CN108358791A - A kind of preparation method of 3- nitros -4- benzyloxy -2- bromoacetophenones - Google Patents
A kind of preparation method of 3- nitros -4- benzyloxy -2- bromoacetophenones Download PDFInfo
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- CN108358791A CN108358791A CN201810113394.XA CN201810113394A CN108358791A CN 108358791 A CN108358791 A CN 108358791A CN 201810113394 A CN201810113394 A CN 201810113394A CN 108358791 A CN108358791 A CN 108358791A
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- benzyloxy
- bromoacetophenones
- nitros
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229940073735 4-hydroxy acetophenone Drugs 0.000 claims abstract description 7
- -1 trimethylphenyl tribromide ammonium Chemical compound 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000010792 warming Methods 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- MAYCUFJXHYDXMY-UHFFFAOYSA-N 2-bromo-1-phenyl-2-phenylmethoxyethanone Chemical compound C=1C=CC=CC=1C(=O)C(Br)OCC1=CC=CC=C1 MAYCUFJXHYDXMY-UHFFFAOYSA-N 0.000 abstract 3
- TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 abstract 2
- 239000000543 intermediate Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 4
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 4
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- FZPFXKQEIUYELF-UHFFFAOYSA-N 1-bromo-2-nitro-3-phenylmethoxybenzene Chemical class [O-][N+](=O)C1=C(Br)C=CC=C1OCC1=CC=CC=C1 FZPFXKQEIUYELF-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229940124056 Histamine H1 receptor antagonist Drugs 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- ZCVMWBYGMWKGHF-UHFFFAOYSA-N Ketotifene Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 ZCVMWBYGMWKGHF-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 102000016966 beta-2 Adrenergic Receptors Human genes 0.000 description 1
- 108010014499 beta-2 Adrenergic Receptors Proteins 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 description 1
- 229960002848 formoterol Drugs 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000000938 histamine H1 antagonist Substances 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 229960004958 ketotifen Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of preparation methods of 3 nitro, 4 benzyloxy, 2 bromoacetophenone; more particularly to using 3 nitro, 4 hydroxy acetophenone and cylite as raw material, 3 nitro, 4 benzyloxy, 2 bromoacetophenone is synthesized through hydroxyl protection, trimethylphenyl tribromide ammonium bromo-reaction high yield.The preparation method for 3 nitro, 4 benzyloxy, 2 bromoacetophenone that this synthetic route provides be a kind of high yield, low cost, it is easy to operate, suitable for industrialized preparation method.
Description
Technical field
The present invention relates to drug fields, and in particular to a kind of preparation side of 3- nitros -4- benzyloxy -2- bromoacetophenones
Method.
Background technology
F Formoterols are a kind of long-acting selective ' beta '3 adrenergic beta 2 receptor excitomotors, have bronchiectatic activity, and
In dose-dependence, the 1st second forced expiratory volume (FEV1), forced vital capacity (FVC) and End--tidal PCO_2 (PER) can be made to increase
Add.Oral 80mg this product, after 4 hours, dilating effect is most strong, and effect is suitable with oral 4mg salbutamols, but persistent.
This product also has antihistamine effect, and pulmonary mastocyte can be inhibited to discharge histamine, and effect and histamine H 1- receptor antagonists, hypertrophy are thin
It is similar that born of the same parents stablize medicine Ketotifen.Since listing, annual growth 30% is sold, the market space is huge.
Key intermediate of the nitro -4- benzyloxy -2- bromoacetophenones as Formoterol, the synthetic method reported at present
There are two types of, a kind of method is using 3- nitros -4-hydroxyacetophenone and cylite as raw material, through hydroxyl protection, bromine bromo-reaction
Synthesize 3- nitro -4- benzyloxy -2- bromoacetophenones；Another method is 3- nitros -4-hydroxyacetophenone and cylite is original
Material synthesizes 3- nitro -4- benzyloxy -2- bromoacetophenones through hydroxyl protection, copper bromide bromo-reaction.There is reaction in above method
The shortcomings of selectivity is bad, yield is not high, the three wastes are more, product quality is poor.
Invention content
In order to solve the problems in the existing technology, the present invention provides a kind of 3- nitros -4- benzyloxy -2- bromobenzenes
The preparation method of ethyl ketone.
The present invention uses following technical scheme：
A kind of preparation method of 3- nitros -4- benzyloxy -2- bromoacetophenones, includes the following steps：
Step 1：Solvent, 3- nitros -4-hydroxyacetophenone, alkali are sequentially added in reaction bulb, and cylite is then added dropwise,
Heating is stirred to react；After reaction, reaction solution is added to the water by concentration of reaction solution, filters, washes, dries, obtains intermediate
1；
Step 2：The intermediate 1 is added in solvent, trimethylphenyl tribromide ammonium, temperature reaction 4 are added
Hour；Concentration, Liquid Residue is added to the water, filters, wash, dry, obtains 3- nitro -4- benzyloxy -2- bromoacetophenones.
Preferably, the solvent described in step 1 is DMF, acetonitrile or DMSO.
Preferably, the warming temperature described in step 1 is controlled in 300C-800C.
Preferably, the alkali described in step 1 is potassium hydroxide, sodium hydroxide, sodium ethoxide, potassium carbonate or sodium carbonate.
Preferably, the Solvents Solvent described in step 2 is one or both of dichloromethane, methanol, dichloroethanes.
Preferably, the volume of the solvent described in step 2 is 5-10 times of volume of the intermediate 1.
Preferably, the warming temperature described in step 2 is controlled in 300C-700C.
Compared with prior art, the present invention the advantage is that：The present invention is with 3- nitros -4-hydroxyacetophenone and cylite
Raw material synthesizes 3- nitro -4- benzyloxy -2- bromobenzenes through hydroxyl protection, trimethylphenyl tribromide ammonium bromo-reaction high yield
Ethyl ketone；The present invention designs the synthetic method of a new bromination reaction, realizes high income, the effect that the three wastes are few, product quality is excellent.
Description of the drawings
Fig. 1 is the synthetic route chart of 3- nitro -4- benzyloxy -2- bromoacetophenones of the embodiment of the present invention.
Specific implementation mode
With reference to embodiments, the technical solution in the present invention is clearly and completely described.Based in the present invention
Embodiment, every other embodiment obtained by those of ordinary skill in the art without making creative efforts, all
Belong to the scope of protection of the invention.
The present embodiment provides a kind of preparation methods of 3- nitros -4- benzyloxy -2- bromoacetophenones, as shown in Figure 1, specifically
Include the following steps：
Step 1：1000ml acetonitriles, 150g 3- nitros -4-hydroxyacetophenone and 100g carbon are sequentially added in reaction bulb
Sour potassium, is then added dropwise 100g cylites, and heating 700C is stirred to react；After reaction, water is added in reaction solution by concentration of reaction solution
In, filtering, washing, drying obtain 210g intermediates 1, yield 93%；
Step 2：200g intermediates 1 are added in 1000ml dichloromethane, 277g trimethylphenyl tribromides are added
Ammonium, heat up 300C, reacts 4 hours；Concentration, Liquid Residue is added to the water, filters, wash, dry, obtains 253g3- nitre
Base -4- benzyloxy -2- bromoacetophenones, yield 98%；
The above described is only a preferred embodiment of the present invention, be not intended to limit the scope of the present invention,
Therefore all technical solutions formed using equivalent substitution or equivalent transformation, it falls within the scope of protection required by the present invention.
Claims (7)
1. a kind of preparation method of 3- nitros -4- benzyloxy -2- bromoacetophenones, which is characterized in that include the following steps：
Step 1：Solvent, 3- nitros -4-hydroxyacetophenone, alkali are sequentially added in reaction bulb, cylite is then added dropwise, and are heated up
It is stirred to react；After reaction, reaction solution is added to the water by concentration of reaction solution, filters, washes, dries, and obtains intermediate 1；
Step 2：The intermediate 1 is added in solvent, trimethylphenyl tribromide ammonium is added, temperature reaction is 4 small
When；Concentration, Liquid Residue is added to the water, filters, wash, dry, obtains 3- nitro -4- benzyloxy -2- bromoacetophenones.
2. a kind of preparation method of 3- nitros -4- benzyloxy -2- bromoacetophenones according to claim 1, feature exist
In：Solvent described in step 1 is DMF, acetonitrile or DMSO.
3. a kind of preparation method of 3- nitros -4- benzyloxy -2- bromoacetophenones according to claim 1, feature exist
In：Warming temperature described in step 1 is controlled at 30 DEG C -80 DEG C.
4. a kind of preparation method of 3- nitros -4- benzyloxy -2- bromoacetophenones according to claim 1, feature exist
In：Alkali described in step 1 is potassium hydroxide, sodium hydroxide, sodium ethoxide, potassium carbonate or sodium carbonate.
5. a kind of preparation method of 3- nitros -4- benzyloxy -2- bromoacetophenones according to claim 1, feature exist
In：Solvents Solvent described in step 2 is one or both of dichloromethane, methanol, dichloroethanes.
6. a kind of preparation method of 3- nitros -4- benzyloxy -2- bromoacetophenones according to claim 1, feature exist
In：The volume of solvent described in step 2 is 5-10 times of the volume of the intermediate 1.
7. a kind of preparation method of 3- nitros -4- benzyloxy -2- bromoacetophenones according to claim 1, feature exist
In：Warming temperature described in step 2 is controlled at 30 DEG C -70 DEG C.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810113394.XA CN108358791A (en) | 2018-02-05 | 2018-02-05 | A kind of preparation method of 3- nitros -4- benzyloxy -2- bromoacetophenones |
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| CN201810113394.XA CN108358791A (en) | 2018-02-05 | 2018-02-05 | A kind of preparation method of 3- nitros -4- benzyloxy -2- bromoacetophenones |
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| CN108358791A true CN108358791A (en) | 2018-08-03 |
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| CN201810113394.XA Pending CN108358791A (en) | 2018-02-05 | 2018-02-05 | A kind of preparation method of 3- nitros -4- benzyloxy -2- bromoacetophenones |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007146867A2 (en) * | 2006-06-09 | 2007-12-21 | Parion Sciences Inc. | Aliphatic pyrazinoylguanidine sodium channel blockers with beta agonist activity |
| WO2016180349A1 (en) * | 2015-05-14 | 2016-11-17 | 四川海思科制药有限公司 | Biphenyl derivative having beta2 receptor excitement and m receptor antagonistic activities and application therefof in medicament |
-
2018
- 2018-02-05 CN CN201810113394.XA patent/CN108358791A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007146867A2 (en) * | 2006-06-09 | 2007-12-21 | Parion Sciences Inc. | Aliphatic pyrazinoylguanidine sodium channel blockers with beta agonist activity |
| WO2016180349A1 (en) * | 2015-05-14 | 2016-11-17 | 四川海思科制药有限公司 | Biphenyl derivative having beta2 receptor excitement and m receptor antagonistic activities and application therefof in medicament |
Non-Patent Citations (1)
| Title |
|---|
| RICHARD S. GIVENS ET AL.: "p-Hydroxyphenacyl photoremovable protecting groups — Robust photochemistry despite substituent diversity", 《CAN. J. CHEM.》 * |
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Application publication date: 20180803 |