CN107805221A - A kind of method for preparing 1H indazole derivatives - Google Patents
A kind of method for preparing 1H indazole derivatives Download PDFInfo
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- CN107805221A CN107805221A CN201610814173.6A CN201610814173A CN107805221A CN 107805221 A CN107805221 A CN 107805221A CN 201610814173 A CN201610814173 A CN 201610814173A CN 107805221 A CN107805221 A CN 107805221A
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- 0 Cc(c([N+]([O-])=O)cc(*)c1)c1[N+]([O-])=O Chemical compound Cc(c([N+]([O-])=O)cc(*)c1)c1[N+]([O-])=O 0.000 description 5
- XTRDKALNCIHHNI-UHFFFAOYSA-N Cc(c([N+]([O-])=O)ccc1)c1[N+]([O-])=O Chemical compound Cc(c([N+]([O-])=O)ccc1)c1[N+]([O-])=O XTRDKALNCIHHNI-UHFFFAOYSA-N 0.000 description 1
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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 discloses a kind of method for preparing 1H indazole derivatives, and using formula (A1) compound or formula (A2) compound as raw material, formula (B) compound is obtained through nitration reaction or halogenating reaction；Using formula (B) compound as raw material, by a nitro in formula (B) compound through reduction reaction, formula (C) compound is obtained；Using formula (C) compound as raw material, in the presence of nitrite, formula (I) 1H indazole derivatives are obtained through diazotising, ring-closure reaction.With existing method ratio, method of the invention can synthesize a variety of 1H indazole derivatives, and synthetic route is short, high income, is more suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of method for preparing 1H- indazole derivatives.
Background technology
Indazole is a kind of critically important medicine intermediate.Indazole derivative has extensive bioactivity, such as anti-inflammatory, town
It is bitterly antipyretic, regulatory protein enzymatic activity and protein kinase, dopamine antagonist, antiviral and antitumor etc..Life of the indazole as indoles
Thing isostere, it is a ten pi-electron aromatic heterocyclic ring systems.The unique structure and properties of indazole compound, permitted them
Multi-field to have quite varied important use, the research about their property and purposes is increasingly by synthesis chemist and medicine
The attention of thing scholar.
However, the synthesis report of the relevant disubstituted 1H- indazole derivatives in 4,6- positions is seldom.The 4- nitros of 6- positions substitution
In the compound of (or amino) -1H- indazoles, only 6- positions are reported for the synthesis of the compound of bromine at present, and its synthetic route
Long, total recovery is low.With the fast development of medical industry, the disubstituted 1H- indazole derivatives in 4,6- positions are as a kind of important
Medicine intermediate has received more and more attention, and researchs and develops a kind of suitable industrial high-efficiency synthesis method, Ke Yiyou
Effect reduces the production cost of this kind of compound, has important actual application value.
The content of the invention
To solve the above problems, the invention provides the method for 1H- indazole derivatives shown in a kind of formula (I),
Wherein, R1Represent hydrogen, halogen atom, alkyl or haloalkyl；
It the described method comprises the following steps：
(1)
Work as R1When representing alkyl or haloalkyl, using formula (A1) compound as raw material, formula (B) chemical combination is obtained through nitration reaction
Thing；
Work as R1When representing halogen atom, using formula (A2) compound as raw material, formula (B) compound is obtained through halogenating reaction；
(2)
Using formula (B) compound as raw material, by a nitro in formula (B) compound through reduction reaction, formula (C) chemical combination is obtained
Thing；
(3)
Using formula (C) compound as raw material, nitrite is added, formula (I) compound is obtained through diazotising, ring-closure reaction.
Further, the alkyl is C1~C4Alkyl, the haloalkyl is C1~C4Haloalkyl.
Preferably, the C1~C4Alkyl be selected from methyl；The C1~C4Haloalkyl be selected from trifluoromethyl, difluoro
Methyl or a methyl fluoride.
Further, the halogen atom is chlorine atom, bromine atoms or iodine atom.
Further, in step (1), the nitration reaction is in any of the concentrated sulfuric acid, concentrated nitric acid or fuming nitric aicd
Carried out with nitrate under the conditions of simultaneous；It is preferred that the concentrated sulfuric acid；
The mol ratio of the nitrate and formula (A1) compound is 1.5~3.5：1.
Further, in step (1), the halogenating agent of the halogenating reaction be selected from bromo- 5, the 5- DMHs of 1,3- bis-,
It is any in N- bromo-succinimides, sym-closene or N- N-iodosuccinimides；It is preferred that 1,3- bis- bromo- 5,5- diformazans
Base glycolylurea；
The halogenating reaction is carried out in the presence of acid；The acid is selected from the concentrated sulfuric acid, concentrated nitric acid, concentrated hydrochloric acid or trifluoro second
Any of acid, the preferably concentrated sulfuric acid.
Further, in step (2), the reduction reaction is carried out in the presence of iron and hydrochloric acid；Preferably, iron with
The mol ratio of formula (B) compound is 2~4:1；
The solvent of the reduction reaction is selected from any of methanol, dioxane, ethanol or water or their mixing is molten
The mixed solvent of agent, preferably methanol and dioxane；
The temperature of the reduction reaction is 20-80 DEG C；It is preferred that 80 DEG C.
Further, in step (3), the nitrite is natrium nitrosum；The solvent of the reaction be hydrochloric acid, sulfuric acid,
Acid or glacial acetic acid, preferably acetic acid.
Further, the mol ratio of the nitrite and formula (C) chemical combination is 1.5~3.5：1；The nitrite is
Added at a temperature of -5 DEG C~5 DEG C.
Present invention also offers a kind of method of formula (II) compound, it is characterised in that：Comprise the following steps：
Wherein, R1It is foregoing to be defined；
Using formula (I) compound as raw material, formula (II) compound is obtained by what nitro was reduced to amino；Formula (I) chemical combination
Thing is prepared as the method previously described.
Further, the reduction is carried out in the presence of iron and ammonium chloride.
In the present invention, the C1~C4Alkyl refer to C1、C2、C3、C4Alkyl, i.e. the straight chain with 1~4 carbon atom
Or the alkyl of side chain, such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, sec-butyl etc..
With existing method ratio, method of the invention can synthesize a variety of 1H- indazole derivatives, and synthetic route is short,
High income, it is more suitable for industrialized production.
Obviously, according to the above of the present invention, according to the ordinary technical knowledge and customary means of this area, do not departing from
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The embodiment of form by the following examples, the above of the present invention is remake further specifically
It is bright.But the scope that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following example.It is all to be based on the above of the present invention
The technology realized belongs to the scope of the present invention.
Embodiment
PE：Petroleum ether.
EA：Ethyl acetate.
Dioxane：Dioxane.
The preparation of the bromo- 4 nitro -1H- indazoles (4) of the 6- of embodiment 1
1st, bromo- 2 methyl isophthalic acids of 5-, the synthesis of 3- dinitro benzenes (2)
Dry 50mL pear shape bottles are taken, with the 30mL concentrated sulfuric acids by 2- methyl isophthalic acids, 3- dinitro benzenes (1) (CAS：606-20-2,
5.00g, 27.45mmol, it is purchased from Chengdu Rui Ouke Reagent Companies) dissolving, it is slowly added to bromo- 5, the 5- bis- of 1,3- bis- under ice bath stirring
Methyl hydantoin (CAS：77-48-5,4.29g, 15.00mmol, it is purchased from Chengdu Rui Ouke Reagent Companies), it is added dropwise, room temperature is stirred
Reaction 15h is mixed, TLC shows that raw material reaction is complete, reaction solution is poured slowly into frozen water, filtered, and filter cake vacuum drying, obtains white
Solid powder (6.59g, yield 92%).
Inventor is screened to technique, i.e., according to the method described above, difference is using different halogenating agents, acid,
As a result it is as shown in table 1 below.
Table 1
2nd, the synthesis of the bromo- 2- methyl-3-nitros aniline (3) of 5-
The 50mL pear shape bottles of a drying are taken, with 20mL methanol and 10mL dioxane by bromo- 2 methyl isophthalic acids of 5-, 3- dinitros
Benzene (2) (5.00g, 19.16mmol) dissolves, be stirred at room temperature down be slowly added to 16.48mL concentrated hydrochloric acids and iron powder (3.22g,
57.47mmol), finishing, rise to 80 DEG C and be stirred at reflux and react 12h, TLC shows that raw material fundamental reaction is complete, and reaction solution is concentrated,
Crude product is through column chromatography (PE:EA=5：1) faint yellow solid powder (2.74g, yield 62%) is purified to obtain.
According to the method described above, difference is using different iron powder additions, acid, solvent, reaction temperature, as a result such as following table
Shown in 2.
Table 2
3rd, the synthesis of the bromo- 4 nitro -1H- indazoles (4) of 6-
Take the 25mL pear shape bottles of a drying, with 7mL glacial acetic acid by the bromo- 2- methyl-3-nitros aniline (3) of 5- (0.40g,
1.73mmol) dissolve, 2mL natrium nitrosums (0.24g, 3.46mmol) solution is slowly dropped to reaction solution under 0 DEG C of mechanical agitation
In, finish, be warmed to room temperature the reaction of stirring reaction 12h, TLC display raw material completely, solid precipitation has been diluted with water into reaction solution,
Filtering, filter cake vacuum drying, then through column chromatography (PE:EA=5：1) yellow solid powder (0.40g, yield 96%) is purified to obtain.
Structural Identification：With mutually isostructural reference substance CAS:885518-46-7 (is purchased from the limited public affairs of Nantong biotechnology
Department) contrast HPLC collection of illustrative plates, it is completely the same.Purity is 98% through HPLC tests；1H-NMR(400MHz,d6-DMSO,ppm):δ
12.46(br,1H),8.30(s,1H),8.20(s,1H),8.12(s,1H),4.60(br,2H).
Inventor is screened to technique, i.e., according to the method described above, difference is to add using different nitrite
Amount, acid, charge temperature, it is as a result as shown in table 3 below.
Table 3
The preparation of embodiment 23, the nitro -1H- indazoles (8) of 6- methyl -4
1st, the synthesis of 2,5- dimethyl -1,3- dinitro benzene (6)
Dry 50mL pear shape bottles are taken, are dissolved dimethylbenzene (5) (2.00mL, 16.23mmol) with the 20mL concentrated sulfuric acids, room temperature
Potassium nitrate (4.91g, 48.68mmol) is slowly added under stirring, is finished, reaction 2h, TLC is stirred at room temperature and shows that raw material has reacted
Entirely, reaction solution is poured slowly into frozen water, filtered, filter cake vacuum drying, then through column chromatography (PE:EA=80：1) purify yellowish
Color solid (6) (1.62g, yield 51%).
Structural Identification：1H-NMR(400MHz,CDCl3,ppm):δ13.0(br,1H,NH),7.42(s,2H,Ar-H),2.45
(s,6H,CH3).ESI-MS:197.05[M+H].
Inventor is screened to technique, i.e., according to the method described above, difference is to use different acid, as a result such as following table
Shown in 4.
Table 4
2nd, the synthesis of 2,5- dimethyl -3- nitroanilines (7)
According to the method that the bromo- 2- methyl-3-nitros aniline (3) of 5- are prepared in embodiment 1, be prepared 2,5- dimethyl-
3- nitroanilines (7), yellow solid, yield 65%.
3rd, the synthesis of the nitro -1H- indazoles (8) of 6- methyl -4
According to the method that the bromo- 4 nitro -1H- indazoles (4) of 6- are prepared in embodiment 1, the nitro -1H- of 6- methyl -4 is prepared
The synthesis of indazole (8), yellow solid, yield 52%.
Purity is 98% through HPLC tests；Structural Identification：1H-NMR(400MHz,d6-DMSO,ppm):δ12.46(br,
1H),8.20(s,1H),8.10(s,1H),7.87(s,1H),2.35(s,3H).ESI-MS:178.18[M+H].
The preparation of the nitro -1H- indazoles (12) of 3 6- trifluoromethyls of embodiment -4
1st, 2- methyl -5- Trifluoromethyl-1s, the synthesis of 3- dinitro benzenes (10)
With 4- trifluoromethyls-toluene (9) (CAS：6140-17-6, it is purchased from Chengdu Rui Ouke Reagent Companies) it is raw material, according to
The method that 2,5- dimethyl -1,3- dinitro benzene (6) is prepared in embodiment 2, preparation obtain 2- methyl -5- Trifluoromethyl-1s,
3- dinitro benzenes (10), yellow solid, yield 75%.
Structural Identification：1H-NMR(400MHz,CDCl3,ppm):δ13.0(br,1H,NH),8.29(s,2H,Ar-H),2.69
(s,3H,CH3).ESI-MS:251.02[M+H].
2nd, the synthesis of 2- methyl -5- trifluoromethyl -3- nitroanilines (11)
According to the method that the bromo- 2- methyl-3-nitros aniline (3) of 5- are prepared in embodiment 1,2- methyl -5- three is prepared
Methyl fluoride -3- nitroanilines (11), yellow solid, yield 68%.
3rd, the synthesis of the nitro -1H- indazoles (12) of 6- trifluoromethyls -4
According to the method that the bromo- 4 nitro -1H- indazoles (4) of 6- are prepared in embodiment 1, the nitre of 6- trifluoromethyls -4 is prepared
Base -1H- indazoles (12), yield 79%.Purity is 98% through HPLC tests.Structural Identification：1H-NMR(400MHz,d6-DMSO,
ppm):δ12.46(br,1H),8.20(s,1H),8.12(s,1H),7.80(s,1H).ESI-MS:232.13[M+H].
The preparation of the formula of embodiment 4 (II) compound
Nitro compound (8.26mmol) is dissolved in the in the mixed solvent of ethanol (20mL) and water (10mL), adds ammonium chloride
(221.5mg, 4.13mmol), first a part of iron powder (1.3g, 23.46mmol) is added thereto, is warming up to 80 DEG C of stirring reactions 5
Minute, then remaining iron powder (1.0g, 17.86mmol) is added, continue stirring reaction 20 minutes.TLC detection raw material reactions are complete
Afterwards, reaction solution is filtered while hot, filter residue is washed with ethanol (10mL).Ethanol is removed in decompression rotation, with ethyl acetate (20mL) aqueous layer extracted
Three times.Merge organic phase, with saturated common salt water washing, anhydrous magnesium sulfate is dried, is spin-dried for, and crosses post (PE:EA=8:1), obtain accordingly
Amino-compound.
1st, the bromo- 1H- indazoles -4- amine (14) of 6-
Yellow solid, yield 92%.Purity is 98% through HPLC tests；1H-NMR(400MHz,d6-DMSO,ppm):δ
12.46(br,1H),8.15(s,1H),7.56(s,1H),6.88(s,1H),5.80(br,2H).ESI-MS:213.05[M+H].
2nd, 6- methyl isophthalic acids H- indazole -4- amine (15)
Yellow solid, yield 75%.Purity is 98% through HPLC tests；1H-NMR(400MHz,d6-DMSO,ppm):δ
12.46(br,1H),7.70(s,1H),7.16(s,1H),6.85(s,1H),4.60(br,2H),2.21(s,3H).ESI-MS:
148.10[M+H].
3rd, 6- Trifluoromethyl-1s H- indazole -4- amine (16)
Yellow solid, yield 95%.Purity is 98% through HPLC tests；1H-NMR(400MHz,CDCl3,ppm):δ13.0
(br,1H,NH),8.10(s,1H,indazole-H),7.21(s,1H,indazole-H),6.58(s,1H,indazole-H),
4.37(br,2H,NH2).ESI-MS:202.05[M+H].
4th, 1H- indazoles -4- amine (17)
Yellow solid, yield 96%.Purity is 98% through HPLC tests；1H-NMR(400MHz,CDCl3,ppm):δ13.0
(br, 1H, NH), 8.10 (s, 1H, indazole-H), 7.60 (d, 1H, J=6.4Hz, indazole-H), 7.20 (m, 1H,
), indazole-H 6.48 (d, 1H, J=6.4Hz, indazole-H), 4.37 (br, 2H, NH2) .ESI-MS:134.05[M+
H].
Inhibitory activity of the experimental example the compounds of this invention to IDO albumen
Recombined human IDO albumen through Bacillus coli expression, nickel affinity chromatographic purifying and obtain.Compound is real to IDO inhibitory activity
Test using L-Trp as substrate.Testing compound is dissolved in 10%DMSO solution and is configured to dilution.Take 5uL dilutions
It is added in 100 μ L reaction systems.Contain 0.5%DMSO, 40nmol/L IDO, 900 μm of ol/LL- colors in 100 μ L reaction systems
Propylhomoserin, and other reaction concurrents (kaliumphosphate buffer, ascorbic acid, catalase, methylene blue).Reactant mixture
Cultivated 180 minutes under 37 degree, add trichloroacetic acid terminating reaction.Existed using Tecan Infinite M1000 ELIASAs
The concentration of N- formoxyl kynurenins caused by measure at 321nm, so as to evaluate inhibitory activity of the compound to IDO.It is negative right
It is that IDO is replaced with 5 μ L buffer solution according to thing.The IDO inhibitor INCB024360 of clinical III phases is as positive control, and checking is originally
Whether effective test the IDO Activity determinations system established.
Each concentration sets up three wells.Data analysis is carried out using software Graphpad Prism.Without test compounds
In the reaction solution of thing, absorbance (At) it is defined as 100% activity.In the reaction solution without IDO, absorbance (Ab) it is defined as 0%
Activity.For testing compound, active calculation formula is：%activity=[(A-Ab)/(At-Ab)] × 100, wherein A is
The absorbance of reaction solution containing testing compound.The calculation formula of inhibiting rate is：%inhibition=100-%activity.
By above experimental method, the inhibitory activity that compound prepared by the present invention is directed to IDO is tested.Specific portion chemical combination
Inhibitory activity of the thing under 1 μM, 10 μM, 100 μM of concentration is shown in Table 5.
Wherein A represents that inhibiting rate is more than 90%, B and represents that inhibiting rate is 70-90%, and C represents that inhibiting rate is 50-69%；D tables
It is 10-49% to show inhibiting rate, and E represents that inhibiting rate is less than 10%；Inhibiting rate of the positive control when concentration is 0.05 μM be
46%.
Inhibitory activity of the compounds of this invention of table 5 to IDO
Tests prove that there is the 1H- indazole compounds that the inventive method is prepared significant suppression to make to IDO
With, it can be used for preventing and/or treat a variety of diseases, the related sense such as Alzheimer disease, cataract, cellular immunity activation
Dye, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism exception etc..
Claims (10)
1. a kind of method of formula (I) compound,
Wherein, R1Represent hydrogen, halogen atom, alkyl or haloalkyl；
It the described method comprises the following steps：
Work as R1When representing alkyl or haloalkyl, using formula (A1) compound as raw material, formula (B) compound is obtained through nitration reaction；
Work as R1When representing halogen atom, using formula (A2) compound as raw material, formula (B) compound is obtained through halogenating reaction；
Using formula (B) compound as raw material, by a nitro in formula (B) compound through reduction reaction, formula (C) compound is obtained；
Using formula (C) compound as raw material, nitrite is added, formula (I) compound is obtained through diazotising, ring-closure reaction.
2. according to the method for claim 1, it is characterised in that：The alkyl is C1~C4Alkyl, the haloalkyl is
C1~C4Haloalkyl；
Preferably, the C1~C4Alkyl be selected from methyl；The C1~C4Haloalkyl be selected from trifluoromethyl, difluoromethyl or
One methyl fluoride.
3. according to the method for claim 1, it is characterised in that：The halogen atom is chlorine atom, bromine atoms or iodine atom.
4. according to the method described in claim any one of 1-3, it is characterised in that：In step (1), the nitration reaction is dense
Any of sulfuric acid, concentrated nitric acid or fuming nitric aicd are carried out with nitrate under the conditions of simultaneous；It is preferred that the concentrated sulfuric acid；
The mol ratio of the nitrate and formula (A1) compound is 1.5~3.5：1.
5. according to the method for claim 4, it is characterised in that：In step (1), the halogenating agent of the halogenating reaction is selected from
It is any in 1,3- bis- bromo- 5,5- DMHs, N- bromo-succinimides, sym-closene or N- N-iodosuccinimides
Kind；It is preferred that 1,3- bis- bromo- 5,5- DMHs；
The halogenating reaction is carried out in the presence of acid；The acid is in the concentrated sulfuric acid, concentrated nitric acid, concentrated hydrochloric acid or trifluoroacetic acid
Any, preferred concentrated sulfuric acid.
6. according to the method described in claim any one of 1-3, it is characterised in that：In step (2), the reduction reaction is in iron
With carry out in the presence of hydrochloric acid；Preferably, the mol ratio of iron and formula (B) compound is 2~4:1；
The solvent of the reduction reaction is selected from any of methanol, dioxane, ethanol or water or their mixed solvent, excellent
Select the mixed solvent of methanol and dioxane；
The temperature of the reduction reaction is 20-80 DEG C；It is preferred that 80 DEG C.
7. according to the method described in claim any one of 1-3, it is characterised in that：In step (3), the nitrite is nitrous
Sour sodium；The solvent of the reaction is hydrochloric acid, sulfuric acid, preferably acid or glacial acetic acid, acetic acid.
8. the method according to claim 6 or 7, it is characterised in that：The mol ratio of the nitrite and formula (C) chemical combination is
1.5~3.5：1；The nitrite adds at a temperature of -5 DEG C~5 DEG C.
A kind of 9. method of formula (II) compound, it is characterised in that：Comprise the following steps：
Wherein, R1As any one of claim 1-4 is defined；
Using formula (I) compound as raw material, formula (II) compound is obtained by what nitro was reduced to amino；Formula (I) compound is
It is prepared according to the method described in claim any one of 1-8.
10. according to the method for claim 9, it is characterised in that：The reduction is carried out in the presence of iron and ammonium chloride.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108689936A (en) * | 2017-04-10 | 2018-10-23 | 西华大学 | The indazole compounds of nitrogenous substituent group and its purposes as IDO inhibitor |
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| CN108689936B (en) * | 2017-04-10 | 2021-09-10 | 西华大学 | Indazoles containing nitrogen substituents and use thereof as IDO inhibitors |
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