CN113480404A - Novel method for synthesizing cyclopropyl bromide - Google Patents
Novel method for synthesizing cyclopropyl bromide Download PDFInfo
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- CN113480404A CN113480404A CN202110731914.5A CN202110731914A CN113480404A CN 113480404 A CN113480404 A CN 113480404A CN 202110731914 A CN202110731914 A CN 202110731914A CN 113480404 A CN113480404 A CN 113480404A
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- Prior art keywords
- cyclopropyl
- bromine
- synthesis method
- bromide
- novel
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- LKXYJYDRLBPHRS-UHFFFAOYSA-N bromocyclopropane Chemical compound BrC1CC1 LKXYJYDRLBPHRS-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 6
- 230000002194 synthesizing effect Effects 0.000 title abstract description 5
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 claims abstract description 9
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 9
- INLLPKCGLOXCIV-UHFFFAOYSA-N bromoethene Chemical compound BrC=C INLLPKCGLOXCIV-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 239000000047 product Substances 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 239000002904 solvent Substances 0.000 claims abstract description 4
- 239000002253 acid Substances 0.000 claims abstract description 3
- 239000012043 crude product Substances 0.000 claims abstract description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- 239000012452 mother liquor Substances 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000010791 quenching Methods 0.000 claims description 4
- 230000000171 quenching effect Effects 0.000 claims description 4
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 229940117389 dichlorobenzene Drugs 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 claims 6
- RFLFDJSIZCCYIP-UHFFFAOYSA-L palladium(2+);sulfate Chemical compound [Pd+2].[O-]S([O-])(=O)=O RFLFDJSIZCCYIP-UHFFFAOYSA-L 0.000 claims 1
- GPNDARIEYHPYAY-UHFFFAOYSA-N palladium(II) nitrate Inorganic materials [Pd+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O GPNDARIEYHPYAY-UHFFFAOYSA-N 0.000 claims 1
- 229910000364 palladium(II) sulfate Inorganic materials 0.000 claims 1
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- 230000003321 amplification Effects 0.000 abstract 1
- 239000006227 byproduct Substances 0.000 abstract 1
- 238000001914 filtration Methods 0.000 abstract 1
- 238000003199 nucleic acid amplification method Methods 0.000 abstract 1
- 238000005406 washing Methods 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-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
- 239000000543 intermediate Substances 0.000 description 2
- SPFYMRJSYKOXGV-UHFFFAOYSA-N Baytril Chemical compound C1CN(CC)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 SPFYMRJSYKOXGV-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229960000740 enrofloxacin Drugs 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229910000474 mercury oxide Inorganic materials 0.000 description 1
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229960004954 sparfloxacin Drugs 0.000 description 1
- DZZWHBIBMUVIIW-DTORHVGOSA-N sparfloxacin Chemical compound C1[C@@H](C)N[C@@H](C)CN1C1=C(F)C(N)=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1F DZZWHBIBMUVIIW-DTORHVGOSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a novel method for synthesizing cyclopropyl bromine, which takes vinyl bromide as raw material and diazomethane in Pd (oAc)2Under the action of a catalyst, performing denitrification cyclization reaction in a solvent to obtain a cyclopropyl bromine crude product, and performing acid washing, filtering and layering, and rectifying under normal pressure to obtain a pure product with the content of more than 99%, wherein the yield is more than 80%. The synthesis route has the advantages of mild conditions, few byproducts, high yield and environmental friendliness, and is suitable for industrial amplification.
Description
Technical Field
The invention relates to a novel method for synthesizing cyclopropyl bromide, and belongs to the technical field of synthesis of medical intermediates.
Background
The cyclopropyl bromide is used as an important medical synthetic intermediate and is mainly applied to synthesizing various cyclopropyl-containing medicaments such as ciprofloxacin, enrofloxacin, sparfloxacin and the like.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides an improved cyclopropyl bromine synthesis route, which is characterized in that vinyl bromide is used as a raw material and is subjected to denitrification and cyclization with diazomethane under the catalysis of palladium to prepare cyclopropyl bromine, and the specific mechanism and the steps are as follows:
the first step is as follows: vinyl bromide is used as an initial raw material, and reacts with diazomethane in a certain amount of solvent at a certain molar ratio and a certain reaction temperature under the action of a palladium catalyst to obtain a cyclopropyl bromine crude product;
the second step is that: slowly adding a certain concentration of dilute acid into the reaction mother liquor, stirring for several hours, standing for layering, and rectifying the organic phase at normal pressure to obtain the cyclopropyl bromine finished product.
Further, in the first step of the above scheme, the reaction solvent is at least one of toluene, xylene, chlorobenzene, dichlorobenzene, acetonitrile, ethanol, diethyl ether, THF, DMF, ethyl acetate.
Further, in the first step of the above scheme, the molar ratio of the vinyl bromide to the diazomethane, palladium catalyst is 1: 1-1.5: 0.005-0.01.
Further, in the first step of the scheme, the reaction temperature is-10-125 ℃, and the reaction time is 10-25 h.
Further, in the second step of the above scheme, the quenching agent is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and nitric acid.
Further, in the second step of the scheme, the concentration of the quenching agent is 1-10%.
The invention has the beneficial effects that:
1) the synthesis route has the advantages of mild reaction conditions, high yield, environmental friendliness and stable product quality;
2) the method avoids the use of highly toxic mercury oxide and tetrachloroethane, uses a catalyst and a solvent with low toxicity, almost does not generate wastewater, is environment-friendly, is suitable for large-scale industrial production, and has very high economic and social significance.
Detailed Description
[ example 1 ] Synthesis of cyclopropyl Bromide
The first step, in a 500ml four-neck flask, under the protection of nitrogen, 200ml toluene is added, the temperature is reduced to-10 ℃, 12.6g (0.30mol) diazomethane and 0.67g (0.003mol) Pd (oAc) are added2Starting stirring, slowly dropwise adding 26.75g (0.25mol) of liquid bromoethylene, reacting for 1h, heating up and refluxing, keeping the temperature for reacting for 6 h-8 h, and cooling to-10 ℃ after TLC detection reaction;
and secondly, slowly dropwise adding 100g of 1% dilute hydrochloric acid into the reaction mother liquor, stirring for 0.5h, standing for liquid separation, and distilling the organic phase at normal pressure to obtain 24.2g of cyclopropyl bromide (purity 99.8%, yield 80%).
[ example 2 ] Synthesis of cyclopropyl Bromide
The first step, 200ml THF is added into a 500ml four-mouth bottle under the protection of nitrogen, the temperature is reduced to-10 ℃, and then 14.7g (0.35 mol) diazomethane and 0.89g (0.004mol) Pd (oAc) are added2Starting stirring, slowly dropwise adding 32.1g (0.30mol) of liquid bromoethylene, reacting for 2 hours, heating up and refluxing, keeping the temperature for reaction for 10 to 12 hours, and cooling to-10 ℃ after TLC detection reaction;
and secondly, slowly dropwise adding 100g of 1% dilute sulfuric acid into the reaction mother liquor, stirring for 0.5h, standing for liquid separation, and distilling the organic phase at normal pressure to obtain 30.85g of cyclopropyl bromide (purity is 99.7%, yield is 85%).
[ example 3 ] Synthesis of cyclopropyl Bromide
Firstly, 200ml of THF/diethyl ether mixed solution (mass ratio of 1: 1) is added into a 500ml four-mouth bottle under the protection of nitrogen, the temperature is reduced to-15 ℃, and then 12.6g (0.30mol) of diazomethane and 0.67g (0.003mol) of Pd (oAc) are added2Starting stirring, slowly dropwise adding 26.75g (0.25mol) of liquid bromoethylene, reacting for 1.5h, heating up and refluxing, keeping the temperature for reaction for 12 h-14 h, and cooling to-10 ℃ after TLC detection reaction is finished;
and secondly, slowly dropwise adding 100g of 3% dilute hydrochloric acid into the reaction mother liquor, stirring for 1.0h, standing for liquid separation, and distilling the organic phase at normal pressure to obtain 25.1g of cyclopropyl bromide (purity is 99.6%, yield is 83%).
Claims (7)
1. A novel cyclopropyl bromine synthesis method is characterized by comprising the following two synthesis steps:
1) vinyl bromide is used as an initial raw material, and reacts with diazomethane in a certain amount of solvent at a certain molar ratio and a certain reaction temperature under the action of a palladium catalyst to obtain a cyclopropyl bromine crude product;
2) slowly adding a certain concentration of dilute acid into the reaction mother liquor, stirring for several hours, standing for layering, and rectifying the organic phase at normal pressure to obtain the cyclopropyl bromine finished product.
2. The novel cyclopropyl bromide synthesis method according to claim 1, characterized in that the reaction solvent in step 1) is at least one of toluene, xylene, chlorobenzene, dichlorobenzene, acetonitrile, ethanol, diethyl ether, THF, DMF and ethyl acetate.
3. The novel cyclopropyl bromide synthesis method according to claim 1, wherein the molar ratio of the vinyl bromide, the diazomethane and the palladium catalyst in the step 1) is 1: 1-1.5: 0.001 to 0.01.
4. The novel cyclopropyl bromine synthesis process according to claim 1, characterized in that step 1) said palladium catalyst is Pd (oAc)2、Pd(NO3)2、PdSO4、Pdcl2、Pd(TFA)2At least one of them.
5. The novel cyclopropyl bromide synthesis method according to claim 1, characterized in that the reaction temperature in the step 1) is-10-125 ℃, and the reaction time is 10-25 h.
6. The novel cyclopropyl bromide synthesis method according to claim 1, wherein the quenching agent in step 2) is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and nitric acid.
7. The novel cyclopropyl bromide synthesis method according to claim 1, characterized in that the concentration of the quenching agent in the step 2) is 1-10%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110731914.5A CN113480404A (en) | 2021-06-30 | 2021-06-30 | Novel method for synthesizing cyclopropyl bromide |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110731914.5A CN113480404A (en) | 2021-06-30 | 2021-06-30 | Novel method for synthesizing cyclopropyl bromide |
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| CN113480404A true CN113480404A (en) | 2021-10-08 |
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| CN202110731914.5A Pending CN113480404A (en) | 2021-06-30 | 2021-06-30 | Novel method for synthesizing cyclopropyl bromide |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114315508A (en) * | 2022-01-15 | 2022-04-12 | 大连双硼医药化工有限公司 | Process for synthesizing cyclopropyl bromine |
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|---|---|---|---|---|
| JPH05194323A (en) * | 1991-07-05 | 1993-08-03 | Dai Ichi Seiyaku Co Ltd | Production of fluorocyclopropanecarboxylic acid derivative |
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| JPH0797353A (en) * | 1993-08-05 | 1995-04-11 | Dai Ichi Seiyaku Co Ltd | Method for selectively removing halogen |
| JP2000159699A (en) * | 1998-11-24 | 2000-06-13 | Mitsubishi Chemicals Corp | Production of 3-(4-chlorophenyl)-1-bromopropane |
| WO2002004398A1 (en) * | 2000-07-11 | 2002-01-17 | Imperial College Of Science, Technology And Medicine | Process for preparing a cyclopropane |
| RU2009124700A (en) * | 2009-06-29 | 2011-01-10 | Учреждение Российской академии наук ИНСТИТУТ НЕФТЕХИМИИ И КАТАЛИЗА РАН (RU) | METHOD FOR PRODUCING (C60-Ih) [5,6] FULLERO [2 ', 3': 1,9] CYCLOPROPANE |
| CN105418452A (en) * | 2015-11-09 | 2016-03-23 | 宜宾久凌化学有限公司 | Method and equipment for preparing diazomethane |
| CN105658604A (en) * | 2013-10-25 | 2016-06-08 | 奇华顿股份有限公司 | Improvements in or relating to organic compounds |
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| WO2021000248A1 (en) * | 2019-07-02 | 2021-01-07 | 凯莱英医药集团（天津）股份有限公司 | Method and apparatus for continuous synthesis of cyclopropane compounds |
-
2021
- 2021-06-30 CN CN202110731914.5A patent/CN113480404A/en active Pending
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|---|---|---|---|---|
| JPH05194323A (en) * | 1991-07-05 | 1993-08-03 | Dai Ichi Seiyaku Co Ltd | Production of fluorocyclopropanecarboxylic acid derivative |
| JPH069499A (en) * | 1992-02-26 | 1994-01-18 | Dai Ichi Seiyaku Co Ltd | Production of halogenocyclopropanecarboxylic acid derivative |
| JPH0797353A (en) * | 1993-08-05 | 1995-04-11 | Dai Ichi Seiyaku Co Ltd | Method for selectively removing halogen |
| JP2000159699A (en) * | 1998-11-24 | 2000-06-13 | Mitsubishi Chemicals Corp | Production of 3-(4-chlorophenyl)-1-bromopropane |
| WO2002004398A1 (en) * | 2000-07-11 | 2002-01-17 | Imperial College Of Science, Technology And Medicine | Process for preparing a cyclopropane |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114315508A (en) * | 2022-01-15 | 2022-04-12 | 大连双硼医药化工有限公司 | Process for synthesizing cyclopropyl bromine |
| CN114315508B (en) * | 2022-01-15 | 2023-10-03 | 大连双硼医药化工有限公司 | Technological method for synthesizing cyclopropyl bromide |
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