CN109796410A - A kind of synthetic method of 5- substituted indazole -3- carboxylic acid - Google Patents
A kind of synthetic method of 5- substituted indazole -3- carboxylic acid Download PDFInfo
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- CN109796410A CN109796410A CN201910130512.2A CN201910130512A CN109796410A CN 109796410 A CN109796410 A CN 109796410A CN 201910130512 A CN201910130512 A CN 201910130512A CN 109796410 A CN109796410 A CN 109796410A
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- carboxylic acid
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- substituted indazole
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 14
- -1 5- substituted indazole -3- carboxylic acid Chemical class 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 6
- GFKHCUPBADPSDI-UHFFFAOYSA-N benzene;hydrazine Chemical class NN.C1=CC=CC=C1 GFKHCUPBADPSDI-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229940126214 compound 3 Drugs 0.000 claims abstract description 4
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 4
- 230000007062 hydrolysis Effects 0.000 claims abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 3
- 150000002367 halogens Chemical class 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 7
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 4
- BHXVYTQDWMQVBI-UHFFFAOYSA-N 1h-indazole-3-carboxylic acid Chemical class C1=CC=C2C(C(=O)O)=NNC2=C1 BHXVYTQDWMQVBI-UHFFFAOYSA-N 0.000 claims description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 9
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims 6
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 6
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 claims 4
- 239000000203 mixture Substances 0.000 claims 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 3
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 claims 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 3
- AJFDBNQQDYLMJN-UHFFFAOYSA-N n,n-diethylacetamide Chemical compound CCN(CC)C(C)=O AJFDBNQQDYLMJN-UHFFFAOYSA-N 0.000 claims 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims 2
- 229910015900 BF3 Inorganic materials 0.000 claims 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 239000002585 base Substances 0.000 claims 1
- 238000006482 condensation reaction Methods 0.000 claims 1
- 235000019441 ethanol Nutrition 0.000 claims 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 229920000137 polyphosphoric acid Polymers 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 1
- 239000011592 zinc chloride Substances 0.000 claims 1
- 235000005074 zinc chloride Nutrition 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 206010054949 Metaplasia Diseases 0.000 abstract 1
- 230000015689 metaplastic ossification Effects 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000000034 method Methods 0.000 description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- QRTAIBBOZNHRMI-UHFFFAOYSA-N 5-methyl-1h-indazole-3-carboxylic acid Chemical compound CC1=CC=C2NN=C(C(O)=O)C2=C1 QRTAIBBOZNHRMI-UHFFFAOYSA-N 0.000 description 3
- AMJVXOOGGBPVCZ-UHFFFAOYSA-N 5-bromo-1h-indazole-3-carboxylic acid Chemical compound C1=C(Br)C=C2C(C(=O)O)=NNC2=C1 AMJVXOOGGBPVCZ-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- PCNFLKVWBDNNOW-UHFFFAOYSA-N 4-hydrazinylbenzoic acid Chemical compound NNC1=CC=C(C(O)=O)C=C1 PCNFLKVWBDNNOW-UHFFFAOYSA-N 0.000 description 1
- MOIQBKKDRVMNMF-UHFFFAOYSA-N Cl.NN.BrC1=CC=CC=C1 Chemical compound Cl.NN.BrC1=CC=CC=C1 MOIQBKKDRVMNMF-UHFFFAOYSA-N 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- MFWNKCLOYSRHCJ-BTTYYORXSA-N granisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-BTTYYORXSA-N 0.000 description 1
- 229960003727 granisetron Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Abstract
The present invention provides a kind of synthetic method of 5- substituted indazole -3- carboxylic acid, wherein R=hydrogen, alkyl, alkoxy, thrihalothaneoxy, halogen.The invention belongs to medical chemistries to synthesize field.The present invention is raw material with benzene hydrazine class compound 3, is condensed, acylated, cyclization; hydrolysis resets deprotection and obtains product, and reaction condition is mild, easily-controllable, product is single, high income, and the chemical purity of product is high; and raw material is cheap and easy to get, and it is easy to operate, it is suitable for the production of industrially scalable metaplasia.
Description
Technical field:
Invention is related to a kind of synthetic method of medicine intermediate, specifically, the present invention relates to a kind of 5- to take
For the synthetic method of indazole -3- carboxylic acid.
Technical background
5- substituted indazole -3- carboxylic acid and relevant derivative have in pharmaceutical chemistry and organic synthesis to be widely applied, such as
Intermediate of the indazole -3- carboxylic acid as Granisetron.
5- substituted indazole -3- carboxylic acid generally uses isatin class compound as raw material through diazotising at present, and reduction reaction is come
Synthesis, diazo-reaction and reduction reaction will use concentrated acid, and wastewater flow rate is big, higher cost unfriendly to environment, and technique is multiple
Miscellaneous, there is an urgent need to safety and environmental protections, and simple technique, carries out scientific production at a low price, improve output, but technology is more difficult at present.
Accordingly, it is desirable to provide a kind of new technical solution solves the above problems.
Summary of the invention
The invention discloses a kind of synthetic method of 5- substituted indazole -3- carboxylic acid, the present invention is original with benzene hydrazine class compound 3
Material, is condensed, acylated, and cyclization, hydrolysis resets deprotection and obtains product, synthetic route are as follows:
Wherein R=hydrogen, alkyl, alkoxy, thrihalothaneoxy, halogen.
3. alkali is selected from sodium hydroxide in a preferred embodiment, in the step (1)；Solvent used is selected from
Water；Reaction temperature used is 25 DEG C~30 DEG C.
4. solvent used is selected from methylene chloride in a preferred embodiment, in the step (2)；Used
Reaction temperature is 40 DEG C.
5. catalyst is selected from alchlor in a preferred embodiment, in the step (3)；Solvent used
Selected from methylene chloride；Reaction temperature used is 30 DEG C or less.
6. acid used is the mixed liquor of hydrochloric acid and acetic acid in a preferred embodiment, in the step (4),
Mixed proportion is 7:1 (acetic acid: 37% hydrochloric acid), and the sour mass ratio with intermediate 6 is 8:1；Reaction temperature used is solvent
Reflux temperature.
7. of the invention be characterized by: by raw material cheap and easy to get, simply and easily operating, provide a kind of 5- substitution Yin
The synthetic method of azoles -3- carboxylic acid.
8. advantage of the invention is: the total recovery of method synthesis 5- substituted indazole -3- carboxylic acid of the invention is stablized in 60%-
85%.
The present invention is further described by the following embodiment, it should be understood by those skilled in the art that example
It is served only for explaining the present invention, be not intended to limit the scope of the present invention.
Specific embodiment scheme
The synthesis of embodiment 1:5- methylindazole -3- carboxylic acid
1. the synthesis of intermediate 4
166.4g (1.05mol) 4- hydrazinobenzoic acid hydrochloride is dissolved in 42g (1.05mol) NaOH+1000ml water, and acutely
Stirring；Then 106g benzaldehyde is slowly added dropwise to it, is added dropwise to complete within 1 hour or so, is stirred to react 2h at 25-30 DEG C；Then cold
To 20 DEG C, filtering, filter cake washing, dry white 4 191g of intermediate do not need purification and direct plunges into down once to react.
2. the synthesis of intermediate 5
27.7g (0.2mol) oxalyl chloride is dissolved in 150ml CH2Cl2, and is to slowly warm up to 40 DEG C；By 42g
(0.2mol) intermediate 4 is dissolved in 500ml CH2Cl2, and is slowly dropped to above-mentioned oxalyl chloride system；It is added dropwise,
40 degree are reacted 3.5 hours, and CH2Cl2 is then recovered under reduced pressure, and residue is intermediate 5, are not needed to purify, be direct plungeed into next
Step reaction；
3. the synthesis of intermediate 6
53.4g (0.2mol) AlCl3 is dissolved in 350ml CH2Cl2, cooling maintains the temperature at 30 degree or less；By upper one
It walks resulting intermediate 5 to be dissolved in CH2Cl2, is slowly dropped to above-mentioned system, process is added dropwise and needs 1 hour or so, is added dropwise to complete
Afterwards, it is heated to reflux 4 hours；Then part CH2Cl2 (450ml) is recovered under reduced pressure, obtains black residue, is slowly added to water to it,
Then there are a large amount of Orange red solids；Filtering, is washed with water three times, dry 50g yellow intermediate 6；
The synthesis of 4.5- methylindazole -3- carboxylic acid 1
40.1g (0.152mol) intermediate 6 is added in [260ml acetic acid, 55ml water, 31% hydrochloric acid of 37.8g] system,
Then it reacts 2 hours at 90 DEG C, is then concentrated under reduced pressure, obtained solid is beaten with ethyl acetate and is filtered, and obtains yellow solid product 5-
Methylindazole -3- carboxylic acid 1.
The synthesis of embodiment 2:5- bromo-indazole -3- carboxylic acid
1. the synthesis of intermediate 4
234.7g (1.05mol) 4- bromobenzene hydrazine hydrochloride is dissolved in [42g (1.05mol) NaOH+1000ml water], and acutely
Stirring；Then 106g benzaldehyde is slowly added dropwise to it, is added dropwise to complete within 1 hour or so, is stirred to react 2h at 25-30 DEG C；Then cold
To 20 DEG C, filtering, filter cake washing, dry white 4 225g of intermediate.It does not need to purify to direct plunge into down once to react.
2. the synthesis of intermediate 5
27.7g (0.2mol) oxalyl chloride is dissolved in 150ml CH2Cl2, and is to slowly warm up to 40 DEG C；By 55g
(0.2mol) intermediate 4 is dissolved in 500ml CH2Cl2, and is slowly dropped to above-mentioned oxalyl chloride system；It is added dropwise,
40 degree are reacted 3.5 hours, and CH2Cl2 is then recovered under reduced pressure, and residue is intermediate 5, are not needed to purify, be direct plungeed into next
Step reaction；
3. the synthesis of intermediate 6
53.4g (0.2mol) AlCl3 is dissolved in 350ml CH2Cl2, cooling maintains the temperature at 30 degree or less；By upper one
It walks resulting intermediate 5 to be dissolved in CH2Cl2, is slowly dropped to above-mentioned system, process is added dropwise and needs 1 hour or so, is added dropwise to complete
Afterwards, it is heated to reflux 4 hours；Then part CH2Cl2 (450ml) is recovered under reduced pressure, obtains black residue, is slowly added to water to it,
Then there are a large amount of Orange red solids；Filtering, is washed with water three times, dry 50g yellow intermediate 6；
The synthesis of 4.5- bromo-indazole -3- carboxylic acid 1
50g (0.152mol) intermediate 6 is added in [260ml acetic acid, 55ml water, 31% hydrochloric acid of 37.8g] system, so
It reacts 2 hours at 90 DEG C, is then concentrated under reduced pressure afterwards, obtained solid is beaten with ethyl acetate and is filtered, and obtains yellow solid product 5- bromine
Indazole -3- carboxylic acid 1.
The present invention is not limited to examples detailed above.The above description is only an embodiment of the present invention, is not intended to limit the invention, all
Within the spirit and principles in the present invention, any modification, equivalent replacement, improvement and so on should be included in guarantor of the invention
Within the scope of shield.
Claims (6)
- The synthetic method of 1.5- substituted indazole -3- carboxylic acid, the present invention is raw material with benzene hydrazine class compound 3, is condensed, acylated, is closed Ring, hydrolysis reset deprotection and obtain product, synthetic route are as follows:Wherein R=hydrogen, alkyl, alkoxy, thrihalothaneoxy, halogen.
- 2. the synthetic method of 5- substituted indazole -3- carboxylic acid according to claim 1, the synthetic method includes following step It is rapid:(1) condensation reaction occurs and obtains intermediate 4 for raw material and benzaldehyde with benzene hydrazine class compound 3；(2) 4 and oxalyl chloride reaction, obtain acylated intermediate 5；(3) by cyclization under the action of alchlor of intermediate 5, intermediate 6 is obtained；(4) intermediate 6 under hydrochloric acid effect, reset deprotection and obtain product 1 by hydrolysis.
- 3. the synthetic method of 5- substituted indazole -3- carboxylic acid according to claim 2, it is characterised in that: in the step (1) In, alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, triethylamine, sodium bicarbonate, pyridine, three isopropyls The mixture of one or more of base amine, saleratus；Solvent used be selected from water, methanol, ethyl alcohol, normal propyl alcohol, isopropanol, Ethyl acetate, tetrahydrofuran, methylene chloride, toluene, ortho-xylene, paraxylene, meta-xylene, N, N- diethylformamide, The mixture of one or more of N, N- diethyl acetamide；Reaction temperature used is the reflux temperature of -20 DEG C~solvent.
- 4. the synthetic method of 5- substituted indazole -3- carboxylic acid according to claim 2, it is characterised in that: in the step (2) In, solvent used be selected from ethyl acetate, tetrahydrofuran, methylene chloride, toluene, ortho-xylene, paraxylene, meta-xylene, N, N- diethylformamide, N, the mixture of one or more of N- diethyl acetamide；Reaction temperature used is -20 DEG C The reflux temperature of~solvent.
- 5. the synthetic method of 5- substituted indazole -3- carboxylic acid according to claim 2, it is characterised in that: in the step (3) In, catalyst is mixed selected from alchlor, ferric trichloride, zinc chloride, polyphosphoric acids, one or more of boron trifluoride ether Close object；Solvent used is selected from ethyl acetate, tetrahydrofuran, methylene chloride, toluene, ortho-xylene, paraxylene, diformazan Benzene, N, N- diethylformamide, N, the mixture of one or more of N- diethyl acetamide；Reaction temperature used is- The reflux temperature of 20 DEG C~solvent.
- 6. the synthetic method of 5- substituted indazole -3- carboxylic acid according to claim 2, it is characterised in that: in the step (4) In, acid is one of hydrochloric acid, sulfuric acid or acetic acid or two or more mixed liquors, and the mass ratio of acid and intermediate 6 is 1-20: 1；Reaction temperature used is the reflux temperature of -20 DEG C~solvent.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120004412A1 (en) * | 2010-06-30 | 2012-01-05 | Jodie Brice | Methods for the preparation of n-(s)-1-azabicyclo[2.2.2]oct-3-yl-1h-indazole-3-carboxamide hydrochloride salt |
| CN102712600A (en) * | 2010-01-12 | 2012-10-03 | 霍夫曼-拉罗奇有限公司 | Methods for the preparation of indazole-3-carboxyclic acid and n-(s)-1-azabicyclo[2.2.2]oct-3-yl-1h-indazole-3-carboxamide hydrochloride salt |
| CN103787978A (en) * | 2012-11-02 | 2014-05-14 | 张家港九木科技有限公司 | Synthesis method of 1-methylindazole-3-formic acid |
| CN104370888A (en) * | 2013-01-24 | 2015-02-25 | 韩冰 | Neuroprotective effect compound and preparation method and use thereof |
-
2019
- 2019-02-21 CN CN201910130512.2A patent/CN109796410A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102712600A (en) * | 2010-01-12 | 2012-10-03 | 霍夫曼-拉罗奇有限公司 | Methods for the preparation of indazole-3-carboxyclic acid and n-(s)-1-azabicyclo[2.2.2]oct-3-yl-1h-indazole-3-carboxamide hydrochloride salt |
| US20120004412A1 (en) * | 2010-06-30 | 2012-01-05 | Jodie Brice | Methods for the preparation of n-(s)-1-azabicyclo[2.2.2]oct-3-yl-1h-indazole-3-carboxamide hydrochloride salt |
| CN103787978A (en) * | 2012-11-02 | 2014-05-14 | 张家港九木科技有限公司 | Synthesis method of 1-methylindazole-3-formic acid |
| CN104370888A (en) * | 2013-01-24 | 2015-02-25 | 韩冰 | Neuroprotective effect compound and preparation method and use thereof |
Non-Patent Citations (1)
| Title |
|---|
| 天津大学有机化学教研室编: "《有机化学》", 30 September 1978, 人民教育出版社 * |
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Application publication date: 20190524 |