CN107778229A - A kind of preparation method of the formonitrile HCN of 7 halo, 6 nitro, 1,4 EEDQ, 4 ketone 3 - Google Patents
A kind of preparation method of the formonitrile HCN of 7 halo, 6 nitro, 1,4 EEDQ, 4 ketone 3 Download PDFInfo
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- CN107778229A CN107778229A CN201711025493.4A CN201711025493A CN107778229A CN 107778229 A CN107778229 A CN 107778229A CN 201711025493 A CN201711025493 A CN 201711025493A CN 107778229 A CN107778229 A CN 107778229A
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- ketone
- halo
- eedq
- isosorbide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
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- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a kind of nitro 1 of 7 halo 6, the preparation method of the formonitrile HCN of 4 EEDQ, 4 ketone 3, comprises the following steps, S1, using the halogen benzoic acid of 2 amino 4 as initiation material, under catalyst action, the esterification generation Aminobenzoate of 4 halo 2 is carried out with simple fatty alcohol；S2, the Aminobenzoate of 4 halo 2 react under acidic catalyst with 3 dimethylaminopropionitriles, generate 4 halo 2 ((2 acrylonitrile base) amino) benzoic ethers；S3, the cyclization under highly basic effect of ((the 2 acrylonitrile base) amino) benzoic ether of 4 halo 2, obtain the formonitrile HCN of 74 ketone of halo Isosorbide-5-Nitrae EEDQ 3；S4, the formonitrile HCN of 74 ketone of halo Isosorbide-5-Nitrae EEDQ 3 are nitrified in the presence of the nitration mixture of strong acid and nitric acid, obtain the formonitrile HCN of 7 halo, 64 ketone of nitro Isosorbide-5-Nitrae EEDQ 3；Process route is novel, obtains the intermediate of novelty, and total recovery is more than 35%, has the characteristics that process route is novel, reaction condition is relatively mild.
Description
Technical field
The present invention relates to organic chemical synthesis field, more particularly, to a kind of 7- halos -6- nitros-Isosorbide-5-Nitrae-dihydro quinoline
The preparation method of quinoline -4- ketone -3- formonitrile HCNs.
Background technology
Before having a various clinical, clinical phase and listing new drug contain 6,7- bis- and substitute -4- substitution -3- formonitrile HCN fragments.Following institute
Show three types drug molecule, and marketed drug such as HKI-272（Neratinib）, clinical the second stage of medicine Pelitinib,
Contain the important feature fragment.
This structure piece has two main synthetic routes at present, and its high temperature cyclization route is as follows.This route
Major defect be that ring closure reaction needs 250 degree or sos of high temperature, in general pharmaceutical equipment is difficult to reach, it is also difficult to which progress is safely
Ground production amplification：
Another synthetic method is following synthetic route.This synthetic route is relatively excellent, and the reagent used is relatively inexpensive, reacts bar
Part is more gentle.
But during this two lines synthesis object construction fragment, the substituent of 7 is fixed as alkoxy, is sieved to high flux
The diversity of the substituent of required compound brings very big challenge when selecting, and it is other substituents that can not particularly synthesize 7
The compound of type.
If, can be by flexible using 7- halos -6- nitro-Isosorbide-5-Nitrae-EEDQ -4- ketone -3- formonitrile HCNs as intermediate
Change nucleophilic displacement of fluorine base Nu1 and Nu2, the problem of adequate solution molecular structure of compounds diversity to be synthesized is bad.
However, 7- halos -6- nitro-Isosorbide-5-Nitrae-EEDQ -4- ketone -3- first nitrile compounds take high temperature cyclization at present
Method is synthesized, and the synthesis and production amplification to this kind of compound bring great difficulty.
In summary, the development need 7- halos -6- nitro-Isosorbide-5-Nitrae-EEDQ -4- ketone -3- formonitrile HCNs of pharmaceutical industry this
Class medicine intermediate, but there are severe reaction conditions in its process route, material security is low, is difficult to the characteristics of production amplification.
The content of the invention
In view of the shortcomings of the prior art, it is anti-to improve preparation 7- halos -6- nitro-Isosorbide-5-Nitrae-EEDQ -4- ketone -3- formonitrile HCNs
Answer that condition is harsh, process safety is low, is difficult to the problems such as production amplification, the invention provides a kind of 7- halos -6- nitro-Isosorbide-5-Nitraes -
The preparation method of EEDQ -4- ketone -3- formonitrile HCNs.
The present invention is realized by the following technical programs：
A kind of preparation method of 7- halos -6- nitros-Isosorbide-5-Nitrae-EEDQ -4- ketone -3- formonitrile HCNs, comprises the following steps,
S1, using 2- amino -4- halogen benzoic acids as initiation material, under catalyst action, esterification life is carried out with simple fatty alcohol
Into 4- halo -2- Aminobenzoates；
S2,4- halo -2- Aminobenzoates react under acidic catalyst with 3- dimethylaminopropionitriles, and generation 4- halos -
2- ((2- acrylonitriles base) amino) benzoic ether；
The cyclization under highly basic effect of S3,4- halo -2- ((2- acrylonitriles base) amino) benzoic ethers, obtains 7- halos-Isosorbide-5-Nitrae-two
Hydrogen quinoline -4- ketone -3- formonitrile HCNs；
S4,7- halo-Isosorbide-5-Nitrae-EEDQ -4- ketone -3- formonitrile HCNs are nitrified in the presence of the nitration mixture of strong acid and nitric acid, obtain 7-
Halo -6- nitro -1,4- EEDQ -4- ketone -3- formonitrile HCNs；
Synthetic route is as follows：
；
Wherein, X is fluorine, chlorine, bromine or iodine；R is methyl, ethyl, isopropyl, n-propyl, normal-butyl or isobutyl group.
Further, R is preferably methyl.
Further, in step S1, the catalyst is the concentrated sulfuric acid, thionyl chloride, POCl3 or dicyclohexyl carbon two
One kind in imines.
Further, in step S1, the catalyst is preferably the concentrated sulfuric acid.
Further, in step S2, the acidic catalyst is in trifluoroacetic acid, acetic acid, methanesulfonic acid or p-methyl benzenesulfonic acid
One kind.
Further, in step S2, the acidic catalyst is preferably acetic acid.
Further, in step S3, the highly basic is DBU, TBD, MTBD, potassium tert-butoxide, butyl lithium, caustic alcohol, methanol
One kind in sodium, hexamethl disilamine base lithium, tert-butyl lithium or isobutyl group lithium.
Further, in step S3, the highly basic is preferably tert-butyl lithium.
Further, in step S4, the strong acid be the concentrated sulfuric acid, chlorosulfonic acid, methanesulfonic acid, polyphosphoric acids, trifluoromethanesulfonic acid,
One kind in trifluoromethanesulfanhydride anhydride or TFAA.
Further, in step S4, the strong acid is preferably polyphosphoric acids.
Compared with prior art, the invention has the advantages that：
1st, 7- halos -6- nitro-Isosorbide-5-Nitrae-EEDQ -4- ketone -3- formonitrile HCNs, process route are prepared using the synthetic route of the present invention
Novelty, the intermediate of novelty is obtained, total recovery is more than 35%, has the characteristics that process route is novel, reaction condition is relatively mild.
2nd, technique is easy to get using raw material, and cost is relatively low, no special operational process, not high to equipment requirement, is adapted to industrialization
Production.
Embodiment
Presently preferred embodiments of the present invention is described in detail below, so that advantages and features of the invention are more easy to by this area skill
Art personnel understand, so as to make apparent define to protection scope of the present invention.
Embodiment 1
1st, the synthesis of 2- amino -4- chloro benzoic ethers
Single port bottle adds 10g 2- amino -4- chlorobenzoic acids, 150ml methanol, is cooled to 0-5 DEG C, 10.4g dichloros are added dropwise in insulation
Sulfoxide.It is added dropwise, temperature rising reflux reaction 24hrs.Room temperature is dropped to, is concentrated under reduced pressure and removes methanol.Addition 100ml ethyl acetate,
The sodium carbonate liquors of 100ml 5%, stirring, stand, separate water layer, organic layer is washed with 100ml, is depressurized after anhydrous sodium sulfate drying
It is concentrated to give 2- amino -4- chloro benzoic ether 8.9g, yield 82%.
2nd, the synthesis of the chloro- 2- of 4- ((2- acrylonitriles base) amino) methyl benzoate
Add 10g 2- amino -4- chloro benzoic ethers in single port bottle, 80ml ethyl acetate, 10ml trifluoroacetic acids, be then added dropwise
6.2g 3- dimethylaminopropionitriles, 2-3hrs is reacted at room temperature, separate out yellow solid, filtering, a small amount of ethyl acetate washing, vacuum
Dry, obtain the chloro- 2- of 10.1g 4- ((2- acrylonitriles base) amino) methyl benzoate, yield 79%.
3rd, the synthesis of the chloro- 1,4- EEDQs -4- ketone -3- formonitrile HCNs of 7-
10g 4- chloro- 2- ((2- acrylonitriles base) amino) methyl benzoate is added in there-necked flask, 150ml THF, is cooled to -78
DEG C, 51ml tert-butyl lithiums are added dropwise（1.9mol pentane solution）.It is added dropwise, insulation reaction 1h, 7.6g is then slowly added dropwise
Acetic acid.Room temperature is raised to, is filtered, vacuum drying, obtains the chloro- Isosorbide-5-Nitraes of 6.5g 7--EEDQ -4- ketone -3- formonitrile HCNs, yield 75%.
4th, the synthesis of the chloro- 6- nitros -1,4- EEDQs -4- ketone -3- formonitrile HCNs of 7-
The chloro- Isosorbide-5-Nitraes of 10 g 7--EEDQ -4- ketone -3- formonitrile HCNs, 30ml trifluoromethanesulfanhydride anhydrides, nitrogen protection are added in there-necked flask
Under be cooled to 0 DEG C, 5ml concentrated nitric acids are added dropwise in insulation, insulation reaction 1h, then control less than 10 DEG C dropwise addition 40ml water of temperature.Insulation
1h is stirred, filtering, a small amount of washing, vacuum drying, obtains the chloro- 6- nitros-Isosorbide-5-Nitrae-EEDQ -4- ketone -3- formonitrile HCNs of 9.2g 7-,
Yield 75%.
The synthetic route total recovery of the chloro- 6- nitros -1,4- EEDQs -4- ketone -3- formonitrile HCNs of 7- is 36.4%.
Embodiment 2
1st, the synthesis of 2- amino -4- methyl-bromobenzoates
Single port bottle adds 10g 2- amino -4- bromobenzoic acids, 150ml methanol, the 10ml concentrated sulfuric acids, heating reflux reaction 24hrs.Drop
To room temperature, it is concentrated under reduced pressure and removes methanol.Add 100ml ethyl acetate, the sodium carbonate liquors of 100ml 5%, stir 5mins after it is quiet
Layering is put, separates water layer, organic layer is washed with 100ml, and 2- amino -4- bromobenzene first is concentrated under reduced pressure to give after anhydrous sodium sulfate drying
Sour methyl esters 9.16g, yield 86%.
2nd, the synthesis of the bromo- 2- of 4- ((2- acrylonitriles base) amino) methyl benzoate
Add 10g 2- amino -4- methyl-bromobenzoates in single port bottle, 60ml ethyl acetate, 6.0g 3- dimethylaminos are then added dropwise
Acrylonitrile, 3-4hrs is reacted at room temperature, 60ml water is added dropwise, 2hrs is then stirred at room temperature, filtered, a small amount of water washing, vacuum drying, obtained
To the bromo- 2- of 10.39g 4- ((2- acrylonitriles base) amino) methyl benzoate, yield 85%.
3rd, the synthesis of the bromo- 1,4- EEDQs -4- ketone -3- formonitrile HCNs of 7-
10g 4- bromo- 2- ((2- acrylonitriles base) amino) methyl benzoate is added in single port bottle, 150ml absolute ethyl alcohols, is added dropwise
16.3g 28% sodium methoxide solution.It is added dropwise, temperature rising reflux reaction 1h, 7.6g acetic acid is then slowly added dropwise.Drop to room temperature, mistake
Filter, a small amount of ethanol washing, vacuum drying, obtains the bromo- Isosorbide-5-Nitraes of 7.09g 7--EEDQ -4- ketone -3- formonitrile HCNs, yield 80%.
4th, the synthesis of the bromo- 6- nitros -1,4- EEDQs -4- ketone -3- formonitrile HCNs of 7-
The 40ml concentrated sulfuric acids are added in there-necked flask, are cooled to 0 DEG C, then add the bromo- Isosorbide-5-Nitraes of 10g 7--EEDQ -4- ketone -3- first
5ml concentrated nitric acids are slowly added dropwise in nitrile, insulation.It is added dropwise, insulation reaction 30mins.Then reaction solution is poured into 200ml frozen water
In, after stirring 20mins, filter, wash, vacuum drying, obtain the bromo- 6- nitros-Isosorbide-5-Nitrae-EEDQ -4- ketone -3- of 9.56g 7-
Formonitrile HCN, yield 81%.
The synthetic route total recovery of the bromo- 6- nitros -1,4- EEDQs -4- ketone -3- formonitrile HCNs of 7- is 47.4%.
The preferred embodiments of the present invention are these are only, are not intended to limit the scope of the invention, it is every to utilize this hair
The equivalent structure or equivalent flow conversion that bright specification is made, or other related technical areas are directly or indirectly used in,
Similarly it is included within the scope of the present invention.
Claims (5)
- A kind of 1. preparation method of 7- halos -6- nitros-Isosorbide-5-Nitrae-EEDQ -4- ketone -3- formonitrile HCNs, it is characterised in that：Including with Lower step,S1, using 2- amino -4- halogen benzoic acids as initiation material, under catalyst action, esterification life is carried out with simple fatty alcohol Into 4- halo -2- Aminobenzoates；S2,4- halo -2- Aminobenzoates react under acidic catalyst with 3- dimethylaminopropionitriles, and generation 4- halos - 2- ((2- acrylonitriles base) amino) benzoic ether；The cyclization under highly basic effect of S3,4- halo -2- ((2- acrylonitriles base) amino) benzoic ethers, obtains 7- halos-Isosorbide-5-Nitrae-two Hydrogen quinoline -4- ketone -3- formonitrile HCNs；S4,7- halo-Isosorbide-5-Nitrae-EEDQ -4- ketone -3- formonitrile HCNs are nitrified in the presence of the nitration mixture of strong acid and nitric acid, obtain 7- Halo -6- nitro -1,4- EEDQ -4- ketone -3- formonitrile HCNs；Synthetic route is as follows：；Wherein, X is fluorine, chlorine, bromine or iodine；R is methyl, ethyl, isopropyl, n-propyl, normal-butyl or isobutyl group.
- 2. the preparation method of 7- halos -6- nitros-Isosorbide-5-Nitrae-EEDQ -4- ketone -3- formonitrile HCNs according to claim 1, its It is characterised by：In step S1, the catalyst is in the concentrated sulfuric acid, thionyl chloride, POCl3 or dicyclohexylcarbodiimide It is a kind of.
- 3. the preparation method of 7- halos -6- nitros-Isosorbide-5-Nitrae-EEDQ -4- ketone -3- formonitrile HCNs according to claim 1, its It is characterised by：In step S2, the acidic catalyst is one kind in trifluoroacetic acid, acetic acid, methanesulfonic acid or p-methyl benzenesulfonic acid.
- 4. the preparation method of 7- halos -6- nitros-Isosorbide-5-Nitrae-EEDQ -4- ketone -3- formonitrile HCNs according to claim 1, its It is characterised by：In step S3, the highly basic is DBU, TBD, MTBD, potassium tert-butoxide, butyl lithium, caustic alcohol, sodium methoxide, hexamethyl One kind in two silicon lithium amides, tert-butyl lithium or isobutyl group lithium.
- 5. the preparation method of 7- halos -6- nitros-Isosorbide-5-Nitrae-EEDQ -4- ketone -3- formonitrile HCNs according to claim 1, its It is characterised by：In step S4, the strong acid is the concentrated sulfuric acid, chlorosulfonic acid, methanesulfonic acid, polyphosphoric acids, trifluoromethanesulfonic acid, fluoroform sulphur One kind in acid anhydrides or TFAA.
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| CN201711025493.4A CN107778229A (en) | 2017-10-27 | 2017-10-27 | A kind of preparation method of the formonitrile HCN of 7 halo, 6 nitro, 1,4 EEDQ, 4 ketone 3 |
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| CN201711025493.4A CN107778229A (en) | 2017-10-27 | 2017-10-27 | A kind of preparation method of the formonitrile HCN of 7 halo, 6 nitro, 1,4 EEDQ, 4 ketone 3 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6297258B1 (en) * | 1998-09-29 | 2001-10-02 | American Cyanamid Company | Substituted 3-cyanoquinolines |
| CN1704404A (en) * | 1999-12-29 | 2005-12-07 | 惠氏公司 | Tricyclic protein kinase inhibitors |
| CN104774184A (en) * | 2015-04-17 | 2015-07-15 | 中国药科大学 | Alpha-cyano-alpha, beta-unsaturated amide compound and medical application thereof |
| CN106243046A (en) * | 2016-08-02 | 2016-12-21 | 南京工业大学 | A kind of preparation method of mesosulfuron |
-
2017
- 2017-10-27 CN CN201711025493.4A patent/CN107778229A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6297258B1 (en) * | 1998-09-29 | 2001-10-02 | American Cyanamid Company | Substituted 3-cyanoquinolines |
| CN1704404A (en) * | 1999-12-29 | 2005-12-07 | 惠氏公司 | Tricyclic protein kinase inhibitors |
| CN104774184A (en) * | 2015-04-17 | 2015-07-15 | 中国药科大学 | Alpha-cyano-alpha, beta-unsaturated amide compound and medical application thereof |
| CN106243046A (en) * | 2016-08-02 | 2016-12-21 | 南京工业大学 | A kind of preparation method of mesosulfuron |
Non-Patent Citations (1)
| Title |
|---|
| ALEXANDER L. RUCHELMAN ET AL.: "Nitro and amino substitution within the A-ring of 5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)dibenzo[c,h][1,6]-naphthyridin-6-ones: influence on topoisomerase I-targeting activity and cytotoxicity", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
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Application publication date: 20180309 |