JPH0377862A - Bicyclo(2,2,1)heptane derivative, purification and its production - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I. EXAMPLE:(5Z)-6-[3-(4-Bromobenzenesulfonylaminomethyl)bicyclo[2,2,1]hep tan-2- yl]hex-5-enoic acid cyclohexylamine salt. USE:An intermediate for producing thromboxane A2 antagonist. A purification process is simplified and the compound shown by formula I can be industrially produced. PREPARATION:A compound shown by formula III according to the reaction formula is subjected to Wittig reaction in an inert organic solvent such as THF in the presence of a base to give a compound shown by formula II. Then this compound is reacted with 1-1.5 equivalent cyclohexylamine in an inert organic solvent such as methylene chloride to give a compound shown by formula II. Then the prepared compound shown by formula I is crystallized, isolated and then returned to an acid to give the purified compound shown by formula II. The compound shown by formula II is esterified with n-decanol to give a compound shown by the formula A, a thromboxane A2 antagonist.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel method for producing a bicyclo[2,2,1]hebutane derivative represented by the formula and a novel intermediate useful as a medical product.

[Prior Art] The compound represented by the formula (A>) is a compound disclosed as an i-daymboxane A2 antagonist in Japanese Patent Application No. 197180/1983 together with its production method.

Japanese Patent Application No. Sho 63-197180 discloses that the compound represented by formula (A>) can be synthesized according to the following reaction scheme.

Each position in the reaction scheme does not represent the following meaning.

In addition, only necessary parts have been excerpted or rewritten.

Reaction scheme B’ (excerpt) Reaction scheme A’ (excerpt) ×2 = halogen atom, R2°: halogen atom, etc.

Furthermore, in the text, a compound represented by the general formula (Ild') is subjected to a Wittig reaction, and in the general formula E, all symbols have the same meanings as above. ] By obtaining a carboxylic acid represented by the formula and subjecting it to a rough esterification reaction, [wherein R11' represents an alkyl group having 1 to 20 carbon atoms, and other symbols have the same meanings as above] . ] A compound represented by the following is obtained.

[Problems with the Prior Art] There are several problems when attempting to industrially produce the compound represented by formula (A) using the production method disclosed in Japanese Patent Application No. 197180/1980. do.

■ Since the compound represented by formula (A) has five asymmetric centers, optical resolution is required, but the disclosed method uses D-men! This compound is not available at low cost.

■ In addition, the method using this men;
The temperature must be kept at several tens of degrees Celsius), which makes it difficult to use equipment.

■ Similarly, when deriving aldehyde from alcohol, s
When wern oxidation is used, the temperature must be kept at a low temperature similar to (2).

(2) Although there are three steps of purification using column chromatography, this production method is not suitable for large-scale synthesis.

(2) Overall yield is poor, and contamination of the final product with geometric isomers (trans isomer) is unavoidable.

Therefore, the method disclosed in the specification is industrially applicable to the formula (
The method for synthesizing the compound represented by I) is not necessarily satisfactory.

[Means for Solving the Problem] As a result of studying industrially advantageous production methods for the compound represented by formula (1), the inventors of the present invention have found that the objective can be achieved by the process represented by the following reaction process formula (A). The present invention was completed based on this discovery.

[Structure of the Invention] The present invention relates to a novel method for producing a compound represented by the formula (1) shown in the reaction scheme <A> on the next page, and a new intermediate.

In the reaction scheme, each symbol represents the following meaning.

X: Chlorine atom, iodine atom.

reaction process formula <A> (continued tree) The reaction of the above reaction scheme <A> will be explained.

Step [al is an esterification reaction, for example, an organic solvent [
Benzene-based (benzene, toluene, xylene, etc.), halogenated hydrocarbon-based (methylene chloride, chloroform, carbon tetrachloride, 1.1,2.2-tetrachloroethylene, perchloroethylene, etc.), hydrocarbon-based (pentane, hexane, etc.) (isooctane, cyclohexane, etc.) or in the absence of a solvent, in the presence or absence of an antioxidant (hydroquinone, etc.), fumaryl chloride and ethyl raphate at 40°C.
A diester can be obtained by reacting at reflux temperature, then adding a tertiary amine (triethylamine, pyridine, dimethylaminopyridine, etc.) to this system and reacting at the same temperature, or a tertiary amine at 0 to 20°C. It is carried out by adding dropwise fumaryl chloride to an organic solution of lactic acid ester (same as above) in the presence of an amine (same as above), followed by reaction at 0° C. to room temperature.

Preferably, the reaction is carried out under reflux in toluene, using triethylamine as the tertiary amine.

This reaction may be facilitated with stirring by passing an inert gas such as nitrogen or argon.

Step [b] is a Diels-Alder reaction, for example, an inert solvent [benzene type (toluene, xylene, benzene, etc.), halogenated hydrocarbon type (methyoneone chloride, chloroform, carbon tetrachloride, 1°1. 2.2-tetrachlorethylene, perchloroethylene, etc.), ethers (tetrahydrofuran, tetrahydrobilane, dioxane,
(diethyl ether, dimethyl ether, diisopropyl ether, biphenyl ether, methyl ethyl ether, etc.), alcohol-based (methanol, ethanol, isobutylene alcohol, etc.), hydrocarbon-based (pentane, hexane, isooctane, cyclohexane, etc.), ketone-based (acetone, methyl ethyl ketone, etc.) , phenylmethylketone, etc.) etc.]
It can be carried out in water or without solvent.

This reaction may be carried out by adding a conventional Lewis acid (ferric chloride, titane tetrachloride, stannic chloride, aluminum chloride, etc.).

Preferably, the reaction is carried out by reacting with diclopentadiene in a benzene solvent at a temperature of -78°C to room temperature, preferably -20 to -10°C.

Step [C] is a saponification reaction, for example, an organic solvent [alcohol type (methanol, ethanol, isopropanol, etc.), ether type (tetrahydrofuran, tetrahydrobilane, dioxane, diethyl ether, dimethyl ether, diisopropyl ether, biphenyl ether,
methyl ethyl ether, etc.), kene series (acetone, etc.),
methyl ethyl ether, phenylmethyl ketone, etc.), sulfoxides (dimethylsulfoxide, etc.), nitrile-types (ace]henitrile, etc.), amide-types (hexamethylene phosphoramide, dimethylformamide, etc.), alkalis ( potassium hydroxide, sodium hydroxide,
The reaction is carried out using an aqueous solution of lithium hydroxide, potassium carbonate, sodium carbonate, etc., at a temperature of 0° C. to the reflux temperature of the solvent.

Preferably, it is carried out using an aqueous solution of 1-lium hydroxide in an alkanol at reflux temperature.

Step [dl] is an iodolactonization reaction, which is carried out, for example, in an iodine-potassium iodide aqueous solution at a temperature of 0 to 50°C.

■Culm [el is an esterification reaction, for example, (1) method using diazomethane, (2) method using alkyl halide, (3) DMF-
Examples include a method using a dialkyl acetal, and (4) a method of reacting with methanol.

To specifically explain these methods, (1) a method using diazomethane is, for example, a method using diazomethane. ether, methyl ethyl ether, etc.), halogenated hydrocarbons (methylene chloride, chloroborum, carbon tetrachloride, 1,
1゜2.2-tetrachlorethylene, perchlorethylene, etc.), ketone type (acetone, methyl ethyl ketone,
phenylmethylketone, etc.), alcohol-based (methanol, ethanol, isopropanol, etc.), ethyl acetate, etc.)
etc.] is carried out during the period.

(2) Methods using alkyl halides include, for example, organic solvents [ketone-based (acetone, methyl ethyl ketone, phenylmethyl ketone, etc.), amide-based (dimethylformamide, N,N-dimethylacetamide, etc.)], sulfoxide-based (dimethyl sulfur fluoride, etc.), bases (
The reaction is carried out using the corresponding alkyl halide in the presence of potassium carbonate, sodium carbonate, potassium hydrocarbon, sodium hydrogen carbonate, calcium hydroxide, etc.).

(3) The method using DMF-dialkyl acetal is
For example, it is carried out using the corresponding DMF-acetal in an inert organic solvent 1 [benzene-based (benzene, toluene, xylene, etc.)].

(4) The method of reacting with methanol is in an inert organic solvent [halogenated hydrocarbon type (methylene chloride, chloroform, carbon tetrachloride, 1,1,2.2-tetrachloroethylene, perchloroethylene, etc.)] or, For example, in methanol without using a solvent, an acid (hydrochloric acid, sulfuric acid, p-h
luenesulfonic acid, hydrogen chloride gas, etc.) or a condensing agent (
DCC, pivaloyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride, etc.).

These reactions are usually carried out at a temperature of -10 to 50°C.

Preferably, using hydrogen chloride gas in methanol, -
It is carried out at 10°C to 30°C.

Step [f] is a dehalogenation reaction, for example, an organic solvent [ketone type (acetone, methyl ethyl ketone, [I-nylmedimethitone, etc.)], amide type (dimethylformamide, etc.), ether type (tetrahydrofuran, tetrahydrobilane, dioxane, diethyl ether, etc.). Dimethyl ether, diisopropyl ether, phenyl ether, methyl ethyl ether, etc.), alcohols (methanol,
ethanol, isopropanol, etc.) or using water in the presence of acids (acetic acid, hydrochloric acid, etc.) and metals (zinc, chromium, tin, titanium, aluminum, etc.) at temperatures ranging from 0°C to reflux temperature. .

Preferably, refluxing is carried out using zinc powder in acetic acid.

Step [0] is a reduction reaction, for example, under normal pressure or pressure in a hydrogen atmosphere, using an organic solvent [alcohol type (methanol, ethanol, isopropanol, etc.), ethyl acetate,
Ethers (te[--rahydrofuran, tetrahydrobilane, diochitin, diethyl ether, dimethyl ether, diisopropyl ether, biphenyl ether, methyl ethyl ether, etc.), hydrocarbons (pentane, hexane, isooctane, cyclohexane, etc.), acetic acid, etc.], Catalyst (palladium-carbon, palladium oxide, platinum black,
Raney nickel, etc.) at a temperature of 0-100°C.

Preferably, it is carried out in an alkanol using palladium on carbon under a hydrogen atmosphere at room temperature.

Step [h] is an amidation reaction, for example, using an inert organic solvent 1. Do not use halogenated hydrocarbons (methylene chloride, chloroform, carbon tetrachloride, 1,1,2゜2-tetrachloroethylene, Burke Nitroethy-1-non, etc.), and use acid halides (oxalic acid dillide, thionyl chlorite, etc.). ) at -20°C to reflux temperature, and the resulting acid halide is reacted with an inert organic solvent (the above and the like) in the presence or absence of a tertiary amine (pyridine, triethylamine, dimethylaminoaniline, dimethylaminopyridine, etc.). same)
-2 using ammonia water or ammonia gas
It is carried out at 0°C to room temperature.

Preferably, the reaction is carried out by using an oxalic acid D-ride in a halogenated hydrocarbon solvent and cooling with water, and passing ammonia gas through the ice-cooled halogenated hydrocarbon solvent. It will be done.

Step [11] is a reduction reaction, for example, six solvents [ether type (tetrahydrofuran, 71-lahydrobilane,
Dioxane, diethyl ether, dimethyl ether, diisopropyl ether, phenyl ether, methyl ethyl 1-thyl, etc.), benzene-based (benzene, toluene,
xylene, etc.), hydrocarbons (pentane, hexane, isooctane, cyclohexane, etc.)], reducing agents (lithium aluminum hydride, sodium bis-(2-methoxyethoxy) aluminum hydride, trimethoxylithium aluminum hydride, aluminum halide, triethyl Lidium BoD hydride, diisobutyl aluminum hydride, sodium diethylaluminum hydride, etc.) is used at a temperature ranging from 0° C. to the reflux temperature of the solvent.

Preferably, the reaction is carried out using lithium aluminum hydride in an ether solvent under reflux.

Step [jl is the synthesis of acid addition salt, for example, organic solution l
s [Benzene type (benzene, toluene, xylene, etc.),
Halogenated hydrocarbons (methinone chloride, chloroform, carbon tetrachloride, 1,1,2゜2-tetrachloroethylene, perchloroethylene, etc.), ethers (tetrahydrofuran, tetrahydrobilane, dioxane, diethyl ether, dimethyl ether, diisopropyl ether) ,
biphenyl ether, methyl ethyl ether, etc.), ethyl acetate, alcohols (methanol, ethanol, isopropanol, etc.), hydrocarbons (pentane, hexane,
isooctane, cyclohexane, etc.) using hydrogen chloride gas at a temperature ranging from -10°C to the reflux temperature of the solvent.

Preferably, this is carried out by passing hydrogen chloride gas through a benzene solvent at 0°C.

The process [kl is a sulbonylation reaction, for example, an inert organic solvent [benzene type (benzene, toluene, xylene, etc.), halogenated hydrocarbon type (methylene chloride, chloroform, carbon tetrachloride, 1.1°2.2 -tetrachlorethylene, perchloroethylene, etc.) at a temperature of -40 to 50°C in the presence of an acid acceptor (triethylamine, pyridine, dimethylaminopyridine, etc.) as a promoter.

Preferably, the reaction is carried out using 1-ethylamine in a benzene solvent under water cooling.

■Process [1] is an oxidation reaction, for example, an inert organic solvent [halogenated hydrocarbon type (methylene chloride, chloroform, carbon tetrachloride, 1.1,2.2-tetrachloroethylene, perchloroethylene, etc.)] ), etc.], alkali metal halides (lithium chloride, sodium chloride, potassium chloride, potassium bromide, sodium bromide, potassium bromide, etc.)
In the presence of catalyst (2,2,6,6-tetramethyl-1-
Piperidinyloxy, 4-methoxy-2,2,6,6-
in the presence of tetramethyl-1-piperidinyloxy, etc.),
Oxidizing agents (sodium hypochlorite, potassium hypochlorite,
-1 using sodium bromite, potassium argentite, etc.
It is carried out at a temperature of 0-30°C.

Preferably in methylene chloride in the presence of potassium bromide,
It is carried out using sodium hypochlorite and 2,2,6°6-tetramethyl-1-piperidinyloxy at a temperature of 0 to 20°C.

In addition to the above-mentioned method, one or more methods can also be used for this oxidation reaction.

(a) Published by Nankodo, edited by Tetsuji Kametani [Paid Synthetic Chemistry ■Results IJ, pages 176-206 (published August 1, 1976)
, or (b) John Wiley & 5ons, Inc.
, Inc. (USA) [C0Iipendflj parrot off
OfgaflIC5ynthetic HetllOd
s.

Section 48 or 168 of Volume 1 (1971), Volume 2 (1974), Volume 3 (1977) (described in detail).

Particularly preferred oxidation under mild and neutral conditions is to oxidize, for example, dimethylsulfide N-chlorosuccinimide complex, thioanisole-N-chlorosuccinimide complex, dimethylsulfide complex, dioanisole complex [hereinafter referred to as J , Aier, Ches, Soe, 94,75
86 (1972)], dicyclohexyl lupodiimide dimyl sulfoxide complexes [, j, Amer, C
he@, Soc, 87.56B1 (1965)], Viridinylamuku Nitrochromat (C5f'5 NH
C,03CfJ) [TetfahedronLet
ters, 2647 (1975)];
SOC, 89, 5505 (1967)], chromyl chloride [J, Aier, Chew, Soc. , 97
5929 (1975)], chromium trioxide-pyridine complexes (e.g. Collins reagent), Jones reagent, chromic acid solution (prepared from chromium dioxide, manganese acid, sulfuric acid and water), oxalic acid chloride and dimethyl sulfoxide [Swan (Swerri) oxidation] using tetramethyl-1-piperidinyloxy and sodium hypochlorite or sodium bromite.

dimethyl sulfide-N-chlorosuccinimide enantiomer,
Oxidation using thioanisole-N-chlorosuccinimide enantiomers, dimethyl sulfide-chlorine complexes, thioanisole-chlorine complexes, in halogenated hydrocarbons such as 1-day form, methylene chloride, carbon tetrachloride, or toluene, -3
It is carried out by reaction at a temperature of 0 to 0°C followed by treatment with triethylamine.

The reaction is carried out in dicyclohexylcarbodiimide-dimethylsulfoxide at room temperature in the presence of an acid catalyst such as phosphoric acid, phosphorous acid, cyanoacetic acid, pyridine-phosphate, or trifluoroacetic acid.

Oxidation using pyridinium chlorochromate is carried out in a halogenated hydrocarbon such as chloroform, methylene chloride, carbon tetrachloride, usually at room temperature in the presence or absence of 1-lium acetate.

Oxidation using an anhydrous sulfuric acid-pyridine complex is usually carried out in dimethyl sulfoxide at room temperature in the presence of triethylamine.

Oxidation using chromyl chloride is usually carried out on a day-to-day basis in halogenated hydrocarbons such as D-form, methylene chloride, carbon tetrachloride.
The reaction is carried out in the presence of eF't-butanol and pyridine at a temperature ranging from -30°C to the reflux temperature of the solvent.

The oxidation using the diromium trioxide-pyridine complex is carried out in a halogenated hydrocarbon such as chloroform, methylene chloride, carbon tetrachloride at a temperature from room temperature to 0°C, preferably 0°C.

Oxidation using Jones' reagent is usually carried out at temperatures below room temperature.

Oxidation using chromic acid solutions is usually carried out in diethyl ether at temperatures of -10°C to 5°C.

Swann oxidation is carried out in a halogenated hydrocarbon such as DD form or dichloromethane at -50°C to -80°C, followed by treatment with triethylamine.

Step [ml] is Wittig reaction, for example, inert organic solvent [ether type (tetrahydrofuran, tetrahydrobilane, dioxane, diethyl ether, dimethyl ether, diisopropyl ether, biphenyl ether, methyl ethyl ether, etc.), benzene type (benzene, toluene, xylene, etc.), a sulfoxide system (dimethyl sulfoxide, etc.)] in the presence of a base (potassium, t-butoxide, lithium diisoprobylamide, sodium hydride, etc.) at a temperature of -78°C to 50°C.

Preferably, the reaction is carried out in an ether solvent in the presence of potassium and t-butoxide at a concentration of 20 to 30°C.

Step [n] is the synthesis and purification of the salt, using an inert organic solvent [
Halogenated hydrocarbons (methylene chloride, chloroborum,
Carbon tetrachloride, 1,1,2.2-tetrachloroethylene,
perchlorethylene, etc.), ether type (tetrahydrofuran, tetrahydrobilane, diquine, diethyl ether, dimethyl ether, diisopropyl ether, biphenyl ether, methyl 1-delether, etc.), benzene type (benzene, toluene, xylene, etc.), ketone type (acetone, methylethylketone, phenylmethylketone, etc.), nitrile type (acetonitrile, etc.)], 1
is carried out by reacting with 1.5 equivalents of amine.

Amines that form such salts with carboxylic acids include, for example, amines that could theoretically be obtained by replacing one or more hydrogen atoms of ammonia with other groups.

The groups may be the same or different when one or more hydrogen atoms are substituted, but for example, an alkyl group having 4 to 8 carbon atoms, a cycloalkyl group having 4 to 7 carbon atoms, a cycloalkyl group having 1 carbon number -6 hydroxyalkyl groups.

Examples of amines are butylamine, pentylamine,
Preferred examples include hexylamine, heptylamine, dibutylamine, dibentylamine, dibutylamine, dibutylamine, cyclopentylamine, cyclohexylamine, cyclohebutylamine, dicyclopentylamine, dicyclohexylamine, dicyclohebutylamine, benzylamine, phenecylamine, etc. is cyclohexylamine.

The synthesized amine salt is isolated by freeze-drying the solution or by filtration, or by partially distilling off the solvent and then filtering.

Step [0] is a conversion from a salt to a carboxylic acid, for example, 1) an aqueous solution of organic M (acetic acid, propionic acid, oxalic acid, p-toluenesulfonic acid, etc.) or an inorganic acid (hydrochloric acid, @
2) using an organic acid (p-4-luenesulfonic acid, trifluoroacetic acid, etc.) in an aqueous solution of an organic solvent [alcohol-based (
methanol, ethanol, isobu-D-panol, etc.), ethers (tetrahydrofuran, tetrahydrobilane, dioxane, diethyl ether, dimethyl ether, diisopropyl ether, biphenyl ether, methyl ethyl ether, etc.) at a temperature of 0 to 50°C.

Preferably, it is carried out in simple acid at room temperature.

Step [p] is an esterification reaction, for example, (1) a method using a diazoalkane, (2) a method using an alkyl halide, (3) a DMF-
Examples include a method using a dialkyl acetal, (4) a method of reacting with a corresponding alkanol, and (5) a method using an acid halide.

To specifically explain these methods, (1) a method using a diazoalkane is, for example, a method using a corresponding diazoalkane, using an inert organic solvent [ether type (tetrahydrofuran, tetrahydrobilane, dioxane, diethyl ether, dimethyl ether, diisopropyl ether,
phenyl ether, methyl ethyl ether, etc.), halogenated hydrocarbons (methylene chloride, chloroform, carbon tetrachloride, 1.1,2.2-tetrachloroethylene, perchloroethylene, etc.), ketones (acetone, methyl ethyl ketone, phenyl methyl ketones, etc.), alcohol-based (
(methanol, ethanol, isopropanol, etc.), ethyl acetate, etc.)].

(2) Methods using alkyl halides are based on organic solvents [[ketones (acetone, methyl ethyl ketone, phenylmethyl ketone, etc.), amide systems (dimethylformamide, N,N-dimethylace-1-amide, etc.]), sulfoxide-based (dimethyl sulfoxide, etc.)] in the presence of a radical (potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, calcium hydroxide, etc.) using the corresponding alkyl halide.

(3) The method using DMF-dialkyl acetal is
For example, it is carried out using the corresponding DMF-acetal in an inert organic solution 1 [benzene-based (benzene, toluene, xylene, etc.)].

(4) The method of reacting with the corresponding alkanol includes, for example, acidic hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, hydrogen chloride gas, etc. in the corresponding alkanol, or a condensing agent (
DCC, Viva Dyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride, etc.).

(5) Methods using acid halides include, for example, inert solvents [halogenated hydrocarbons (methylene chloride, DO form, carbon tetrachloride, 1,1.2°2-tetrachloroethylene, perchloroethylene, etc.)] etc.] or without a solvent, with an acid halide (oxalyl chloride, thionyl chloride, etc.) at -20°C to reflux temperature, and the resulting acid halide is reacted with a tertiary amine (pyridine, triethylamine,
dimethylaniline, dimethylaminopyridine, etc.), the corresponding alkanol and an inert organic solvent [halogenated hydrocarbon type (methylene chloride, chloroform, carbon tetrachloride, 1,1,2.2-tetrachloroethylene, perchloroethylene, etc.) etc.] or without solvent, 0-=40℃
This is done by reacting with

These reactions are usually carried out at a temperature of -10 to 40°C.

Preferably, the reaction is carried out by reacting with oxalic acid chloride in a halogenated hydrocarbon solvent, and reacting the obtained acid halide with n-decanol in the presence of triethylamine in a halogenated hydrocarbon solvent.

[Effects of the Invention] The present invention provides the following features: 1) using reagents that are easy to obtain at low prices, 2) at temperatures that are easy to control industrially, and 3) manufacturing by column chromatography in the final step. 4) A novel method for producing a compound represented by formula (I>) that can be obtained in high yield, and a novel intermediate obtained by the process. It is something.

[Reference Examples and Examples] Hereinafter, the present invention will be explained in detail with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Unless otherwise specified, IR is measured by the liquid film method.

Synthesis of mouse delta doctor Juhis ((S)-ethyl lactate) fumarate H e Toluene (300 d) and hydroquinone (20 d) were added to 3
00- and stirred in an argon stream. Fumaryl chloride (10,8d) was added dropwise to the reaction solution, and then (S)-ethyl lactate (34sff>) was added dropwise.

While passing argon gas through the reaction solution, it was heated to 100° C. and refluxed for 7 hours. The reaction solution was cooled to O'C, and triethylamine (27,9d) was added dropwise over 20 minutes. After stirring at the same temperature for 40 minutes, 2N hydrochloric acid (1O0
d) and n-hexane (100Id>) were added. The organic layer was washed with 2Nm acid, 2N aqueous I.lium hydroxide solution, and saturated water (1), dried, and concentrated under reduced pressure. It had the following physical properties. The title compound (3291) was obtained.

TLC: Rf O,66(n-hex+,in:[1i
J4 Roux 3:1): MS:rn/Z 3164M), 271,226
, 199, 101: IR Niji 1750.1740
．． 1725.1640.1445.1285°1200
．． 1090 ata-' Hair boiled blue 2 Bicyclo[2,2゜1]hept-5-ene-2,3-dicarboxylic acid dilacic acid ethyl ester synthesis In an argon stream, the compound synthesized in Reference Example 1 (32g>
was dissolved in toluene (100%) and cooled to -10°C. While stirring the reaction solution, add cyclopentadiene (9.
91) was added dropwise over a period of 15 minutes, and the mixture was stirred at -5=-10°C for 2 hours. The reaction solution was concentrated to obtain the title compound (38.39 ml) having the following physical properties.

TLC: Rf 0.67 (n-hexane:ethyl acetate-3:1); MS: rn/Z 382 (M), 337,317
, 271, 199, 119.

101, 91, 61: IR Niji 1740, t450, I375, 13
00, 1270, 1205.

1165, 1095 rats-' 11~-5-ene-2,3- to tsutari-sotan bicyclo[2.2,1]
Synthesis of potassium dicarboxylic acid salt The compound synthesized in Reference Example 2 (38.3 g) was added to a 100M solution of potassium hydroxide (44.99) in water (44.eas).
g>The solution was slowly added and stirred. 1 of the reaction solution
After refluxing for an hour, the mixture was allowed to cool and concentrated. Water (1
00d) was added and stirred, and dry ice (>100 g) was added little by little and left overnight to obtain a solution of the title compound.

Hair Toyoka A 5-Hydroxy-6-iodobicyclo[2.2.

1] Synthesis of heptane-2,3-dicarboxylic acid-5,3-lactone Iodine (25.49') was added to a solution of potassium iodide (99.69) in water (100 #4).

Reference @3 The above solution (90d) was slowly added dropwise at room temperature to the aqueous solution (O.IM>) of the compound synthesized in 3, and 3
0 molecules were stirred (). After the reaction solution was cooled, it was acidified with hydrochloric acid and left at 3° C. overnight.

The formed crystals were collected by filtration, washed with water, and dried. The obtained crystals were heated and dissolved in ethyl acetate (100ml, n
-Hexane (200d) was added and left overnight at room temperature to produce the title compound (11.28 9 ) having the following physical properties (
It's straddling. After concentrating the mother liquor in a colander, ethyl acetate (50a
T! The residue was heated and dissolved, and n-hexane (
100d) and left overnight at room temperature to give the title compound (6
．． 16g) was obtained.

[α]25: +53.1° (C-3.03, ethanol): rTlp: 185-186°C: TLC: Rf O, 33 (methylene chloride: methanol = 9:1).

Hair lambda alternation 2-methoxycarbonyl-5-hydroxy-6-iodobicyclo[2.2.1]hebutane-3=carboxylic acid-5
, 3-Lactone Synthesis The compound synthesized in Reference Example 4 (569.8 g) and methanol (200 d) were placed in an ION reaction solution, cooled on ice, and stirred while passing hydrogen chloride gas for 60 minutes. Stirred for an additional 4 hours. After that, the apparatus was heated overnight.The reaction solution was concentrated.
The title compound (595.7 g) was dried and had the following physical properties.
) was obtained.

TLC: Rf 0154 (n-hexane:ethyl acetate-2:1).

Zinc powder (241
,99> was added little by little. The reaction mixture was heated to reflux (65-110°C, 2 hours) in an oil bath. The mixture was left to cool for a while and then filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (25,005 ml and 1,500 ml of water!)
was added and shaken. The organic layer was soaked in 1N hydrochloric acid (300ad!
X2>, water (300adX2), saturated saline (300d
This was washed with >, dried, and dried under reduced pressure to obtain the title compound (366,49) having the following physical properties.

TLC: Rf 0.60 (methylene chloride:methanol=9:1).

Synthesis of 2-methoxycarbonylbicyclohebutane-3-carboxylic acid The compound (595.79) prepared in Reference Example 5 and acetic acid (1300d) were placed in a reaction vessel No. 101, and palladium-carbon (content: A suspension of 10%:25g> in ethanol (100d) was placed in a 5g reaction vessel, a solution of the compound synthesized in Reference Example 6 (361.4g) in ethanol (1500iae) was added thereto, and the mixture was heated at room temperature under a hydrogen atmosphere. It was stirred vigorously for 6 hours. The reaction solution was filtered, and the filtrate was concentrated. 1-Toluene was added to the residue, the solvent was removed by azeotropic distillation, and the title compound (346.6 9
> obtained.

Dog blood 2-methoxycarbonylbisic D[2.2.11 Synthesis of butane-3-carboxamide A solution of the compound (34G, Gg) synthesized in Reference Example 7 in methylene chloride (1500d) was cooled on ice. Oxalyl chloride (305d) was added dropwise over 25 minutes. The reaction solution was stirred at room temperature for 1 hour and 30 minutes and at 30° C. for 1 hour, and then concentrated under reduced pressure. The residue was dissolved in methylene chloride (300
0am! ), cooled on ice, and passed ammonia gas through it for 45 minutes while stirring.

The reaction solution was filtered through Celite, and the filtrate was dried and concentrated under reduced pressure to obtain the title compound.

X1 plate 2 3-amythomederbicyclo[2.2.1]hebutane-2
- Synthesis of methanol Put lithium aluminum hydride (104.4 9 >
JI! > was added over 5 minutes. Reflux the reaction mixture;
A solution of the compound synthesized in Example 1 (295.3 g) in THF (1200 d) was added dropwise to this over 2 hours.

The reaction mixture was stirred (refluxed) for 2 hours. After the reaction,
After cooling on ice, a saturated aqueous solution of sodium chloride (300 d) was added, stirred, and kept in the apparatus overnight. The reaction mixture was filtered, and the filtrate was dried once and dried under reduced pressure to obtain the title compound (181.7 9 ) having the following physical properties.

TLC: Rf 0.08 (@midilene:methanol-2:1).

X Dust ■ Yu 3-7 Minomethylbicyclo[2.2.1] Hebutane-2
- Synthesis of methanol hydrochloride The compound (95,79> synthesized in Example 2) was mixed with toluene (
330d). Cool this solution with ice water,
Hydrogen chloride gas was passed through the mixture while stirring.

After the reaction, the solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (
150d) was added and washed by refluxing.

After cooling, the crystals were collected by filtration and washed with ethyl acetate.
Dry with a pump to obtain the title compound (53
G. Og> was obtained.

[α]', 7: +19.7° (C-1,18,
ethanol): mp: 130-133°C: MS-m/Z 155 (M), 137,125,
Synthesis of 3-(4-bromobenzenesulfonylaminomethyl)bicyclo[2.2.1]heptane-2-methanol The compound synthesized in Example 3 (5.94 g) was mixed with toluene (
60d) The solution was cooled to 0°C, and triethylamine (21,6d) was added dropwise to it over 6 minutes.

After stirring the reaction mixture at the same temperature for 14 minutes, a solution of 4-promobenzenesulfonyl chloride (7.92 g) in toluene (30 ad) was added dropwise at the same temperature over 26 minutes. After stirring for 4 hours with
Hydrochloric acid-ice water (poured into 150 liters). Ethyl acetate was added, and the organic layer was washed with water, an aqueous sodium bicarbonate solution, and saturated brine, dried, and concentrated under reduced pressure to obtain the title compound (11.9 g) having the following physical properties. > obtained.

TLC: Rf 0.68 (n-hexane:ethyl acetate-1:1).

Synthesis of 3-(4-bromobenzenesulfonylaminemethyl)bicyclo[2°2.1]hebutane-2-carbaldehyde Methylene chloride (21d) of the compound synthesized in Example 4 (4,239>) Cool the solution to 5°C and, with stirring, add 2.
2,6,6-tetramethyl-1-piperidinyloxy (
884), then O,5M aqueous potassium bromide solution (2,
26d) was added. An aqueous sodium hypochlorite solution (0.37M, 56d) was added dropwise to the vigorously stirred reaction solution over 10 minutes. Methylene chloride (150 d) was added to the reaction solution, and the organic layer was washed with saturated brine, dried, and concentrated under reduced pressure to obtain the title compound (4.27 g) having the following physical properties.

TLC: Rf O, 47 (n-hexane:ethyl acetate-2:1).

Large dust ■5 (5Z)-6-[3-(4-bromobenzenesulfonylaminomethyl)bicyclo[2,2,1]hebutane-2-
Synthesis of dried 4-j3-lupoxybutyltriphenylphosbonium 71 mite (1G
. Potassium t-butoxide (7,999) was added little by little to a THF (43d) suspension of Og) at 5°C under an Algol flow.

The reaction mixture was stirred at 20°C for 1 hour. The reaction mixture is
Cool to 1 C Compound synthesized in Example 5 (4°219)
A solution of THF (1(5d)) was added dropwise over 10 minutes.

After stirring at 10°C for 30 minutes, the reaction mixture was poured into ice water. Ether (5C)dX2) was added, the layers were separated, and the aqueous layer was acidified with concentrated hydrochloric acid. Ether was added for extraction, and the organic layer was washed with saturated brine, dried, and concentrated under reduced pressure. The residue was dissolved in ether and filtered. The filtrate was again concentrated under reduced pressure to obtain the title compound (4,
6g) was obtained.

TLC:, Rf 0.60 (ethyl acetate:hexane 2
:1).

Tokuo, [(5Z)-6-[3-(4-bromobenzenesulfonylaminomethyl)bicyclo[2,2,1]hebutane-2-
Synthesis of cyclohexylamine salt of hex-5-enoic acid The compound synthesized in Example 6 was diluted with methylene chloride (89at
e) and add cyclohexylamine (1
, 3d> was added and the apparatus was heated overnight. The formed crystals were washed with methylene chloride (10 tons) and dried with a pump to obtain the title compound (4,619>) having the following physical properties.

[α]2o5:+24.0' (C-1,01, ethanol): mp: 140-145°C: MS: m/Z 455 (M"), 437,395,3
42,248,236゜200 Daio Sodan (52)-6-[3-(4-bromobenzenesulfonylaminomethyl)bicyclo[2o2゜1]heptane-2-
Synthesis of Example 7 The compound (4,379) synthesized in Example 7 was added to 4N hydrochloric acid (88ad) and stirred. After the reaction was completed, it was extracted with ether C88dX2>, and the organic layer was dissolved in saturated brine. Wash with water, dry, and prepare the title compound (
3.76 g) was obtained.

Example 9 (5Z)=6-[3-(4-bromobenzenesulfonylaminomethyl)bicyclo[2,2,11butane-2
-yl]hexate-5-enoic acid decyl ester The compound synthesized in Example 8 (3°76 g) was dissolved in methylene chloride (16d), and oxalic acid chloride (1,377) was dissolved at 0°C under an argon atmosphere. was added and stirred at room temperature for 1 hour and 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, toluene was added, and excess reagent was removed by azeotropy. The residue was dissolved in methylene chloride (16 ad
n-decanol (1,8d
> Then, pyridine (0.95d) was added dropwise and stirred for 1 hour. After the reaction was completed, methylene chloride (100ate) was added, washed with 1N hydrochloric acid, aqueous sodium bicarbonate solution, and saturated brine, dried, concentrated under reduced pressure, and subjected to silica gel column chromatography (n-hexane: ethyl acetate 10:1).
) to obtain the title compound (4,37
9) was obtained.

TLC: Rf 0.40 (n-hexane: ethyl acetate = 3:1): MS: m/z 595,456,437,40
4,388,376.360.

Claims (1)

[Claims] 1) A bicyclo[2.2.1]heptane derivative represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. 2) A method for purifying the compound represented by the formula (II), which is characterized by reacting the compound represented by the formula ▲numerical formula, chemical formula, table, etc.▼ with an amine, crystallizing it, and then converting it back to an acid. 3) 2,2,6,6-tetramethyl-1- as a catalyst
Manufacture of a compound represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ which is characterized by oxidizing the compound represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. Method.