CN108752164B

CN108752164B - Preparation method of d-borneol

Info

Publication number: CN108752164B
Application number: CN201810692617.2A
Authority: CN
Inventors: 姜迎庆; 於江华; 闵江
Original assignee: Wuxi Jiyu Shanhe Pharmaceutical Co Ltd; Jiangxi Jemincare Group Co Ltd
Current assignee: Wuxi Jiyu Shanhe Pharmaceutical Co Ltd; Jiangxi Jemincare Group Co Ltd
Priority date: 2018-06-29
Filing date: 2018-06-29
Publication date: 2021-12-24
Anticipated expiration: 2038-06-29
Also published as: CN108752164A

Abstract

The invention relates to a preparation method of d-borneol, which comprises the following steps: in the presence of an organic solvent and a chiral reagent (R) -BINAP-H as a catalyst, reacting natural camphor at 0-40 ℃ for 1-8 hours, wherein the preferable ratio of the organic solvent to the chiral reagent (R) -BINAP-H and camphor is 10-30 ml: 20-50 mmol:18 mmol.

Description

Preparation method of d-borneol

Technical Field

The invention relates to a preparation method of d-borneol, in particular to a method for preparing d-borneol by taking natural camphor as a raw material.

Background

Borneol, also known as borneol, in Chinese patent medicine preparationHas multiple functions. Has effects in inducing resuscitation, refreshing mind, clearing away heat, and relieving pain, and can be used for treating fever unconsciousness, convulsion, apoplexy, phlegm syncope, qi stagnation, syncope, central aversion to coma, thoracic obstruction, cardiodynia, conjunctival congestion, aphtha, sore throat, and purulence in ear canal. Meanwhile, borneol is used as an important spice and is also widely used for preparing rosemary and lavender essence. The natural borneol has a left-handed isomer and a right-handed isomer, and the synthesized product is a raceme. The corresponding stereoisomers are formed by the different spatial positions of the hydroxyl groups. The borneol is colorless semitransparent hexagonal flaky crystal with molecular formula C₁₀H₁₇OH, molecular weight 154.25, chemical name 1, 7, 7-trimethylbicyclo [2, 2, 1 ]]Heptan-2-ol.

Generally, the isoborneol in the chemically synthesized borneol is high in content, is racemic, has poor drug effect and cannot meet the requirements of people. Therefore, the effective preparation method of borneol is sought, and the borneol is greatly concerned by people in the field of organic synthesis.

Effective substance basis and impurities of borneol: the 2010 version pharmacopoeia part regulates the quality standard of borneol, and the borneol contains borneol not less than 55.0%, camphor not more than 0.50%, heavy metal not more than five parts per million, arsenic not more than two parts per million, and nonvolatile matter not more than 3.5mg per 10 g. According to pharmacopoeia standards, the real effective substance of borneol is borneol, the amount of the borneol is not less than 55.0%, and the rest is impurities which cannot exceed the standards. Calculated by percentage, heavy metal, arsenic salt and nonvolatile matter are ignored, the isobornol content is 100% -0.50% -55.0%, 44.50%, the isobornol content in borneol is not more than 44.50%, and isobornol is also an impurity. As shown in the first route, the borneol comprises levo-borneol and dextro-borneol, the camphor comprises levo-camphor and dextro-camphor, the isoborneol comprises levo-isoborneol and dextro-isoborneol, the dextro-isoborneol has the structure (1), levo-isoborneol has the structure (2), dextro-isoborneol has the structure (3), levo-isoborneol has the structure (4), dextro-camphor has the structure (5), and levo-camphor has the structure (6).

Synthetic method of borneolThe method mainly comprises the following steps: (1) esterification-saponification method: isomerizing alpha-pinene at high temperature or in special catalyst to camphene, esterifying camphene to produce ethyl acetate, and saponifying to obtain borneol. Similarly to this process, solid superacid SO is used₄ ^-4/AL₂O₃Catalyzing esterification reaction of alpha-pinene and anhydrous oxalic acid, preparing and generating oxalic acid dinonyl ester, and then performing saponification reaction to synthesize borneol. The main technical defects of the method are that the reaction route is long, and ion exchange resin is required to be used in isomerization. (2) A hydration method: isomerizing alpha-pinene into camphene at high temperature or in the presence of special catalyst, and directly carrying out hydration reaction on the camphene without esterification reaction to obtain borneol. The method has the main technical characteristics that one-step chemical reaction is reduced, the process technology is mature, but the unit consumption of raw materials is high, and meanwhile, the defects that the productivity is not easy to expand, some auxiliary post-treatment processes need to be added and the like exist.

Disclosure of Invention

The invention aims to provide a method for preparing d-borneol with high atom utilization rate and high optical rotation by using a mode of reducing natural camphor through chiral induction.

The technical scheme of the invention is that the preparation method of the d-borneol comprises the following steps:

A. adding a hand reagent (R) -BINAP-H into an anhydrous solvent under the protection of nitrogen, then adding natural camphor, stirring and reacting for 1-20H at the temperature of 0-40 ℃, and tracking the reaction progress by using gas chromatography;

B. after the reaction is finished, methanol is dripped to stop the reaction, then dilute hydrochloric acid solution is dripped, standing is carried out, the solution of the product is separated into an upper organic layer by a separating funnel, a lower water layer is extracted for 3 times by a solvent, the organic layers are combined and dried by anhydrous magnesium sulfate, and then washing, drying, distilling and sublimating are carried out to obtain the reaction product mainly containing d-borneol. Finally, the composition of the reaction product was analyzed with a gas chromatograph and a polarimeter.

In the step A, the chiral reagent (R) -BINAP-H is LiALH modified by R- (+) -BINAP₄And obtaining the compound. The modification method comprises the following steps:

in a conical flask equipped with magnetic rodsAdding anhydrous ether, adding a certain amount of LiALH under stirring₄Then, equimolar R- (+) -BINAP was added dropwise to the flask over 1h, and stirring was continued for 0.5 h. And dissolving absolute ethyl alcohol in absolute ethyl ether, dropwise adding the absolute ethyl alcohol into the prepared mixed solution within 10min, stirring for 2h, and refluxing to obtain the chiral reagent required by chiral synthesis.

The structural formula is as follows:

the sources are as follows:

Noyori R,Tomino I,Tanimoto Y,et al.Rational designing of efficient chiral reducing agents:Highly enantioselec-tive reduction of aromatic ketones by binaphtho-l modified lithium aluminum hydride reagents[J].J Am Chem Soc,1984,106(22):6 709～6 716

lin nationality, Chen Zuang Quan, Chen Xin Zi, etc. chiral synthesis-asymmetric reaction and its application [ M ]. Beijing, scientific Press, 2000.262-265;

wangninghui, Zhao Peng, Wang Weide, etc. Camphor chiral synthesis Dexiong borneol, university of Huaqiao, proceedings of Nature science, 2006,27(1): 89-91;

the mode of adding the catalyst into the reaction system is as follows:

dissolving Camphora in anhydrous diethyl ether, loading into dropping funnel, and slowly adjusting knob to drop into conical flask containing chiral reagent for a prescribed time.

In the step A, the preferable proportion of the solvent, the chiral reagent (R) -BINAP-H and the camphor is 10-30 ml: 20-50 mmol:18 mmol. Wherein the ratio in 10ml (96 mmol): 0.95g (25 mmol): 2.74g (18mmol) was used as the optimum condition.

In the step A, the reaction temperature range is 0-40 ℃, wherein the optimal temperature is 30 ℃; the reaction time is 1-8 h, preferably 4 h.

In the step A, the anhydrous solvent is anhydrous diethyl ether and anhydrous tetrahydrofuran, wherein the anhydrous diethyl ether is used as the optimal reaction solvent.

The synthetic route involved in the invention is shown as a second route:

the theory of the method is based on: the method utilizes the thermodynamic stability of molecules of reduction transition products to obtain the borneol which is more thermodynamically stable rather than isoborneol.

The invention has the positive effects that: (1) small solvent dosage, simple synthesis path, mild reaction condition and high conversion yield. And the outstanding advantage of using BINAP modified reducing agent to make the product optical purity higher.

The beneficial effects of the present invention are further illustrated by experimental data as follows:

through the improvement of the preparation method, the preparation method is superior to the prior art, and the following comparative experiments are carried out:

	molar ratio of chiral agent to camphor	Conversion rate	Yield of	Relative rotation
					Method of the invention	1.39	89.1％	42.6％	79.2％
By prior art methods	2.57	82.4％	24.6％	69.2％

Detailed Description

The present invention will be further described with reference to the following specific examples.

Example 1:

adding the following components in sequence under the protection of nitrogen: anhydrous ether, chiral reagent (R) -BINAP-H, camphor. The quantitative ratio of the materials was 10ml (96 mmol): 0.95g (25 mmol): 2.74g (18 mmol). The reaction was stirred at 30 ℃ for 4h and the progress of the reaction was followed by gas chromatography. And tracking the reaction progress by using a gas chromatograph, dropwise adding 1.5mL of methanol after the reaction is finished to stop the reaction, dropwise adding 5mL of 2mol/L hydrochloric acid, and standing. The ethanol solution of the product was separated into an upper organic layer by a separatory funnel, a lower aqueous layer was extracted with ether 3 times, and the organic layers were combined and dried over anhydrous magnesium sulfate. Washing, drying, distilling and sublimating to obtain a reaction product mainly containing d-borneol. Column chromatography separation and purification yielded 1.18g of white crystals. The conversion was 89.1%, the yield was 42.6%, and the relative optical rotation was 79.2%. The relative optical rotation of the reduced product (the ratio of the optical rotation of the product to that of the pure natural borneol x 100%).

Example 2 to example 4:

each example is substantially the same as example 1 except that: chiral reagent (R) -BINAP-H, camphor molar ratio. The material amount ratio of each example and the results of the effect on the reaction are shown in Table 1. In the table, n is the molar ratio of the chiral agent to camphor, G₁,G₂Conversion and yield, respectively, and α is the relative optical rotation.

TABLE 1 Effect of different n on the reaction

Serial number	n	G₁/(％)	G₂/(％)	α/(％)
					1	1.39	89.1	42.6	79.2
2	1.11	62.4	24.6	64.2
					3	1.67	53.8	36.2	84.6
4	1.94	50.2	31.9	85.8

As can be seen from table 1, camphor conversion increases with increasing n; however, if n continues to increase, the conversion decreases instead, the product yield shows the same trend, i.e., increases with increasing n; continuing to increase n, yield decreases instead. Considering the conversion rate, relative optical rotation, yield and cost, n is 1.39.

Examples 5 to 9:

each example is substantially the same as example 1 except that: the reaction temperature and the reaction time are respectively 30 ℃, 0 ℃ and 2-8 hours. The results of the temperature, time and effect on the reaction for each example are shown in Table 2.

TABLE 2 Effect of temperature and reaction time on the reaction

Serial number	￠/(％)	t/(h)	G₁/(％)	G₂/(％)	α/(％)
						1	30	4	89.1	42.6	79.2
5	30	2	45.1	23.2	69.4
						6	30	6	89.4	40.5	79.4
7	30	8	91.2	36.2	79.6
						8	0	6	28.0	4.2	83.6
9	0	8	36.4	6.3	87.4

As can be seen from Table 2, high temperature is advantageous for increasing the conversion and low temperature is advantageous for increasing the enantioselectivity. The relative optical rotation of the reaction is improved in terms of reaction time, but the increase is not so great. The yield of the d-borneol reaches the maximum value when the reaction time is 4 hours.

Example 10:

example 10 is essentially the same as example 1, except that: the solvent is anhydrous tetrahydrofuran. The results of the effect of the solvent on the reaction are shown in Table 3.

TABLE 3 Effect of solvent on the reaction

Serial number	Solvent(s)	G₁/(％)	G₂/(％)	α/(％)
					1	Et₂O	89.1	42.6	79.2
10	THF	74.3	38.1	78.6

It can be seen from Table 3 that the reaction effect of anhydrous diethyl ether is superior to that of anhydrous tetrahydrofuran.

Claims

1. A preparation method of d-borneol is characterized by comprising the following steps:

adding the following components in sequence under the protection of nitrogen: anhydrous ether, chiral reagent (R) -BINAP-H and camphor, wherein the material weight ratio is 10 ml: 0.95 g: 2.74g, stirring and reacting for 4 hours at 30 ℃, tracking the reaction progress by using a gas chromatograph, dropwise adding 1.5mL of methanol to stop the reaction after the reaction is finished, dropwise adding 5mL of 2mol/L hydrochloric acid, standing, separating an upper organic layer from an ether solution of a product by using a separating funnel, extracting a lower water layer by using ether for 3 times, combining organic phases, drying by using anhydrous magnesium sulfate, washing, drying, distilling and subliming to obtain a reaction product mainly containing d-borneol, and separating and purifying by using column chromatography to obtain white crystals.