CN108948057A - The method for preparing cyclopropylboronic acid based on Cabbeen insertion - Google Patents
The method for preparing cyclopropylboronic acid based on Cabbeen insertion Download PDFInfo
- Publication number
- CN108948057A CN108948057A CN201811262292.0A CN201811262292A CN108948057A CN 108948057 A CN108948057 A CN 108948057A CN 201811262292 A CN201811262292 A CN 201811262292A CN 108948057 A CN108948057 A CN 108948057A
- Authority
- CN
- China
- Prior art keywords
- cyclopropylboronic acid
- preparing
- cyclopropylboronic
- acid according
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims abstract description 23
- 238000003780 insertion Methods 0.000 title claims abstract description 6
- 230000037431 insertion Effects 0.000 title claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- -1 methylene carbene Chemical class 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 claims description 13
- 229910052751 metal Inorganic materials 0.000 claims description 9
- 239000002184 metal Substances 0.000 claims description 9
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 claims description 8
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 7
- 229940043237 diethanolamine Drugs 0.000 claims description 7
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 5
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical group [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000004327 boric acid Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- YCIMNLLNPGFGHC-UHFFFAOYSA-N o-dihydroxy-benzene Natural products OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- 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
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 150000001642 boronic acid derivatives Chemical class 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 239000003863 metallic catalyst Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 239000003054 catalyst Substances 0.000 claims 1
- RWMJRMPOKXSHHI-UHFFFAOYSA-N ethenylboron Chemical compound [B]C=C RWMJRMPOKXSHHI-UHFFFAOYSA-N 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- HHRKFGMMAHZWIM-UHFFFAOYSA-N ethenoxyboronic acid Chemical compound OB(O)OC=C HHRKFGMMAHZWIM-UHFFFAOYSA-N 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- YFXCNIVBAVFOBX-UHFFFAOYSA-N ethenylboronic acid Chemical class OB(O)C=C YFXCNIVBAVFOBX-UHFFFAOYSA-N 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- BMQDAIUNAGXSKR-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid Chemical compound CC(C)(O)C(C)(C)OB(O)O BMQDAIUNAGXSKR-UHFFFAOYSA-N 0.000 description 5
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 5
- 238000000605 extraction Methods 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- LKXYJYDRLBPHRS-UHFFFAOYSA-N bromocyclopropane Chemical compound BrC1CC1 LKXYJYDRLBPHRS-UHFFFAOYSA-N 0.000 description 3
- 238000005336 cracking Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- GAGHFJHBGGAFDQ-UHFFFAOYSA-N cyclopropylboron Chemical compound [B]C1CC1 GAGHFJHBGGAFDQ-UHFFFAOYSA-N 0.000 description 2
- 238000006114 decarboxylation reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 229910000474 mercury oxide Inorganic materials 0.000 description 2
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- UPZFLZYXYGBAPL-UHFFFAOYSA-N 2-ethyl-2-methyl-1,3-dioxolane Chemical compound CCC1(C)OCCO1 UPZFLZYXYGBAPL-UHFFFAOYSA-N 0.000 description 1
- ZZPNDIHOQDQVNU-UHFFFAOYSA-N 2-hydroxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OB(O)OC1(C)C ZZPNDIHOQDQVNU-UHFFFAOYSA-N 0.000 description 1
- QGNZMQZSDSGSKL-UHFFFAOYSA-N 4-ethyl-n-nitrosobenzenesulfonamide Chemical compound CCC1=CC=C(S(=O)(=O)NN=O)C=C1 QGNZMQZSDSGSKL-UHFFFAOYSA-N 0.000 description 1
- 235000001674 Agaricus brunnescens Nutrition 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- TWJVNKMWXNTSAP-UHFFFAOYSA-N azanium;hydroxide;hydrochloride Chemical compound [NH4+].O.[Cl-] TWJVNKMWXNTSAP-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- AUNNTHNQWVSPPP-UHFFFAOYSA-N cyclopropyloxyboronic acid Chemical compound OB(O)OC1CC1 AUNNTHNQWVSPPP-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 239000003344 environmental pollutant Substances 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005360 mashing Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229960005112 moxifloxacin hydrochloride Drugs 0.000 description 1
- IDIIJJHBXUESQI-DFIJPDEKSA-N moxifloxacin hydrochloride Chemical compound Cl.COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 IDIIJJHBXUESQI-DFIJPDEKSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 229960003296 pitavastatin calcium Drugs 0.000 description 1
- RHGYHLPFVJEAOC-FFNUKLMVSA-L pitavastatin calcium Chemical compound [Ca+2].[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1.[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 RHGYHLPFVJEAOC-FFNUKLMVSA-L 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The invention discloses a kind of methods for preparing cyclopropylboronic acid based on Cabbeen insertion, belong to technical field of organic synthesis.Using following steps: (1) vinyl borate (or salt) and methylene carbene reaction become cyclopropylboronic acid ester；(2) cyclopropylboronic acid ester (salt) resolves into cyclopropylboronic acid.Reaction condition of the present invention is mild, and raw material is easy to get, easy to operate, is easy to purify, and is suitable for being mass produced, and provides a new way for cyclopropylboronic acid synthesis.
Description
Technical field
The present invention relates to a kind of methods for preparing cyclopropylboronic acid, and in particular to prepares cyclopropyl boron based on Cabbeen insertion
The method of acid belongs to the intermediate synthesis field of pharmaceutical chemistry.
Background technique
Cyclopropyl structure unit is widely present in the structure of some drugs, such as blood lipid-lowering medicine pitavastatin calcium tablet and anti-
Mushroom drug: Ciprofloxacin, moxifloxacin hydrochloride magnitude.Cyclopropyl connects the upper group due to the particularity of structure in the molecule
Most simple effective method exactly is coupled to obtain using the Suzuki of cyclopropylboronic acid and aryl halides.
As the important source material of cyclopropyl, the synthesis of cyclopropylboronic acid obtains more and more pay attention to.Cyclopropyl boron
Acid is mainly reacted by Cyclopropyl Bromide with metal Mg or Li, is formed cyclopropyl metal carbonyl compound, is then reacted with borate,
Gained cyclopropylboronic acid ester is hydrolyzed, and generates cyclopropylboronic acid.
This method haves the defects that several important: being starting material Cyclopropyl Bromide first, often goes out from ethylene-acetic acid
Hair, obtains, toxicity is big, seriously polluted through mercury oxide/bromine decarboxylation bromination；Secondly, the pairs such as autoimmunity syndrome can occur for metal reagent
Reaction, causes yield low；In addition, metal reagent itself be easy to cause security risk to moisture and air-sensitive.
Leng Yan state etc. reports another method for preparing cyclopropylboronic acid in CN105001249A.From cyclopropyl first
Acid sets out, and in the solution after being added to n-BuLi and organic base reaction at low temperature, borating agent is then added, obtains 1- carboxylic
Cyclopropyl boric acid heats decarboxylation, forms cyclopropylboronic acid tripolymer after dehydration, obtains cyclopropylboronic acid after hydrolysis.
Although this method raw material is easy to get, but still needs (- 70 DEG C) the metal reagent butyl using danger under ultralow temperature
Lithium, severe reaction conditions and there are security risk are not suitable for being mass produced.
Summary of the invention
The shortcomings that in order to overcome prior art, the present invention use vinyl boron ester (salt) for raw material, are inserted by Cabbeen anti-
Cyclopropylboronic acid ester should be obtained, using hydrolysis, generates cyclopropylboronic acid.
The method for preparing cyclopropylboronic acid based on Cabbeen insertion, which comprises the steps of: 1) by vinyl
Boronic acid derivatives and methylene carbene reaction generate cyclopropylboronic acid derivative；2) cyclopropylboronic acid derivative, by hydrolyzing,
Obtain cyclopropylboronic acid.
Reaction equation is expressed as follows:
Further, in the above-mentioned technical solutions, boronic acid derivatives be selected from pinacol borate, boric acid neopentyl glycol ester,
Boric acid catechol ester or three potassium fluoborate salt.
Further, in the above-mentioned technical solutions, step 1 is preferably carried out using in micro passage reaction.
Further, in the above-mentioned technical solutions, Cabbeen in step 1, by diazomethane generation or methylene halide and alkane
Alkylmetal reagent reaction generates.
When further, in the above-mentioned technical solutions, using diazomethane, the catalysis of 0.0001-0.5 equivalents of metal is added
Agent, metallic catalyst preferably are selected from palladium acetate.
Further, in the above-mentioned technical solutions, methylene halide and alkylmetal reagent be respectively selected from diiodomethane and
Diethyl zinc.
Further, in the above-mentioned technical solutions, diiodomethane, diethyl zinc and vinyl boronic acids derivative molar ratio are
0.8-2.0:0.8-2.0:1.
Further, in the above-mentioned technical solutions, the 1) step carried out in reaction dissolvent, reaction dissolvent is selected from aromatic hydrocarbons, alkane
Hydrocarbon or ethers.
Further, in the above-mentioned technical solutions, the 2) in step, hydrolysis using sodium metaperiodate, inorganic acid, diethanol amine,
It is completed under inorganic base or silica gel neutrallty condition.
Further, in the above-mentioned technical solutions, 2) in step, preferably uses periodic acid for boric acid pinacol ester hydrolysis
Sodium, neopentyl glycol ester and catechol ester preferably use inorganic acid, and trifluoroborate preferably uses inorganic base or silica gel to carry out water
Solution.
Further, above-mentioned two-step method obtains the process of product, preferably reaction specific steps are as follows:
The first step, Cabbeen cyclisation:
Scheme one, vinyl borate or trifluoroborate are dissolved in organic solvent, and diethyl zinc and two are added at 0 DEG C
Iodomethane is then heated to 50-80 DEG C, after reaction, dilute hydrochloric acid is added and is quenched.After organic solvent extraction, washing, bicarbonate
Sodium water solution washing, concentration are directly used in and react in next step.
Vinyl borate (salt) is dissolved in organic solvent by scheme two, and the palladium acetate of catalytic amount is added, then micro- logical
In road reactor, reacted between 0 DEG C to 30 DEG C with diazomethane solution.After reaction, it pours into the buffer of pH=7,
Extraction is washed, concentration.
Second step, hydrolysis:
Gained cyclopropylboronic acid ester or trifluoroborate are dissolved in organic solvent, with sodium metaperiodate/acid or diethanol amine
Reaction.After reaction, it extracts, is concentrated, crystallization obtains target product.
Beneficial effect of the present invention
It is starting material the invention avoids Cyclopropyl Bromide, to eliminate common severe toxicity pollutant in its production process
The use of mercury oxide；Reaction condition is mild, avoids under ultralow temperature using dangerous metal reagent.In addition, in diazomethane ring
In monocyclopropanated reaction, using micro passage reaction, so that reaction condition is more mild controllable.It is environmentally friendly, with higher receipts
Rate obtains cyclopropylboronic acid, provides a new way for the synthesis of such compound.
Specific embodiment
The present invention is described in detail below by embodiment, but the present invention is not limited to following embodiments.
Embodiment 1:
For step (1) using vinyl borate as raw material, diazomethane provides Cabbeen；Step (2) sodium metaperiodate/hydrochloric acid water
Solution
The preparation of diazomethane: the methyl tertiary butyl ether(MTBE) of the 650mL methyl-N-nitroso-p- toluenesulfonamide of N- containing 41g
Solution and 400mL NaOH containing 10g aqueous solution inject microchannel plate respectively at 35 DEG C with 13mL/min and 8mL/min constant flow pump
Device is answered, is reacted 50 minutes, diazomethane reaction mixture is cooled to a point water column；Contain the methyl tertbutyl of diazomethane in upper layer
Ethereal solution is directly used in lower step cyclopropanization reaction to collecting tank.
The preparation of step 1 cyclopropylboronic acid ester: under nitrogen protection, by vinyl boronic acids pinacol ester (18.5 grams,
0.12mol) and palladium acetate (0.81g, 3.6mmol) is dispersed in 200mL methyl tertiary butyl ether(MTBE), obtains vinyl boronic acids pinacol
Ester solution.At room temperature, by diazomethane solution and vinyl boronic acids pinacol ester solution, perseverance is used respectively than the year-on-year time by metering
Stream pump is injected into micro passage reaction.Reaction mixture is transferred to 5L kettle, kettle include 1% aqueous acetic acid of 1L be quenched it is remaining
Then diazomethane is extracted with methyl tertiary butyl ether(MTBE), wash, dry, is concentrated to get crude product.Crude product methylene chloride/n-hexane
Mixed solvent mashing, obtains cyclopropylboronic acid ester 15.7g, yield 78%.
Step 2 cracking reaction: above-mentioned pinacol borate (10mmol, 1.68g) is dissolved in THF (30mL), is added
NaIO4(10mmol, 2.14g) and water (16mL), reaction mixture are stirred at room temperature 3 minutes, addition aqueous hydrochloric acid solution (2N,
3.33mL), it after being stirred at room temperature 1 hour, is extracted with ethyl acetate, washs, dry, concentration.Gained crude product is beaten in n-hexane
Slurry, obtains white cyclopropylboronic acid 0.74g, yield 86%, HNMR purity 98.5%, and 92-94 DEG C of fusing point.
Embodiment 2:
Diazomethane provides Cabbeen；Diethanol amine cracks pinacol borate
Step 1 is same as Example 1.
Step 2 (borate cracking): by above-mentioned pinacol borate (20mmol, 3.36g) and methyl tertiary butyl ether(MTBE)
Lower dropwise addition diethanol amine (20mmol, 2.10g) is stirred in (40mL) mixing, is then heated to 40 DEG C and is reacted 10 hours.It is cooled to 0
DEG C or so, it filters, washing.Filter cake is taken out, is suspended in 200 milliliters methylene chloride/1N hydrochloride (1/1) mixed liquor, instead
It answers mixture to be stirred at room temperature 4 hours, is layered, extraction merges organic phase, continuously uses aqueous ammonium chloride solution and water washing, and it is dry,
Concentration.Gained crude product is beaten in n-hexane, obtains white cyclopropylboronic acid 1.45g, yield 84%, HNMR purity 98.5%,
92-94 DEG C of fusing point.
Embodiment 3:
Diiodomethane provides Cabbeen；With sodium metaperiodate/hydrochloric acid hydrolysis
Step 1: vinyl boronic acids pinacol ester (32.2mmol, 4.96 grams) is dispersed with stirring in anhydrous methyl tertbutyl ether
Be added in (50mL), under nitrogen protection diethyl zinc (1M in hexane, 32.2mL) and diiodomethane (45.1mmol,
3.63mL) reaction mixture is heated to gentle reflux, and after four hours, another diethyl zinc (32.2mL) and diiodo- is added
Methane (45.1mmol, 3.63mL).After continuing gentle reflux 10 hours, reaction mixture is cooled to room temperature, pours into ammonium chloride water
In solution (100mL).Methyl tertiary butyl ether(MTBE) extraction, is washed, dry, and concentration, gained crude product is recrystallized in DCM/PE, obtained
4.17 grams of cyclopropylboronic acid ester, yield 77%.
Step 2 is identical as step 2 in embodiment 1.
Embodiment 4:
Diiodomethane provides Cabbeen；Diethanol amine hydrolysis
Step 1: vinyl boronic acids pinacol ester (32.2mmol, 4.96 grams) is dispersed with stirring in anhydrous methyl tetrahydrofuran
Be added in (50mL), under nitrogen protection diethyl zinc (1M in hexane, 64.4mL) and diiodomethane (90.2mmol,
After 7.26mL) reaction mixture is heated to 60 degree, reaction 12 hours, it is cooled to room temperature, pours into aqueous ammonium chloride solution (100mL)
In.Ethyl acetate extraction, is washed, dry, and concentration, gained crude product recrystallizes in DCM/PE, obtains cyclopropylboronic acid ester 3.90
Gram, yield 72%.
Step 2 (borate cracking): by above-mentioned pinacol borate (20mmol, 3.36g) and methyltetrahydrofuran
Lower dropwise addition diethanol amine (20mmol, 2.10g) is stirred in (40mL) mixing, is then heated to 55 DEG C and is reacted 4 hours.It is cooled to 0 DEG C
Left and right is filtered, washing.Filter cake is taken out, is suspended in 200 milliliters methylene chloride/1N hydrochloride (1/1) mixed liquor, is reacted
Mixture is stirred at room temperature 4 hours, is layered, extraction, merges organic phase, continuously uses aqueous ammonium chloride solution and water washing, dry, dense
Contracting.Gained crude product is beaten in n-hexane, obtains white cyclopropylboronic acid 1.41g, yield 82%, and HNMR purity 98.5% melts
92-94 DEG C of point.
Embodiment above describes basic principles and main features of the invention and advantages.The technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (10)
1. the method for preparing cyclopropylboronic acid based on Cabbeen insertion, which comprises the steps of: 1) by vinyl boron
Acid derivative and methylene carbene reaction generate cyclopropylboronic acid derivative；2) cyclopropylboronic acid derivative is obtained by hydrolysis
To cyclopropylboronic acid.
2. preparing the method for cyclopropylboronic acid according to claim 1, it is characterised in that: where boronic acid derivatives are selected from boric acid frequency
Alcohol ester, boric acid neopentyl glycol ester, boric acid catechol ester or three potassium fluoborate salt.
3. preparing the method for cyclopropylboronic acid according to claim 1, it is characterised in that: Cabbeen in step 1, by diazomethane
It generates or methylene halide reacts generation with alkylmetal reagent.
4. preparing the method for cyclopropylboronic acid according to claim 3, it is characterised in that: when using diazomethane, be added
0.0001-0.5 equivalents of metal catalyst.
5. preparing the method for cyclopropylboronic acid according to claim 4, it is characterised in that: metallic catalyst is selected from palladium acetate.
6. preparing the method for cyclopropylboronic acid according to claim 3, it is characterised in that: methylene halide and metal alkyl examination
Agent is respectively selected from diiodomethane and diethyl zinc.
7. preparing the method for cyclopropylboronic acid according to claim 6, it is characterised in that: diiodomethane, diethyl zinc and second
Ene boric acid derivative molar ratio is 0.8-2.0:0.8-2.0:1.
8. preparing the method for cyclopropylboronic acid according to claim 1, it is characterised in that: 1) step in reaction dissolvent into
Row, reaction dissolvent are selected from aromatic hydrocarbons, alkane or ethers.
9. preparing the method for cyclopropylboronic acid according to claim 1, it is characterised in that: the 2) in step, and hydrolysis uses high iodine
Sour sodium, inorganic acid, diethanol amine, inorganic base or silica gel.
10. preparing the method for cyclopropylboronic acid according to claim 1, it is characterised in that: 1) step answered using microchannel plate
Device carries out.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811262292.0A CN108948057A (en) | 2018-10-27 | 2018-10-27 | The method for preparing cyclopropylboronic acid based on Cabbeen insertion |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811262292.0A CN108948057A (en) | 2018-10-27 | 2018-10-27 | The method for preparing cyclopropylboronic acid based on Cabbeen insertion |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108948057A true CN108948057A (en) | 2018-12-07 |
Family
ID=64481058
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811262292.0A Pending CN108948057A (en) | 2018-10-27 | 2018-10-27 | The method for preparing cyclopropylboronic acid based on Cabbeen insertion |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108948057A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109305983A (en) * | 2018-12-23 | 2019-02-05 | 沧州普瑞东方科技有限公司 | A kind of synthetic method of cyclopropylboronic acid |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044473A (en) * | 2012-12-20 | 2013-04-17 | 大连联化化学有限公司 | Method for preparing cyclopropylboric acid |
-
2018
- 2018-10-27 CN CN201811262292.0A patent/CN108948057A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044473A (en) * | 2012-12-20 | 2013-04-17 | 大连联化化学有限公司 | Method for preparing cyclopropylboric acid |
Non-Patent Citations (4)
| Title |
|---|
| PIERRE FONTANI等: "A CONVENIENT HIGHLY STEROSELECTIVE SYNTHESIS OF CYCLOPROPYLBORONATES", 《TETRAHEDRON LETTERS》 * |
| PIERRE FONTANI等: "Synthesis of Cyclopropylboronic Acid Esters by Carbene Transfer to 1-Alkenylboronic Acid Esters", 《SYNTHESIS》 * |
| 刘福龙: "硼酸吖啶衍生物的设计、合成与活性研究", 《中国博士学位论文全文数据库 医药卫生科技辑》 * |
| 杨光富 主编: "《有机合成 第二版》", 31 August 2016, 华东理工大学出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109305983A (en) * | 2018-12-23 | 2019-02-05 | 沧州普瑞东方科技有限公司 | A kind of synthetic method of cyclopropylboronic acid |
| CN109305983B (en) * | 2018-12-23 | 2021-01-05 | 沧州普瑞东方科技有限公司 | Synthesis method of cyclopropylboronic acid |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102010287A (en) | Method for synthesizing (trans)-4-alkyl-3-alkene biphenyl derivative monomer liquid crystals | |
| CN108948057A (en) | The method for preparing cyclopropylboronic acid based on Cabbeen insertion | |
| CN101671352A (en) | Method for preparing fluoride-bearing phenyloboric acid | |
| CN103833560A (en) | Preparation method of (S)-5-chloro-alpha-cyclopropinyl-2-amino-alpha-trifluoromethyl phenylcarbinol | |
| CN102557952B (en) | Method for preparing di-tert-butyl dicarbonate | |
| CN101671242B (en) | Method for synthesizing trans-4-(trans-4'-alkyl cyclohexyl) cyclohexanal | |
| CN101381338A (en) | Method for preparing cis-hexahydroisoindoline | |
| CN111995565B (en) | Preparation method of (S) -2-piperidinecarboxylic acid | |
| CN112979402A (en) | Industrial production method of benzo [ a ] anthracene | |
| CN102757455B (en) | Preparation method of cyclopropylboronic acid | |
| CN112047842A (en) | 1, 4-diene compound and preparation method and application thereof | |
| CN106518944A (en) | Preparation method of methylprednisone | |
| CN114751852B (en) | Preparation method of silodosin key intermediate | |
| CN102558207A (en) | Substituted alkyl borate compounds and preparation method thereof | |
| CN116082111A (en) | Method for synthesizing 1, 2-triarylethane | |
| CN106279236B (en) | Method for synthesizing 2-triisopropyl silicon-based acetylene indole compound | |
| CN111138350B (en) | Asymmetric synthesis method of dexchlorpheniramine and dexbrompheniramine | |
| CN102399235A (en) | Synthesis method of 2-amino-5-pyrimidine pinacol borate | |
| CN113121432A (en) | Synthesis method of aliphatic alkene with guide group | |
| CN106380469A (en) | Synthesis method of 1-aromatic carbonyl-2-aryl-3-ester imidazolone compounds | |
| CN104926847B (en) | A kind of synthesis boron aminated compounds technique and products application | |
| CN101747343B (en) | Sulbactam pivoxil preparation method | |
| CN103539734B (en) | The preparation method of 3-allyl group quinoline | |
| CN107602339A (en) | A kind of method for synthesizing 4 hydroxymethyl biphenyls | |
| CN107827845A (en) | novel method for synthesizing butyrolactone derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20181207 |