CN109081810A - The synthetic method of 1- methyl-3-((methylamino) methyl)-1H- pyrazoles-5- nitrile - Google Patents
The synthetic method of 1- methyl-3-((methylamino) methyl)-1H- pyrazoles-5- nitrile Download PDFInfo
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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
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Abstract
The invention belongs to pharmaceutical technology fields, it is related to the synthetic method of 1- methyl -3- ((methylamino) methyl) -1H- pyrazoles -5- nitrile, it is starting material from diethy-aceto oxalate and acetone simple and easy to get, through condensation, cyclisation, methylation, at amide, oxidation, bromo, 7 step of amination reacts to obtain 1- methyl -3- ((methylamino) methyl) -1H- pyrazoles -5- nitrile.The present invention realizes the preparation that anti-tumor drug Laura replaces Buddhist nun (PF-06463922) key intermediate 1- methyl -3- ((methylamino) methyl) -1H- pyrazoles -5- nitrile, total recovery is up to 5.7% or more, it is easy to operate, convenient post-treatment, it is time-consuming short, it is at low cost, it is conducive to realize industrialization.The intermediate and fluoro- -1 (3H) -one of 3- methyl isobenzofuran of 5- finally synthesize Laura by reaction steps such as ammonolysis, substitution, coupling, chiral resolutions and replace Buddhist nun, provide new method for anti-tumor drug Laura for the synthesis of Buddhist nun.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, are related to drug Laura for Buddhist nun (PF-06463922) key intermediate 1- methyl-
The synthetic method of 3- ((methylamino) methyl) -1H- pyrazoles -5- nitrile.The intermediate and the fluoro- 3- methyl isobenzofuran -1 of 5-
(3H) -one synthesizes Laura finally by reaction steps such as ammonolysis, substitution, coupling, chiral resolutions for Buddhist nun, is anti-tumor drug Laura
New method is provided for the synthesis of Buddhist nun.
Background technique
Laura is Pfizer (Pfizer) company by replacing Buddhist nun (Crizotinib) to gram azoles for Buddhist nun (PF-06463922)
The ALK inhibitor of transformation enters clinical test in the drug 2014, for the treatment of lung cancer, inhibits mainly for first generation ALK
Agent gram azoles is drug resistant for Buddhist nun (Alectinib) for Buddhist nun's drug resistance and second generation ALK inhibitor Ceritinib (Ceritinib) and Ai Le
Patients with Non-small-cell Lung.In the patent WO 2013132376 that it is delivered, US 8680111, JP 2015510879, EP
In 2822953, CN 104169286, US 2016115178, WO 2014207606, the four of the drug and its intermediate are described
Synthetic route, the synthetic method in relation to intermediate 1- methyl -3- ((methylamino) methyl) -1H- pyrazoles -5- nitrile, patent WO
2013132376 give a kind of synthetic method, but its synthetic route is long, and at high cost, time-consuming, and yield is low.Therefore, having must
A kind of new preparation method is developed, has the advantages that raw material is easy to get, step is short, at low cost, post-processing operation is easy, is easy to work
Industry.
Summary of the invention
Technical problem to be solved by the invention is to provide a kind of 1- methyl -3- ((methylamino) methyl) -1H- pyrazoles -5-
The synthetic method of nitrile, this method have the characteristics that raw material is easy to get, step is short, at low cost, high income.
The present invention is achieved through the following technical solutions:
The present invention using diethy-aceto oxalate and acetone simple and easy to get as starting material, through condensation, cyclisation, methylation, at acyl
Amine, oxidation, bromo, 7 step of amination react to obtain 1- methyl -3- ((methylamino) methyl) -1H- pyrazoles -5- nitrile.
The present invention includes the following steps:
(1) diethy-aceto oxalate (I) and acetone (II) generation condensation reaction obtain (Z) -1- ethyoxyl -1,4- dioxolanes -2-
The sodium salt (III) of alkene -2- carboxylic ester；
(2) sodium salt (III) of (Z) -1- ethyoxyl -1,4- dioxolanes -2- alkene -2- carboxylic ester and hydration hydrazine reaction obtain 3-
Methyl-1 H- pyrazoles -5- carboxylic acid, ethyl ester (IV)；
(3) 3- methyl-1 H- pyrazoles -5- carboxylic acid, ethyl ester (IV) and methylating reagent flow back under alkaline condition is made 1,3-
Dimethyl -1H- pyrazoles -5- carboxylic acid, ethyl ester (V)；
(4) 1,3- dimethyl -1H- pyrazoles -5- carboxylic acid, ethyl ester (V), which reacts in alcoholic solvent or water with ammonia reagent, is made 1,3-
Dimethyl -1H- pyrazoles -5- formamide (VI)；
(5) 1,3- dimethyl -1H- pyrazoles -5- formamide (VI) flows back through dehydrating agent and 1,3- dimethyl -1H- pyrazoles-is made
5- nitrile (VII)；
(6) 1,3- dimethyl -1H- pyrazoles -5- nitrile (VII) reacts the obtained 3- (bromine of reflux with bromide reagent in organic solvent
Methyl) -1- methyl-1 H- pyrazoles -5- nitrile (VIII)；
(7) 3- (bromomethyl) -1- methyl-1 H- pyrazoles -5- nitrile (VIII) is reacted in organic solvent with methylamine reagent and is made
1- methyl -3- ((methylamino) methyl) -1H- pyrazoles -5- nitrile (IX).
The synthetic route of 1- methyl -3- ((methylamino) methyl) -1H- pyrazoles -5- nitrile of the present invention is as follows:
Wherein, in step (1), prepared by the sodium salt (III) of (Z) -1- ethyoxyl-Isosorbide-5-Nitrae-dioxolanes -2- alkene -2- carboxylic ester
Method is as follows: under organic solvent system, diethy-aceto oxalate (I) and acetone (II) under alkaline condition, at a temperature of 15-50 DEG C
It carries out reacting the sodium salt (III) that (Z) -1- ethyoxyl-Isosorbide-5-Nitrae-dioxolanes -2- alkene -2- carboxylic ester is made, preferable temperature 15-
20℃；The organic solvent be C1-C4 unitary alcoholic solution, the alkali be the alcohol selected from C1-C4 sodium salt organic base or
Sodium hydroxide, potassium hydroxide, sodium hydride, LDA inorganic base.
In step (2), the preparation method of 3- methyl-1 H- pyrazoles -5- carboxylic acid, ethyl ester (IV) is as follows, ethyoxyl -1 (Z) -1-,
3- first is made in the sodium salt (III) and hydrazine hydrate of 4- dioxolanes -2- alkene -2- carboxylic ester in organic acid soln under the conditions of 0-80 DEG C
Base -1H- pyrazoles -5- carboxylic acid, ethyl ester (IV), the organic acid is selected from formic acid, glacial acetic acid, propionic acid, butyric acid, oxalic acid, described
(Z) molar ratio of the sodium salt (III) of -1- ethyoxyl-Isosorbide-5-Nitrae-dioxolanes -2- alkene -2- carboxylic ester and hydrazine hydrate is 1:1-2,
Reaction time is 2-5h.
In step (3), the preparation method of 1,3- dimethyl -1H- pyrazoles -5- carboxylic acid, ethyl ester (V) is as follows, in organic solvent or
In aqueous solvent, 3- methyl-1 H- pyrazoles -5- carboxylic acid, ethyl ester (IV) and methylating reagent dimethyl suflfate, iodomethane are in alkaline condition
1,3- dimethyl -1H- pyrazoles -5- carboxylic acid, ethyl ester (V) is made in lower flow back, and the organic solvent is selected from halogenated C1-C4 alkane, ether
Class, DMF, DMSO or alcoholic solvent, the alkali be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine, pyridine or
DIEA, 3- methyl-1 H- pyrazoles -5- carboxylic acid, ethyl ester (IV): methylating reagent: the molar ratio of alkali is 1:1-3:1-5.
In step (4), the preparation method of 1,3- dimethyl -1H- pyrazoles -5- formamide (VI) is as follows, 1,3- dimethyl -
1H- pyrazoles -5- carboxylic acid, ethyl ester (V), which reacts in alcoholic solvent or water with ammonia reagent, is made 1,3- dimethyl -1H- pyrazoles -5- formyl
Amine (VI), the alcoholic solvent be selected from methanol, ethyl alcohol, isopropanol, the ammonia reagent be selected from ammonium hydroxide, ammonia, ammonia alcoholic solution or
Ammonium carbonate, ammonium hydrogen carbonate, ammonium chloride, urea, 1,3- dimethyl -1H- pyrazoles -5- carboxylic acid, ethyl ester (V): ammonia reagent=1:1-30
(molar ratio), 0-25 DEG C of temperature.
In step (5), the preparation method of 1,3- dimethyl -1H- pyrazoles -5- nitrile (VII) is as follows, 1,3- dimethyl -1H- pyrrole
Azoles -5- formamide (VI) flows back through dehydrating agent is made 1,3- dimethyl -1H- pyrazoles -5- nitrile (VII), and the dehydrating agent is selected from chlorine
Changing sulfoxide, phosphorus oxychloride, DCC, sodium hydroxide, tetrabutylammonium bromide, triethylbenzyl ammonium bromide or trifluoroacetic anhydride, dosage is
1-20 times of raw material, return time 1-5h, solvent are selected from tetrahydrofuran, dichloroethanes, methylene chloride or chloroform.
In step (6), the preparation method of 3- (bromomethyl) -1- methyl-1 H- pyrazoles -5- nitrile (VIII) is as follows, 1,3- diformazan
Base -1H- pyrazoles -5- nitrile (VII) reacts reflux with bromide reagent in organic solvent and 3- (bromomethyl) -1- methyl-1 H- pyrrole is made
Azoles -5- nitrile (VIII), the bromide reagent are selected from NBS, bromine or hypobromite, copper bromide, and organic solvent is selected from methylene chloride, chlorine
Imitative, carbon tetrachloride or dichloroethanes, initiator are selected from BPO or azodiisobutyronitrile.
In step (7), the preparation method of 1- methyl -3- ((methylamino) methyl) -1H- pyrazoles -5- nitrile (IX) is as follows, 3-
(bromomethyl) -1- methyl-1 H- pyrazoles -5- nitrile (VIII) reacts in organic solvent with methylamine reagent is made 1- methyl -3- ((first
Amino) methyl) -1H- pyrazoles -5- nitrile (IX), the methylamine reagent is selected from methylamine water solution, methylethylolamine solution, methylamine first
Alcoholic solution, organic solvent are selected from ether, tetrahydrofuran, methyl tertiary butyl ether(MTBE), methylene chloride, methanol or ethyl alcohol, and reaction temperature is
10-40℃。
The resulting 1- methyl -3- of preparation method of the invention ((methylamino) methyl) -1H- pyrazoles -5- nitrile total recovery is reachable
5.7% or more, higher than the total recovery of previously referenced patent records, the present invention have raw material is easy to get, step is short, it is at low cost, after
The advantage of processing operation simplicity is conducive to realize industrialization.
Specific embodiment
Embodiment 1:
(1) synthesis of the sodium salt of 2- hydroxyl -4- oxo -2,3- pentenoic acid ethyl ester
Dehydrated alcohol 300.0ml is added in the three-necked bottle of 500ml, the metallic sodium 5.77g (0.251mol) handled well is added
Enter in dehydrated alcohol, is reacted under room temperature.To sodium all dissolve, be cooled to 0 DEG C, by diethy-aceto oxalate 30.8ml (0.228mol) with
The mixed solution of acetone 16.9ml (0.228mol) is slowly added drop-wise in sodium alkoxide, and keeping temperature is 0 DEG C, is added dropwise, 0 DEG C of reaction
3.5h.Post-reaction treatment filters, dry, obtains faint yellow solid 38.37g.Yield 93.5%.ESI-MS (m/z): 181.0 [M
+ H]+, 213.1 [M+Na]+, 361.0 [2M+H]+, 383.0 [2M+Na]+.
(2) synthesis of 3- methylpyrazole -5- Ethyl formate
Acetic acid 27.9ml is added in 100ml three-necked bottle, hydrazine hydrate 12.4ml is slowly added dropwise at 20-25 DEG C
(0.256mol) is added dropwise and is cooled to 10 DEG C, by the sodium salt 38.37g of 2- hydroxyl -4- oxo -2,3- pentenoic acid ethyl ester
(0.213mol) is added portionwise in reaction solution, and temperature control removes cooling at 20-25 DEG C after adding, using exothermic heat of reaction by 2- hydroxyl
The sodium salt of base -4- oxo -2,3- pentenoic acid ethyl ester dissolves, but maintains the temperature at 35 DEG C hereinafter, to 2- hydroxyl -4- oxo -2,3-
After the sodium salt of pentenoic acid ethyl ester all dissolves, 35 DEG C of reaction 3h.Post-reaction treatment is cooled to room temperature, and water 40.0ml, solid is added
It is 7 that sodium carbonate, which adjusts pH, and white solid is precipitated, and is filtered, dry, obtains white solid 30.08g.Yield 91.3%.ESI-MS
(m/z): 154.9 [M+H]+, 176.9 [M+Na]+, 308.8 [2M+H]+, 330.8 [2M+Na]+。
(3) synthesis of 1,3- dimethyl -1H- pyrazole-5-ethyl formate
3- methylpyrazole -5- Ethyl formate 30.08g (0.195mol) is added in 500ml three-necked bottle, with 200.0ml bis-
Chloromethanes (DCM) is reaction dissolvent, and agitation and dropping dimethyl suflfate 37.2ml (0.390mol), is added dropwise under room temperature
Afterwards, 19.59g (0.195mol) sodium bicarbonate is made saturated solution and is added drop-wise in reaction solution, be added dropwise, flow back 5h.Reaction
Post-processing, it is 8 that sodium carbonate, which adjusts pH, carries out liquid separation with separatory funnel, extracts (3 × 80.0ml) water layer with DCM, merges DCM extraction
Liquid is taken, saturated salt solution washing is primary, and DCM layers are dried 3h, concentrated by rotary evaporation, silica gel column chromatography (petroleum ether: second with anhydrous sodium sulfate
Acetoacetic ester=10:1) purifying, it rotates and removes solvent, obtain weak yellow liquid 17.88g.Yield 54.3%.ESI-MS (m/z):
168.9[M+H]+,1H-NMR(600MHz,CDCl3) δ (ppm) 6.57 (d, J=4.2Hz, 1H), 4.40-4.38 (m, 2H), 3.86
(t, J=2.2Hz, 3H), 2.30 (d, J=3.6Hz, 3H), 1.40-1.37 (m, 3H).
(4) synthesis of 1,3- dimethyl -1H- pyrazoles -5- formamide
After 1,3- dimethyl -1H- pyrazole-5-ethyl formate 17.88g (0.106mol) is added in the mono- neck bottle of 250ml, add
Enter methanol 30.0ml, add ammonium hydroxide 62.3ml (1.060mol), ammonium hydrogen carbonate 7.30g (0.159mol) seals bottleneck, room temperature
Reaction is for 24 hours.Most of methanol is concentrated in post-reaction treatment, and stirring and crystallizing 30min under ice-water bath is filtered, washed, dry.It obtains white
Color solid 8.90g.Yield 62.9%.ESI-MS (m/z): 139.9 [M+H]+,1H-NMR(600MHz,DMSO-d6)δ(ppm)
7.80(s,1H),7.39(s,1H),6.60(s,1H),3.40(s,3H),2.14(s,3H)。
(5) synthesis of 1,3- dimethyl -1H- pyrazoles -5- nitrile
1,3- dimethyl -1H- pyrazoles -5- formamide 8.90g (0.067mol) is added in single neck bottle of 100ml, is added
Phosphorus oxychloride 30.0ml (0.333mol) is warming up to reflux, reacts 3h.Post-reaction treatment, concentrated by rotary evaporation removal most three
Chlorethoxyfos, ice-water bath are cooling, add water 50.0ml, under the conditions of ice-water bath sodium hydroxide adjust pH be 8, DCM extraction (3 ×
60.0ml), the dry 3h of anhydrous sodium sulfate, revolving remove solvent, obtain transparent oily liquid 6.83g.Yield 88.1%.GC-MS
(m/z): 121.1 [M]+,1H-NMR(600MHz,DMSO-d6)δ(ppm)6.88(s,1H),3.93(s,3H),2.20(s,3H)。
(6) synthesis of 1- methyl -3- bromomethyl -1H- pyrazoles -5- nitrile
1,3- dimethyl -1H- pyrazoles -5- nitrile 6.83g (0.059mol) is added in the mono- neck bottle of 100ml, N- bromo is added
Succimide (NBS) 10.00g (0.059mol), azodiisobutyronitrile (AIBN) 0.93g (0.006mol), carbon tetrachloride
70.0ml is warming up to reflux, reacts 2h.Post-reaction treatment stirs 30min at 5 DEG C, unreacted NBS is precipitated, is filtered to remove
NBS, filtrate concentrated by rotary evaporation.Silica gel column chromatography (petroleum ether: ethyl acetate=20:1) purifying, revolving remove solvent, obtain transparent
Liquid 7.59g.Yield 67.4%.GC-MS (m/z): 199 [M]+,1H-NMR(600MHz,CDCl3)δ(ppm)6.88(s,1H),
446(s,2H),4.03(s,3H)。
(7) synthesis of 1- methyl -3- ((methylamino) methyl) -1H- pyrazoles -5- nitrile
40% methylamine water solution 147.0ml (1.990mol), tetrahydrofuran (THF) are added in the three-necked bottle of 500ml
140.0ml, stirring are cooled to 0 DEG C.The THF of-the 3- of methyl containing 1- bromomethyl -1H- pyrazoles -5- nitrile 7.59g (0.040mol) is added
Solution reacts at 10 DEG C.Post-reaction treatment, revolving remove THF, and DCM extracts (3 × 100.0ml), and saturated common salt washing is primary,
Anhydrous sodium sulfate dries 3h, rotates away solvent, obtains transparency liquid 3.93g.Yield 69.0%.ESI-MS (m/z): 151.1
[M+H]+,1H-NMR(600MHz,DMSO-d6) δ (ppm) 6.98 (d, J=3.2Hz, 1H), 3.96 (s, 3H), 3.61 (s, 2H),
2.58(s,1H),2.25(s,3H)。
Claims (9)
- The synthetic method of 1.1- methyl-3-((methylamino) methyl)-1H- pyrazoles-5- nitrile, which is characterized in that with diethy-aceto oxalate It is starting material with acetone, through condensation, cyclisation, methylation, at amide, oxidation, bromo, 7 step of amination reacts to obtain 1- methyl -3- ((methylamino) methyl) -1H- pyrazoles -5- nitrile.
- 2. synthetic method as described in claim 1, which is characterized in that(1) diethy-aceto oxalate (I) and acetone (II) generation condensation reaction obtain (Z) -1- ethyoxyl -1,4- dioxolanes -2- alkene -2- The sodium salt (III) of carboxylic ester；(2) sodium salt (III) of (Z) -1- ethyoxyl -1,4- dioxolanes -2- alkene -2- carboxylic ester and hydration hydrazine reaction obtain 3- first Base -1H- pyrazoles -5- carboxylic acid, ethyl ester (IV)；(3) 3- methyl-1 H- pyrazoles -5- carboxylic acid, ethyl ester (IV) and methylating reagent flow back under alkaline condition is made 1,3- diformazan Base -1H- pyrazoles -5- carboxylic acid, ethyl ester (V)；(4) 1,3- dimethyl -1H- pyrazoles -5- carboxylic acid, ethyl ester (V), which reacts in alcoholic solvent or water with ammonia reagent, is made 1,3- diformazan Base -1H- pyrazoles -5- formamide (VI)；(5) 1,3- dimethyl -1H- pyrazoles -5- formamide (VI) flows back through dehydrating agent and 1,3- dimethyl -1H- pyrazoles -5- nitrile is made (VII)；(6) 1,3- dimethyl -1H- pyrazoles -5- nitrile (VII) reacts obtained 3- (the bromine first of reflux with bromide reagent in organic solvent Base) -1- methyl-1 H- pyrazoles -5- nitrile (VIII)；(7) 3- (bromomethyl) -1- methyl-1 H- pyrazoles -5- nitrile (VIII) reacts in organic solvent with methylamine reagent is made 1- first Base -3- ((methylamino) methyl) -1H- pyrazoles -5- nitrile (IX).
- 3. synthetic method as claimed in claim 2, which is characterized in thatIn step (1), under organic solvent system, diethy-aceto oxalate (I) and acetone (II) under alkaline condition, 15-50 DEG C At a temperature of carry out react be made (Z) -1- ethyoxyl-Isosorbide-5-Nitrae-dioxolanes -2- alkene -2- carboxylic ester sodium salt (III), described has Solvent is the unitary alcoholic solution of C1-C4, and the alkali is the sodium salt organic base or sodium hydroxide, hydrogen-oxygen of the alcohol selected from C1-C4 Change potassium, sodium hydride, LDA inorganic base.
- 4. synthetic method as claimed in claim 2, which is characterized in thatIn step (2), the sodium salt (III) and hydrazine hydrate of (Z) -1- ethyoxyl-Isosorbide-5-Nitrae-dioxolanes -2- alkene -2- carboxylic ester are having In machine acid solution under the conditions of 0-80 DEG C be made 3- methyl-1 H- pyrazoles -5- carboxylic acid, ethyl ester (IV), the organic acid be selected from formic acid, Glacial acetic acid, propionic acid, butyric acid, oxalic acid, the sodium salt of (Z) -1- ethyoxyl-Isosorbide-5-Nitrae-dioxolanes -2- alkene -2- carboxylic ester It (III) is 1:1-2, reaction time 2-5h with the molar ratio of hydrazine hydrate.
- 5. synthetic method as claimed in claim 2, which is characterized in thatIn step (3), in organic solvent or aqueous solvent, 3- methyl-1 H- pyrazoles -5- carboxylic acid, ethyl ester (IV) and methylating reagent Dimethyl suflfate, iodomethane flow back under alkaline condition is made 1,3- dimethyl -1H- pyrazoles -5- carboxylic acid, ethyl ester (V), described Organic solvent is selected from halogenated C1-C4 alkane, ethers, DMF, DMSO or alcoholic solvent, and the alkali is selected from sodium hydroxide, hydroxide Potassium, sodium carbonate, potassium carbonate, triethylamine, pyridine or DIEA, 3- methyl-1 H- pyrazoles -5- carboxylic acid, ethyl ester (IV): methylating reagent: The molar ratio of alkali is 1:1-3:1-5.
- 6. synthetic method as claimed in claim 2, which is characterized in thatIn step (4), 1,3- dimethyl -1H- pyrazoles -5- carboxylic acid, ethyl ester (V), which reacts in alcoholic solvent or water with ammonia reagent, to be made 1,3- dimethyl -1H- pyrazoles -5- formamide (VI), the alcoholic solvent are selected from methanol, ethyl alcohol, isopropanol, the ammonia reagent choosing From ammonium hydroxide, ammonia, the alcoholic solution of ammonia or ammonium carbonate, ammonium hydrogen carbonate, ammonium chloride, urea, 1,3- dimethyl -1H- pyrazoles -5- carboxylic acid Ethyl ester (V): ammonia reagent=1:1-30 (molar ratio), 0-25 DEG C of temperature.
- 7. synthetic method as claimed in claim 2, which is characterized in thatIn step (5), the preparation method of 1,3- dimethyl -1H- pyrazoles -5- nitrile (VII) is as follows, 1,3- dimethyl -1H- pyrazoles - 5- formamide (VI) flows back through dehydrating agent is made 1,3- dimethyl -1H- pyrazoles -5- nitrile (VII), and the dehydrating agent is selected from protochloride Sulfone, phosphorus oxychloride, DCC, sodium hydroxide, tetrabutylammonium bromide, triethylbenzyl ammonium bromide or trifluoroacetic anhydride, dosage are raw material 1-20 times, return time 1-5h, solvent be selected from tetrahydrofuran, dichloroethanes, methylene chloride or chloroform.
- 8. synthetic method as claimed in claim 2, which is characterized in thatIn step (6), the preparation method of 3- (bromomethyl) -1- methyl-1 H- pyrazoles -5- nitrile (VIII) is as follows, 1,3- dimethyl - 1H- pyrazoles -5- nitrile (VII) reacts reflux with bromide reagent in organic solvent and 3- (bromomethyl) -1- methyl-1 H- pyrazoles -5- is made Nitrile (VIII), the bromide reagent are selected from NBS, bromine or hypobromite, copper bromide, and organic solvent is selected from methylene chloride, chloroform, four Chlorination carbon or dichloroethanes, initiator are selected from BPO or azodiisobutyronitrile.
- 9. synthetic method as claimed in claim 2, which is characterized in thatIn step (7), the preparation method of 1- methyl -3- ((methylamino) methyl) -1H- pyrazoles -5- nitrile (IX) is as follows, 3- (bromine first Base) -1- methyl-1 H- pyrazoles -5- nitrile (VIII) with methylamine reagent in organic solvent react be made 1- methyl -3- ((methylamino) Methyl) -1H- pyrazoles -5- nitrile (IX), it is molten that the methylamine reagent is selected from methylamine water solution, methylethylolamine solution, methylamine methanol Liquid, organic solvent are selected from ether, tetrahydrofuran, methyl tertiary butyl ether(MTBE), methylene chloride, methanol or ethyl alcohol, reaction temperature 10-40 ℃。
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| CN110590771A (en) * | 2019-09-05 | 2019-12-20 | 南通大学 | [1,5-a ] -pyridylimidazole-1-nitrile and chemical synthesis method thereof |
| CN112209879A (en) * | 2020-10-19 | 2021-01-12 | 河北省药品医疗器械检验研究院 | Sildenafil impurity and preparation method and application thereof |
| CN113336703A (en) * | 2021-05-17 | 2021-09-03 | 西华大学 | Synthesis of 1,3,4, 5-tetrasubstituted 1H-pyrazole derivatives |
| CN114716378A (en) * | 2022-04-06 | 2022-07-08 | 西华大学 | Synthesis method of 1,3, 4-trisubstituted-5-cyanopyrazole derivative |
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