JPH08333327A - Production of 1,4-cross-linked cyclohexane-based carboxylic acid derivative - Google Patents

Abstract

PURPOSE: To simply and safely obtain the subject compound useful as a synthetic intermediate for medicines by reacting a compound prepared by oximation, reduction, sulfonylation and oxidation treatment of a specific keto compound as a starting substance with a specified ylide and then reacting the resultant compound with a specific amine. CONSTITUTION: A compound of formula I is used as a starting substance and oximation, reducing reaction, sulfonylation and oxidizing reaction thereof are successively carried out to provide a compound of formula II [R is a (substituted) aryl or aralkyl], which is then reacted with a compound of the formula (R<1> )3 P=CH(CH2 )n COOM [R<1> is a lower alkyl or an aryl; M is an alkali metal; (n) is 2-4] to afford a compound of formula III. The resultant compound of formula III is subsequently treated with methoxybenzeneethaneamine, fulfurylamine, 4-methylbenzylamine or 4-methoxybenzylamine to provide a compound of formula IV (R<2> is an amine residue), which, as necessary, is treated with an acid to afford a free carboxylic acid. Thereby, an alkali (alkaline earth) metallic salt thereof is obtained.

Description

Detailed Description of the Invention

[0001]

The present invention relates to 2,3-trans-1,
The present invention relates to a method for producing a Z-type isomer of a 4-bridged cyclohexane carboxylic acid derivative.

[0002]

2. Description of the Related Art Formula IX :

Embedded image (In the formula, R is an aryl or aralkyl which may be substituted, and n is an integer of 2 to 4.) Z-type 2,
A 3-trans-1,4-bridged cyclohexane-based carboxylic acid derivative is an important synthetic intermediate for a 1,4-bridged cyclohexane-based compound which is clinically useful as an antagonist of thromboxane A ₂ (Japanese Patent Publication No. 5-79060). Issue). Prostaglandins are derived from eicosaporienoic acids such as arachidonic acid in the animal body, namely, platelets,
It is a physiologically active substance enzymatically produced in the blood vessel wall and various cells. Among them, thromboxane A ₂ is known to have a strong physiological action such as aggregation of platelets and contraction of smooth muscles such as bronchi, coronary arteries and pulmonary arteries,
Excessive presence of thromboxane A ₂ is considered to be one of the etiological factors such as myocardial infarction, cerebral infarction, bronchial asthma and thrombosis. The strong action is easily understood from the fact that the action expression concentration is also said to be 10 ⁻¹¹ to 10 ⁻¹² M. Therefore, if a thromboxane A ₂ inhibitor, that is, an inhibitor of the biosynthetic enzyme of the substance or an antagonist of the substance is obtained, it is expected to be effective for the treatment or prevention of the above-mentioned various diseases. . However, the inhibitor clinically competes with thromboxane A ₂ because it shows an inhibitory effect on other physiologically active substances similar to thromboxane such as prostaglandins and accumulates inconvenient precursors. Therefore, an antagonist that specifically inhibits the binding to the receptor is more desirable.

From the above viewpoints, the present inventors have conducted extensive research for the purpose of developing thromboxane A ₂ antagonists, synthesized various chemically and biochemically stable compounds, and disclosed them ( Japanese Patent Publication No. 5-79060).
The Z-type 2,3-trans-1,4-bridged cyclohexane-based carboxylic acid is an intermediate for the production of a particularly useful compound in the series of compounds. Conventionally, these compounds are prepared by using, for example, a compound represented by the formula X obtained by an oxidation reaction using a reagent, metachlorperbenzoic acid (MCPBA), which is extremely dangerous for use on an industrial scale, as a starting material. The following reaction formula:

[Chemical 9] (In the formula, Prot-N is benzyloxycarbonyl, tert-
Represents butoxycarbonyl or triphenylmethyl)
According to the method described above, the product XI was obtained by the Wittig reaction (Japanese Patent Publication No. 5-79060). Also the formula:

Embedded imageThis Wittig reaction product mixture, as shown inXI
When the optical purity of the raw material system is less than 100% ee,
Contains 3α-E, Z and 3β-E as minor impurities.
In order to obtain a 3β-Z form with a purity suitable for the purpose of use,
Must use lica gel column chromatography
(JP-A-2-256650). like this
In addition, the conventional method is complicated and difficult to operate.
It was unsuitable for industrial production of the final target substance.

[0004]

The present invention solves the above-mentioned problems by reacting a carboxylic acid, which is a mixture of stereoisomers of formula VIII , with certain amine compounds. The fact that Z-form, especially 3β-Z-form carboxylic acid salt crystallizes preferentially and can be easily separated from other isomers, enables omission of column chromatography separation. Highly explosive MCP
It is also based on the fact that if ozone is used to safely oxidize on a production scale without using BA, the oxidation reaction can be achieved cleanly and the desired raw material VI can be obtained easily and in a large amount.

That is, the present invention provides formula II :

[Chemical 11] The compound represented by the formula III :

[Chemical 12] A compound represented by
IV :

[Chemical 13] A compound of formula V 2 is obtained by subjecting the compound to a sulfonylation reaction.

Embedded image (Wherein R represents an optionally substituted aryl or aralkyl), and the compound is subjected to an oxidation reaction to give a compound of the formula VI :

[Chemical 15] (Wherein R has the same meaning as described above), and the compound and the compound of formula VII : (R ¹ ) ₃ P═CH (CH ₂ ) nCOOM VII (wherein R ¹ is lower alkyl or Aryl; M is an alkali metal; n is an integer of 2 to 4) and is subjected to a Wittig reaction to form a compound of formula VIII :

Embedded image (Wherein R and n have the same meanings as described above), and the compound is an amine compound selected from methoxybenzeneethaneamine, furfurylamine, 4-methylbenzylamine and 4-methoxybenzylamine. Treated with formula I :

[Chemical 17] (Wherein R ² is an amine residue; R and n have the same meanings as described above), and a salt of a Z-type 2,3-trans-1,4-bridged cyclohexane-based carboxylic acid is obtained. The present invention provides a process for producing an alkali metal salt or an alkaline earth metal salt, which comprises subjecting the salt to an acid treatment to obtain a free carboxylic acid.

In particular, according to the method of the invention, the formula VIII
By reacting the compound of formula (I) with an amine, the Z-type 2,3-trans-1,4-formula ( I) of formula
Crosslinked cyclohexane-based carboxylic acid salts are produced. If the compound I is recrystallized from an alcohol solvent such as methanol-water according to the purpose, a highly pure compound I can be obtained. Amines applicable to the method of the present invention include methoxybenzeneethanamine (MBA), furfurylamine, 4-methylbenzylamine and 4-methoxybenzylamine described above, with MBA being particularly preferred.

The terms used in this specification are defined below. “Lower alkyl” means C ₁ -C ₈ linear or branched alkyl, for example, methyl, ethyl, n
-Propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, heptyl or octyl and the like can be mentioned. “Lower alkoxy” means C ₁ -C ₈ linear or branched alkoxy, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy or octyl. Oxy etc. can be mentioned. “Aryl” is an atomic group remaining after removing one hydrogen atom from an aromatic hydrocarbon, and examples thereof include phenyl and naphthyl, with phenyl being preferred. “Aralkyl” is an atomic group remaining after removing one hydrogen atom from a side chain of an aromatic hydrocarbon having a side chain, in which an alkyl group is substituted with an aryl group, for example, benzyl, methylbenzyl, naphthyl. Methyl is mentioned.

Substituents for aryl or aralkyl include hydroxy, nitro, halogen, lower alkyl, lower alkoxy and the like. Examples of the "alkali metal salt" include lithium salt, sodium salt, potassium salt and the like. Examples of the "alkaline earth metal salt" include calcium salt and the like. "Halogen" means fluorine,
Means chlorine, bromine or iodine. Of the compounds prepared by the method of the present invention, R in formula I is phenyl,
A compound in which n is 3 and R ² is an MBA residue is preferable,
(5Z) -7- [2-exo-3-endo-3-phenylsulfonylaminobicyclo [2.2.1] hept-2
An MBA salt of -yl] -5-heptenoic acid (hereinafter referred to as the present compound A ) is particularly preferable.

The reaction of the carboxylic acid of formula VIII with the amine can be carried out under conventional reaction conditions known to those skilled in the art. Examples of the solvent include ethyl acetate-methylene chloride, toluene-methanol, acetonitrile and the like.
When the amine is used in a molar ratio of 1 to 3 with respect to the carboxylic acid VIII and the reaction is carried out in a suitable solvent at a temperature of 0 to 50 ° C., only the amine salt of the Z-form is crystallized, and other E- Separate from the body. The product is filtered off and recrystallized if necessary, whereby a high-purity Z-form can be easily obtained. Therefore, according to the method of the present invention, the amine salt I of Z-form can be selectively obtained from the mixture of E- / Z-form without column chromatography. The obtained amine salt is used as it is or after being treated according to a conventional method to be converted into a free carboxylic acid or a derivative thereof, and used for producing an antagonist of thromboxane A ₂ which is a final target substance.
Hereinafter, the present invention will be described in more detail with reference to examples.

[0010]

【Example】

Embedded image Example 1 15.0 g (91.4 mmol) hydroxylamine sulphate were dissolved in 25 ml water and 75 ml methanol were added. 25.0 g (166.4 mmol) of compound II was added to this mixture.
-1 was added at 20-40 ° C, followed by 14.0 g (16
(8 mmol) 48% sodium hydroxide was added dropwise at 20-40 ° C. After carrying out the reaction aging for 1 hour at room temperature, the reaction mixture was added to a mixed solution of water (120 ml) -toluene (75 ml) for extraction. The organic layer was concentrated under reduced pressure to dryness and the oily residue was converted to 5
After adding 0 ml of ethanol, the mixture was concentrated to dryness again to give the compound
An oil containing III-1 was obtained. This residue was directly used as a raw material in Example 2. Compound III-1 : Production rate 96%, bp.120-124
℃ / 2 torr

Example 2 The concentrated residue obtained in Example 1 (containing 27 g (163 mmol) of compound III-1 equivalent) was dissolved in 250 ml of ethanol and heated to 70 ° C. 29g here (1.2
(6 mol) metallic sodium was added at an internal temperature of 105 ° C or lower, and after reaction aging at 100 to 110 ° C for 1 hour, 27 ml of water was added at 95 ° C or lower. Cool the mixture to room temperature,
The reaction of Example 3 was subsequently carried out. Compound IV-1 : Production rate 98%, bp. 89-93 ° C / 1
5 torr

Example 3 The mixture obtained in Example 2 (about 2% as compound IV-1)
5 ml (corresponding to 0.16 mmol) was added with 54 ml of ethanol and cooled to 0 to 15 ° C. 145 g (1.39 mol)
After adding 35% hydrochloric acid of above at 25 ℃ or less, 41 g (0.40
5 mol) triethylamine was added, followed by 31 g
(0.17 mol) benzenesulfonyl chloride was added at 20 ° C. or below and stirred for 30 minutes. To the reaction mixture, 416 ml of water was added at 20 ° C. or below, and the mixture was crystallized with stirring for 30 minutes, then the crystals were separated by filtration, washed with water and dried. Compound V-1 : yield 45.1 g, yield 93% (compound II
-1 yield), mp.103 ° C

Example 4 To 45 g (0.15 mol) of compound V-1 was added 60 ml of methanol and 600 ml of dichloromethane, and the mixture was stirred at -70 ° C.
After cooling to 7.4, 7.4 g of ozone was introduced at −65 ° C. or lower to react. After removing excess ozone gas from this mixture, 48.6 g (0.18 mol) of a solution of triphenylphosphine in dichloromethane (50 ml) was added at -60 ° C or below. The reaction mixture was washed twice with 180 ml of water, then 18
It was washed with 0 ml of 5% aqueous sodium chloride, and the extract was subsequently concentrated under reduced pressure. To the residue was added 135 ml of toluene,
It was concentrated to dryness again and solid containing Compound VI-1 (45 g)
I got Compound VI-1 : production rate 98 to 100%, mp. 107 ° C

Example 5 To 89.0 g (0.2 mol) of (4-carboxybutyl) triphenylphosphonium bromide, 135 ml of toluene and 45 ml of dimethyl sulfoxide (DMSO) were added, and the mixture was cooled to -5 ° C. 64.1 g (0.57 mol) of potassium-t-butoxide was added at 35 ° C or lower and the reaction was carried out for 1 hour. D of the concentrated residue obtained in the previous step (45 g of Compound VI-1 ; corresponding to 0.15 mol) was added to this reaction solution.
A mixed solvent solution of MSO (90 ml) -toluene (90 ml) was added at -15 ° C, and the reaction was aged for 2 hours. The reaction mixture was extracted with 270 ml of water and then washed with 270 ml of toluene. Subsequently, the extracted aqueous layer was extracted with 450 ml of ethyl acetate under acidic conditions, the organic layer was washed with 225 ml of saturated saline and then concentrated under reduced pressure to dryness. The concentrated residue containing the compound VIII-1 was directly used as a raw material in Example 6. 80 g of concentrated residue. Compound VIII-1 ; mp. 66 ° C

Example 6 32.7 g in the concentrated residue of 80 g (58.1 g as compound VIII-1 ; containing 0.15 mol equivalent) obtained in Example 5
(0.22 mol) p-methoxybenzeneethanamine (MBA) and 226 ml methanol were added, and about 120 ml was added.
It was concentrated under reduced pressure. The concentrated residue was diluted with 360 ml of methanol, 540 ml of water was added, the mixture was stirred at 32 to 38 ° C. for 3 hours, and then gradually cooled to 0 ° C. for crystallization. The crystals were separated by filtration and washed with 500 ml of 75% hydrous methanol. Obtained crude compound I-1 undried crystal 120
g was used as a raw material of Example 7 without drying. Compound I-1 : 61 g of dry matter equivalent, 85% yield

Example 7 (first recrystallization) Crude compound I- obtained in Example 6
120 g of the undried crystals of 1 was dissolved by adding 428 ml of methanol, 550 ml of water was added, and the mixture was stirred at 40 ° C. or lower for 3 hours, and further slowly cooled to 0 ° C. for crystallization. The crystals were separated by filtration and washed with 500 ml of 75% hydrous methanol. The thus-obtained undried crystals (100 g, dry matter-equivalent yield: about 55 g; yield: about 90%) were used as a raw material for the second recrystallization step without being dried. (Second recrystallization) To 100 g of undried crystals, 385 ml of methanol was added and dissolved, and 500 ml of water was added. After that, recrystallization was repeated under the same conditions as the first recrystallization. 100 g of undried crystals of purified compound I-1
(Dry product conversion yield of about 49.4 g, yield 90%) was used as a raw material for the next step without drying. Purified compound I-1 ; mp. 131 ° C

Example 8 To 100 g of the undried crystals of the purified compound I-1 obtained in Example 7 (dry matter equivalent yield 49.4 g; corresponding to 93.4 mmol), 168 ml of water, 198 ml of toluene and 1
3.5 g (0.13 mol) of 35% hydrochloric acid was added and stirred for 10 minutes. After liquid separation, the organic layer was mixed with 89 ml of 1% hydrochloric acid and 84
It was washed successively with ml of water. Subsequently, 262 ml of DIW
(Deionized water) was added, and 81.3 g (96.6 mol (purity 8
(6%)), 7.7% potassium hydroxide was added, and the mixture was stirred and then separated, and the obtained aqueous layer was diluted with 74 ml of DIW, and then the dissolved toluene was distilled off under reduced pressure. PH with 2N-hydrochloric acid
Was adjusted to 10, and then 13.7 g (93.2 mmol) was added to this solution.
Calcium chloride dihydrate was dissolved in 53 ml of DIW and added, and the mixture was stirred at room temperature for 1 hour and crystallized at 5 ° C. for 1 hour. The crystals were separated by filtration and washed with 400 ml of DIW. 50 g of the undried crystal of the obtained crude compound XII-1 (calcium salt dihydrate of the present compound A ) was recrystallized in a water-methanol mixed solvent without drying to give compound XII-1 3.
3.1 g was obtained. Compound XII-1 ; yield about 90%, mp. 300 ° C (de
c.), [α] ²⁴ _D +21.3 (c = 1.0 methanol)

Crude compound obtained in Example 6 aboveI-1
And the compound after recrystallization obtained in Example 7.I-1Of Z body
The composition ratio of the E form is shown below.

Table 1 HPLC (area percentage composition ratio) (Z) (E) Product of Example 1 (1) (crude compound I-1 ) 97.3% 2.7% Production of Example 1 (2) Product (Purified Compound I-1 ) First recrystallization 99.4% 0.6% Second recrystallization 99.8% 0.2% The above results were obtained in Example 6 according to the method of the present invention. Although the amine salt contains a Z-form salt at a high content rate, it is shown that compound I-1 having a higher purity can be obtained by performing recrystallization twice.

[0019]

Industrial Applicability The important synthetic intermediate of a 2,3-trans-1,4-bridged cyclohexane compound, which is clinically useful as an antagonist of thromboxane A ₂ , can be easily produced, and the antagonist can be mass-produced. Can contribute to.

Claims (3)

[Claims] 1. Formula II : embedded image In equation subjected compound represented by the oximation reaction III: ## STR2 ## A compound represented by
IV : A compound of formula V : embedded image which is subjected to a sulfonylation reaction. (Wherein R represents an optionally substituted aryl or aralkyl), and the compound is subjected to an oxidation reaction to give a compound of the formula VI : (Wherein R has the same meaning as described above), and the compound and the compound of formula VII : (R ¹ ) ₃ P═CH (CH ₂ ) nCOOM VII (wherein R ¹ is lower alkyl or Aryl; M is an alkali metal; n is an integer of 2 to 4) and is subjected to a Wittig reaction to give a compound of formula VIII : (Wherein R and n have the same meanings as described above), and the compound is an amine compound selected from methoxybenzeneethaneamine, furfurylamine, 4-methylbenzylamine and 4-methoxybenzylamine. And treated with Formula I : (Wherein R ² is an amine residue; R and n have the same meanings as described above), and a salt of a Z-type 2,3-trans-1,4-bridged cyclohexane-based carboxylic acid is obtained. A process for producing an alkali metal salt or an alkaline earth metal salt, which comprises subjecting the salt to an acid treatment to obtain a free carboxylic acid. 2. Preparation of a Z-type 2,3-trans-1,4-bridged cyclohexane-based carboxylic acid salt of the formula I , characterized in that the compound of the formula VIII is reacted with methoxybenzeneethanamine. Method. 3. The production method according to claim 1, which comprises recrystallizing the compound represented by the formula I from an alcoholic solvent.