CN109232562A - A kind of synthetic method of the chloro- 6- carboxylic acid of 7- azaindole -5- - Google Patents
A kind of synthetic method of the chloro- 6- carboxylic acid of 7- azaindole -5- Download PDFInfo
- Publication number
- CN109232562A CN109232562A CN201811245323.1A CN201811245323A CN109232562A CN 109232562 A CN109232562 A CN 109232562A CN 201811245323 A CN201811245323 A CN 201811245323A CN 109232562 A CN109232562 A CN 109232562A
- Authority
- CN
- China
- Prior art keywords
- compound
- azaindole
- dissolved
- carboxylic acid
- added
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The present invention relates to a kind of synthetic methods of chloro- 6- carboxylic acid of 7- azaindole -5-.It mainly solves to have no the technical issues of it is suitable for industrialization efficient synthesis now.Synthesis step of the present invention: 3,6- dichloropyridine -2- carboxylic acids are dissolved in the solvent of the tert-butyl alcohol and pyridine, and paratoluensulfonyl chloride is added, and obtain compound 1, product is without purification；Compound 1 and NSC 334072 are in Pd2(dba)3It is coupled under the catalysis of xant-Phos, adds hydroxylamine hydrochloride, crude product column Chromatographic purification obtains compound 2；Compound 2, which is dissolved in acetic acid, is added NIS heating reaction, and crude product column Chromatographic purification obtains compound 3；Compound 3 is dissolved in tetrahydrofuran, and trimethylsilyl acetylene, cuprous iodide, Pd (PPh is added3)2Cl2And triethylamine, it reacts under nitrogen protection, products therefrom 4 is without purification；Compound 4 is dissolved in dry N-Methyl pyrrolidone, potassium tert-butoxide is added, overnight, crude product ethyl acetate is washed, and target product is obtained by filtration for heating reaction.
Description
Technical field
The present invention relates to azaindole heterocyclic compounds, are related specifically to a kind of chloro- 6- carboxylic acid of 7- azaindole -5-
The synthetic method of (No. CAS is 1246088-49-2).
Background technique
Azaindole heterocyclic compounds are widely distributed important organic compounds in a kind of nature, there is the life of multiplicity
Object activity and high pharmaceutical chemistry researching value.Such as variolin B(Chem. Rev., 2009,109,3080-
3098) be exactly the compound of a kind of ring of azaindole containing 7- separated from the sponge of the South Pole, research shows that be it is a kind of very
Promising anticancer agent.There are also diazarebeccamycin(Eur. J. Med. Chem., 2003,38,123-140),
A kind of 7- 7-azaindole derivatives being synthesized, are also proved to have good anticancer activity.
The chloro- 6- carboxylic acid of 7- azaindole -5- can be used for synthesizing a variety of 7- 7-azaindole derivatives as medicine intermediate.
But it is suitable for the not disclosed report of industrialized synthetic method about it so far.
Summary of the invention
The object of the present invention is to provide a kind of synthetic methods of chloro- 6- carboxylic acid of 7- azaindole -5-, mainly solve present
Have no the technical issues of it is suitable for industrialization efficient synthesis.
Technical solution of the present invention is as follows: a kind of synthetic method of the chloro- 6- carboxylic acid of 7- azaindole -5-, comprising the following steps:
(1) 3,6- dichloropyridine -2- carboxylic acid are dissolved in the solvent of the tert-butyl alcohol and pyridine, and paratoluensulfonyl chloride is added, obtains chemical combination
Object 1, product is without purification；
(2) compound 1 and NSC 334072 are in Pd2(dba)3It is coupled under the catalysis of xant-Phos, adds hydroxylamine hydrochloride,
Crude product column Chromatographic purification, obtains compound 2；
(3) compound 2, which is dissolved in acetic acid, is added NIS, and heating reaction, crude product column Chromatographic purification obtains compound 3；
(4) compound 3 is dissolved in tetrahydrofuran, and trimethylsilyl acetylene, cuprous iodide, Pd (PPh is added3)2Cl2And triethylamine, nitrogen
The lower reaction of protection, products therefrom 4 is without purification；
(5) compound 4 is dissolved in dry N-Methyl pyrrolidone, and potassium tert-butoxide is added, and heating reaction is stayed overnight, crude product ethyl acetate
It washes, target product is obtained by filtration.
Reaction route of the invention is as follows:
In above-mentioned reaction, pyridine is dry with molecular sieve, and paratoluensulfonyl chloride adds under ice-water bath, and temperature is 0 DEG C ~ 5 DEG C.Step 2
85 DEG C ~ 95 DEG C of coupling reaction temperature, preferable reaction temperature is 90 DEG C, and the reaction time 1 ~ 2 hour, the preferably time was 1.5 hours, is added
After complete hydroxylamine hydrochloride, react at room temperature 1 hour.Step 3 reaction temperature is 50 DEG C ~ 60 DEG C, and preferable reaction temperature is 55 DEG C, reaction 6
Hour.Step 4 reaction temperature is 20 DEG C ~ 35 DEG C, and preferable reaction temperature is 30 DEG C, and the reaction time is 0.5 ~ 2 hour, preferably instead
It is 1 hour between seasonable.Step 5 reaction temperature is 60 DEG C ~ 70 DEG C, and preferable reaction temperature is 65 DEG C.
Present invention abbreviation meaning: TosCL: paratoluensulfonyl chloride；NIS:N- N-iodosuccinimide；Xant-Phos:4,5-
Bis- (diphenylphosphine) -9,9- xanthphos；T-BuOK: potassium tert-butoxide.
The beneficial effects of the present invention are: agents useful for same is cheap, reaction condition is simple, and target product and intermediate are easily purified,
The target product of high-purity can be obtained in mashing in ethyl acetate.
Specific embodiment
Embodiment 1: the preparation chloro- 6- carboxylic acid of 7- azaindole -5-.
Step 1:
3,6- dichloropyridine -2- carboxylic acids (78.3 g, 0.408 mol) are dissolved in the tert-butyl alcohol (780 mL) and pyridine (215 mL),
Ice-water bath is cooled to 0 DEG C.Paratoluensulfonyl chloride (185 g, 0.97 mol) is added portionwise, adds to be warmed to room temperature and is stirred overnight.Instead
Answer liquid concentration dry, 5% aqueous citric acid solution of mass percentage concentration (2 L) is added in residue, ethyl acetate (2 L) extraction.Organic phase
It is washed again with 5% sodium bicarbonate aqueous solution of mass percentage concentration (500 mL), saturated salt solution (500 mL) is washed, the anhydrous sulphur of organic phase
Sour sodium dries, filters, and compound 1(100 g, 98% yield are done to obtain in concentration).1H NMR (400 MHz, CDCl3) 1.63(s,
9H), 7.35(d,J=8.4 Hz, 1H), 7.71(d,J=8.4 Hz, 1H).
Step 2:
Compound 1(50 g, 0.202 mol), cesium carbonate (132 g, 0.404 mol), Pd2(dba)3(9.27 g, 0.01
Mol) and xant-Phos(11.71 g, 0.02 mmol) be added Isosorbide-5-Nitrae-dioxane (1 L) in, nitrogen replace 3 times.Hexichol first
Imines (44 g, 0.242 mol) is added thereto, and is reacted 1.5 hours at 90 DEG C.It is cooled to room temperature, it is dilute that ethyl acetate (2 L) is added
It releases, filters, filtrate water is washed.Organic phase anhydrous sodium sulfate is dry, is concentrated under reduced pressure dry.Gained crude product is dissolved in methanol (1 L), is added
Enter sodium acetate (50 g, 0.6 mol) and hydroxylamine hydrochloride (28 g, 0.4 mol), is stirred at room temperature 1 hour.Reaction solution pours into 1N's
In sodium hydrate aqueous solution (2 L), methylene chloride extracts (1 L * 2).It is dry to merge organic phase anhydrous sodium sulfate, is concentrated under reduced pressure
Dry, crude product column Chromatographic purification (petroleum ether: ethyl acetate volume ratio=3:1) obtains compound 2(15 g, 32% yield).
Step 3:
Compound 2(15 g, 65.6 mmol) it is dissolved in acetic acid (200 mL) addition NIS(16.3 g, 72.1 mmol), mixed liquor exists
It is stirred 6 hours at 55 DEG C.It is cooled to room temperature, is concentrated under reduced pressure acetic acid, residue is dissolved in ethyl acetate (1 L) with unsaturated carbonate hydrogen
Sodium water solution is washed, and organic phase anhydrous sodium sulfate is dry, is concentrated under reduced pressure dry.Remaining crude product column Chromatographic purification (petroleum ether: ethyl acetate
Volume ratio=5:1) obtain compound 3(10.8 g, 46% yield).
Step 4:
Compound 3(9.7 g, 27 mmol) it is dissolved in tetrahydrofuran (50 mL), it is added triethylamine (16 mL), cuprous iodide (104
Mg, 0.54 mmol) and palladium diphenyl phosphine dichloride (387 mg, 0.54 mmol).After nitrogen is replaced 3 times, trimethyl is added
Silico acetylene (3.5 g, 35 mmol), reaction solution stirs 1 hour at 30 DEG C.Ethyl acetate (200 mL) dilution is added, washes,
Saturated common salt washing, organic phase anhydrous sodium sulfate is dry, is concentrated under reduced pressure and does to obtain compound 4(7.5 g, 85% yield), without mentioning
It is pure, it throws in next step.
Step 5:
Compound 4(3.5 g, 10.8 mmol) it is dissolved in dry N-Methyl pyrrolidone (80 mL), potassium tert-butoxide (6.6 is added
G, 22.7 mmol) then react overnight at 65 DEG C.Second day, reaction solution was cooled to room temperature, and was poured into water (300 mL).Use 1M
Aqueous hydrochloric acid solution tune pH to 5 ~ 6, methylene chloride/methanol (5/1 v/v) extraction.Organic phase anhydrous sodium sulfate is dry, depressurizes dense
Contracting is dry.Ethyl acetate (30 mL) stirring is added in crude product, filters to obtain product (1.0 g, 37% yield).1H NMR (400 MHz,
DMSO-d6) 6.51(dd,J=3.2 Hz, 1.6Hz, 1H), 7.73(t,J=2.8 Hz, 1H), 8.18(s, 1H), 12.11(s,
1H), 13.44(br, 1H).
Embodiment 2, step 2 coupling reaction temperature are 85 DEG C, the reaction time 2 hours；Step 3 reaction temperature is 50 DEG C；Step
Rapid 4 reaction temperature is 20 DEG C, and the reaction time is 2 hours；Step 5 reaction temperature is 60 DEG C.Remaining is the same as embodiment 1.
Embodiment 3, step 2 coupling reaction temperature are 95 DEG C, the reaction time 1 hour；Step 3 reaction temperature is 60 DEG C；Step
Rapid 4 reaction temperature is 35 DEG C, and the reaction time is 0.5 hour；Step 5 reaction temperature is 70 DEG C.Remaining is the same as embodiment 1.
Claims (6)
1. a kind of synthetic method of the chloro- 6- carboxylic acid of 7- azaindole -5-, it is characterized in that: the following steps are included:
(1) 3,6- dichloropyridine -2- carboxylic acid are dissolved in the solvent of the tert-butyl alcohol and pyridine, and paratoluensulfonyl chloride is added, obtains chemical combination
Object 1, product is without purification；
(2) compound 1 and NSC 334072 are in Pd2(dba)3It is coupled under the catalysis of xant-Phos, adds hydroxylamine hydrochloride, slightly
Capo Chromatographic purification obtains compound 2；
(3) compound 2, which is dissolved in acetic acid, is added NIS, and heating reaction, crude product column Chromatographic purification obtains compound 3；
(4) compound 3 is dissolved in tetrahydrofuran, and trimethylsilyl acetylene, cuprous iodide, Pd (PPh is added3)2Cl2And triethylamine, nitrogen
The lower reaction of protection, products therefrom 4 is without purification；
(5) compound 4 is dissolved in dry N-Methyl pyrrolidone, and potassium tert-butoxide is added, and heating reaction is stayed overnight, crude product ethyl acetate
It washes, target product is obtained by filtration, synthetic line is as follows:
。
2. the synthetic method of a kind of chloro- 6- carboxylic acid of 7- azaindole -5- according to claim 1, it is characterized in that: described
One step, pyridine is dry with molecular sieve, and paratoluensulfonyl chloride adds under ice-water bath, and temperature is 0 DEG C ~ 5 DEG C.
3. the synthetic method of a kind of chloro- 6- carboxylic acid of 7- azaindole -5- according to claim 1, it is characterized in that: described
Two steps, coupling reaction temperature are 85 DEG C ~ 95 DEG C, are reacted 1 ~ 2 hour；After adding hydroxylamine hydrochloride, react at room temperature 1 hour.
4. the synthetic method of a kind of chloro- 6- carboxylic acid of 7- azaindole -5- according to claim 1, it is characterized in that: described
Three steps, reaction temperature are 50 DEG C ~ 60 DEG C, are reacted 6 hours.
5. the synthetic method of a kind of chloro- 6- carboxylic acid of 7- azaindole -5- according to claim 1, it is characterized in that: described
Four steps, reaction temperature are 20 DEG C ~ 35 DEG C, are reacted 0.5 ~ 2 hour.
6. the synthetic method of a kind of chloro- 6- carboxylic acid of 7- azaindole -5- according to claim 1, it is characterized in that: described
Five steps, reaction temperature are 60 DEG C ~ 70 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811245323.1A CN109232562A (en) | 2018-10-24 | 2018-10-24 | A kind of synthetic method of the chloro- 6- carboxylic acid of 7- azaindole -5- |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811245323.1A CN109232562A (en) | 2018-10-24 | 2018-10-24 | A kind of synthetic method of the chloro- 6- carboxylic acid of 7- azaindole -5- |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109232562A true CN109232562A (en) | 2019-01-18 |
Family
ID=65081979
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811245323.1A Pending CN109232562A (en) | 2018-10-24 | 2018-10-24 | A kind of synthetic method of the chloro- 6- carboxylic acid of 7- azaindole -5- |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109232562A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110713457A (en) * | 2019-10-09 | 2020-01-21 | 中国农业大学 | Sulfapyridine hapten and artificial antigen as well as preparation method and application thereof |
| CN114380732A (en) * | 2021-12-16 | 2022-04-22 | 上海毕得医药科技股份有限公司 | Preparation method of fluoro-indole carboxylic acid compounds |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101676285A (en) * | 2004-03-30 | 2010-03-24 | 沃泰克斯药物股份有限公司 | Azaindoles useful as inhibitors of JAK and other protein kinases |
| WO2012138734A1 (en) * | 2011-04-07 | 2012-10-11 | Merck Sharp & Dohme Corp. | C5-c6 oxacyclic-fused thiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
| US20170174688A1 (en) * | 2014-12-18 | 2017-06-22 | Abbvie Inc. | Substituted Indoles |
| CN107001357A (en) * | 2014-08-27 | 2017-08-01 | Viiv保健英国第五有限公司 | Imidazo [1,2 a] pyridine derivate as human immunodeficiency virus replication inhibitor |
| CN107011256A (en) * | 2017-06-09 | 2017-08-04 | 康化（上海）新药研发有限公司 | A kind of synthetic method of the aminopyridine of 5 iodine, 4 methoxyl group 2 |
| CN107056781A (en) * | 2017-05-18 | 2017-08-18 | 康化（上海）新药研发有限公司 | A kind of synthetic method of the formaldoxime of (E) 5 methyl 1H pyrrolo-es [2,3 b] pyridine 3 |
| CN108026113A (en) * | 2015-08-10 | 2018-05-11 | Viiv保健英国第五有限公司 | Imidazopyridine macrocyclic compounds as the inhibitor of human immunodeficiency virus replication |
-
2018
- 2018-10-24 CN CN201811245323.1A patent/CN109232562A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101676285A (en) * | 2004-03-30 | 2010-03-24 | 沃泰克斯药物股份有限公司 | Azaindoles useful as inhibitors of JAK and other protein kinases |
| WO2012138734A1 (en) * | 2011-04-07 | 2012-10-11 | Merck Sharp & Dohme Corp. | C5-c6 oxacyclic-fused thiadiazine dioxide compounds as bace inhibitors, compositions, and their use |
| CN107001357A (en) * | 2014-08-27 | 2017-08-01 | Viiv保健英国第五有限公司 | Imidazo [1,2 a] pyridine derivate as human immunodeficiency virus replication inhibitor |
| US20170174688A1 (en) * | 2014-12-18 | 2017-06-22 | Abbvie Inc. | Substituted Indoles |
| CN108026113A (en) * | 2015-08-10 | 2018-05-11 | Viiv保健英国第五有限公司 | Imidazopyridine macrocyclic compounds as the inhibitor of human immunodeficiency virus replication |
| CN107056781A (en) * | 2017-05-18 | 2017-08-18 | 康化（上海）新药研发有限公司 | A kind of synthetic method of the formaldoxime of (E) 5 methyl 1H pyrrolo-es [2,3 b] pyridine 3 |
| CN107011256A (en) * | 2017-06-09 | 2017-08-04 | 康化（上海）新药研发有限公司 | A kind of synthetic method of the aminopyridine of 5 iodine, 4 methoxyl group 2 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110713457A (en) * | 2019-10-09 | 2020-01-21 | 中国农业大学 | Sulfapyridine hapten and artificial antigen as well as preparation method and application thereof |
| CN114380732A (en) * | 2021-12-16 | 2022-04-22 | 上海毕得医药科技股份有限公司 | Preparation method of fluoro-indole carboxylic acid compounds |
| CN114380732B (en) * | 2021-12-16 | 2024-01-23 | 上海毕得医药科技股份有限公司 | Preparation method of fluoroindole carboxylic acid compound |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102675314A (en) | Method for synthesizing apixaban | |
| CN106432030A (en) | Preparation method of brivaracetam | |
| CN109232562A (en) | A kind of synthetic method of the chloro- 6- carboxylic acid of 7- azaindole -5- | |
| CN102617434B (en) | Process for preparing Vildagliptin by one-pot method | |
| CN101817773A (en) | Preparation method of chiral alpha-non-natural amino acid | |
| CN103980188B (en) | The synthetic method of a kind of pyrrole Lun Panai and the synthetic method of intermediate and intermediate thereof | |
| CN105272966A (en) | Preparation method of ALK inhibitor crizotinib and analogue or salt thereof | |
| TWI540119B (en) | Compound, method for producing the same, and method for producing oseltamivir phosphate | |
| CN107540575B (en) | Preparation method of sitagliptin intermediate | |
| WO2016141835A1 (en) | Method for synthesizing pharmaceutical intermediate phenanthrene compound using copper trifluomethanesulfonate | |
| JP2016198736A (en) | Catalyst having amino-salicylaldimine ligand coordinated to metal and method for producing iodine cyclized product using the same | |
| CN107236015A (en) | A kind of Abiraterone acetate reduction impurity and preparation method thereof | |
| CN110963937B (en) | Asymmetric synthesis method of colchicine and allocolchicine | |
| US20230348390A1 (en) | Method for preparing methyl(s)-2-amino-3-(4-(2,3-dimethylpyridin-4-yl)phenylpropionate and salt thereof | |
| CN108947919A (en) | A kind of novel processing step and its key intermediate of gout suppressant Lesinurad | |
| WO2020177347A1 (en) | Oxygen-guided synthesis method for 7-alkynyl indole compound | |
| CN110015978A (en) | O- [2- [[tertbutyloxycarbonyl] amino] ethyl]-N- [fluorenylmethyloxycarbonyl]-l-tyrosine synthetic method | |
| CN106317060A (en) | Preparation method of conivaptan hydrochloride | |
| CN114262293B (en) | Preparation method of 2-amino-3-bromopyridine | |
| CN110092802B (en) | Method for preparing trepetidine intermediate | |
| CN113956268B (en) | 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine and synthetic method | |
| WO2023216317A1 (en) | Method for synthesizing nirmatrelvir intermediate | |
| CN110551069B (en) | Synthesis method of 5-phenylpentanol compound and intermediate thereof | |
| WO2007049812A1 (en) | 3-HYDROXYMETHYLBENZO[b]THIOPHENE DERIVATIVE AND METHOD FOR PRODUCING SAME | |
| CN116925001A (en) | Synthesis method of letrozole analogue of breast cancer resisting medicine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190118 |