WO2001096273A1 - Process for the preparation of 1-substituted-cyclo-hexanecarbonyl halides - Google Patents

Abstract

A process is provided, by which 1-substituted-cyclo-hexanecarbonyl halides of the general formula [1] can be prepared industrially practically at an extremely low cost: [1] wherein R is linear or branched C1-10 alkyl, C3-10 cycloalkyl, cycloalkyl(C3-10)alkyl(C1-10), or aralkyl; and X is halogeno.

Description

 Specification

Method for producing 1-substituted-cyclohexanecarbonyl halide compounds

 The present invention relates to a novel method for producing a mono-substituted cyclohexanecarbonyl halide compound. More specifically, the present invention relates to a cholesterol ester described in Japanese Patent No. 2894445 and Japanese Patent Application No. 10-296593. The present invention relates to a method for producing a mono-substituted cyclohexane carbol halide compound which is an intermediate for producing a compound useful as a transfer protein (CE TP) inhibitor. In addition, the present invention relates to a method for producing an intermediate for producing a 1-substituted monocyclane hexanecarbonyl halide compound, and an intermediate for producing the intermediate. Background art

 (1) As described above, mono-substituted cyclohexanyl propylonyl halide compounds are described in the following compounds described in Japanese Patent No. 2894445 and Japanese Patent Application No. 10-296593.

Wherein, R ', is 1 monosubstituted over cycloalkyl group, X had X _2, X _3, X ₄ water atom, a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group , Is a hydrogen atom, and YiR (where is CO or CS And is an optionally substituted alkyl group, a heterocyclic group, etc.) and the like. More specifically, for example, N- (2-mercaptophenyl) _1_ (2-ethinolevuchi ^ shown below) ) Cyclohexane power boxamid,

2-Methylthiopropionic acid S— [2- (1-Isoptylcyclohexanecarboniamine / reamino) Feel Ί Estenole

And the like, and a method for producing the same has already been specifically disclosed in the official gazette and the specification. That is, as Example 2 of the publication, a synthesis method shown by the following scheme is described.

しかしながら、 これら公知の製造方法は、 経済的又は工業的に十分満足できる ものではなかった。 特に、 公知の製造方法を用いた場合、 各工程で使用される試 薬及ぴ溶媒、 例えば L D A (リチウムジイソプロピルアミ ド） 、 水素化ナトリウ ム及び T H F (テトラヒ ドロフラン） 等に加え、 出発原料であるシクロへキサン カルボン酸が極めて高価であり、 経済的に考えてあまり実用的ではなかった。 従 つて、 C E T P阻害剤として有用な化合物をより安価で、 より実用的に製造する ためには、 これら高価な原材料及び試薬、 溶媒をできる限り使用せず、 又は使用 量を削減することにより、 その中間体である 1一置換一へキサンカルボ-ルハラ ィド化合物をより安価に製造することが求められていた。 発明の開示

However, these known production methods are economically or industrially satisfactory. It was not something. In particular, when a known production method is used, in addition to the reagents and solvents used in each step, such as LDA (lithium diisopropylamide), sodium hydride, and THF (tetrahydrofuran), the starting materials are used. Cyclohexanecarboxylic acid was extremely expensive and not very practical from an economic standpoint. Therefore, in order to produce a compound useful as a CETP inhibitor at lower cost and more practically, these expensive raw materials, reagents, and solvents should be used as little as possible or by reducing the amount of use. It has been demanded to produce the mono-substituted mono-hexanecarbohalide compound as an intermediate at lower cost. Disclosure of the invention

 The present inventors have conducted intensive studies to solve the above problems, and as a result, have found an industrially practical and inexpensive manufacturing method as compared with conventional manufacturing methods, and have completed the present invention. Reached.

 That is, the present invention relates to a method for producing a mono-substituted cyclohexanyl compound, a method for producing an intermediate thereof, and an intermediate for producing the same as shown in the following (1) to (11).

 (1) General formula (1)

[1]

(Wherein, R is a linear or branched C _w alkyl group, C ₃ -.. A i cycloalkyl group, C ₃ _ ₁₀ cycloalkyl C ^ alkyl group or Ararukiru group, X is Oh a halogen atom A method for producing a monosubstituted-cyclohexanecarbonyl halide compound represented by the formula: wherein benzoic acid is treated with an alcohol in the presence of an alkali metal Z liquid ammonia, and then a compound R— (wherein, is a halogen atom Wherein R is the same as defined above).

(Wherein R is as described above) by catalytic reduction of the compound represented by the general formula [3]

 (Wherein R is as defined above), and treating the compound with an acid halide agent.

(2) Rw is a linear or branched _Cw . The production method according to the above (1), which is an alkyl group.

(3) The production method according to the above (2), wherein R is a 2-ethylbutyl group.

 (4) The production method according to the above (1) to (3), wherein X is a chlorine atom.

 (5) The method according to any one of the above (1) to (4), wherein X is a bromine atom.

(6) General formula (3)

(Wherein, R is as defined in the above (1)) A method for producing a monosubstituted-cyclohexane force rubonic acid compound represented by the formula: wherein benzoic acid is reacted with alcohol And then reacting with a compound R—Xi (wherein R and X ₃ are as defined in (1) above) to obtain a compound of the general formula [2] ′ [2]

Wherein R is as defined in the above (1). The manufacturing method characterized by the above-mentioned.

 (7) R is linear or branched. The production method according to the above (6), which is an alkyl group.

(8) The production method according to the above (7), wherein R is a 2-ethylbutyl group.

 (9) The production method according to any one of the above (6) to (8), wherein X is a chlorine atom.

 The production method according to any one of the above (6) to (9), wherein (10) is a bromine atom.

 (1 1) General formula

Production intermediate represented by

 Here, the definition of each substituent used in this specification is as follows.

The “linear or branched C _w . Alkyl group” means an alkyl group having 1 to 10 carbon atoms which may be linear or branched, and specifically, methyl Group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec. Butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-ethylbutyl group , 2-ethylbutyl, 1-propylbutyl, 1,1-dimethylbutyl, 1-isobutyl-3-methylbutyl, 1-ethylpentyl, 1-propylpentyl, 1-isobutylpentyl, 2-ethylpentyl, 2- Isopropylpropyl, 2-tert-butylpentyl, 3-ethylpentyl, 3- ^ fsopropylpentyl, 4-methylpentyl, 1,4-dimethylpentyl, 2,4-dimethylpentyl, 1-ethyl 4-methylpentyl, hexyl, 1-ethylhexyl, 1-propylhexyl, 2-ethylhexyl, 2-isopropylhexyl, 2-tert -Butylhexyl, 3-ethylhexyl, 3-isopropylhexyl, 3-tert-butynolehexyl, 4-ethylhexyl, 5-methylhexyl Group, heptyl group, 1-ethylheptyl group, 1-isopropylheptyl group, 2-ethylheptyl group, 2-isopropylheptyl group, 3-propylheptyl group, 4-propylheptyl group, 5-ethylheptyl group, 6 —Methylheptyl group, octyl group, 1-ethyloctyl group, 2-ethyloctyl group, nor group, 1-methylnull group, 2-methylnonyl group, decyl group and the like. Preferably, it is a linear or branched alkyl group having 1 to 8 carbon atoms, and specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group Group, pentyl group, isopentyl group, 2,2-dimethylpropyl group, 4-methylpentyl group, 2-ethylbutyl group, etc., and particularly preferably 2-ethylbutyl group.

“C _M .cycloalkyl group” means a cycloalkyl group having 3 to 10 carbon atoms which may be monocyclic or polycyclic, and specifically, a cyclopropyl group, Cyclopentyl, cyclopentyl, cyclohexyl / le, cycloheptyl / le, cyclooctyl, octahydrinoindenyl, decahydronaphthyl, bicyclo [2.2.1] heptyl, adamantyl and the like. Preferably, it is a cycloalkyl group having 3 to 7 carbon atoms, specifically, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group and the like.

The “C ₃ -i. Cycloalkyl.alkyl group” is the aforementioned straight or branched C w. As described above for the alkyl group. Means one or more cycloalkyl groups substituted, specifically, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cyclohexylcyclopentylmethyl group, dicyclohexylmethyl group, 1-cyclopentylethyl Group, 1-cyclohexylethyl group, 2-cyclopropylethyl group, 2-cyclopentylethyl group, 2-cyclohexylethyl group, 2-cycloheptylethyl group, 1-cyclohexyl-1-methylethyl group, 1-cyclohexino Repropynole group, 2-cyclopentyl / repropizole group, 3-cyclopentyl / Reb mouth pill group, 3-cyclopentylpropyl group, 3-cyclohexylpropyl group, 3 _cycloheptyl pill mouth group, 1-cyclopropyl-1-methylpropyl mouth Pill group, one Cyclohexyl 2-methylpropyl group, 1-cyclopentylbutyl group, 1-cyclohexyl butyl group, 3-cyclohexyl butyl group, 4-cyclopropyl / butyl group, 4-cyclobutyl butyl group, 4-cyclopentyl butyl group Group, 1-cyclohexyl 1-methylbutyl group, 1-cyclopentyl-2-ethylbutylinole group, 1-cyclohexylone 1-methylbutyl group, 1-cyclopentylpentyl group, 1-cyclohexylpentyl group , 1-cyclohexylmethylpentyl group, 2-cyclohexylpentyl group, 2- (hexylmethyl) pentyl group, 3-cyclopentyltinolepentynole group, 1-cyclohexynole-1-pentynolepenty Nore group, 5-six-hole pliers / re-pent / le group, 1-six-hole pliers / re-hexinole group, 1-six-hole hexinole hexinole 1- (pentylmethyl) hexyl group, 2-cyclopentylhexyl group, 2- (cyclopropylethyl) hexyl group, 3-cyclopentylhexyl group, 1-hexylhexylheptyl group, 1-cyclyl Mouth pentyl 1-methylheptyl group, 1-cyclohexyl-1,6-dimethylheptyl group, 1-cyclohexyloctylol group, 2-cyclopentyloctyl group, 3-cyclohexyloctyl group, 2- (cyclopentynolemethyl) Octyl group, 1-cyclopentyl nonyl group, 1-cyclohexylnonyl group, 3-cyclopropyl nonyl group, 1-cyclopentyldecyl group and the like. Preferably, C ₃ - a _cycloalkyl group, in particular sheet Kuropuropi / Remechiru group, 2-Shikuropuropi / Reechiru group, 2-cyclopentyl / Reechi group, cyclohexylmethyl group cyclohexylene, Kishiruechiru group to 2-cyclopropyl And so on.

The "Ararukiru group", phenyl in C _M alkyl group, a naphthyl group, means that Ariru groups such Bifuweniru group is substituted one or more, in particular base Njiru group, Baie Nzuhi drill group, trityl group, Phenethyl group, 3-phenylphenol group, 2-phenylpropyl group, 4-phenylphenyl group, naphthylmethyl group, 2-naphthylethyl group, 4-biphenylmethyl group, 3_ (4-biphenyl) propyl And the like. Preferable is a phenylalkyl group, specifically a benzyl group, a phenethyl group and the like. “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom and the like, and preferably a chlorine atom and a bromine atom. Particularly in X, preferred is a chlorine atom, and preferred in is preferred is a bromine atom.

 “Alkali metal” refers to lithium, sodium, potassium, etc., and particularly preferably sodium.

 The term "alcohol" refers to methanol, ethanol, tert-butylanolecone, and the like, and particularly preferably tert-butyl alcohol.

 "Acid halide agents" include oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide and the like. Preferable are oxalyl chloride and thionyl chloride, and particularly preferable is thiol chloride.

 "Catalytic reduction" is a reaction in which a compound is reduced using hydrogen in the presence of a catalyst. As the catalyst, metals such as platinum, palladium, nickel, cobalt, iron, and copper are used, and generally, the activity is devised to enhance the activity. The catalyst used in the present invention is preferably palladium carbon, Raney nickel, palladium black, palladium hydroxide, etc., and particularly preferably palladium carbon. Next, a method for producing the mono-substituted monocyclohexanecarbonyl halide compound represented by the general formula [1] will be specifically described.

 [2] [3] [1]

Note that R, X, and the like in the above formula are as described above.

 (Process 1)

Compound [2] is prepared by preparing a solution of an alcohol such as methanol, ethanol or tert-butyl alcohol and a solution of benzoic acid in tetrahydrofuran with lithium, sodium, The reaction is carried out in liquid ammonia in the presence of an alkali metal such as potassium at a temperature of 133 to -78 ° C, preferably at a temperature of 150 to 160 ° C, for 10 to 120 minutes, preferably 30 minutes, and then the obtained reaction The compound can be synthesized by reacting the compound with R- at a temperature of 133 to 178 ° C, preferably 150 to -60 ° C for 10 to 120 minutes, preferably 30 minutes.

 According to the present invention, inexpensive benzoic acid can be used as a raw material, and the amount of tetrahydrofuran used can be reduced by about 84% as compared with the conventional method.

 (Process 2)

Compound (3) is prepared by converting compound (2) into an organic solvent such as ethanol, dimethylformamide, dioxane, tetrahydrofuran, acetic acid, ethyl acetate or a mixed solvent thereof, preferably in ethyl acetate, palladium carbon, Raney nickel, palladium It can be synthesized by catalytic reduction with hydrogen gas at a pressure of 1 to 5 kg / cm ^{2 in} the presence of a metal catalyst such as black or palladium hydroxide, preferably palladium carbon.

 (Process 3)

 Compound (1) is obtained by converting compound (3) to an acid halide such as oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide or the like, preferably in the presence of thionyl chloride in the presence of an organic compound such as dimethylformamide or toluene. The synthesis can be carried out by reacting in a solvent or a mixed solvent thereof, preferably in toluene, at 40 to 70 ° C, preferably at 50 ° C.

BEST MODE FOR CARRYING OUT THE INVENTION

 Next, the present invention will be described specifically with reference to examples, but the present invention is not limited thereto.

Example 1 Method for producing 1- (2-ethylbutyl) -cyclohexanecarboxylic acid (Compound [3]: R = 2-ethylbutyl)

 Step 1) 1- (2-Ethylbutyl) -hex mouth hexa 2,5-dicarboxylic acid (compound [2])

 Under a nitrogen atmosphere, a solution of benzoic acid (20.0 g) and tert-butyl alcohol (15.lg) in tetrahydrofuran (66 ml) was added dropwise to liquid ammonia (300 ml) at a temperature of 50 ° C to -60 ° C. . After the dropwise addition, sodium metal (16.4 g) was dividedly added dropwise at a temperature of 150 ° C to 160 ° C, and the mixture was stirred at the same temperature for 30 minutes or more. Then, 1-bromo-2-ethyl / levbutane (50.5 g) was added dropwise to the reaction solution at 50 ° C and 60 ° C, and the mixture was stirred at the same temperature for 30 minutes or more. After the completion of the reaction, the temperature was gradually raised to room temperature, and ammonia was distilled off. Then, ethyl acetate (100 ml), water (25 ml) and 35% hydrochloric acid (25 ml) were added to adjust the pH of the aqueous layer to 2 or less. After standing separation, the aqueous layer was removed, and the obtained organic layer was washed with water (50 ml) to obtain a solution of the title compound in ethyl acetate.

Step 2) 1- (2-ethyl / lebutyl) -cyclohexanecarboxylic acid (compound [3]) The solution obtained in the above step 1) is sufficiently replaced with nitrogen, and a 5% palladium-carbon catalyst (50% wet) After the addition of 1.Og), a pressure of 3 kg / cm ² was maintained at room temperature under a hydrogen gas atmosphere. After the completion of the reaction, the catalyst was filtered, and the residue was washed with ethyl acetate (20 ml). The obtained ethyl acetate filtrate was concentrated under reduced pressure, and the solvent was replaced with toluene to obtain a toluene solution of the title compound.

Example 2

 Method for producing 1- (2-ethylbutyl) monocyclohexanecarboyl chloride (Compound [1]: R = 2-ethyl: tyl, X = chlorine atom)

 Step 3) 1- (Ethylbutyl) -cyclohexanecarbonyl chloride (Compound [1])

The solution obtained in Example 1 above was heated to 50 ° C, and thionyl chloride (23.3 g) was used. Was added dropwise at the same temperature. After completion of the dropwise addition, the reaction solution was stirred at 50 ° C for 1 hour or more. Excessive low boiling compounds such as thionyl chloride were distilled off by concentration under reduced pressure, followed by distillation under reduced pressure to obtain the title compound (29.7 g, yield 63.2%) as a pale yellow oil.

 b.p .: 103 ° C / 0.33 kPa

- negation _{R (300fflz, CDC1 3, TMS} ):

 δ 0.83 (6H, t), 1.2 to 1.5 (10H, m), 1.5 to; 1.7 (5H, m), 2.1 to 2.2 (2H, m) Possibility of industrial use

 As is clear from the above, according to the present invention, it is possible to produce a 1-substituted-cyclohexanecarbonyl halide compound which is practically industrially practical and extremely inexpensive as compared with the conventional production method. is there.

Claims

The scope of the claims [1]

(Wherein, R is a linear or branched C _H. Alkyl group, CH. Cycloalkyl group, C ₃ _ ₁₀ cycloalkyl C _chi _ ₁₀ alkyl or Ararukiru group, X is Ru Oh halogen atom A method for producing a mono-substituted cyclohexanecarbonyl halide compound represented by the formula: wherein benzoic acid is treated in an alcohol in the presence of an alkali metal / liquid ammonia, and then a compound R— (where X is a halogen And R is as described above), which is obtained by reacting with the general formula [2]  R -Π00Η _r  Two (Wherein R is as defined above) by catalytic reduction to obtain a compound represented by the general formula [3] r,  [3

(Wherein R is as defined above), and treating the compound with an acid halide agent. 2. C _{W wherein} R is straight or branched. 2. The production method according to claim 1, wherein the production method is an alkyl group. 3. The method according to claim 2, wherein R is a 2-ethylbutyl group.  4. The production method according to claim 1, wherein X is a chlorine atom. 5. The method according to claim 1, wherein is a bromine atom. 6. General formula [3]

(Wherein R is as defined in claim 1), wherein the benzoic acid is treated with an alcohol in the presence of an alkali metal Z liquid ammoea, represented by the formula: compound R- (wherein, R及Pi X _t is as defined claim 1) is obtained by reacting with the general formula [2]

(Wherein, R is as defined in claim 1).  R is a straight or branched C ^. 7. The production method according to claim 6, which is an alkyl group. 8. The method according to claim 7, wherein is a 2-ethylbutyl group.  9. The method according to claim 6, wherein X is a chlorine atom.  10. The production method according to claim 6, wherein the compound is a bromine atom.  General formula

Production intermediate represented by