CN103275087A - Triazolo pyrimidine derivative and preparation method thereof - Google Patents

Abstract

The invention relates to a triazolo pyrimidine derivative and a preparation method thereof. A structural general formula of the triazolo pyrimidine derivative is as Formula (I) as shown in the specification, wherein R is hydroxyalkyl such as -CH(CH3)CH2OH, -CH(CH2CH3)CH2OH and -C(CH3)2CH2OH.

Description

- Species triazolo pyrimidine derivatives and preparation method

FIELD

[0001] The present invention relates to the field of medicine, in particular to a triazole pyrimidine derivatives and their preparation.

Background technique

[0002] Thrombosis is small at the surface of the blood vessel inner surface spalling cardiovascular system or patch formed at. In the fluid-dependent variable, the insoluble fibrin from the thrombus, platelet deposition, accumulation of white blood cells and red blood cells into the composition.

[0003] Human blood platelets are mainly three different ADP receptor MX1, PZY1, P2Y12. PZX1 an ATP-gated cation channels, P2Xi receptors in the nervous excitement signal and the non-excitatory cell-mediated, is the key role of inflammation and cardiovascular function; Ρ2ΥρΡ2Υ12 as two kinds of G protein-coupled receptors. After binding of ADP receptors P2Yi, P2Yi and Gq-protein coupled receptors activate phospholipase C leading to the extracellular Ca2 + from intracellular flows, the intracellular Ca2 + concentration increased activation of protein kinase C induced platelet aggregation and deformation; ADP binding to the receptor P2Y12, P2Y12 receptor coupled to Gi protein to suppress adenylate cyclase activated platelets (adenylylcyclase), reducing the level of cAMP in platelets, to induce platelet aggregation. So P2YpP2Y12 ADP receptor blocking drugs are targets. P2Y12 platelet number greater than the number P2t on platelets. Therefore, ADP-induced platelet aggregation is the major receptor P2Y12.

[0004] Studies have shown that P2Y12 receptor is involved in activation of the fibrinogen receptor, thrombosis, generating thromboxane A2, platelet aggregation caused by traumatic procedure. By the human P2Y12 342 amino acids, mainly in the platelets and the brain tissue, the antithrombotic thiophene pyridine compound target. Stimulating factors such as endogenous binding P2Y12 ADP receptor will activate other like PI3K pathway is activated Paplb, Akt, ERK pathway common cause activation of the fibrinogen receptor, fibrinogen binding, to initiate thrombosis or platelet aggregation. This process can be achieved in the case of P2Y12 receptor activated simultaneously. Thus P2Y12 receptor blockade significantly inhibit ADP-induced and other stimulating factors in small Xu aggregation and thrombosis.

[0005] Currently, P2Y12 receptor antagonists published application include patent applications W01999005143, W02000034283, W0200103642.

[0006] While there has been disclosed a series of anti-platelet aggregation drugs and thrombosis, there remains a need to develop new and better drugs having efficacy, the present invention contemplates a compound of a novel structure of the general formula (I) is.

SUMMARY

[0007] The object of the present invention to provide a formula (I) shown in novel triazole and pyrimidine derivatives.

[0008]

[0009] wherein R is -CH (CH3) hydroxyalkyl CH2OH, -CH (CH2CH3) CH2OH, -C (CH3) 2CH20H like.

[0010] Intermediates of general formula (I), (II)

[0011]

[0012] wherein R is -CH (CH3) hydroxyalkyl CH2OH, -CH (CH2CH3) CH2OH, -C (CH3) 2CH20H like.

BRIEF DESCRIPTION

[0013] 1H-NMR spectrum of compound A graph.

Detailed ways

[0014] The following examples of the present invention will be further described in detail, the purpose of illustrating embodiments and not limitation.

[0015] Example

[0016] The first step

[0017] N- [(3aS, 4R, 6S, 6aR) _6_ _2,2_ dimethyl hydroxy - tetrahydro _3aH_ cyclopenteno _ [d] [I, 3] - dioxol ring - 4- ol] carbamate synthesis

[0018] in 500mL three-neck flask, was added (3aR, 4S, 6R, 6aS) _6_ amino _2,2_ dimethyl-tetrahydro-cyclopenta [d] [l, 3] dioxol-burning Shu 4-ol (5.0Og, 28.87mmol, 1.0eq), sodium carbonate (6.12g, 57.74mmol, 2.0eq), ethyl acetate (200mL) magnetically stirred, ice-salt bath cooling to _20 ° C, a solid system muddy liquid suspension, slowly dropwise benzyl chloroformate (5.42g, 31.77mm0l, l.1eq) ethyl acetate solution, maintaining the temperature at _20 ° C~15 ° C, dropwise. Reaction was followed by TLC, naturally warmed to room temperature, the reaction was stirred for 2h ends. Solid was filtered off with suction, the filter cake with ethyl acetate (10 mL x 3) rinsing, the filtrate and washing liquid were combined, dried over anhydrous sodium sulfate, and rotary evaporated to dryness under reduced pressure ethyl acetate solvent, to give a white solid (8.0lg, 26.06mmol), the crude product rate of 90.31%, the product directly into the next step without purification.

[0019] The second step

[0020] 2- [[(3aS, 4R, 6S, 6aR) _6_ benzyloxy carboxyamino _2,2_ dimethyl-tetrahydro _3aH_ 4,5,6,6a_ cyclopenta [d] [l, 3] dioxol-4-yl] oxy] -2-propanoate synthesized

[0021] placed in a cold trap 250mL three-neck flask, compound I (8.0lg, 26.06mmol, 1.0eq), anhydrous tetrahydrofuran (IOOmL), the cooling system is mechanically stirred until -20 ° C, was added tert-butyl batches potassium alcohol (3.51g, 31.28mol, 1.2eq), the addition, to maintain _20 ° C stirred lh. Was slowly added dropwise ethyl bromoacetate (5.66g, 31.27m m0l, 1.3eq) maintaining -20 ° C After 2h the reaction, three-necked flask cold trap was removed, the reaction followed by TLC natural temperature rise, the end of the reaction for 5h. Water was added (IOOmL), stirred 0.5h, and extracted with ethyl acetate (100 ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure rotary ethyl acetate and tetrahydrofuran, to give colorless oil (8.53 g, 20.93mol), a crude yield of 80.32%.

[0022] Step

[0023] N- [(3aS, 4R, 6S, 6aR) -6- (2- ethyl-yl) -2,2-dimethyl-tetrahydro -3aH_ cyclopentene -4,5,6,6a_ and [d] [l, 3] dioxol-4-yl] carbamate synthesis

[0024] placed in a cold trap 500mL three-necked flask was added anhydrous tetrahydrofuran (200 mL), lithium chloride (1.79g, 42.23mmol, 2.0eq), stirred mechanically to a cooling system is -20 ° C, was added boron batches potassium hydride (2.28g, 42.27mmol, 2.0eq), the addition, to maintain _15 ° C stirred for 2h. Was slowly added dropwise compound 2 (8.53g, 20.93mmol, 1.0eq) in anhydrous tetrahydrofuran, maintained _20 ° C~-10 ° C. Dropwise, followed by TLC natural warming of the reaction, the reaction for 4h at room temperature the reaction was completed. Cooled to -10 ° c System dropwise addition of saturated aqueous ammonium chloride solution, bubbling system exothermic, the addition was completed, extracted with ethyl acetate (IOOmLX 3), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure rotating ethyl acetate and tetrahydrofuran, to give colorless oil (4.85g, 13.27mol), a crude yield of 63.40%.

[0025] The fourth step

[0026] 2 ~ {[(3aS, 4R, 6S, 6aR) -6- atmosphere-2, 2-methyl -4, 5,6,6a- four dilute oxygen -3aH- ring and Shu [d] [1,3] dioxin Shu burning 4-yl] oxy} -2-propanol synthesized

[0027] in 250mL single-necked flask, compound 3 (4.85g, 13.27mmol, 1.0eq), palladium on carbon (0.5g,

0.leq), methanol (IOOmL), pump displacement gas three times; magnetic stirring the reaction through hydrogen, the reaction was followed TLC, the reaction was stirred at room temperature 4h end. Palladium carbon was filtered off with suction, the filter cake was rinsed with methanol (10 mL x 3), the combined filtrate and rinse solution, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure rotary methanol to give colorless oil (2.82g, 12.1911111101), crude yield 91.86 (%.

[0028] The fifth step

[0029] 2- {[(3aS, 4R, 6S, 6aR) _6_ [(5_-6-gas atmosphere propylthio ~ 2 ~ - ~ 4 ~ Jie Li adhesion yl) atmosphere yl] dimethyl ~ 2,2_ group -4, 5,6,6a- four ring Shu dilute oxygen _3aH_ and [d] [I, 3] dioxol-4 ~ yl ~ Shu burning] oxy} ~ 2 ~ propanol synthesis

[0030] in 250mL three-necked flask was added compound 4 (2.82g, 12.19mmol, 1.0eq), 4,6_-dichloro _2_ (propylthio) -5- Jie Li dense atmosphere yl (2.90g, 12.1 QmmoI, 1.0eq), N, N- diisopropylethylamine (2.00g, 15.5ImmoI,

1.2 eq), was heated in an oil bath with magnetic stirring, heated to reflux, TLC trace of the reaction, the reaction was stirred for 4h end. Water was added (IOOmL), stirred for 30min, extracted with ethyl acetate (IOOmLX3), the combined organic phases were washed with water (50 ml x 3) The organic layer was washed paint, dried over anhydrous sodium sulfate, and rotary evaporated to dryness under reduced pressure ethyl acetate solvent, to give a pale yellow oily liquid (4.57g, 10.78mmol), a crude yield of 86.55% 0

[0031] The sixth step

[0032] 2 - {[(3aR, 4S, 6R, 6aS) -6_ [7- chloro-5-thio - triazolo [4,5_d] pyrimidin _3_ yl] 2,2_ dimethyl - 4, 5,6,6a- four ring Shu dilute oxygen _3aH_ and [d] [I, 3] dioxol-2 ~ propanol synthesized Shu burn ~ ~ 4-yl] oxy} ~

[0033] 25011 ^ in three-necked flask, compound 5 (4.57g, 10.78mmol, 1.0eq), sodium nitrite (0.87g, 12.61mmol, 1.2eq), acetic acid (3.80g, 63.28mmol, 6.0eq), toluene (IOOmL), water (20 mL), magnetic embrace Xiang, the reaction followed by TLC at room temperature, the reaction was stirred for 30min ends. Saturated aqueous sodium carbonate solution, adjusted to pH 8-9, the organic layer was separated, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure rotary toluene to give a pale yellow oily liquid (3.41g, 7.68mmol), crude yield 72.71% . [0034] The seventh step

[0035] N - {[(IR, 2S) -2- (3,4- difluorophenyl) cyclopropyl] _6- [7_ chloro _5_ propylthio - triazolo [4,5_d ] B dense Li 3-yl] _2,2_ dimethyl _4,5,6,6a_ four ring Shu dilute oxygen _3aH_ and [d] [I, 3] dioxin-4-shu yl] oxy} -2-propanol synthesized

[0036] In IOOmL three-necked flask, compound 5 (3.41g, 7.68mmol, 1.0eq), (1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamine (1.30g, 7.68mmol, 1.0eq), N, N- diisopropylethylamine (1.27g, 9.78mmol, 1.3eq), dichloromethane (70 mL), stirred magnetically, the reaction followed by TLC at room temperature, the reaction was stirred 15h ends. With 0.0lmol / L System was washed with dilute hydrochloric acid to a pH of 7 system, the organic layer was separated, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure rotary dichloromethane, to give colorless oil (3.50g, 6.07mmol), the crude yield 81%.

[0037] Eighth Step

[0038] (11, 21, 35,510-3- {5-epithiopropyl -7--?? [[(11, 25) -2- (3,4-difluorophenyl) cyclopropyl]? amino] triazolo [4,5-d] pyrimidine-3} -5 (2-hydroxy-isopropoxy) cyclopentyl-yl-1,2-diol synthesis and Characterization

[0039] In IOOmL-neck flask, was added compound 7 (3.50g, 6.07mmol, 1.0eq), 12mol / L of concentrated hydrochloric acid (5 mL), methanol (80 mL), stirred magnetically, the reaction followed by TLC at room temperature, the reaction was stirred for 4h end. Sodium carbonate was added to adjust the pH 8-9, the solid was filtered off with suction, the filter cake was rinsed with methanol (IOmLX 3), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and rotation, to obtain a colorless oily liquid (2.80g, 5.22mmol) crude yield of 86.00%. The product was purified by column chromatography, eluent (methylene chloride: methanol = 60: 1) to give a white solid, i.e. Compound A (l.lg, 2.05mmol).

IHNMR (CD3OD, 400MHz): 0.97 (t, J = 7.5Ηζ, 3Η, CH3), 1.18 (t, J = 7.5Ηζ, 3Η, CH3), 1.31 ~1.41 (m, 2H, CH2), L 47 ~L 52 (m, 1H, CH), L 58 ~L 64 (m, 2H, CH2), 2.17 ~2.23 (m, 2H, CH2), 2.76 ~2.82 (m, 1H, CH), 2.96 ~3.02 (m, 1H, CH), 3.03-3.06 (m, 1H, CH), 3.08 (S, 1H, CH), 3.53 ~3.57 (m, 2H, CH2), 3.64-3.78 (m, 1H, CH), 4.07 (t , 1H, CH), 4.10 (t, 1H, CH),

4.78 (t, 1H, CH), 4.83 (br, 4H, OH, NH), 5.10 ~5.16 (m, 1H, CH), 7.09 (s, 1H, C6H5), 7.15 ~7.26 (m, 2H, C6H5) .

Claims (3)

Triazole represented by (I) 1. and pyrimidine derivatives of general formula

Wherein R is -CH (CH3) CH2OH, -CH (CH2CH3) CH2OH, -C (CH3) 2CH2OH hydroxyalkyl group and the like; preferably -CH (CH3) CH2OH, -CH (CH2CH3) CH2OH, -C (CH3) 2CH2OH0

According to claim 1 of the formula (I), its derivatives and pyrimidine intermediates of formula (II) azole-triazole represented by

Wherein R is -CH (CH3) CH2OH, -CH (CH2CH3) CH2OH, -C (CH3) 2CH2OH hydroxyalkyl group and the like; preferably -CH (CH3) CH2OH, -CH (CH2CH3) CH2OH, -C (CH3) 2CH2OH0

1 according to the formula (I) as claimed in claim, when R is -CH (CH3) CH2OH group, the compound of structure