CN106854173A - A kind of preparation method of the carboxylate methyl ester of 2 carbonyl indolone 6 - Google Patents
A kind of preparation method of the carboxylate methyl ester of 2 carbonyl indolone 6 Download PDFInfo
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- CN106854173A CN106854173A CN201611201518.7A CN201611201518A CN106854173A CN 106854173 A CN106854173 A CN 106854173A CN 201611201518 A CN201611201518 A CN 201611201518A CN 106854173 A CN106854173 A CN 106854173A
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- indolone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
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- Organic Chemistry (AREA)
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Abstract
It is related to a kind of new method for preparing the carboxylate methyl ester of 2 carbonyl indolone 6 the present invention relates to formula, the method reactions steps are simple, high income, and can be with volume production.
Description
1st, technical field
The invention belongs to pharmaceutical technology field, it is related to a kind of method for preparing 2- carbonyl indolone -6- carboxylate methyl esters.
2nd, background technology
Nintedanib is many kinds of kinase inhibitors of VEGFR, PDGFR, FGFR and FLT3, researched and developed by Boehringer Ingelheim
The medicine for treating idiopathic pulmonary fibrosis is planted, listing is ratified by food and medicine Surveillance Authority of the U.S. first in 2014.10.
Idiopathic pulmonary fibrosis (IPF) is that a kind of reason is not clear, scorching with Diffuse alveolar and alveolar structure disorder ultimately results in interstitial lung
The disease prognosis that fibrosis is characterized are bad, even if early-stage cases have reaction to hormone therapy, life cycle typically also only has 5 years.
At present in the prior art, the preparation on Nintedanib and its intermediate is described if in WO2009071524
Method, but preparation method is cumbersome, and yield is low, and optical purity is low.6- methoxycarbonyls are described in CN102267934A
The preparation method of indolone, but the method reduces (palladium carbon or Raney's nickel) using metal catalytic is susceptible to heavy-metal residual,
Deal with improperly and take final products to and can produce injury to people, and since it is desired that hydro-reduction, has used hydriding reactor to need High Pressure Hydrogen
Change, blast easily occurs dangerous.
3rd, the content of the invention
It is an object of the invention to provide it is a kind of synthesize it is simple, safely, be easy to amplify the 2- carbonyl indolone -6- carboxylic acids of production
The preparation method of methyl esters, concrete technical scheme is as follows：
A () 3- aminobenzoic acids under activator effect, carry out esterification and obtain (E) -3- (2- (hydroxyls with hydroxylamine hydrochloride
Base imines) acetylamino) benzoic acid；
B () (E) -3- (2- (hydroxyl imide) acetylamino) benzoic acid is dehydrated under the conditions of sulfuric acid, parental materials occur anti-
2,3- dicarbapentaborane indolone -6- carboxylic acids should be obtained；
C there is reduction reaction in () 2,3- dicarbapentaborane indolone -6- carboxylic acids, with acid for adjusting pH, then carry out that 2- carbonyls are obtained by extraction
Base indolone -6- carboxylic acids；
D () 2- carbonyls indolone -6- carboxylic acids carry out esterification and obtain 2- carbonyl indolone -6- carboxylics under activator effect
Sour methyl esters.
Activator in the step a is trifluoro acetaldehyde, bromal or trichloroacetaldehyde, preferably trichloroacetaldehyde；Reaction temperature
It is 40~100 DEG C to spend, preferably 80~90 DEG C；Reaction time is 1~10 hour, preferably 2~4 hours；3- aminobenzoic acids and work
The mol ratio of agent is 1:1~1:2, preferably 1:1.1~1:1.2.
Reaction temperature in the step b is 40~110 DEG C, preferably 70~90 DEG C；Reaction time is 8~24 hours, excellent
Select 10~14 hours.
The reaction dissolvent of the step c is methyl alcohol, ethanol, tetrahydrofuran, isopropanol, the tert-butyl alcohol, glycol dimethyl ether, second
One or more in glycol monomethyl ether, DMF, preferably methyl alcohol；The acid for using is hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or vinegar
Acid, preferably hydrochloric acid；Regulation pH is 0-5, preferably 1~2；The extractant for using is dichloromethane or ethyl acetate, preferably dichloromethane
Alkane；Extraction times are 1-5 times, preferably 2~3 times；Reaction temperature is 40~80 DEG C, preferably 50~60 DEG C；Reaction time is 2~8
Hour, preferably 3~4 hours.
The activator of the step d is POCl3, oxalyl chloride or thionyl chloride, preferably thionyl chloride；2- carbonyl indoles
Ketone -6- carboxylic acids are 1 with the mol ratio of activator:1~1:3, preferably 1:1.1~1:1.5；Mashing solvent is methyl alcohol, ethanol, oil
Ether, n-hexane, hexamethylene, preferably one or more of normal heptane, methyl alcohol；Reaction temperature is 20~65 DEG C, preferably 55~60 DEG C；
Reaction time is 1~10 hour, preferably 4~6 hours.
The present invention has advantages below：
1) reaction condition of the present invention is gentle, it is easy to operation and control；
2) high income of reactions steps of the invention；
3) reaction raw materials of the present invention are easy to get, low cost；
4) present invention reduces pollution of the heavy metal to environment without using palladium carbon or heavy metal reducing agent；
5) production technology of the present invention can realize industrialization, can carry out hundred feather weight productions.
4th, specific embodiment
The specific embodiment of form, makees further specifically to the above of the invention by the following examples
It is bright.But this scope for being interpreted as above-mentioned theme of the invention should not be only limitted to following examples.
The preparation of the 2- carbonyl indolone -6- carboxylate methyl esters of embodiment 1
1st, the preparation of (E) -3- (2- (hydroxyl imide) acetylamino) benzoic acid
1.5L water, 1kg sodium sulphate, water and trichloroacetaldehyde (180.4g, 1.1mol) are added in 5L reaction bulbs, it is slow to add
Enter the mixed liquor of 3- aminobenzoic acids (137g, 1mol) and hydrochloric acid, stirring add hydroxylamine hydrochloride the aqueous solution (6mol/L,
500ml), 100 degree are warming up to.Stirring 2 hours, reaction is finished, and room temperature is down to naturally and separates out solid, and suction filtration, solid is washed with water,
60 DEG C of forced air dryings obtain white crystalline solid (E) -3- (2- (hydroxyl imide) acetylamino) benzoic acid 142g, yield to dry
68%.
2nd, the preparation of 2,3- dicarbapentaborane indolone -6- carboxylic acids
By in 200ml sulfuric acid addition reaction bulb, (E) -3- (2- (hydroxyl imide) acetylamino) benzoic acid is slowly added to
(100g, 0.48mol), stirring is warming up to 70 degree, stirs 14 hours, after completion of the reaction, reaction solution is slowly dropped to the water of 1L
In, solid is separated out, suction filtration obtains product 2,3- dicarbapentaborane indolone -6- carboxylic acid 52g, yield 56% after drying.
3rd, the preparation of 2- carbonyls indolone -6- carboxylic acids
Hydrazine hydrate (60ml) in 2,3- dicarbapentaborane indolone -6- carboxylic acids to 500ml methyl alcohol, will be slowly added dropwise, stirred
It is warmed up to 60 degree.Reaction steams methyl alcohol after 4 hours, add watery hydrochloric acid, and regulation pH value is 2-3, is extracted with DCM (500ml)
Three times, merge organic phase, solid is gone out after being evaporated, filter to obtain 2- carbonyl indolone -6- carboxylic acid 45g, yield：69%.
4th, the preparation of 2- carbonyls indolone -6- carboxylate methyl esters
Will be during 2- carbonyls indolone -6- carboxylic acids (40g, 0.23mol) add reaction bulb, in adding methyl alcohol 200ml, stirring,
Thionyl chloride (32g, 0.27mol) is slowly added dropwise, 60 degree are warmed up to.Reaction 6 hours, after reaction completely, is evaporated, and is beaten with methyl alcohol
Slurry, filtering, dries to obtain 2- carbonyl indolone -6- carboxylate methyl ester 40g, yield：93%.
1H NMR(400MHz,25℃,DMSO-d6)：
10.53 (s, 1H), 7.57 (dd, J=7.72Hz, J=2.88Hz, 1H), 7.34 (d, J=7.72Hz, 2H), 3.84
(s, 3H), 3.57 (s, 1H).
Claims (9)
1. a kind of preparation method of 2- carbonyls indolone -6- carboxylate methyl esters, it is characterised in that comprise the following steps：
A () 3- aminobenzoic acids under activator effect, carry out esterification and obtain (E) -3- (2- (hydroxyl Asias with hydroxylamine hydrochloride
Amine) acetylamino) benzoic acid；
B () (E) -3- (2- (hydroxyl imide) acetylamino) benzoic acid is dehydrated under the conditions of sulfuric acid, electrophilic substitution reaction occurs and obtains
To 2,3- dicarbapentaborane indolone -6- carboxylic acids；
C there is reduction reaction in () 2,3- dicarbapentaborane indolone -6- carboxylic acids, with acid for adjusting pH, then carry out that 2- carbonyls Yin is obtained by extraction
Diindyl ketone -6- carboxylic acids；
D () 2- carbonyls indolone -6- carboxylic acids carry out esterification and obtain 2- carbonyl indolone -6- carboxylic acid first under activator effect
Ester.
2. preparation method according to claim 1, it is characterised in that：
Activator in the step a is trifluoro acetaldehyde, bromal or trichloroacetaldehyde；
Reaction temperature is 40~100 DEG C；
Reaction time is 1~10 hour；
3- aminobenzoic acids are 1 with the mol ratio of activator:1~1:2.
3. preparation method according to claim 2, it is characterised in that：
Activator in the step a is trichloroacetaldehyde；
Reaction temperature is 80~90 DEG C；
Reaction time is 2~4 hours；
3- aminobenzoic acids are 1 with the mol ratio of activator:1.1~1:1.2.
4. preparation method according to claim 1, it is characterised in that the reaction temperature in the step b is 40~110
℃；Reaction time is 8~24 hours.
5. preparation method according to claim 4, it is characterised in that reaction temperature is 70~90 DEG C in the step b；Instead
It is 10~14 hours between seasonable.
6. preparation method according to claim 1, it is characterised in that：
The reaction dissolvent of the step c is methyl alcohol, ethanol, tetrahydrofuran, isopropanol, the tert-butyl alcohol, glycol dimethyl ether, ethylene glycol
One or more in monomethyl ether, DMF；
The acid for using is hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid or acetic acid；Regulation pH is 0-5；
The extractant for using is dichloromethane or ethyl acetate；Extraction times are 1-5 times；
Reaction temperature is 40~80 DEG C；
Reaction time is 2~8 hours.
7. preparation method according to claim 6, it is characterised in that：
The reaction dissolvent of the step c is methyl alcohol；
The acid for using is hydrochloric acid；Regulation pH is 1~2；
The extractant for using is dichloromethane；Extraction times are 2~3 times；
Reaction temperature is 50~60 DEG C；
Reaction time is 3~4 hours.
8. preparation method according to claim 1, it is characterised in that：
The activator of the step d is POCl3, oxalyl chloride or thionyl chloride；
2- carbonyls indolone -6- carboxylic acids are 1 with the mol ratio of activator:1~1:3；
Mashing solvent be methyl alcohol, ethanol, petroleum ether, n-hexane, hexamethylene, one or more of normal heptane；
Reaction temperature is 20~65 DEG C；
Reaction time is 1~10 hour.
9. preparation method according to claim 1, it is characterised in that：
The activator of the step d is thionyl chloride；
2- carbonyls indolone -6- carboxylic acids are 1 with the mol ratio of activator:1.1~1:1.5；
Mashing solvent is methyl alcohol；
Reaction temperature is 55~60 DEG C；
Reaction time is 4~6 hours.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611201518.7A CN106854173A (en) | 2016-12-23 | 2016-12-23 | A kind of preparation method of the carboxylate methyl ester of 2 carbonyl indolone 6 |
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| CN201611201518.7A CN106854173A (en) | 2016-12-23 | 2016-12-23 | A kind of preparation method of the carboxylate methyl ester of 2 carbonyl indolone 6 |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006064044A1 (en) * | 2004-12-17 | 2006-06-22 | Boehringer Ingelheim International Gmbh | Indolinones and their use as antiproliferative agents |
| TW200730495A (en) * | 2005-12-20 | 2007-08-16 | Ube Industries | Process for producing 2-oxindole compound |
| WO2013079223A1 (en) * | 2011-12-02 | 2013-06-06 | Phenex Pharmaceuticals Ag | Pyrrolo carboxamides as modulators of orphan nuclear receptor rar-related orphan receptor-gamma (rorϒ, nr1f3) activity and for the treatment of chronic inflammatory and autoimmune diseases |
| CN103288709A (en) * | 2013-05-17 | 2013-09-11 | 安徽世华化工有限公司 | Synthesis method of 5-fluorine-indol-2-ketone |
| US20150284327A1 (en) * | 2014-04-04 | 2015-10-08 | Auspex Pharmaceuticals, Inc. | Oxindole inhibitors of tyrosine kinase |
| CN105272901A (en) * | 2014-07-25 | 2016-01-27 | 牛誉博 | 5-carboxylic acid indolinone preparation method |
-
2016
- 2016-12-23 CN CN201611201518.7A patent/CN106854173A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006064044A1 (en) * | 2004-12-17 | 2006-06-22 | Boehringer Ingelheim International Gmbh | Indolinones and their use as antiproliferative agents |
| TW200730495A (en) * | 2005-12-20 | 2007-08-16 | Ube Industries | Process for producing 2-oxindole compound |
| WO2013079223A1 (en) * | 2011-12-02 | 2013-06-06 | Phenex Pharmaceuticals Ag | Pyrrolo carboxamides as modulators of orphan nuclear receptor rar-related orphan receptor-gamma (rorϒ, nr1f3) activity and for the treatment of chronic inflammatory and autoimmune diseases |
| CN103288709A (en) * | 2013-05-17 | 2013-09-11 | 安徽世华化工有限公司 | Synthesis method of 5-fluorine-indol-2-ketone |
| US20150284327A1 (en) * | 2014-04-04 | 2015-10-08 | Auspex Pharmaceuticals, Inc. | Oxindole inhibitors of tyrosine kinase |
| CN105272901A (en) * | 2014-07-25 | 2016-01-27 | 牛誉博 | 5-carboxylic acid indolinone preparation method |
Non-Patent Citations (1)
| Title |
|---|
| GERALD J. ROTH，等: "Design, Synthesis, and Evaluation of Indolinones as Triple Angiokinase Inhibitors and the Discovery of a Highly Specific 6-Methoxycarbonyl-Substituted Indolinone (BIBF 1120)", 《J. MED. CHEM.》 * |
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