CN101948433B - Method for separating and purifying substituted indazole isomers - Google Patents
Method for separating and purifying substituted indazole isomers Download PDFInfo
- Publication number
- CN101948433B CN101948433B CN2010102759155A CN201010275915A CN101948433B CN 101948433 B CN101948433 B CN 101948433B CN 2010102759155 A CN2010102759155 A CN 2010102759155A CN 201010275915 A CN201010275915 A CN 201010275915A CN 101948433 B CN101948433 B CN 101948433B
- Authority
- CN
- China
- Prior art keywords
- indazole
- amino
- ethyl
- purity
- hydroxyethyl
- 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.)
- Expired - Fee Related
Links
- 0 *N1N=CC2=CI=CC=C12 Chemical compound *N1N=CC2=CI=CC=C12 0.000 description 2
- YHDSYPAEALUJCG-UHFFFAOYSA-N CCCN1CC(CCC(OC)OC)CC1 Chemical compound CCCN1CC(CCC(OC)OC)CC1 YHDSYPAEALUJCG-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a method for separating and purifying substituted indazole derivative isomers with structural general formulas shown in the specification, which belongs to the field of organic chemistry. In the method, a mixed solvent is used for recrystallizing; and two indazole derivative isomers are separated to obtain a single isomer compound with the purity of over 99 percent. The method has the advantages of simple and convenient separation and purification and easy industrialized production.
Description
Technical field
The present invention relates to a kind of separation purification method of substituted indazole isomer, the separation purification method of particularly a kind of 1-position and 2-position substituted indazole isomer belongs to organic chemistry filed.
Background technology
Indazole compounds is a kind of important pharmaceutical intermediate; Its verivate has the NO synthetic enzyme and suppresses, hinders sperm generation, pain relieving, antiviral, hiv protease restraining effect; Therefore in treatments such as antitumor, virus and fungi, have a good application prospect, about indazole derivatives synthesize and bioactive research receives extensive concern in recent years.Because the indazole parent nucleus is very rare at nature, so its synthetic is most important.The 1-position of indazole and 2-position are active amidos; Can introduce the various active group easily, and verivate biologically active all, therefore carry out functionalization in the 1-position and the 2-position of indazole; Thereby expand indazole derivatives application, improve its activity, many research reports have been arranged.In present 1 preparation process with the substituted indazole derivatives in 2-position, because the selectivity of 1-position and the reaction of 2 position functionals is very poor, cause the generation of mixture, separation purification method all adopts column chromatography at present, is inappropriate for suitability for industrialized production.The visible I.Shimada of relevant report, K.Maeno, K.-ichi Kazuta, et al, Bioorg.Med.Chem., 2008,1966; A.Schmidt, A.Beutler, B.Snovydovych, Eur.J.Org.Chem., 2008,4073., 1 separation purification method with the substituted indazole derivatives in 2-position is studied, satisfying the suitability for industrialized production demand is present urgent problem for this reason.
Summary of the invention
Be difficult to the suitability for industrialized production problem to 1-position and 2-position substituted indazole derivatives isomer separation purifying, the object of the invention be to provide a kind of simple, practical, separation and purification is effective, 1 and the separation purification method of 2-position substituted indazole derivatives active being convenient to suitability for industrialized production.
For realizing the object of the invention, technical scheme is following:
The 1-position of institute's separation and purification and 2-position substituted indazole derivatives active isomer have following structure:
Its preparation method can be referring to A.J.Souers, J.Gao, et al, J.Med.Chem., 2005,1318; J.A.May, A.P.Dantanarayana, et al, J.Med.Chem.2006,318.
Its separation purification method is following:
With the substituted indazole derivatives isomer in 1-position and 2-position recrystallization in the mixed solvent of acetone, ethanol, methyl alcohol, acetonitrile or the THF of different ratios and water, obtain purity respectively greater than 99% single 1-position and 2-position substituted indazole isomer.
The mixed solvent volume ratio preferred 3/1～2/5 of used acetone, ethanol, THF, acetonitrile or methyl alcohol and water.
Preferred 5-amino-1-(2-hydroxyethyl)-indazole and the separation and purification of 5-amino-2-(2-hydroxyethyl)-indazole mixture and separation and purification of 4-amino-1-(2-pyrrolidyl ethyl)-indazole and 4-amino-2-(2-pyrrolidyl ethyl)-indazole mixture.
The principle of the invention is: utilize want isolating indazole isomer to have wetting ability hydroxyl, amido and nitro; Select water miscible organic solvent for use; According to the solvability difference of two kinds of indazole isomer in the mixed solvent of the organic solvent of different ratios and water, thereby separate.
Separation purification method advantage of the present invention is: through recrystallization solvent is screened; Adopt the mixed solvent recrystallization; Purifies and separates is carried out in 1-position and 2-position substituted indazole isomer, substitute present column chromatography method, step is few, easy and simple to handle, method is practical; Be easy to realize suitability for industrialized production, and separate the single 1-position obtain and 2-position substituted indazole isomer purity all greater than 99%.
Embodiment
For the present invention is explained better, it is following to lift embodiment:
Embodiment 1
The separation purification method of 5-amino-1-(2-hydroxyethyl)-indazole and 5-amino-2-(2-hydroxyethyl)-indazole mixture; Operate as follows: mix said mixture 10g with 30mL acetone/10mL water; Heating for dissolving, naturally cooling, filtration then obtains 5-amino-1-(2-hydroxyethyl)-indazole 5.3g; Purity 99.5%, its characteristic is following:
1H?NMR(DMSO-d6)：δ2.05(d，J＝18.9Hz，2H)，4.16～4.18(m，2H)，4.54～4.56(m，2H)，7.54(d，J＝7.2Hz，1H)，8.25(s，1H)，8.29(dd，J＝1.5，1.5Hz，1H)，8.74(d，J＝1.5Hz，1H).MS(ESI)m/z?178(M+H)
+。
Obtain 5-amino-2-(2-hydroxyethyl)-indazole 3.6g, purity 99.6%, its characteristic is following:
1H?NMR(DMSO-d6)：δ4.17～4.19(m，2H)，4.61～4.63(m，2H)，7.76(d，J＝7.2Hz，1H)，8.13(dd，J＝1.5，1.5Hz，1H)，8.30(s，1H)，8.74(d，J＝1.2Hz，1H).MS(ESI)m/z?178(M+H)
+。
Embodiment 2
The separation purification method of 5-amino-1-(2-hydroxyethyl)-indazole and 5-amino-2-(2-hydroxyethyl)-indazole mixture; Operate as follows: mix said mixture 10g with 20mL acetone/40mL water; Heating for dissolving; Naturally cooling, filtration then obtains 5-amino-2-(2-hydroxyethyl)-indazole 3.2g, purity 99.8%; 5-amino-1-(2-hydroxyethyl)-indazole 4.8g, purity 99.5%.Its characteristic such as embodiment 1.
Embodiment 3
The separation purification method of 5-amino-1-(2-hydroxyethyl)-indazole and 5-amino-2-(2-hydroxyethyl)-indazole mixture; Operate as follows: mix said mixture 8g with 16mL ethanol/30mL water; Heating for dissolving, naturally cooling, filtration then obtains incarnadine needle-like shape crystal; 5-amino-1-(2-hydroxyethyl)-indazole 4.7g, purity 99.2%; 5-amino-2-(2-hydroxyethyl)-indazole 4.3g, purity 99.3%.
Embodiment 4
The separation purification method of 5-amino-1-(2-hydroxyethyl)-indazole and 5-amino-2-(2-hydroxyethyl)-indazole mixture; Operate as follows: mix said mixture 8g with 25mL ethanol/18mL water; Heating for dissolving, naturally cooling, filtration then obtains the incarnadine needle-like crystal; 5-amino-2-(2-hydroxyethyl)-indazole 4.2g, purity 99.4%; 5-amino-1-(2-hydroxyethyl)-indazole 3.9g, purity 99.6%.
Embodiment 5
The separation purification method of 5-amino-1-(2, the 2-dimethoxy-ethyl)-indazole and 5-amino-2-(2, the 2-dimethoxy-ethyl)-indazole mixture; Operate as follows: mix said mixture 10g with 22mL THF/15mL water heating for dissolving, naturally cooling, filtration then; Obtain 5-amino-1-(2; The 2-dimethoxy-ethyl)-and indazole 5.1g, purity 99.8%, its characteristic is following:
1H?NMR(DMSO-d6)：δ3.17-3.28，4.36(d，J＝5.4Hz，2H)，4.72(t，J＝5.6Hz，1H)，4.82(s，2H)，6.72(m，1H)，6.81(dd，J＝8.8，2.0Hz，1H)，7.36(d，J＝8.8Hz，1H)，7.72(s，1H)。MS(ESI)m/z?222(M+H)
+。
5-amino-2-(2, the 2-dimethoxy-ethyl)-indazole 3.5g, purity 99.3%, its characteristic is following:
1H NMR (DMSO-d6): δ 3.26 (s, 6H), 4.37 (d, J=5.8Hz, 2H), 4.80 (m, 3H), 6.55 (m, 1H), 6.74 (m, 1H), 7.32 (m, 1H).MS(ESI)m/z?222(M+H)
+。
Embodiment 6
The separation purification method of 5-amino-1-(2, the 2-dimethoxy-ethyl)-indazole and 5-amino-2-(2, the 2-dimethoxy-ethyl)-indazole mixture; Operate as follows: mix said mixture 10g with 12mL THF/30mL water; Heating for dissolving, naturally cooling, filtration then obtains 5-amino-2-(2; The 2-dimethoxy-ethyl)-and indazole 3.7g, purity 99.1%; Obtain 5-amino-1-(2, the 2-dimethoxy-ethyl)-indazole 5.2g, purity 99.7%, its characteristic such as embodiment 5.
Embodiment 7
The separation purification method of 6-nitro-1-(2-pyrrolidyl ethyl)-indazole and 6-nitro-2-(2-pyrrolidyl ethyl)-indazole mixture; Operate as follows: mix said mixture 12g with 32mL methyl alcohol/15mL water; Heating for dissolving; Naturally cooling, filtration then obtains 6-nitro-1-(2-pyrrolidyl ethyl)-indazole 5.4g, purity 99.8%; Its characteristic is following:
1H?NMR(DMSO-d6)：δ1.60(m，4H)，2.46(m，4H)，2.89(t，2H)，4.68(t，2H)，7.93(d，J＝8.8Hz，1H)，7.99(d，J＝8.8Hz，1H)，8.31(m，1H)，8.76(s，1H)。MS(ESI)m/z?261(M+H)
+。
Obtain 6-nitro-2-(2-pyrrolidyl ethyl)-indazole 4.2g, purity 99.3%; Its characteristic is following:
1H NMR (DMSO-d6): δ 1.66 (m, 4H), 2.49 (m, 4H), 3.01 (t, 2H), 4.65 (t, 2H), 7.81 (dd, J=9.1,1.8Hz, 1H), 7.98 (d, J=9.1Hz, 1H), 8.63 (m, 1H), 8.69 (s, 1H).MS(ESI)m/z?261(M+H)
+。
Embodiment 8
The separation purification method of 6-nitro-1-(2-pyrrolidyl ethyl)-indazole and 6-nitro-2-(2-pyrrolidyl ethyl)-indazole mixture; Operate as follows: mix said mixture 12g with 16mL ethanol/36mL water; Heating for dissolving; Naturally cooling, filtration then obtains 6-nitro-1-(2-pyrrolidyl ethyl)-indazole 4.8g, purity 99.2%; 6-nitro-2-(2-pyrrolidyl ethyl)-indazole 5.7g, purity 99.6%.Its characteristic such as embodiment 7.
Embodiment 9
The separation purification method of 4-amino-1-(2-pyrrolidyl ethyl)-indazole and 4-amino-2-(2-pyrrolidyl ethyl)-indazole mixture; Operate as follows: mix said mixture 10g with 28mL acetonitrile/12mL water; Heating for dissolving; Naturally cooling, filtration then obtains 4-amino-1-(2-pyrrolidyl ethyl)-indazole 4.8g, purity 99.3%; Its characteristic is following:
1H?NMR(DMSO-d6)：δ1.63(m，4H)，2.45(m，4H)，2.82(t，2H)，4.35(t，2H)，5.74(s，2H)，6.14(d，J＝7.5Hz，2H)，6.67(d，J＝8.5Hz，1H)，7.02(dd，J＝7.8，8.5，1H)，8.06(s，1H)。MS(ESI)m/z?231(M+H)
+。
Obtain 4-amino-2-(2-pyrrolidyl ethyl)-indazole 3.5g, purity 99.8%; Its characteristic is following:
1H NMR (DMSO-d6): δ 1.67 (m, 4H), 2.45 (m, 4H), 2.51 (t, 2H), 2.97 (t, 2H), 4.45 (t, 2H), 5.52 (s, 1H), 6.71 (d, J=8.5Hz, 1H), 6.89 (d, J=8.5Hz, 1H), 6.92 (m, 1H), 8.29 (s1H).MS(ESI)m/z?231(M+H)
+.。
Embodiment 10
The separation purification method of 4-amino-1-(2-pyrrolidyl ethyl)-indazole and 4-amino-2-(2-pyrrolidyl ethyl)-indazole mixture; Operate as follows: mix said mixture 10g with 16mL acetonitrile/22mL water; Heating for dissolving; Naturally cooling, filtration then obtains 4-amino-2-(2-pyrrolidyl ethyl)-indazole 5.2g, purity 99.7%; 4-amino-1-(2-pyrrolidyl ethyl)-indazole 4.1g, purity 99.4%.Its characteristic such as embodiment 9.
Claims (2)
1. separation purification method with substituted indazole isomer of following general structure is characterized in that: adopt recrystallization method that it is separated, used recrystallization solvent is the mixed solvent of acetone, ethanol, THF, acetonitrile or methyl alcohol and water,
Above-mentioned general formula is represented: 5-amino-1-(2-hydroxyethyl)-indazole and 5-amino-2-(2-hydroxyethyl)-indazole; 5-amino-1-(2; The 2-dimethoxy-ethyl)-indazole and 5-amino-2-(2; The 2-dimethoxy-ethyl)-and indazole, 6-nitro-1-(2-pyrrolidyl ethyl)-indazole and 6-nitro-2-(2-pyrrolidyl ethyl)-indazole, 4-amino-1-(2-pyrrolidyl ethyl)-indazole and 4-amino-2-(2-pyrrolidyl ethyl)-indazole.
2. the separation purification method of substituted indazole isomer according to claim 1 is characterized in that: the mixed solvent volume ratio preferred 3/1～2/5 of used acetone, ethanol, THF, acetonitrile or methyl alcohol and water.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102759155A CN101948433B (en) | 2010-09-02 | 2010-09-02 | Method for separating and purifying substituted indazole isomers |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102759155A CN101948433B (en) | 2010-09-02 | 2010-09-02 | Method for separating and purifying substituted indazole isomers |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101948433A CN101948433A (en) | 2011-01-19 |
| CN101948433B true CN101948433B (en) | 2012-05-09 |
Family
ID=43452077
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010102759155A Expired - Fee Related CN101948433B (en) | 2010-09-02 | 2010-09-02 | Method for separating and purifying substituted indazole isomers |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101948433B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1568790A (en) * | 1966-10-25 | 1969-05-30 | ||
| US7071182B2 (en) * | 2003-12-23 | 2006-07-04 | Abbott Laboratories | Antagonists of melanin concentrating hormone effects on the melanin concentrating hormone receptor |
| WO2008086404A1 (en) * | 2007-01-10 | 2008-07-17 | Albany Molecular Research, Inc. | 5-pyridinone substituted indazoles |
| CN101463031A (en) * | 2007-12-20 | 2009-06-24 | 中国医学科学院药物研究所 | Indazole and tetrahydrochysene indazole compounds, and preparation, pharmaceutical composition and use thereof |
-
2010
- 2010-09-02 CN CN2010102759155A patent/CN101948433B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1568790A (en) * | 1966-10-25 | 1969-05-30 | ||
| US7071182B2 (en) * | 2003-12-23 | 2006-07-04 | Abbott Laboratories | Antagonists of melanin concentrating hormone effects on the melanin concentrating hormone receptor |
| WO2008086404A1 (en) * | 2007-01-10 | 2008-07-17 | Albany Molecular Research, Inc. | 5-pyridinone substituted indazoles |
| CN101463031A (en) * | 2007-12-20 | 2009-06-24 | 中国医学科学院药物研究所 | Indazole and tetrahydrochysene indazole compounds, and preparation, pharmaceutical composition and use thereof |
Non-Patent Citations (5)
| Title |
|---|
| Kym, Philip R. et al.Screening for Cardiovascular Safety: A Structure-Activity Approach for Guiding Lead Selection of Melanin Concentrating Hormone Receptor 1 Antagonists.《Journal of Medicinal Chemistry》.2006,2339-2352. * |
| May, Jesse A. et al.1-((S)-2-Aminopropyl)-1H-indazol-6-ol: A Potent Peripherally Acting 5-HT2 Receptor Agonist with Ocular Hypotensive Activity.《Journal of Medicinal Chemistry》.2006,318-328. * |
| Souers Andrew J. et al.Identification of 2-(4-Benzyloxyphenyl)-N- [1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol- 6-yl]acetamide |
| Souers, Andrew J. et al.Identification of 2-(4-Benzyloxyphenyl)-N- [1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol- 6-yl]acetamide, an Orally Efficacious Melanin-Concentrating Hormone Receptor 1 Antagonist for the Treatment of Obesity.《Journal of Medicinal Chemistry》.2005,1318-1321. * |
| Souers, Andrew J. et al.Synthesis and evaluation of urea-based indazoles as melanin-concentrating hormone receptor 1 antagonists for the treatment of obesity.《Bioorganic & Medicinal Chemistry Letters》.2005,2752-2757. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101948433A (en) | 2011-01-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7145854B2 (en) | Pyrazolo-heteroaryl derivatives, their preparation and medical uses | |
| JP6839104B2 (en) | A novel substitution aminothiazolopyrimidinedione for the treatment and prevention of viral infections | |
| CN109071489B (en) | Indazole synthesis | |
| CN109071491B (en) | Indazole synthesis | |
| WO2013102935A2 (en) | Cu-MEDIATED ANNULATION FOR THE EFFECTIVE SYNTHESIS OF 3-SUBSTITUTED PHTHALIDES | |
| CA3070070A1 (en) | Intermediates useful for the synthesis of a selective inhibitor against protein kinase and processes for preparing the same | |
| CN102603627B (en) | Naphthlamide derivative used as protein kinase inhibitor and histone deacetylase inhibitor and preparation method of naphthlamide derivative | |
| CN101948433B (en) | Method for separating and purifying substituted indazole isomers | |
| JP2014508805A (en) | Method for producing pemetrexed salt | |
| CN104159884B (en) | The method of compound is prepared as the novel reversal of the Michael addition of additive by using water or multiple acid | |
| CN103360326A (en) | Method for refining Gefinitib crystal form I | |
| CN103172637B (en) | Pyrimido [1, 2-a] benzimidazole compound and method for preparing same | |
| CN104326954B (en) | A kind of synthetic method of Fudosteine | |
| CN104250251B (en) | Preparation method for ticagrelor | |
| CN101735220B (en) | Crystal form of 6, 7-dihydro-6-mercapto-5H-pyrazolo[1,2-alpha][1,2,4] triazoliumchloride and preparation method thereof | |
| CN106432126A (en) | 1-oxy-2,8-diazacyclononane derivatives and synthetic method thereof | |
| CN103319422A (en) | New gefitinib crystal form and preparation method thereof | |
| CN109988108B (en) | Preparation method of cabozantinib | |
| CN110678453A (en) | Preparation method and intermediate of oxaspiro derivative | |
| CN104447294A (en) | Chiral resolution method of 3-cyclohexene-1-formic acid | |
| CN104119240A (en) | Preparation method for (S)-(-)-alpha-methylaminopropiophenone | |
| CN113980012A (en) | Purification method of emtricitabine | |
| WO2016067182A2 (en) | Process for the preparation of amino alcohol derivatives or salts thereof | |
| CN104974208A (en) | Preparation method of high-purity methylprednisolone aceponate | |
| CN105315161A (en) | Method for preparing key intermediate of PKB/Akt inhibitor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120509 Termination date: 20120902 |