CN105618135A - Preparation method of chiral CBS catalyst - Google Patents
Preparation method of chiral CBS catalyst Download PDFInfo
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- CN105618135A CN105618135A CN201610010971.3A CN201610010971A CN105618135A CN 105618135 A CN105618135 A CN 105618135A CN 201610010971 A CN201610010971 A CN 201610010971A CN 105618135 A CN105618135 A CN 105618135A
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- cbs catalyst
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 239000012004 corey–bakshi–shibata catalyst Substances 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000001914 filtration Methods 0.000 claims abstract description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000001816 cooling Methods 0.000 claims abstract description 7
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 7
- -1 phenyl grignard reagent Chemical class 0.000 claims abstract description 7
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims abstract description 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims abstract description 6
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052796 boron Inorganic materials 0.000 claims abstract description 6
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 54
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 49
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 239000000047 product Substances 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000000706 filtrate Substances 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000000376 reactant Substances 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 238000010792 warming Methods 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- KLKFAASOGCDTDT-UHFFFAOYSA-N ethoxymethoxyethane Chemical compound CCOCOCC KLKFAASOGCDTDT-UHFFFAOYSA-N 0.000 claims description 4
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical group [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000012265 solid product Substances 0.000 claims description 3
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims description 2
- BLHLJVCOVBYQQS-UHFFFAOYSA-N ethyllithium Chemical compound [Li]CC BLHLJVCOVBYQQS-UHFFFAOYSA-N 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 2
- YSQFBLFEYNOIBW-UHFFFAOYSA-N lithium;cyclopropane Chemical compound [Li+].C1C[CH-]1 YSQFBLFEYNOIBW-UHFFFAOYSA-N 0.000 claims description 2
- XBEREOHJDYAKDA-UHFFFAOYSA-N lithium;propane Chemical compound [Li+].CC[CH2-] XBEREOHJDYAKDA-UHFFFAOYSA-N 0.000 claims description 2
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 2
- 238000011017 operating method Methods 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 14
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000002425 crystallisation Methods 0.000 abstract description 2
- 230000008025 crystallization Effects 0.000 abstract description 2
- OGCGXUGBDJGFFY-UHFFFAOYSA-N diphenylprolinol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)C1CCCN1 OGCGXUGBDJGFFY-UHFFFAOYSA-N 0.000 abstract description 2
- 230000006340 racemization Effects 0.000 abstract description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 abstract 2
- 150000001335 aliphatic alkanes Chemical class 0.000 abstract 1
- 150000001735 carboxylic acids Chemical class 0.000 abstract 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 238000010791 quenching Methods 0.000 abstract 1
- 230000000171 quenching effect Effects 0.000 abstract 1
- 239000005051 trimethylchlorosilane Substances 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 5
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 4
- 239000004327 boric acid Substances 0.000 description 4
- ONIBWKKTOPOVIA-SCSAIBSYSA-N D-Proline Chemical compound OC(=O)[C@H]1CCCN1 ONIBWKKTOPOVIA-SCSAIBSYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000011261 inert gas Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 3
- VMKAFJQFKBASMU-QGZVFWFLSA-N (r)-2-methyl-cbs-oxazaborolidine Chemical compound C([C@@H]12)CCN1B(C)OC2(C=1C=CC=CC=1)C1=CC=CC=C1 VMKAFJQFKBASMU-QGZVFWFLSA-N 0.000 description 2
- HVVNJUAVDAZWCB-YFKPBYRVSA-N [(2s)-pyrrolidin-2-yl]methanol Chemical compound OC[C@@H]1CCCN1 HVVNJUAVDAZWCB-YFKPBYRVSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- NRTLTGGGUQIRRT-UHFFFAOYSA-N triethylazanium;bromide Chemical compound [Br-].CC[NH+](CC)CC NRTLTGGGUQIRRT-UHFFFAOYSA-N 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- IUZGJZUZTFYVLF-UHFFFAOYSA-N Cl[SiH3].[N] Chemical compound Cl[SiH3].[N] IUZGJZUZTFYVLF-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- IWCVDCOJSPWGRW-UHFFFAOYSA-M magnesium;benzene;chloride Chemical compound [Mg+2].[Cl-].C1=CC=[C-]C=C1 IWCVDCOJSPWGRW-UHFFFAOYSA-M 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000012946 outsourcing Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0272—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255
- B01J31/0275—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255 also containing elements or functional groups covered by B01J31/0201 - B01J31/0269
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of a chiral CBS catalyst. The preparation method comprises the following steps: by adopting proline as a raw material, protecting nitrogen and carboxylic acid by trimethyl chlorosilane, and reacting with a phenyl grignard reagent to obtain diphenyl prolinol; then reacting with boron trihalide and lithium alkylide, after the reaction is ended, quenching by acetic acid, performing backflow filtering on alkane, and performing cooling crystallization to obtain a chiral product. The process is short in synthetic route, the operation is simple, the raw material is easy to get, the yield and the product purity are high, racemization of a chiral center is avoided in the whole preparation process, and the method is more suitable for large-scale production.
Description
Technical field
The preparation method that the present invention relates to a kind of chirality CBS catalyst, belongs to medicine intermediate synthesis field.
Background technology
Chipal compounds has been widely present in a lot of marketed drug, and route of synthesis generally has fractionation and two kinds of methods of asymmetric reduction. CBS catalyst is as one of reducing carbonyl method becoming chiral alcohol, owing to its enantioselectivity is high, is recently increasingly subject to the extensive favor of academia and industrial quarters.
The current usual way of synthesis of CBS catalyst is all: the Prolinol of chirality obtains solid product after obtaining toluene solution or high vacuum distillation with boric acid or boric acid trimer after reflux in toluene dehydration. The synthetic method of chirality Prolinol is more; employing proline sets out; adopt methylchloroformate to protect nitrogen and carboxylic acid simultaneously; or stepped approach adopts Boc to protect nitrogen; carboxylic acid is become methyl ester by thionyl chloride; or adopt phosgene to become lactonic ring, obtain after direct or deprotection after react with Grignard reagent or lithium reagent subsequently.
There is following defect in above-mentioned synthetic method: agents useful for same relates to toxic articles, buys and is subject to control, or reactions steps is long, complex operation, product variable color in high vacuum distillation product process, or need outsourcing boric acid, adds extra cost.
Summary of the invention
In order to overcome above-mentioned deficiency, the preparation method that the present invention provides a kind of chirality CBS catalyst. Adopting D or L-PROLINE is raw material, first reacts with trimethyl base chlorosilane nitrogen and carboxylic acid are protected into estersil simultaneously, react with phenyl grignard reagent more subsequently, obtain diphenylprolinol after acid hydrolysis deprotection. Then, after reacting with boron trihalides, alkyl lithium reagents attack, reaction is distilled after terminating acetic acid cancellation, adds normal hexane or normal heptane backflow, filtered while hot cooling crystallize, obtains chirality CBS catalyst sterling after again filtering again.
The preparation method of a kind of chirality CBS catalyst, it is characterised in that include following operating procedure:
The first step: control reaction temperature at-10 DEG C to 10 DEG C, proline, 2.0-5.0 equivalent organic base and solvent are mixed, dropping 2.0-2.5 equivalent trim,ethylchlorosilane, after completion of the reaction, it is evaporated reactant liquor, after adding toluene, filtering out the salt produced in course of reaction, filtrate is directly used in the next step after being evaporated;
Second step: above-mentioned first step product is added in oxolane, it is cooled to-10 DEG C to 0 DEG C, it is slowly added dropwise into 2.0-3.0 equivalent phenyl grignard reagent, after reaction terminates, add hydrochloric acid reaction, be filtrated to get off-white color solid, add 5-15% sodium hydroxide and adjust PH=10-12, distilling after dichloromethane extraction, normal heptane is pulled an oar, and is filtrated to get chirality diaryl Prolinol;
3rd step: by above-mentioned second step product white solid, after adding solvent and the dissolving of 2.0-3.0 equivalent organic base, control reaction temperature-10 DEG C to 0 DEG C, it is slowly added to 1.0-1.1 equivalent boron trihalides, after reaction terminates, being evaporated reactant liquor, add toluene and filter out the salt that reaction generates, filtrate is directly used in the next step after being evaporated;
4th step: above-mentioned 3rd step product is added in anhydrous ether solvent, is cooled to-10 DEG C to 0 DEG C, is slowly added dropwise into 1.0-1.2 equivalent lithium alkylide; after reaction terminates addition acetic acid; solvent is distilled to dry, adds normal hexane or normal heptane, be warming up to backflow; airtight kieselguhr filters while hot; filtrate nitrogen protection borehole cooling, to-10 DEG C to 0 DEG C, precipitates out white crystal, after airtight filtration; obtain chirality CBS solid product, can be configured to different solution forms as required.
Further, in technique scheme, the first step and in the 3rd step, solvent is selected from dichloromethane or 1,2-dichloroethanes.
Further, in technique scheme, the first step and in the 3rd step, organic base is selected from triethylamine, diisopropyl ethyl amine or pyridine.
Further, in technique scheme, in the first step, proline is selected from D type or L-type, D type second step corresponding to L-type and the 4th step product chirality respectively R configuration and S configuration.
Further, in technique scheme, in the 3rd step, boron trihalides is selected from boron chloride or Boron tribromide.
Further, in technique scheme, in the 4th step, anhydrous ether solvent is selected from ether, oxolane, 2-methyltetrahydrofuran, cyclopentyl-methyl ether or diethoxymethane.
Further, in technique scheme, in the 4th step, lithium alkylide is selected from lithium methide, ethyl-lithium, n-pro-pyl lithium, cyclopropyl lithium, n-BuLi or s-butyl lithium.
Further, in technique scheme, in the 4th step, different solutions form is selected from toluene, oxolane or dichloromethane solution.
Invention beneficial effect:
This technique adopts raw material cheap and easy to get, the preparation of boric acid is combined with Product formation, shortens reactions steps, simplifies operation, and in whole preparation process, chiral centre is without racemization.
This technique can obtain White crystal product by simple crystallization, can be configured to the various ways such as toluene, oxolane or dichloromethane solution as required and uses, meets the different market demands.
Detailed description of the invention:
Embodiment 1:
The synthesis of S-MeCBS:
The first step: in reaction bulb, it is sequentially added into L-PROLINE (115g, 1mol), triethylamine (253g, 2.5mol) and dichloromethane (1600mL), it is cooled to-5 DEG C to 5 DEG C, dropping trim,ethylchlorosilane (239g, 2.2mol), after completion of the reaction, it is evaporated reactant liquor, after adding 650mL toluene, filtering out generation triethylamine hydrochloride in course of reaction, filtrate is directly used in the next step after being evaporated;
Second step: above-mentioned first step product is added in 850mL oxolane, it is cooled to-10 DEG C to 0 DEG C, it is slowly added dropwise into 2M phenyl-magnesium-chloride (1.1L, 2.2mol), after reaction terminates, add 15% aqueous hydrochloric acid solution and adjust PH=1-2, filter the off-white color solid generated, add 15% sodium hydroxide and adjust PH=10-12, after dichloromethane (1500mL) extracts four times, merge organic layer, anhydrous magnesium sulfate dries, and distills organic layer, and 650mL normal heptane is pulled an oar, it is filtrated to get 200g white crystalline solid S-diphenyl Prolinol, HPLC:99.2%;
3rd step: by above-mentioned S-diphenyl Prolinol (200g, 0.79mol), after adding dichloromethane (1800mL) and triethylamine (177g, 1.75mol) dissolving, control reaction temperature-10 DEG C to 0 DEG C, it is slowly added to Boron tribromide (205g, 0.82mol), reaction is evaporated reactant liquor after terminating, adding 820mL toluene and filter out reaction generation triethylamine hydrobromide, filtrate is directly used in the next step after being evaporated;
4th step: above-mentioned 3rd step product is added in diethoxymethane, it is cooled to-10 DEG C to 0 DEG C, it is slowly added dropwise into 3.0M lithium methide (283mL, diethoxymethane solution 0.85mol), reaction terminate to add in acetic acid and after, solvent is distilled to dry, add 840mL normal heptane, it is warming up to backflow, after distilling out about 40-50mL normal heptane, airtight kieselguhr filters while hot, filtrate inert gas shielding borehole cooling is to-10 DEG C to 0 DEG C, white crystal is precipitated out after stirring, after airtight filtration, obtain 169g product S-MeCBS, four step total recoverys 61%, GC:98.3%, HNMR: > 97%, add 455mL toluene and be configured to 1M toluene solution.
Embodiment 2:
The synthesis of R-MeCBS:
The first step: in reaction bulb, it is sequentially added into D-PROLINE (115g, 1mol), triethylamine (253g, 2.5mol) and dichloromethane (1600mL), it is cooled to-10 DEG C to-5 DEG C, dropping trim,ethylchlorosilane (239g, 2.2mol), after completion of the reaction, it is evaporated reactant liquor, after adding 650mL toluene, filtering out generation triethylamine hydrochloride in course of reaction, filtrate is directly used in the next step after being evaporated;
Second step: above-mentioned first step product is added in 850mL oxolane, it is cooled to-10 DEG C to 0 DEG C, it is slowly added dropwise into 1M phenyl-magnesium-bromide (2.2L, 2.2mol), after reaction terminates, add 15% aqueous hydrochloric acid solution and adjust PH=1-2, filter the off-white color solid generated, add 15% sodium hydroxide and adjust PH=10-12, after dichloromethane (1700mL) extracts four times, merge organic layer, anhydrous magnesium sulfate dries, and distills organic layer, and 650mL normal heptane is pulled an oar, it is filtrated to get 193g white crystalline solid R-diphenyl Prolinol, HPLC:99.4%;
3rd step: by above-mentioned R-diphenyl Prolinol (193g, 0.76mol), after adding dichloromethane (1800mL) and triethylamine (177g, 1.75mol) dissolving, control reaction temperature-10 DEG C to 0 DEG C, it is slowly added to Boron tribromide (205g, 0.82mol), reaction is evaporated reactant liquor after terminating, adding 850mL toluene and filter out reaction generation triethylamine hydrobromide, filtrate is directly used in the next step after being evaporated;
4th step: above-mentioned 3rd step product is added in 2-methyltetrahydrofuran, it is cooled to-10 DEG C to 0 DEG C, it is slowly added dropwise into 1.0M lithium methide (780mL, 2-methyltetrahydrofuran solution 0.78mol), reaction terminate to add in acetic acid and after, solvent is distilled to dry, add 880mL normal heptane, it is warming up to backflow, after distilling out about 50-60mL normal heptane, airtight kieselguhr filters while hot, filtrate inert gas shielding borehole cooling is to-10 DEG C to 0 DEG C, white crystal is precipitated out after stirring, after airtight filtration, obtain 158g product R-MeCBS, four step total recoverys 57%, GC:98.6%, HNMR: > 97%, it is configured to 1M dichloromethane solution after adding dichloromethane.
Embodiment 3:
The synthesis of R-BuCBS:
The first step: in reaction bulb, it is sequentially added into D-PROLINE (115g, 1mol), pyridine (172g, 2.2mol) and dichloromethane (1600mL), it is cooled to-5 DEG C to 5 DEG C, dropping trim,ethylchlorosilane (239g, 2.2mol), after completion of the reaction, it is evaporated reactant liquor, after adding 700mL toluene, filtering out generation pyridine hydrochloride in course of reaction, filtrate is directly used in the next step after being evaporated;
Second step: above-mentioned first step product is added in 850mL oxolane, it is cooled to-10 DEG C to 0 DEG C, it is slowly added dropwise into 1M phenyl-magnesium-bromide (2.2L, 2.2mol), after reaction terminates, add 10% aqueous hydrochloric acid solution and adjust PH=1-2, filter the off-white color solid generated, add 10% sodium hydroxide and adjust PH=10-12, after dichloromethane (1800mL) extracts four times, merge organic layer, anhydrous magnesium sulfate dries, and distills organic layer, and 650mL normal heptane is pulled an oar, it is filtrated to get 202g white crystalline solid R-diphenyl Prolinol, HPLC:99.1%;
3rd step: by above-mentioned R-diphenyl Prolinol (202g, 0.80mol), after adding dichloromethane (1800mL) and triethylamine (177g, 1.75mol) dissolving, control reaction temperature-10 DEG C to 0 DEG C, it is slowly introducing boron chloride (98.4g, 0.84mol), reaction is evaporated reactant liquor after terminating, adding 850mL toluene and filter out reaction generation triethylamine hydrochloride, filtrate is directly used in the next step after being evaporated;
4th step: above-mentioned 3rd step product is added in oxolane, it is cooled to-10 DEG C to 0 DEG C, it is slowly added dropwise into 2.5M n-BuLi (328mL, hexane solution 0.82mol), reaction terminate to add in acetic acid and after, solvent is distilled to dry, add 800mL normal heptane, it is warming up to backflow, after distilling out about 30-40mL normal heptane, airtight kieselguhr filters while hot, filtrate inert gas shielding borehole cooling is to-10 DEG C to 0 DEG C, white crystal is precipitated out after stirring, after airtight filtration, obtain 176g product R-BuCBS, four step total recoverys 55%, GC:98.8%, HNMR: > 97%.
Claims (8)
1. the preparation method of a chirality CBS catalyst, it is characterised in that include following operating procedure:
The first step: control reaction temperature at-10 DEG C to 10 DEG C, proline, 2.0-5.0 equivalent organic base and solvent are mixed, dropping 2.0-2.5 equivalent trim,ethylchlorosilane, after completion of the reaction, it is evaporated reactant liquor, after adding toluene, filtering out the salt produced in course of reaction, filtrate is directly used in the next step after being evaporated;
Second step: above-mentioned first step product is added in oxolane, it is cooled to-10 DEG C to 0 DEG C, it is slowly added dropwise into 2.0-3.0 equivalent phenyl grignard reagent, after reaction terminates, add hydrochloric acid reaction, be filtrated to get off-white color solid, add 5-15% sodium hydroxide and adjust PH=10-12, distilling after dichloromethane extraction, normal heptane is pulled an oar, and is filtrated to get chirality diaryl Prolinol;
3rd step: by above-mentioned second step product white solid, after adding solvent and the dissolving of 2.0-3.0 equivalent organic base, control reaction temperature-10 DEG C to 0 DEG C, it is slowly added to 1.0-1.1 equivalent boron trihalides, after reaction terminates, being evaporated reactant liquor, add toluene and filter out the salt that reaction generates, filtrate is directly used in the next step after being evaporated;
4th step: above-mentioned 3rd step product is added in anhydrous ether solvent, is cooled to-10 DEG C to 0 DEG C, is slowly added dropwise into 1.0-1.2 equivalent lithium alkylide; after reaction terminates addition acetic acid; solvent is distilled to dry, adds normal hexane or normal heptane, be warming up to backflow; airtight kieselguhr filters while hot; filtrate nitrogen protection borehole cooling, to-10 DEG C to 0 DEG C, precipitates out white crystal, after airtight filtration; obtain chirality CBS solid product, can be configured to different solution forms as required.
2. the preparation method of a kind of chirality CBS catalyst according to claim 1, it is characterised in that: the first step and in the 3rd step, solvent is selected from dichloromethane or 1,2-dichloroethanes.
3. the preparation method of a kind of chirality CBS catalyst according to claim 1, it is characterised in that: the first step and in the 3rd step, organic base is selected from triethylamine, diisopropyl ethyl amine or pyridine.
4. the preparation method of a kind of chirality CBS catalyst according to claim 1, it is characterised in that: in the first step, proline is selected from D type or L-type, D type second step corresponding to L-type and the 4th step product chirality respectively R configuration and S configuration.
5. the preparation method of a kind of chirality CBS catalyst according to claim 1, it is characterised in that: in the 3rd step, boron trihalides is selected from boron chloride or Boron tribromide.
6. the preparation method of a kind of chirality CBS catalyst according to claim 1, it is characterised in that: in the 4th step, anhydrous ether solvent is selected from ether, oxolane, 2-methyltetrahydrofuran, cyclopentyl-methyl ether or diethoxymethane.
7. the preparation method of a kind of chirality CBS catalyst according to claim 1, it is characterised in that: in the 4th step, lithium alkylide is selected from lithium methide, ethyl-lithium, n-pro-pyl lithium, cyclopropyl lithium, n-BuLi or s-butyl lithium.
8. the preparation method of a kind of chirality CBS catalyst according to claim 1, it is characterised in that: in the 4th step, different solutions form is selected from toluene, oxolane or dichloromethane solution.
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