CN102219798A - Method for preparing diisopinocampheylborane and methoxydiisopinocampheylborane - Google Patents
Method for preparing diisopinocampheylborane and methoxydiisopinocampheylborane Download PDFInfo
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Abstract
The invention provides a method for preparing diisopinocampheylborane and methoxydiisopinocampheylborane, which comprises the following steps of: dripping (+)-alpha-pinene or (-)-alpha-pinene into borane tetrahydrofuran solution slowly, and adding glycol dimethyl ether into precipitated white solids for multiple times to obtain (-)-diisopinocampheylborane or (+)-diisopinocampheylborane; and reacting the (+)-diisopinocampheylborane and the (-)-diisopinocampheylborane with absolute methanol respectively to prepare (+)-B-methoxydiisopinocampheylborane and (-)-B-methoxydiisopinocampheylborane. The method is simple and convenient, stable and reliable, low in cost, high in purity and high in production rate.
Description
Technical field
The invention belongs to technical field of pharmaceutical chemistry, especially the preparation method of methoxyl group two different loose camphyl borines and diisopinocampheylchloroborane thiazolinyl borine.
Technical background
The medicine chirality is the important topic of new drug design, discovery, exploitation, listing and sale.Stereochemistry is pharmacological basic sides.The progress of three-dimensional selection bioanalysis causes solid is selected the new knowledge of pharmacodynamics and pharmacokinetics, makes and can distinguish enantiomorph to overall pharmaceutically-active Relative Contribution.When a kind of enantiomorph was undertaken certain interested pharmaceutical activity, its pairing enantiomorph may be non-activity or have some interesting activity, was a kind of antagonist of active enantiomorph or had possibility and need or unwanted not same-action.Consider these possibilities, use the pure medicine of stereochemistry as if to have more advantage, for example reduce total dosage, expansion treatment window, reduce variability and more accurate estimation dosage-response relation between individuality.These factors cause industry and code administration department to pay attention to single enantiomer more.U.S. FDA had at first formally been announced the chiral drug code administration guide that is entitled as " new stereoisomerism drug development statement of the policy " in 1992, and European Union has also announced the file of " chiral material research " in 1994 subsequently.According to estimates, the sales volume sustainable growth of world's single enantiomer form chiral drug.The market share of single enantiomer shape pharmaceutical preparation is increased to about 39% (1,519 hundred million dollars) in 2002 from 27% (74,400,000,000 dollars) in 1996.Anti-hepatitis b new drug Entecavir is the efabirenz in the antiviral, and this medicine can destroy duplicating of hepatitis B virus and quantity.Produce by Bristol Myers Squibb group, ratified and the medicine of the conduct control hepatitis B state of an illness through FDA Food and Drug Administration in 2005.Its most critical intermediate (1R, 2S)-2-(benzyloxymethyl)-3-cyclopentenes-1-is pure to be prepared from by diisopinocampheylchloroborane thiazolinyl borine in the patent of the present invention exactly.
The present invention mainly is the main raw material at reduction reaction in the chiral drug, is reduced to alcohol, two key and triple-linked reduction etc. as ketone.Methoxyl group two different loose camphyl borines and diisopinocampheylchloroborane thiazolinyl borine all are the strong and difficult chiral reduction reagent for preparing of reducing power, and the specific product title is respectively (+)-diisopinocampheylchloroborane thiazolinyl borine (CAS:21947-87-5), (-)-diisopinocampheylchloroborane thiazolinyl borine (CAS:21932-54-7), (+)-B-methoxyl group two different loose camphyl borines (CAS:99438-28-5) and (-)-B-methoxyl group two different loose camphyl borines (CAS:85134-98-1).They are the key intermediates in the chiral drug preparation process such as Entecavir, and these pharmaceutical intermediates mainly by import, cost an arm and a leg.The yet own preparation of the domestic company that has at present, but their employed raw material: 1, α-Pai Xi does not reach requirement owing to homemade, needs import yet; 2, the borine tetrahydrofuran solution also is import, and price is very high.If 3 borine dimethyl sulphides with import, price height not only, smell also is very unpleasant.
Summary of the invention
The objective of the invention is to overcome the deficiency of prior art, it is homemade, as the to have overcome imported raw material high shortcoming of cost that the preparation method of the diisopinocampheylchloroborane thiazolinyl borine that a kind of technology is simple, with low cost, purity is high, whole raw material are provided.
Another purpose of the present invention is to provide a kind of preparation method of methoxyl group two different loose camphyl borines.
The preparation method of diisopinocampheylchloroborane thiazolinyl borine of the present invention comprises following step:
(1) the borine tetrahydrofuran solution is cooled to-20 ℃～10 ℃ with the cryosel bath, to wherein slowly dripping (+)-α-Pai Xi (CAS:7785-70-8) or (-)-α-Pai Xi (CAS:7785-26-4), keeps temperature under the nitrogen protection less than 0 ℃; After being added dropwise to complete, under 0 ℃ of temperature, left standstill 10～24 hours, have a large amount of white solids to separate out;
(2) supernatant liquid is shifted, stay layer solid and, solid is heated to 40 ℃～80 ℃ together, allow it slowly cool to room temperature then to wherein adding glycol dimethyl ether; With the ice bath cooling, left standstill 10～24 hours then, have a large amount of white solids to separate out;
(3) repeating step (2) operating process is 2～3 times;
(4) in step (1), drip (+)-α-Pai Xi (CAS:7785-70-8) and make (-)-diisopinocampheylchloroborane thiazolinyl borine (CAS:21932-54-7); In step (1), drip (-)-α-Pai Xi (CAS:7785-26-4) and make (+)-diisopinocampheylchloroborane thiazolinyl borine (CAS:21947-87-5).
Described borine Preparation of lithium triethylborohydride method, it comprises the steps:
(1) under the condition of nitrogen protection, will put into there-necked flask with the tetrahydrofuran (THF) that the sodium silk was handled, to wherein adding sodium borohydride, be cooled to-25 ℃～-15 ℃; Then to wherein slowly dripping boron trifluoride ether solution; In the dropping process, keep temperature-25 ℃～-15 ℃;
(2) be added dropwise to complete after, allow temperature slowly rise to room temperature, leave standstill and separated out a large amount of solids in 10～24 hours, obtaining upper strata water white transparency liquid is exactly the borine tetrahydrofuran solution;
Wherein, the used composition of raw materials ratio of above-mentioned processing step is: tetrahydrofuran (THF) 3～4L, sodium borohydride 0.08～0.12kg, boron trifluoride ether solution 0.4～0.5L.
The preparation method of methoxyl group two different loose camphyl borines of the present invention comprises (+)-preparation of B-methoxyl group two different loose camphyl borines (CAS:99438-28-5) and (-) B-methoxyl group two different loose camphyl borines (CAS:85134-98-1).
(+)-diisopinocampheylchloroborane thiazolinyl borine (CAS:21947-87-5) that above-mentioned steps is made makes (+) B-methoxyl group two different loose camphyl borines (CAS:99438-28-5) with the anhydrous methanol reaction.
Concrete grammar comprises the steps:
(1) (+) that above-mentioned steps is made-diisopinocampheylchloroborane thiazolinyl borine (CAS:21947-87-5) nitrogen protection is dry down, after the accurate weighing, nitrogen protection is transferred in the there-necked flask in glove box, add anhydrous methanol to there-necked flask, under-20～0 ℃ of temperature, react;
(2) after reaction was finished, solvent evaporated with anhydrous n-hexane washing 2 times, obtained (+)-B-methoxyl group two different loose camphyl borines (CAS:99438-28-5).
(-)-diisopinocampheylchloroborane thiazolinyl borine (CAS:21932-54-7) that above-mentioned steps is made makes (-)-B-methoxyl group two different loose camphyl borines (CAS:85134-98-1) with the anhydrous methanol reaction.
Concrete grammar comprises the steps:
(1) (-) that above-mentioned steps is made-diisopinocampheylchloroborane thiazolinyl borine (CAS:21932-54-7) nitrogen protection is dry down, after the accurate weighing, nitrogen protection is transferred in the there-necked flask in glove box, add anhydrous methanol to there-necked flask, under-20～0 ℃ of temperature, react;
(2) after reaction was finished, solvent evaporated with anhydrous n-hexane washing 2 times, obtained (-)-B-methoxyl group two different loose camphyl borines (CAS:85134-98-1).
The present invention has following advantage: the inventive method is easy, process stabilizing is reliable, and is with low cost, purity height, productivity height.In the present invention, we use homemade firpene (ee value 55%～70%); To also have other raw materials all be homemade, overcome with high costs that imported raw material brings, and it is low also to have overcome product purity, the unsettled shortcoming of quality.Certainly, need to prove, in this patent,, use our production method, can reach the effect among the embodiment equally if use imported raw material.
Embodiment
The present invention is further described below in conjunction with specific embodiment.
Embodiment 1 borine Preparation of lithium triethylborohydride:
(1) tetrahydrofuran (THF) that 3.5L was handled is put into the 10L there-necked flask, to wherein adding the 100g sodium borohydride, is cooled to-25 ℃; To wherein slowly dripping the 400ml boron trifluoride ether solution, more than react nitrogen protection then, in the dropping process, keep temperature less than-15 ℃.
(2) be added dropwise to complete after, allow temperature slowly rise to room temperature, leave standstill 12 hours bottoms and have a large amount of solids and separate out, careful and lentamente the upper strata colourless transparent liquid is transferred in the 10L there-necked flask, make the borine tetrahydrofuran solution; Nitrogen protection is with standby.
Embodiment 2 borine Preparation of lithium triethylborohydride:
(1) tetrahydrofuran (THF) that 3.5L was handled is put into the 10L there-necked flask, and to wherein adding the 100g sodium borohydride, ice bath is cooled to-25 ℃; To wherein slowly dripping the 450ml boron trifluoride ether solution, more than react nitrogen protection then, in the dropping process, keep temperature less than-15 ℃.
(2) be added dropwise to complete after, allow temperature slowly rise to room temperature, leave standstill 12 hours bottoms and have a large amount of solids and separate out, careful and lentamente the upper strata colourless transparent liquid is transferred in the 10L there-necked flask, make the borine tetrahydrofuran solution; Nitrogen protection is with standby.
Embodiment 3 (+)-diisopinocampheylchloroborane thiazolinyl borine (CAS:21947-87-5) preparation:
(1) the borine tetrahydrofuran solution that embodiment 1 is made is bathed with cryosel and is cooled to-20 ℃～10 ℃, is homemade (-)-α-Pai Xi (CAS:7785-26-4) of 55% to wherein slowly dripping ee value under the nitrogen protection, and the maintenance temperature is less than 0 ℃; After being added dropwise to complete, under 0 ℃ of temperature, left standstill 12 hours, have a large amount of white solids to separate out;
(2) supernatant liquid is shifted, stay layer solid and, solid is heated to 50 ℃ together, allow it slowly cool to room temperature then to wherein adding glycol dimethyl ether; With the ice bath cooling, left standstill 12 hours then, have a large amount of white solids to separate out;
(3) repeating step (2) operating process is 3 times;
(4) obtain (+)-diisopinocampheylchloroborane thiazolinyl borine (CAS:21947-87-5) (ee 99.15%) of high purity and optical purity at last.
Embodiment 4 (+)-diisopinocampheylchloroborane thiazolinyl borine (CAS:21947-87-5) preparation:
(1) the borine tetrahydrofuran solution that embodiment 1 is made is bathed with cryosel and is cooled to-20 ℃～10 ℃, is homemade (-)-α-Pai Xi (CAS:7785-26-4) of 70% to wherein slowly dripping ee value under the nitrogen protection, and the maintenance temperature is less than 0 ℃; After being added dropwise to complete, under 0 ℃ of temperature, left standstill 12 hours, have a large amount of white solids to separate out;
(2) supernatant liquid is shifted, stay layer solid and, solid is heated to 50 ℃ together, allow it slowly cool to room temperature then to wherein adding glycol dimethyl ether; With the ice bath cooling, left standstill 12 hours then, have a large amount of white solids to separate out;
(3) repeating step (2) operating process is 3 times;
(4) obtain (+)-diisopinocampheylchloroborane thiazolinyl borine (CAS:21947-87-5) (ee 99.25%) of high purity and optical purity at last.
Embodiment 5 (-)-diisopinocampheylchloroborane thiazolinyl borine (CAS:21932-54-7) preparation:
(1) the borine tetrahydrofuran solution that embodiment 1 is made is bathed with cryosel and is cooled to-20 ℃～10 ℃, is homemade (+)-α-Pai Xi (CAS:7785-70-8) of 60% to wherein slowly dripping ee value under the nitrogen protection, and the maintenance temperature is less than 0 ℃; After being added dropwise to complete, under 0 ℃ of temperature, left standstill 10～24 hours, have a large amount of white solids to separate out;
(2) supernatant liquid is shifted, stay layer solid and, solid is heated to 50 ℃ together, allow it slowly cool to room temperature then to wherein adding glycol dimethyl ether; With the ice bath cooling, left standstill 12 hours then, have a large amount of white solids to separate out;
(3) repeating step (2) operating process is 3 times;
(4) obtain (-)-diisopinocampheylchloroborane thiazolinyl borine (CAS:21932-54-7) (ee 99.43%) of high purity and optical purity at last.
Embodiment 6 (-)-diisopinocampheylchloroborane thiazolinyl borine (CAS:21932-54-7) preparation:
(1) the borine tetrahydrofuran solution that embodiment 1 is made is bathed with cryosel and is cooled to-20 ℃～10 ℃, is homemade (+)-α-Pai Xi (CAS:7785-70-8) of 70% to wherein slowly dripping ee value under the nitrogen protection, and the maintenance temperature is less than 0 ℃; After being added dropwise to complete, under 0 ℃ of temperature, left standstill 10～24 hours, have a large amount of white solids to separate out;
(2) supernatant liquid is shifted, stay layer solid and, solid is heated to 50 ℃ together, allow it slowly cool to room temperature then to wherein adding glycol dimethyl ether; With the ice bath cooling, left standstill 12 hours then, have a large amount of white solids to separate out;
(3) repeating step (2) operating process is 3 times;
(4) obtain (-)-diisopinocampheylchloroborane thiazolinyl borine (CAS:21932-54-7) (ee 99.30%) of high purity and optical purity at last.
Embodiment 7 (+)-B-methoxyl group two different loose camphyl borine (CAS:99438-28-5) preparation methods comprises the steps:
(1) (+) that embodiment 2 is made-diisopinocampheylchloroborane thiazolinyl borine (CAS:21947-87-5) nitrogen protection is down dry, in glove box accurately behind the weighing 286.3g; , nitrogen protection is transferred in the 5L there-necked flask, adds the 4L anhydrous methanol to there-necked flask, reacts under-20～0 ℃ of temperature;
(2) after reaction was finished, solvent evaporated with anhydrous n-hexane washing 2 times, obtained (+)-B-methoxyl group two different loose camphyl borine (CAS:99438-28-5) 306g productive rate 96.8%.
Embodiment 8 (-) B-methoxyl group two different loose camphyl borine (CAS:85134-98-1) preparation methods comprise the steps:
(1) (-) that embodiment 3 is made-diisopinocampheylchloroborane thiazolinyl borine (CAS:21932-54-7) nitrogen protection is down dry, in glove box accurately behind the weighing 286.3g; , nitrogen protection is transferred in the 5L there-necked flask, adds the 4L anhydrous methanol to there-necked flask, reacts under-20～0 ℃ of temperature;
(2) after reaction was finished, solvent evaporated with anhydrous n-hexane washing 2 times, obtained (-)-B-methoxyl group two different loose camphyl borine (CAS:85134-98-1) 306g productive rate 96.8%.
The mensuration of embodiment 9 (+)-diisopinocampheylchloroborane thiazolinyl borine optical purity:
(1) gets (+)-diisopinocampheylchloroborane thiazolinyl borine (CAS:21947-87-5) solid 2g that obtains among the embodiment 3,, drip 2～3ml water under the stirring at room to wherein adding the 5ml glycol dimethyl ether; To the sodium hydroxide solution that wherein adds 5ml 2M, reacted 10 minutes then;
(2) to the hydrogen peroxide that wherein adds 5ml 30%, 50-60 ℃ was reacted 1 hour.
(3) cooling back separatory, organic phase is collected; Water ethyl acetate extraction 2 times; Merge organic phase, saturated common salt water washing 2 times, anhydrous magnesium sulfate drying;
(4) remove by filter anhydrous magnesium sulfate, collect solution;
(5) remove solvent ethylene glycol dme and ethyl acetate with Rotary Evaporators, the oily liquids that obtains Skellysolve A recrystallization.Obtain white solid;
(6) measure fusing point, 53-55 ℃;
(7) measure optically-active, be+35.4 °, ee value 99.15% (+35.7 ° (maximum c=10 benzene)).
The mensuration of embodiment 10 (-)-diisopinocampheylchloroborane thiazolinyl borine (CAS:21932-54-7) optical purity:
(1) gets (-)-diisopinocampheylchloroborane thiazolinyl borine (CAS:21932-54-7) solid 2g that obtains among the embodiment 5,, drip 2～3ml water under the stirring at room to wherein adding the 5ml glycol dimethyl ether; To the sodium hydroxide solution that wherein adds 5ml 2M, reacted 10 minutes then;
(2) to the hydrogen peroxide that wherein adds 5ml 30%, 50-60 ℃ was reacted 1 hour.
(3) cooling back separatory, organic phase is collected; Water ethyl acetate extraction 2 times; Merge organic phase, saturated common salt water washing 2 times, anhydrous magnesium sulfate drying;
(4) remove by filter anhydrous magnesium sulfate, collect solution;
(5) remove solvent ethylene glycol dme and ethyl acetate with Rotary Evaporators, the oily liquids that obtains Skellysolve A recrystallization.Obtain white solid;
(6) measure fusing point, 53-55 ℃;
(7) measure optically-active, be-35.5 °, ee value 99.43% (35.7 ° (maximum c=10 benzene)).
Claims (6)
1. the preparation method of diisopinocampheylchloroborane thiazolinyl borine comprises following step:
(1) the borine tetrahydrofuran solution is cooled to-20 ℃～10 ℃ with the cryosel bath, to wherein slowly dripping (+)-α-Pai Xi (CAS:7785-70-8) or (-)-α-Pai Xi (CAS:7785-26-4), keeps temperature under the nitrogen protection less than 0 ℃; After being added dropwise to complete, under 0 ℃ of temperature, left standstill 10～24 hours, have a large amount of white solids to separate out;
(2) supernatant liquid is shifted, stay layer solid and, solid is heated to 40 ℃～80 ℃ together, allow it slowly cool to room temperature then to wherein adding glycol dimethyl ether; With the ice bath cooling, left standstill 10～24 hours then, have a large amount of white solids to separate out;
(3) repeating step (2) operating process is 2～3 times;
(4) in step (1), drip (+)-α-Pai Xi (CAS:7785-70-8) and make (-)-diisopinocampheylchloroborane thiazolinyl borine (CAS:21932-54-7); In step (1), drip (-)-α-Pai Xi (CAS:7785-26-4) and make (+)-diisopinocampheylchloroborane thiazolinyl borine (CAS:21947-87-5).
2. according to the preparation method of the described diisopinocampheylchloroborane thiazolinyl of claim 1 borine, it is characterized in that: described borine Preparation of lithium triethylborohydride method, it comprises the steps:
(1) under the condition of nitrogen protection, will put into there-necked flask with the tetrahydrofuran (THF) that the sodium silk was handled, to wherein adding sodium borohydride, be cooled to-25 ℃～-15 ℃; Then to wherein slowly dripping boron trifluoride ether solution; In the dropping process, keep temperature-25 ℃～-15 ℃;
(2) be added dropwise to complete after, allow temperature slowly rise to room temperature, leave standstill and separated out a large amount of solids in 10～24 hours, obtaining upper strata water white transparency liquid is exactly the borine tetrahydrofuran solution;
Wherein, the used composition of raw materials ratio of above-mentioned processing step is: tetrahydrofuran (THF) 3～4L, sodium borohydride 0.08～0.12kg, boron trichloride diethyl ether solution 0.4～0.5L.
3. the preparation method of (+)-B-methoxyl group two different loose camphyl borines (CAS:99438-28-5) is characterized in that: (+)-diisopinocampheylchloroborane thiazolinyl borine (CAS:21947-87-5) and the anhydrous methanol reaction of claim 1 preparation are made (+)-B-methoxyl group two different loose camphyl borines (CAS:99438-28-5).
4. according to the preparation method of claim 3 described (+)-B-methoxyl group two different loose camphyl borines (CAS:99438-28-5), comprise the steps:
(1) (+)-diisopinocampheylchloroborane thiazolinyl borine (CAS:21947-87-5) nitrogen protection of claim 1 preparation is dry down, after the accurate weighing, nitrogen protection is transferred in the there-necked flask in glove box, add anhydrous methanol to there-necked flask, under-20～0 ℃ of temperature, react;
(2) after reaction was finished, solvent evaporated with anhydrous n-hexane washing 2 times, obtained (+)-B-methoxyl group two different loose camphyl borines (CAS:99438-28-5).
5. the preparation method of (-)-B-methoxyl group two different loose camphyl borines (CAS:85134-98-1) is characterized in that: (-)-diisopinocampheylchloroborane thiazolinyl borine (CAS:21932-54-7) and the anhydrous methanol reaction of claim 1 preparation are made (-)-B-methoxyl group two different loose camphyl borines (CAS:85134-98-1).
6. according to the preparation method of claim 5 described (-)-B-methoxyl group two different loose camphyl borines (CAS:85134-98-1), comprise the steps:
(1) (-)-diisopinocampheylchloroborane thiazolinyl borine (CAS:21932-54-7) nitrogen protection of claim 1 preparation is dry down, after the accurate weighing, nitrogen protection is transferred in the there-necked flask in glove box, add anhydrous methanol to there-necked flask, under-20～0 ℃ of temperature, react;
(2) after reaction was finished, solvent evaporated with anhydrous n-hexane washing 2 times, obtained (-)-B-methoxyl group two different loose camphyl borines (CAS:85134-98-1).
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103030658A (en) * | 2012-06-29 | 2013-04-10 | 山东威智医药工业有限公司 | Industrial production method of diisopinocampheyl chloroborane |
| CN103880785A (en) * | 2013-12-31 | 2014-06-25 | 无锡市华斌生物科技有限公司 | Industrial pollution-free production method of borane ester complex |
| WO2016008387A1 (en) * | 2014-07-18 | 2016-01-21 | 上海格物致知医药科技有限公司 | Method for preparing high purity borane gas and use of the borane gas |
| CN108329338A (en) * | 2016-06-30 | 2018-07-27 | 苏州大学 | A method of preparing borate |
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| CN1778805A (en) * | 2004-11-22 | 2006-05-31 | 浙江大学 | Production of methy borate alkane tetrahydrofuran complex solution |
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| CN1778805A (en) * | 2004-11-22 | 2006-05-31 | 浙江大学 | Production of methy borate alkane tetrahydrofuran complex solution |
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| GEORGE W. KABALKA, ET AL.: "A SIMPLE AND CONVENIENT METHOD FOR THE OXIDATION OF ORGANOBORANES USING SODIUM PERBORATE: (+)- ISOPINOCAMPHEOL", 《ORGANIC SYNTHESES, COLL.》, vol. 9, 31 December 1998 (1998-12-31), pages 116 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103030658A (en) * | 2012-06-29 | 2013-04-10 | 山东威智医药工业有限公司 | Industrial production method of diisopinocampheyl chloroborane |
| CN103030658B (en) * | 2012-06-29 | 2015-08-19 | 山东威智医药工业有限公司 | The industrialized preparing process of diisopinocampheylchloroborane |
| CN103880785A (en) * | 2013-12-31 | 2014-06-25 | 无锡市华斌生物科技有限公司 | Industrial pollution-free production method of borane ester complex |
| WO2016008387A1 (en) * | 2014-07-18 | 2016-01-21 | 上海格物致知医药科技有限公司 | Method for preparing high purity borane gas and use of the borane gas |
| CN108329338A (en) * | 2016-06-30 | 2018-07-27 | 苏州大学 | A method of preparing borate |
| CN108329338B (en) * | 2016-06-30 | 2019-09-10 | 苏州大学 | A method of preparing borate |
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