Preparation method of d-borneol

Abstract

The invention relates to a method for preparing d-borneol by taking natural camphor as a raw material, which comprises the following steps: taking a borane complex as a reducing agent, and obtaining the d-borneol under the catalysis of a chiral catalyst; the molar ratio of the borane complex to the dextro-camphor is 0.6-5; the catalyst is (R)-2-methyl-CBS-oxazole borane, and the catalyst is an organic solvent; the molar ratio of the (R)-2-methyl-CBS-oxazole borane to the dextrorotation camphor is 0.04 to 1.

Description

Technical Field

[0001] The invention relates to a method for preparing d-borneol, and more particularly to a method for preparing d-borneol by taking natural camphor as a raw material. Background Art

[0002] Borneol is a colorless, transparent or white flaky crystal. It is also called borneol because of its crystal-like appearance. It has the effects of dispersing stagnant fire, improving eyesight, relieving pain and reducing swelling. It is mainly used to treat stroke, shock, pain, phlegm, heat pain, mouth sores, deafness, otitis media, throat paralysis, hemorrhoids, worm disease, etc. To this day, many traditional Chinese medicines, such as Yunnan Baiyao and Shuangliao Houfengsan, still use natural borneol as medicine.

[0003] At present, the chemical synthesis methods of d-borneol mainly include pinene synthesis method and camphor reduction method, but the d-borneol obtained by these two methods contains a large amount of isoborneol. Therefore, it is very necessary to develop a preparation method that is efficient, cheap and suitable for large-scale production.

[0004] Since right-handed camphor is cheap and readily available, many researchers hope to prepare right-handed borneol using right-handed camphor as a raw material through a one-step reduction reaction. Some researchers use a sodium / liquid ammonia system for the selective reduction of right-handed camphor. Although the content of right-handed camphor can be increased to 85% (J.Org.Chem., 1979, 44(4), 594-599; J.Am.Chem.Soc., 1968, 90(23), 6486-6492; Tetrahedron Lett; 1987, 28(29); 3315-3318), the reaction needs to be carried out at -40°C, and the reaction conditions are harsh. In addition, the reaction requires the use of a large amount of alkali metal elements, which is complicated to operate and has a high safety risk, and is not suitable for industrial production. Zhao Peng et al. ("Preparation of dextrorotatory borneol by asymmetric reduction of camphor in alkali metal / tetrahydrofuran system", Journal of Huaqiao University (Natural Science Edition), 2010, 31(6): 671-673) studied the asymmetric reduction of camphor in an alkali metal / tetrahydrofuran system. After optimizing the conditions such as the amount of alkali metal, the amount of solvent, the reaction time and the reaction temperature, the camphor conversion rate obtained by the reaction was 93%, and the dextrorotatory borneol yield was only 72%. KIM et al. ("Reduction of ketones to corresponding alcohols with magnesium metal in absolute alcohols", KIM, JY, Tetrahedron Lett. 47 (2006) 1, 9-12; Korea Res. Inst. Chem. Technol., Taejon 305-600, S. Korea; Eng.) studied the use of alkali metal magnesium as a reducing agent and mercuric chloride as a catalyst to reduce camphor to dextrorotatory borneol. Although the yield was 92% and the de value was 91.87%, the reaction required column purification to achieve such purity, which was difficult to achieve industrial production. In addition, the reaction used mercuric chloride as a catalyst, which was not only highly toxic but also prone to explosion and was not suitable for industrial production.

[0005] In 2018, Wuxi Jimin Kexin Shanhe Pharmaceutical Co., Ltd. developed a new method for selective reduction synthesis of d-borneol (CN108752164A). The patent uses a homemade chiral reagent (R)-BINAP-H as a catalyst to selectively reduce d-camphor to d-borneol. The cost of the chiral catalyst in this method is high, and the conversion rate, yield and product purity have not reached the ideal level.

[0006] Therefore, there is currently a need for a method with high yield, high purity and suitable for large-scale production to prepare d-borneol using natural camphor as a raw material. Summary of the invention

[0007] The invention provides a method for preparing d-borneol from natural camphor, which has high yield and high purity, is suitable for large-scale production and has simple subsequent purification process and low cost.

[0008] The present invention solves the above technical problems through the following technical solutions:

[0009] The present invention provides a preparation method of dextrorotatory camphor as shown in formula I to obtain dextrorotatory borneol as shown in formula III, characterized in that a borane complex is used as a reducing agent and a chiral catalyst is used to obtain dextrorotatory borneol as shown in formula III.

[0010]

[0011] In the present invention, the borane complex is selected from borane tetrahydrofuran, borane dimethyl sulfide, diethyl methoxyborane, borane NN-diethylaniline, preferably borane tetrahydrofuran, borane dimethyl sulfide, more preferably borane dimethyl sulfide.

[0012] In the present invention, the molar ratio of the borane complex to the right-rotatory camphor is 0.6-5, preferably 0.6-2, more preferably 0.7-2, and most preferably 0.7.

[0013] The catalyst in the present invention is (R)-2-methyl-CBS-oxazaborolidine.

[0014] In the present invention, the molar ratio of (R)-2-methyl-CBS-oxazaborolidine to dextrorotatory camphor is 0.04-1, preferably 0.04-0.2, more preferably 0.05-0.2, and most preferably 0.05.

[0015] The present invention provides a preparation method, which comprises the following steps:

[0016] 1) Add the chiral catalyst alkane to the reaction bottle, add tetrahydrofuran and dissolve it.

[0017] 2) dissolving the borane complex in tetrahydrofuran and adding dropwise to the reaction solution in step 1);

[0018] 3) adding a tetrahydrofuran solution of right-rotatory camphor dropwise to the reaction solution obtained in step 2);

[0019] Alternatively, the present invention provides a preparation method comprising the following steps:

[0020] 1) Add (R)-2-methyl-CBS-oxazaborolidine to the reaction bottle, add tetrahydrofuran and dissolve.

[0021] 2) dissolving borane dimethyl sulfide in tetrahydrofuran and adding dropwise to the reaction solution in step 1),

[0022] 3) Add a tetrahydrofuran solution of right-rotatory camphor dropwise to the reaction solution obtained in step 2).

[0023] Alternatively, the preparation method provided by the present invention comprises the following steps:

[0024] 1) Add chiral catalyst and right-rotation camphor into a reaction bottle, add tetrahydrofuran and dissolve.

[0025] 2) dissolving the borane complex in tetrahydrofuran and adding dropwise to the reaction solution in step 1);

[0026] Alternatively, the preparation method provided by the present invention comprises the following steps:

[0027] 1) Add (R)-2-methyl-CBS-oxazaborolidine and right-rotatory camphor into a reaction bottle, add tetrahydrofuran and dissolve.

[0028] 2) Dissolve borane dimethyl sulfide in tetrahydrofuran and add dropwise to the reaction solution in step 1).

[0029] The present invention also provides a preparation method, which comprises the following steps: after the reaction is completed, methanol is added to quench the reaction, the reaction solution is decompressed and dried by rotation, petroleum ether is added to dissolve, and then hydrochloric acid-ethyl acetate is added, filtered, and the filtrate is dried by rotation to obtain dextrorotatory borneol.

[0030] The method for preparing d-borneol from natural camphor has the advantages of high yield, high purity, suitability for large-scale production, and simple subsequent purification process and low cost. Specific embodiments

[0031] When there is more than one asymmetric center in the molecular formula of a compound, its diastereomeric composition can be described as "diastereomeric excess" or "diastereomeric excess percentage de%, which refers to the excess of one diastereomer over the other diastereomers. The calculation formula is: De = (SR) / (S + R)

[0032] The 4N hydrochloric acid-ethyl acetate in the present invention is a commercially available product purchased from Chemart Laboratories Inc. with a purchase batch number of XYS371054623.

[0033] Example 1

[0034] D-camphor (2 g, 13.13 mmol) was dissolved in tetrahydrofuran (25 mL). A solution of red aluminum (3.64 mL, 13.13 mmol) in tetrahydrofuran (4 mL) was added dropwise under ice bath. The mixture was reacted at room temperature for 6.5 h. TLC showed that a small amount of raw material remained. LCMS showed that the De value of isoborneol was 50%. The reaction solution was evaporated to dryness under reduced pressure. The yield of the mixture was 80%.

[0035] Example 2

[0036] LiAlH4 (598 mg, 15.76 mmol) was added in batches to a solution of right-rotatory camphor (2 g, 13.13 mmol) in tetrahydrofuran (40 mL). The reaction was carried out in an ice bath for 30 min and then at room temperature for 1.5 h. The De value of isoborneol detected by LCMS was 54%. The reaction solution was evaporated to dryness under reduced pressure. The yield of the mixture was 90%.

[0037] Example 3

[0038] Dissolve right-rotatory camphor (4 g, 26.31 mmol) in methanol (30 mL), add sodium borohydride (1.09 g, 28.95 mmol) under ice bath, react at 0°C for 1 h, LCMS detected the De value of isoborneol to be 37%, evaporate the reaction solution to dryness under reduced pressure, the yield of the mixture was 95%.

[0039] Example 4

[0040] D-camphor (5 g, 32.89 mmol) was dissolved in methanol (60 mL), and Pd / C (500 mg) was added. The atmosphere was replaced with nitrogen three times, and hydrogen was introduced. The reaction was carried out at room temperature for 7 h. TLC showed that a large amount of raw material remained, and no product was generated.

[0041] Example 5

[0042] D-camphor (152 mg, 1 mmol) was dissolved in tetrahydrofuran (10 mL), and BH3·THF (1 mL, 1 mmol) was added dropwise. The mixture was reacted at room temperature for 2.5 h. The De value of D-borneol detected by LCMS was 0%. The reaction solution was evaporated to dryness under reduced pressure. The yield of the mixture was 95%.

[0043] Example 6

[0044] (R)-Me-CBS (183 mg, 0.66 mmol) was added to the reaction bottle, tetrahydrofuran (5 mL) was added, and the mixture was stirred to dissolve. BH3·THF (4.6 mL, 4.6 mmol) was dissolved in 5 mL tetrahydrofuran at room temperature and added dropwise to the above reaction solution. After the addition was complete, the mixture was stirred at room temperature for 20 minutes. A tetrahydrofuran solution (5 mL) of right-handed camphor (1.0 g, 6.6 mmol) was slowly added dropwise to the above reaction solution. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction was detected by TLC to be complete. The reaction solution was spin-dried to dryness, methanol (10 mL) was added to quench the reaction, the reaction solution was decompressed and spin-dried to dryness, petroleum ether (10 mL) was added to dissolve, and then 4N hydrochloric acid-ethyl acetate (2.5 mL) was added. The mixture was stirred for ten minutes, filtered, and the filtrate was spin-dried to obtain right-handed borneol. The yield was 95%, and the De value of right-handed borneol detected by GCMS was 88.69%.

[0045] Example 7

[0046] (R)-Me-CBS (183 mg, 0.66 mmol) was added to the reaction bottle, tetrahydrofuran (5 mL) was added, and the mixture was stirred to dissolve. BH3·Me2S (0.46 mL, 4.6 mmol) was dissolved in 5 mL tetrahydrofuran at room temperature and added dropwise to the above reaction solution. After the addition was complete, the mixture was stirred at room temperature for 20 minutes. A tetrahydrofuran solution (5 mL) of right-handed camphor (1.0 g, 6.6 mmol) was slowly added dropwise to the above reaction solution. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction was detected by TLC to be complete. The reaction solution was spin-dried to dryness, methanol (10 mL) was added to quench the reaction, the reaction solution was spin-dried under reduced pressure, petroleum ether (10 mL) was added to dissolve, and then 4N hydrochloric acid-ethyl acetate (2.5 mL) was added. The mixture was stirred for ten minutes, filtered, and the filtrate was spin-dried to obtain right-handed borneol. The yield was 95%, and the De value of right-handed borneol detected by GCMS was 95.28%.

[0047] Example 8

[0048] (R)-Me-CBS (91 mg, 0.33 mmol) was added to the reaction bottle, tetrahydrofuran (5 mL) was added, and the mixture was stirred to dissolve. BH3·Me2S (0.46 mL, 4.6 mmol) was dissolved in 5 mL tetrahydrofuran at room temperature and added dropwise to the above reaction solution. After the addition was complete, the mixture was stirred at room temperature for 20 minutes. A tetrahydrofuran solution (5 mL) of right-handed camphor (1.0 g, 6.6 mmol) was slowly added dropwise to the above reaction solution. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction was detected by TLC to be complete. The reaction solution was spin-dried to dryness, methanol (10 mL) was added to quench the reaction, the reaction solution was spin-dried under reduced pressure, petroleum ether (10 mL) was added to dissolve, and then 4N hydrochloric acid-ethyl acetate (2.5 mL) was added. The mixture was stirred for ten minutes, filtered, and the filtrate was spin-dried to obtain right-handed borneol. The yield was 95%, and the De value of right-handed borneol detected by GCMS was 96.8%.

[0049] Example 9

[0050] Add right-rotating camphor (1g, 6.6mmol) and (R)-Me-CBS (183mg, 0.66mmol) to the reaction bottle, add tetrahydrofuran (10mL), and stir at room temperature for 20 minutes. Dissolve BH3·Me2S (0.46mL, 4.6mmol) in 5mL tetrahydrofuran at room temperature and slowly drop it into the above reaction solution. After the addition is complete, stir at room temperature for 2 hours. TLC detection shows that the reaction is complete, spin dry the reaction solution, add methanol (10mL) to quench the reaction, decompress the reaction solution and spin dry it, add petroleum ether (10mL) to dissolve it, then add 4N hydrochloric acid-ethyl acetate (2.5mL), stir for ten minutes, filter, spin dry the filtrate to obtain right-rotating borneol, with a yield of 95%, and the De value of right-rotating borneol detected by GCMS is 90.8%.

[0051] Example 10

[0052] Add right-rotating camphor (1.0 g, 6.6 mmol) and (R)-Me-CBS (91 mg, 0.33 mmol) to the reaction flask, add tetrahydrofuran (10 mL), and immediately add BH 3· Me2S (0.46mL, 4.6mmol) was dissolved in 5mL tetrahydrofuran and slowly added dropwise to the above reaction solution. After the addition was complete, the mixture was stirred at room temperature for 2 hours. TLC detected that the reaction was complete, the reaction solution was spin-dried, methanol (10mL) was added to quench the reaction, the reaction solution was spin-dried under reduced pressure, petroleum ether (10mL) was added to dissolve, and then 4N hydrochloric acid-ethyl acetate (2.5mL) was added, stirred for ten minutes, filtered, and the filtrate was spin-dried to obtain d-borneol with a yield of 95%. The De value of d-borneol detected by GCMS was 96.8%.

[0053] Embodiment 11

[0054] (R)-Me-CBS (91 mg, 0.33 mmol) was added to the reaction bottle, tetrahydrofuran (5 mL) was added, and the mixture was stirred to dissolve. BH3·Me2S (0.39 mL, 3.9 mmol) was dissolved in 5 mL tetrahydrofuran at room temperature and added dropwise to the above reaction solution. After the addition was complete, the mixture was stirred at room temperature for 20 minutes. A tetrahydrofuran solution (5 mL) of right-rotating camphor (1.0 g, 6.6 mmol) was slowly added dropwise to the above reaction solution. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction was detected by TLC to be complete. The reaction solution was spin-dried to dryness, methanol (10 mL) was added to quench the reaction, the reaction solution was spin-dried under reduced pressure, petroleum ether (10 mL) was added to dissolve, and then 4N hydrochloric acid-ethyl acetate (2.5 mL) was added. The mixture was stirred for ten minutes, filtered, and the filtrate was spin-dried to obtain right-rotating borneol. The yield was 95%, and the De value of right-rotating borneol detected by GCMS was 95.64%.

[0055] Example 12

[0056] (R)-Me-CBS (91 mg, 0.33 mmol) was added to the reaction bottle, tetrahydrofuran (5 mL) was added, and the mixture was stirred to dissolve. BH3·Me2S (1.32 mL, 13.2 mmol) was dissolved in 5 mL tetrahydrofuran at room temperature and added dropwise to the above reaction solution. After the addition was complete, the mixture was stirred at room temperature for 20 minutes. A tetrahydrofuran solution (5 mL) of right-rotating camphor (1 g, 6.6 mmol) was slowly added dropwise to the above reaction solution. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction was detected by TLC to be complete. The reaction solution was spin-dried to dryness, methanol (10 mL) was added to quench the reaction, the reaction solution was spin-dried under reduced pressure, petroleum ether (10 mL) was added to dissolve, and then 4N hydrochloric acid-ethyl acetate (2.5 mL) was added. The mixture was stirred for ten minutes, filtered, and the filtrate was spin-dried to obtain right-rotating borneol. The yield was 96%, and the De value of right-rotating borneol detected by GCMS was 95.88%.

[0057] Embodiment 13

[0058] (R)-Me-CBS (73 mg, 0.26 mmol) was added to the reaction bottle, tetrahydrofuran (5 mL) was added, and the mixture was stirred to dissolve. BH3·Me2S (0.46 mL, 4.6 mmol) was dissolved in 5 mL tetrahydrofuran at room temperature and added dropwise to the above reaction solution. After the addition was complete, the mixture was stirred at room temperature for 20 minutes. A tetrahydrofuran solution (5 mL) of right-handed camphor (1.0 g, 6.6 mmol) was slowly added dropwise to the above reaction solution. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction was detected by TLC to be complete. The reaction solution was spin-dried to dryness, methanol (10 mL) was added to quench the reaction, the reaction solution was spin-dried under reduced pressure, petroleum ether (10 mL) was added to dissolve, and then 4N hydrochloric acid-ethyl acetate (2.5 mL) was added. The mixture was stirred for ten minutes, filtered, and the filtrate was spin-dried to obtain right-handed borneol. The yield was 95%, and the De value of right-handed borneol detected by GCMS was 95.51%.

[0059] Embodiment 14

[0060] (R)-Me-CBS (366 mg, 1.32 mmol) was added to the reaction bottle, tetrahydrofuran (5 mL) was added, and the mixture was stirred to dissolve. BH3·Me2S (0.46 mL, 4.6 mmol) was dissolved in 5 mL tetrahydrofuran at room temperature and added dropwise to the above reaction solution. After the addition was complete, the mixture was stirred at room temperature for 20 minutes. A tetrahydrofuran solution (5 mL) of right-handed camphor (1.0 g, 6.6 mmol) was slowly added dropwise to the above reaction solution. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction was detected by TLC to be complete. The reaction solution was spin-dried to dryness, methanol (10 mL) was added to quench the reaction, the reaction solution was decompressed and spin-dried to dryness, petroleum ether (10 mL) was added to dissolve, and then 0.4 N hydrochloric acid-ethyl acetate (2.5 mL) was added. The mixture was stirred for ten minutes, filtered, and the filtrate was spin-dried to obtain right-handed borneol. The yield was 95%, and the De value of right-handed borneol detected by GCMS was 96.33%.

[0061] Embodiment 15

[0062] (R)-Me-CBS (1.82 g, 6.58 mmol) was added to the reaction bottle, tetrahydrofuran (40 mL) was added, and the mixture was stirred to dissolve. BH3·Me2S (9.2 mL, 92.1 mmol) was added dropwise to the reaction solution at room temperature, and the mixture was stirred at room temperature for 20 minutes. A solution of right-handed camphor (20 g, 131.6 mmol) in tetrahydrofuran (60 mL) was slowly added dropwise to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The reaction was complete by TLC detection, and methanol (10 mL) was added to quench the reaction. The reaction solution was decompressed and dried, and petroleum ether (50 mL) was added to dissolve the mixture, and then 4N hydrochloric acid-ethyl acetate (2.5 mL) was added, and the mixture was stirred for ten minutes, filtered, and the filtrate was dried to obtain 19.3 g of right-handed borneol, with a yield of 95%. The De value of right-handed borneol detected by GCMS was 97.4%.

Claims

1. A method for preparing dextrorotatory borneol as shown in formula III by reducing dextrorotatory camphor as shown in formula I, characterized in that: Borane complex is used as a reducing agent and chiral catalyst is used to obtain dextrorotatory borneol as shown in formula III.

2. The preparation method according to claim 1, characterized in that: The borane complex is selected from borane tetrahydrofuran, borane dimethyl sulfide, diethyl methoxyborane, borane NN-diethylaniline; preferably borane tetrahydrofuran, borane dimethyl sulfide; more preferably borane dimethyl sulfide.

3. The preparation method according to claim 2, characterized in that: The molar ratio of the borane complex to dextrorotatory camphor is 0.6-5, preferably 0.6-2, more preferably 0.7-2, and most preferably 0.

7.

4. The preparation method according to claim 1, characterized in that: The catalyst is (R)-2-methyl-CBS-oxazaborolidine.

5. The preparation method according to claim 4, characterized in that: The molar ratio of (R)-2-methyl-CBS-oxazaborolidine to dextrorotatory camphor is 0.04-1, preferably 0.04-0.2, more preferably 0.05-0.2, and most preferably 0.

05.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The following steps are included: 1) Add the chiral catalyst alkane to the reaction bottle, add tetrahydrofuran and dissolve it. 2) dissolving the borane complex in tetrahydrofuran and adding dropwise to the reaction solution in step 1); 3) Add a tetrahydrofuran solution of right-rotatory camphor dropwise to the reaction solution obtained in step 2).

7. The preparation method according to any one of claims 1 to 5, characterized in that: The following steps are included: 1) Add (R)-2-methyl-CBS-oxazaborolidine to the reaction bottle, add tetrahydrofuran and dissolve. 2) dissolving borane dimethyl sulfide in tetrahydrofuran and adding dropwise to the reaction solution in step 1), 3) Add a tetrahydrofuran solution of right-rotatory camphor dropwise to the reaction solution obtained in step 2).

8. The preparation method according to any one of claims 1 to 5, characterized in that: The following steps are included: 1) Add chiral catalyst and right-rotation camphor into a reaction bottle, add tetrahydrofuran and dissolve. 2) dissolving the borane complex in tetrahydrofuran and adding dropwise to the reaction solution in step 1).

9. The preparation method according to any one of claims 1 to 5, characterized in that: The following steps are included: 1) Add (R)-2-methyl-CBS-oxazaborolidine and right-rotatory camphor into a reaction bottle, add tetrahydrofuran and dissolve. 2) Dissolve borane dimethyl sulfide in tetrahydrofuran and add dropwise to the reaction solution in step 1).

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