CN102219798A - Method for preparing diisopinocampheylborane and methoxydiisopinocampheylborane - Google Patents
Method for preparing diisopinocampheylborane and methoxydiisopinocampheylborane Download PDFInfo
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- CN102219798A CN102219798A CN2010101457745A CN201010145774A CN102219798A CN 102219798 A CN102219798 A CN 102219798A CN 2010101457745 A CN2010101457745 A CN 2010101457745A CN 201010145774 A CN201010145774 A CN 201010145774A CN 102219798 A CN102219798 A CN 102219798A
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- MPQAQJSAYDDROO-VMAIWCPRSA-N bis[(1r,3r,4s,5r)-4,6,6-trimethyl-3-bicyclo[3.1.1]heptanyl]boron Chemical compound C([C@H]([C@@H]1C)[B][C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@H]2C)[C@H]2C(C)(C)[C@@H]1C2 MPQAQJSAYDDROO-VMAIWCPRSA-N 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 title claims abstract description 17
- XOKSLPVRUOBDEW-UHFFFAOYSA-N pinane of uncertain configuration Natural products CC1CCC2C(C)(C)C1C2 XOKSLPVRUOBDEW-UHFFFAOYSA-N 0.000 title abstract 2
- 239000007787 solid Substances 0.000 claims abstract description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 33
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims abstract description 9
- GRWFGVWFFZKLTI-RKDXNWHRSA-N (+)-α-pinene Chemical compound CC1=CC[C@H]2C(C)(C)[C@@H]1C2 GRWFGVWFFZKLTI-RKDXNWHRSA-N 0.000 claims abstract description 7
- 229910000085 borane Inorganic materials 0.000 claims description 56
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 56
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 46
- 238000002360 preparation method Methods 0.000 claims description 29
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 13
- 239000007788 liquid Substances 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 11
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- IAQXEQYLQNNXJC-UHFFFAOYSA-N methoxy-bis(4,6,6-trimethyl-3-bicyclo[3.1.1]heptanyl)borane Chemical compound C1C(C2(C)C)CC2C(C)C1B(OC)C(C1C)CC2C(C)(C)C1C2 IAQXEQYLQNNXJC-UHFFFAOYSA-N 0.000 claims description 10
- 239000002994 raw material Substances 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 8
- -1 lithium triethylborohydride Chemical compound 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 239000006228 supernatant Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 238000005303 weighing Methods 0.000 claims description 6
- 229910015900 BF3 Inorganic materials 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000012545 processing Methods 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- MPQAQJSAYDDROO-UHFFFAOYSA-N bis(4,6,6-trimethyl-3-bicyclo[3.1.1]heptanyl)boron Chemical compound CC1C(C2(C)C)CC2CC1[B]C(C1C)CC2C(C)(C)C1C2 MPQAQJSAYDDROO-UHFFFAOYSA-N 0.000 abstract 4
- GRWFGVWFFZKLTI-UHFFFAOYSA-N rac-alpha-Pinene Natural products CC1=CCC2C(C)(C)C1C2 GRWFGVWFFZKLTI-UHFFFAOYSA-N 0.000 abstract 3
- 229930006718 (+)-alpha-pinene Natural products 0.000 abstract 1
- 229930006720 (-)-alpha-pinene Natural products 0.000 abstract 1
- WTARULDDTDQWMU-UHFFFAOYSA-N Pseudopinene Natural products C1C2C(C)(C)C1CCC2=C WTARULDDTDQWMU-UHFFFAOYSA-N 0.000 abstract 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 abstract 1
- IAQXEQYLQNNXJC-JPDDNCELSA-N methoxy-bis[(1s,3s,4r,5s)-4,6,6-trimethyl-3-bicyclo[3.1.1]heptanyl]borane Chemical compound C([C@@H]([C@H]1C)B([C@@H]2[C@H]([C@@H]3C[C@@H](C3(C)C)C2)C)OC)[C@@H]2C(C)(C)[C@H]1C2 IAQXEQYLQNNXJC-JPDDNCELSA-N 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000008676 import Effects 0.000 description 4
- 238000012423 maintenance Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 3
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229960000980 entecavir Drugs 0.000 description 2
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical class CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 238000011953 bioanalysis Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
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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| 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 kind of method for preparing boric acid ester |
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| CN1778805A (en) * | 2004-11-22 | 2006-05-31 | 浙江大学 | The preparation method of borane tetrahydrofuran complex solution |
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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 kind of method for preparing boric acid ester |
| CN108329338B (en) * | 2016-06-30 | 2019-09-10 | 苏州大学 | A method of preparing borate |
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