CN103497156A - 1-N-substitution method of fused ring pyrazole compounds - Google Patents
1-N-substitution method of fused ring pyrazole compounds Download PDFInfo
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- CN103497156A CN103497156A CN201310429834.XA CN201310429834A CN103497156A CN 103497156 A CN103497156 A CN 103497156A CN 201310429834 A CN201310429834 A CN 201310429834A CN 103497156 A CN103497156 A CN 103497156A
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- pyrazole compounds
- ring fused
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
Abstract
The invention relates to preparation methods of compounds, in particular to a 1-N-substitution method of fused ring pyrazole compounds. The 1-N-substitution method of fused ring pyrazole compounds comprises: carrying out a substitution reaction on compounds with a general formula of IV in the presence of an alkaline reagent and carrying out a substitution reaction on compounds with a general formula of III in an organic solvent, the reaction equation is shown in the specification, wherein X refers to CH or N; M1 refers to C2-C10 alkyls, halogenated C2-C10 alkyls or M21-5 benzyls; each M2 independently refers to H, C1-C3 alkyls, halogen, cyano, C1-6 alkoxy or trifluoromethyl; L refers to a leaving group; and the alkaline reagent is potassium tert-butoxide or sodium tert-butoxide. According to the technical scheme provided by the invention, the reaction conditions are mild, the operation is simple and convenient, the agent is easy to obtain, a side substitution reaction on the 2 site can be avoided and the yield of a target product is higher than 80%, so that the 1-N-substitution method is very suitable for large-scale industrial production.
Description
Technical field
The present invention relates to the preparation method of compound, be specifically related to a kind of ring fused pyrazole compounds 1-N-substitution technique.
Background technology
The ring fused pyrazole compounds, because of the mutability of its structure and the biological activity of high-efficiency broad spectrum, has a wide range of applications in field of fine chemical such as medicine and agricultural chemicals.
Such as disclosing a kind of novel therapeutic central nervous system disease medicine in US2011028447A1, its important intermediate is exactly the ring fused pyrazole compounds, be specially the indazole that 1-N-replaces-3-carboxylic acid, Indole-3-Carboxylic Acid that 1-N-replaces, azaindazole that 1-N-replaces-3-carboxylic acid, the azaindole that 1-N-replaces-series compounds such as 3-carboxylic acid, its general structure is formula I, patent Chinese style I compound is that to take formula II compound synthetic through esterification, replacement and saponification three-step reaction successively as raw material, and concrete reaction equation is as follows:
Why need three-step reaction, be mainly because in formula II compound except the 1-N position, substitution reaction all can occur in 2-N position and 3-carboxylic acid, possible product is many, purity and yield all are difficult to control.By replacing the replacement that can avoid the 3-carboxylic acid after carboxy protective, but overall yield is low, and cost is high; energy consumption is large, complex operation, and because of the generation with isomer; it is upper that about 10% replacement occurs in 2-N, makes the separation and purification of the product difficult that becomes, and is unfavorable for large-scale industrial production.
Summary of the invention
Technical problem to be solved by this invention is that ring fused pyrazole compounds 1-N-substitution reaction step is many, and cost is high, and purification difficult is unsuitable for suitability for industrialized production, in order to overcome above deficiency, provides a kind of ring fused pyrazole compounds 1-N-substitution technique.
In order to solve the problems of the technologies described above, technical scheme of the present invention is: described ring fused pyrazole compounds 1-N-substitution technique, general formula I V compound is under the alkaline reagents existence condition, and compound of formula III is substituted reaction and obtains in organic solvent, and reaction equation is as follows:
Wherein X is CH or N;
Replace reagent M
1m in-L
1c
2-C
10alkyl, halo C
2-C
10alkyl or M
2 1-5benzyl;
Each M wherein
2h, C independently
1-C
3alkyl, halogen, cyano group, C
1-C
6alkoxyl group or trifluoromethyl;
L is leavings group;
Described alkaline reagents is potassium tert.-butoxide or sodium tert-butoxide.
Preferably, the mol ratio of described alkaline reagents and formula III compound is 2.1~2.8:1.
Preferably, described replacement reagent M
1the mol ratio of-L and formula III compound is 1.1~1.5:1.
Preferably, L is halogen, methylsulfonyl or benzene methylsulfonyl.
Preferably, L is Br-or Cl-.
Preferably, described organic solvent is more than one in DMF, DMSO, acetonitrile, tetrahydrofuran (THF), dioxane and acetone.
Preferably, described organic solvent is DMF.
Preferably, the temperature of reaction of described substitution reaction is 5~40 ℃.
Preferably, M
1c
1-C
9alkyl-(CH
2)-, fluoro C
1-C
9alkyl-(CH
2)-or M
2 1-5benzyl;
Each M wherein
2h, F-or trifluoromethyl independently.
Preferably, described M
1be
Definition
Listed as follows the definition of various terms used herein:
Symbol
mean tie point.
Term " alkyl " refers to carbochain (carbocyclic ring) substituting group of saturated straight chain, side chain, monocycle or a plurality of thick and ring.The example of abovementioned alkyl is as ethyl, the propyl group of straight chain, the sec.-propyl of side chain, isobutyl-, the cyclohexyl of monocycle, cyclopentyl, the adamantyls of a plurality of thick and rings etc.
Term " alkoxyl group " refers to non-annularity alkyl-O-, and wherein the non-annularity alkyl refers to saturated straight or branched base.The example of above-mentioned alkoxyl group is as methoxyl group, isopropoxy etc.
Term " halogen " or " halogen " refer to fluorine, chlorine, bromine or iodine.
Technical scheme provided by the invention has reduced esterification and saponification two-step reaction than the method for former US2011028447A1 patent, the reaction conditions gentleness, easy and simple to handle, reagent is easy to get, also avoided the side reaction of the replacement on the 2-position to occur simultaneously, the target compound productive rate, up to more than 80%, is applicable to large-scale industrial production very much.
Embodiment
The present invention further illustrates by following examples, and following examples only, for the preferred embodiment of the present invention more specifically is described, is not used in technical scheme of the present invention is limited.The technical scheme of the invention described above all can realize the object of the invention.Be temperature that following examples adopt and reagent, all available relevant temperature mentioned above and reagent substitute to realize the present invention's purpose.
In following preparation example:
Nucleus magnetic resonance is by 400M Bruker nmr determination, and TMS is interior mark, and chemical shift unit is ppm.
In embodiment, agents useful for same is commercial goods.
Indazole-3-carboxylic acid (formula III-1 compound) is purchased from the anti-Jilin Chemical of peace
7-azaindazole-3-carboxylic acid (formula III-2 compound) is purchased from Nanjing remedies medicament research and development company limited
The preparation of embodiment 11-cyclohexylmethyl-indazole-3-carboxylic acid (formula IV-1 compound)
5 grams (1 equivalent) indazole-3-carboxylic acid (formula III-1 compound) is dissolved in to DMF(80ml), add sodium tert-butoxide (6.8 grams under normal temperature, 2.3 equivalent), stir after 10 minutes and drip cyclohexyl methyl bromine (7.1g, 1.3 equivalent), at the 25oC stirring reaction, after question response is complete, add 400 ml waters and 200 milliliters of methyl tertiary butyl ethers in reaction mixture, stratification is collected water, regulate pH1-2 with 1N hydrochloric acid, continue at room temperature to stir 2 hours, there is solid to separate out, the dry 6.4 gram off-white color solids that obtain after filtering, it is product type IV-1 compound, productive rate 81%, purity 96%.
1H?NMR(DMSO--d
6,400MHz),δ1.0-1.3(m,5H),1.5-1.7(m,5H),2.0(m,1H),4.4(d,2H),7.3(t,1H),7.5(t,1H),7.8(d,1H),8.1(d,1H),13(br?s,1H)。
The preparation of embodiment 21-(4-luorobenzyl)-indazole-3 carboxylic acid (formula IV-2 compound)
5 grams (1 equivalent) indazole-3-carboxylic acid (formula III-1 compound) is dissolved in to DMF(80ml), add sodium tert-butoxide (6.2 grams under normal temperature, 2.1 equivalent), stir after 10 minutes and drip 4-fluorine bromobenzyl (6.9g, 1.2 equivalent), at the 20oC stirring reaction, after question response is complete, add 400 ml waters and 200 milliliters of methyl tertiary butyl ethers in reaction mixture, stratification is collected water, regulate pH1-2 with 1N hydrochloric acid, continue at room temperature to stir 2 hours, there is solid to separate out, the dry 7.0 gram off-white color solids that obtain after filtering, it is product type IV-2 compound, productive rate 85%, purity 95%.
1H?NMR(DMSO-d
6,400MHz),δ5.8(s,2H),7.15(t,2H),7.30(t,1H),7.35(t,2H),7.45(t,1H),7.8(d,1H),8.15(d,1H)。
The preparation of embodiment 31-amyl group-indazole-3 carboxylic acid (formula IV-3 compound)
5 grams (1 equivalent) indazole-3-carboxylic acid (formula III-1 compound) is dissolved in to DMF(80ml), add sodium tert-butoxide (7.7 grams under normal temperature, 2.6 equivalent), stir after 10 minutes and drip 1-bromo pentane silane (6.9g, 1.5 DMF solution equivalent), at the 30oC stirring reaction, after question response is complete, add 400 ml waters and 200 milliliters of methyl tertiary butyl ethers in reaction mixture, stratification is collected water, regulate pH1-2 with 1N hydrochloric acid, continue at room temperature to stir 2 hours, there is solid to separate out, the dry 6.0 gram off-white color solids that obtain after filtering, it is product type IV-3 compound, productive rate 80%, purity 90%.
1H?NMR(CDCl
3-d
6,400MHz),δ0.9(t,3H),1.3(m,4H),2.0(m,2H),4.5(t,2H),7.3(d,1H),7.5(m,2H),8.3(d,1H)。
The preparation of embodiment 41-(5-fluorine amyl group)-indazole-3 carboxylic acid (formula IV-4 compound)
5 grams (1 equivalent) indazole-3-carboxylic acid (formula III-1 compound) is dissolved in to DMF(80ml), add sodium tert-butoxide (7.4 grams under normal temperature, 2.5 equivalent), stir after 10 minutes and drip the fluoro-pentane (6.1g of the bromo-5-of 1-, 1.2 DMF solution equivalent), at the 15oC stirring reaction, after question response is complete, add 400 ml waters and 200 milliliters of methyl tertiary butyl ethers in reaction mixture, stratification is collected water, regulate pH1-2 with 1N hydrochloric acid, continue at room temperature to stir 2 hours, there is solid to separate out, the dry 6.5 gram off-white color solids that obtain after filtering, it is product type IV-4 compound, productive rate 88%, purity 97%.
1H?NMR(CMSO-d
6,400MHz),δ1.4(m,2H),1.7(m,2H),1.9(m,2H),4.3-4.5(m,4H),7.3(t,1H),7.5(t,1H),7.8(d,1H),8.1(d,1H)。
Embodiment 5~8 is changed to potassium tert.-butoxide for sodium tert-butoxide in embodiment 1~4, and result is similar.
Embodiment 9~12 is changed to chlorine (Cl) for the leavings group bromine (Br) in embodiment 1~4, and result is similar.
Claims (10)
1. a ring fused pyrazole compounds 1-N-substitution technique, is characterized in that, general formula I V compound is under the alkaline reagents existence condition, and compound of formula III is substituted reaction and obtains in organic solvent, and reaction equation is as follows:
Wherein X is CH or N;
Replace reagent M
1m in-L
1c
2-C
10alkyl, halo C
2-C
10alkyl or M
2 1-5benzyl;
Each M wherein
2h, C independently
1-C
3alkyl, halogen, cyano group, C
1-C
6alkoxyl group or trifluoromethyl;
L is leavings group;
Described alkaline reagents is potassium tert.-butoxide or sodium tert-butoxide.
2. a kind of ring fused pyrazole compounds 1-N-substitution technique according to claim 1, is characterized in that, the mol ratio of described alkaline reagents and formula III compound is 2.1~2.8:1.
3. a kind of ring fused pyrazole compounds 1-N-substitution technique according to claim 1, is characterized in that described replacement reagent M
1the mol ratio of-L and formula III compound is 1.1~1.5:1.
4. a kind of ring fused pyrazole compounds 1-N-substitution technique according to claim 1, is characterized in that, L is halogen, methylsulfonyl or benzene methylsulfonyl.
5. a kind of ring fused pyrazole compounds 1-N-substitution technique according to claim 4, is characterized in that, L is Br-or Cl-.
6. a kind of ring fused pyrazole compounds 1-N-substitution technique according to claim 1, is characterized in that, described organic solvent is more than one in DMF, DMSO, acetonitrile, tetrahydrofuran (THF), dioxane and acetone.
7. a kind of ring fused pyrazole compounds 1-N-substitution technique according to claim 6, is characterized in that, described organic solvent is DMF.
8. a kind of ring fused pyrazole compounds 1-N-substitution technique according to claim 1, is characterized in that, the temperature of reaction of described substitution reaction is 5~40 ℃.
9. a kind of ring fused pyrazole compounds 1-N-substitution technique according to claim 1, is characterized in that M
1c
1-C
9alkyl-(CH
2)-, fluoro C
1-C
9alkyl-(CH
2)-or M
2 1-5benzyl;
Each M wherein
2h, F-or trifluoromethyl independently.
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Cited By (1)
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CN112752753A (en) * | 2018-07-14 | 2021-05-04 | Fmc公司 | Pesticidal mixtures comprising indazole compounds |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1429816A (en) * | 2003-01-23 | 2003-07-16 | 宁波市天衡制药厂 | New method of preparing Granisetron intermediate |
CN1594297A (en) * | 2004-06-23 | 2005-03-16 | 上海复星朝晖药业有限公司 | Process for synthesis of lonidamine |
WO2005120498A2 (en) * | 2004-06-03 | 2005-12-22 | Threshold Pharmaceuticals, Inc. | Method for synthesis of lonidamine and related indazole derivatives |
-
2013
- 2013-09-18 CN CN201310429834.XA patent/CN103497156A/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1429816A (en) * | 2003-01-23 | 2003-07-16 | 宁波市天衡制药厂 | New method of preparing Granisetron intermediate |
WO2005120498A2 (en) * | 2004-06-03 | 2005-12-22 | Threshold Pharmaceuticals, Inc. | Method for synthesis of lonidamine and related indazole derivatives |
CN1594297A (en) * | 2004-06-23 | 2005-03-16 | 上海复星朝晖药业有限公司 | Process for synthesis of lonidamine |
Non-Patent Citations (1)
Title |
---|
徐宝财,等: "1-甲基吲唑-3-羧酸的制备", 《精细石油化工》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112752753A (en) * | 2018-07-14 | 2021-05-04 | Fmc公司 | Pesticidal mixtures comprising indazole compounds |
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Application publication date: 20140108 |