CN109796409A - A kind of method of tetrahydrobiopterin synthesis indazole compound - Google Patents
A kind of method of tetrahydrobiopterin synthesis indazole compound Download PDFInfo
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Abstract
The invention belongs to technical field of medicine synthesis, and in particular to a kind of method of tetrahydrobiopterin synthesis indazole compound.The synthetic method includes 5; 5- dimethyl -2- acetyl group -1; the synthesis of hydroresorcinol, the synthesis of the fluoro- 4- diazanyl benzonitrile of 2-, the fluoro- 4- (3 of 2-; 6,6- trimethyl -4- oxygen -4,5; 6; 7- tetrahydro -1H- indazole -1-) synthesis of benzonitrile, 2- (4- hydroxy cyclohexylphenyl amino) -4- (3,6,6- trimethyl -4- oxygen -4; 5; 6,7- tetrahydro -1H- indazole -1-) benzonitrile synthesis and 2- (4- hydroxy cyclohexylphenyl amino) -4- (3,6; 6- trimethyl -4- oxygen -4; 5,6,7- tetrahydro -1H- indazole -1-) benzamide synthesis.The yield of the fluoro- 4- of intermediary 2- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1-) benzonitrile is up to 93%, and purity is high keeps the tetrahydrochysene indazole compound purity being prepared high, is suitble to produce in enormous quantities.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of method of tetrahydrobiopterin synthesis indazole compound.
Background technique
Tetrahydrochysene indazole compound is a kind of antiviral drugs novel, with fine prospect.It is especially right to a variety of viruses
Herpesviral I and II type, Coxsackie virus type III (CVB3) have apparent inhibiting effect, and patent document CN101273991A is public
The application of tetrahydro-indolone/tetrahydroindazolone//tetrahydrocarbazole derivatives and its salt in preparation antiviral drugs has been opened, has illustrated four
Hydrogen indazole ketone compound has activity well to hepatitis B etc..In addition, patent document CN1896060A discloses tetrahydro Yin
The derivative of diindyl ketone and the derivative of tetrahydro-indazolone and their application, while tetrahydrochysene indazole compound is also referred to anti-swollen
It also has potential application, is acted in view of the various active of tetrahydrochysene indazole compound, market is to tetrahydrochysene indazole in terms of tumor
The demand for closing object also increasingly increases.
In the prior art, the synthesis of tetrahydrochysene indazole compound takes linear method, that is, passes through 5,5- dimethyl -1,3- ring
Acetyl butyryl and excess acetyl chloride obtain acetyl group -1 5,5- dimethyl -2-, hydroresorcinol, then obtain 3,6 with hydration hydrazine reaction,
6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazoles then react to obtain the fluoro- 4- (3,6,6- of 2- with 2,4- difluorobenzonitrile
Trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1-) benzonitrile, then reacts to obtain 2- with trans- 4- hydroxy cyclohexylphenyl amine
(4- hydroxy cyclohexylphenyl amino) -4- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1-) benzonitrile, it is last and
KOH/ hydroperoxidation obtains tetrahydrochysene indazole compound.
The disadvantage of this technique is in the preparation fluoro- 4- of 2- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- Yin
Azoles -1-) benzonitrile the step of in simultaneously production about 40% the fluoro- 2- of 4- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -
1H- indazole -1-) benzonitrile by-product, and this by-product and principal product are difficult to separate, and need the side using silica gel column chromatography
Method is purified.Therefore, the process route is there are at high cost, at least wastes the 3 of half, 6,6- trimethyl -4- oxygen -4,5, and 6,
7- tetrahydro -1H- indazole and 2,4 difluorobenzene formonitrile HCN.
Therefore, to meet the market demand, research and develop one it is simple, low cost, production tetrahydrochysene indazole can be amplified
The synthetic route of compound has necessity.
Summary of the invention
A kind of intermediate 3,6,6- the present invention is intended to provide method of tetrahydrobiopterin synthesis indazole compound, in the synthetic method
The synthetic ratio of trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazoles and 2,4- difluorobenzonitrile is high, makes the tetrahydro Yin finally synthesized
Azole compounds yield was once high, economized on resources, and was suitble to mass production.
In order to achieve the above object, the invention adopts the following technical scheme:
The present invention provides a kind of method of tetrahydrobiopterin synthesis indazole compound, synthetic method the following steps are included:
The synthesis of S1:5,5- dimethyl -2- acetyl group-hydroresorcinol:
Dimethyl -1 5,5- is weighed, hydroresorcinol, which is added in organic solvent, to be dissolved, and triethylamine and 4- diformazan ammonia are added
Yl pyridines under 0 DEG C~4 DEG C condition of ice bath, are added dropwise chloroacetic chloride, react 2.5-3.5h under the conditions of being placed in 0 DEG C~60 DEG C, filter, take
Organic layer adds anhydrous Na after saturated salt solution cleaning is added2SO4It is dry, be removed under reduced pressure solvent, column chromatographic purifying to get；
The synthesis of the fluoro- 4- diazanyl benzonitrile of S2:2-:
It weighs 2,4- difluorobenzonitrile and is added in organic solvent and dissolve, add hydrazine hydrate, stirred under the conditions of 20 DEG C~80 DEG C
Reaction 10-14h is mixed, decompression is spin-dried for, and after saturated salt solution cleaning is added, adds anhydrous Na2SO4It is dry, solvent is removed under reduced pressure,
Be added re-crystallizing in ethyl acetate to get；
The synthesis of the fluoro- 4- of S3:2- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1-) benzonitrile:
It weighs compound 5,5- dimethyl -2- acetyl group-hydroresorcinol that step S1 is obtained and step S2 obtains
The fluoro- 4- diazanyl benzonitrile of compound 2- is added in organic solvent, adds glacial acetic acid, reacts 6-12h under the conditions of 25 DEG C~80 DEG C,
Decompression removal solvent, is added ethyl acetate extraction, and saturation NaHCO is first added3Cleaning, adds saturated common salt water washing, repeats
Cleaning 2-3 time, it is dry to add anhydrous Na 2SO4, concentrated solvent, addition ethyl alcohol recrystallization to get；
S4:2- (4- hydroxy cyclohexylphenyl amino) -4- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1-) benzene
The synthesis of formonitrile HCN:
Trans- 4- hydroxy cyclohexylphenyl amine is weighed, the fluoro- 4- of compound 2- (3,6, the 6- trimethyl -4- that it is obtained with step S3
Oxygen -4,5,6,7- tetrahydro -1H- indazole -1-) benzonitrile adds in dimethyl sulfoxide, K is added2CO3, under the conditions of 25 DEG C~80 DEG C
After reacting 10-12h, be cooled to room temperature, reaction solution be added in distilled water, filtering takes filter residue, be added ethyl alcohol recrystallization to get；
S5:2- (4- hydroxy cyclohexylphenyl amino) -4- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1-) benzene
The synthesis of formamide:
Weigh compound 2- (4- hydroxy cyclohexylphenyl amino) -4- that step S4 obtains (oxygen -4,5,6 3,6,6- trimethyl -4-,
7- tetrahydro -1H- indazole -1-) benzonitrile is dissolved in dimethyl sulfoxide, add the H of KOH and 30% (v/v)2O2Solution, in room temperature
Under the conditions of react 2h after, by reaction solution be added distilled water in, filtering, take filter residue, add ethyl alcohol recrystallization to get tetrahydrochysene indazole chemical combination
Object: 2- (4- hydroxy cyclohexylphenyl amino) -4- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1-) benzamide.
Further, triethylamine, 4-dimethylaminopyridine and chloroacetic chloride and 5,5- dimethyl -1,3- in the step S1
The molar ratio of cyclohexanedione is (1.5-2): (0.25-0.5): (1.05-1.525): 1.
Further, the organic solvent in the step S1 is one of acetonitrile, dioxane or ethyl acetate.
Further, the hydrazine hydrate and 2 in the step S2, the molar ratio of 4- difluorobenzonitrile are (1.0-2): 1.
Further, the organic solvent in the step S2 is methanol, ethyl alcohol, benzyl alcohol, ethylene glycol, methylene chloride, two
One of six ring of oxygen.
Further, acetyl group -1 5,5- dimethyl -2-, hydroresorcinol rub with the fluoro- 4- diazanyl benzonitrile of 2-
You are than being 1:1；The glacial acetic acid and 5,5- dimethyl -2- acetyl group-hydroresorcinol molar ratio are (1.0-1.5): 1；
Organic solvent in the step S3 is one of methanol, ethyl alcohol and dioxane.
Further, trans- 4- hydroxy cyclohexylphenyl amine and K in the step S42CO3With the fluoro- 4- of 2- (3,6,6- trimethyl -4-
Oxygen -4,5,6,7- tetrahydro -1H- indazole -1-) benzonitrile molar ratio be 2:4.35:1.
Further, the H of the KOH in the step S5 and 30% (v/v)2O2Solution and 2- (4- hydroxy cyclohexylphenyl amino) -4-
The molar ratio of (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1-) benzonitrile is (0.012-0.048): 1:1.
Further, the reaction temperature in the step S1 is 20 DEG C~35 DEG C；Reaction temperature in the step S2
It is 50 DEG C~80 DEG C；Reaction temperature is 60 DEG C~80 DEG C in the step S3；Reaction temperature is 60 DEG C~80 in the step S4
℃。
The fluoro- 4- of 2- in the method for tetrahydrobiopterin synthesis indazole compound provided by the invention (oxygen -4,5 3,6,6- trimethyl -4-,
6,7- tetrahydro -1H- indazole -1-) benzonitrile yield be 74%-93%, which is 1.5-2.5 times of the prior art, is synthesized
By-product production amount in journey is few, in synthetic route provided by the invention can also by the fluoro- 4- of 2- (3,6,6- oxygen -4 trimethyl -4-,
5,6,7- tetrahydro -1H- indazole -1-) benzonitrile and the fluoro- 2- of by-product 4- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -
1H- indazole -1-) benzonitrile separation completely, improve purity.
In addition intermediary 5,5- dimethyl -2- acetyl group-hydroresorcinol yield is 78%-95%；The fluoro- 4- hydrazine of 2-
Base benzonitrile yield is 52%-63%；2- (4- hydroxy cyclohexylphenyl amino) -4- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -
1H- indazole -1-) benzonitrile yield be 65%-97%；2- (4- hydroxy cyclohexylphenyl amino) -4- (oxygen -4,5 3,6,6- trimethyl -4-,
6,7- tetrahydro -1H- indazole -1-) benzamide yield is 83%-95%, the yield of each intermediate product is high, the synthesis road preferably gone out
Line is at low cost, for producing in enormous quantities.
Compared with prior art, the method for tetrahydrobiopterin synthesis indazole compound provided by the invention has the advantage that
(1) intermediary 2- fluoro- 4- (the 3,6,6- trimethyl-of the method for tetrahydrobiopterin synthesis indazole compound provided by the invention
4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1-) yield of benzonitrile is up to 93%, and it can be with the fluoro- 2- of by-product 4- (3,6,6- tri-
Methyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1-) benzonitrile separation completely, product purity is high.
(2) synthetic method of tetrahydrochysene indazole compound provided by the invention reduces the generation of by-product, is prepared
Tetrahydrochysene indazole compound purity is high, and synthetic method is fast and effective, and synthesis cost is low, is suitble to produce in enormous quantities.
Detailed description of the invention
Fig. 1 is the synthetic route of tetrahydrochysene indazole compound, 1 in figure are as follows: 5,5- dimethyl -2- acetyl group 1,3- hexamethylene two
Ketone；2 are as follows: the fluoro- 4- diazanyl benzonitrile of 2-；3 are as follows: the fluoro- 4- of 2- (- 3,6,6- trimethyl -4- oxo -4,5,6,7- tetrahydro -1H- Yin
Azoles -1- base) benzonitrile；4 are as follows: 2- (4- hydroxy cyclohexylphenyl amino) -4- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- Yin
Azoles -1- base) benzonitrile；5 are as follows: 2- (4- hydroxy cyclohexylphenyl amino) -4- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- Yin
Azoles -1- base) benzamide.
Specific embodiment
The specific embodiment of form by the following examples makees further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following embodiment.
The method of embodiment 1, tetrahydrobiopterin synthesis indazole compound
The synthesis of S1:5,5- dimethyl -2- acetyl group hydroresorcinol:
Dimethyl -1 5,5- of 20.0mmol is weighed, hydroresorcinol is dissolved in 10mL acetonitrile, and the three of 30.0mmol are added
The chloroacetic chloride of 25.0mmol is added dropwise under 0 DEG C~4 DEG C condition of ice bath, is placed in 25 DEG C for the 4-dimethylaminopyridine of ethamine and 5.0mmol
Under the conditions of react 3h, filter, take organic layer, saturated salt solution cleaning is added, adds anhydrous Na2SO4It is dry, it is removed under reduced pressure molten
Agent, column chromatographic purifying obtain pale yellow oily liquid 1.4g；
The synthesis of the fluoro- 4- diazanyl benzonitrile of S2:2-:
2, the 4- difluorobenzonitrile for weighing 7.19mmol, which is added in 10mL methylene chloride, to be dissolved, and the water of 7.19mmol is added
Hydrazine is closed, is stirred to react 10h under the conditions of 25 DEG C, decompression is spin-dried for, and saturated salt solution cleaning is added, adds anhydrous Na2SO4It is dry, subtract
Pressure removes solvent, and recrystallizing methanol is added and obtains white solid product 0.56g, and 137-138 DEG C of fusing point；
The conjunction of the fluoro- 4- of S3:2- (- 3,6,6- trimethyl -4- oxo -4,5,6,7- tetrahydro -1H- indazole -1- base) benzonitrile
At:
Weigh compound 5,5- dimethyl -2- acetyl group-hydroresorcinol that 9.9mmol step S1 is obtained and
The fluoro- 4- diazanyl benzonitrile of the compound 2- that 9.9mmol step S2 is obtained is added in 30mL methanol, adds 10mmol glacial acetic acid,
12h is reacted under the conditions of 25 DEG C, decompression removal solvent is extracted with ethyl acetate, saturation NaHCO is first added3Cleaning, adds saturation
Brine It, repeated washing and washing 2-3 times, add anhydrous Na2SO4Dry, concentrated solvent is added ethyl alcohol recrystallization, obtains
To white solid product 2.2g, 150-151 DEG C of fusing point；
S4:2- (4- hydroxy cyclohexylphenyl amino) -4- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1- base)
The synthesis of benzonitrile:
Weigh the fluoro- 4- of 2- (- 3,6,6- trimethyl -4- made from the 4- hydroxy cyclohexylphenyl amine and 10mmol step S3 of 20mmol
Oxo -4,5,6,7- tetrahydro -1H- indazole -1- bases) benzonitrile adds in 40mL dimethyl sulfoxide, the K of 43.5mmol is added2CO3,
10h is reacted under the conditions of 50 DEG C, is cooled to room temperature, reaction solution is added in 150mL distilled water, filtering takes filter residue, and ethyl alcohol is added
Recrystallization, obtains solid product 3.0g, and 191-192 DEG C of fusing point；
S5:2- (4- hydroxy cyclohexylphenyl amino) -4- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1- base)
The synthesis of benzamide:
Weigh compound 2- (4- hydroxy cyclohexylphenyl amino) -4- (3,6,6- trimethyl -4- oxygen-that 2.5mmol step S4 is obtained
4,5,6,7- tetrahydro -1H- indazole -1-) benzonitrile is dissolved in 10mL dimethyl sulfoxide, add 1.2mmol KOH and
The H of 30% (v/v) of 2.5mmol2O2Solution, after reacting 2h under the conditions of 25 DEG C, reaction solution is added in distilled water, and filtering takes
Filter residue adds ethyl alcohol recrystallization to obtain product 0.87g, and 220-221.0 DEG C of fusing point.
Synthetic route chart is shown in Fig. 1.
The method of embodiment 2, tetrahydrobiopterin synthesis indazole compound
The synthesis of S1:5,5- dimethyl -2- acetyl group hydroresorcinol:
Dimethyl -1 5,5- of 20.0mmol is weighed, hydroresorcinol is dissolved in 20mL dioxane, and 30.0mmol is added
Triethylamine and 5.0mmol 4-dimethylaminopyridine, the chloroacetic chloride of 25.0mmol is added dropwise under 0 DEG C~4 DEG C condition of ice bath, is placed in
40 DEG C of conditioned response 3h, filtering take organic layer, and saturated salt solution cleaning is added, adds anhydrous Na2SO4It is dry, it is removed under reduced pressure
Solvent, column chromatographic purifying obtain pale yellow oily liquid 3.3g；
The synthesis of the fluoro- 4- diazanyl benzonitrile of S2:2-:
2, the 4- difluorobenzonitrile for weighing 10mmol, which is added in 15mL dioxane, to be dissolved, and the hydration of 15mmol is added
Hydrazine is stirred to react 12h under the conditions of 50 DEG C, and decompression is spin-dried for, and saturated salt solution cleaning is added, adds anhydrous Na2SO4It is dry, decompression
Solvent is removed, re-crystallizing in ethyl acetate is added and obtains white solid product 0.89g, 136.5-138 DEG C of fusing point；
The conjunction of the fluoro- 4- of S3:2- (- 3,6,6- trimethyl -4- oxo -4,5,6,7- tetrahydro -1H- indazole -1- base) benzonitrile
At:
Weigh compound 5,5- dimethyl -2- acetyl group-hydroresorcinol that 9.9mmol step S1 is obtained and
The fluoro- 4- diazanyl benzonitrile of the compound 2- that 9.9mmol step S2 is obtained is added in 30mL dioxane, adds 15mmol ice second
Acid, 8h is reacted under the conditions of 50 DEG C, and decompression removal solvent is extracted with ethyl acetate, saturation NaHCO is first added3Cleaning, adds full
And brine It, repeated washing 2-3 times add anhydrous Na2SO4Dry, concentrated solvent is added ethyl alcohol recrystallization, obtains white
Color solid product 2.7g, 149-150 DEG C of fusing point；
S4:2- (4- hydroxy cyclohexylphenyl amino) -4- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1- base)
The synthesis of benzonitrile:
Weigh 2- fluoro- 4- (- 3,6,6- trimethyl-made from the trans- 4- hydroxy cyclohexylphenyl amine of 20mmol and 10mmol step S3
4- oxo -4,5,6,7- tetrahydro -1H- indazole -1- bases) benzonitrile adds in 40mL dimethyl sulfoxide, it is added 43.5mmol's
K2CO3, 12h is reacted under the conditions of 65 DEG C, is cooled to room temperature, reaction solution is added in 150mL distilled water, filtering takes filter residue, adds
Enter ethyl alcohol recrystallization, obtains solid product 3.7g, 192-193 DEG C of fusing point；
S5:2- (4- hydroxy cyclohexylphenyl amino) -4- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1- base)
The synthesis of benzamide:
Weigh compound 2- (4- hydroxy cyclohexylphenyl amino) -4- (3,6,6- trimethyl -4- oxygen-that 2.5mmol step S4 is obtained
4,5,6,7- tetrahydro -1H- indazole -1-) benzonitrile is dissolved in 10mL dioxane, add the KOH and 2.6mmol of 0.5mmol
30% (v/v) H2O2Solution, after reacting 2h under the conditions of 25 DEG C, reaction solution is added in distilled water, and filtering takes filter residue, adds
Ethyl alcohol recrystallization obtains product 0.97g, and 220-222.0 DEG C of fusing point.
Synthetic route chart is shown in Fig. 1.
The method of embodiment 3, tetrahydrobiopterin synthesis indazole compound
The synthesis of S1:5,5- dimethyl -2- acetyl group hydroresorcinol:
Dimethyl -1 5,5- of 20.0mmol is weighed, hydroresorcinol is dissolved in 20mL ethyl acetate, and 30.0mmol is added
Triethylamine and 8.2mmol 4-dimethylaminopyridine, the chloroacetic chloride of 30.5mmol is added dropwise under 0 DEG C~4 DEG C condition of ice bath, is placed in
60 DEG C of conditioned response 3h, filtering take organic layer, and saturated salt solution cleaning is added, adds anhydrous Na2SO4It is dry, it is removed under reduced pressure
Solvent, column chromatographic purifying obtain pale yellow oily liquid 3.5g；
The synthesis of the fluoro- 4- diazanyl benzonitrile of S2:2-:
2, the 4- difluorobenzonitrile for weighing 10mmol, which is added in 15mL ethyl alcohol, to be dissolved, and adds the hydrazine hydrate of 12mmol, and 80
8h is stirred to react under the conditions of DEG C, decompression is spin-dried for, and saturated salt solution cleaning is added, adds anhydrous Na2SO4It is dry, it is removed under reduced pressure molten
Agent is added recrystallizing methanol and obtains white solid product 0.95g, and 137-138 DEG C of fusing point；
The conjunction of the fluoro- 4- of S3:2- (- 3,6,6- trimethyl -4- oxo -4,5,6,7- tetrahydro -1H- indazole -1- base) benzonitrile
At:
Weigh compound 5,5- dimethyl -2- acetyl group-hydroresorcinol that 9.9mmol step S1 is obtained and
The fluoro- 4- diazanyl benzonitrile of the compound 2- that 9.9mmol step S2 is obtained is added in 30mL ethyl alcohol, adds 12.5mmol ice second
Acid, 6h is reacted under the conditions of 80 DEG C, and decompression removal solvent is extracted with ethyl acetate, saturation NaHCO is first added3Cleaning, adds full
And brine It, repeated washing and washing 2-3 times, add anhydrous Na2SO4Dry, recrystallizing methanol is added in concentrated solvent,
Obtain white solid product 2.67g, 150-151 DEG C of fusing point；
S4:2- (4- hydroxy cyclohexylphenyl amino) -4- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1- base)
The synthesis of benzonitrile:
Weigh 2- fluoro- 4- (- 3,6,6- trimethyl-made from the trans- 4- hydroxy cyclohexylphenyl amine of 20mmol and 10mmol step S3
4- oxo -4,5,6,7- tetrahydro -1H- indazole -1- bases) benzonitrile adds in 40mL dimethyl sulfoxide, it is added 43.5mmol's
K2CO3, 10h is reacted under the conditions of 80 DEG C, is cooled to room temperature, reaction solution is added in 150mL distilled water, filtering takes filter residue, adds
Enter ethyl alcohol recrystallization, obtains solid product 3.8g, 191-193 DEG C of fusing point；
S5:2- (4- hydroxy cyclohexylphenyl amino) -4- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1- base)
The synthesis of benzamide:
Weigh compound 2- (4- hydroxy cyclohexylphenyl amino) -4- (3,6,6- trimethyl -4- oxygen-that 2.5mmol step S4 is obtained
4,5,6,7- tetrahydro -1H- indazole -1-) benzonitrile is dissolved in 10mL ethyl alcohol, add the KOH's and 2.6mmol of 0.51mmol
The H of 30% (v/v)2O2Solution, after reacting 2h under the conditions of 25 DEG C, reaction solution is added in distilled water, and filtering takes filter residue, adds second
Alcohol is recrystallized to give product 0.90g, and 221-222.0 DEG C of fusing point.
Synthetic route chart is shown in Fig. 1.
Test example one, yield
1. experimental subjects: the method for the tetrahydrobiopterin synthesis indazole compound of embodiment 1-3.
2. target product tetrahydrochysene indazole compound is synthesized according to the method for the tetrahydrobiopterin synthesis indazole compound of embodiment 1-3,
Calculate each No. 1: 5,5- dimethyl -2- acetyl group hydroresorcinol of intermediate product；No. 2: 2- fluoro- 4- diazanyl benzonitrile；No. 3:
The fluoro- 4- of 2- (- 3,6,6- trimethyl -4- oxo -4,5,6,7- tetrahydro -1H- indazole -1- base) benzonitrile；No. 4: 2- (4- hydroxyl ring
Own amino) -4- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1- base) benzonitrile；No. 5: 2- (4- hydroxyl ring
Own amino) -4- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1- base) benzamide synthetic ratio (%).
3. experimental result such as table 1.
Each embodiment intermediate product yield (%) of table 1.
| Product | Embodiment 1 | Embodiment 2 | Embodiment 3 |
| 1 | 78 | 91 | 95 |
| 2 | 52 | 59 | 63 |
| 3 | 74 | 93 | 90 |
| 4 | 77 | 95 | 97 |
| 5 | 83 | 95 | 88 |
By data in table 1 it is found that intermediate product 1:5,5- dimethyl -2- acetyl group 1, the maximum yield of hydroresorcinol are
95%；The maximum yield of the fluoro- 4- diazanyl benzonitrile of intermediate product 2:2- is 63%；The fluoro- 4- of intermediate product 3:2- (- 3,6,6- three
Methyl -4- oxo -4,5,6,7- tetrahydro -1H- indazole -1- base) benzonitrile maximum yield be 93%；Intermediate product 42- (4- hydroxyl
Base Cyclohexylamino) maximum yield of -4- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1- base) benzonitrile is
97%；Product 5 is that the maximum yield of tetrahydrochysene indazole compound is 95%.Using the synthetic route, final product tetrahydro can be reduced
The synthesis cost of indazole compound is realized and is produced in enormous quantities to meet the market demand.
The above-described embodiments merely illustrate the principles and effects of the present invention, and is not intended to limit the present invention.It is any ripe
The personage for knowing this technology all without departing from the spirit and scope of the present invention, carries out modifications and changes to above-described embodiment.Cause
This, institute is complete without departing from the spirit and technical ideas disclosed in the present invention by those of ordinary skill in the art such as
At all equivalent modifications or change, should be covered by the claims of the present invention.
Claims (9)
1. a kind of method of tetrahydrobiopterin synthesis indazole compound, which is characterized in that synthetic method the following steps are included:
Acetyl group -1 S1:5,5- dimethyl -2-, the synthesis of hydroresorcinol:
Dimethyl -1 5,5- is weighed, hydroresorcinol, which is added in organic solvent, to be dissolved, and triethylamine and 4- dimethylamino pyrrole are added
Pyridine under 0 DEG C~4 DEG C condition of ice bath, is added dropwise chloroacetic chloride, reacts 2.5-3.5h under the conditions of being placed in 0 DEG C~60 DEG C, filters, take organic
Layer adds anhydrous Na after saturated salt solution cleaning is added2SO4It is dry, be removed under reduced pressure solvent, column chromatographic purifying to get；
The synthesis of the fluoro- 4- diazanyl benzonitrile of S2:2-:
It weighs 2,4- difluorobenzonitrile and is added in organic solvent and dissolve, add hydrazine hydrate, stirred under the conditions of 20 DEG C~80 DEG C anti-
10-14h is answered, decompression is spin-dried for, and after saturated salt solution cleaning is added, adds anhydrous Na2SO4It is dry, solvent is removed under reduced pressure, is added
Re-crystallizing in ethyl acetate to get；
The synthesis of the fluoro- 4- of S3:2- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1-) benzonitrile:
Weigh the chemical combination that compound 5,5- dimethyl -2- acetyl group-hydroresorcinol and step S2 that step S1 is obtained is obtained
The fluoro- 4- diazanyl benzonitrile of object 2- is added in organic solvent, adds glacial acetic acid, reacts 6-12h under the conditions of 25 DEG C~80 DEG C, depressurizes
Solvent is removed, ethyl acetate extraction is added, saturation NaHCO is first added3Cleaning, adds saturated common salt water washing, repeated washing
2-3 times, it is dry to add anhydrous Na 2SO4, concentrated solvent, be added ethyl alcohol recrystallization to get；
S4:2- (4- hydroxy cyclohexylphenyl amino) -4- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1-) benzonitrile
Synthesis:
Trans- 4- hydroxy cyclohexylphenyl amine is weighed, the fluoro- 4- of compound 2- that itself and step S3 are obtained (3,6,6- oxygen -4 trimethyl -4-,
5,6,7- tetrahydro -1H- indazole -1-) benzonitrile adds in dimethyl sulfoxide, K is added2CO3, reacted under the conditions of 25 DEG C~80 DEG C
After 10-12h, be cooled to room temperature, reaction solution be added in distilled water, filtering takes filter residue, be added ethyl alcohol recrystallization to get；
S5:2- (4- hydroxy cyclohexylphenyl amino) -4- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1-) benzoyl
The synthesis of amine:
Weigh compound 2- (4- hydroxy cyclohexylphenyl amino) -4- (3,6,6- trimethyl -4- oxygen -4,5,6,7- four that step S4 is obtained
Hydrogen -1H- indazole -1-) benzonitrile is dissolved in dimethyl sulfoxide, add the H of KOH and 30% (v/v)2O2Solution, in room temperature condition
After lower reaction 2h, reaction solution is added in distilled water, filtering takes filter residue, adds ethyl alcohol recrystallization to get tetrahydrochysene indazole compound:
2- (4- hydroxy cyclohexylphenyl amino) -4- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1-) benzamide.
2. the method for tetrahydrobiopterin synthesis indazole compound according to claim 1, which is characterized in that three second in the step S1
Amine, 4-dimethylaminopyridine and chloroacetic chloride and 5,5- dimethyl-hydroresorcinol molar ratio are (1.5-2): (0.25-
0.5):(1.05-1.525):1。
3. the method for tetrahydrobiopterin synthesis indazole compound according to claim 1, which is characterized in that having in the step S1
Solvent is one of acetonitrile, dioxane and ethyl acetate.
4. the method for tetrahydrobiopterin synthesis indazole compound according to claim 1, which is characterized in that the water in the step S2
The molar ratio for closing hydrazine and 2,4 difluorobenzene formonitrile HCN is (1.0-2): 1.
5. the method for tetrahydrobiopterin synthesis indazole compound according to claim 1, which is characterized in that having in the step S2
Solvent is one of methanol, ethyl alcohol, benzyl alcohol, ethylene glycol, methylene chloride and dioxane.
6. the method for tetrahydrobiopterin synthesis indazole compound according to claim 1, which is characterized in that 5, the 5- dimethyl-
The molar ratio of 2- acetyl group-hydroresorcinol and the fluoro- 4- diazanyl benzonitrile of 2- is 1:1；The glacial acetic acid and 5,5- dimethyl-
2- acetyl group-hydroresorcinol molar ratio is (1.0-1.5): 1；Organic solvent in the step S3 is methanol, ethyl alcohol
One of with dioxane.
7. the method for tetrahydrobiopterin synthesis indazole according to claim 1, which is characterized in that trans- 4- hydroxyl in the step S4
Cyclohexylamine and K2CO3With mole of the fluoro- 4- of 2- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H- indazole -1-) benzonitrile
Than for 2:4.35:1.
8. the method for tetrahydrobiopterin synthesis indazole according to claim 1, which is characterized in that KOH in the step S5 and
The H of 30% (v/v)2O2Solution and 2- (4- hydroxy cyclohexylphenyl amino) -4- (3,6,6- trimethyl -4- oxygen -4,5,6,7- tetrahydro -1H-
Indazole -1-) benzonitrile molar ratio be (0.012-0.048): 1:1.
9. the method for tetrahydrobiopterin synthesis indazole according to claim 1, which is characterized in that the reaction temperature in the step S1
It is 20 DEG C~35 DEG C；Reaction temperature in the step S2 is 50 DEG C~80 DEG C；In the step S3 reaction temperature be 60 DEG C~
80℃；Reaction temperature is 60 DEG C~80 DEG C in the step S4.
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| CN114213332A (en) * | 2022-02-21 | 2022-03-22 | 深圳市人民医院 | A kind of tetrahydroindazole compound and its preparation method and application |
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