CN106674116A - 4-amino-1,3-dimethyl pyrazol and compound method for pharmaceutical acceptable salt thereof - Google Patents
4-amino-1,3-dimethyl pyrazol and compound method for pharmaceutical acceptable salt thereof Download PDFInfo
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- CN106674116A CN106674116A CN201611183307.5A CN201611183307A CN106674116A CN 106674116 A CN106674116 A CN 106674116A CN 201611183307 A CN201611183307 A CN 201611183307A CN 106674116 A CN106674116 A CN 106674116A
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- dimethyl
- amino
- pyrazoles
- synthetic method
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- WMEWGPRHFFHUAV-UHFFFAOYSA-N Cc1n[nH]cc1N Chemical compound Cc1n[nH]cc1N WMEWGPRHFFHUAV-UHFFFAOYSA-N 0.000 description 1
- AXLKRXWNAFFPDB-UHFFFAOYSA-N Cc1n[n](C)cc1N Chemical compound Cc1n[n](C)cc1N AXLKRXWNAFFPDB-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
- C07D231/38—Nitrogen atoms
Abstract
The invention discloses 4-amino-1,3-dimethyl pyrazol and a compound method for pharmaceutical acceptable salt thereof. The method comprises the following steps: taking methylhydrazine and 4,4-dimethoxy-2-butanone as initial raw materials; firstly, compounding 1,3-dimethyl pyrazol, and then adding concentrated nitric acid for nitrating, thereby acquiring 4-nitro-1,3-dimethyl pyrazol; and directly reducing into the pharmaceutical acceptable salt or reducing nitro into amino and then converting into 4-amino-1,3-dimethyl pyrazol. The raw materials used in the compound method disclosed by the invention are low in cost and are easily acquired. According to the invention, the compounding route is short, the yield is high, and the acquired products are high in chemical purity; all the reactions require no special production equipment; and column chromatography and crystallizing purification are not required for the acquired intermediates and end products.
Description
Technical field
The present invention relates to a kind of preparation method of medicine intermediate, and in particular to 4- amino -1,3- dimethyl pyrazoles and its
The synthetic method of pharmaceutically acceptable salt.
Background technology
4- amino -1,3- dimethyl pyrazoles and its pharmaceutically acceptable salt are used as a kind of important chemical industry or medicine intermediate quilt
Extensively application, such as 4- amino -1,3- dimethyl pyrazole triazole hydrochlorides：
4- amino -1,3- dimethyl pyrazoles hydrochloride compound is widely used in synthesizing the activity of the various diseases for the treatment of because of it
Drug molecule and it is wide concerned.Such as it is used for synthesis treatment malignant tumor, cardiovascular disease, chemotactic factor relevant disease (such as asthma,
The diseases such as allergy, rheumatic arthritis), nervous system disease, antibacterial and virus infection, immune system relevant disease, cancer etc.
Medicine.
And 4- amino -1, the synthesis of 3- dimethyl pyrazole hydrochloride compounds is rarely reported.Known method is patent PCT
Int.APPl., 2015153959, synthesis 4- amino -1 of report, the method for 3- dimethyl pyrazoles.The method is with 3- amino 2- fourths
Alkene nitrile be raw material, and methyl hydrazine backflow obtain within three hours final product 4- amino -1,3- dimethyl pyrazoles.3- amino in the method
2-butylene nitrile is expensive, and industrial amplification cost is high, and oneself synthesis 3- amino 2-butylene nitrile need to use the dangerous examination such as sodium, Sodamide.
Agent, operational hazards are difficult to be amplified production.
The content of the invention
The technical problem to be solved in the present invention is the defect for overcoming prior art, there is provided 4- amino -1,3- dimethyl pyrazoles
And its synthetic method of pharmaceutically acceptable salt, the method cost hands over relatively low, and easily operation, yield are higher.
To solve above-mentioned technical problem, the technical solution used in the present invention is：
A kind of 4- amino -1, the synthetic method of 3- dimethyl pyrazoles, including step：
(1) 4,4- dimethyl-2-butanones and methyl hydrazine reaction, the compound of production 1 are made：1,3- dimethyl pyrazole；
(2) by 1,3 dimethyl pyrazoles react with concentrated nitric acid, obtain formula II compound：4- nitro -1,3- dimethyl pyrazoles；
(3) by 4- nitro -1, the reduction of 3- dimethyl pyrazoles generates formula III:4- amino -1,3- dimethyl pyrazoles：
Preferably, it is further comprising the steps of in step (1)：
a1：Methyl hydrazine is added to 4,4- dimethyl-2-butanones, then adds and is warmed up to 60-90 DEG C, stirring reaction；Further
Preferred temperature conditionss are 90 DEG C；
a2：Reaction, extraction, concentrating under reduced pressure after a1 has been reacted, distillation obtain 1,3- dimethyl pyrazoles.
Preferably, the mol ratio for having methyl hydrazine and 4,4- dimethyl-2-butanone is 1~1.5:1~2:1.
Preferably, also it is added with sour a in 1,3- dimethyl pyrazoles and the reaction of concentrated nitric acid in step (2).
Preferably, the organic solvent for extracting in step a2 is methyl tertiary butyl ether(MTBE).
Preferably, the envelope-bulk to weight ratio of sour a and 1,3- dimethyl pyrazole is 5~20ml:1g.
Preferably, sour a is selected from concentrated sulphuric acid, phosphoric acid, trifluoroacetic acid, one or more in acetic anhydride.
4- amino -1, the synthetic method of 3- dimethyl pyrazole pharmaceutically acceptable salts, also including step are prepared using said method
Suddenly (4)：4- amino -1 that step (3) is obtained, 3- dimethyl pyrazoles are converted into 4- amino -1, and 3- dimethyl pyrazoles pharmacy can connect
By salt；Or, replace step (3) with step (3-1)：Directly by 4- nitro -1, the reduction salinization of 3- dimethyl pyrazoles obtain 4- amino -
1,3- dimethyl pyrazole pharmaceutically acceptable salt.
Preferably, pharmaceutically acceptable salt is selected from hydrochlorate, sulfate, citrate, benzene sulfonate, hydrobromate, hydrogen
Fluorate, phosphate, acetate, propionate, oxalates, succinate, fumarate, maleate or tartrate.
Preferably, pharmaceutically acceptable salt is hydrochlorate, and step (3-1) also includes：4- nitro -1,3- dimethyl pyrazoles are used
SnCl2Reduction, generates formula IV compound：4- amino -1,3- dimethyl pyrazole triazole hydrochlorides：
Preferably, 4- nitro -1,3- dimethyl pyrazole SnCl2What reduction was carried out under conditions of sour b, the sour b choosings
From hydrochloric acid or acetic acid.
It is further preferred that step (3-1) also includes：
b1：By 4- nitro -1,3- dimethyl pyrazoles are dissolved in sour b, under conditions of 40-80 DEG C, stirring reaction；Further
Preferred temperature conditionss are 60 DEG C.Stirring 3h, wherein acid b and 4- nitro -1, the envelope-bulk to weight ratio of 3- dimethyl pyrazoles for 5~
20ml:1g；
b2：Extraction, is dried, and hydrogen chloride gas are passed through in solution, then filters beating, is dried to obtain 4- amino -1,3- diformazans
Base pyrazole hydrochloride.
Explanation：Reagent used in the present invention, such as concentrated sulphuric acid, concentrated hydrochloric acid, concentrated nitric acid etc., are commercially available conventional chemicals.
As concentrated sulphuric acid refers to sulfuric acid solution of the mass fraction more than or equal to 70%, concentrated hydrochloric acid or concentrated hydrochloric acid solution refer to that mass fraction is not less than
20% concentrated hydrochloric acid solution.Concentrated nitric acid refers to the concentrated nitric acid solution that mass fraction is about 65%.
The beneficial effect that the present invention is reached：
Cost of material that synthetic method of the present invention is used is low, with low cost, be readily obtained.And present invention synthesis
Route is short, yield is high, obtain product chemical purity is high, and all reactions are not required to special producing equipment, gained intermediate and most
End-product is all not required to column chromatography and crystallization purifying.Present invention reduces production cost, is easy to industry's enlarging production, provide for market
High purity product, so as to obtain higher economic benefit.
Description of the drawings
Fig. 1 is the synthetic route chart of embodiment 1 and embodiment 7；
Fig. 2 be 4- nitro -1, the nuclear magnetic spectrogram of 3- dimethyl pyrazoles,1HNMR(CDCl3.ppm),8.1(s,1H),3.88
(s,3H),2.5(s,3H)；
Fig. 3 be 4- amino -1, the nuclear magnetic spectrogram of 3- dimethyl pyrazoles,1HNMR(DMSO.ppm),6.9(s,1H),3.63
(s,2H),3.57(s,3H),1.97(s,3H)。
Specific embodiment
Below in conjunction with the accompanying drawings the invention will be further described.Following examples are only used for clearly illustrating the present invention
Technical scheme, and can not be limited the scope of the invention with this.
4- amino -1 of embodiment 1, the synthesis of 3- dimethyl pyrazoles, synthetic route is shown in Fig. 1, comprises the following steps：
The synthesis of (1) 1,3- dimethyl pyrazole：Raw material methyl hydrazine is added in 4,4- dimethyl-2-butanones, methyl hydrazine 4,
The mol ratio of 4- dimethyl-2-butanones is 1~1.5:1~2:1, it is cold in 90 DEG C of degree stirrings to reacting completely (about 2.5h or so)
But to 68 degree, 3N hydrochloric acid is added, and stirring 1h. is cooled to 30 degree, adjusts pH value to extract to 14. t-butyl methyl ethers with 50% sodium hydroxide
Take, anhydrous sodium sulfate drying, concentrating under reduced pressure distill, 70 degree evaporate collection and get 1,3- dimethyl pyrazoles, yield：50%；
(2) 4- nitro -1, the synthesis of 3- dimethyl pyrazoles：1, the 3- dimethyl pyrazoles that step (1) is obtained add dense sulfur
In acid, concentrated sulphuric acid 1, the envelope-bulk to weight ratio (ml/g) of 3- dimethyl pyrazoles is 1~5:1,1,3- dimethyl pyrazole sulfuric acid solution adds
Enter in the mixing acid of concentrated sulphuric acid and nitric acid, wherein the envelope-bulk to weight ratio (ml/g) of concentrated sulphuric acid and 1,3- dimethyl pyrazole for 1~
5:1, the mol ratio of nitric acid and 1,3- dimethyl pyrazole is 1~2:1, drip rear 50-60 degree and stir complete to reaction, it is cooled to
Room temperature is added in frozen water by filtering, being dried, obtain 4- nitro -1,3- dimethyl pyrazoles, yield 70-80%.
(3) 4- amino -1, the synthesis of 3- dimethyl pyrazole triazole hydrochlorides：By 4- nitro -1 described in step (2), 3- dimethyl
It is dividedly in some parts the concentrated hydrochloric acid solution of stannum dichloride.Described concentrated hydrochloric acid and described 4- nitro -1, the dimethylated volume weights of 3-
Amount is 5~20 than (ml/g):1, described stannum dichloride and described 4- nitro -1, the dimethylated mol ratios of 3- are 1~3:1,
Ethanol is added in reactant liquor, and reactant liquor becomes clarification.Described ethanol and described 4- nitro -1, the dimethylated volume weights of 3-
It is 2~1 than (ml/g):1.To reacting complete, concentrating under reduced pressure, unsaturated carbonate potassium solution and dchloromethane divide for 60 degree of stirrings
Layer, organic faciess anhydrous sodium sulfate drying, filtration, is passed through hydrogen chloride gas, stirs 30 minutes, and reduce pressure sucking filtration, gained crude product dichloro
Methane is beaten, and decompression sucking filtration obtains white solid, yield 80-90%.
Embodiment 2：The synthesis of 1,3- dimethyl pyrazole：
87 grams of 40% methyl hydrazine aqueous solution and 4,4- dimethyl-2-butanone are added in three mouthfuls of reaction bulbs with agitator
100 grams, extremely react complete in 90 DEG C of degree stirring 2.5h or so, be cooled to 68 degree, 200 milliliters of additions of 3N hydrochloric acid, stirring 1h. is cooled down
To 30 degree, pH value is adjusted to 1 liter of 14. t-butyl methyl ethers extraction, anhydrous sodium sulfate drying, concentrating under reduced pressure for 75 grams with 50% sodium hydroxide
Distillation, 70 degree evaporate collection and get water white oil 1,36.4 grams of 3- dimethyl pyrazoles, GC purity more than 93%, yield：50%；
Embodiment 3：The synthesis of 1,3- dimethyl pyrazole：
174 grams of 40% methyl hydrazine aqueous solution and 4,4- dimethyl -2- fourths are added in three mouthfuls of reaction bulbs with agitator
100 grams of ketone, 2.5h or so are stirred to reacting complete in 90 DEG C of degree, are cooled to 68 degree, and the 200 milliliters of additions of 3N hydrochloric acid stir 1h. cold
But to 30 degree, pH value is adjusted to 1 liter of 14. t-butyl methyl ethers extraction, anhydrous sodium sulfate drying, decompression for 100 grams with 50% sodium hydroxide
Concentration distillation, 70 degree evaporate collection and get water white oil 1,35 grams of 3- dimethyl pyrazoles, GC purity more than 90%, yield：48%；
Embodiment 4：4- nitro -1, the synthesis of 3- dimethyl pyrazoles：
12.7 grams of 50 milliliters of concentrated sulphuric acid and nitric acid, 1,3- dimethyl pyrazole are added in three mouthfuls of reaction bulbs with agitator
9.7 grams 10 milliliters of solution of concentrated sulphuric acid are slowly added dropwise in mixing acid, are dripped rear 50-60 degree and are stirred complete to reaction, cold
But it is added in 100 grams of frozen water to room temperature, filters, be dried, obtain 4- nitro -1,11.4 grams of 3- dimethyl pyrazoles, LC purity
More than 90%, yield：80%.
Embodiment 5：4- nitro -1, the synthesis of 3- dimethyl pyrazoles：
12.7 grams of 50 milliliters of acetic anhydride and nitric acid, 1,3- dimethyl pyrazole are added in three mouthfuls of reaction bulbs with agitator
9.7 grams 10 milliliters of solution of acetic anhydride are slowly added dropwise in mixing acid, are dripped rear 50-60 degree and are stirred complete to reaction, cold
But it is added in 100 grams of frozen water to room temperature, filters, be dried, obtain 4- nitro -1,12 grams of 3- dimethyl pyrazoles, LC purity 80%,
Yield：84%.
Embodiment 6：4- amino -1, the synthesis of 3- dimethyl pyrazole triazole hydrochlorides：
56 milliliters of 22.6 grams of stannum dichloride and concentrated hydrochloric acid, 10 milliliters of ethanol are added in three mouthfuls of reaction bulbs with agitator
Add, solution becomes clarification.4- nitro -1,5.6 grams of 3- dimethyl is slowly added in batches, and 60 degree are stirred 3h to having reacted after adding
Entirely, concentrating under reduced pressure, 100 milliliters of unsaturated carbonate potassium solution and dichloromethane milliliter are added, and layering, organic faciess anhydrous sodium sulfate is done
Dry, filtration, is passed through hydrogen chloride gas 30 minutes, stirs 30 minutes, and reduce pressure sucking filtration, the 40 milliliters of beating of dichloromethane of gained crude product,
Decompression sucking filtration obtains 5.3 grams of white solid, LC purity more than 98%, yield 88%.
Embodiment 7：4- amino -1, the synthesis of 3- dimethyl pyrazole triazole hydrochlorides：
56 milliliters of 22.6 grams of stannum dichloride and acetic acid, 10 milliliters of ethanol is added to add in three mouthfuls of reaction bulbs with agitator
Enter, solution becomes clarification.4- nitro -1,5.6 grams of 3- dimethyl is slowly added in batches, and 60 degree of stirring 3h are complete to reaction after adding,
Concentrating under reduced pressure, 100 milliliters of unsaturated carbonate potassium solution and dichloromethane milliliter are added, layering, organic faciess anhydrous sodium sulfate drying, mistake
Filter, is passed through hydrogen chloride gas 30 minutes, stirs 30 minutes, and reduce pressure sucking filtration, and gained crude product 40 milliliters of beating of dichloromethane, decompression is taken out
Filter to obtain 4.5 grams of white solid, LC purity more than 98%, yield 74.7%.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, on the premise of without departing from the technology of the present invention principle, some improvement and deformation can also be made, these improve and deform
Also should be regarded as protection scope of the present invention.
Claims (10)
1. a kind of 4- amino -1, the synthetic method of 3- dimethyl pyrazoles, it is characterised in that including step：
(1) 4,4- dimethyl-2-butanones and methyl hydrazine reaction, the compound of production 1 are made：1,3- dimethyl pyrazole；
(2) by 1,3 dimethyl pyrazoles react with concentrated nitric acid, obtain formula II compound：4- nitro -1,3- dimethyl pyrazoles；
(3) by 4- nitro -1, the reduction of 3- dimethyl pyrazoles generates formula III:4- amino -1,3- dimethyl pyrazoles：
2. 4- amino -1 according to claim 1, the synthetic method of 3- dimethyl pyrazoles, it is characterised in that：In step (1)
It is further comprising the steps of：
a1：Methyl hydrazine is added to 4,4- dimethyl-2-butanones, then adds and is warmed up to 60-90 DEG C, stirring reaction；
a2：Reaction, extraction, concentrating under reduced pressure after a1 has been reacted, distillation obtain 1,3- dimethyl pyrazoles.
3. 4- amino -1 according to claim 2, the synthetic method of 3- dimethyl pyrazoles, it is characterised in that：It is described to have first
The mol ratio of base hydrazine and 4,4- dimethyl-2-butanone is 1~1.5:1~2:1.
4. 4- amino -1 according to claim 1, the synthetic method of 3- dimethyl pyrazoles, it is characterised in that：In step (2)
Sour a is also added with 1,3- dimethyl pyrazole and the reaction of concentrated nitric acid.
5. 4- amino -1 according to claim 4, the synthetic method of 3- dimethyl pyrazoles, it is characterised in that：Sour a and 1,3-
The envelope-bulk to weight ratio of dimethyl pyrazole is 5~20ml:1g.
6. 4- amino -1 according to claim 5, the synthetic method of 3- dimethyl pyrazoles, it is characterised in that：Sour a is selected from dense
Sulphuric acid, phosphoric acid, trifluoroacetic acid, one or more in acetic anhydride.
7. 4- amino -1, the conjunction of 3- dimethyl pyrazole pharmaceutically acceptable salts are prepared using any one of claim 1-6 synthetic method
Into method, also including step (4)：4- amino -1 that step (3) is obtained, 3- dimethyl pyrazoles are converted into 4- amino -1,3- bis-
Methylpyrazole pharmaceutically acceptable salt；Or, replace step (3) with step (3-1)：Directly by 4- nitro -1,3- dimethyl pyrazoles
Reduction salinization obtains 4- amino -1,3- dimethyl pyrazole pharmaceutically acceptable salts.
8. 4- amino -1 according to claim 7, the synthetic method of 3- dimethyl pyrazole pharmaceutically acceptable salts, its feature exists
In pharmaceutically acceptable salt is selected from hydrochlorate, sulfate, citrate, benzene sulfonate, hydrobromate, hydrofluoride, phosphoric acid
Salt, acetate, propionate, oxalates, succinate, fumarate, maleate or tartrate.
9. 4- amino -1 according to claim 7, the synthetic method of 3- dimethyl pyrazole pharmaceutically acceptable salts, its feature exists
In pharmaceutically acceptable salt is hydrochlorate, and step (3-1) also includes：4- nitro -1,3- dimethyl pyrazole SnCl2Reduction, it is raw
Into formula IV compound：4- amino -1,3- dimethyl pyrazole triazole hydrochlorides：
10. 4- amino -1 according to claim 9, the synthetic method of 3- dimethyl pyrazole pharmaceutically acceptable salts, its feature
It is, 4- nitro -1,3- dimethyl pyrazole SnCl2What reduction was carried out under conditions of sour b, the sour b is selected from hydrochloric acid or vinegar
Acid.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112574095A (en) * | 2020-12-21 | 2021-03-30 | 常州大学 | Novel method for nitrifying isatin derivative |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015025197A1 (en) * | 2013-08-22 | 2015-02-26 | Jubilant Biosys Limited | Substituted pyrimidine compounds, compositions and medicinal applications thereof |
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2016
- 2016-12-20 CN CN201611183307.5A patent/CN106674116A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015025197A1 (en) * | 2013-08-22 | 2015-02-26 | Jubilant Biosys Limited | Substituted pyrimidine compounds, compositions and medicinal applications thereof |
Non-Patent Citations (2)
| Title |
|---|
| MUSTAFA M. EL-ABADELAH, ET AL: "Synthesis and Properties of iso Viagra [1]. A 2-Methyl-2H-pyrazolo[4,3-d]pyrimidin-7-one Isomer of Viagra", 《J.HETEROCYCLIC CHEM.》 * |
| STEPHEN R. GRAHAM, ET AL: "Practical and Scalable Process for the Preparation of 4-Amino-1,3-dimethylpyrazole Hydrochloride", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112574095A (en) * | 2020-12-21 | 2021-03-30 | 常州大学 | Novel method for nitrifying isatin derivative |
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