CN108752164A - A kind of preparation method of d-Bomeol - Google Patents
A kind of preparation method of d-Bomeol Download PDFInfo
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- CN108752164A CN108752164A CN201810692617.2A CN201810692617A CN108752164A CN 108752164 A CN108752164 A CN 108752164A CN 201810692617 A CN201810692617 A CN 201810692617A CN 108752164 A CN108752164 A CN 108752164A
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- binap
- organic solvent
- camphor
- chiral reagent
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- 0 CC(C)(C(CC1)CC2*)[C@@]12C=C Chemical compound CC(C)(C(CC1)CC2*)[C@@]12C=C 0.000 description 3
- DSSYKIVIOFKYAU-OMNKOJBGSA-N CC(C)(C(CC1)C2)[C@@]1(C)C2=O Chemical compound CC(C)(C(CC1)C2)[C@@]1(C)C2=O DSSYKIVIOFKYAU-OMNKOJBGSA-N 0.000 description 1
- DSSYKIVIOFKYAU-MHPPCMCBSA-N CC(C)(C(CC1)C2)[C@]1(C)C2=O Chemical compound CC(C)(C(CC1)C2)[C@]1(C)C2=O DSSYKIVIOFKYAU-MHPPCMCBSA-N 0.000 description 1
- GNPWJQYHKDDCCU-XNWIYYODSA-N CC(C)(CC[C@H]1CC2)C2CC1O Chemical compound CC(C)(CC[C@H]1CC2)C2CC1O GNPWJQYHKDDCCU-XNWIYYODSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
- C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of preparation methods of d-Bomeol, and the method, steps are as follows：In organic solvent and in the presence of chiral reagent (R)-BINAP-H is catalyst, it is 1~8 hour that natural camphor react at 0~40 DEG C, and wherein organic solvent and chiral reagent (R)-BINAP-H, camphor are preferably in a proportion of 10~30ml:20~50mmol:18mmol.
Description
Technical field
More specifically it is to be related to one kind using natural camphor as raw material system the present invention relates to a kind of preparation method of d-Bomeol
The method of standby d-Bomeol.
Background technology
Borneol also known as borneol, play multiple efficacies in Chinese patent medicine preparation.The effect of with inducing resuscitation of having one's ideas straightened out, clearing away heat to and alleviating pain,
For pyreticosis coma, convulsions, apoplexy coma due to blocking of the respiratory system, bstruction of the circulation of vital energy is fainted cruelly, middle evil is gone into a coma, chest impediment and cardialgia, hot eyes, aphtha, abscess of throat, duct
It the illnesss such as suppurates.Meanwhile borneol is also widely used in as a kind of important fragrance and prepares rosemary, lavender type essence.Naturally
It is racemic modification that borneol, which has left and right rotation body, composite,.The spatial position where hydroxyl has been differently formed corresponding alloisomerism
Body.Borneol is the hexagonal flake crystalline solid of semi-transparent clear, molecular formula C10H17OH, molecular weight 154.25, chemical name 1,7,
Bicyclic [2,2,1] the hept- 2- alcohol of 7- trimethyls.
It is generally acknowledged that in chemically synthesized borneol, isoborneol content is higher, and is racemic modification, and drug effect is poor, Wu Faman
Sufficient people's demand.Therefore seek effective preparation method of borneol, received much attention in organic synthesis field.
The active principle basis of borneol and impurity：The quality standard of 2010 editions pharmacopeia, one regulation borneol, must not containing borneol
Less than 55.0%, camphor, which must not cross 0.50%, heavy metal, must not cross 5/1000000ths, and arsenic amount must not cross 2/1000000ths, not wave
Hair object must not cross 3.5mg per 10g.According to standards of pharmacopoeia, the real active principle of borneol is borneol, and the amount of borneol is no less than
55.0%, remaining is impurity, no more than standard.It being calculated as a percentage, heavy metal, arsenic, nonvolatile matter are ignored,
Isoborneol amount is 100%-0.50%-55.0%=44.50%, and isoborneol amount in borneol of counting must not exceed 44.50%, isoborneol
It is also impurity.As shown in route one, borneol includes L-Borneol and d-Bomeol, and camphor includes levo-camphor and gum camphor,
Isoborneol includes left-handed isoborneol and dextrorotation isoborneol, d-Bomeol structure (1), L-Borneol such as structure (2), dextrorotation isoborneol
Such as structure (3), left-handed isoborneol such as structure (4), gum camphor such as structure (5), levo-camphor such as structure (6).
The synthetic method of present borneol mainly has：(1) esterification-saponification method：At high temperature or special catalyst by australene
Under be isomerized to amphene, amphene carries out esterification, generates ethyl acetate, then carry out saponification and obtain borneol.With this method phase
Seemingly, also with solid super-strong acid SO4 -4/AL2O3It is catalyzed the esterification of australene and anhydrous oxalic acid, first prepares and generates two dragon of oxalic acid
Brain ester, then through saponification, it can also borneolum syntheticum.The major technique deficiency of such methods is that reaction route is longer, isomerization
When need use ion exchange resin.(2) hydration method：Australene is deposited at high temperature or is isomerized in the presence of special catalyst
Amphene, amphene directly carry out hydration reaction and obtain borneol without esterification.The technical characteristics of the method are the reduction of a step
Chemical reaction, comparison of technology is ripe, but raw material consumption is higher, while there is also productivity to be not easy to expand, needs to increase
The deficiencies of some attached aftertreatment technologies.
Invention content
It is an object of the present invention to provide a kind of in such a way that chiral induction restores natural camphor, high atom utilization, high optically-active
The method for preparing d-Bomeol of degree.
A kind of technical solution of the present invention, preparation method of d-Bomeol, includes the following steps：
A, chiral reagent (R)-BINAP-H is added in anhydrous solvent under nitrogen protection, then adds natural camphor,
It is stirred to react 1~20h under the conditions of 0~40 DEG C, extent of reaction is tracked with gas-chromatography；
B, dropwise addition methanol is reacted by its stopping after having reacted, then dilute hydrochloric acid solution is added dropwise, and the solution of standing products, which is used, to be divided
Liquid funnel separates upper organic layer, lower aqueous layer solvent extraction 3 times, merges and dries through water with anhydrous magnesium sulfate after organic phase
It washes, dry, distill, distil, obtain the reaction product based on d-Bomeol.Finally, it is analyzed with gas chromatograph and polarimeter anti-
Answer the composition of product.
In step A, the chiral reagent (R)-BINAP-H is to modify LiALH by R- (+)-BINAP4And it obtains.It is described
Method of modifying is as follows：
Anhydrous ether is added in the conical flask equipped with magnetic bar, is added with stirring a certain amount of LiALH4, then by etc. rub
Your R- (+)-BINAP instill conical flask in 1h, continue to stir 0.5h.Absolute ethyl alcohol is dissolved in anhydrous ether, in 10min
It is inside added drop-wise in obtained above-mentioned mixed liquor, stirs 2h, reflux obtains the chiral required chiral reagent of synthesis.
Its structural formula is as follows：
Its source is 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
Woods Guoqiang, Chen Yaoquan, Chen Xinzi wait chiralitys to synthesize --- asymmetric reaction and its Beijing application [M]:Science goes out
Version society, 2000.262~265；
Wang Ninghui, Zhao Peng, Wang Weide wait Chiral Reduction of Camphor into D-Borneol Huaqiao University journal:Natural science edition,
2006,27(1):89-91；
It is as follows that it is added to the mode in reaction system：
Camphor is dissolved in a certain amount of anhydrous ether, is loaded into dropping funel, after slowly adjust knob by its
The conical flask equipped with chiral reagent is instilled in the defined time.
In step A, the solvent and chiral reagent (R)-BINAP-H, camphor are preferably in a proportion of 10~30ml:20~
50mmol:18mmol.Wherein with 10ml (96mmol)：0.95g(25mmol)：2.74g (18mmol) is optimal conditions.
In step A, the range of reaction temperature is 0~40 DEG C, wherein best with 30 DEG C；Reaction time range is 1~
8h, wherein being best with 4h.
In step A, the anhydrous solvent is anhydrous ether, anhydrous tetrahydro furan, wherein being best anti-with anhydrous ether
Answer solvent.
Synthetic route of the present invention is as shown in route two：
The theory of this method is to be based on：It is to obtain thermodynamics more using the thermodynamic stability of the molecule of reduction transiting product
Stable borneol rather than isoborneol.
The positive effect that the present invention has is：(1) it uses quantity of solvent small, has synthesis path simple and direct, reaction condition temperature
With conversion yields height.And the reducing agent for using BINAP to modify makes the higher outstanding advantages of optical purity of products.
The advantageous effect further illustrated the present invention below by way of experimental data：
The improvement of preparation method by the present invention, preparation method of the invention are better than using the prior art, are below comparison
Experiment：
| The molar ratio of chiral reagent and camphor | Conversion ratio | Yield | Opposite optical activity | |
| The method of the present invention | 1.39 | 89.1% | 42.6% | 79.2% |
| Use art methods | 2.57 | 82.4% | 24.6% | 69.2% |
Specific implementation mode
The present invention is further explained in the light of specific embodiments.
Embodiment 1：
It is sequentially added under nitrogen protection：Anhydrous ether, chiral reagent (R)-BINAP-H, camphor.Inventory ratio is 10ml
(96mmol)：0.95g(25mmol)：2.74g(18mmol).It is stirred to react 4h under the conditions of 30 DEG C, is tracked and is reacted with chromatography of gases
Progress.Extent of reaction is tracked with gas chromatograph, methanol 1.5mL is added dropwise after having reacted, it is allowed to stop reaction, then 2mol/ is added dropwise
The hydrochloric acid 5mL of L is stood.The ethanol solution of product separates upper organic layer with separatory funnel, lower aqueous layer extracted by ether 3 times,
It is dried with anhydrous magnesium sulfate after merging organic phase.Through washing, drying, distillation, distillation, the reaction production based on d-Bomeol is obtained
Object.Column chromatography for separation purifies to obtain 1.18g white crystals.Conversion ratio is 89.1%, yield 42.6%, and opposite optical activity is
79.2%.The opposite optical activity (the ratio x100% of product and pure natural borneol optical activity) of reduzate.
2~embodiment of embodiment 4：
Each embodiment is substantially the same manner as Example 1, the difference is that：Mole of chiral reagent (R)-BINAP-H, camphor
Than.The results are shown in Table 1 for the inventory ratio of each embodiment and the influence to reaction.In table, n is rubbing for chiral reagent and camphor
That ratio, G1,G2Respectively conversion ratio and yield, α are opposite optical activity.
Influences of the different n of table 1 to 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 known from Table 1, camphor conversion ratio increases with n and accordingly improves；But if n is continued growing, conversion ratio declines instead
Products collection efficiency shows identical trend, i.e., increases with n and improve；N is continued growing, yield declines instead.Consider reaction to turn
Rate, opposite optical activity, yield and cost, select n for 1.39.
Embodiment 5~9：
Each embodiment is substantially the same manner as Example 1, the difference is that：Reaction temperature and reaction time is respectively 30 DEG C, 0
DEG C and 2~8 hours.The results are shown in Table 2 for the temperature of each embodiment, time and influence to reaction.
The influence of 2 temperature of table and reaction time to 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 shown in Table 2, high temperature is conducive to improve conversion ratio, and favors low temperature is in raising enantioselectivity.Come from the reaction time
It sees, the opposite optical activity of reaction increases, but increasing degree and not very big.Consider when the reaction time is 4h, it is right
Rotation borneol yield reaches maximum value.
Embodiment 10：
Implement it is 10 substantially the same manner as Example 1, the difference is that：Solvent is anhydrous tetrahydro furan.Solvent is to reaction
The results are shown in Table 3 for influence.
Influence of 3 solvent of table to reaction
| Serial number | Solvent | G1/ (%) | G2/ (%) | α/(%) |
| 1 | Et2O | 89.1 | 42.6 | 79.2 |
| 10 | THF | 74.3 | 38.1 | 78.6 |
Anhydrous ether reaction effect is better than anhydrous tetrahydro furan as can be seen from Table 3.
Claims (8)
1. a kind of preparation method of d-Bomeol, characterized in that in organic solvent and chiral reagent (R)-BINAP-H is catalyst
In the presence of, it is 1~8 hour, wherein organic solvent, chiral reagent (R)-BINAP-H, camphor tree that natural camphor is reacted at 0~40 DEG C
The ratio of brain is 10~30ml:20~50mmol:18mmol.
2. preparation method as described in claim 1, characterized in that described chiral reagent (the R)-BINAP-H is by R- (+)-
BINAP modifies LiALH4And it obtains.
3. preparation method as described in claim 1, characterized in that the solvent, chiral reagent (R)-BINAP-H, camphor
Ratio be 10ml (96mmol)：0.95g(25mmol)：2.74g(18mmol).
4. preparation method as described in claim 1, characterized in that the reaction temperature is 30 DEG C.
5. preparation method as described in claim 1, characterized in that the reaction time is 4 hours.
6. preparation method as described in claim 1, characterized in that the organic solvent is ether or tetrahydrofuran.
7. preparation method as described in claim 1, characterized in that steps are as follows for the method：
Chiral reagent (R)-BINAP-H is added in anhydrous organic solvent under nitrogen protection, then adds natural camphor,
It is stirred to react 1~8h under the conditions of 0~40 DEG C, extent of reaction is tracked with gas-chromatography；Methanol is added dropwise after having reacted by it to stop
It only reacts, then dilute hydrochloric acid solution is added dropwise, stand, the solution of product separates upper organic layer, lower aqueous layer nothing with separatory funnel
The organic solvent of water extracts 3 times, is dried with anhydrous magnesium sulfate after merging organic phase, through washing, drying, distillation, distillation, obtains the right side
Revolve borneol.
8. preparation method as claimed in claim 7, characterized in that the organic solvent is anhydrous ether.
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| CN201810692617.2A CN108752164B (en) | 2018-06-29 | 2018-06-29 | Preparation method of d-borneol |
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| CN201810692617.2A CN108752164B (en) | 2018-06-29 | 2018-06-29 | Preparation method of d-borneol |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2801886A1 (en) * | 1999-12-02 | 2001-06-08 | Fournier Ind & Sante | New (R)- or (S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl derivatives useful for preparing metal complexes for use as asymmetric hydrogenation catalysts |
| CN101501099A (en) * | 2006-08-09 | 2009-08-05 | 共荣社化学株式会社 | Polymer having bis(diphenylphosphino)binaphthyl group |
| CN101906022A (en) * | 2010-07-26 | 2010-12-08 | 华侨大学 | Method for preparing borneol by using natural camphor powder as raw material |
| JP2015042632A (en) * | 2013-07-22 | 2015-03-05 | 日本曹達株式会社 | Ruthenium complex |
-
2018
- 2018-06-29 CN CN201810692617.2A patent/CN108752164B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2801886A1 (en) * | 1999-12-02 | 2001-06-08 | Fournier Ind & Sante | New (R)- or (S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl derivatives useful for preparing metal complexes for use as asymmetric hydrogenation catalysts |
| CN101501099A (en) * | 2006-08-09 | 2009-08-05 | 共荣社化学株式会社 | Polymer having bis(diphenylphosphino)binaphthyl group |
| CN101906022A (en) * | 2010-07-26 | 2010-12-08 | 华侨大学 | Method for preparing borneol by using natural camphor powder as raw material |
| JP2015042632A (en) * | 2013-07-22 | 2015-03-05 | 日本曹達株式会社 | Ruthenium complex |
Non-Patent Citations (7)
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