CN105906563B - The synthetic method of 7,8- difluoro-quinoline -3- formic acid - Google Patents
The synthetic method of 7,8- difluoro-quinoline -3- formic acid Download PDFInfo
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- CN105906563B CN105906563B CN201610292128.9A CN201610292128A CN105906563B CN 105906563 B CN105906563 B CN 105906563B CN 201610292128 A CN201610292128 A CN 201610292128A CN 105906563 B CN105906563 B CN 105906563B
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- quinoline
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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
-
- 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
- C07D215/18—Halogen atoms or nitro radicals
-
- 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
- C07D215/38—Nitrogen atoms
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- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
Abstract
The present invention provides a kind of 3- amino -7; the synthetic method of 8- difluoro-quinoline and its intermediate; wherein 3- amino -7; 8- difluoromethyl quinoline is by 7; substitution reaction, 3- bromo- 7 occur for 8- difluoro-quinoline; condensation reaction occurs for 8- difluoro-quinoline, the tertiary oxygen carbonyl amino quinoline of the fluoro- 3- of 7,8- bis- occurs three step of amino deprotection reaction and obtains；7,8- difluoro-quinoline -3- formic acid are that three step of hydrolysis occurs and obtains by 7,8- difluoro-quinoline generation substitution reaction, the slotting carbonyl reaction of bromo- 7, the 8- difluoro-quinoline generation of 3-, 7,8- difluoro-quinoline -3- methyl formate.Synthetic method synthetic route of the invention is succinct, and total recovery is high, easy to operate, post-processing is simple, does not use poisonous reagent, is suitble to large-scale production.
Description
The application is that application No. is CN201410626253.X, entitled 3- amino -7,8- difluoro-quinoline and wherein
The synthetic method of mesosome, the divisional application that the applying date is on November 10th, 2014.
Technical field
The invention belongs to pharmaceutical intermediate synthesis technical fields, and in particular to the synthesis side of 7,8- difluoro-quinoline -3- formic acid
Method.
Background technique
3- amino -7,8- difluoro-quinoline and its intermediate are compounds important in organic synthesis and pharmaceutical chemistry.
With 3- amino -7,8- difluoro-quinoline or in which mesosome 7,8- difluoro-quinoline -3- formic acid sets out, and reacts generation with a series of acid or amine
Amide have good bioactivity, be very important molecule drug candidate.It recent studies have shown that, these candidate molecules remove
It can inhibit the combination of mutual 1 α of phagocyte inflammatory protein (MIP-1 α) and chemokine receptors 1 (CCR1), to have good
Antiinflammation and immunoregulation effect isoreactivity, moreover it is possible to be used to treat HIV and inhibit the diseases such as endometrial hyperplasia and restenosis
(US6403587B1；US2002137741A1).In recent years, by 3- amino -7,8- difluoro-quinoline and its intermediate and some
Specific structure is connected to seek the good screening drug of some activity or develop its other biological activities to have become drug
One of hot spot of educational circles.
The synthesis of 3- amino -8- Trifluoromethylquinocarboxylic, current main method are by 2,3- difluoroaniline and ethyoxyl
Methene propylmalonic acid diethyl ester condensation, product are cyclized in diphenyl ether high temperature and generate the fluoro- Isosorbide-5-Nitrae of 4- oxo -7,8- bis--dihydro quinoline
Quinoline -3- Ethyl formate；The fluoro- Isosorbide-5-Nitrae of 4- oxo -7,8- bis--dihydroquinoline -3- Ethyl formate is with phosphorus oxychloride reaction and through being catalyzed hydrogen
Change dechlorination and obtains intermediate 2,3- difluoro-quinoline -3- Ethyl formate.2,3- difluoro-quinoline -3- Ethyl formates hydrolyze to obtain 2,3- bis-
It reacts to obtain 2,3- difluoro-quinoline -3- formamide, the change again with ammonia after fluorine quinoline -3- formic acid, the latter and thionyl chloride reaction
Object is closed to reset to obtain 3- amino -7,8- difluoro-quinoline with sodium hypobromite generation Hofmann under strongly alkaline conditions.This method exists
Following disadvantage: (1) synthetic route is longer, and post-processing trouble is unable to fairly large production；(2) condensation needs in diphenyl ether
250 DEG C or more carry out, and risk is high；(3) severe toxicity has been used and to the disagreeableness phosphorus oxychloride of environment, and in catalytic hydrogenation dechlorination
The middle dihydroquindine derivates for generating a large amount of over reduction, cause yield relatively low, post-processing trouble；(4) 2,3- difluoro-quinoline-
3- formamide occurs to have used a large amount of bromine in the reaction that Hofmann is reset, and environmental protection pressure is big.
Summary of the invention
A kind of 3- amino -7,8- difluoro-quinoline and among it is provided the purpose of the present invention is overcome the deficiencies in the prior art
The synthetic method of body, this method synthetic route is succinct, and total recovery is high, easy to operate, post-processing is simple, does not use poisonous reagent,
It is suitble to large-scale production.
According to an aspect of the present invention, the synthetic method of bromo- 7, the 8- difluoro-quinoline of 3-, passes through 7,8- difluoro-quinoline and N-
Bromosuccinimide, reaction generates bromo- 7, the 8- difluoro-quinoline of 3- in a heated condition.
According to another aspect of the present invention, the synthetic method of 3- amino -7,8- difluoro-quinoline passes through bromo- 7, the 8- bis- of 3-
Fluorine quinoline reacts in the presence of palladium acetate and cesium carbonate with t-butyl carbamate generates the tertiary oxygen carbonyl amino quinoline of the fluoro- 3- of 7,8- bis-
Quinoline, the compound are protected to obtain 3- amino -7,8- difluoromethyl quinoline in the in the mixed solvent deamination of hydrochloric acid and methanol,
In, bromo- 7, the 8- difluoro-quinoline of 3- is to synthesize to obtain by above-mentioned method.
According to another aspect of the present invention, the synthetic method of 7,8- difluoro-quinoline -3- formic acid passes through bromo- 7, the 8- bis- of 3-
Fluorine quinoline generates 7,8- difluoro-quinoline -3- methyl formate in the presence of palladium acetate, in methyl alcohol with reaction of carbon monoxide；The latter's warp
Basic hydrolysis generates 7,8- difluoro-quinoline -3- formic acid；Wherein, bromo- 7, the 8- difluoro-quinoline of 3- is to synthesize to obtain by above-mentioned method.
Reaction equation is as follows:
The specific process is as follows:
The synthetic route of 3- amino -7,8- difluoromethyl quinoline:
The first step is substitution reaction: reaction substrate 7,8- difluoro-quinoline (compound 1), and substitution reagent is N- bromo amber
Acid imide, reaction dissolvent are acetic acid, and reaction temperature is 110 DEG C, reaction time 12h, obtain bromo- 7, the 8- difluoro-quinoline of 3- and (change
Close object 2)；Wherein the molar ratio of 7,8- difluoro-quinoline and N-bromosuccinimide is 1:1.2.
Second step is condensation reaction: bromo- 7, the 8- difluoro-quinoline (compound 2) of 3- and t-butyl carbamate in palladium acetate and
In the presence of cesium carbonate, using Isosorbide-5-Nitrae-dioxane as reaction dissolvent, in 90 DEG C of reaction 4h, the tertiary oxygen carbonyl ammonia of the fluoro- 3- of 7,8- bis- is obtained
Base quinoline (compound 3), wherein the molar ratio of each substrate is bromo- 7, the 8- difluoro-quinoline of 3-: t-butyl carbamate: cesium carbonate:
Palladium acetate=1:1.1:2:0.055.
Third step is the deprotection reaction of amino: under room temperature, 7, the 8- bis- fluoro- tertiary oxygen carbonyl amino quinoline (compound 3) of 3- exist
Mixed solution (the V of methanol and hydrochloric acidMethanol:VConcentrated hydrochloric acid=1:1) in, (the change of 3- amino -7,8- difluoromethyl quinoline is obtained after reacting 14h
Close object 4).
The synthetic route of 7,8- difluoro-quinoline -3- formic acid:
The first step is substitution reaction: reaction substrate 7,8- difluoro-quinoline (compound 1), and substitution reagent is N- bromo amber
Acid imide, reaction dissolvent are acetic acid, and reaction temperature is 110 DEG C, reaction time 12h, obtain bromo- 7, the 8- difluoro-quinoline of 3- and (change
Close object 2)；Wherein the molar ratio of 7,8- difluoro-quinoline and N-bromosuccinimide is 1:1.2.
Second step is to insert carbonyl reaction: bromo- 7, the 8- difluoro-quinoline (compound 2) of 3- is made molten in the presence of palladium acetate, with methanol
Agent, with reaction of carbon monoxide generate 7,8- difluoro-quinoline -3- methyl formate (compound 5), wherein bromo- 7, the 8- difluoro-quinoline of 3- and
The mass ratio of palladium acetate is 1:0.5, and the pressure of carbon monoxide is 60psi, and reaction temperature is 60 DEG C.
Third step is hydrolysis: 7,8- difluoro-quinoline -3- methyl formates (compound 5) are obtained through basic hydrolysis at room temperature
To 7,8- difluoro-quinoline -3- formic acid (compound 6).
Synthetic method synthetic route of the invention is succinct, and total recovery is high, easy to operate, post-processing is simple, without using severe toxicity
Reagent is suitble to large-scale production.
Specific embodiment
Embodiment 1
The first step, the synthesis of bromo- 7, the 8- difluoro-quinoline of 3-
At 110 DEG C, in acetic acid (800mL) solution of 7,8- difluoro-quinoline (40g, 0.24mol), N- bromo amber is added
Acid imide (51.0g, 0.29mol), mixture continue to be heated to reflux.After reacting 12h, acetic acid is evaporated, and ammonium hydroxide is added to mixed
Closing liquid pH is 9, and gained mixed liquor is extracted with dichloromethane, and organic phase is washed with saturated sodium bicarbonate, is dried over anhydrous sodium sulfate
After be spin-dried for, crude product crosses column and obtains bromo- 7, the 8- difluoro-quinoline of 3- (45g, 77%).
1HNMR (400MHz, CDCl3): 7.45-7.58 (m, 2H), 8.36 (t, J=2.0Hz, 1H), 8.99 (d, J=
2.0Hz, 1H).
Second step, the synthesis of tertiary oxygen carbonyl amino -7, the 8- difluoromethyl quinoline of 3-
By bromo- 7, the 8- difluoro-quinoline (32g, 132mmol) of 3-, t-butyl carbamate (17g, 145mmol), cesium carbonate
Isosorbide-5-Nitrae-dioxane (500mL) solution of (85g, 264mmol), palladium acetate (2g, 7.2mmol) are stirred to react 4h at 90 DEG C.
10min is stirred the mixture for after adding 800mL ethyl acetate, organic phase is spin-dried for after drying after mixture filtering, crude product
It crosses column and obtains tertiary oxygen carbonyl amino -7, the 8- difluoromethyl quinoline of 3- (30g, 81%).
Step 3: the synthesis of 3- amino -7,8- difluoro-quinoline
It is added in methanol (280mL) solution of tertiary oxygen carbonyl amino -7, the 8- difluoromethyl quinoline (28g, 99.9mmol) of 3-
14h is stirred at room temperature in mixture after concentrated hydrochloric acid (280mL), after mixed liquor is evaporated, 100mL water and 500mL ethyl acetate is added,
And ammonium hydroxide is added to pH=9 or so.Organic layer is spin-dried for after aqueous phase separation, residue obtains 3- amino -8- three with petroleum ether
Methyl fluoride quinoline (16g, 90%).
1HNMR (400MHz, CDCl3): 7.24-7.28 (m, 1H), 7.32-7.35 (m, 2H), 8.59 (d, J=2.4Hz,
1H)。
Step 4: the synthesis of 7,8- difluoro-quinoline -3- methyl formates
Palladium acetate (2.4g) is added in methanol (480mL) solution of bromo- 7, the 8- difluoro-quinoline (48g, 197mmol) of 3-,
Reaction system reacts 8h under 60 DEG C and 60psi pressure after being replaced three times with CO.After mixed liquor is evaporated be added 250mL water and
500mL methylene chloride.Organic layer is spin-dried for after aqueous phase separation, residue obtains 7,8- difluoro-quinoline 3- formic acid first with petroleum ether
Ester (32g, 73%).
Step 5: the synthesis of 7,8- difluoro-quinoline 3- formic acid
It is water-soluble in the NaOH that 2N is added in methanol (100mL) solution of 7,8- difluoro-quinoline 3- methyl formate (10g, 45mmol)
4h is stirred at room temperature after liquid (100mL), by the 2N aqueous hydrochloric acid solution tune pH to 5~6 of mixture after methanol rotary evaporation.Mixture mistake
Solid is dried to obtain 7,8- difluoro-quinoline -3- formic acid (8g, 85%) after being washed with water by filter, filter cake.
1HNMR (400MHz, DMSO-d6): 7.88 (m, 1H), 8.12-7.16 (m, 1H), 9.08 (t, J=2.0Hz, 1H),
9.37 (d, J=2.0Hz, 1H), 13.66 (s, 1H).
Claims (1)
- The synthetic method of 1.7,8- difluoro-quinoline -3- formic acid, it is characterised in that: the following steps are included:Step 1,7,8- difluoro-quinoline and N-bromosuccinimide, reaction generates bromo- 7, the 8- difluoro quinoline of 3- in a heated condition Quinoline, reaction dissolvent are acetic acid, and reaction temperature is 110 DEG C, reaction time 12h, and 7,8- difluoro-quinolines and N- bromo succinyl are sub- The molar ratio of amine is 1:1.2；Step 2, bromo- 7, the 8- difluoro-quinoline of 3- in the presence of palladium acetate, with carbon monoxide in a heated condition, reaction generate 7,8- Difluoro-quinoline -3- methyl formate, with methanol as solvent, the mass ratio of bromo- 7, the 8- difluoro-quinoline of 3- and palladium acetate is 1:0.5, one The pressure of carbonoxide is 60 psi, and reaction temperature is 60 DEG C；Step 3,7,8- difluoro-quinoline -3- methyl formate obtained by step 2 obtains 7,8- difluoro-quinoline-through basic hydrolysis at room temperature 3- formic acid.
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| CN201610292128.9A CN105906563B (en) | 2014-11-10 | 2014-11-10 | The synthetic method of 7,8- difluoro-quinoline -3- formic acid |
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| CN201410626253.XA CN104447543B (en) | 2014-11-10 | 2014-11-10 | 3-amino-7,8-difluoro-quinoline and the synthetic method of intermediate thereof |
| CN201610292128.9A CN105906563B (en) | 2014-11-10 | 2014-11-10 | The synthetic method of 7,8- difluoro-quinoline -3- formic acid |
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| CN113912533B (en) * | 2021-11-23 | 2023-06-20 | 西安凯立新材料股份有限公司 | Method for preparing 3, 6-dichloropicolinic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1659143A (en) * | 2001-03-01 | 2005-08-24 | 盐野义制药株式会社 | Nitrogen-containing heteroaryl compounds having HIV integrase inhibitory activity |
| CN102702098A (en) * | 2012-05-24 | 2012-10-03 | 盛世泰科生物医药技术(苏州)有限公司 | Synthesis of 6-methoxyl-1, 2, 3, 4 tetrahydroquinoline-5 methyl ester carboxylate |
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| AU6288700A (en) * | 1999-06-30 | 2001-01-22 | Aventis Pharma S.A. | Novel benzo[f]naphthyridine, preparation and compositions containing them |
| FR2804430B1 (en) * | 2000-01-28 | 2002-03-22 | Sanofi Synthelabo | 4-HETEROARYL-1,4-DIAZABICYCLO [3.2.2] NONANE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1659143A (en) * | 2001-03-01 | 2005-08-24 | 盐野义制药株式会社 | Nitrogen-containing heteroaryl compounds having HIV integrase inhibitory activity |
| CN102702098A (en) * | 2012-05-24 | 2012-10-03 | 盛世泰科生物医药技术(苏州)有限公司 | Synthesis of 6-methoxyl-1, 2, 3, 4 tetrahydroquinoline-5 methyl ester carboxylate |
Non-Patent Citations (1)
| Title |
|---|
| Selective Metal Cation Activation of a DNA Alkylating Agent: Synthesis and Evaluation of Methyl 1,2,9,9a-Tetrahydrocyclopropa[c]pyrido[3,2-e]indol-4-one-7-carboxylate (CPyI);Dale L. Boger et al.,;《J. Org. Chem.》;20000510;第65卷;第4090页Scheme 1和第4096页右栏第3段 |
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