7.49

Reference Example 16 and Examples 12 and 13

Reference Example 16

5 (Z) -Methyl 7- [endo-3-carboxy-7-oxabicyclo [2,2,1] hept-endo-2-yl] -5-heptenic acid 21

15 ml of acetone of 1.47 g of 5 (Z) -methyl 7- [endo-3-hydroxymethyl-7-oxabicyclo [2,2,1] hept-endo-2-yl] -5-pentenoic acid 20 Dissolved in the solution, and, under ice-cooling, the Jones reagent is added dropwise until the solution turns red, and ice water is added. The reaction solution is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous sodium sulfate, and distilled off under reduced pressure. The residue was purified by silica gel (50 g) chromatography with hexane-ethyl acetate (1: 3) as the eluent to yield 0.877 g of the title compound.

Yield 56.7%

¹ H-NMR (CDCl₃) δppm: 1.4 ~ 2.6 (13H), 3.09 (1H, dd, J = 5,11Hz), 3.68 (3H, s), 4.52 (1H, t, J = 3Hz), 5.35 (2H , m), 81. (1H, br.s)

Compound Ia-a (2S * -c) is obtained through the intermediate shown below in the same manner as in Reference Example 9 and Example 5 of Example Ia-2.

5 (Z) -7- [endo-3-tert-butoxycarbonylamino-7-oxabicyclo [2,2,1] hept-endo-2-yl] -5-heptenic acid methyl ester

: IIa (2S ^* -c)

Yield 49.6%

IR: υmax (film) 3370,1739,1716,1698 cm ^-1

¹ H-NMR: δppm (CDCl₃): 1.44 (9H, s), 1.5 ~ 2.5 (13H), 3.67 (3H, s), 4.05 (1H, m), 4.47 (1H, m), 4.55 (1H, m ), 4.57 (1H, m, NH), 5.34 (2H, m)

5 (Z) -7- [endo-3-benzenesulfonamide-7-oxabicyclo [2,2,1] hept-endo-2-yl] -5-heptenic acid methyl ester

Ia-aa (2S ^* -c)

Yield 56.4%

IR: υmax (film) 3300,1737,1343,1163 cm ^-1

¹ H-NMR: δppm (CDCl₃): 1.4 ~ 2.4 (13H), 3.60 (1H, m), 4.33 (2H, m), 5.25 (2H, m), 5.35 (1H, m), 7.55 (3H, m ), 7.88 (2H, m)

: Ia-aa (2S * -c) and salts thereof: Ia-ca (2S * -c)

Free carboxylic acid:

Yield 94.0%

IR υmax (film) 3290,1709,1340,1162 cm ^-1

NMR: δppm (CDCl₃) 1.4 ~ 2.5 (13H, m), 3.66 (1H, m), 4.27 (1H, m), 4.38 (1H, m), 5.27 (2H, m), 5.65 (1H, d, J = 9 Hz), 7.58 (3H, m), 7.90 (2H, m), 8.14 (1H, br.s)

Sodium salt IR υmax (KBr) 3430,1558,1339,1158 cm ^-1

Reference Example 17, Example 14

Reference Example 17

(1S, 2R, 3S, 5R) -3-hydroxy-6,6-dimethyl-2- [2-tetrahydropyran-2-yloxy) ethyl] bicyclo [3,1,1] heptane 22 (2R -c)

15.4 g of (1S, 2S, 5R) -6,6-dimethyl-3-keno-2- [2- (tetrahydropyran-2-yloxy) ethyl] bicyclo [3,1,1] heptane 22 ' (2S) is dissolved in 160 ml (1.11 M) of sodium methoxide at room temperature and stirred at room temperature for 2 hours. The NMR spectrum shows a mixture of about 11: 1 of isomerized ketone 22 '(2R) and raw material 22' (2S). Reduction of the mixture is performed using sodium borohydride in accordance with the method for reducing ketones. The product was subjected to silica gel chromatography using hexane-ethyl acetate (10: 1) as the eluting solvent to obtain the title compound in 9.03% yield.

¹ H-NMR (CDCl₃) δ ppm: 0.92 (3H, s), 1.91 (3H, s), 1.25 (1H, d, J = 10Hz), 1.35 ~ 2.53 (14H), 3.35 ~ 4.15 (6H), 4.65 ( 1H, m)

In the same manner as in Reference Examples 12 to 15 and Examples 10 and 11, Compound Ib (2R-c) can be obtained via the intermediates shown below.

(-)-5 (2) -7-[(1S, 2R, 3S, 5R) -3-benzenesulfonamide-6,6-dimethylbicyclo [3,1,1] hept-2-yl] -5 -Heptenic acid and salts thereof

Yield 82.0%

[α] ²³ _D -31.3 (C 3.452, methanol)

CD (methanol); λ nm (Δε): 269 (-0.236), 262.5 (-0.312), 255.5 (-0.321), 223 (-4.24).

NMR: δ ppm (CDCl ₃ ) 0.73 (3H, s), 1.02 (1H, d, J = 10 Hz), 1.14 (3H, s), 1.33-2.60 (14H), 3.83 (1H, m), 3.12-3.51 ( 3H), 7.37-7.73 (3H), 7.87-7.98 (2H), 8.86 (1H, br, s).

1R υmax (CHCl ₃ ): 3525, 3400, 3280, 1721, 1352, 1330, 1310, 1161, 1095 cm ^-1

Dicyclohexylamine Salt:

Melting Point 122 ~ 124

[α] ²⁵ D-17.6 (cl. 051, methanol)

NMRδ ppm (CDCl ₃ ) 0.73 (3H, S), 1.14 (3H, S), 0.88 ~ 2.43 (36H), 2.70 ~ 3.13 (2H), 3.78 (1H, brS), 5.03 ~ 5.56 (2H), 5.85 (1H , br, αJ = 6Hz), 7.36 ~ 7.67 (3H), 7.77 ~ 8.03 (2H), 8.24 (1H, br, S)

IR υmax (KBr) 3440,3180,3080,1624,1553,1310,1154,1096 cm ^-1

Elemental Analysis C ₃₄ H ₅₄ N₂O₄S

Calculated (%): C; 69.58, H; 9.27, N; 4.77, S; 5.46

Found (%): C; 69.55, H; 9.21, N; 4.63, S; 5.29

Sodium salt:

IR υmax (KBr) 1560,1327,1309,1160,1093 cm ^-1

Elemental Analysis C ₂₂ H ₃₀ NO₄SNa

Calculated (%): C; 61.81, H; 7.07, N; 3.28, S; 7.50

Found (%): C; 61.50, H; 7.03, N; 3.37, S; 7.47

Reference Example 18, Example 15

Reference Example 18

(1S, 2R, 3R, 5R) -2- [2- (tetrahydropyran-2-yloxy) ethyl] -3-argan-6,6-dimethylbicyclo [3,1,1] heptene

23 (2R-t)

Under a nitrogen atmosphere, 20 g of azo dicarboxylic acid diethyl ester was mixed with 6.11 g of 22 (2R-c), 30 g of triphenylphosphine and 5.83 g of 350 ml of benzene suspension of methanesulfonylzinc [Zn (CH₃SO₃) ₂]. Drop wise, and stirred at room temperature for 3 hours. The reaction solution is washed with water, dried over anhydrous sodium sulfate and distilled off under reduced pressure. The residue was subjected to flash chromatography analysis using hexane-ethyl acetate (5: 1) as the eluting solvent to obtain 6.7 g of crude mesylate. The resulting mesylate is treated with sodium azide by the method of Reference Example 1 (2) of Example IV-2 to yield 2.05 g of the title compound 23 (2R-t).

Yield 31.3%

¹ H-NMR (CDCl₃) δ ppm: 0.86 (3H, s), 1.21 (3H, s), 1.28 (1H, d, J = 10 Hz), 1.40 to 2.50 (14H), 3.22 to 4.00 (5H), 4.57 ( 1H, m)

Reference Example 12 (3) to 15 and the same method as in Examples 10 and 11, the compound Ib (2R-t) was obtained via the following intermediate.

(-)-(1S, 2R, 3R, 5R) -2- [2- (tetrahydropyran-2-yloxy) ethyl] -3-benzenesulfonamide-6,6-dimethylbicyclo [3,1, 1] heptane:

Yield: 85.6%

Melting Point: 119 ~ 121 ℃

[α] ²⁵ _D -26.3 (C 0.883, methanol)

NMR δ ppm (CDCl ₃ ) 0.80 (3H, s), 1.13 (3H, s), 1.20 (1H, d, J = 10 Hz), 1.35-2.30 (14H), 2.90-4.10 (5H), 4.40-4.60 (1H) ), 5.03-5.21 (1 / 2H, d, J = 6 Hz), 7.35-7.68 (3H), 7.86-7.97 (2H)

IR υmax (KBr) 3270,1322,1168 cm ^-1

Elemental Analysis (C ₂₂ H ₃₃ NO₄S)

Calculated (%): C; 64.83, H; 8.16, N; 3.44, S; 7.87

Found (%): C; 64.89, H; 8.12, N; 3.42, S; 7.77

:

Yield 90.6%.

[α] ²³ _D -31.6 (C 1.094, methanol)

NMR δ ppm (CDCl ₃ ) 0.80 (3H, s), 1.14 (3H, s), 1.21 (1H, d, J-10Hz), 1.35 ~ 2.18 (8H), 2.30 (1H, br, s), 3.20 (1H , q, J = 9Hz), 3.57 (2H, t, J = 6Hz), 5.65 (1H, d, J = 7Hz), 7.36 ~ 7.63 (3H), 7.88 ~ 7.99 (2H)

IR υmax (CHCl₃) 3025,3530,3385,3275,1327,1310,1160,1091 cm ^-1

(-)-(1S, 2R, 3R, 5R) -2-formylmethyl-3-benzenesulfonamide-6,6-dimethylbicyclo [3,1,1] heptane:

Yield 95.9%.

[∂] ²³ _D -19.3 (C 2.754, Methanol)

NMR δ ppm (CDCl ₃ ) 0.82 (3H, s), 1.13 (3H, s), 1.22 (1H, d, J = 10Hz), 1.49 ~ 2.78 (8H), 3.24 (1H, m), 5.51 (1H, d , J = 9Hz), 7.38 ~ 7.73 (3H,), 7.88 ~ 7.99 (2H) 9.65 (1H, d, J = 2Hz)

IR υmax (CHCl₃) 3390,3280,1723,1330,1161 cm ^-1

Example 15

(-)-5 (2) -7-[(1S, 2R, 3R, 5R) -3-benzenesulfonamide-6,6-dimethylbicyclo [3,1,1] hept-2-yl] -5 Heptenoic Acid

Ib-ab (2R-t)

Yield 95.1%.

[α] _D ²³ -2.4, [α] ₂₆₅ ²³ +17.6, (C 2.154, methanol)

NMR δ ppm (CDCl ₃ ) 0.76 (3H, s), 1.13 (3H, s), 1.22 (1H, d, J-10 Hz), 1.35 to 2.50 (14H), 3.20 (1H, m), 5.30 (1H, m ), 5.42 (2H, d, J = 9 Hz), 7.35-7.63 (3H,), 7.63 (1H, br, s), 7.86-7.97 (2H).

IR υmax (film) 3280,1710,1325,1310,1160,1093 cm ^-1

(-)-5 (2) -7-[(1S, 2S, 3R, 5R) -3-benzenesulfonamide-6,6-dimethylbicyclo [3,1,1] hept-2-yl] -5 Heptenoic Acid Methyl Ester

Ib-aa (2R-t)

[α] _D ²³ -1.6, [α] ₃₆₅ ²³ +24.8, (C 2.498, methanol), CD (methanol) λ nm (Δε): 268.5 (+0.085), 261 (+0.112), 258sh (+0.155), 225 (+2.52).

NMR δ ppm (CDCl ₃ ) 0.76 (3H, s), 1.13 (3H, s), 1.23 (1H, d, J = 10Hz), 1.40 ~ 2.43 (14H), 3.23 (1H, m), 3.69 (3H, s ), 5.30 (2H, m), 5.62 (1H, d, J = 9 Hz), 7.36-7.70 (3H), 7.92-8.03 (2H).

IR υmax (film) 3290,1740,1329,1161,1096 cm ^-1

Elemental Analysis C ₂₃ H ₃₃ NO₄S

Calculated (%): C; 65.84, H; 7.93, N; 3.34, S; 7.64

Found (%): C; 65.78, H; 7.98, N; 3.42, S; 7.49

Sodium Salt: Ib-ac (2R-t):

IR υmax (KBr) 1560,1323,1308,1160,1093 cm ^-1

The objective compound of the present invention acts as a powerful antagonist against the thromboxane A 2 receptor and significantly inhibits platelet aggregation due to thromboxane A 2. It is a compound which can be an antithrombotic agent or an anti-vascular contractor useful for the above matter. Regarding the typical compounds thereof, the effect of inhibiting platelet aggregation in vitro is shown in the following experimental examples.

[Test Materials and Test Methods]

From a carotid artery of a male rabbit (NIBS-JW, body weight 2.2-2.7 kg), a pre-bleed was performed with a syringe of 3.8% sodium citrate in a plastic syringe containing 7.2 ml of blood and 8 ml of total volume. The blood was mixed in a plastic test tube, gently shaken, mixed, and centrifuged at 210 ° C. for 10 minutes at 20 ° C., and the upper layer of multi-platelet plasma [PRP (platelet rich plasma)] was collected. The remaining blood was centrifuged at 3000 rpm (about 1900 g) at 20 ° C. for 10 minutes to obtain deficient platelet plasma [ppp: (platelet poor plasma)].

Dilution was adjusted as ppp so that the platelet count of PRP was 50-55 × 10 ⁴ / μ 1 and used for the aggregation measurement.

Platelet aggregation response was measured using an agglomometer (Model AUTO RAM-61, Ewha Electric Co., Ltd.) according to the present method (Born, GVR, Nature, 194, 927-929 (1962)). In other words, PRP 400μ1 adjusted to platelet count of 50 ~ 50 × 10 ⁴ / μ1 was put in the measuring cubit and placed in an agglomeration system, stirred at 37 ° C for 1 minute (1200rpm), pre-warmed and then the test compound solution (physiological When dissolved in saline solution, 50 μl, and when dissolved in dimethyl sulfoxide, 2 μl of the solution and 48 μl of physiological saline are added, and after 2 minutes, 50 μl of arachidonic acid (sodium salt, Sigma) is added as a coagulation substance, and the solution is agglomerated by aggregation. Changes in the resulting light transmittance were recorded over time.

As for the aggregation rate of platelets, the light transmittance of PRP and PPP was made into 0% and 100%, respectively, and the maximum light transmittance of PRP after addition of a coagulation substance was made into the maximum aggregation rate.

The aggregation inhibition rate (%) was computed from the ratio of the maximum aggregation rate of the test compound addition group with respect to the maximum aggregation rate of a control bacterium (carrier addition group).

[result]

The test results are shown in the table below. Prostaglandin (PG) E₁ was used as a standard.

TABLE 1

* The compound number corresponds to the compound number in the examples.

The objective compound of the present invention exhibits strong inhibition against platelet aggregation by thromboxane.

The objective compound of the present invention is to strongly inhibit platelet aggregation, vasoconstriction, and bronchial contraction caused by thromboxane A2, thereby treating and improving symptoms such as atherosclerosis, myocardial infarction, acute myocardial ischemia, circulatory shock, and sudden death. It can be used, the compound is expected to apply the pharmacological effect.

The target compound of the present invention can be administered orally or parenterally. For example, it can be made into tablets, capsules, pills, granules, granules, homemade, emulsions, suppositories, intravenous injections, intramuscular injections or subcutaneous injections. In the case of formulation, the appropriate carrier or excipient used for bankbook is used.

The compound of the present invention is about 10 mg to 800 mg per day for oral administration in adults.

Claims (5)

As a method for producing a sulfonamide derivative represented by the following general formula (I) or a salt thereof, a compound represented by the following general formula (II) may be selected from Hal-So₃-R2 (wherein R2 is methoxy, nitro, hydroxy, carboxy, Cyano, lower alkyl, amino, lower alkylamino, optionally substituted lower alkylamino, alkanoylamino and phenyl substituted by one or more substituents selected from the group consisting of halogen and Hal represents halogen) Method for producing a sulfonamide derivative or a salt thereof, characterized in that the reaction with a compound of.

[Wherein, R 'represents hydrogen, lower alkyl or salt forming group; R '' represents hydrogen and lower alkyl; R2 is phenyl substituted with one or more substituents selected from the group consisting of methoxy, nitro, hydroxy, carboxy, cyano, lower alkyl, amino, lower alkylamino, lower alkylamino, alkanoylamino and halogen, Unsubstituted phenyl; And

As a method for producing a sulfonamide derivative represented by the following general formula (I) or a salt thereof, a compound represented by the following general formula (III) is represented by (Ar) ₃

A method for producing a sulfonamide derivative or a salt thereof, which is reacted with a compound of CH2CH2CH2COOR ', wherein R' is hydrogen, lower alkyl and Ar represents an aromatic hydrocarbon group.

[Wherein, R 'represents hydrogen, lower alkyl or salt forming group; R2 is phenyl substituted with one or more substituents selected from the group consisting of methoxy, nitro, hydroxy, carboxy, cyano, lower alkyl, amino, lower alkylamino, lower alkylamino, alkanoylamino and halogen, Unsubstituted phenyl; And

As a method for producing a sulfonamide derivative represented by the following general formula (I) or a salt thereof, a compound represented by the following general formula (II) is selected from Hal-So ₂ -R₂ (wherein R2 is methoxy, nitro, hydroxy and carboxy). , Cyano, lower alkyl, amino, lower alkylamino, lower alkylamino, alkylnoylamino and halogen which may be different from each other, or phenyl substituted with one or more substituents selected from the group Hal and halogen And a deprotection reaction or a salt formation reaction.

[Wherein, R 'represents hydrogen, lower alkyl or salt forming group; R _{1 '} represents hydrogen or lower alkyl; R2 is phenyl substituted with one or more substituents selected from the group consisting of methoxy, nitro, hydroxy, carboxy, cyano, lower alkyl, amino, lower alkylamino, lower alkylamino, alkanoylamino and halogen, Unsubstituted phenyl; And

As a method for producing a sulfonamide derivative represented by the following general formula (I) or a salt thereof, a compound represented by the following general formula (II) is selected from Hal-So ₂ -R₂ (wherein R2 is methoxy, nitro, hydroxy and carboxy). , Cyano, lower alkyl, amino, lower alkylamino, lower alkylamino, alkanoylamino, or halogen, which may be different from each other, or phenyl substituted by one or more substituents selected from the group Hal represents halogen And a deprotection reaction or a salt formation reaction after the reaction with the compound.

[Wherein, R 'represents hydrogen, lower alkyl or salt forming group; R _{1 '} represents hydrogen or lower alkyl; R2 is phenyl substituted with one or more substituents selected from the group consisting of methoxy, nitro, hydroxy, carboxy, cyano, lower alkyl, amino, lower alkylamino, lower alkylamino, alkanoylamino and halogen, Unsubstituted phenyl; and

As a method for producing a sulfonamide derivative represented by the following general formula (I) or a salt thereof, a compound represented by the following general formula (III) is represented by (Ar) ₃

A method for producing a sulfonamide derivative or a salt thereof, which is reacted with a compound of CH2CH2COOR ', wherein R' is hydrogen, lower alkyl and Ar represents an aromatic hydrocarbon group.

[Wherein, R 'represents hydrogen, lower alkyl or salt forming group; R2 is methoxy, nitro, hydroxy, carboxy, cyano, lower alkyl, amino, lower alkylamino, lower alkylamino which may be different from each other, and alkanoyl R2 is methoxy, nitro, hydroxy, carboxy, cyano, lower Alkyl, amino, lower alkylamino, lower alkylamino, alkanoylamino and phenyl substituted with one or more substituents selected from the group consisting of halogen or unsubstituted phenyl; And