CN110003218A - The preparation method of my Ge Lieting intermediate - Google Patents
The preparation method of my Ge Lieting intermediate Download PDFInfo
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- CN110003218A CN110003218A CN201910233630.6A CN201910233630A CN110003218A CN 110003218 A CN110003218 A CN 110003218A CN 201910233630 A CN201910233630 A CN 201910233630A CN 110003218 A CN110003218 A CN 110003218A
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Abstract
The present invention provides a kind of preparation method of my Ge Lieting intermediate, include the following steps: (1) N, dinethylformamide (I) and acyl chlorides occur Vilsmiere reaction and generate Vilsmiere reagent, bromoacetic acid (II) is added dropwise in above-mentioned Vilsmiere reagent, temperature reaction, then hydrolyze to obtain dicarbaldehyde ethylhexanal (III)；(2) dicarbaldehyde ethylhexanal (III) and 3- amino-5-methylpyrazole (IV) are dissolved in alcohol/sodium alkoxide system, heat up and return stirring generates 6- carboxaldehyde radicals -2- methyl pyrazole simultaneously [1,5-a] pyrimidine (V)；(3) by 6- carboxaldehyde radicals -2- methyl pyrazole, simultaneously [1,5-a] pyrimidine (V) aoxidizes generation 2- methyl pyrazole simultaneously [1,5-a] pyrimidine -6- carboxylic acid (VI) in highly basic.This invention simplifies reaction steps, easy to operate, and the three wastes are few, high income.
Description
Technical field
The present invention relates to a kind of preparation methods of my Ge Lieting intermediate, belong to chemical pharmacy field.
Background technique
I is the entitled N- [2- [[2- [(2S) -2- cyano -1- pyrrolidinyl] -2- oxoethyl] amino]-of Ge Lieting chemistry
2- methyl-prop alkyl] -2- methyl -6- pyrazolo [1,5-a] pyrimidine carboxamide (VIII), it is three He of Amada Co., Ltd. that original, which grinds unit,
Chemistry institute, in September, 2012 obtain Japanese pharmaceutical product medical instrument comprehensive organ (PMDA) approval listing, are that one is a kind of high
Selective dipeptidyl peptidase-IV (DPP-4) inhibitor is inhibited for treating type II diabetes drug by selectivity, duration
DPP-4 enhances the activity of glucagon-like peptide (GLP-1) and gastrointestinal inhibitory peptide (GIP) and plays hypoglycemic effect.
According to document (WO2014147640, WO2015104602, Bioorganic&Medicinal Chemistry
2011 (23) 7221 etc.) report, compound (VIII) is by three main sections 2- methyl pyrazoles simultaneously [1,5-a] pyrimidine -6- carboxylic acid
(VI), (2S)-N- chloracetyl -2- cyano nafoxidine (VII), 2- amino-2-methyl propylamine etc. are Material synthesis (VIII).
Simultaneously [1,5-a] pyrimidine -6- carboxylic acid (VI) synthesizes the Chinese medicine intermediate of my Ge Lieting to 2- methyl pyrazole, currently, its
Synthetic method and document report are simultaneously few.Patent WO2014147640, IN2013MU00848, CN103819478 etc. are described
3- amino-5-methylpyrazole, dicarbaldehyde ethyl are used, 2- first is condensed to yield under anhydrous and oxygen-free and strong alkaline condition
Base-pyrazolo [1,5-a] pyrimidine -6- carboxylic acid, ethyl ester, then 2- methyl pyrazole simultaneously [1,5-a] pyrimidine -6- carboxylic acid is obtained through hydrolysis
(VI) method:
This method is the more commonly used synthetic method of current compound VI, and wherein dicarbaldehyde ethyl acetate is by vinyl ethyl
Ether and trichloro-acetic chloride are obtained through following steps:
Synthetic method is cumbersome, and waste water and gas is more, since dicarbaldehyde ethyl is unstable, in anhydrous and oxygen-free and
By 3,3- diethoxy ethyl propionate and Ethyl formate fabricated in situ under conditions of highly basic, then with 3- amino-5-methylpyrazole contract
It closes, higher cost, and using sodium hydride is highly basic acid binding agent, reaction also has certain risk, leads to the city of compound VI
Field is expensive.
Document Bioorganic&Medicinal Chemistry, 2011 (23), 7221 describe with 2- methyl pyrazole simultaneously
[1,5-a] pyrimidine -6- formamide is raw material, and the method for adjusting acid again through basic hydrolysis synthesizes 2- methyl pyrazole simultaneously [1,5-a] pyrimidine -
6- carboxylic acid (VI):
Equally by 2- methyl pyrazole, simultaneously [1,5-a] pyrimidine -6- carboxylic acid, ethyl ester is at high cost through amidation for this method, effect
Rate is low, no industrialization meaning.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation methods of my new Ge Lieting intermediate, to reduce my lattice column
The manufacturing cost of spit of fland intermediate improves combined coefficient.
Present invention employs following technical solutions:
The purpose of the present invention is to provide my Ge Lieting intermediate 2- methyl pyrazole simultaneously [1,5-a] pyrimidine -6- carboxylic acids
(VI) synthesis technology, using n,N-Dimethylformamide and bromoacetic acid as raw material, reacted through Vilsmiere reaction, condensation and cyclization,
Oxidation reaction synthesizes 2- methyl pyrazole simultaneously [1,5-a] pyrimidine -6- carboxylic acid.Above-mentioned technique includes the following steps:
(1) Vilsmiere reaction generation occurs for N,N-dimethylformamide (I, DMF) and acyl chlorides under cryogenic
Bromoacetic acid (II) is added dropwise to temperature reaction in reaction system, then hydrolyzes to obtain dicarbaldehyde ethylhexanal by Vilsmiere reagent
(Ⅲ)；
(2) dicarbaldehyde ethylhexanal (III) and 3- amino-5-methylpyrazole (IV) are dissolved in alcohol, and sodium alkoxide is highly basic, is warming up to
Return stirring generates 6- carboxaldehyde radicals -2- methyl pyrazole simultaneously [1,5-a] pyrimidine (V)；
(3) simultaneously [1,5-a] pyrimidine (V) aoxidizes generation 2- methyl pyrazole simultaneously to 6- carboxaldehyde radicals -2- methyl pyrazole in highly basic
[1,5-a] pyrimidine -6- carboxylic acid (VI)；
In the step (1), acyl chlorides be independently selected from but not limited to phosphorus oxychloride, thionyl chloride, oxalyl chloride, chloroacetic chloride,
Propionyl chloride etc., preferably phosphorus oxychloride；The dosage of acyl chlorides is the 100%-500%, preferably 250- of the amount of compound ii substance
350%.
In step (1), reaction temperature preferably is selected from 50-100 DEG C independently selected from being 0-150 DEG C.
In step (2), the alcohol/sodium alkoxide system may be selected from but not limited to methanol/sodium methoxide, ethyl alcohol/sodium ethoxide, isopropyl
Alcohol/sodium isopropylate, the tert-butyl alcohol/sodium tert-butoxide etc., preferably methanol/sodium methoxide system, the dosage of sodium alkoxide are compound (III) substance
Amount 100%-400%, preferably 200-300%.
In step (2), reaction temperature preferably is selected from 50-100 DEG C independently selected from 0 DEG C -150 DEG C；It is concentrated after reaction,
Dissolution is washed, and is concentrated, and is recrystallized, and filtering is dried to obtain compound (V).
In step (3), compound (V) is obtained compound (VI) by oxidation reaction, oxidant is optional but is not limited to double
The one or more combination of oxygen water, potassium permanganate, sodium chlorite, sodium bromite, sodium hypochlorite, sodium hypobromite, potassium bichromate etc.,
It is preferred that wherein dioxygen water consumption is the 50%- of the amount of compound (V) substance with sodium chlorite and hydrogen peroxide combined system
150%, preferably 90-100%, sodium chlorite dosage are the 50%-150%, preferably 95- of the amount of compound (V) substance
105%.
In step (3), selection sodium chlorite be oxidant, solvent solely may be selected from but not limited to n,N-Dimethylformamide,
N,N-dimethylacetamide, N-Methyl pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, acetone etc., preferably dimethyl sulfoxide.
The product of oxidation reaction is neutralized, decolourize, filter, be acidified, filtering, dry 2- methyl pyrazole is simultaneously [1,5-a] phonetic
Pyridine -6- carboxylic acid (VI).
Advantageous effect of the invention
Compared with the prior art, the advantages of the present invention are as follows with cheap and easily-available raw material n,N-Dimethylformamide and bromine second
Acid can easily synthesize 2- methyl pyrazole simultaneously [1,5-a] pyrimidine -6- carboxylic acid by three-step reaction, avoid using cumbersome
Method synthesizes dicarbaldehyde ethyl, avoids condensation cyclization in the process using dangerous sodium hydride, using cheap and easily-available
Oxidant sodium chlorite and hydrogen peroxide can convenience and high-efficiency obtain product, simplify reaction step, easy to operate, the three wastes are few,
High income.Three-step reaction total recovery reaches 45-50%, much higher than the synthesis yield of the intermediate of previous literature report；And
Reaction condition is mild, environmentally friendly, at low cost, hence it is evident that is superior to other synthetic technology routes of prior art report.It utilizes
The stable product quality that the method for the present invention obtains is very suitable to my Ge Lieting industrialized production.
Detailed description of the invention
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of intermediate 2- methyl pyrazole of the present invention simultaneously [1,5-a] pyrimidine -6- carboxylic acid (VI).
Fig. 2 is the HPLC-UV detection of intermediate 2- methyl pyrazole of the present invention simultaneously [1,5-a] pyrimidine -6- carboxylic acid (VI).
Specific embodiment
Present invention is further described in detail with reference to embodiments.For a person skilled in the art, it is based on
The equivalent replacement of reagent and the adjustment of design parameter that thinking of the invention is carried out still fall within protection scope of the present invention it
It is interior.
Embodiment 1:
The preparation of dicarbaldehyde ethylhexanal (III)
Equipped with mechanical stirring, condenser pipe, thermometer 500mL four-hole bottle in be added N,N-dimethylformamide (DMF)
300ml, stirring are cooled to 0~5 DEG C, keep temperature that phosphorus oxychloride 45.83g (0.3mol) is added dropwise, drip off subsequent continuous insulated and stirred
0.5 hour, bromoacetic acid 41.5g (0.3mol) is added portionwise, adds within 20 minutes, is warming up to 70~75 DEG C, stirs 16 hours, cooling
To room temperature, reaction solution is poured into 200g ice water, and keeping temperature to be adjusted to PH with sodium hydroxide lower than 40 DEG C is 5~6, is stirred at room temperature
1 hour, methylene chloride extraction (100ml × 3) is added, merges organic phase, dries, filters, be concentrated to get yellow orange solid diformazan
Aldehyde radical acetaldehyde (III) 12.1g can carry out next step reaction, yield: 40.3% without purification.
Phosphorus oxychloride dosage is the mole dosage of bromoacetic acid in present embodiment: 100%
Embodiment 2:
The preparation of dicarbaldehyde ethylhexanal (III)
Equipped with mechanical stirring, condenser pipe, thermometer 500mL four-hole bottle in be added N,N-dimethylformamide (DMF)
325ml, stirring are cooled to 0~5 DEG C, keep temperature that phosphorus oxychloride 137.5g (0.9mol) is added dropwise, drip off subsequent continuous insulated and stirred
0.5 hour, bromoacetic acid 41.5g (0.3mol) is added portionwise, adds within 20 minutes, is warming up to 70~75 DEG C, stirs 16 hours, cooling
To room temperature, reaction solution is poured into 200g ice water, and keeping temperature to be adjusted to PH with sodium hydroxide lower than 40 DEG C is 5~6, is stirred at room temperature
1 hour, methylene chloride extraction (100ml × 3) is added, merges organic phase, dries, filters, be concentrated to get yellow orange solid diformazan
Aldehyde radical acetaldehyde (III) 16.3g can carry out next step reaction, yield: 54.3% without purification.
Phosphorus oxychloride dosage is the mole dosage of bromoacetic acid in present embodiment: 300%
Embodiment 3:
The preparation of dicarbaldehyde ethylhexanal (III)
Equipped with mechanical stirring, condenser pipe, thermometer 500mL four-hole bottle in be added DMF220ml, stirring is cooled to 0~
It 5 DEG C, keeps temperature that oxalyl chloride 57.2g (0.45mol) is added dropwise, drips off subsequent continuous insulated and stirred 0.5 hour, bromoacetic acid is added portionwise
20.8g (0.15mol) is added for 20 minutes, is warming up to 70~75 DEG C, is stirred 16 hours, is cooled to room temperature, reaction solution pours into 100g
In ice water, keeping temperature to be adjusted to PH with sodium hydroxide lower than 40 DEG C is 5~6, is stirred 1 hour at room temperature, and methylene chloride extraction is added
It takes (50ml × 3), merges organic phase, dry, filter, be concentrated to get yellow orange solid (III) 4.6g, yield: 30.5%.
Phosphorus oxychloride dosage is the mole dosage of bromoacetic acid in present embodiment: 300%
Embodiment 4
The preparation of dicarbaldehyde ethylhexanal (III)
Equipped with mechanical stirring, condenser pipe, thermometer 500mL four-hole bottle in be added DMF250ml, stirring is cooled to 0~
It 5 DEG C, keeps temperature that oxalyl chloride 95.3g (0.75mol) is added dropwise, drips off subsequent continuous insulated and stirred 0.5 hour, bromoacetic acid is added portionwise
20.8g (0.15mol) is added for 20 minutes, is warming up to 140~150 DEG C, is stirred 16 hours, is cooled to room temperature, reaction solution pours into
In 100g ice water, keeping temperature to be adjusted to PH with sodium hydroxide lower than 40 DEG C is 5~6, stirs 1 hour at room temperature, dichloromethane is added
Alkane extracts (50ml × 3), merges organic phase, dries, filters, be concentrated to get yellow orange solid (III) 5.3g, yield: 35.1%.
Phosphorus oxychloride dosage is the mole dosage of bromoacetic acid in present embodiment: 500%.
Embodiment 5:
The preparation of 6- carboxaldehyde radicals -2- methyl pyrazole simultaneously [1,5-a] pyrimidine (V)
Methanol 200ml, dicarbaldehyde ethylhexanal (III) are added in the 1000mL four-hole bottle equipped with mechanical stirring, thermometer
50g (0.5mol) and 3- amino-5-methylpyrazole (IV) 49g (0.5mol), stirring are warming up to 50 DEG C of reflux, methanol are slowly added dropwise
The solution of sodium 27g (0.5mol) and methanol 400ml drip for 0.5 hour, and insulated and stirred 3 hours, reflux unit was changed to distill,
It is cooled to 0 DEG C after steaming 500~550ml methanol, 300ml methylene chloride and 200ml water is added, stirring is layered after five minutes, organic
Layer is washed with water (50ml × 2), and 300ml recrystallizing methanol is added after organic layer concentration, obtains yellow solid 6- carboxaldehyde radicals -2- first
Base-pyrazolo [1,5-a] pyrimidine (V) 49.5g, yield 61.5%, fusing point: 150~152 DEG C.
Sodium methoxide dosage is the mole dosage of dicarbaldehyde ethylhexanal in present embodiment: 100%
Embodiment 6:
The preparation of 6- carboxaldehyde radicals -2- methyl pyrazole simultaneously [1,5-a] pyrimidine (V)
Methanol 200ml, dicarbaldehyde ethylhexanal (III) are added in the 1000mL four-hole bottle equipped with mechanical stirring, thermometer
50g (0.5mol) and 3- amino-5-methylpyrazole (IV) 49g (0.5mol), stirring are warming up to 75 DEG C of reflux, methanol are slowly added dropwise
The solution of sodium 54g (1.0mol) and methanol 400ml drip for 0.5 hour, and insulated and stirred 3 hours, reflux unit was changed to distill,
10~15 DEG C are cooled to after steaming 500~550ml methanol, 300ml methylene chloride and 200ml water is added, stirring divides after five minutes
Layer, organic layer are washed with water (50ml × 2), and 300ml recrystallizing methanol is added after organic layer concentration, obtains yellow solid 6- formaldehyde
Base -2- methyl pyrazole simultaneously [1,5-a] pyrimidine (V) 66.5g, yield 82.6%, fusing point: 150~152 DEG C.
Sodium methoxide dosage is the mole dosage of dicarbaldehyde ethylhexanal in present embodiment: 200%
Embodiment 7:
The preparation of 6- carboxaldehyde radicals -2- methyl pyrazole simultaneously [1,5-a] pyrimidine (V)
Ethyl alcohol 150ml, dicarbaldehyde ethylhexanal (III) are added in the 1000mL four-hole bottle equipped with mechanical stirring, thermometer
36.0g (0.36mol) and 3- amino-5-methylpyrazole (IV) 35.3g (0.36mol), stirring are warming up to 100 DEG C of reflux, slowly
The solution of sodium ethoxide 49.0g (0.72mol) and ethyl alcohol 300ml is added dropwise, drips within 0.5 hour, insulated and stirred 3 hours, reflux dress
It sets and is changed to distill, be cooled to 10~15 DEG C after steaming 350~400ml ethyl alcohol, 200ml methylene chloride and 150ml water, stirring is added
It is layered after five minutes, organic layer is washed with water (50ml × 2), and 200ml recrystallizing methanol is added after organic layer concentration, it is solid to obtain yellow
Body 6- carboxaldehyde radicals -2- methyl pyrazole simultaneously [1,5-a] pyrimidine (V) 46.5g, yield 80.3%.
Sodium ethoxide dosage is the mole dosage of dicarbaldehyde ethylhexanal in present embodiment: 200%
Embodiment 8:
The preparation of 6- carboxaldehyde radicals -2- methyl pyrazole simultaneously [1,5-a] pyrimidine (V)
Methanol 100ml, dicarbaldehyde ethylhexanal (III) are added in the 1000mL four-hole bottle equipped with mechanical stirring, thermometer
25g (0.25mol) and 3- amino-5-methylpyrazole (IV) 24.5g (0.25mol), stirring are warming up to reflux, methanol are slowly added dropwise
The solution of sodium 21.6g (0.4mol) and methanol 200ml drip for 0.5 hour, and insulated and stirred 3 hours, reflux unit was changed to steam
It evaporates, is cooled to 10~15 DEG C after steaming 250~280ml methanol, 150ml methylene chloride and 100ml water is added, stirring is after five minutes
Layering, organic layer are washed with water (25ml × 2), and 150ml recrystallizing methanol is added after organic layer concentration, obtains yellow solid 6- formaldehyde
Base -2- methyl pyrazole simultaneously [1,5-a] pyrimidine (V) 66.5g, yield 65.3%, fusing point: 150~152 DEG C.
Sodium methoxide dosage is the mole dosage of dicarbaldehyde ethylhexanal in present embodiment: 160%
Embodiment 9:
The preparation of 6- carboxaldehyde radicals -2- methyl pyrazole simultaneously [1,5-a] pyrimidine (V)
Methanol 100ml, dicarbaldehyde ethylhexanal (III) are added in the 1000mL four-hole bottle equipped with mechanical stirring, thermometer
25g (0.25mol) and 3- amino-5-methylpyrazole (IV) 24.5g (0.25mol), stirring are warming up to 150 DEG C of reflux, slowly drip
Add the solution of sodium methoxide 54.0g (1.0mol) and methanol 200ml, drip within 0.5 hour, insulated and stirred 3 hours, reflux unit changed
For distillation, 15 DEG C are cooled to after steaming 250~280ml methanol, 150ml methylene chloride and 100ml water is added, stirring is after five minutes
Layering, organic layer are washed with water (25ml × 2), and 150ml recrystallizing methanol is added after organic layer concentration, obtains yellow solid 6- formaldehyde
Base -2- methyl pyrazole simultaneously [1,5-a] pyrimidine (V) 47.6g, yield 46.7%, fusing point: 150~152 DEG C.
Sodium methoxide dosage is the mole dosage of dicarbaldehyde ethylhexanal in present embodiment: 400%
Increase embodiment 10:
The preparation of 2- methyl pyrazole simultaneously [1,5-a] pyrimidine -6- carboxylic acid (VI)
Water 100ml, 6- carboxaldehyde radicals -2- methyl pyrazole are added in the 500mL four-hole bottle equipped with mechanical stirring, thermometer
And [1,5-a] pyrimidine (V) 35.2g (0.22mol), 30% hydrogen peroxide 13.95g (0.11mol), sodium chlorite 9.95g
(0.11mol) is warming up to 50 DEG C and reacts 1 hour, be cooled to 20 DEG C, and TLC shows fully reacting, is adjusted to starch iodine with sodium sulfite
It is non-discolouring to change potassium reagent, with hydrochloric acid tune PH to 2~3, filtering, solid 200ml ethyl alcohol recrystallization obtains white solid 2- first
Base-pyrazolo [1,5-a] pyrimidine -6- carboxylic acid (VI) 23.3g, yield 59.8%.
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of intermediate 2- methyl pyrazole of the present invention simultaneously [1,5-a] pyrimidine -6- carboxylic acid (VI).
Compound VI 1H NMR (400MHz, DMSO-d6): δ 13.54 (s, 1H), 9.32 (s, 1H), 8.78 (s, 1H),
6.61(s,1H),2.43(s,3H)。
Dioxygen water consumption is the mole dosage of compound V in present embodiment: 50%
Sodium chlorite dosage is the mole dosage of compound V in present embodiment: 50%
Fig. 2 is the HPLC-UV detection of intermediate 2- methyl pyrazole of the present invention simultaneously [1,5-a] pyrimidine -6- carboxylic acid (VI).
Parameter in table 1: Fig. 1 in HPLC-UV detection
| Component name | Retention time | Peak height | Peak area | Concentration | Tailing factor | Theoretical tray |
| 5.520 | 3.03 | 44.324 | 0.182 | 1.84 | 3212 | |
| 9.465 | 1665.05 | 74310.100 | 99.818 | 1.16 | 1015 | |
| Σ: | 1668.08 | 74354.424 | 100.000 |
Embodiment 11:
The preparation of 2- methyl pyrazole simultaneously [1,5-a] pyrimidine -6- carboxylic acid (VI)
Water 100ml, 6- carboxaldehyde radicals -2- methyl pyrazole are added in the 500mL four-hole bottle equipped with mechanical stirring, thermometer
And [1,5-a] pyrimidine (V) 35.2g (0.22mol), 30% hydrogen peroxide 27.9g (0.22mol), sodium chlorite 19.9g
(0.22mol) is warming up to 50 DEG C and reacts 1 hour, be cooled to 20 DEG C, and TLC shows fully reacting, is adjusted to starch iodine with sodium sulfite
It is non-discolouring to change potassium reagent, with hydrochloric acid tune PH to 2~3, filtering, solid 200ml ethyl alcohol recrystallization obtains white solid 2- first
Base-pyrazolo [1,5-a] pyrimidine -6- carboxylic acid (VI) 35.6g, yield 91.5%.
Dioxygen water consumption is the mole dosage of compound V in present embodiment: 100%
Sodium chlorite dosage is the mole dosage of compound V in present embodiment: 100%
Embodiment 12
The preparation of 2- methyl pyrazole simultaneously [1,5-a] pyrimidine -6- carboxylic acid (VI)
Water 100ml, 6- carboxaldehyde radicals -2- methyl pyrazole are added in the 500mL four-hole bottle equipped with mechanical stirring, thermometer
And [1,5-a] pyrimidine (V) 10.0g (0.06mol), 30% hydrogen peroxide 4.5g (0.04mol), sodium chlorite 3.6g
(0.04mol), is warming up to 50 DEG C and reacts 1 hour, be cooled to 20 DEG C, and it is non-discolouring to be adjusted to starch potassium iodide reagents with sodium sulfite,
With hydrochloric acid tune PH to 2~3, filtering, solid 100ml ethyl alcohol recrystallization obtains white solid 2- methyl pyrazole simultaneously [1,5-a]
Pyrimidine -6- carboxylic acid (VI) 7.8g, yield 71.1%.
Dioxygen water consumption is the mole dosage of compound V in present embodiment: 66%
Sodium chlorite dosage is the mole dosage of compound V in present embodiment: 66%
Embodiment 13:
The preparation of 2- methyl pyrazole simultaneously [1,5-a] pyrimidine -6- carboxylic acid (VI)
Water 100ml, 6- carboxaldehyde radicals -2- methyl pyrazole are added in the 500mL four-hole bottle equipped with mechanical stirring, thermometer
And [1,5-a] pyrimidine (V) 35.2g (0.22mol), 30% hydrogen peroxide 41.9g (0.33mol), sodium chlorite 29.9g
(0.33mol) is warming up to 50 DEG C and reacts 1 hour, be cooled to 20 DEG C, and TLC shows fully reacting, is adjusted to starch iodine with sodium sulfite
It is non-discolouring to change potassium reagent, with hydrochloric acid tune PH to 2~3, filtering, solid 200ml ethyl alcohol recrystallization obtains white solid 2- first
Base-pyrazolo [1,5-a] pyrimidine -6- carboxylic acid (VI) 29.8g, yield 76.7%.
Dioxygen water consumption is the mole dosage of compound V in present embodiment: 150%
Sodium chlorite dosage is the mole dosage of compound V in present embodiment: 150%
Embodiment 14:
The preparation of 2- methyl pyrazole simultaneously [1,5-a] pyrimidine -6- carboxylic acid (VI)
5% liquor potassic permanganate 1000ml, hydroxide is added in the 2000mL four-hole bottle equipped with mechanical stirring, thermometer
Potassium 2g keeps 10~15 DEG C of temperature primary addition 6- carboxaldehyde radicals -2- methyl pyrazoles simultaneously [1,5-a] pyrimidine (V) 35g
(0.22mol), 10~15 DEG C of stirring 30min after adding are filtered, and it is constant that water phase with sodium sulfite is adjusted to starch potassium iodide reagents
Active carbon 0.5g stirring is added decoloration 30 minutes in color, and filtering, filtrate is with concentrated hydrochloric acid tune PH to 2~3, filtering, solid 200ml
Ethyl alcohol recrystallization obtains off-white powder 2- methyl pyrazole simultaneously [1,5-a] pyrimidine -6- carboxylic acid (VI) 17.8g, yield 45.8%.
Claims (10)
1. a kind of preparation method of my Ge Lieting intermediate, which comprises the steps of:
(1) Vilsmiere reaction generation Vilsmiere reagent occurs for n,N-Dimethylformamide (I) and acyl chlorides, by bromoacetic acid
(II) it is added dropwise in above-mentioned Vilsmiere reagent, temperature reaction, then hydrolyzes to obtain dicarbaldehyde ethylhexanal (III)；
(2) dicarbaldehyde ethylhexanal (III) and 3- amino-5-methylpyrazole (IV) are dissolved in alcohol/sodium alkoxide system, heat up and flows back
Stirring generates 6- carboxaldehyde radicals -2- methyl pyrazole simultaneously [1,5-a] pyrimidine (V)；
(3) by 6- carboxaldehyde radicals -2- methyl pyrazole, simultaneously [1,5-a] pyrimidine (V) aoxidizes generation 2- methyl pyrazole simultaneously in highly basic
[1,5-a] pyrimidine -6- carboxylic acid (VI).
2. the preparation method of my Ge Lieting intermediate as described in claim 1, it is characterised in that:
In step (1), the reaction temperature of n,N-Dimethylformamide (I) and acyl chlorides generation Vilsmiere reaction is 0-150 DEG C,
The mole dosage of acyl chlorides is the 100%-500% of bromoacetic acid mole dosage.
3. the preparation method of my Ge Lieting intermediate as described in claim 1, it is characterised in that:
In step (1), the reaction temperature of n,N-Dimethylformamide (I) and acyl chlorides generation Vilsmiere reaction is 50-100 DEG C,
The mole dosage of acyl chlorides is the 250%-350% of bromoacetic acid mole dosage.
4. the preparation method of my Ge Lieting intermediate as described in claim 1, it is characterised in that:
In step (2), the alcohol/sodium alkoxide system, selected from methanol/sodium methoxide, ethyl alcohol/sodium ethoxide, isopropanol/sodium isopropylate or
Wherein one group of the tert-butyl alcohol/sodium tert-butoxide, preferably methanol/sodium methoxide system, the dosage of sodium alkoxide are dicarbaldehyde ethylhexanal (III) object
The 100%-400% of the amount of matter, preferably 200-300%.
5. the preparation method of my Ge Lieting intermediate as described in claim 1, it is characterised in that:
In step (2), reaction temperature is 0 DEG C -150 DEG C, and preferably 50-100 DEG C, concentrated after reaction, dissolution washes, is dense
Contract, recrystallize, filter and be dried to obtain 6- carboxaldehyde radicals -2- methyl pyrazole simultaneously [1,5-a] pyrimidine (V).
6. the preparation method of my Ge Lieting intermediate as described in claim 1, it is characterised in that:
In step (3), by 6- carboxaldehyde radicals -2- methyl pyrazole, simultaneously [1,5-a] pyrimidine (V) by oxidation reaction obtains 2- methyl -
Pyrazolo [1,5-a] pyrimidine -6- carboxylic acid (VI), oxidant are selected from hydrogen peroxide, potassium permanganate, sodium chlorite, sodium bromite, secondary chlorine
Sour sodium, sodium hypobromite, the one of which of potassium bichromate or at least two combination.
7. the preparation method of my Ge Lieting intermediate as described in claim 1, it is characterised in that:
In step (3), by 6- carboxaldehyde radicals -2- methyl pyrazole, simultaneously [1,5-a] pyrimidine (V) by oxidation reaction obtains 2- methyl -
Pyrazolo [1,5-a] pyrimidine -6- carboxylic acid (VI), oxidant are sodium chlorite and hydrogen peroxide combined system, wherein dioxygen water consumption
For the 50%-150% of the 6- carboxaldehyde radicals -2- methyl pyrazole simultaneously amount of [1,5-a] pyrimidine (V) substance, sodium chlorite dosage is 6-
The 50%-150% of the carboxaldehyde radicals -2- methyl pyrazole simultaneously amount of [1,5-a] pyrimidine (V) substance.
8. the preparation method of my Ge Lieting intermediate as described in claim 1, it is characterised in that:
In step (3), by 6- carboxaldehyde radicals -2- methyl pyrazole, simultaneously [1,5-a] pyrimidine (V) by oxidation reaction obtains 2- methyl -
Pyrazolo [1,5-a] pyrimidine -6- carboxylic acid (VI), oxidant are sodium chlorite and hydrogen peroxide combined system, wherein dioxygen water consumption
For the 90-100% of the 6- carboxaldehyde radicals -2- methyl pyrazole simultaneously amount of [1,5-a] pyrimidine (V) substance, sodium chlorite dosage is 6- first
The 95-105% of the aldehyde radical -2- methyl pyrazole simultaneously amount of [1,5-a] pyrimidine (V) substance.
9. the preparation method of my Ge Lieting intermediate as claimed in claim 7, it is characterised in that:
In step (3), when oxidant uses sodium chlorite, solvent is selected from n,N-Dimethylformamide, N, N- dimethylacetamide
The one of which of amine, N-Methyl pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, acetone.
10. the preparation method of my Ge Lieting intermediate as claimed in claim 7, it is characterised in that:
The product of oxidation reaction is neutralized, decolourizes, and filters, and is acidified, filtering, dries to obtain 2- methyl pyrazole simultaneously [1,5-a] pyrimidine-
6- carboxylic acid (VI).
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