KR100874835B1 - Process for preparing cyclohexanol derivative - Google Patents

Abstract

A process for preparing a cyclohexanol derivative of formula (I) is described by reacting a compound of formula (II) with a compound of formula (III) in the presence of a base catalyst of formula (IV) or (V).

Formula I

Formula II

Formula III

Formula IV

Formula V

In Chemical Formulas I, II, III, IV and V,

R ₁ to R ₉ , A, B, X and p have the meanings defined in the specification.

Cyclohexanol derivatives, non-organometallic base catalysts, p-methoxy-phenylacetonitrile, amidine, guanidine

Description

Process for preparation of cyclohexanol derivatives

The present invention relates to a process for the preparation of cyclohexanol derivatives such as 1- [cyano (4-methoxyphenyl) methyl] cyclohexanol.

Cyclohexanol derivatives such as 1- [cyano (4-methoxyphenyl) methyl] cyclohexanol, such as venlafaxine, exhibit antidepressant effects by inhibiting the reintroduction of neurotransmitters norepinephrine and serotonin. Useful intermediates for preparing compounds. As described in US Pat. No. 4,535,186, cyclohexanol derivatives can be prepared by reacting cycloalkanones or cycloalkenones with an appropriately substituted-(ortho or para) -phenylacetonitrile anion. have.

The process described in US Pat. No. 4,535,186, above, uses organometallic bases such as n-butyl lithium to derive phenylacetonitrile anions during the reaction. These organometallic bases are expensive and at least 1 equivalent should be used for the reactants at low temperatures below -50 ° C. Due to their nature, they are susceptible to moisture in the air and are at risk of fire or explosion. Obtained in reaction yield. Thus, organometallic bases appear to be difficult to actually use for industrial scale synthesis.

US Pat. No. 5,043,466 describes a process for preparing cyclohexanol derivatives using organometallic bases such as lithium diisopropylamide, as shown in the reaction mechanism below. U.S. Pat.No. 5,043,466 varied the mixing ratio of hydrocarbon solvents to improve reaction temperature and yield, but lithium isopropylamide base is too expensive, difficult to handle and also risks fire or explosion, but still lithium The problem remains that diisopropylamide base is impractical for synthesis on an industrial scale.

Chinese Patent No. 1,225,356 (CN01225356A) uses cyclobases such as sodium methoxide, sodium ethoxide, sodium hydride, and sodium amide to increase the reaction temperature in the range of 0 to 5 ° C. However, the bases described must be used in amounts of at least 1 equivalent to the reactants and are too dangerous to be burned or exploded.

The known method comprises two steps: reacting phenylacetonitrile with a base to generate an anion and coupling the anion and a ketone compound. In particular, the reaction of the anion generation step is slightly difficult in terms of determining the end point of the step and quantitative analysis of the resulting anions. This problem causes yield variations in the coupling step, which is difficult for industrial applications.

Summary of the Invention

Accordingly, the present invention relates to a method for preparing cyclohexanol, which substantially overcomes the problems and disadvantages of the prior art.

SUMMARY OF THE INVENTION An object of the present invention is to provide a production method capable of economically and reasonably mass-producing cyclohexanol derivatives by reacting phenylacetonitrile with cyclohexanone.

It is yet another object of the present invention to provide a method of preparation that is simpler than conventional synthesis by mixing all of the reactants in one reaction, safe, environmentally friendly and without the risk of fire or explosion.

One aspect of the present invention provides a cyclohexane of Formula I, comprising reacting a compound of Formula II with a compound of Formula III in the presence or absence of a reaction solvent, in the presence of a non-organometallic base catalyst of Formula IV or V It is a method for preparing all derivatives.

In Chemical Formulas I, II, III, IV and V,

R ₆ and R ₇ are hydrogen, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₇ -C ₉ aralkoxy, C ₂ -C ₇ alkanoyloxy, C ₁ -C ₆ alkylmercapto Ortho or para substituents independently selected from the group consisting of halo or trifluoromethyl;

R ₈ is hydrogen or C ₁ -C ₆ alkyl;

p is one of the integers 0, 1, 2, 3 and 4;

R ₉ is hydrogen or C ₁ -C ₆ alkyl;

A is-(CH ₂ ) _n- , where n is an integer from 2 to 4;

B is-(CH ₂ ) _m- , where m is an integer from 2 to 5;

X is CH ₂ , O, NH or NR ′, wherein R ′ is C ₁ -C ₄ alkyl or acyl, or an alkyl support polymer;

R ₁ to R ₄ are each independently hydrogen, alkyl, cycloalkyl or alkyl or cycloalkyl support polymer, and not all of R ₁ to R ₄ are hydrogen;

R ₅ is alkyl, cycloalkyl, or an alkyl or cycloalkyl support polymer,
Here, when R ₉ is alkyl, the alkyl group is introduced by alkylation.

Non-organometallic bases used in the present invention include amidines or guanidines of formula IV or V. More specifically, examples of non-organometallic bases of the invention include amidine, for example 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU) and 1,5-dia Zacyclocyclo [4,3,0] non-5-ene (DBN); Cyclic guanidines such as 1,5,7-triazabicyclo [4,4,0] dec-5-ene (TBD) and 7-methyl-1,5,7-triazabicyclo [4,4, 0] dec-5-ene (MTBD); Alkyl guanidines such as tetramethylguanidine (TMG), tetra butylguanidine, penta methylguanidine, penta butylguanidine and N'-butyl-N ", N" -dicyclohexylguanidine and the like. The base catalyst of the present invention may be a homogeneous catalyst or a catalyst containing an amidine- or guanidine-based organic amine base immobilized on a polymer support (eg polystyrene) or an inorganic support (eg silica). The non-organometallic base of the present invention is at least one base selected from the group consisting of the bases mentioned above.

The amount of the non-organometallic base of the present invention is not particularly limited but will be in the range of about 0.0001 to about 2 equivalents, more preferably about 0.005 to 0.5 equivalents, per 1 equivalent of the compound of formula II. The reaction of the present invention can be successfully achieved using only base catalysts used in catalytic amounts, which is advantageous.

The present invention may optionally not use organic solvents comprising hydrocarbons and ethers as required in conventional synthesis. The use of organic solvents is optimally determined by one skilled in the art, but it is generally preferred to not use organic solvents.

In preparing cyclohexanol derivatives such as 1- [cyano (4-methoxyphenyl) methyl] cyclohexanol of the general formula (I) according to the invention, the reaction temperature is preferably about -20 to 80 ° C, more preferably. Preferably in the range of about 10 to 30 ° C. The process of the invention can also be carried out at room temperature, which is advantageous.

The present invention according to Scheme I is suitably substituted in the presence of a non-organometallic amine base such as DBU, DBN, TBN, MTBD, TMG or N'-butyl-N ", N" -dicyclohexylguanidine. Provided is a method for preparing cyclohexanol derivatives by reacting para-phenylacetonitrile with cyclohexanone.

In the above scheme, R ₆ to R ₉ , and p are as defined above and when R ₉ is alkyl it is introduced by alkylation.

In preparing cyclohexanol derivatives such as 1- [cyano (4-methoxyphenyl) methyl] cyclohexanol of formula I, non-organic metal bases which are amine bases, for example DBU, DBN, TBD, MTBD , TMG or N'-butyl-N ", N" -dicyclohexylguanidine, instead of organometallic bases such as n-butyl lithium or lithium diisopropyl amide used in conventional manufacturing methods, induce phenylacetonitrile anions Used to The use of relatively small amounts of non-organic metal bases, which are relatively inexpensive, less susceptible to hydration, capable of working at room temperature and without the risk of fire or explosion, enables mass production through safe and relatively simple industrial processes. . Only catalytic amounts of non-organometallic bases are needed in the present invention, which results in high purity, high yield cyclohexanol derivatives.

In addition, the process of the present invention is environmentally friendly and simpler, without involving the production of organometallic by-products since the use of organic solvents is excluded.

The invention will be described in more detail with reference to the following examples, but the scope of the invention is not limited thereto.

Example 1

100 g (0.68 mole) of p-methoxyphenylacetonitrile, 100 g (1.02 mole) of cyclohexanone, and 32 g (0.21 mole) of 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU) ) Was placed in the flask and stirred for 48 hours while maintaining 15-20 ° C. 1N HCl was then added to the resulting solution to adjust the pH to acidic levels. After stirring for 1 hour at room temperature, the resulting precipitate was isolated by filtration, washed with purified water and then with ethyl acetate and n-hexane to give the desired compound 1- [cyano (4-methoxyphenyl) as a white solid. 140 g of methyl] cyclohexanol (yield 84%, melting point 123.7 ° C.) were obtained.

¹ H NMR analysis (DMSO-d6): δ 7.27-6.93 (4H, q, aromatic). 4.85 (1H, s, OH), 4.05 (3H, s, OCH ₃ ), 3.76 (1H, s, CHCN), 1.69-1.08 (1OH, m, cyclohexyl)

¹ H NMR analysis (CDC1 ₃ ): δ 7.23-6.89 (4H, q, aromatic). 3.82 (3H, s, OCH ₃ ), 3.73 (1H, s, CHCN), 1.72-1.16 (10H, m, cyclohexyl)

¹³ C NMR analysis (DMSO-d6): δ 159.4, 131.3, 125.8, 121.4, 114.1, 72.2, 55.8, 48.8, 36.0, 34.7, 25.9, 22.0, 21.9

Mass spectral analysis: molecular weight 245 [M ⁺ by CIMS]

IR (KBr Palette): 3408cm ^-1 (-OH), 2249cm ^-1 (-CN)

Example 2

52.7 g (0.36 mole) of p-methoxyphenylacetonitrile, 35.8 g (0.36 mole) of cyclohexanone, and 28.6 g (0.19 mole) of 1,8-diazabicyclo [5,4,0] undec-7-ene ) Was placed in the flask and stirred for 90 hours while maintaining 15 to 20 ° C. 1N HCl was then added to the resulting solution to adjust the pH to acidic levels. After stirring for 1 hour at room temperature, the resulting precipitate was isolated by filtration, washed with purified water and then with ethyl acetate and n-hexane to give the desired compound 1- [cyano (4-methoxyphenyl) as a white solid. 62 g (70% yield) of methyl] cyclohexanol were obtained.

Example 3

The process was carried out in the same manner as described in Example 1 above, except that 0.5 equivalent of 1,8-diazabicyclo [5,4,0] undec-7-ene was used for the 6 day reaction. Thus, 67 g (yield 80%) of the title compound 1- [cyano (4-methoxyphenyl) methyl] cyclohexanol was obtained as a white solid.

Example 4

Flask 100 g (0.68 mole) of p-methoxyphenylacetonitrile, 167 g (1.70 mole) of cyclohexanone, and 52 g (0.34 mole) of 1,8-diazabicyclo [5,4,0] undec-7-ene And kept at 0 ° C. and stirred for 60 hours. 1N HCl was then added to the resulting solution to adjust the pH to acidic levels. After stirring for 1 hour at room temperature, the resulting precipitate was isolated by filtration, washed with purified water and then with ethyl acetate and n-hexane to give the desired compound 1- [cyano (4-methoxyphenyl) as a white solid. 147 g (yield 88%) of methyl] cyclohexanol were obtained.

Example 5

The process was carried out in the same manner as described in Example 1 above, except that 0.5 equivalent of 1,8-diazabicyclo [5,4,0] undec-7-ene was used for the reaction of 8 hours. Thus, 116 g (yield 70%) of the target compound 1- [cyano (4-methoxyphenyl) methyl] cyclohexanol was obtained as a white solid.

Example 6

25.4 g (0.17 mole) of p-methoxyphenylacetonitrile, 41.8 g (0.42 mole) of cyclohexanone, and 13.2 g (0.087 mole) of 1,8-diazabicyclo [5,4,0] undec-7-ene ) Was placed in the flask and maintained at 25 ° C. and stirred for 24 hours. 1N HCl was then added to the resulting solution to adjust the pH to acidic levels. After adding 50 ml of methyl alcohol and stirring at room temperature for 1 hour, the resulting precipitate was separated by filtration, washed with purified water and then washed with ethyl acetate and n-hexane to give the desired compound 1- [cyano ( 23.7 g (yield 56.1%) of 4-methoxyphenyl) methyl] cyclohexanol were obtained.

Example 7

50.3 g (0.34 mole) of p-methoxyphenylacetonitrile, 34.8 g (0.35 mole) of cyclohexanone, and 43.3 g (0.35 mole) of 1,5-diazabicyclo [4,3,0] non-5-ene Put into flask and keep at 20-25 ° C. and stir for 90 hours. 50 ml of methyl alcohol and 200 ml of purified water were added to the obtained solution. After stirring for 1 hour at room temperature, the resulting precipitate was isolated by filtration, washed with purified water and then with ethyl acetate and n-hexane to give the desired compound 1- [cyano (4-methoxyphenyl) as a white solid. 116 g (70% yield) of methyl] cyclohexanol were obtained.

Example 8

20 g (0.14 mole) of p-methoxyphenylacetonitrile, 13.7 g (0.14 mole) of cyclohexanone, and 21.2 g (0.14 mole) of 1,8-diazabicyclo [5,4,0] undec-7-ene Into the flask, and diluted with 100 ml of methyl alcohol, and stirred for 20 hours while maintaining 15 to 20 ℃. 20 ml of methyl alcohol and 150 ml of purified water were added to the obtained solution. After stirring for 1 hour at room temperature, the resulting precipitate was isolated by filtration, washed with purified water and then with ethyl acetate and n-hexane to give the desired compound 1- [cyano (4-methoxyphenyl) as a white solid. 17.4 g (yield 52%) of methyl] cyclohexanol were obtained.

Example 9

The process was carried out in the same manner as described in Example 1 above, except that 0.1 equivalent of 1,8-diazabicyclo [5,4,0] undec-7-ene was used for the 6 day reaction. Thus, 76.1 g (yield 90.5%) of the target compound 1- [cyano (4-methoxyphenyl) methyl] cyclohexanol was obtained as a white solid.

Example 10

25.4 g (0.17 mole) of p-methoxyphenylacetonitrile, 83.6 g (0.85 mole) of cyclohexanone, and 26.7 g (0.17 mole) of 1,8-diazabicyclo [5,4,0] undec-7-ene ) Was placed in the flask and maintained at 20-25 ° C. and stirred for 24 hours. 50 ml of methyl alcohol and 200 ml of purified water were added to the obtained solution. After stirring for 1 hour at room temperature, the resulting precipitate was isolated by filtration, washed with purified water and then with ethyl acetate and n-hexane to give the desired compound 1- [cyano (4-methoxyphenyl) as a white solid. 18.0 g (yield 42.6%) of methyl] cyclohexanol was obtained.

Example 11

The process was carried out in the same manner as described in Example 1, except that the reaction temperature was maintained in the range of 35 to 40 ° C., to give the desired compound 1- [cyano (4-methoxyphenyl) as a white solid. 30.6g (yield 36.8%) of methyl] cyclohexanol was obtained.

Example 12

100 g (0.68 mole) of p-methoxyphenylacetonitrile, 100 g (1.02 mole) of cyclohexanone, and 0.47 g of 1,5,7-triazabicyclo [4,4,0] dec-5-ene (TBD) 0.0034 mol) was placed in a flask and maintained at 20-25 ° C., and stirred for 10-12 hours. 1N HCl was then added to the resulting solution to adjust the pH to acidic levels. After stirring for 1 hour at room temperature, the resulting precipitate was isolated by filtration, washed with purified water and then with ethyl acetate and n-hexane to give the white desired compound 1- [cyano (4-methoxyphenyl). 128 g (77% yield) of methyl] cyclohexanol were obtained.

Example 13

Example 1, except that 0.03 equivalent of 7-methyl-1,5,7-triazabicyclo [4,4,0] dec-5-ene (MTBD) was used in the reaction of 20 to 22 hours The process was carried out in the same manner as described above to give 128 g (yield 77%) of the title compound 1- [cyano (4-methoxyphenyl) methyl] cyclohexanol as a white solid.

Example 14

50 g (0.34 mole) of p-methoxyphenylacetonitrile, 50 g (0.51 mole) of cyclohexanone, and 0.24 g of 1,5,7-triazabicyclo [4,4,0] dec-5-ene (TBD) 0.0017 mol) was placed in a flask and maintained at 20-25 ° C., and stirred for 19 hours. The reaction mixture was dissolved in 500 ml of ethyl acetate and neutralized with 6N HCl after adding 200 ml of purified water. After phase separation at 30 to 35 ° C., the organic solvent was removed under reduced pressure, and 500 ml of ethyl acetate and 200 ml of purified water were added to the filtrate. After stirring for 1 hour at room temperature, the resulting precipitate was isolated by filtration, washed with purified water and then with ethyl acetate and n-hexane to give the desired compound 1- [cyano (4-methoxyphenyl) as a white solid. 74 g (yield 89%) of methyl] cyclohexanol were obtained.

Example 15

25 g (0.17 mole) of p-methoxyphenylacetonitrile, 25 g (0.25 mole) of cyclohexanone, and 2.5 g (0.0090 mol) of N'-butyl-N ", N" -dicyclohexylguanidine were placed in a flask. Maintain 25 ° C. and stir for 24 hours. 1N HCl was then added to the resulting solution to adjust the pH to acidic levels. After stirring for 1 hour at room temperature, the resulting precipitate was isolated by filtration, washed with purified water and then with ethyl acetate and n-hexane to give the desired compound 1- [cyano (4-methoxyphenyl) as a white solid. 30 g (72% yield) of methyl] cyclohexanol was obtained.

Comparative Example 1

50 g (0.34 mole) of p-methoxyphenylacetonitrile were diluted with 250 ml of anhydrous tetrahydrofuran (THF) and cooled to -70 ° C under nitrogen atmosphere. 210 ml (0.34 mol) of n-butyl lithium (n-BuLi) were dripped at the said obtained solution, and the temperature of this solution was kept at -50 degreeC or less. The solution was stirred for 30 minutes, 50 g (0.51 mole) of cyclohexanone was added and then further stirred for 45 minutes while maintaining the temperature of the solution below -50 ° C. The temperature of the reaction solution was then raised to 0 ° C. and saturated ammonium chloride solution was added to stop phase separation. The aqueous layer was extracted with diethyl ether and combined with the organic layer. The organic solvent was removed under reduced pressure to give 25.2 g (yield 34.2%) of the desired compound 1- [cyano (4-methoxyphenyl) methyl] cyclohexanol.

Melting point: 123-126 ° C

Mass spectral analysis: molecular weight 245 [M ⁺ by CIMS]

¹ H NMR analysis (DMSO-d6): δ 7.32, 6.95 (4H, q, p-substituted aromatic), 3.8 (3H, s, O-CH ₃ ), 3.76 (1H, s, CH-CN), 1.56 (1OH, m, aliphatic cyclohexyl)

Comparative Example 2

In a lithium diisopropyl amide solution prepared by adding 73 ml of diisopropyl amine to 325 ml of 6M BuLi and 300 ml of toluene under nitrogen atmosphere, 76.5 g of p-methoxyphenylacetonitrile diluted to 75 ml of toluene was maintained at an internal temperature of 10 ° C. or lower. And slowly added. After stirring for 30 minutes, 46.0 g of cyclohexanone diluted with 50 ml of toluene were slowly added while maintaining the internal temperature at 10 ° C. or lower, followed by further stirring for about 30 minutes or more. Thereafter, the obtained solution was added to 100 ml of 12N aqueous hydrochloric acid solution and 1 L of purified cold water. After filtration, the filtrate was diluted with dichloromethane and washed with purified water. After dichloromethane was replaced with diisopropyl ether, the solvent was removed under reduced pressure, the filtrate was cooled and filtered to give 91.0 g of the desired compound 1- [cyano (4-methoxyphenyl) methyl] cyclohexanol as a white solid. (Yield 79%) was obtained.

Reference Example

12 g (0.05 mol) of 1- [cyano (4-methoxyphenyl) methyl] cyclohexanol prepared in Example 1 was dissolved in 250 ml of an ammonia / ethanol mixture in a 2: 8 (v / v) mixing ratio and alumina phase 2.8 g of 5% rhodium was added to cause a hydrogenation reaction. The catalyst was removed by filtration and washed with ethanol and the filtrate was concentrated under reduced pressure to give the compound in oil form which was then diluted with 100 ml of toluene and acidified to pH 2. After filtration, 9 g (yield 57%) of the target compound 1- [2-amino-1- (4-methoxyphenyl) ethyl] cyclohexanol was obtained as a white solid.

Melting Point: 168-172 ° C

Mass spectral analysis: molecular weight 250 [M ⁺ by CIMS]

¹ H NMR analysis (DMSO-d6): δ 7.85 (3H, s, NH ³⁺ ), 3.75 (3H, s, O-CH ₃ ), 3.20 (3H, m, CHCH ₂ ), 1.35 (1OH, m, Aliphatic cyclohexyl)

As noted above, the present invention provides a safe and relatively simple process for the mass production of cyclohexanol derivatives, such as 1- [cyano (4-methoxyphenyl) methyl] cyclohexanol, of formula (I). do. The present invention provides a high yield of high purity 1- [cyano (4-methoxyphenyl) methyl] cyclohexanol using a small amount of relatively inexpensive, environmentally friendly non-metal base and excluding organic solvents. do.

Claims (11)

A process for preparing a cyclohexanol derivative of formula (I) comprising reacting a compound of formula (II) with a compound of formula (III) in the presence or absence of a reaction solvent, in the presence of a non-organometallic base catalyst of formula (IV) or (V). Formula I

Formula II

Formula III

Formula IV

Formula V

In Chemical Formulas I, II, III, IV and V, R ₆ and R ₇ are hydrogen, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₇ -C ₉ aralkoxy, C ₂ -C ₇ alkanoyloxy, C ₁ -C ₆ alkylmercapto Ortho or para substituents independently selected from the group consisting of halo or trifluoromethyl; R ₈ is hydrogen or C ₁ -C ₆ alkyl; p is one of the integers 0, 1, 2, 3 and 4; R ₉ is hydrogen or C ₁ -C ₆ alkyl; A is-(CH ₂ ) _n- , where n is an integer from 2 to 4; B is-(CH ₂ ) _m- , where m is an integer from 2 to 5; X is CH ₂ , O, NH or NR ′, wherein R ′ is C ₁ -C ₄ alkyl or acyl, or an alkyl support polymer; R ₁ to R ₄ are each independently hydrogen, alkyl, cycloalkyl, or alkyl or cycloalkyl support polymers, and not all of R ₁ to R ₄ are hydrogen; R ₅ is alkyl, cycloalkyl, or an alkyl or cycloalkyl support polymer, Here, when R ₉ is alkyl, the alkyl group is introduced by alkylation. The method of claim 1, wherein the compound of Formula II is p-methoxy-phenylacetonitrile. The method of claim 1, wherein the compound of Formula III is cyclohexanone. The process of claim 1, wherein the non-organometallic base catalyst is a mixture of catalysts selected from one or more of amidine or guanidine of formula IV or V. 5. The process according to claim 1, wherein the base catalyst is homogeneous or immobilized on a polymer support. The non-organometallic base of claim 1, wherein the non-organometallic base is a 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU), 1,5-diazabi. Cyclo [4,3,0] non-5-ene (DBN), 1,5,7-triazabicyclo [4,4,0] deck-5-ene (TBD), 7-methyl-1,5, 7-triazabicyclo [4,4,0] dec-5-ene (MTBD), tetramethylguanidine (TMG), and N'-butyl-N ", N" -dicyclohexylguanidine Way. The process according to any one of claims 1 to 3, wherein the amount of non-organometallic base used is 0.005 to 0.5 equivalents to 1 equivalent of the compound of formula II. The method according to claim 1, wherein no solvent is used. The process according to any one of claims 1 to 3, wherein the reaction temperature is -20 to 80 ° C. The method of claim 9, wherein the reaction temperature is 10 to 30 ° C. 11. The process according to claim 1, wherein the compound of formula II and the compound of formula III and the base catalyst are used in an equivalent ratio of 1: 1 to 1.5: 0.005 to 0.5.