739364-95-5

Usage

Uses

Used in Pharmaceutical Industry:
2-Methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid is used as a reactant for the preparation of DPP-IV inhibitors, which are important in the development of drugs for the treatment of type 2 diabetes and other metabolic disorders. Its unique structure allows for the creation of potent and selective DPP-IV inhibitors, making it a valuable component in the synthesis of these therapeutic agents.

InChI:InChI=1S/C8H7N3O2/c1-5-2-7-9-3-6(8(12)13)4-11(7)10-5/h2-4H,1H3,(H,12,13)

Synthetic route

2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester → 2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (739364-95-5)

Conditions	Yield
With water; sodium hydroxide at 60℃; Large scale;	92%
With sodium hydroxide In tetrahydrofuran at 0℃; for 0.5h; Reagent/catalyst; Solvent; Temperature;	92.4%
With lithium hydroxide In tetrahydrofuran; water at 20℃; for 2h;	85.96%

2-methylpyrazolo[1,5-a]pyrimidine-6-carbaldehyde (933692-37-6) → 2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (739364-95-5)

Conditions	Yield
With sodium chlorite; dihydrogen peroxide In water at 50℃; for 1h; Reagent/catalyst; Temperature; Solvent;	76.7%

2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid amide (338953-49-4) → 2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (739364-95-5)

Conditions	Yield
With sodium hydroxide In ethanol at 70℃; for 1h;	63%
Stage #1: 2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid amide With potassium hydroxide In ethanol; water at 70℃; for 1h; Stage #2: With hydrogenchloride Further stages;	63%

2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (739364-95-5) + 2-chloro-4,6-dimethoxy-1 ,3,5-triazine (3140-73-6) → C13H12N6O4

Conditions	Yield
With triethylamine In dichloromethane	95%

2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (739364-95-5) + (S)-1-[(2-amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitrile dihydrochloride → (S)-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid {2-[(2-cyanopyrrolidin-1-yl)-2-oxoethylamino]-2-methylpropyl}amide

Conditions	Yield
Stage #1: 2-methylpyrazolo[1,5-a] pyrimidine-6-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile for 0.5h; Stage #2: (S)-1-[(2-amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitrile dihydrochloride In acetonitrile at 20℃; for 3h;	88%
Stage #1: 2-methylpyrazolo[1,5-a] pyrimidine-6-carboxylic acid With 1,1'-carbonyldiimidazole In dichloromethane at 25 - 35℃; for 4h; Stage #2: (S)-1-[(2-amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitrile dihydrochloride With triethylamine In dichloromethane at 10 - 35℃; for 2h;	53.2 g

2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (739364-95-5) + C11H20N4O*ClH → (S)-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid {2-[(2-cyanopyrrolidin-1-yl)-2-oxoethylamino]-2-methylpropyl}amide

Conditions	Yield
With triethylamine; 1,1'-carbonyldiimidazole In dichloromethane at 0 - 20℃; Reagent/catalyst; Solvent; Concentration; Temperature; Large scale;	87%

1-hydroxy-pyrrolidine-2,5-dione (6066-82-6) + 2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (739364-95-5) → C12H10N4O4

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 8h; Cooling with ice;	86%

2,4-Dichloro-6-methoxy-1,3,5-triazine (3638-04-8) + 2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (739364-95-5) → C12H9ClN6O3

Conditions	Yield
With pyridine In tetrahydrofuran Solvent;	84%

1,3,5-trichloro-2,4,6-triazine (108-77-0) + 2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (739364-95-5) → C11H6Cl2N6O2

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran Solvent;	70%

2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (739364-95-5) + (2S)-1-{[(1-amino-2-methylpropan-2-yl)amino]acetyl}pyrrolidine-2-carbonitrile methane sulfonate → (S)-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid {2-[(2-cyanopyrrolidin-1-yl)-2-oxoethylamino]-2-methylpropyl}amide

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane	69.3%

2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (739364-95-5) + (S)-1-(2-((1-amino-2-methylpropan-2-yl)amino)acetyl)pyrrolidine-2-carbonitrile (794460-89-2) → (S)-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid {2-[(2-cyanopyrrolidin-1-yl)-2-oxoethylamino]-2-methylpropyl}amide

Conditions	Yield
Stage #1: 2-methylpyrazolo[1,5-a] pyrimidine-6-carboxylic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 25 - 30℃; for 3h; Stage #2: (S)-1-(2-((1-amino-2-methylpropan-2-yl)amino)acetyl)pyrrolidine-2-carbonitrile In tetrahydrofuran for 15h; Reagent/catalyst; Solvent;	62%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20 - 50℃; for 2h; Temperature;	55%

2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (739364-95-5) + N,N,dimethyl-1,4-butanediamine (83686-55-9) → 2-Methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (4-amino-4-methylpentyl)amide

Conditions	Yield
Stage #1: 2-methylpyrazolo[1,5-a] pyrimidine-6-carboxylic acid With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 0 - 20℃; for 0.5h; Stage #2: N,N,dimethyl-1,4-butanediamine With triethylamine In tetrahydrofuran at 0 - 20℃;	55%

2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (739364-95-5) + C15H20N4O2 → C21H21N7O3

Conditions	Yield
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 24h;	46.67%

2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (739364-95-5) + 5-chloro-6-(difluoromethoxy)pyridin-3-amine → 1-(5-chloro-6-(difluoromethoxy)pyridin-3-yl)-3-(2-methylpyrazolo[1,5-a]pyrimidin-6-yl)urea

Conditions	Yield
Stage #1: 2-methylpyrazolo[1,5-a] pyrimidine-6-carboxylic acid With diphenyl phosphoryl azide; triethylamine In 1,4-dioxane at 20℃; for 0.833333h; Inert atmosphere; Stage #2: 5-chloro-6-(difluoromethoxy)pyridin-3-amine at 100℃; for 2h; Inert atmosphere;	15%

2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (739364-95-5) + 1-(aminomethyl)cyclopentanamine (5062-66-8) → 2-Methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (1-aminocyclopentylmethyl)amide

Conditions	Yield
Stage #1: 2-methylpyrazolo[1,5-a] pyrimidine-6-carboxylic acid With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 0 - 20℃; for 3h; Stage #2: 1-(aminomethyl)cyclopentanamine With potassium carbonate In tetrahydrofuran at -60 - 20℃; for 22.5h;	12%

2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (739364-95-5) → C8H6ClN3O

Conditions	Yield
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 6.16667h;

2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (739364-95-5) → Anagliptin hydrochloride (1359670-56-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: tetrahydrofuran / 4 h / 20 °C 2.1: triethylamine / tetrahydrofuran / 20 °C / Cooling with ice 2.2: 0.17 h / 10 °C View Scheme

2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (739364-95-5) + 1,1'-carbonyldiimidazole (530-62-1) → C12H9N5O3

Conditions	Yield
In tetrahydrofuran at 20℃; for 4h;

2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (739364-95-5) + 1,1-dimethylethylenediamine (811-93-8) → N-(2-amino-2-methylpropyl)-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide

Conditions	Yield
Stage #1: 2-methylpyrazolo[1,5-a] pyrimidine-6-carboxylic acid With 1,1'-carbonyldiimidazole In dichloromethane at 25 - 30℃; for 1h; Inert atmosphere; Stage #2: 1,1-dimethylethylenediamine In dichloromethane at 0 - 10℃;	8.8 g

2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (739364-95-5) + 1,1'-carbonyldiimidazole (530-62-1) → C11H9N5O

Conditions	Yield
In tetrahydrofuran at 20℃; for 4h;

2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (739364-95-5) + (S)-1-(2-((1-amino-2-methylpropan-2-yl)amino)acetyl)pyrrolidine-2-carbonitrile (794460-89-2) → C19H27N7O3

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 3 h / 25 - 30 °C 1.2: 15 h 2.1: sodium hydroxide; water / 5.08 h / 5 °C View Scheme

2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (739364-95-5) → (S)-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid {2-[(2-cyanopyrrolidin-1-yl)-2-oxoethylamino]-2-methylpropyl}amide

Conditions	Yield
Multi-step reaction with 2 steps 1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 8 h / 20 °C / Cooling with ice 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 5 h View Scheme

2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (739364-95-5) + (S)-1-[(2-amino-1,1-dimethylethyl)aminoacetyl]pyrrolidine-2-carbonitrile dihydrochloride → (S)-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid {2-[(2-cyanopyrrolidin-1-yl)-2-oxoethylamino]-2-methylpropyl}amide hydrochloride

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 1,1'-carbonyldiimidazole / dichloromethane / 4 h / 25 - 35 °C 1.2: 2 h / 10 - 35 °C 2.1: isopropyl alcohol hydrogen chloride / 1,4-dioxane; diethyl ether / 1 h / 25 - 30 °C View Scheme

Upstream product

• 933692-37-6 2-methylpyrazolo[1,5-a]pyrimidine-6-carbaldehyde 
• 1263061-14-8 2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid ethyl ester 
• 338953-49-4 2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid amide 

Downstream Products

• 739366-20-2 (S)-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid {2-[(2-cyanopyrrolidin-1-yl)-2-oxoethylamino]-2-methylpropyl}amide 
• 1359670-56-6 N-[2-({2-[(2S)-2-cyanopyrrolidine-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride 

Relevant academic research and scientific papers

Preparation method of anagliptin intermediate

The invention provides a preparation method of an anagliptin intermediate. The preparation method comprises the following steps: (1) N,N-dimethylformamide (I) and acyl chloride are subjected to a Vilsmiere reaction to produce a Vilsmiere reagent, bromoacetic acid (II) is dropwise added to the Vilsmiere reagent for a heating reaction, hydrolysis is performed, and dicarbaldehyde acetaldehyde (III) is obtained; (2) dimethyl acetaldehyde (III) and 3-amino-5-methyl pyrazole (IV) are dissolved in an alcohol/sodium alcoholate system, heating and reflux stirring are performed, and 6-carbaldehyde-2-methyl-pyrazo[1,5-a]pyrimidine (V) is produced; (3) 6-carbaldehyde-2-methyl-pyrazo[1,5-a]pyrimidine (V) is oxidized in strong base to produce 2-methyl-pyrazo[1,5-a]pyrimidine-6-carboxylic acid (VI). Thereaction steps are simplified, operation is convenient, few three wastes are produced, and the yield is high.

PYRAZOLOPYRIMIDINE AS MALT-1 INHIBITORS

The invention provides a compound of formula (I): herein R1, R2 and R3 of series (x), (y) and (z) are as defined in the specification which are potent inhibitors of the enzyme MALT1 and are useful in an immunooncology approach to the treatment of cancer, especially bladder cancer, colon cancer, hepatocellular cancer or small cell or non-small cell lung cancer.

A method for synthesizing allah Geleg sandbank (by machine translation)

The invention relates to a method for preparing anti-II type diabetes drug allah Geleg sandbank method for the synthesis of bulk drug (Anagliptin). The lack of commercial synthetic allah Geleg sandbank solve the technical problems of the method. Synthetic method comprises the following steps : (1) with vinyl ether and trichloro acetyl chloride as the raw material, passes through the three-step reaction to obtain the aldehyde protected intermediates 4 ; The 3-amino-5-methyl pyrazole condensation for dehydrating and gets pyrazolo pyrimidine mother nucleus; Carboxy b ester hydrolysis to obtain 2-methyl-pyrazolo [1,5-a] pyrimidin 6-carboxylic acid 6 ; (2) to L-proline as a raw material, passes through the methyl esterification, ammoniation, acetylation, Carbonitride reaction to obtain the chiral cyano pyrrolizinone intermediate 11 ; Chiral cyano pyrrolizinone intermediate 11 And diamine fragment 12 In alkaline conditions to obtain intermediate affinity substituted 13 ; Finally, intermediate 13 Under the conditions of the hydrochloric acid removal protection Boc base namely obtain cyanopentanoyl Azolylamine intermediate 14 ; (3) 2-methyl-pyrazolo [1,5-a] pyrimidine-6-carboxylic acid 6 The cyano Azolylamine intermediate 14 The condensation conditions to obtain the bulk drug allah Geleg sandbank coupled. (by machine translation)

Intermediate allah Geleg sandbank 2-methyl-pyrazolo [1,5-A] pyrimidine-6-carboxylic acid

The invention discloses a preparation method of a gulag column dean intermediate 2-methyl-pyrazolo[1,5-A] pyrimidine-6-carboxylic acid, and belongs to the technical field of a medicine. The method concretely comprises the following steps: S1, condensation reaction, carrying out condensation on 3-amino-5-methylpyrazole and 2-formoxyl-3-oxo-propionic acid ethyl ester to generate an intermediate I in a solvent, and adding an acid-binding agent in the reaction process; S2, hydrolysis reaction, adding the intermediate I, aqueous alkali and a reaction solvent to a reaction container, carrying out hydrolysis reaction, rotating out a liquid phase after reaction, adjusting the pH of the liquid phase to 4 by using a concentrated hydrochloric acid, filtering and drying the separated solid, wherein the obtained product is 2-methyl-pyrazolo[1,5-A] pyrimidine-6-carboxylic acid. The method disclosed by the invention has the advantages of being simple and short in synthetic route, mild in reaction condition, environmental friendly, low in cost, and applicable to industrial large-scale production.

Discovery and pharmacological characterization of N-[2-({2-[(2S)-2- cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo[1,5-a] pyrimidine-6-carboxamide hydrochloride (anagliptin hydrochloride salt) as a potent and selective DPP-IV inhibitor

In the course of our program for discovery of novel DPP-IV inhibitors, a series of pyrazolo[1,5-a]pyrimidines were found to be novel DPP-IV inhibitors. We identified N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2- methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride (4a) and described its pharmacological profiles.

COMPOUND INHIBITING DIPEPTIDYL PEPTIDASE IV

The invention aims to provide a dipeptidyl peptidase IV inhibitor which is satisfactory in respect of activity, stability and safety and has an excellent action as a pharmaceutical agent. The invention is directed to a compound represented by the following general formula or a pharmaceutically acceptable salt thereof: wherein R1 and R2 each represents hydrogen, an optionally substituted C1-6 alkyl group, or -COOR5 whereupon R5 represents hydrogen or an optionally substituted C1-6 alkyl group, or R1 and R2, together with a carbon atom to which they are bound, represent a 3- to 6-membered cycloalkyl group, R3 represents hydrogen or an optionally substituted C6-10 aryl group, R4 represents a hydrogen or a cyano group, D represents -CONR6-, -CO- or -NR6CO-, R6 represents hydrogen or an optionally substituted C1-6 alkyl group, E represents -(CH2)m- whereupon m is an integer of 1 to 3, -CH2OCH2-, or -SCH2-, n is an integer of 0 to 3, and A represents an optionally substituted bicyclic heterocyclic group or bicyclic hydrocarbon group.