A process for the preparation of cis-2-pyridin-2-ylcyclohexanol

Abstract

The application discloses a preparation method of cis-2-pyridin-2-ylcyclohexanol, which comprises the following steps: reacting pyridine N-oxide with cyclohexenyl morpholine under the action of benzoyl chloride to obtain 2-(pyridin-2-yl)cyclohexan-1-one; finally, reducing the ketone in the presence of sodium borohydride and boric acid tris(trifluoroethanol) ester to obtain cis / trans-2-pyridin-2-ylcyclohexanol, then reacting with acyl chloride, and finally carrying out post-treatment and separation to obtain cis-2-pyridin-2-ylcyclohexanol. The cis-2-pyridin-2-ylcyclohexanol prepared by the preparation method has high purity, good quality, relatively simple post-treatment, and easy separation of the product, avoids the column chromatography separation method, and is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to a method for preparing cis-2-pyridin-2-ylcyclohexanol, belonging to the field of organic chemistry technology. Background Technology

[0002] Cis-2-pyridin-2-ylcyclohexanol is a novel N,P-ligand with a cyclohexane skeleton and a chiral amino alcohol complex. Due to the basicity and antioxidant properties of pyridine, it forms an asymmetric transformation catalyst with high-valence transition metals. Its characteristics include a wide tolerance range and high selectivity. Transition metal-catalyzed asymmetric transformations in the presence of chiral ligands have wide applications in organocatalysis, natural product preparation, and pharmaceutical intermediate preparation.

[0003] Currently, cis-2-pyridin-2-ylcyclohexanol is mainly obtained by reducing 2-(pyridin-2-yl)cyclohexane-1-one with sodium borohydride to racemic 2-pyridin-2-ylcyclohexanol, followed by column chromatography to separate cis-2-pyridin-2-ylcyclohexanol and trans-2-pyridin-2-ylcyclohexanol (see reference [Chemistry-A European Journal, 2002, vol. 8, #24, pp. 5551-5564]). The yield of trans-2-pyridin-2-ylcyclohexanol is 55%, while the yield of cis-2-pyridin-2-ylcyclohexanol is not given. Following this method, experiments showed that column chromatography, performed according to the literature, not only yielded the trans isomer but also the cis isomer, with a cis:trans isomer ratio of 38:62, predominantly trans-2-pyridin-2-ylcyclohexanol.

[0004] A similar method for synthesizing cis-2-pyridin-2-ylcyclohexanol involves the Mitsunobu reaction of (1R,2S)-2-pyridin-2-ylcyclohexanol with 4-nitrobenzoic acid, resulting in configuration inversion, followed by saponification to yield cis-(1S,2S)-2-pyridin-2-ylcyclohexanol. (Reference: [Tetrahedron Letters, 2007, vol.48, #12, pp.2101-2104]).

[0005] The above methods do not provide a clear or rapid way to obtain cis-2-pyridin-2-ylcyclohexanol. Therefore, how to effectively obtain cis-2-pyridin-2-ylcyclohexanol in a convenient, short, and cost-effective manner has become one of the urgent technical problems to be solved in the field of cis-2-pyridin-2-ylcyclohexanol preparation. Summary of the Invention

[0006] To address the aforementioned problems in the existing technology, the present invention aims to provide a method for preparing cis-2-pyridin-2-ylcyclohexanol, suitable for industrial production applications, which can conveniently prepare the pure configuration, i.e., cis-2-pyridin-2-ylcyclohexanol. This discovery discloses a method for preparing cis-2-pyridin-2-ylcyclohexanol, the process of which involves reacting pyridine nitrogen oxides with 4-cyclohexylmorpholine in the presence of benzoyl chloride to obtain 2-(pyridin-2-yl)cyclohexane-1-one, and finally reducing the ketone with sodium borohydride acetate to obtain cis / trans-2-pyridin-2-ylcyclohexanol, followed by reaction with acyl chloride, and post-treatment separation to obtain cis-2-pyridin-2-ylcyclohexanol. The cis-2-pyridin-2-ylcyclohexanol obtained by the method of the present invention has high purity and good quality, the post-treatment is relatively simple, the product is easy to separate, avoiding column chromatography separation methods, and is suitable for industrial production.

[0007] To achieve the above objective, a process for preparing cis-2-pyridin-2-ylcyclohexanol includes the following steps:

[0008] Step S1: Pyridine nitride is mixed with 4-cyclohexenylmorpholine in an organic solvent and reacted in the presence of benzoyl chloride to give 2-(pyridin-2-yl)cyclohexane-1-one;

[0009] Step S2: Mix 2-(pyridin-2-yl)cyclohexane-1-one, tri(trifluoroethanol) borate and organic solvent, cool to 0-5℃, add sodium borohydride acetate in batches to react and obtain cis / trans-2-pyridin-2-ylcyclohexanol, extract with dichloromethane, then react with acyl chloride in the presence of triethylamine as an acid binder, and post-treatment to obtain cis-2-pyridin-2-ylcyclohexanol.

[0010] The reaction route of this invention is shown below:

[0011]

[0012] Furthermore, in step S1, the organic solvent is selected from dichloromethane or chloroform.

[0013] Further, in step S1, the molar ratio of pyridine nitride, benzoyl chloride and 4-cyclohexenylmorpholine is 1:1.15-1.20:1.8-2.0.

[0014] Further, in step S2, the molar ratio of 2-(pyridin-2-yl)cyclohexane-1-one, tri(trifluoroethanol) borate, and sodium borohydride acetate is 1:0.1-1.0:1.2-1.5.

[0015] Further, in step S2, the acyl chloride is selected from benzoyl chloride, acetyl chloride, or 4-methoxybenzoyl chloride; the organic solvent is selected from ethanol, tetrahydrofuran, or trifluoroethanol.

[0016] Further, in step S2, the molar ratio of cis / trans-2-pyridin-2-ylcyclohexanol to acyl chloride is 1:0.5-0.55.

[0017] Further, the post-processing operation in step S2 is as follows: after the reaction with acyl chloride is complete, the mixture is washed with dilute hydrochloric acid, sodium bicarbonate solution and water, the organic phase is concentrated to remove dichloromethane, replaced with MTBE, and the mixture of MTBE and isopropanol is recrystallized to obtain cis-2-pyridin-2-ylcyclohexanol.

[0018] Furthermore, the ratio of the recrystallization solvent in step S2 is 10:1.

[0019] Beneficial effects of the invention

[0020] Using sodium borohydride acetate as a reducing agent can effectively control racemization, maintaining the cis isomer content at approximately 49-51%. As an improvement, the cis isomer ratio can be increased to 75-83% in the presence of trifluoroethanol borate.

[0021] 2. By utilizing the esterification of acyl chlorides and alcohols in the presence of a base, experiments have shown that the cis isomers are basically not esterified with acyl chlorides. Based on this property, the cis isomers obtained by recrystallization have very high purity. Specific Implementation

[0022] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0023] Example 1

[0024]

[0025] Add 95.1 g of pyridine oxide (1.0 mol) and 600 mL of dichloromethane to a reaction flask, cool to -5 °C, and add 168.7 g of benzoyl chloride (1.2 mol) dropwise under nitrogen protection. Stir for 30-60 minutes within the range of -5 to 0 °C. Slowly add a mixture of 301.1 g of morpholinocyclohexeneamine (1.8 mol) and 300 mL of dichloromethane. React at -5 to 0 °C for 40 minutes, then slowly raise the temperature to 25-30 °C and react for 7 hours. The pH of the aqueous phase was adjusted to 1-2 with water and concentrated hydrochloric acid. Dichloromethane was concentrated under reduced pressure to remove it. Methyl tert-butyl ether was added to extract impurities. The pH of the aqueous phase was adjusted to 11-12 with 30% sodium hydroxide solution. Dichloromethane was extracted, and the phase was washed with saturated brine. 5g of activated carbon was added to the organic phase, and the mixture was refluxed for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to 2.5V. Heptane was added to precipitate the solid, yielding 122.1g of 2-(pyridin-2-yl)cyclohexane-1-one, with a yield of 69.7% and an HPLC resolution of 98.1%. 1H-NMR(400MHz, CDCl3)δ:8.56(dd,0.25H),8.32(d,0.75H),7.67-7.65(m,1H),7.19-7.15(m,0.5H) ,7.12-7.07(m,0.8H),7.00-6.95(m,0.75H),3.84(d,0.25H),2.38-2.34(m,4H),1.79-1.75(m,4H).

[0026] Example 2

[0027]

[0028] Add 95.1 g of pyridine oxide (1.0 mol) and 500 mL of chloroform to a reaction flask, cool to -5 °C, and add 168.7 g of benzoyl chloride (1.2 mol, 1.2 eq) dropwise under nitrogen protection. Stir for 30-60 minutes within the range of -5 to 0 °C. Slowly add a mixture of 301.1 g of morpholinocyclohexeneamine (1.8 mol, 1.8 eq) and 400 mL of chloroform. React at -5 to 0 °C for 40 minutes, then slowly raise the temperature to 25-28 °C and react for 16 minutes. After 2 hours, water and concentrated hydrochloric acid were added to adjust the pH to 1-2. The chloroform was removed by concentration under reduced pressure. Methyl tert-butyl ether was added to extract impurities. The pH of the aqueous phase was adjusted to 11-12 with 30% sodium hydroxide solution. Chloroform extraction was performed, and the phase was washed with saturated brine. 5g of activated carbon was added to the organic phase, and the mixture was heated and refluxed for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to 2.5V. Heptane was added to precipitate 144.9g of solid 2-(pyridin-2-yl)cyclohexane-1-one, with a yield of 82.7% and an HPLC yield of 98.6%.

[0029] Example 3

[0030]

[0031] Method A: 87.6 g of 2-(pyridin-2-yl)cyclohexane-1-one (0.5 mol) and 600 mL of trifluoroethanol were added to a reaction flask. The mixture was cooled to 0-5 °C, and 127.2 g of sodium borohydride acetate (0.6 mol) was added in five batches at 30-minute intervals. After the addition was complete, the mixture was slowly heated to room temperature and reacted for 3 hours. HPLC analysis showed that almost no raw material remained. The mixture was quenched with water and concentrated hydrochloric acid, and the solid was filtered off. The filtrate was allowed to stand and separate into layers. The aqueous layer was extracted with dichloromethane, and the lower organic phases were combined. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum concentration to obtain 86.8 g of a mixture of cis / trans-2-pyridin-2-ylcyclohexanol. The HPLC ratio of cis / trans-2-pyridin-2-ylcyclohexanol was 51 / 49.

[0032] Method B: 87.6 g of 2-(pyridin-2-yl)cyclohexane-1-one (0.5 mol), 600 mL of trifluoroethanol and 30.8 g (0.1 mol) B(OCH2CF3)3 were added to a reaction flask and cooled to 0-5 °C. Subsequent operations were the same as above to obtain 86.9 g of a mixture of cis and trans isomers. The HPLC cis / trans ratio was 86 / 14.

[0033] Example 4

[0034]

[0035] In Example 3, Method A, 17.7 g of a mixture of cis / trans-2-pyridin-2-ylcyclohexanol (0.1 mol), 4.3 g of acetyl chloride (0.055 mol, 0.55 eq), and 180 mL of dichloromethane were added to a reaction flask. The mixture was cooled to -15°C, and 6.7 g of triethylamine (0.066 mol, 0.66 eq) was slowly added dropwise. The reaction was carried out at -15 to -10°C for 3 hours. The pH was adjusted to 5-6 with dilute hydrochloric acid aqueous solution. The mixture was allowed to stand and separate into layers. The dichloromethane phase was washed with 5% sodium bicarbonate solution and water, respectively. The lower organic phase was concentrated under reduced pressure to remove the solvent. 100 mL of methyl tert-butyl ether was added to replace the solvent, and the mixture was concentrated under reduced pressure to remove the solvent again. 80 mL of methyl tert-butyl ether was added, and the mixture was heated to 50°C and stirred until homogeneous. 8 mL of isopropanol was added and stirred until dissolved. The mixture was slowly cooled to 0°C, and a white solid precipitated. The solid was filtered, and the filter cake was dried to obtain 6.7 g of cis-2-pyridin-2-ylcyclohexanol, with a yield of 37.8%. (HPLC) 99.5%; using 17.7g of the cis-trans mixture from Method B of Example 3, after treatment under the same conditions, 13.1g of the cis product was obtained, with a yield of 74.2% and HPLC 99.3%. 1 H NMR(400MHz, CDCl3)δ:8.55(d,1H),7.55(d,1H),7.21(d,1H),7.08(d,1H),4.10(s,1H), 3.38(d,1H),2.74-2.70(m,1H),1.97-1.81(m,2H),1.80-1.66(m,2H),1.59-1.37(m,4H).

[0036] Example 5

[0037]

[0038] In Example 3, Method B, 17.7 g of a mixture of cis / trans-2-pyridin-2-ylcyclohexanol (0.1 mol), 7.7 g of benzoyl chloride (0.055 mol, 0.55 eq), and 180 mL of dichloromethane were added to a reaction flask. The mixture was cooled to -15°C, and 6.7 g of triethylamine (0.066 mol, 0.66 eq) was slowly added dropwise. The reaction was carried out at -15 to -10°C for 3 hours. The pH was adjusted to 3-4 by adding dilute hydrochloric acid aqueous solution, and the mixture was allowed to stand. The mixture was separated into layers. The dichloromethane phase was washed with 5% sodium bicarbonate solution and water, respectively. The lower organic phase was concentrated under reduced pressure to remove the solvent. 100 mL of methyl tert-butyl ether was added to replace the solvent, and the mixture was concentrated under reduced pressure to remove the solvent again. 80 mL of methyl tert-butyl ether was added, and the mixture was heated to 50 °C and stirred until homogeneous. 8 mL of isopropanol was added and stirred until dissolved. The mixture was slowly cooled to 0 °C, and a white solid precipitated. The solid was filtered, and the filter cake was dried to obtain 14.0 g of cis-2-pyridin-2-ylcyclohexanol, with a yield of 79.2% and an HPLC accuracy of 99.7%.

[0039] Example 6

[0040]

[0041] In Example 3, Method B, 17.7 g of a mixture of cis / trans-2-pyridin-2-ylcyclohexanol (0.1 mol), 9.4 g of 4-methoxybenzoyl chloride (0.055 mol, 0.55 eq), and 180 mL of dichloromethane were added to a reaction flask. The mixture was cooled to -15°C, and 6.7 g of triethylamine (0.066 mol, 0.66 eq) was slowly added dropwise. The reaction was carried out at -15 to -10°C for 3 hours. Diluted hydrochloric acid was added to adjust the pH to 5-6. The mixture was allowed to stand and separate into layers. The dichloromethane phase was washed with 5% sodium bicarbonate solution and water, respectively. The lower organic phase was concentrated under reduced pressure to remove the solvent. 100 mL of methyl tert-butyl ether was added to replace the solvent, and the mixture was concentrated under reduced pressure to remove the solvent again. 80 mL of methyl tert-butyl ether was added, and the mixture was heated to 50 °C and stirred until homogeneous. 8 mL of isopropanol was added and stirred until dissolved. The mixture was slowly cooled to 0 °C, and a white solid precipitated. The solid was filtered, and the filter cake was dried to obtain 14.2 g of cis-2-pyridin-2-ylcyclohexanol, with a yield of 80.5% and an HPLC resolution of 99.6%.

[0042] The contents described in this specification are merely an enumeration of the implementation forms of the inventive concept, and the scope of protection of this invention should not be regarded as limited to the specific forms described in the embodiments.

Claims

1. A method for preparing cis-2-pyridin-2-ylcyclohexanol, characterized in that, Includes the following steps: ； Step S1: Pyridine nitride is mixed with 4-cyclohexenylmorpholine in an organic solvent and reacted in the presence of benzoyl chloride to give 2-(pyridin-2-yl)cyclohexane-1-one; Step S2: 2-(pyridin-2-yl)cyclohexane-1-one, tri(trifluoroethanol) borate, and an organic solvent are mixed and cooled to 0-5°C. Sodium borohydride acetate is added in batches to react and give cis / trans-2-pyridin-2-ylcyclohexanol. The mixture is extracted with dichloromethane and then reacted with an acyl chloride in the presence of triethylamine as an acid binder. The post-treatment yields cis-2-pyridin-2-ylcyclohexanol. The specific post-treatment operation is as follows: after the reaction with the acyl chloride, the mixture is washed sequentially with dilute hydrochloric acid, sodium bicarbonate solution, and water. The organic phase is concentrated to remove dichloromethane, replaced with MTBE, and recrystallized from a mixed solvent of MTBE and isopropanol to obtain cis-2-pyridin-2-ylcyclohexanol.

2. The method for preparing cis-2-pyridin-2-ylcyclohexanol according to claim 1, characterized in that, In step S1, the organic solvent is selected from dichloromethane or chloroform.

3. The method for preparing cis-2-pyridin-2-ylcyclohexanol according to claim 1, characterized in that, In step S1, the molar ratio of pyridine nitride, benzoyl chloride and 4-cyclohexenylmorpholine is 1:1.15-1.20:1.8-2.

0.

4. The method for preparing cis-2-pyridin-2-ylcyclohexanol according to claim 1, characterized in that: In step S2, the molar ratio of 2-(pyridin-2-yl)cyclohexane-1-one, tri(trifluoroethanol) borate, and sodium borohydride acetate is 1:0.1-1.0:1.2-1.

5.

5. The method for preparing cis-2-pyridin-2-ylcyclohexanol according to claim 1, characterized in that: In step S2, the acyl chloride is selected from benzoyl chloride, acetyl chloride, or 4-methoxybenzoyl chloride; the organic solvent is selected from ethanol, tetrahydrofuran, or trifluoroethanol.

6. The method for preparing cis-2-pyridin-2-ylcyclohexanol according to claim 1, characterized in that: In step S2, the molar ratio of cis / trans-2-pyridin-2-ylcyclohexanol to acyl chloride is 1:0.5-0.

55.

7. The method for preparing cis-2-pyridin-2-ylcyclohexanol according to claim 1, characterized in that: The volume ratio of the MTBE and isopropanol mixed solvent is 10:1.

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