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Chemical Structure| 486460-00-8
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Product Details of [ 486460-00-8 ]

CAS No. :486460-00-8 MDL No. :MFCD06659147
Formula : C15H18F3NO4 Boiling Point : -
Linear Structure Formula :- InChI Key :TUAXCHGULMWHIO-SECBINFHSA-N
M.W : 333.30 Pubchem ID :7146288
Synonyms :

Calculated chemistry of [ 486460-00-8 ]

Physicochemical Properties

Num. heavy atoms : 23
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.47
Num. rotatable bonds : 8
Num. H-bond acceptors : 7.0
Num. H-bond donors : 2.0
Molar Refractivity : 76.02
TPSA : 75.63 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.38 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.38
Log Po/w (XLOGP3) : 2.75
Log Po/w (WLOGP) : 4.28
Log Po/w (MLOGP) : 3.4
Log Po/w (SILICOS-IT) : 3.39
Consensus Log Po/w : 3.24

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -3.3
Solubility : 0.166 mg/ml ; 0.000497 mol/l
Class : Soluble
Log S (Ali) : -3.99
Solubility : 0.0339 mg/ml ; 0.000102 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.39
Solubility : 0.0136 mg/ml ; 0.0000407 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 3.2

Safety of [ 486460-00-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 486460-00-8 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 486460-00-8 ]

[ 486460-00-8 ] Synthesis Path-Downstream   1~67

  • 1
  • [ 486460-21-3 ]
  • [ 486460-00-8 ]
  • [ 486460-23-5 ]
YieldReaction ConditionsOperation in experiment
86% EXAMPLE 7 This example is about step 7 of the process of the invention, production of tert-butyl-4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-yl-carbamate, compound (X) with R = tert-butyl (amide formation with EDC/N-HOBT) N-hydroxybenzotriazole (150 mg, 1.08mmol) is added at 0 C to a solution of (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid (300 mg, 0.90 mmol) and <strong>[486460-21-3]3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine</strong> (170 mg, 0.90 mmol) in CH2Cl2 (10ml); after 10 minutes EDC (260 mg, 1.35mmol) is added. The mixture is stirred under nitrogen at room temperature for 4 hours monitoring by TLC (AcOEt). The reaction is quenched by addition of a saturated solution of NaHCO3 (5 mL); after phase separation the organic layer is washed with brine (5 mL), dried over sodium sulphate, concentrated to a residue and purified by flash chromatography eluting with AcOEt obtaining the title product (406 mg, 86%) as a off-white solid. 1H NMR (400 MHz, CDCl3) delta 7.14-7.04 (m, 1 H), 6.97-6.83 (m, 1 H), 5.32-5.24 (bs, 1 H), 5.16-5.00 (m, 1 H), 4.94 (s, 1 H), 4.33-3.94 (m, 5H), 3.02-2.62 (m, 4H) 1.38 (s, 9H).
82% To a solution of (R)-3-[(tert-butyloxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)- butanoic acid (1.36 g, 4.080 mmol) in acetonitrile (20 ml) was added Diisopropylethylamine (2.47 g, 19.12 mmol) and 1 ,1-Carbonyl diimidazole (0.94 g, 5.82 mmol) at room temperature. The reaction mixture was stirred for 30 min at room temperature. S-iTrifluoromethylJ-S.ej.e-tetrahydro-l ,2,3-triazolo[4,3- a]pyrazine (0.750 g, 3.88 mmol) was added to the above reaction mixture at room temperature. The reaction mixture was heated to 65-70C for 22 h. After completion of the reaction, the mixture was concentrated under vacuum and the crude mass was dissolved in ethyl acetate (15 ml) and washed with 5% aqueous NaHC03 solution followed by twice with water (2 x 30 ml). The ethyl acetate layer was concentrated under reduced pressure to get crude mass and recrystallized from mixture of 10 % ethyl acetate and petroleum ether (50 ml) to get 1.5 g (82%) of tert-butyl{(1 R)-3-oxo-1 -(2,4,5-trifluorobenzyl)-3-[3-(trifluoromethyl)-5-6- dihydro[1 ,2,4] triazole[4,3-a]pyrazin-7(8H)-yl]propyl}carbamate.
81% With hydrogenchloride; benzotriazol-1-ol; 1,2-dichloro-ethane; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 15h; 3.0 g of intermediate V (4.5 mmol) was dissolved in 25 mL of DMF,2.06 g of EDC.HCl (10.8 mmol) and1.46 g of HOBT (10.8 mmol) followed by 1.80 g of starting material X (9.0 mmol) and 1.30 mL of triethylamine (9.0 mmol)Stirred at room temperature for 15 h,Add water to extract the reaction,Ethyl acetate extraction, organic NaHCO3 aqueous solution and saturated brine,No waterNa2SO4. The solvent was evaporated under reduced pressure and the column chromatography (EtOAc / petroleum ether = 7: 3) gave the product as a white solid intermediate
71.8% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; To a solution of (R) -3- [N- (tert- butoxycarbony1) amino] -4- (2, 4, 5-trifluoro-phenyl) butanoic acid ( 0.333 g, lmmol) of Example 8 and 3- ( trif luoromethyl- 5, 6, 7, 8-tetrahydro-l, 2, 4-triazolo [4, 3a] pyrozine (0.192 g, 1 mmol) in DMF (12 ml) was added HOBT (0.162 g, 1.2mmol) and EDC (0.230 g. 1.2 mmol) at 0 0C. After being stirred at room temperature for 16 h, DMF was evaporated and the residue extracted with ethyl acetate (3 X 20 ml) . The organic extracts were washed with NaHSO4 aq, then NaHCO3, then brine, and then dried over Na2SO4. Concentration was followed by purification by flash chromatography to afford 0.375 g of the title compound (71.8%) . 1H NMR (300 MHz, CDCl3) 7.10-7.00 (m, IH), 7.00-6.90 (m, IH), 5.25-5.35 (br, IH), 5.10-5.00 (m, IH), 4.90 (s, IH), 4.30-3.90 (m, 5H), 3.00-2.90 (m, 2H), 2.80-2.60 (m, 2H), 1.35 (s, 9H)
47.5% Comparative Example 1: Preparation of Compound of formula 2 wherein R is Boc, according to the method disclosed in U.S. Patent No. 6,699,871, Example 7, STEP A [42] (R)-3-Boc-amino-4-(2,4,5-trifluorophenyl)-butanoic acid (50.1mg, 0.15mmol) was dissolved in dichloromethane (2.5ml) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-alpha]pyrazine (39.2mg, 0.20mmol) was added thereto. While maintaining a temperature of 0 to 5C, HOBT (17.2mg, 0.21mmol) was added to the mixture, followed by reaction for 10 minutes. Thereafter, EDC (48.3mg, 0.25mmol) was added at 0C, and the reaction mixture was warmed to room temperature and stirred for 14 hours. After the reaction was completed, the reaction liquid was concentrated under reduced pressure and a desired compound was purified by column chromatography eluting with 100% ethyl acetate to afford 29mg (yield: 47.5%) of the title compound as a solid.

  • 2
  • [ 486460-25-7 ]
  • [ 486460-00-8 ]
YieldReaction ConditionsOperation in experiment
94% With silver benzoate; In 1,4-dioxane; water; for 1.5h;Sonication; 4.6 (R)-3-(tert-Butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid 7 To a solution of (R)-2-(tert-butoxycarbonylamino)-3-(2,4,5-trifluorophenyl)propanoic acid 5 (465 mg, 1.45 mmol) in 12 mL of diethyl ether at -20 C were added sequentially 0.214 mL (1.54 mmol) of triethylamine and 0.200 mL (1.54 mmol) of isobutylchloroformate, and stirred for 15 min. A cooled solution of diazomethane was added until a yellow color persisted and stirring was continued for 1 h. The excess diazomethane was quenched by the dropwise addition of acetic acid. The reaction mixture was diluted with ethyl acetate, and washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous Na2SO4, and concentrated in vacuum. The crude product was purified by column chromatography eluting with 20% ethyl acetate in hexane to afford diazoketone 6 (440 mg, 88%). To a solution of diazoketone (440 mg, 1.27 mmol) in 15 mL of 1,4-dioxane/water (5:1) was added 30 mg (0.127 mmol) of silver benzoate. The resultant solution was sonicated for 90 min before diluting with ethyl acetate and being washed sequentially with 1 M hydrochloric acid and brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by column chromatography eluting with 25% ethyl acetate in hexane to afford 7 as a white powder (400 mg, 94%). Mp: 121-124 C; {lit. 15 mp: 124-125 C}; [alpha]D24.3 = +27.8 (c 0.13, CHCl3); {lit. 15 [alpha]D20 = +32.3 (c 1.0, CHCl3)}; 1H NMR (400 MHz, CDCl3) delta 1.37 (s, 9H), 2.66-2.57 (m, 2H), 2.88 (d, J = 4.9 Hz, 2H), 4.14 (br s, 1H), 5.07 (br s, 1H), 6.94-6.87 (m, 1H), 7.09-7.03 (m, 1H); 13C NMR (100 MHz, CDCl3) delta 28.2, 29.6, 32.9, 33.9, 37.9, 38.4, 47.6, 48.8, 79.9, 81.3, 105.1, 105.3, 105.4, 105.6, 119.0, 119.1, 121.3, 145.3, 145.4, 147.5, 147.7, 150.0, 150.2, 150.3, 155.0, 155.2, 156.9, 157.5, 175.1, 176.2; MS (ESI) m/z: 355.9 (M+Na)+. HRMS (ESI) (M+Na)+: calcd for C15H18F3NO4Na: 356.1080; found: 356.1068.
With silver benzoate; In 1,4-dioxane; water; for 2h;Sonographic reaction; To a solution of 0.37 g (1.16 mmol) of(K)-N-( fe?t-butoxycarbonyl)-2,4,5-trifluorophenylalanine in 10 mL of diethyl ether at -20 C were added sequentially 0.193 mL (1.3 mmol)of triethylamine and 0.18 mL (1.3 mmol) of isobutyl chloroformate, and the reaction was stirred at thistemperature for 15 min. A cooled ethereal solution of diazomethane was then added until the yellowcolor persisted and stirring was continued for a further 1 h. The excess diazomethane was quenched bydropwise addition of acetic acid, and the reaction was diluted with ethyl acetate and washed sequentiallywith saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate andconcentrated in vacuo. Purification by flash chromatography (silica gel, 3:1 hexane:ethyl acetate)afforded 0.36 g of diazoketone. To a solution of 0.35 g (1.15 mmol) of the diazoketone dissolved in 12mL of 1,4-dioxane: water (5:1) was added 26 mg (0.113 mmol) of silver benzoate. The resultant solutionwas sonicated for 2 h before diluting with ethyl acetate and washing sequentially with IN hydrochloric acid and brine, drying over magnesium sulfate and concentrating in vacuo. Purification by flashchromatography (silica gel, 97:2:1 dichloromethane:methanol: acetic acid) afforded the title compound.IH NMR (500 MHz, CDCls); 5 7.06 (m, 1H), 6.95 (m, 1H), 5.06 (bs, 1H), 4.18 (m, 1H), 2.98 (m, 2H),2.61 (m, 2H), 1.39 (s, 9H).
To a solution of 0.37 g (1.16 mmol) of [(R)-N-(L, L-DIMETHYLETHOXY-] [CARBONYL) -2,4, 5-TRIFLUOROPHENYLALANINE IN 10 ML OF DIETHYL ETHER AT-20 C WERE ADDED] sequentially 0.193 mL (1.3 mmol) of triethylamine and 0.18 mL (1.3 mmol) of isobutyl chloroformate, and the reaction was stirred at this temperature for 15 min. A cooled ethereal solution of diazomethane was then added until the yellow color persisted and stirring was continued for a further 1 h. The excess diazomethane was quenched by dropwise addition of acetic acid, and the reaction was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (silica gel, 3: 1 hexane: ethyl acetate) afforded 0.36 g of diazoketone. To a solution of 0.35 g (1.15 mmol) of the diazoketone dissolved in 12 mL of 1,4-dioxane : water (5: 1) was added 26 mg (0.113 mmol) of silver benzoate. The resultant solution was sonicated for 2 h before diluting with ethyl acetate and washing sequentially with IN hydrochloric acid and brine, drying over magnesium sulfate and concentrating in vacuo. Purification by flash chromatography (silica gel, 97: 2: 1 dichloromethane: methanol: acetic acid) afforded 401 mg of the title compound. 1H NMR (500 MHz, [CDC13)] [8] 7.06 (m, 1H), 6.95 (m, 1H), 5.06 (bs, 1H), 4.18 (m, [1H),] 2.98 (m, 2H), 2.61 (m, 2H), 1.39 (s, 9H).
With water;silver benzoate; In 1,4-dioxane; for 2h;Sonographic reaction; Step D. (3R)-3-r (1, 1-Dimethyletycarbonyl) aminol-4(2, 4, 5- trifluorophenyl)-butanoic acid; To a solution of 0.37 g (1.16 mmol) of (R)-N-(l, l- dimethylethoxycarbonyl) -2,4, 5-trifluorophenylalanine in 10 mL of diethyl ether at-20 C were added sequentially 0.193 mL (1.3 mmol) of triethylamine and 0.18 mL (1.3 mmol) of isobutyl chloroformate, and the reaction was stirred at this temperature for 15 min. A cooled ethereal solution of diazomethane was then added until the yellow color persisted and stirring was continued for a further 1 h. The excess diazomethane was quenched by dropwise addition of acetic acid, and the reaction was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (silica gel, 3: 1 hexane: ethyl acetate) afforded 0.36 g of diazoketone. To a solution of 0.35 g (1.15 mmol) of the diazoketone dissolved in 12 mL of 1,4-dioxane : water (5: 1) was added 26 mg (0.113 mmol) of silver benzoate. The resultant solution was sonicated for 2 h before diluting with ethyl acetate and washing sequentially with 1N hydrochloric acid and brine, drying over magnesium sulfate and concentrating in vacuo. Purification by flash chromatography (silica gel, 97: 2: 1 dichloromethane: methanol: acetic acid) afforded 401 mg of the title compound. 1H NMR (500 MHz, CDC13) 6 7.06 (m, 1H), 6.95 (m, 1H), 5.06 (bs, 1H), 4.18 (m, 1H), 2.98 (m, 2H), 2.61 (m, 2H), 1.39 (s, 9H).
To a solution of 0.37 g (1.16 mmol) of (R)-N-(TERT-BUTOXYCARBONYL)-2, 4,5- trifluorophenylalanine in 10 ML of diethyl ether at-20 C were added sequentially 0.193 mL (1.3 mmol) of triethylamine and 0.18 mL (1.3 mmol) of isobutyl CHLOROFORMATE, and the reaction was stirred at this temperature for 15 min. A cooled ethereal solution of diazomethane was then added until the yellow color persisted and stirring was continued for a further 1 h. The excess diazomethane was quenched by dropwise addition of acetic acid, and the reaction was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (silica gel, 3: 1 hexane: ethyl acetate) afforded 0.36 g of diazoketone. To a solution of 0.35 g (1.15 mmol) of the diazoketone dissolved in 12 mL of 1,4-dioxane : water (5: 1) was added 26 mg (0.113 mmol) of silver benzoate. The resultant solution was sonicated for 2 h before diluting with ethyl acetate and washing sequentially with 1N hydrochloric acid and brine, drying over magnesium sulfate and concentrating in vacuo. Purification by flash chromatography (silica gel, 97: 2: 1 dichloromethane: methanol: acetic acid) afforded the title compound. 1H NMR (500 MHz, CDC13) : 8 7.06 (m, 1H), 6.95 (m, 1H), 5.06 (bs, 1H), 4.18 (m, 1H), 2.98 (m, 2H), 2.61 (m, 2H), 1.39 (s, 9H).

  • 3
  • [ 936630-57-8 ]
  • [ 24424-99-5 ]
  • [ 486460-00-8 ]
YieldReaction ConditionsOperation in experiment
91% With sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃; for 24h; Under stirring at room temperature,To a solution of 300 mL of a mixed solvent of 300 mL of tetrahydrofuran and water (vTHF: v H2O = 1: 1)Three reaction bottles,The compound (66.7 g, 0.2 mol, 1 eq) prepared in Example 4, Boc2O (52.4 g, 0.24 mol, 1.2 eq)NaHCO3 (20.2 g, 0.24 mol, 1.2 eq),The reaction was carried out at room temperature for 24h, and the reaction was monitored by TLC.After the reaction is completed,Add 3M diluted hydrochloric acid solution, adjust Ph to 2-3, the aqueous phase was extracted three times with ethyl acetate,The combined organic phases were dried over anhydrous sodium sulfate, Remove most of the solvent,Recrystallization from ethyl acetate n-hexane gave a white solid in 91% yield.
85% With triethylamine; In dichloromethane; at 20℃; for 3h; (R) -3-amino-4- (2,4,5-trifluorophenyl) butyric acid (SM1, 46.6 g, 0.20 mol)Was added to 500 ml of dichloromethane,Further, di-tert-butyl dicarbonate (Boc anhydride, 43.65 g, 0.2 mol) and triethylamine (60.71 g, 0.60 mol)The reaction was stirred at room temperature for 3 hours.System by adding 100ml 5% dilute hydrochloric acid washing,The organic layer was washed with water, separated, and the organic layer was washed with saturated brine,Dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated to dryness,Crystallization of 200 ml of n-hexane gave a white solid(I.e., Compound II, 56.7 g, 85%).
81.7% With triethylamine; In dichloromethane; at 20℃; for 10h; To a solution of 3 g <strong>[936630-57-8](R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid</strong> in 200 ml dichloromethane was added 3.5 di-t-butyl dicarbonate and 2 g triethylamine. The reaction was carried out at 20 C. for 10 h. After completion of the reaction, the solid was filtered off. The filtrate was neutralized with 10% diluted aqueous hydrochloride acid solution. The solution was concentrated, followed by purification by column chromatography. The column was eluted with ethyl acetate/n-hexane (½) to obtain 3.5 g (R)-N-(tert-butoxycarbonyl)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid, with a yield of 81.7%.
81.7% With triethylamine; In dichloromethane; at 20℃; for 10h; To a solution of 3g <strong>[936630-57-8](R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid</strong> in 200ml dichloromethane was added 3.5 di-t-butyl dicarbonate and 2 g triethylamine. The reaction was carried out at 20 C for 10h. After completion of the reaction, the solid was filtered off. The filtrate was neutralized with 10% diluted aqueous hydrochloride acid solution. The solution was concentrated, followed by purification by column chromatography. The column was eluted with ethyl acetate/n-hexane (1/2) to obtain 3.5g (R)-N-(tert-butoxycarbonyl)-3-amino-4-(2,4,5-trifluorophenyl), with a yield of 81.7%.
81.7% With triethylamine; In dichloromethane; at 20℃; for 10h; Preparation method of BOC-<strong>[936630-57-8](R)-<strong>[936630-57-8]3-amino-4-(2,4,5-trifluorophenyl)butyric acid</strong></strong>:3 g of <strong>[936630-57-8](R)-<strong>[936630-57-8]3-amino-4-(2,4,5-trifluorophenyl)butyric acid</strong></strong> was dissolved in 200 ml of dichloromethane.Add 3.5 g of di-tert-butyl dicarbonate and 2 g of triethylamine.The reaction was carried out at 20 C for 10 hours.After the reaction is completed, the solid is filtered off.The filtrate was adjusted to pH 1-2 with 10% dilute aqueous hydrochloric acid solution.After concentration, 3.5(R)-N-(tert-butoxycarbonyl)-3-amino-4-(2,4,5-trifluorophenyl) is obtained.The yield is 81.7%.The purity is about 99.82%,The liquid phase spectrum is shown in Figure 4.20 g of BOC-<strong>[936630-57-8](R)-<strong>[936630-57-8]3-amino-4-(2,4,5-trifluorophenyl)butyric acid</strong></strong> obtained in Example 4,Separated by a silica gel column,(n-hexane: ethyl acetate = 3:1),During the elution process,Constant point control,The eluent was collected when only the condensation impurity spots appeared.Point board control,When the condensation impurity spot disappears or other impurity spots appear, the collection of the eluate is stopped.Concentrate the eluent to dryness,After drying, a white solid was obtained.The liquid phase detection spectrum is shown in Figure 1.
60.6% In tetrahydrofuran; In a 50ml single-necked flask,5.5 ml of a 1.83 M aqueous solution of isopropylamine (rhoEta = 8.5) 2.5 ml of crude transaminase solution (ImM / L of pyridoxal phosphate PLP), 2 ml of 500 mM solution of 3-oxo-3- (2,4,5-trifluorophenyl) Hydroxyethyl butyrate in DMSO were added, the reaction mixture was stirred at 45 C for 24 hours. Lithium hydroxide was added and the pH of the resulting solution was adjusted to pH> 10. Isopropylamine was distilled off under reduced pressure. Then, 427 mg of Boc anhydride (Boc) 2O and 3 ml of tetrahydrofuran were added and allowed to react overnight, extraction was carried out with 10 mL of ethyl acetate, extraction was performed twice, the extracts were combined, dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation and evaporated under reduced pressure to give 200 mg of Boc- (R) -<strong>[936630-57-8]3-amino-4-(2,4,5-trifluorophenyl)butyric acid</strong> in 60.6% yield, purity> 96% and optical purity> 98.6%.
With sodium hydrogencarbonate; In methanol; at 0 - 20℃; for 6h; 1.31 g of (R)-t-butyl 3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoate, 16 mL of methylene chloride, and 16 mL of trifluoroacetic acid were added to 100 mL flask and the resulting reaction solution was stirred for 6 hours. After completing the reaction, the reaction solution was concentrated under reduced pressure and 16 mL of methanol was added to the concentrated residue. The reaction solution was cooled to 0 C., 2.82 g of sodium hydrogen carbonate and 0.77 mL of di-t-butyl dicarbonate were added, and then stirred for 6 hours while the reaction temperature was naturally increased to room temperature. After completing the reaction, the reaction solution was concentrated under reduced pressure; then 30 mL of ethyl acetate and 30 mL of water were added; and then stirred for 10 minutes. An aqueous layer was isolated, cooled to 0 C., and then 2 N hydrochloric acid aqueous solution was dropped to adjust to pH 3-4. The aqueous layer was extracted with methylene chloride:methanol=10:1 solvent, dehydrated with magnesium sulfate, and then concentrated under reduced pressure to obtain 828 mg of a title compound. 1H NMR (CDCl3, 400 MHz) delta 7.04 (m, 1H), 6.89 (m, 1H), 6.08 (br, 1H), 5.04 (br, 1H), 4.13 (br, 1H), 2.88 (br, 2H), 2.62 (m, 2H), 1.36 (s, 18H) Mass (M+Na): 356
30 g With sodium carbonate; In tetrahydrofuran; water; at 25 - 30℃; (R) - 3-amino-4 - (2, 4, 5-trifluorophenyl) butanoic acid benzyl ester (32g) dissolved in methanol (300 ml) in, under the protection of nitrogen by adding 7% Pd-C (3.2g), a system is replaced by a hydrogen atmosphere, 25-30 C lower normal pressure reaction 12-16 hours. After the reaction, filtration, the cake is washed with a small amount of methanol, the filtrate concentrated under reduced pressure to obtain white solid. The resultant white solid is dispersed in tetrahydrofuran (300 ml) in, to add a second di-tert-butyl dicarbonate (26g) and saturated sodium carbonate aqueous solution (200 ml), 25-30 C stirring reaction under 6-8 hours. After the reaction, separation, the aqueous phase with ethyl acetate (200 ml) of a re-extraction. Combined with the phase, using saturated aqueous sodium chloride solution (200 ml) washing, drying by anhydrous sodium sulfate, filtered, concentrated under reduced pressure, to obtain white solid 30g, yield 92%. 1 HNMR (400MHz, CDCl 3) delta 1.38 (s, 9H), 2.59 (m, 2H), 2.96 (m, 2H), 4.15 (m, 1H), 5.03 (b, 1H), 6.89-6.93 (m, 1H), 6.97-7.04 (m, 1H).
88.8 g In water; at 20℃; In 500 ml of water,Add 80 grams of R-3-amino-4-(2,4,5-trifluorophenyl)butanoyl-4-hydroisoxazole,Add 27 grams of sodium hydroxide,The temperature was raised to 50 C for 2 hours.Add 90 grams of Boc anhydride to the room temperature after cooling.React at room temperature for 4-5 hours,After the end, acidify to pH=1.5 with hydrochloric acid.Crystallized filtration, washed with water and dried to give 88.8 g.The yield was 96% and the chemical purity was 99.5%.The 1H NMR spectrum of the product is shown in Figure 3.

  • 4
  • [ 99822-50-1 ]
  • [ 486460-00-8 ]
  • [3-oxo-3-(3-oxo-[1,4]diazepan-1-yl)-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid <i>tert</i>-butyl ester [ No CAS ]
  • 5
  • [ 89990-53-4 ]
  • [ 486460-00-8 ]
  • [ 939964-17-7 ]
  • 6
  • [ 881995-73-9 ]
  • [ 486460-00-8 ]
YieldReaction ConditionsOperation in experiment
95.1% With lithium hydroxide monohydrate; water; In tetrahydrofuran; for 16h; To a solution of (R) -Methyl-3- [N- (tert- butoxycarbonyl) amino] -4- ( 2, 4, 5 -tri-fluorophenyl) butanoate of Example 4 (1.28 g, 3.69 mmol) in 15 mL THF and 15 mL water was added 3 equiv. LiOH-H2O. The reaction mixture was stirred for 16 h. 10 ml saturated NaHCO3 was added. THF was evaporated and the aq solution was acidified to pH 2-3 with NaHSO4, then extracted by ethyl acetate (3 X 15 mL) . The combined organic phase was washed with brine and dried over Na2SO4. Concentration in vacuo afforded 1.17 g of white solid (95.1%) . 1H NMR (300 MHz, CD3OD) 7.13-7.03 (m, 2H), 4.20-4.10 (m, IH), 3.00-2.90 (m, IH), 2.75-2.60 (m, IH), 2.45-2.55 (m, 2H), 1.35 (s, 9H)
95% This example illustrates step 6 of the process of the invention, hydrolisys of the methyl-ester group of the carbamate obtained in example 5, producing (R)-3-(Tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid, compound (VIII) with R = tert-butyl. [Show Image] Lithium hydroxide (144 mg, 6.0 mmol) and water (3.0 mL) are added to a solution obtained by dissolving 400 mg (1.15 mmol) of (R)-methyl-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoate in MeOH (10 mL). The mixture is stirred at room temperature for 24 hours monitornig by TLC (hexane-AcOEt 8 : 2) When the ester is completely hydrolized, methanol is removed under reduced pressure and the residue is taken up in AcOEt (20 mL) and 1 N HCl is added (5 mL). The phases are separated and the organic layer is washed with brine (5 mL), dried over sodium sulfate and concentrated to a residue, affording the title product as a pale yellow solid (364 mg, 95%) 1H NMR (400 MHz, CDCl3) delta: 7.13-7.03 (m, 1 H), 6.98-6.88 (m, 1 H), 5.09 (d, J=8.3Hz, 1 H), 4.25-4.04 (m, 1 H), 2.98-2.83 (m, 2H), 2.72-2.45 (m, 2H), 1.40 (s, 9H).
94% With lithium hydroxide monohydrate; In methanol; water; at 30 - 40℃; To a 2 L three-necked flask was added methyl (R)-beta-tert-butoxycarbonylamino-2,4,5-trifluorophenylbutanoate (347.1 g, 1.00 mol).Methanol (1.0L),Hot water bath,Stir,System clarification.Then add LiOH·H 2 O (50.2 g, 1.20 mol) of deionized water (1.0 L),There are a lot of white solids,Stirring reaction at 30 C - 40 C,After about 3-5 hours,System clarification,TLC monitors the reaction,The reaction is completed,Rotate most of the methanol,Dichloromethane was added to the concentrate, and the pH was adjusted to about 2 with 2N HCl.The organic phase was dried to give a white solid (313.4 g, yield: 94%, e.e.% = 98.8%).
93.3% With lithium hydroxide; In tetrahydrofuran; water; at 15 - 25℃; To 4-neck flask compound 3.5g into 7,30ml tetrahydrofuran, with stirring, 3N aqueous lithium hydroxide solution was added dropwise 6ml, dropwise, stirred incubated at 15 ~ 25 10 ~ 16h, PH adjusted to 2.0 with citric acid to 3.0, transfer completion, separated and the aqueous layer was extracted with 30ml of ethyl acetate, the combined organic phases were washed with 20ml saturated brine, dried over sodium sulfate. Filtered and concentrated to dryness to give crude compound 8, purified through the column to obtain 3.1g, Yield: 93.3%, HPLC purity 99.8%, ee value ?99%.
92% Example 9 Preparation of (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)n-butyric acid To a clean flask, 34.73 g (R)-methyl 3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butyrate, 100 ml toluene, 160 ml water and 4.8 g sodium hydroxide were added. The mixture was warmed to 60 C. and kept at this temperature for 3 hours. 4.73 g hydrochloric acid was added dropwisely. After completion, the resulting mixture was kept at 20-30 C. for 2 hours and filtrated to obtain 30.66 g (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)n-butyric acid (yield: 92%).
92% To a clean flask, 34.73g (R)-methyl 3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butyrate, 100ml toluene, 160ml water and 4.8g sodium hydroxide were added. The mixture was warmed to 60C and kept at this temperature for 3 hours. 4.73g hydrochloric acid was added dropwisely. After completion, the resulting mixture was kept at 20-30C for 2 hours and filtrated to obtain 30.66g (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl) n-butyric acid (yield: 92%).
ExampIe-7: Preparation of (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifIuoro phenyl)butanoic acid compound of formula-9a.; To 12 gms of mandelic acid salt of compound of formula- 15a added 50 ml of water. Basified it using aqueous sodium carbonate solution. Extracted the reaction mixture using methylene chloride. Distilled off the solvent completely under reduced pressure. Added 40 ml of tetrahydrofuran and 40 ml of water to the obtained compound. Added lithium hydroxide (2.0 gms) to the reaction mixture. Cooled the reaction mixture to 0-50C, added di-tert-butyldicarbonate (8.0 gms) slowly to it and stirred for 90 minutes at the same temperature. Raised the temperature to 25C and added ethyl acetate (50 ml) and water (40 ml). Stirred the reaction mixture for 15 minutes. Separated the both aqueous and organic layers. Extracted the aqueous layer with ethyl acetate. Distilled off the solvent completely under reduced pressure. Added 55 ml of tetrahydrofuran and 55 ml of water to the obtained compound. Added lithium hydroxide(10 gms) to the reaction mixture and stirred for 4 hours at 25-30C temperature. Acidify the reaction mixture using cone, hydrochloric acid and extracted the compound using ethyl acetate. Distilled off the solvent completely under reduced pressure. Added n-heptane (120 ml) to the obtained compound and cooled the reaction mixture to 0-5C. Stirred the reaction mixture for 45 minutes at same temperature and filtered the precipitated solid. Dried the material to get the title compound. Yield: 10 gms.
With water; lithium hydroxide; In tetrahydrofuran; at 0 - 20℃; for 6h; 53 mg of (R)-methyl 3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoate, 1.5 mL of tetrahydrofuran, and 0.5 mL of water were added to 25 mL flask and the resulting reaction solution was cooled to 0 C. 7.32 mg of lithium hydroxide was added to the reaction solution and stirred for 6 hours while the reaction temperature was naturally increased to room temperature. After completing the reaction, 5 mL of ethyl acetate and 5 mL of water were added to the reaction solution and stirred for 10 minutes. An aqueous layer was isolated, cooled at 0 C., and 2 N hydrochloric acid aqueous solution was dropped to adjust to pH 3-4. The aqueous layer was extracted with methylene chloride:methanol=10:1 solvent, dehydrated with magnesium sulfate, and then concentrated under reduced pressure to obtain 40.8 mg of a title compound. 1H NMR (CDCl3, 400 MHz) delta 7.04 (m, 1H), 6.89 (m, 1H), 6.08 (br, 1H), 5.04 (br, 1H), 4.13 (br, 1H), 2.88 (br, 2H), 2.62 (m, 2H), 1.36 (s, 18H) Mass (M+Na): 356

  • 8
  • [ 209995-38-0 ]
  • [ 486460-00-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: 95 percent / N,N-dimethylaminopyridine; N,N-diisopropylethylamine; trimethylacetylchloride / acetonitrile / 3 h / 45 °C 2: 88.7 percent / toluene / 3 h / Heating 3: 95 percent / ammonium acetate / methanol / 7 h / Heating 4: 68 percent / H2; (R) chiral ferrocenyl derivative / chloro(1,5-cyclooctadiene)rhodium(I) dimer / 2,2,2-trifluoro-ethanol / 40 h / 50 °C / 5171.62 Torr 5: 93 percent / CH2Cl2 / 3 h / 20 °C 6: 99 percent / aq. LiOH / tetrahydrofuran; methanol / 3 h / 20 °C
Multi-step reaction with 6 steps 1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 3 h / 50 °C 2.1: ethanol / 3 h / 70 °C 3.1: formic acid / ethanol / 3 h / Reflux 3.2: 2 h / 40 °C / Reflux 4.1: methanol / Reflux 5.1: sodium carbonate / water; methanol / 3 h / 30 °C / pH 10 6.1: sodium hydroxide; water / methanol / 2 h / 40 - 45 °C 6.2: pH 3 / Acidic conditions
Multi-step reaction with 8 steps 1.1: 1,1'-carbonyldiimidazole 1.2: 3 h / 50 °C 2.1: 3 h / 70 °C 3.1: ethanol / 3 h / Reflux 4.1: ethanol; sodium cyanoborohydride / 2 h / 40 °C / Reflux 5.1: methanol / Reflux 6.1: Basic conditions 7.1: sodium carbonate / water; methanol / 3 h / 30 °C / pH 10 8.1: sodium hydroxide / water; methanol / 2 h / 40 - 45 °C 8.2: pH 3
Multi-step reaction with 5 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dmap / dichloromethane / 36 h / 20 °C / Cooling with ice 2.1: ethanol / ethanol / 12 h / 70 °C 3.1: ammonium acetate / methanol / 3 h / Reflux 4.1: hydrogen / chloro(1,5-cyclooctadiene)rhodium(I) dimer; (R)-1-[(S)-2-(diphenyl phosphino)ferrocenyl]-ethyl-tert-butylphosphine / water; methanol / 24 h / 30 °C / 5069.54 Torr 5.1: sodium hydroxide; water / methanol / 1.5 h / 40 - 45 °C 5.2: pH 2 - 3
Multi-step reaction with 5 steps 1.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / 36 h / 20 °C / Cooling with ice 2.1: 12 h / 70 °C 3.1: ammonium acetate / hexane; methanol / 3 h / Reflux 4.1: hydrogen / chloro(1,5-cyclooctadiene)rhodium(I) dimer; (R)-1-[(SP)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine / methanol / 24 h / 30 °C / 5069.54 Torr 5.1: sodium hydroxide; water / methanol / 40 - 45 °C 5.2: pH 2 - 3 / Cooling with ice
Multi-step reaction with 8 steps 1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 25 - 30 °C 1.2: 6 h / 50 - 55 °C 2.1: 60 - 63 °C 3.1: ammonium acetate / methanol / 60 - 63 °C 4.1: sulfuric acid / methanol / -10 - 0 °C 4.2: 2 h / -10 - 0 °C 4.3: pH 8 - 9 5.1: isopropyl alcohol / 3 h / 25 - 30 °C 6.1: sodium carbonate / water / pH 8 - 9 7.1: water; lithium hydroxide / tetrahydrofuran / 0 - 30 °C 8.1: water; tetrahydrofuran / 6 h / 25 - 30 °C 8.2: pH 2
Multi-step reaction with 3 steps 1.1: dmap; N-ethyl-N,N-diisopropylamine; pivaloyl chloride / acetonitrile / 20 - 45 °C 1.2: 0.5 h / 0 °C 2.1: 3 h / 100 °C 3.1: water; recombinant aminotransferase from Arthobacter sp.; pyridoxal 5'-phosphate; isopropylamine / dimethyl sulfoxide / 24 h / 45 °C / Green chemistry; Enzymatic reaction 3.2: 3 h / 45 °C / Green chemistry 3.3: 35 °C / Green chemistry
Multi-step reaction with 5 steps 1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 36 h / Cooling with ice 2: 12 h / 70 °C 3: ammonium acetate / methanol / Reflux 4: hydrogen; chloro(1,5-cyclooctadiene)rhodium(I) dimer; (R)-1-[(S)-2-(diphenylphosphine)ferrocenyl]ethyl-tertiary butyl phosphine / methanol / 24 h / 30 °C / 5069.54 Torr / Autoclave 5: sodium hydroxide / methanol; water / 40 - 45 °C
Multi-step reaction with 4 steps 1.1: acetonitrile / 0 - 45 °C / Inert atmosphere 2.1: acetonitrile / 24 h / 80 - 84 °C / Inert atmosphere 3.1: salicylic acid; ammonium acetate; Ru(OAc)2((R)-dm-Segphos); hydrogen / 20 h / 40 - 80 °C / Green chemistry 4.1: triethylamine / ethyl acetate / 7 h / 20 - 30 °C 4.2: 2 h / 20 - 30 °C
Multi-step reaction with 5 steps 1.1: pivaloyl chloride; dmap; N-ethyl-N,N-diisopropylamine / acetonitrile / 0.75 h / 20 °C / Cooling with ice 1.2: 45 °C 2.1: acetonitrile / 65 °C 3.1: sodium tetrahydroborate; ethanol / 65 °C / Cooling with ice 4.1: hydrogenchloride / methanol / 20 °C / pH 1 5.1: sodium hydrogencarbonate / tetrahydrofuran; water / 24 h / 20 °C
Multi-step reaction with 5 steps 1: triethylamine / N,N-dimethyl acetamide / 5 h / 35 °C 2: sodium hydroxide / tetralin / 0.33 h / 100 °C 3: propan-2-amine hydrochloride; pyridoxal 5'-phosphate; triethylamine / water; methanol / 12 h / 40 °C / pH 8 4: sodium hydroxide; water / 3 h / 60 °C 5: water / 20 °C
Multi-step reaction with 5 steps 1: triethylamine / N,N-dimethyl acetamide / 5 h / 35 °C 2: sodium hydroxide / toluene / 0.5 h / 101 °C 3: propan-2-amine hydrochloride; pyridoxal 5'-phosphate; triethylamine / water; methanol / 12 h / 45 °C / pH 8.5 4: sodium hydroxide; water / 2 h / 50 °C 5: water / 20 °C
Multi-step reaction with 5 steps 1.1: 1,1'-carbonyldiimidazole / acetonitrile / 3 h / 25 - 30 °C 2.1: triethylamine; magnesium chloride / acetonitrile / 2 h / 50 °C / Inert atmosphere 2.2: 16 h / 0 - 25 °C 3.1: triethylamine; pyridoxal 5'-phosphate / water; hydrogenchloride; dimethyl sulfoxide / 6 h / 45 °C / liquid HCl 4.1: lithium hydroxide / water / 16 h / 95 °C 5.1: sodium hydroxide / water / 25 - 30 °C
Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 0.5 h / 10 - 35 °C 2.1: triethylamine; magnesium chloride / acetonitrile / 2 h / 50 °C / Inert atmosphere 2.2: 16 h / 0 - 25 °C 3.1: triethylamine; pyridoxal 5'-phosphate / water; hydrogenchloride; dimethyl sulfoxide / 6 h / 45 °C / liquid HCl 4.1: lithium hydroxide / water / 16 h / 95 °C 5.1: sodium hydroxide / water / 25 - 30 °C
Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 10 - 35 °C 2.1: triethylamine; magnesium chloride / acetonitrile / 2 h / 50 °C / Inert atmosphere 2.2: 16 h / 0 - 25 °C 3.1: triethylamine; pyridoxal 5'-phosphate / water; hydrogenchloride; dimethyl sulfoxide / 6 h / 45 °C / liquid HCl 4.1: lithium hydroxide / water / 16 h / 95 °C 5.1: sodium hydroxide / water / 25 - 30 °C
Multi-step reaction with 5 steps 1.1: oxalyl dichloride / dichloromethane / 6 h / 40 °C / Inert atmosphere 2.1: triethylamine; magnesium chloride / acetonitrile / 3 h / 10 - 25 °C / Inert atmosphere 2.2: 16 h / 0 - 25 °C 3.1: triethylamine; pyridoxal 5'-phosphate / water; hydrogenchloride; dimethyl sulfoxide / 6 h / 45 °C / liquid HCl 4.1: lithium hydroxide / water / 16 h / 95 °C 5.1: sodium hydroxide / water / 25 - 30 °C
Multi-step reaction with 6 steps 1.1: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 6 h / 40 °C / Inert atmosphere 2.1: triethylamine; magnesium chloride / dichloromethane / 3 h / 10 - 25 °C / Inert atmosphere 2.2: 16.5 h / -3 - 20 °C / Inert atmosphere 3.1: hydrogenchloride / ethanol; water / 16 h / 20 °C 4.1: triethylamine; hydrogenchloride; pyridoxal 5'-phosphate / dimethyl sulfoxide / 6 h / 45 °C 5.1: lithium hydroxide / water / 16 h / 95 °C 6.1: sodium hydroxide / water / 25 - 30 °C
Multi-step reaction with 6 steps 1.1: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 6 h / 40 °C / Inert atmosphere 2.1: magnesium chloride / acetonitrile / 1 h / 40 °C / Inert atmosphere 2.2: 1 h / 15 - 25 °C / Inert atmosphere 2.3: 16 h / 0 - 25 °C 3.1: sodium hydroxide; water / methanol / 16 h / Reflux 4.1: triethylamine; hydrogenchloride; pyridoxal 5'-phosphate / dimethyl sulfoxide / 6 h / 45 °C 5.1: lithium hydroxide / water / 16 h / 95 °C 6.1: sodium hydroxide / water / 25 - 30 °C
Multi-step reaction with 6 steps 1.1: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 6 h / 40 °C / Inert atmosphere 2.1: magnesium chloride / acetonitrile / 1 h / 40 °C / Inert atmosphere 2.2: 1 h / 15 - 25 °C / Inert atmosphere 2.3: 16 h / 0 - 25 °C / Inert atmosphere 3.1: trifluoroacetic acid / dichloromethane / 4 h / Reflux 4.1: triethylamine; hydrogenchloride; pyridoxal 5'-phosphate / dimethyl sulfoxide / 6 h / 45 °C 5.1: lithium hydroxide / water / 16 h / 95 °C 6.1: sodium hydroxide / water / 25 - 30 °C
Multi-step reaction with 5 steps 1.1: dimethylsulfide borane complex / diethyl ether / 1 h / 0 - 20 °C 2.1: potassium bromide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hypochlorite; sodium hydrogencarbonate / dichloromethane; water / 1 h / 0 °C 3.1: pyridinium p-toluenesulfonate; magnesium sulfate / dichloromethane / 4 h / 20 °C 4.1: potassium carbonate; sodium iodide / 4 h / 20 °C 5.1: hydrogenchloride; water / 9 h / Reflux 5.2: 20 °C
Multi-step reaction with 5 steps 1.1: dimethylsulfide borane complex / diethyl ether / 1 h / 0 - 20 °C 2.1: potassium bromide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hypochlorite; sodium hydrogencarbonate / dichloromethane; water / 1 h / 0 °C 3.1: pyridinium p-toluenesulfonate; magnesium sulfate / dichloromethane / 4 h / 20 °C 4.1: potassium carbonate; sodium iodide / 6 h / 0 °C 5.1: hydrogenchloride; water / 18 h / Reflux 5.2: 20 °C / pH 8
Multi-step reaction with 5 steps 1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 3 h / 0 - 20 °C 1.2: 16 h / 20 °C 2.1: 4 h / 60 °C 2.2: 10 h / 60 °C 3.1: pyridine / tetrahydrofuran / 20 h / Reflux 4.1: hydrogen; bis(norbornadiene)rhodium(l)tetrafluoroborate; MeO-BIBOP / methanol / 36 h / 20 °C / 7500.75 Torr 5.1: hydrogenchloride / water / Reflux 5.2: 5 h / 20 °C / pH > 13.5

Reference: [1]Ahn, Jin Hee; Shin, Mi Sik; Jun, Mi Ae; Jung, Sun Ho; Kang, Seung Kyu; Kim, Kwang Rok; Rhee, Sang Dal; Kang, Nam Sook; Kim, Sun Young; Sohn, Sang-Kwon; Kim, Sung Gyu; Jin, Mi Sun; Lee, Jie Oh; Cheon, Hyae Gyeong; Kim, Sung Soo [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 9, p. 2622 - 2628]
[2]Current Patent Assignee: JIANGSU HENGRUI MEDICINE CO., LTD. - EP2308829, 2011, A1
[3]Current Patent Assignee: JIANGSU HENGRUI MEDICINE CO., LTD. - US2011/130587, 2011, A1
[4]Current Patent Assignee: JIANGSU HENGRUI MEDICINE CO., LTD. - EP2404921, 2012, A1
[5]Current Patent Assignee: JIANGSU HENGRUI MEDICINE CO., LTD. - US2012/65209, 2012, A1
[6]Current Patent Assignee: VIATRIS INC - US2012/108598, 2012, A1
[7]Hou, Anwei; Deng, Zixin; Ma, Hongmin; Liu, Tiangang [Tetrahedron, 2016, vol. 72, # 31, p. 4660 - 4664]
[8]Current Patent Assignee: JIANGSU HENGRUI MEDICINE CO., LTD. - TWI522358, 2016, B
[9]Current Patent Assignee: ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD. - CN105566138, 2016, A
[10]Current Patent Assignee: AMATEK SCIENT - CN107501112, 2017, A
[11]Current Patent Assignee: NANJING REDWOOD FINE CHEMICAL; CHINA FORTUNE WAY - CN108586346, 2018, A
[12]Current Patent Assignee: NANJING REDWOOD FINE CHEMICAL; CHINA FORTUNE WAY - CN108586346, 2018, A
[13]Current Patent Assignee: ABIOCHEM BIOTECHNOLOGY CO LTD - CN111039900, 2020, A
[14]Current Patent Assignee: ABIOCHEM BIOTECHNOLOGY CO LTD - CN111039900, 2020, A
[15]Current Patent Assignee: ABIOCHEM BIOTECHNOLOGY CO LTD - CN111039900, 2020, A
[16]Current Patent Assignee: ABIOCHEM BIOTECHNOLOGY CO LTD - CN111039900, 2020, A
[17]Current Patent Assignee: ABIOCHEM BIOTECHNOLOGY CO LTD - CN111039901, 2020, A
[18]Current Patent Assignee: ABIOCHEM BIOTECHNOLOGY CO LTD - CN111039901, 2020, A
[19]Current Patent Assignee: ABIOCHEM BIOTECHNOLOGY CO LTD - CN111039901, 2020, A
[20]Current Patent Assignee: CHONG KUN DANG PHARMACEUTICAL CORP. - KR2016/8873, 2016, A
[21]Current Patent Assignee: CHONG KUN DANG PHARMACEUTICAL CORP. - KR2016/8873, 2016, A
[22]Current Patent Assignee: ZHEJIANG MEDICINE CO., LTD. - CN113636950, 2021, A
  • 10
  • [ 157911-56-3 ]
  • [ 486460-00-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: n-BuLi / tetrahydrofuran / -78 °C 1.2: tetrahydrofuran / -78 °C 2.1: aq. HCl / acetonitrile / 72 h / 20 °C 2.2: 2.41 g / triethylamine / CH2Cl2 / 16 h / 20 °C 3.1: aq. LiOH / tetrahydrofuran / 20 °C 4.1: isobutyl chloroformate; triethylamine / diethyl ether / 0.25 h / -20 °C 4.2: 0.36 g / diethyl ether / 1 h 5.1: 401 mg / aq. silver benzoate / dioxane / 2 h / 20 °C / sonication
Multi-step reaction with 4 steps 1.1: magnesium / diethyl ether / Inert atmosphere 1.2: 3 h / 0 - 20 °C / Inert atmosphere 2.1: chloro(1,5-cyclooctadiene)rhodium(I) dimer; pyridinium p-toluenesulfonate; (2S)-1-[(1S)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(diphenylphosphino)ferrocene; Benzophenone imine / 1,2-dichloro-ethane / 36 h / 80 °C / Schlenk technique; Inert atmosphere; Sealed tube 2.2: 12 h / 20 °C / Schlenk technique; Inert atmosphere; Sealed tube 3.1: dichloro bis(acetonitrile) palladium(II); p-benzoquinone / <i>tert</i>-butyl alcohol / 18 h / 20 °C / Inert atmosphere 4.1: sodium dihydrogenphosphate; sodium chlorite; water; 2-methyl-but-2-ene / <i>tert</i>-butyl alcohol; tetrahydrofuran / 2 h / 20 °C / Inert atmosphere
  • 12
  • [ 233278-56-3 ]
  • [ 486460-00-8 ]
  • C20H24F3N5O3 [ No CAS ]
  • 13
  • [ 681249-57-0 ]
  • [ 486460-00-8 ]
  • [ 681249-58-1 ]
  • 14
  • [ 486460-00-8 ]
  • [ 762240-92-6 ]
  • [ 486460-23-5 ]
YieldReaction ConditionsOperation in experiment
96% With triethylamine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In methanol; at 20 - 50℃; (3R)-3-[(l,l-Dimemylethoxycarbonyl)ammo]-4-(2,4,5-trifluorophenyl)butanoic acid (10 g) is mixed with 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (10 g) in methanol (100 ml) at the laboratory temperature. 3-(Trifluoromethyl)-5,6,7,8-tetrahydro- [l,2,4]triazolo[4,3-a]pyrazine hydrochloride (7 g) is added to the resulting solution and triethylamine (4.7 ml) is added to the stirred suspension. During 2-3 minutes a solution is obtained that is further stirred at the laboratory temperature. After approximately 1 hour, white suspension of the product starts to separate. The reaction mixture is heated up to 50C and distilled water (35 ml) is added to the resulting solution and the reaction mixture is cooled down to 15C under stirring during 2 h. The separated product is filtered off and washed with 15 ml of a methanol/water (2/ 1 ) mixture. After drying the desired product is obtained with the yield of 96% and HPLC quality of >99%. Example 2
95% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In acetonitrile; at 0 - 20℃; for 24h; Into a 50 mL round-bottom flask was added 20 mL acetonitrile, followed by the addition of the phenyl-butyric acid derivative obtained in Example 46 (3.32 g, 0.01 mol) and triazolopyrazine hydrochloride (228 g, 0.01 mol). The temperature of the reaction mixture was cooled down to 0 C. in an ice-salt bath. 1-Hydroxylbenzotriazole (1.62 g, 0.012 mol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.29 g, 0.012 mol) were further added. 3 g Triethylamine was then added dropwise and the mixture was stirred at room temperature for 24 h. The reaction solution was washed with 3 X 20 mL distilled water. The obtained organic layers were collected and dried over anhydrous magnesium sulfate for 1 h. Then, the desiccant was filtered off and the resulting reactant was concentrated to 4.81 g. The yield was 95%. [alpha] D20=+22.2 (c 1.0, CHCl3). M.p. 188-191 C. IR (cm-1): 3374, 2897, 1686, 1635, 1519, 1368, 1164, 1128, 1016. 1H NMR (400 MHz, CDCl3) delta 7.187.05 (m, 1H), 7.02-6.85 (m, 1H), 5.31 (s, 1H), 5.154.76 (m, 2H), 4.433.78 (m, 5H), 2.982.92 (m, 2H), 2.712.61 (m, 2H), 1.36 (s, 9H). ESI-MS: 508.0 (M++1). HRMS Calcd. for: C21H23F6N5O3Na (M+Na)+ requires 530.1598, found 530.1604.
95% With 2,6-dimethylpyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 3h; 15 g (45 mmol) of the compound (2) (R) -3- (tert-butoxycarbonylamino) -4- (2,4,5-trifluorophenyl) butyric acid,Compound (3) 3- (Trifluoromethyl) -5,6,7,8-tetrahydro- [1,2,4] triazolo [4,3-a] pyrazine hydrochloride 11.3 g(49.5mmo 1),HOBT 7.3 g (54 mmol) was added to 150 ml of dichloromethane.At room temperature,14.4 g (135 mmol) of 2,6-dimethylpyridine was added,Then add 10.3 g (54 mmol) of EDC-HC1,The mixture was stirred at room temperature for 3 hours.Add 5% sodium carbonate aqueous solution to adjust rhoH- = 9,Layered,The methylene chloride layer was washed with 150 ml of water,Layered,The methylene chloride layer was dried over anhydrous sodium sulfate,filter,The filtrate was evaporated at 35 C under reduced pressure to give 21.7 g of the compound (1)Yield 95%HPLC 94.5%.
94% Example 1: Preparation of tert-butyl (R)-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-alpha]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)-4-oxobutan-2-ylcarbamate (Compound of formula 2 wherein R is Boc) [35] (R)-3-Boc-amino-4-(2,4,5-trifluorophenyl)-butanoic acid (3.0g, 9.0mmol) and tetrahydrofuran (THF, 30ml) were charged and dissolved in a dry flask, and N-methylmorpholine (2.97ml, 27.0mmol) was added thereto. Then, the mixture was cooled to a temperature of 0 to 5C, and 2-chloro-4,6-dimethoxy-1,3,5-triazine (2.05g, 11.7mmol) was added thereto. After being stirred at a temperature of 0 to 5C for one hour, 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-alpha]pyrazine hydrochloride (2.47g, 10.8mmol) was added and the reaction mixture was stirred while elevating to a temperature of 20 to 25C. After the completion of the reaction was confirmed by TLC, the reaction liquid was cooled to 10C, and dichloromethane (30.0ml) and water (30.0ml) were added thereto, followed by separation of layers. The organic layer was washed with saturated sodium bicarbonate (30.0ml) and saline (30.0ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then crystallized from ethyl acetate (12.0ml) and isopropyl alcohol (6.0ml) to afford 4.29g (yield: 94.0%) of tert-butyl (R)-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-alpha]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)-4-oxobutan-2-ylcarbamate.[36] 1H NMR delta 7.04(dd, 1H, J=0.012), 6.84(dd, 1H, J=0.013), 5.01(s, 2H), 4.90(NH), 4.20(s, 2H), 4.10(t, 2H), 4.04(t, 2H), 3.97(m, 1H), 2.97(t, 2H), 2.70(t, 2H),[37] mp: 183.0 to 183.5C (as measured using a capillary melting point apparatus Mettler FP90 at an elevation rate of 2C/min)
94.98% With 2-Chlorobenzeneboronic acid; N-ethyl-N,N-diisopropylamine; In toluene; for 48h;Dean-Stark; Reflux; 25 g of 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl) butyric acid of formula (II) was charged with 200 ml of toluene into a 500 ml 4 necked round bottom flask attached with dean stark apparatus, followed by the addition of 25 ml of Hunig's base at room temperature. Then 25 g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a] pyrazine HCl was charged and stirred for 5 minutes. 11.5 g of 2-chloro phenyl boronic acid was charged to the reaction mass. After 48 hours of stirring at reflux temperature, the reaction was complete. The reaction mass was cooled to room temperature and 250 ml of water was added to it. The organic layer was separated and washed twice with 125 ml of IN HC1. The organic layer was separated and washed with 125 ml of water followed by 6% NaHCO3 and finally by 125 ml of water. The organic layer was then separated and the solvent was distilled out under vacuum. The solid obtained was stirred with 125 ml of diisopropyl ether for 2 hours, filtered and then dried under vacuum at 50C for 12-15 hours. HPLC was used to obtain the chromatographic purity and chiral purity. Weight: 36.15 g (144.6 % w/w, 94.98%)Chromatographic purity: > 99.0%Chiral purity (calculated as [desired enantiomer]/[desired enantiomer + undesired enantiomer] x 100): > 99.5%
92% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 24h; 4.7 (R)-tert-Butyl 4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-ylcarbamate 9 (R)-3-(tert-Butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid 7 (200 mg, 0.59 mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinehydrochloride 8 (115 mg, 0.59 mmol) in anhydrous DCM (3 mL) were cooled to 0 C. To that solution was added HOBT (96 mg, 0.7 mmol), followed by EDC·HCl (134 mg, 0.7 mmol) and DIEPA (152 mg, 1.18 mmol). After being stirred for 24 h, DCM was evaporated, and the viscous residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography eluting with 80% ethyl acetate in hexane to afford 9 as a white powder (280 mg, 92% yield). Mp: 189-192 C; {lit. 8a mp: 188-191 C}; [alpha]D25.1 = +20.8 (c 0.11, CHCl3); {lit. 8a [alpha]D20 = +22.2 (c 1.0, CHCl3)}; 1H NMR (500 MHz, CDCl3) delta 1.35 (s, 9H), 2.93-2.67 (m, 4H), 4.17-3.97 (m, 5H), 4.92 (s, 1H), 5.07-5.00 (m, 1H), 5.28 (s, 1H), 6.88 (s, 1H), 7.08-7.06 (d, J = 6.36 Hz, 1H). 13C NMR (125 MHz, CDCl3) delta 28.2, 32.9, 36.7, 38.0, 39.2, 41.8, 42.6, 43.1, 43.6, 48.2, 48.4, 79.7, 105.2, 105.3, 105.4, 105.5, 117.1, 119.0, 119.1, 121.4, 143.7, 144.0, 145.6, 147.7, 147.9, 149.4, 149.9, 150.2, 155.2, 157.1, 169.5, 169.9; MS (ESI) m/z: 507.9 (M+H)+. HRMS (ESI) (M+H)+: calcd for C21H23F6N5O3: 508.1778; found: 508.1778.
90% With 2,6-dimethylpyridine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; In dichloromethane; at 0 - 20℃; The (R) - 3 - (tert-butoxycarbonylamino) - 4 - (2, 4, 5-trifluorophenyl) butanoic acid (26.6g), 2,6-dimethyl pyridine (18g) and 3 - (trifluoromethyl) - 5, 6, 7, 8-tetrahydro-[ 1, 2, 4] triazolo [4,3-a] pyrazine hydrochloride (17.3g) are sequentially added dichloromethane (300 ml) in, cooling to 0-5C, stirring, add TBTU (28.2g), natural recovery to the room temperature, to continue reaction 8-10 hours. After the reaction, the organic phase for sequentially 1NHCl (200 ml), water (200 ml), 5% sodium carbonate aqueous solution (200 ml), saturated aqueous sodium chloride solution (200 ml) washing, dry anhydrous sodium sulfate, filtered, concentrated under reduced pressure, to obtain white foam solid 36g, yield 90%. 1 HNMR (400MHz, CDCl 3) delta 1.39 (s, 9H), 2.59-2.72 (m, 2H), 2.79-2.96 (m, 2H), 3.96-4.38 (m, 5H), 4.95 (s, 1H), 4.98-5.10 (m, 1H), 5.31 (b, 1H), 6.89-6.93 (m, 1H), 6.97-7.06 (m, 1H).
85% (3R)-3-te/-t-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid (40 g, 0.12 mol) was dissolved in dimethylformamide (DMF)(240 mL) at room temperature while the reaction flask was under N2, then, cooled with ice bath and stirred for 30 minutes. In a different flask, DCC (32.21 g, 0.16 mol) was dissolved in DMF (160 mL) to obtain a 200 mL solution. To the (3R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro- phenyl)-butanoic acid solution was added 70 mL from the DCC solution drop-wise, 3- (trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine hydrochloride (32.94 g, 0.14 mol) and Et3N (24.82 g, 0.24 mol). The reaction was stirred for 10 minutes, then, DMAP was added (8.8 g, 0.07 mol). The reaction was stirred for 2 hours, then, 65 mL of DCC solution was added drop-wise, and after another 1 hour of stirring in an ice bath, the last 65 mL of DCC solution was added drop- wise. The reaction was stirred at room temperature over night. The mixture was filtrated by vacuum filtration and washed with DMF 2X50 mL. The solvent was evaporated and EtOAc was added (1400 mL), the organic phase washed with 90 mL of 5% citric acid, 60 mL of 10% citric acid, and 100 mL of saturated NaHCO3, dried over Na2SO4 and evaporated to yield a beige solid. The product was dissolved in IPA (300 mL) by heating to reflux. When the solution became clear-yellow the solution was cooled to room temperature and stirred over night. The product was isolated by vacuum filtration, washed isopropanol, and dried in a vacuum oven at 4O0C overnight to obtain tert-butyl (R)-4-(3-(trifluoromethyl)-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-l-(2,4,5-trifluorophenyl)-4-oxobutan-2-yl- carbamate (52 g, 85 % yield).
85.9% With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at -5 - 25℃; for 4h;Large scale; N,N-dimethylformamide (96.0 L) to (3R)-3-[N-(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (12.00 kg) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-alpha]pyrazine hydrochloride (9.05 kg) was added, stirring and the temperature was cooled to -5 C to 0 C. N-methylmorpholine (4.01 kg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (8.28 kg) were added, After stirring for 1 hour at -5 C to 0 C and warmed to 20 C to 25 C and stirred for 3 hours. Ethyl acetate (192.0 L) and purified water (96.0 L) were added to the reaction mixture, which was then stirred for 10 minutes. The organic layer was separated, and the separated water layer was extracted with ethyl acetate (48.0 L) once more for 10 minutes to collect the organic layers. The combined organic layer was washed successively with 5% aqueous sodium carbonate solution and washed with a (sodium carbonate: 96.0 L: 4.8 kg, purified water). Dehydrated with anhydrous magnesium sulfate (12.0 kg) for 10 minutes, filtered and washed with ethyl acetate (24.0 L) and concentrated under reduced pressure. cyclohexane (240.0 L) was put into the obtained residue, and it stirred at 70 degreeC-72 degreeC for 5 minutes. After cooling to 20 to 25 stirred for 1 hour, filtered and washed with cyclohexane (36.0 L). Vacuum drying at 40 C to 45 C. the desired compound 7-[(3R)-3-[(N-tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-alpha]pyrazine (15.70 kg, yield : 85.9%) was obtained.
83.37% In a flask (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid (3.0 g, 9.00 mmol) was dissolved in pyridine (6.0 mL, 8.3 mmol).Diphenyl phosphite(DPP; 1.90 mL, 9.90 mmol)The mixture was added dropwise for 10 minutes, and after stirring for 30 minutes at room temperature 3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride(2.26 g, 9.90 mmol), and the reaction solution was stirred at room temperature for 1 hour.After the reaction was completed by TLC, dichloromethane (6 mL) and purified water (6 mL) were added. After stirring at room temperature for 30 minutes, the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate (0.1 g), concentrated under reduced pressure, and then crystallized with isopropyl alcohol (9 mL) to give the title compound (3.81 g, 83.37%)
81% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 30℃; for 13h; 7-[(3R)-3-[N-(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoro-methyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine (12)To a solution of 3-trifluoromethyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (11) (1.0 eq, 28.0 gm), diisopropylethylamine (2.0 eq, 31.0 gm), 1-hydroxybenzotriazole (1.2 eq, 22.0 gm), and EDC-HCl (1.2 eq, 28.0 gm) in N,N-dimethylformamide (4.0 vol, 160.0 ml), a solution of (3R)-3-[N-(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (07) (40.0 gm, 0.12 mol) in N,N-dimethylformamide (4.0 vol, 160.0 ml) was charged at 0-5 C. within 1 hour. The clear pale yellow solution was further stirred for 12 hours at 25-30 C. After stirring for 12 hours, the N,N-dimethylformamide was distilled out completely at 55-65 C. under reduced pressure to give a brown coloured residue. The brown coloured residue was further basified with 10% Na2CO3 solution (1.0 vol, 40.0 ml) and the product was extracted in ethyl acetate (3×10.0 vol, 3×400.0 ml). The combined ethyl acetate layers were washed with water, charcoalized and filtered, and the ethyl acetate was distilled out completely to give a white coloured product. The product was triturated with hexane (10.0 vol, 400.0 ml) and filtered at 25-30 C. The crude Boc-protected sitagliptin free base (12) was further purified by crystallising it from a mixture of isopropanol (20.0 vol) and water (2.0 vol).Molar Yield: 75-81% (56 gm)Chemical Purity: 95-97% (as measured by HPLC)
80% With dmap; triethylamine; dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 20℃; for 24h; Compound II (20 g, 0.06 mol),N, N-dicyclohexylcarbodiimide (DCC, 24.74 g, 0.12 mol)3- (trifluoromethyl) -5,6,7,8-tetrahydro- [1,2,4] triazolo [4,3, alpha] pyrazine hydrochloride (SM2, 13.72 g, 0.06 mol )add to300 ml of N, N-dimethylformamide,Triethylamine (18.21 g, 0.18 mol) was added at room temperature,And N, N-dimethylaminopyridine(0.73 g, 0.006 mol),The reaction was stirred at room temperature for 24 hours.The reaction was filtered and the filtrate was added to 200 ml of dichloromethane and 50 mlWater, and the aqueous layer was extracted three times with 100 ml of methylene chloride. The organic layers were washed with saturated sodium bicarbonate and saturated brine, respectively,The organic layer was dried over anhydrous magnesium sulfate for 1 h, filtered, the filtrate was concentrated to dryness,To give a white solid (i.e., Compound III, 24.36 g, 80%).
75 - 81% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 30℃; for 13h; 7-[(3R)-3-pS[-(tert-butoxycarbonyl)amino]-4-(2.4.5-trifluorophenyl)butanoyl]-3--(trifluoro- methyl)-5.6.7.8-tetrahydro-1.2.4-tria2olo[4.3-a]pyra2ine (12)To a solution of 3-trifluoromemyl-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]pyrazine hydrochloride (11) (1.0 eq, 28.0 gm), diisopropylethylamine (2.0 eq, 31.0 gm), 1- hydroxybenzotriazole (1.2 eq, 22.0 gm), and EDC-HCl (1.2 eq, 28.0 gm) in N5N- dimethylformamide (4.0 vol, 160.0 ml), a solution of (3R)-3-[N-(tert-butoxycarbonyl) amino]-4-(2,4,5-trifiuorophenyl)butanoic acid (07) (40.0 gm, 0.12 mol) in N5N- dimethylformatnide (4.0 vol, 160.0 ml) was charged at 0-5C within 1 hour. The clear pale yellow solution was further stirred for 12 hours at 25-3O0C. After stirring for 12 hours, the N,N-dimethylformamide was distilled out completely at 55-650C under reduced pressure to give a brown coloured residue. The brown coloured residue was further basified with 10% Na2CO3 solution (1.0 vol, 40.0 ml) and the product was extracted in ethyl acetate (3 x 10.0 vol, 3 x 400.0 ml). The combined ethyl acetate layers were washed with water, charcoalized and filtered, and the ethyl acetate was distilled out completely to give a white coloured product. The product was triturated with hexane (10. 0 vol, 400.0 ml) and filtered at 25- 300C. The crude Boc-protected sitagliptin free base (12) was further purified by crystallising it from a mixture of isopropanol (20.0 vol) and water (2.0 vol). Molar Yield: 75-81% (56 gm) Chemical Purity: 95-97% (as measured by HPLC)
With dmap; dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 0 - 25℃; Example-8: Preparation of 7-[(3R)-3-amino-l-oxo-4-(2,4,5-trifluorophenyl) butyl] - 5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazoIo [4.3-a] pyrazine compound of formula- 1.; To 24 ml of dimethylformamide added 4 gms of (R)-3-(tert-butoxycarbonylamino)-4- (2,4,5-trifluorophenyl)butanoic acid and cooled the reaction mixture to 0-5C. 3.3 gms of NjN'-dicyclohexylcarbodiimide (DCC) was dissolved in 10 ml of dimethylformamide and make upto 20 ml. Added 7 ml of above prepared NjN'-dicyclohexylcarbodiimide (DCC) solution to the above 0-5 C cooled reaction mixture. Added 3.15 gms of 3-(trifluoromethyl)-5,6,7,8-tetra hydro-[l,2,4]triazolo[4,3-a]pyrazine hydrochloride and 3.3 ml of triethylamine to the reaction mixture and stirred for 15 minutes. Added 0.9 gms of dimethylaminopyridine (DMAP) and stirred the reaction mixture for 3 hrs at 0-50C. Added 6.5 ml of N,N'-dicyclohexylcarbodiimide solution and stirred for 3 hrs. Again added 6.5 ml of N,N'-dicyclohexylcarbodiimide solution and stirred for 3 hrs at 0-50C. Raised the temperature to 25C and stirred the reaction mixture for 12 hrs at same temperature. The unwanted precipitated solids were separated by filtration and to the filtrate added water and ethyl acetate. Separated the both aqueous and organic layers. Washed the organic layer with 5% hydrochloric acid solution followed by washed with 5% sodium bicarbonate solution. Distilled off the solvent completely under reduced pressure. Added 30 ml of isopropyl alcohol to the obtained compound and stirred for 45 minutes at 25-300C temperature. Filtered the precipitated solid and dried the material. To the obtained compound added 10 ml of isopropyl alcohol and 3.8 ml of cone, hydrochloric acid. Stirred the reaction mixture for 3 hrs at 500C. Cooled the reaction mixture to 25C and added water. Extracted the compound from reaction mixture with methylene chloride. Distilled off the solvent completely to get the title compound. Yield: 2.5 gms.
2.2 g With 1,1'-carbonyldiimidazole; In ethyl acetate; at 50 - 55℃; for 15h; A mixture of Boc acid (1.8 gm, 0.005 moles) from Example 11 and carbomyldiimidazole (1.05 gm, 0.0064 moles) in ethylacetate (20ml) was reacted with 3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]pyrazine hydrochloride (Synthon 2) (1.48 gm, 0.0064 moles) at room temperature. The resulting reaction mass was heated to 50-55C for 15 hrs. After completion of reaction by TLC the reaction mass was quenched with water (18ml) at room temperature and cooled to 10-15C. The precipitated product was collected to give 2.2 gm of product. SOR (1% in methanol) +3.6 Melting point 189-192.8C Chiral purity by HPLC 99.30%
151.9 g With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In water; N,N-dimethyl-formamide; at 0 - 5℃; for 1h; Example-1 Preparation of (R)-tert-butyl 4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl) butan-2-ylcarbamate of Formula (III) In 250 mL three necked round bottom flask equipped with mechanical stirrer, thermometer and an addition funnel, were added 400 mL DMF, 100 g (3R)-N-(tert-butoxycarbonyl)-3-amino-4-(2,4,5-trifluorophenyl) butanoic acid of Formula (V) and 72 g 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo-[4,3-a]pyrazine hydrochloride of Formula (IV). The reaction mixture was cooled to 0 to 5 C. and 106 g TBTU was added. 116.3 g DIPEA was added to the reaction mixture and stirred for 1 hour. After the completion of reaction, 1 L water and 600 mL 1% NaHCO3 was added. The reaction mixture was stirred for 1 hour at 25 C. to 35 C. The precipitates were filtered and washed with water. The product was dried under vacuum at 60 C. for 4 hours to obtain 151.9 g of title compound.
140 g 100 g of 3-tert-butoxycarbonylamino-4-(2,4,5-trif- luorophenyl)butyric acid of formula (II) was charged with 800 ml of toluene into a 2 litre 4 necked round bottom flask attached with dean stark apparatus followed by 70 ml of triethyl amine at room temperature. Then 100 g of 3-(trifluo- romethyl)-5,6,7,8-tetrahydro-[ 1 ,2,4]triazolo[4,3-a]pyrazine HC1 was charged and stirred for 5 minutes. 7.5 g of phenyl boronic acid was charged to the reaction mass. Afier 48 hours of stirring at reflux temperature, the reaction was complete. The reaction mass was cooled to room temperature and 1000 ml of water was added to it. The organic layer was separated and washed twice with 500 ml of iN HC1. The organic layer was separated and washed with 500 ml of water followed by 6% NaHCO3 and finally by 500 ml ofwater. The organic layer was then separated, treated with sodium sulfate and then with charcoal and filtered. The solvent was distilled out under vacuum. The solid obtained was stirred with 500 ml of diisopropyl ether for 2 hours, filtered, washed with diisopropyl ether and then dried under vacuum at 50 C. for 12-15 hours. 10078] HPLC was used to obtain the chromatographic purity and chiral purity.Weight: 140 g (140.0% w/w, 91.95%) Chromatographic purity: >98.0%Chiral purity (calculated as [desired enantiomer]/[desired enantiomer+undesired enantiomer]x 100): >99.5%
151.9 g With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 5℃; for 1h; Preparation-1: Preparation of (R)-tert-butyl 4-oxo-4-(3-(trifluoromethyl)-5,6- dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yI)-l-(2,4,5-trifluorophenyl) butan-2-ylcarbamate (0089) In 2 L three necked round bottom flask equipped with mechanical stirrer, thermometer and an addition funnel, were added 400 mL DMF, 100 g (3i?)-N- (tert-butoxycarbonyl)-3-amino-4-(2,4,5-trifluorophenyl) butanoic acid and 72 g 3- (trifluoromethyl)-5,6,7,8-tetrahydro-l,2,4-triazolo-[4,3-a]pyrazine hydrochloride. The reaction mixture was cooled to 0 to 5C and 106 g TBTU was added. 116.3 g DIPEA was added to the reaction mixture and stirred for 1 hour. After the completion of reaction, 1 L water and 600 mL 1% NaHC03 was added. The reaction mixture was stirred for 1 hour at 25C to 35C. The precipitates were filtered and washed with water. The product was dried under vacuum at 60C for 4 hours to obtain 151.9 g of title compound.
4.81 g With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In acetonitrile; at 0 - 20℃; for 24h; Add 20 mL of acetonitrile to a 50 mL round bottom flask.Add (3R)-3-[(1,1-dimethylethoxycarbonyl)-amino]-4-(2,4,5-trifluorophenyl)butanoic acid (3.32 g, 0.01 mol) and 3 -(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazole[4,3-alpha]piperazine hydrochloride (2.28 g, 0.01 mol),The temperature of the reaction system was cooled to 0 C with an ice salt bath, and 1-hydroxybenzotriazole (HOBT) (1.62 g, 0.012 mol) was added.1-ethyl-3-(3-dimethylaminopropyl)carbimide hydrochloride (EDC·HCl) (2.29 g, 0.012 mol),3 g of triethylamine was added dropwise, and the reaction was stirred at room temperature for 24 hours, and the reaction solution was washed with 3×20 mL of distilled water.The organic layer was dried over anhydrous magnesium sulfate for 1 hour, then filtered and evaporated. The desiccant was filtered off and concentrated to give 4.81 g of product.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0℃; for 24h; In a 250 ml three-necked flask,Add 100 ml of dichloromethane,(3R)-3 tert-Butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butyric acid (VI) (6.6 g, 0.02 mol) and3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (VII) (4.6 g, 0.02 mol) ,Cool to 0 C with an ice salt bath.Add 1-hydroxybenzotriazole (HOBT) (2.7 g, 0.02 mol),1-ethyl-3-(3-dimethylaminopropyl)carbimide hydrochloride (EDC.HCl) (3.82 g, 0.02 mol),Triethylamine (6 g, 0.03 mol) was added dropwise.Reaction for 24h,The reaction solution was washed twice with 50 ml of distilled water.dry,filter,Concentration gave the crude product (9.62 g, 0.019 mol).The yield was 95%.

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[2]Patent: US2013/281695,2013,A1 .Location in patent: Paragraph 0255-0257
[3]Tetrahedron Letters,2013,vol. 54,p. 6807 - 6809
[4]Patent: CN102603749,2017,B .Location in patent: Paragraph 0034-0035
[5]Patent: WO2012/99381,2012,A2 .Location in patent: Page/Page column 4
[6]Patent: WO2014/23930,2014,A1 .Location in patent: Page/Page column 16; 17
[7]Tetrahedron Asymmetry,2014,vol. 25,p. 1026 - 1030
[8]Patent: CN102757431,2016,B .Location in patent: Paragraph 0072-0073
[9]Patent: WO2009/64476,2009,A1 .Location in patent: Page/Page column 17
[10]Patent: KR2019/60235,2019,A .Location in patent: Paragraph 0043-0044
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[19]Patent: US2015/87834,2015,A1 .Location in patent: Paragraph 0108; 0109
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  • 15
  • [ 117009-97-9 ]
  • [ 486460-00-8 ]
  • [ 1006706-47-3 ]
  • 16
  • [ 33305-08-7 ]
  • [ 486460-00-8 ]
  • [ 1041611-83-9 ]
YieldReaction ConditionsOperation in experiment
77% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 12h; 1.1 Step 1: Preparation of methyl 3-[(R)-3-t-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butyryl]-thiazolidine-2-carboxylate; (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid (5.13 g, 15.40 mmol) is dissolved in CH2Cl2. Thereto, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 2.95 g, 15.4 mmol), dimethylaminopyridine (376 mg, 3.00 mmol), methyl thiazolidine-2-carboxylate.HCl (2.82 g, 15.40 mmol) and triethylamine (10.73 ml, 76.96 mmol) are added, followed by stirring for 12 hours at room temperature. The resulting mixture is washed with brine and extracted with CH2Cl2. The entire extracts are dried over MgSO4. The organic layer is concentrated under a reduced pressure and separated by column chromatography (EtOAc:hexane=1:1) to obtain the compound, methyl 3-((R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoyl)thiazolidine-2-carboxylate (5.48 g, 77%) as a white solid.1H NMR (CDCl3, 300 MHz) δ 7.16-7.06 (m, 1H), 6.94-6.85 (m, 1H), 5.59 (d, J=3.3 Hz, 1H), 4.13-4.10 (m, 1H), 3.95-3.92 (m, 1H), 3.79 (s, 3H), 3.77-3.72 (m, 1H), 3.37-3.34 (m, 1H), 3.11-3.09 (m, 1H), 2.94-2.92 (m, 2H), 2.65-2.60 (m, 2H), 1.37 (s, 9H); LC-MS m/z (relative intensity) 463 (MH+).
  • 17
  • [ 1041676-35-0 ]
  • [ 486460-00-8 ]
  • [ 1041612-08-1 ]
YieldReaction ConditionsOperation in experiment
70% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 12h; Step 2: Preparation of (S)-ethyl 3-((R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoyl)thiazolidine-2-carboxylate; (R)-3-t-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butyric acid (20 g, 60 mmol), (S)-ethyl thiazolidine-2-carboxylate (9.7 g, 60 mmol) obtained in step 1 above, EDC (14 g, 73 mmol) and DMAP (7.4 g, 60 mmol) are suspended in CH2Cl2 (500 ml). Thereto, triethylamine (17 g) is added, followed by stirring for 12 hours at room temperature. The resulting mixture was washed with brine and extracted with CH2Cl2. The entire extracts are dried over anhydrous sodium sulfate and concentrated. The residue is purified by silica gel column chromatography to obtain the compound, (S)-ethyl 3-((R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoyl)thiazolidine-2-carboxylate (20 g, 70%).1H NMR (300 MHz, CDCl3) 7.12-7.03 (m, 1H), 6.93-6.84 (m, 1H), 5.59 (brd, 1H), 5.47 (s, 1H), 4.24 (q, J=7.1 Hz, 2H), 4.16-4.09 (m, 1H), 3.98-3.82 (m, 1H), 3.77-3.68 (m, 1H), 3.40-3.31 (m, 1H), 3.11-3.05 (m, 1H), 2.93 (d, J=7.2 Hz, 2H), 2.64 (d, J=5.1 Hz, 2H), 1.38 (s, 9H), 1.30 (t, J=7.1 Hz, 3H).
70% With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 12h; General Procedure: (R)-3-t-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butyric acid (20 g, 60 mmol), (S)-ethyl thiazolidine-2-carboxylate (9.7 g, 60 mmol), EDCI (14 g, 73 mmol) and DMAP (7.4 g, 60 mmol) were suspended in CH2Cl2 (500 ml). Thereto, triethylamine (17 g) was added, followed by stirring for 12 hours at room temperature. The resulting mixture was washed with brine and extracted with CH2Cl2. The entire extracts are dried over anhydrous sodium sulfate and concentrated. The residue is purified by silica gel column chromatography to obtain the compound, (S)-ethyl 3-((R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoyl)-thiazolidine-2-carboxylate (20 g, 70%). 1H NMR (300 MHz, CDCl3) 7.12-7.03 (m, 1H), 6.93-6.84 (m, 1H), 5.59 (brd, 1H), 5.47 (s, 1H), 4.24 (q, J = 7.1 Hz, 2H), 4.16-4.09 (m, 1H), 3.98-3.82 (m, 1H), 3.77-3.68 (m, 1H), 3.40-3.31 (m, 1H), 3.11-3.05 (m, 1H), 2.93 (d, J =7.2 Hz, 2H), 2.64 (d, J = 5.1 Hz, 2H), 1.38 (s, 9H), 1.30 (t, J = 7.1 Hz, 3H).
  • 18
  • [ 24424-99-5 ]
  • [ 1204818-19-8 ]
  • [ 486460-00-8 ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate In tetrahydrofuran at 0 - 20℃; 8 A suspension of (R) -Methyl-3-N-acetylamino-4- (2, 4, 5-trifluorophenyl) butanoate of Example 7 in 6N HCl was heated to reflux overnight . The clear solution was evaporated to dryness and the residue was dissolved in sodium carbonate solution (0.85 g in 20 ml H2O) . To this solution was added BoC2O (1.92 g, 8.81mmol) in THF (20 ml) dropwise at 0 0C with stirring. The mixture was warmed to room temperature with stirring for Ih. THF was evaporated and the aq solution was acidified to pH 2-3 with NaHSO4, then extracted by ethyl acetate (3 X 15 ml) . The combined organic phase was washed with brine and dried over Na2SO4. Concentration in vacuo afforded 2.32 g of white solid (86.9%) . 1H NMR (300 MHz, CD3OD) 7.13-7.03 (m, 2H), 4.20- 4.10 (m, IH), 3.00-2.90 (m, IH), 2.75-2.60 (m, IH), 2.45- 2.55 (m, 2H), 1.35 (s, 9H)
  • 19
  • [ 959238-29-0 ]
  • [ 486460-00-8 ]
  • [ 1152439-77-4 ]
YieldReaction ConditionsOperation in experiment
88% Under a nitrogen atmosphere, 3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid 1k (8.6 g, 45 mmol) and 9.4 mL of triethylamine were dissolved in 300 mL of dichloromethane under stirring. After stirring at room temperature for 5 minutes, 3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine 1f (15.0 g, 45 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (17.1 g, 67.3 mmol) were added to the solution successively. The reaction mixture was reacted at room temperature for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-propyl]-carbamic acid tert-butyl ester 1l (20.0 g, yield 88%) as a white solid. 1H NMR (400 MHz, CD3OD): delta 7.25 (m, 1H), 7.11 (m, 1H), 7.032 (s, 1H), 4.93 (m, 2H), 4.35 (m, 3H), 4.05 (m, 2H), 2.99 (m, 2H), 2.73 (m, 2H), 1.34 (s, 9H)
88% (R)-3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid 1f (8.6 g, 45 mmol) and 9.4 mL of triethylamine were dissolved in 300 mL of dichloromethane. After stirring for 5 minutes, 3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine 1k (15.0 g, 45 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (17.1 g, 67.3 mmol) were added to the solution successively. The reaction mixture was reacted for 2 hours and then concentrated under reduced pressure. The resulting residues were purified by silica gel column chromatography with system B as eluant to obtain the title compound tert-Butyl (R)-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-propyl]-carbamate 1m (20.0 g, yield 88%) as a white solid. 1H NMR (400 MHz, CD3OD, ppm): delta 7.25 (m, 1H), 7.11 (m, 1H), 7.032 (s, 1H), 4.93 (m, 2H), 4.35 (m, 3H), 4.05 (m, 2H), 2.99 (m, 2H), 2.73 (m, 2H), 1.34 (s, 9H).
88% The (R) -3- third-butoxycarbonyl-4- (2,4,5-trifluoro-phenyl) - butyric acid 1f (8.6 g, 45 mmol) and 9.4 mL of triethylamine in 300 mL dichloromethane, after stirring for 5 minutes, followed by adding 3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo [1,5-a] pyridin 1k (15.0 g, 45 mmol) and bis ( 2- oxo-3-oxazolidinyl) phosphinic acyl chloride (17.1 g, 67.3 mmol). The reaction was stirred for 2 hours, the reaction solution was concentrated under reduced pressure, silica gel column chromatography with eluent system B to the resulting residue was purified to give (R) - [3- oxo-1- (2,4,5-trimethyl fluorobenzyl) -3- (3-trifluoromethyl-5,6-dihydro--8H- imidazo [1,5-a] pyridin-7-yl) - propyl] - carbamic acid t-butoxide ester 1m (20.0 g, white solid), yield: 88%.
  • 20
  • [ 881995-69-3 ]
  • [ 24424-99-5 ]
  • [ 486460-00-8 ]
YieldReaction ConditionsOperation in experiment
85.5% The compound V (32.0 g, 0.129 mol), (Boc) 2O (29.5 g, 0.135 mol) and triethylamine (21.2 g, 0.210 mol) were dissolved in ethyl acetate (150 mL) and reacted at a temperature of 20 to 30 C . TLC monitoring, 7h reaction is complete, add 10mL water washing, concentrated organic phase, the crude product. The crude product was dissolved in ethanol, adding 10% sodium hydroxide solution, temperature 20 ~ 30 reaction 2h. TLC detection, complete reaction, adding water 30mL, 3M hydrochloric acid pH = 1 ~ 2, a large number of solid precipitation, filtration and drying products 36.8g, yield 85.5%, ee% = 99.3%.
80 - 85% 3R)-3-[N-(tert-butoxycarbonyl)amino]-4-(2.4.5-trifluoiOphenyl)butanoic acid (07)The methyl (3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoate (76.0 gm) (31) was charged in tetrahydrofuran (5.0 vol, 380.0 ml) and water (5.0 vol, 380.0 ml) at 25-300C. The clear pale yellow solution was further chilled at 0-50C. To the clear pale yellow solution, lithium hydroxide (3.0 eq, 38.73 gm) was charged at 0-50C and the reaction mixture was stirred at 25-3O0C for 9-10 hours. After stirring for 9-10 hours, di-tert-butyl pyrocarbonate (3.0 eq, 202.0 gm) was charged to the reaction mixture at 25-3O0C. The white suspension was stirred for 6 hours before the tetrahydrofuran was distilled out completely to give an off- white residue. The residue was further treated 10% NaHSO4 solution (5.0 vol, 380 ml) to give pH 2. The product was extracted in ethyl acetate (2 x 10.0 vol, 2 x 760 ml). The combined ethyl acetate layers were washed with water (2 x 10.0 vol, 2 x 760 ml). The white coloured product was isolated by complete distillation of the ethyl acetate under reduced pressure at 40-45C. The white coloured product was further triturated with hexane (10.0 vol, 760.0 ml), filtered and dried in a vacuum oven at 45-50C for 4-5 hours. Molar Yield: 80-85% (100.0 gm) Chemical Purity: 96-98% (as measured by HPLC)
  • 21
  • [ 486460-00-8 ]
  • [ 1204818-19-8 ]
YieldReaction ConditionsOperation in experiment
82.8% With hydrogenchloride In ethyl acetate at 20℃; for 4h; 7 Example 7 1.0 g (3.0 mmol) of R-beta-t-butoxyl carbonyl amino-2,4,5-trifluorophenylbutyric acid (Ic) was added to 20 mL of the mixture of ethyl acetate and HCl (2 M). The mixture was stirred for 4 hours at room temperature. The solution was concentrated to half its volume at low temperature, and crystals precipitated from the solution. The resulting precipitates were collected by filtration and dried to obtain 0.67 g of R-beta-amino-2,4,5-trifluorophenylbutyric acid hydrochloride salt (Ia). Melting point: 204.5-207.5° C. [a]D25=-6.8° (C=0.8, methanol). Yield: 82.8%.
With hydrogenchloride; water In ethyl acetate at 20℃; for 4h; 7 EXAMPLE 7 1.0 g (3.0 mmol) of R-beta-t-butoxyl carbonyl amino-2,4,5-trifluorophenylbutyric acid (Ic) was added to 20 mL of the mixture of ethyl acetate and HCI (2 M). The mixture was stirred for 4 hours at room temperature. The solution was concentrated to half its volume at low temperature, and crystals precipitated from the solution. The resulting precipitates were collected by filtration and dried to obtain 0.67 g of R-beta-amino-2,4,5-trifluorophenylbutyric acid hydrochloride salt (Ia). Melting point: 204.5-207.5°C. [a]D 25= -6.8° (C=0.8, methanol). Yield: 82.8%.
  • 22
  • [ 1152439-74-1 ]
  • [ 486460-00-8 ]
YieldReaction ConditionsOperation in experiment
95% With lithium hydroxide monohydrate; In methanol; water; at 30 - 40℃; To a 2 L three-necked flask was added (R)-beta-tert-butoxycarbonylamino-2,4,5-trifluorophenylbutyric acid ethyl ester (64.5 g, 180 mmol).Methanol (200 mL),Hot water bath,Stir,System clarification.Then LiOH.H2O (9.1 g, 216 mmol) in deionized water (200 mL) was added.There are a lot of white solids,Stirring reaction at 30 C - 40 C,After about 3-5 hours,System clarification,TLC monitors the reaction,The reaction is completed,Rotate most of the methanol,Adding dichloromethane to the concentrate,Adjust the pH to 2 with 2N HCl,Liquid separation,The organic phase is dried,A white solid (56.9 g, yield 95%, e.e.% = 94.1%).
EXAMPLE 6 1 g (3.84 mmol) of R-beta-amino-2,4,5-trifluorophenylbutyric acid ethyl ester (Ib) was added to the mixture of methanol (10 mL) and sodium carbonate aqueous solution (10 mL), in which the pH value was 10, and then 1.0 g of (BOC)2O was added. The reaction mixture was reacted at 30C for 3 hours. After the reaction was completed, 4 M NaOH (8 mL) was added to the mixture. The hydrolyzation was carried out at 40-45C. After 2 hours, the reaction was detected by TLC. The solvent was evaporated, and the pH was slowly adjusted to 3. The mixture was extracted with ethyl acetate and washed with acidic water. The organic phrase was dried and concentrated, and then crystals precipitated to obtain 1.14 g of R-beta-t-butoxyl carbonyl amino-2,4,5-trifluorophenylbutyric acid (Ic). Melting point: 127-128C. [a]D 25= 14.2 (C=1, methanol). Yield: 89.1 %.
Example 6 1 g (3.84 mmol) of R-beta-amino-2,4,5-trifluorophenylbutyric acid ethyl ester (Ib) was added to the mixture of methanol (10 mL) and sodium carbonate aqueous solution (10 mL), in which the pH value was 10, and then 1.0 g of (BOC)2O was added. The reaction mixture was reacted at 30 C. for 3 hours. After the reaction was completed, 4 M NaOH (8 mL) was added to the mixture. The hydrolyzation was carried out at 40-45 C. After 2 hours, the reaction was detected by TLC. The solvent was evaporated, and the pH was slowly adjusted to 3. The mixture was extracted with ethyl acetate and washed with acidic water. The organic phrase was dried and concentrated, and then crystals precipitated to obtain 1.14 g of R-beta-t-butoxyl carbonyl amino-2,4,5-trifluorophenylbutyric acid (Ic). Melting point: 127-128 C. [a]D25=14.2 (C=1, methanol). Yield: 89.1%.
Step 5 (R)-3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid Refer to the common known method . 3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)- butyric acid ethyl ester 1e (10 g, 27.7 mmol) and sodium hydroxide (3.32 g, 83.1 mmol) were dissolved in 150 mL of the mixture of methanol and water (v:v = 1:1). The reaction mixture was stirred at 40-45C for 1-1.5 hours, then part of the solution was evaporated under reduced pressure. The residues were added with a little of water, then the pH was adjusted to 2-3 with 1 M hydrochloric acid in an ice-water bath. The mixture was extracted with ethyl acetate (200 mL*3), and the combined organic phase was washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then the residues were recrystallized from ethyl acetate/n-hexane to obtain the title compound (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)- butyric acid 1f (9.2 g) as a white solid, which was directly used in the next step. MS m/z (ESI): 332.3 [M-1].
Refer to the common known method Tetrahedron Asymmetry, 2006, 17(2), 205-209. 3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester 1e (10 g, 27.7 mmol) and sodium hydroxide (3.32 g, 83.1 mmol) were dissolved in 150 mL of the mixture of methanol and water (v:v=1:1). The reaction mixture was stirred at 40-45 C. for 1-1.5 hours, then part of the solution was evaporated under reduced pressure. The residues were added with a little of water, then the pH was adjusted to 2-3 with 1 M hydrochloric acid in an ice-water bath. The mixture was extracted with ethyl acetate (200 mL*3), and the combined organic phase was washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then the residues were recrystallized from ethyl acetate/n-hexane to obtain the title compound (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid 1f (9.2 g) as a white solid, which was directly used in the next step. MS m/z (ESI): 332.3 [M-1].
1.8 g With water; sodium hydroxide; In tetrahydrofuran; at 0 - 25℃; for 5h; (R)-Methyl-4-(2,4,5-trifluorophenyl)butanoate (3g, 0.012 moles) in THF (12.5 ml) was added to aq. NaOH (lg in 12.5 ml H20) at room temperature and cooled to 0- 5C. To this Boc anhydride (3.16 gm, 0.014 moles) was added slowly and maintained at this temperature for 4-5 hrs. After completion of reaction at 0-5C additional lot of aq. NaOH (Igm in 12.5 ml) and THF (12.5 ml) were added to the reaction mass and allowed to stir at 20-25C for 5 hrs for completion of ester hydrolysis. The reaction mass was acidified with 30% aq.citric acid at pH 5.5-6.0. The resulting solution was extracted with MDC (3x 100 ml). The organic layer was washed with brine, dried over sodium sulphate and concentrated to give a thick residue. This thick mass was triturated with n-Hexane to give 1.8 gm of product. SOR (1% CHCI3) + 26.928, Melting point 123.9-127.2C R isomer content by chiral HPLC 99.40%
9.2 g With sodium hydroxide; In methanol; water; at 40 - 45℃; Using known methods Tetrahedron Asymmetry, 2006,17 (2), 205-209, the (R) -3- third-butoxycarbonyl-4- (2,4,5-trifluoro-phenyl) - butyric acid ethyl ester 1e (10 g, 27.7 mmol) and sodium hydroxide (3.32 g, 83.1 mmol) was dissolved in 150 mL of methanol and water (V / V = 1: 1) mixed solvent. In 40 to 45 , the reaction was stirred for 1 to 1.5 hours, concentrated under reduced pressure to remove the solvent portion. A small amount of water was added, under ice-cooling, the reaction solution was added dropwise 1M hydrochloric acid to pH 2 to 3, (200 mL × 3) and extracted with ethyl acetate, the combined organic phase was washed with saturated brine (200 mL), dried over anhydrous dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, ethyl acetate / n-hexane was recrystallized to give (R) -3- third-butoxycarbonyl-4- (2,4,5-trifluorophenyl) - butyric acid 1f (9.2 g, white solid), was used directly in the next reaction.

  • 23
  • [ 1211538-23-6 ]
  • [ 486460-00-8 ]
  • [ 1293996-34-5 ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; General Procedure for the synthesis of 5a-y General Procedure: After removal of N-protected Boc group of previously prepared intermediate amines (7a, 7c, 9), the resulting amino 15 were added to β-aminoamide 16 under the typical HOBt/EDC/TEA/CH2Cl2 conditions. After being stirred at ambient temperature for 14-18 h, DCM was evaporated to give a viscous, which was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, concentrated, and chromatographed on silica gel to give 17. After removal of Boc group of 17, we can get the target compounds 5a-y
  • 24
  • [ 345310-98-7 ]
  • [ 486460-00-8 ]
  • [ 1314097-07-8 ]
  • 25
  • [ 345310-98-7 ]
  • [ 486460-00-8 ]
  • [ 1314097-42-1 ]
  • 26
  • [ 59702-07-7 ]
  • [ 486460-00-8 ]
  • [ 1314097-06-7 ]
  • 27
  • [ 59702-07-7 ]
  • [ 486460-00-8 ]
  • [ 1314097-41-0 ]
  • 29
  • [ 1246960-23-5 ]
  • [ 486460-00-8 ]
YieldReaction ConditionsOperation in experiment
81% With sodium hydroxide; In ethanol; at 75 - 85℃; Tert-butyl (R) -l-cyano-3- (2,4,5-trifluorophenyl) propan-2-ylcarbamate (2.0 g, 6.0 mmol) was mixed with 20 ml of 50% ethanol Dissolved by stirring, and then 2.4 g of sodium hydroxide was added thereto. Subsequently, the reaction solution was heated to 75 to 85 C to a reaction of 10 to 14 smallPost-reaction treatment: The reaction solution was cooled to room temperature, acetic acid was added to the reaction solution, the pH of the reaction solution was adjusted to 7, And extracted twice with 40 ml of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Finally, to the concentration The product was recrystallized from 20 ml of methanol, filtered and dried in vacuo to give the off-white solid compound as the compound of formula (1-a)1.7 g of the compound was obtained in a yield of 81%.
75% With dihydrogen peroxide; sodium hydroxide; In water; at 100℃; for 3h; 4.2.14 (R)-3-((tert-Butoxycarbonyl)amino)-4-(2,4,5-trifluorophenyl)butanoic acid 4 To a stirred solution of N-Boc protected cyano compound 19 (0.5 g, 1.5 mmol) were added 3 M NaOH (10 mL), H2O2 (35%, 6 mL, 22 mmol) and refluxed at 100 C for 3 h. After the reaction was completed, the reaction mixture was cooled to 0 C. To remove organic impurities, Et2O (50 mL) was added and the ether phase was removed. The aqueous phase was acidified with 6 M HCl to neutralize pH and was extracted with Et2O (50 mL), and dried over Na2SO4. Filtration and evaporation of the solvent gave the crude product, which was purified by column chromatography over silica gel using petroleum ether/ethyl acetate (4:1) to afford the corresponding pure compound 4 as a colorless solid. Yield: 0.375 g, 75%; mp: 122-125 C; {lit. 21 mp: 124-125 C}; [alpha]D25 = +31.8 (c 1, CHCl3) {lit. 21 [alpha]D25 = +32.3 (c 1, CHCl3)}; IR (CHCl3, cm-1): 3101, 2956, 1770, 1685, 1366, 1095; 1H NMR (200 MHz, CDCl3): delta 1.35 (s, 9H), 2.62-2.56 (m, 2H), 2.88 (d, J = 4.9 Hz, 2H), 4.10 (br s, 1H), 5.07 (br s, 1H), 6.94-6.87 (m, 1H), 7.09-7.03 (m, 1H; 13C NMR (50 MHz, CDCl3): delta 14.1, 28.57, 32.71, 47.95, 61.5, 80.73, 105.8 (dd, J = 20.6, 28.5 Hz), 118.2(dd, J = 10.7, 6.2 Hz), 124.5 (ddd, J = 4.5, 9.5, 18.2 Hz), 146.7 (ddd, J = 4.1, 5.5, 229.9 Hz), 148.9 (ddd, J = 255.5, 12.5, 2.9 Hz), 158.2 (ddd, J = 244.4, 11.2, 9.7 Hz), 175.1, 177.3; Anal. Calcd for C17H22F3NO4 requires C 56.50; H 6.14; N 3.88%; found C 56.53; H 6.16; N 3.89%.
Step e: Preparation of (R)-3-amine-protecting group-amino-4-(2,4,5-trifluorophenyl)butanoic acid (Chemical Formula 2)<Step e-1> Preparation of (R)-3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid (Chemical Formula 2)2.0 g of (R)-t-butyl 1-cyano-3-(2,4,5-trifluorophenyl)propane-2-ylcarbamate produced in the above Step d-1 was dissolved in 20 mL mixed solution of ethanol:water=1:1 in 250 mL flask; then 3.4 g of 85% potassium hydroxide was added thereto; and then the resulting reaction solution was stirred for 12 hours at 80 C. The reaction solution was cooled to room temperature; 8.0 g of oxalic acid dihydrate was slowly added to the cooled reaction solution. After completing the reaction, 40 mL of ethyl acetate and 20 mL of water were added and then the resulting reaction solution stirred for 20 minutes. An organic layer was isolated; dehydrated with magnesium sulfate; and then concentrated under reduced pressure. The concentrated residue was isolated with column chromatography (chloroform:methanol=10:1) and then concentrated under reduced pressure to obtain 1.10 g of a title compound.1H NMR (CDCl3, 400 MHz) delta 7.04 (m, 1H), 6.89 (m, 1H), 6.08 (br, 1H), 5.04 (br, 1H), 4.13 (br, 1H), 2.88 (br, 2H), 2.62 (m, 2H), 1.36 (s, 18H)Mass (M+Na): 356
  • 30
  • [ 486460-21-3 ]
  • [ 486460-00-8 ]
  • (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine hydrochloride [ No CAS ]
  • 31
  • [ 1364122-92-8 ]
  • [ 486460-00-8 ]
  • [ 1174568-20-7 ]
YieldReaction ConditionsOperation in experiment
65% Stage #1: (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid With N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole In acetonitrile at 20℃; for 0.5h; Stage #2: 1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-one hydrochloride In acetonitrile at 65 - 70℃; for 22h; 3 To a solution of (R)-3-[(ferf-butyloxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)- butanoic acid (0.927 g, 2.78 mmol) in acetonitrile (15 ml) was added Diisopropylethylamine (2.84 g, 22.02 mmol) and 1 ,1-Carbonyl diimidazole (0.615 g, 3.797 mmol) at room temperature. The reaction mixture was stirred for 30 min at room temperature. 1 ,3,4,5-Tetrahydro-benzo[e][1 ,4]diazepin-2-one hydrochloride (0.5 g, 2.531 mmol) (synthesized in accordance with the procedure given in WO-2009093269, which is incorporated in its entirety herein by reference) was added to the above reaction mixture at room temperature. The reaction mixture was heated to 65-70°C for 22 h. After completion of the reaction, the mixture was concentrated under vacuum and the crude mass was dissolved in ethyl acetate (15 ml) and washed twice with water (2 x 30 ml). The ethyl acetate layer was concentrated under reduced pressure to get crude mass and was purified by column chromatography using mixture of 2% methanol in dichloromethane (500 ml) to get 0.679 g (65%) of [(R)-3-oxo-3-(2-oxo-1 , 2,3,5- tetrahydro-benzo[e][1 ,4]diazepin-4-yl)-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester. The above obtained solid was treated with Hydrochloric acid to get the Hydrochloric acid salt of (R)-4-[3-amino-4-(2,4,5-trifluorophenyI)-butyryl]-1 , 3,4,5- tetrahydro-benzo[e][1 ,4]diazipin-2-one.
  • 32
  • [ 1364122-92-8 ]
  • [ 486460-00-8 ]
  • (R)-4-[3-amino-4-(2,4,5-trifluorophenyl)butyryl]-1,3,4,5-tetrahydrobenzo[e][1,4]diazipin-2-one hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole / acetonitrile / 0.5 h / 20 °C 1.2: 22 h / 65 - 70 °C 2.1: hydrogenchloride / water
  • 33
  • [ 1364122-94-0 ]
  • [ 486460-00-8 ]
  • (R)-[3-(7-methoxy-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-yl)-3-oxo-1-(2,4,5-trifluorophenyl)propyl]carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
92% To a solution of (R)-3-[(terf-butyloxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)- butanoic acid (0.241 g, 2.197 mmol) in acetonitrile (15 ml) was added Diisopropylethylamine (2.47 g,19.12 mmol) and 1 ,1-Carbonyl diimidazole (0.534 g, 3.296 mmol) at room temperature. The reaction mixture was stirred for 30 min at room temperature. 7-methoxy-1 ,3,4,5-tetrahydro-benzo[e][1 l4]diazepin-2-one hydrochloride (0.5 g, 2.197 mmol) (synthesized in accordance with the procedure given in WO-2009093269, which is incorporated in its entirety herein by reference) was added to the above reaction mixture at room temperature. The reaction mixture was heated to 65-70C for 22 h. After completion of the reaction, the mixture was concentrated under vacuum and the crude mass was dissolved in ethyl acetate (15 ml) and washed twice with water (2 x 30 ml). The ethyl acetate layer was concentrated under reduced pressure to get crude mass and which was purified by column chromatography using mixture of 2% methanol in dichloromethane (500 ml) to get 0.9 g (92%) of (R)-[3-(7-methoxy-2-oxo-1 , 2,3,5- tetrahydro-benzo[e][1 ,4]diazepine-4-yl)-3-oxo-1-(2,4,5-trifluorophenyl-propyl]- carbamic acid fe/t-butyl ester.The above obtained solid was treated with Hydrochloric acid to get the Hydrochloric acid salt of (R)-4-(3-amino-4-(2,4,5-trifluorophenyl)-butanoyl)-7- methoxy-4,5-dihydro-1 H-benzo[e][1 ,4] diazipin-2(3H)-one.
  • 34
  • [ 1276113-61-1 ]
  • [ 486460-00-8 ]
YieldReaction ConditionsOperation in experiment
90% Example 10 Preparation of (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)n-butyric acid To a clean flask, 34.73 g (R)-cyclohexyl 3-(tert-butoxycarbonyl amino)-4-(2,4,5-trifluorophenyl)butyrate, 300 ml water and 5.2 g potassium carbonate were added. The mixture was warmed to 60 C. and kept at this temperature for 3 hours. 4.73 g hydrochloric acid was added dropwisely. After completion, the resulting mixture was kept at 20-30 C. for 2 hours and filtrated to obtain 29.99 g (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)n-butyric acid (yield: 90%).
90% To a clean flask, 34.73g (R)-cyclohexyl 3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butyrate, 300ml water and 5.2g potassium carbonate were added. The mixture was warmed to 60C and kept at this temperature for 3 hours. 4.73g hydrochloric acid was added dropwisely. After completion, the resulting mixture was kept at 20-30C for 2 hours and filtrated to obtain 29.99g (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl) n-butyric acid (yield: 90%).
  • 35
  • [ 691394-20-4 ]
  • [ 486460-00-8 ]
  • [ 910550-48-0 ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine
  • 36
  • [ 691394-19-1 ]
  • [ 486460-00-8 ]
  • [ 910550-98-0 ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine
  • 37
  • [ 102391-98-0 ]
  • [ 486460-00-8 ]
  • [ 1395397-44-0 ]
  • 38
  • [ 68104-63-2 ]
  • [ 486460-00-8 ]
  • [ 1395397-29-1 ]
  • 39
  • [ 68104-63-2 ]
  • [ 486460-00-8 ]
  • [ 1395395-65-9 ]
  • 40
  • [ 115761-79-0 ]
  • [ 486460-00-8 ]
  • [ 1395397-09-7 ]
  • 41
  • [ 115761-79-0 ]
  • [ 486460-00-8 ]
  • [ 1395395-55-7 ]
  • 42
  • [ 51639-48-6 ]
  • [ 486460-00-8 ]
  • [ 1395397-17-7 ]
  • 43
  • [ 51639-48-6 ]
  • [ 486460-00-8 ]
  • [ 1395395-59-1 ]
  • 44
  • 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-α]pyrazine hydrochloride [ No CAS ]
  • [ 486460-00-8 ]
  • [ 486460-32-6 ]
YieldReaction ConditionsOperation in experiment
96% 30 g of compound V was added to 250 ml of ethyl acetate, the temperature was lowered at 15 C, 28 g of thionyl chloride was added, the temperature was raised to 26 C, and the reaction was carried out for 2 hours, and 23 g of triethylamine was added.223 g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride was added.Maintain the temperature at 25 C for 5-6 hours, then add 200 ml of water after the end,The layer and the organic layer were concentrated and crystallized to obtain 35.2 g of sitagliptin dry product, the purity was 99.9%, the chiral purity was 100%, and the yield was 96%
90% Example 1 The mixture of 8.04 g of (fi)-3-((terf-butoxycarbonyl)amino)-4-(2,4,5- trifluorophenyl)butanoic acid (HPLC: 99.9%, ee (by HPLC): 99.9%), 5.54 g of 3- (trifluoromethyl)-5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3-a]pyrazine hydrochloride (HPLC: 99.6%) and 40 ml of N- methylimidazole is cooled to 0C. Then 5.46 g of Lambda/-(3- Dimethylaminopropyl)-/V-ethylcarbodiimide hydrochloride-a (EDC-HCI) is added and the mixture is stirred for 16 h at room temperature. To the reaction mixture 200 ml of isopropyl acetate and 200 ml of water are added. The phases are separated and aqueous phase is again extracted with 100 ml of ethyl acetate. Collected organic phases are washed with 200 ml of water (2*). The organic phase is evaporated to around 100 ml.To concentrated organic phase 20 ml of 8M HCI/EtOH is added and the mixture is stirred at room temperature for 18 h. After the reaction is completed 50 ml of water is added and pH of the mixture is adjusted with 1 M NaOH to 10-12. Then phases are separated. Aqueous phase is reextracted with 100 ml of isopropyl acetate. Collected organic phases are washed with 80 ml of water (2*) and evaporated. To the residue 60 ml of tert-butyl methyl ether is added. The obtained suspension is cooled below 0C and then filtered and dried.Yield: 8.84g (90%)HPLC: 99.86%, R isomer 100.0% S isomer 0.0%
  • 45
  • 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-α]pyrazine hydrochloride [ No CAS ]
  • [ 486460-00-8 ]
  • [ 486460-23-5 ]
YieldReaction ConditionsOperation in experiment
95% With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 0 - 20℃; for 16h; a) Condensation step The mixture of 4.02 g of Boc(R)-3-Amino-(2,4,5-trifluorophenyl)butanoic acid, 2.77 g of 3-(Trifluoromethyl)-5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3-a] pyrazine hydrochloride-a and 25 ml of pyridine is cooled to 0C. Then 2.73 g of N-(3-Dimethylaminopropyl)-/ - ethylcarbodiimide hydrochloride-a (EDC) is added and the mixture is stirred for 16h at room temperature. The to the reaction mixture 100 ml of isopropyl acetate and 100ml of water are added. The phases are separated and aqueous phase is again extracted with 100 ml of ethyl acetate. Collected organic phases are washed with 100 ml of water and then to organic phase 100 ml of water is added and pH of the mixture is adjusted to around 3. Phases are separated and organic phase is evaporated. The residue is collected and dried.Yield: 5.88g (95%)HPLC: 97.6 %
95% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In acetonitrile; at 0 - 20℃; for 24h; [0165] Into a 50 mL round- bottom flask was added 20 mL acetonitrile, followed by the addition of the phenyl- butyricacid derivative obtained in Example 46 (3.32 g, 0.01 mol) and triazolopyrazine hydrochloride (228 g, 0.01 mol) . Thetemperature of the reaction mixture was cooled down to 0C in an ice- salt bath. 1- Hydroxylbenzotriazole (1.62 g, 0.012mol) and 1- ethyl- 3- (3- dimethylaminopropyl) carbodiimide hydrochloride (2.29 g, 0.012 mol) were further added. 3 gTriethylamine was then added dropwise and the mixture was stirred at room temperature for 24 h. The reaction solutionwas washed with 3320 mL distilled water. The obtained organic layers were collected and dried over anhydrous magnesiumsulfate for 1 h. Then, the desiccant was filtered off and the resulting reactant was concentrated to 4.81 g. Theyield was 95%.[alpha] D20 = + 22.2 (c 1.0, CHCl3) . M.p. 188- 191C. IR (cm- 1) : 3374, 2897, 1686, 1635, 1519, 1368, 1164, 1128, 1016. 1HNMR (400 MHz, CDCl3) delta 7.18?7.05 (m, 1H), 7.02- 6.85 (m, 1 H), 5.31 (s, 1 H), 5.15? 4.76 (m, 2H), 4.43?3.78 (m, 5H),2.98?2.92 (m, 2H), 2.71?2.61 (m, 2H), 1.36 (s, 9H) . ESI- MS: 508.0 (M+ +1) . HRMS Calcd. for: C21H23F6N5O3Na (M+ Na) + requires 530.1598, found 530.1604
92.10% Toluene (300 mL) and (3R)-3 -[(tert-butoxycarbonyl)aminoj -4-(2,4,5 -trifluorophenyl)butanoic acid (Formula 2; 20 g, 1.0 equivalent) were charged to a round bottom flask. Triisopropyl borate (12.42 g, 1.1 equivalents) and concentrated sulfuric acid (2 drops) were charged at 20C to 25C. The temperature was raised to reflux and refluxed for 2 hours. The reaction mixture was cooled to 80C to 85C. 3- (Trifluoromethyl)-5 ,6,7,8-tetrahydro- [1 ,2,4jtriazolo[4,3 -alpyrazine hydrochloride(Formula 3; 15 g, 1.1 equivalents) and triethylamine (7.27 g, 1.2 equivalents) were charged at 80C to 85C to the reaction mixture and the temperature was raised to reflux and refluxed for 36 hours to 38 hours using a Dean-Stark apparatus. On completion of the reaction, toluene was recovered completely under vacuum at 50C to 55C. Water (100 mL) was charged to the solid residue, and the mixture was stirred for 2 hours at 20C to25C. The solid was filtered under vacuum, washed with water (100 mL), and then dried in an air drier at 50C to 55C for 14 hours to 16 hours to obtain the title compound.Yield: 28 g (92.10%)
92% EXAMPLE 5: Preparation of: (R)-t-Butyl 4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-alpha]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-ylcarbamate (Chemical Formula 5a) [199] To 100 ml of dimethylformamide was added 33.3 g (0.10 mole) of (R)-3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid, and the solution was stirred at 25 for 20 min. The solution was mixed with 16.7 ml (0.12 mole) of triethylamine, and stirred for 20 min. To the reaction solution was added 30.4 g (0.10 mole) of bis(4-nitrophenyl)carbonate, and the suspension was stirred at 70 for 4 hrs. [200] After completion of the reaction as monitored by TLC, 25.1 g (0.11 mole of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-alpha]pyrazine hydrochloride was added to the resulting solution, followed by stirring at 70 for 8 hrs. After completion of the reaction as monitored by TLC, 100 ml of 2-propanol and 330 ml of water were added to the reaction solution, and stirred at room temperature for 2 hrs or longer. The precipitated solid was filtered under reduced pressure. To the filtrate was added 100 ml of 2-propanol, and the solution was stirred under reflux for 2 hrs or longer. The resulting reaction mixture was slowly cooled to 10 or less, filtered in a vacuum, washed, and dried to afford 46.5 g (92.0%) of (R)-t-butyl 4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-alpha]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-ylcarbamate as a solid. [201] HPLC content: 99.3% [202] Here, the same spectrum data as in Example 4 was obtained
BOC- (R) -3-amino-4- (2,4,5-trifluorophenyl) butanoic acid 16.6g (0.05mol) was added in sequence, and 40g of acetonitrile was added,Diisopropylethylamine 21.3g (0.16mol),Cool down to -10 ~ 0 , add pivaloyl chloride 6.3g (0.0525mol) dropwise,Maintain the temperature -10 ~ 0 , keep the temperature for 1 hour after dropping,Keep temperature -10 ~ 0 and add slowly3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo [4,3-a] pyrazine hydrochloride 12.57g (0.055mol), keep warm 2 hour,Keep the temperature -10 ~ 0 , slowly add 100g water dropwise, stir for 2 hours,Filter and dry at 70 to obtain 23.24g (0.0458mol) of white solid,The quality yield is 140%,The molar yield is 91.6% and the purity is 99.6%.

  • 46
  • 2,2,2-trifluoro-1-((3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)ethanone [ No CAS ]
  • [ 486460-00-8 ]
  • [ 1350553-74-0 ]
YieldReaction ConditionsOperation in experiment
85% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 4h; (R)-3-(tertbutoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butyric acid 1d (435 mg, 1.30 mmol) and 2,2,2-trifluoro-1-((3aR,6aR)-hexahydropyrrolo [3,4-b]pyrrol-5(1H)-yl)ethanone 1c (272 mg, 1.30 mmol) were dissolved in dichloromethane (10 ml), added sequentially 1-hydroxylbenzotriazole (HOBt) (202 mg, 1.50 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (288 mg, 1.50 mmol) and triethylamine (151 mg, 1.50 mmol), stirred for 4 hours at room temperature. Organic phase was washed by 1N diluted hydrochloric acid (10 ml) and saturated sodium bicarbonate (10 ml) in order, dried by anhydrous sodium sulfate, concentrated, residues were purified by column chromatography to give title compound 1e (578 mg, 85 %) as white solid. MS m/z (ESI): 524.2 (M+1).
  • 47
  • 2,2,2-trifluoro-1-((3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)ethanone [ No CAS ]
  • [ 486460-00-8 ]
  • tertbutyl(R)-4-((3aS,6aS)-5-(2,2,2-trifluoroacetyl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-1-(2,4,5-trifluorophenyl)-4-oxybutan-2-ylcarbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% With benzotriazol-1-ol; 1,2-dichloro-ethane; triethylamine; In dichloromethane; at 20℃; for 4h; Step 3: Preparation of tertbutyl(R)-4-((3aS,6aS)-5-(2,2,2-trifluoroacetyl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-1-(2,4,5-trifluorophenyl)-4-oxybutan-2-ylcarbamate 1e (R)-3-(tertbutoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butyric acid 1d (435 mg, 1.30 mmol) and 2,2,2-trifluoro-1-((3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)ethanone 1c (272 mg, 1.30 mmol) were dissolved in dichloromethane (10 mL), added sequentially 1-hydroxylbenzotriazole (HOBt) (202 mg, 1.50 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (288 mg, 1.50 mmol) and triethylamine (151 mg, 1.50 mmol), stirred for 4 hours at room temperature. Organic phase was washed by 1N diluted hydrochloric acid (10 mL) and saturated sodium bicarbonate (10 mL) in order, dried by anhydrous sodium sulfate, concentrated, residues were purified by column chromatography to give title compound 1e (578 mg, 85%) as white solid. MS m/z (ESI): 524.2 (M+1).
  • 48
  • [ 59408-74-1 ]
  • [ 486460-00-8 ]
  • 49
  • [ 1048703-14-5 ]
  • [ 486460-00-8 ]
YieldReaction ConditionsOperation in experiment
98% With sodium hypochlorite; sodium chlorite; disodium hydrogenphosphate; sodium dihydrogenphosphate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; In water; acetonitrile; at 38℃; for 0.333333h; In a 30 L dry reaction kettle, 2.5 kg of water, 86 g of disodium hydrogen phosphate and 37.5 g of sodium dihydrogen phosphate were added, it was stirred until solids were dissolved, 1.8L of acetonitrile, compound 6 (350g), TEMPO (12g)was added, the temperature was raised to about 38 C, an aqueous solution of sodium chlorite (250 g of sodium chlorite, 1 kg of water) and an aqueous solution (75 ml) of sodium hypochlorite (20 ml) were added in portions, added in ten portions, and added in batches every 20 min. The HPLC was followed until the reaction was complete, the control temperature was 10C or less, an aqueous solution of saturated sodium sulfite was added dropwise, the external temperature was 50C, the internal temperature was 40-45C, and acetonitrile was distilled under reduced pressure, the temperature of the reaction solution was reduced to about 15 C, ethyl acetate 350ml, 3N hydrochloric acid 1.3kg were added to adjust pH 3-4, the reaction solution was added with 2.5 L of water, and the temperature was stirred at 15-20 C for 30 min, filtered, and the filter cake was washed twice with water, 1.5 L each time, the filter cake was blow dried 65 C to give compound 2 (361 g), as a white powder, yield 98%, see FIG 3,4,5
90% With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; sodium bromide; In dichloromethane; at 0℃; for 2h; [0157] Into a three-necked flask equipped with constant-pressure dropping funnel and thermometer were added crudealcohol product (5.6 g, 0.0175 mol), 75 ml dichloromethane, 50 mL NaHCO3 (5% solution), TEMPO (0.28 g, 1.75mmol)and NaBr (0.18 g, 1.75mmol). NaClO (50mmol, 74 ml, 5%) was then added dropwise at 0 C. The reaction was completedafter 2h. To the obtained reaction mixrure was added saturated 10 mL sodium thiosulfate and the pH of the reactionmixture was adjusted to 2-3 by neutralization with 2 N hydrochloric acid. After extracted with 50 mL dichloromethanethree times, the obtained orgainc layers were collected together and further dried over anhydrous magnesium sulfate.The solvent was removed under a reduced pressure to obtain a solid crude product. Then, the obtained solid crudeproduct was recrystallized from methanol to obtain an off-white solid (5.24 g, 0.0157 mol). The yield was 90%.1H NMR (500 MHz, CDCl3) delta 7.09 (d, J = 7.7 Hz, 1 H), 6.91 (d, J = 6.7 Hz, 1 H), 5.03 (d, J = 4.0 Hz, 1H), 4.36 (s, 1 H),3.06 ?2.75 (m, 3H), 2.62 (dd, J = 16.4, 5.6 Hz, 1 H), 2.50 (d, J = 8.2 Hz, 1H), 1.33 (s, 9H). Ms(M++1): 334.
90% Into a three-necked flask equipped with constant-pressure dropping funnel and thermometer were added crude alcohol product (5.6 g, 0.0175 mol), 75 ml dichloromethane, 50 mL NaHCO3 (5% solution), TEMPO (0.28 g, 1.75 mmol) and NaBr (0.18 g, 1.75 mmol). NaClO (50 mmol, 74 ml, 5%) was then added dropwise at 0 C. The reaction was completed after 2 h. To the obtained reaction mixture was added saturated 10 mL sodium thiosulfate and the pH of the reaction mixture was adjusted to 2-3 by neutralization with 2 N hydrochloric acid. After extracted with 50 mL dichloromethane three times, the obtained organic layers were collected together and further dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure to obtain a solid crude product. Then, the obtained solid crude product was recrystallized from methanol to obtain an off-white solid (5.24 g, 0.0157 mol). The yield was 90%. 1H NMR (500 MHz, CDCl3) delta 7.09 (d, J=7.7 Hz, 1H), 6.91 (d, J=6.7 Hz, 1H), 5.03 (d, J=4.0 Hz, 1H), 4.36 (s, 1H), 3.062.75 (m, 3H), 2.62 (dd, J=16.4, 5.6 Hz, 1H), 2.50 (d, J=8.2 Hz, 1H), 1.33 (s, 9H). Ms(M++1): 334.
  • 50
  • [ 51372-93-1 ]
  • [ 486460-00-8 ]
  • 51
  • [ 144284-25-3 ]
  • [ 486460-00-8 ]
  • 52
  • [ 80875-98-5 ]
  • [ 486460-00-8 ]
  • C24H31F3N2O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
General procedure: (d) To a solution of (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid 9 in CH2Cl2 was added HOBt, EDCI, DMAP, and triethylamine. After stirring for 30min 8a was added. The reaction mixture was stirred overnight. The reaction was monitored by TLC. After the starting materials were completely consumed, the mixture was diluted with CH2Cl2, washed sequentially with 1N HCl and brine. The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by a flash column chromatography (petroleum ether/ethyl acetate=4:1, v/v, as an eluent) to afford compound 10a as a white solid (72% yield).
  • 53
  • [ 186581-53-3 ]
  • [ 486460-09-7 ]
  • [ 486460-00-8 ]
YieldReaction ConditionsOperation in experiment
401 mg To a solution of 0.37 g (1.16 mmol) of <strong>[486460-09-7](R)-N-(1,1-dimethylethoxycarbonyl)-2,4,5-trifluorophenylalanine</strong> in 10 mL of diethyl ether at -20 C. were added sequentially 0.193 mL (1.3 mmol) of triethylamine and 0.18 mL (1.3 mmol) of isobutyl chloroformate, and the reaction was stirred at this temperature for 15 min. A cooled ethereal solution of diazomethane was then added until the yellow color persisted and stirring was continued for a further 1 h. The excess diazomethane was quenched by dropwise addition of acetic acid, and the reaction was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (silica gel, 3:1 hexane:ethyl acetate) afforded 0.36 g of diazoketone. To a solution of 0.35 g (1.15 mmol) of the diazoketone dissolved in 12 mL of 1,4-dioxane:water (5:1) was added 26 mg (0.113 mmol) of silver benzoate. The resultant solution was sonicated for 2 h before diluting with ethyl acetate and washing sequentially with 1N hydrochloric acid and brine, drying over magnesium sulfate and concentrating in vacuo. Purification by flash chromatography (silica gel, 97:2:1 dichloromethane:methanol:acetic acid) afforded 401 mg of the title compound. 1H NMR (500 MHz, CDCl3) delta 7.06 (m, 1H), 6.95 (m, 1H), 5.06 (bs, 1H), 4.18 (m, 1H), 2.98 (m, 2H), 2.61 (m, 2H), 1.39 (s, 9H).
  • 54
  • [ 1659-31-0 ]
  • [ 486460-00-8 ]
  • (R)-pyridin-2-yl 3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
91.4% EXAMPLE 3: Preparation of (R)-pyridin-2-yl 3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoate (Chemical Formula 1c) [187] To 100 ml of dimethylformamide was added 33.3 g (0.10 mole) of (R)-3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid, and the solution was stirred at 25 for 20 min. The solution was mixed with 16.7 ml (0.12 mole) of triethylamine, and stirred for 20 min. To the reaction solution was added 21.6 g (0.10 mole) of di-2-pyridyl carbonate, and the suspension was stirred at 70 for 2 hrs. After completion of the reaction as monitored by TLC, 33 ml of 2-propanol and 330 ml of water were added to the resulting reaction solution, followed by stirring at room temperature for 2 hrs or longer. The precipitated solid was filtered under reduced pressure at room temperature, and the filtrate was washed and dried to afford 37.5 g (91.4%) of (R)-pyridin-2-yl 3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoate as a solid. [188] 1H NMR (CDCl3,400MHz): delta 1.38 (s, 9H), 2.81-2.92 (m, 4H), 4.27-4.28 (m, 1H), 5.14-5.16 (m, 1H), 6.90-8.41 (m, 6H) [189] Elemental analysis for C20H21F3N2O4 [190] Calculated - C: 58.5, H: 5.2, N: 6.8 [191] Measured - C: 58.5, H: 5.3, N: 6.9 [192] m.p.: 134 ~ 137
  • 55
  • [ 59483-84-0 ]
  • [ 486460-00-8 ]
  • (R)-pentafluorophenyl 3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
92.3% EXAMPLE 1: Preparation of (R)-pentafluorophenyl 3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoate (Chemical Formula 1a) [173] To 100 ml of dimethylformamide was added 33.3 g (0.10 mole) of (R)-3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid, and the solution was stirred at 25 for 20 min. The solution was mixed with 16.7 ml (0.12 mole) of triethylamine, and stirred for 20 min. To the reaction solution was added 39.4 g (0.10 mole) of <strong>[59483-84-0]bis(pentafluorophenyl)carbonate</strong>, and the suspension was stirred at 25 for 2 hrs. After completion of the reaction as monitored by TLC, 165 ml of 2-propanol and 330 ml of water were added to the resulting reaction solution, followed by stirring at room temperature for 2 hrs or longer. The precipitated solid was filtered under reduced pressure at room temperature, and the filtrate was washed and dried to afford 46.1 g (92.3 %) of (R)-pentafluorophenyl 3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoate as a solid. [174] 1H NMR (CDCl3, 400MHz): delta 1.41 (s, 9H), 2.95-2.96 (m, 4H), 4.25-4.29 (m, 1H), 4.91-4.92 (m, 1H), 6.92-7.09 (m, 2H) [175] Elemental analysis for C21H17F8NO4 [176] Calculated - C: 50.5, H: 3.4, N: 2.8 [177] Measured - C: 50.8, H: 3.5, N: 2.8 [178] m.p.: 129 ~ 131 [179]
  • 56
  • [ 5070-13-3 ]
  • [ 486460-00-8 ]
  • (R)-4-nitrophenyl 3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
91.9% EXAMPLE 2: Preparation of (R)-4-nitrophenyl 3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoate (Chemical Formula 1b) [180] To 100 ml of dimethylformamide was added 33.3 g (0.10 mole) of (R)-3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid, and the solution was stirred at 25 for 20 min. The solution was mixed with 16.7 ml (0.12 mole) of triethylamine, and stirred for 20 min. To the reaction solution was added 30.4 g (0.10 mole) of bis(4-nitrophenyl) carbonate, and the suspension was stirred at 70 for 4 hrs. After completion of the reaction as monitored by TLC, 100 ml of 2-propanol and 330 ml of water were added to the resulting reaction solution, followed by stirring at room temperature for 2 hrs or longer. The precipitated solid was filtered under reduced pressure at room temperature, and the filtrate was washed and dried to afford 41.7 g (91.9%) of (R)-4-nitrophenyl 3-(t-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoate as a solid. [181] 1H NMR (CDCl3, 400MHz): delta 1.39 (s, 9H), 2.81-2.96 (m, 4H), 4.32 (m, 1H), 5.04 (m, 1H), 6.94-8.26 (m, 6H) [182] Elemental analysis for C21H21F3N2O6 [183] Calculated - C: 55.8, H: 4.7, N: 6.2 [184] Measured - C: 55.8, H: 4.8, N: 6.1 [185] m.p.: 138 ~ 140
  • 57
  • 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-α]pyrazine hydrochloride [ No CAS ]
  • [ 486460-00-8 ]
  • N-Boc-sitagliptin [ No CAS ]
YieldReaction ConditionsOperation in experiment
95% With 4-(dimethylamino)pyridine N-oxide; sodium hydroxide; 2,6-difluorophenylboronic acid; In fluorobenzene; water; at 100℃; for 23h;Molecular sieve; General procedure: As shown in equation described in the upper part of Table 1, we were synthesized N-Boc-sitagliptin. These are the carboxylic acids, an example in which the amino acids with two hydrogen atoms in position alpha having a protected amino group in the beta-position. Representative experimental examples, shown below The procedure of Experimental Example 1-4. 5,6,7,8-tetrahydro-3- (trifluoromethyl) -1,2,4-triazolo [4,3-a] pyrazine hydrochloride 114mg (0.50mmol) in 4M aqueous sodium hydroxide solution 0.125mL (0 .50mmol) was evaporated to dryness and water after the addition of. This fluorobenzene 2.5mL, (3R) -N-Boc-4- (1,3,4- trifluorophenyl) -3-amino - butanoic acid 183 mg (0.55 mmol), phenylboronic acid as further catalyst ( 6.1mg, 0.05mmol), DMAPO the (6.9mg, 0.05mmol) added as an additive, for 23 hours at 100 C (oil bath temperature) was reacted while the azeotropic dehydration. The reaction mixture was concentrated, dissolved in ethyl acetate 2 mL, by slow dropwise addition of hexane 40 mL, to obtain a N-Boc-sitagliptin of interest as a white solid 233mg (92% yield). Other experimental examples in Table 1 were also carried out in accordance with this procedure. The results of Experimental Examples 1-1 to 1-8 are shown in Table 1. In Experimental Examples 1-1 and 1-2, boric acid (B (OH) 3) was used as a catalyst, DMAPO was not added in Experimental Example 1-1, and DMAPO was added in Example 1-2. In Experimental Examples 1-3 and 1-4, phenylboronic acid (PhB (OH) 2) was used as a catalyst, DMAPO was not added in Experimental Example 1-3, and DMAPO was added in Example 1-4. In Experimental Examples 1-5 and 1-6, 2,6-difluorophenylboronic acid was used as a catalyst, DMAPO was not added in Experimental Example 1-5, and DMAPO was added in Example 1-6. In Experimental Examples 1-7 and 1-8, 2-trifluoromethylphenylboronic acid was used as a catalyst, DMAPO was not added in Experimental Example 1-7, and DMAPO was added in Example 1-8. As is apparent from the experimental examples 1-1 to 1-8, the yield of N-Boc-sitagliptin was improved when DMAPO was added as compared with the case where it was not added. That is, a reaction promoting effect by DMAPO was observed.
  • 58
  • [ 486460-00-8 ]
  • [ 762240-92-6 ]
  • [ 486460-32-6 ]
YieldReaction ConditionsOperation in experiment
96.5% To the 1 OOgm(3R)-3- [(1,1 -dimethyl ethoxy carbonyl)amino}-4-(2,4,5-trifluorophenyl butanoic acid charged 700m1 methylenedichioride and 67gm triethylamineandstirred for 10 minutes.Added 68gmNN?-Dicyclohexylcarbodiimide, 44.6 gm of anhydrous 1 - hydroxylbenzotriazole and maintained for about 10-20 minutes.Added75.5gm 3- trifluromentyl 5,6,7,8-tetrahydro (1 ,2,4) triazolo[4,3-a] pyrazineHCl and heated to 25- 30C and maintained for 4 hours. After completion of reaction,filtered the reaction mass and filtrate was washed with 2x350m1 2.5%sodium bicarbonate solutionandwashed with 2x500m1 of water.MDC layer was taken without purification and Cooled to 0-10C.400m1 1 6%Methanolic HCI added and raised the temperature to 25-30C and Stirred for 4 hours.After completion of the reaction added 1000m1 water and separatedlayers.ExtractedtheMDClayer with 2x300m1 DM water.Aqueous layer was washed with 300m1 MDC and pH of the aqueous layer was adjusted to 10-1 1%with 1 0%sodium hydroxide solution. 1 000m1 MDC charged and Stirred for I 0mm. The organic layer separated and the Aq layer was extracted twice with 300 ml MDC. The organic layer was separated and washed with 300 ml of water followed by 300m1 5% NaCl; and driedthe organic layer with anhydrous sodium sulfate. The organic layer separated and the solvent was distilled out under vacuum. 1 OOm1IPA was added to residue and again distilled under vacuum followed by addition of 800m1 heptane. Filtered the crystallized Material and dried under vacuum at 50C for 12-15 hours to get 96.5% titled compound.BPLC purity:99-99.9% Chiral purity: 99.9%
  • 59
  • C16H20F3NO2 [ No CAS ]
  • [ 486460-00-8 ]
YieldReaction ConditionsOperation in experiment
89% With potassium permanganate; In acetone; at 20℃; for 3h; Potassium permanganate (21.3 g 134.7 mmol) was added to 4 (15.6 g 44.9 mmol) of acetone (160 mL),The reaction was stirred at room temperature for 3 h, quenched with saturated sodium sulfite, neutralized with saturated sodium dihydrogen phosphate, added methyl tert-butyl ether (200 ml*2), and concentrated to give 14.7 g of product 2 in an overall yield of 89%.
70% With ruthenium trichloride; sodium periodate; In water; acetonitrile; at -10℃; for 2h; 3.15 g of compound 5 (10 mmol) was dissolved in acetonitrile and water, and 7.48 g ofsodium periodate (35 mmol) and 4 mg of RuCl3(0.02 mmol)were sequentially added at -10 C (ice-salt bath).Add Bi, to maintain this temperature stirring 2h.The reaction was completed by TLC andextracted with ethyl acetate. The organic layer was washed with water, saturated thiosulfate solution and saturated brine successively, dried over anhydrous sodiumsulfate and concentrated to give a crude product, which was recrystallized from n-hexane / ethyl acetate to give 2.3 g White solid (1), yield 70%
  • 60
  • [ 397246-14-9 ]
  • [ 486460-00-8 ]
  • 61
  • [ 486460-00-8 ]
  • [ 762240-92-6 ]
  • Sitagliptin hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
97% In a 250 ml flask, 50 ml of dimethylformamide (DMF)(3R) -3 - [(1,1-dimethylethoxycarbonyl) amino] -4- (2,4,5-trifluorophenyl)10.0 g and3- (Trifluoromethyl) -5,6,7,8-tetrahydro- [1,2,4] triazolo [4,3-a] pyrazine hydrochlorideAnd the mixture is stirred for 10 minutes to dissolve.The resulting reaction solution2-chloro-1, 3-dimethylimidazolinium chloride(2-chloro-1,3-dimethylimidazolinium chloride (DMC))5.3gAt 20 to 25 and stirred for 5 hours.To the reaction solution were added 100 ml of water and ethyl acetate (ethyl acetate (EA)) was added and the mixture was stirred for 30 minutes to separate the layers.In the resulting reaction solution, ethyl acetate(ethyl acetate (EA)) layer,This was concentrated under reduced pressure at 40 ,Is dissolved in 100 ml of isopropyl alcohol.0.8 ml of hydrochloric acid was added and the mixture was refluxed for 3 hours.The reaction was cooled to 5-10 [deg.] C,Stir for 3 hours.The precipitated solid is filtered off and washed with 10 ml of isopropyl alcohol.The obtained wetDried at 60 & lt; 0 & gt;Formula 1Indicated by(2R) -4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3- a] pyrazin-7 (8H) ] -1- (2,4,5-trifluorophenyl) butan-2-amine hydrochloride was obtained (yield: 97%).
  • 62
  • [ 486460-00-8 ]
  • [ 654671-77-9 ]
  • 63
  • [ 936630-57-8 ]
  • [ 486460-00-8 ]
  • C25H26F6N2O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In acetonitrile; at 20 - 30℃; 10 g (0.03 mol) of BOC-<strong>[936630-57-8](R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid</strong> was placed in a 500 ml four-necked flask.<strong>[936630-57-8](R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid</strong> 8 g (0.0297 mol),HOBT 5g (0.036mol),EDC-HCl 7g(0.036mol),The acetonitrile was stirred at 90 g to uniformly disperse the solid.Add 4 g (0.04 mol) of triethylamine dropwise.Control temperature 20-30 C,The heat preservation reaction is controlled until the end point.Acetonitrile is recovered by distillation under reduced pressure.A solid crude material is obtained.The concentrate was purified on a silica gel column (dichloromethane: ethyl acetate = 8:1).Concentrated to dryness,Obtained a white solid 11.5g, purity about99%, the yield is about 70%.The solid prepared in Example 1 was analyzed by the above mass spectrometry method.Obtain BOC-(R)-3-ammoniaMass spectrum of condensed impurities of keto-4-(2,4,5-trifluorophenyl)butanoic acid,As shown in Figure 5.The solid obtained in Example 1 was prepared,Dissolve the material in a 10 mg/ml solution with deuterated dimethyl sulfoxide.Using the Bruke AVANCE III 500MHz instrument,Obtaining condensation of BOC-<strong>[936630-57-8](R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid</strong>Hydrogen spectrum of impurities,As shown in Figure 6.The solid prepared in Example 1 was dissolved in deuterated dimethyl sulfoxide to dissolve the material in a solution of 30-40 mg/ml. Using a Bruke AVANCE III 500 MHz instrument, BOC-(R)-3-amino-4-(2,4) was obtained. Carbon spectrum of a 5-pentafluorophenyl)butyric acid condensation impurity,As shown in Figure 7.
  • 64
  • 2-(piperazin-2-yl)acetic acid ethyl ester [ No CAS ]
  • [ 486460-00-8 ]
  • 2-[4-[(3R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoyl]piperazin-2-yl]acetic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 0 - 30℃; for 1h;Inert atmosphere; At 0C , triethylamine (0.45mL, 3.2mmol) was added to (3R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid ( 0.35g, 1.1mmol), 2-(piperazin-2-yl)acetic acid ethyl ester 2c (0.18g, 1.0mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.48g, 1.2mmol) in dichloromethane (15mL) was stirred at rt for 1 h. water was added (5mL) the reaction was quenched, liquid separation, the organic phase was washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated, the residue was purified by silica gel column chromatography [100% ethyl acetate] to give the title compound (0.45 g of, 88.0% yield) as a white solid.
  • 65
  • 1-(1-methanesulfonylpiperazin-2-yl)cyclopropylcarboxylic acid methyl ester [ No CAS ]
  • [ 486460-00-8 ]
  • 1-[4-[(3R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoyl]-1-methanesulfonylpiperazin-2-yl]cyclopropylcarboxylic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
97% With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 0 - 30℃; for 1h;Inert atmosphere; At 0 C,Triethylamine (0.38 mL, 2.7 mmol) was slowly added dropwise to (3R)-3-((tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid (0.32 g) , 0.96 mmol), 1-(1-methanesulfonylpiperazin-2-yl)cyclopropylcarboxylic acid methyl ester 4 h (0.23 g, 0.88 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.40 g, 1.0 mmol) in dichloromethane (12 mL),The reaction was carried out for 1 hour at room temperature. Add water (10mL) to quench the reaction, separate the liquid, use the organic phaseWash with saturated sodium chloride solution (10 mL), dry over anhydrous sodiumThe residue was subjected to silica gel column chromatography[100% ethyl acetate] purified,The title compound 4j (0.49 g, yield 97%) was obtained.It is a white solid.
  • 66
  • [ 24424-99-5 ]
  • (R)-3-((R)-1-phenylethylamino)-4-(2,4,5-trifluorophenyl)-N-phenyl butanamide [ No CAS ]
  • [ 486460-00-8 ]
YieldReaction ConditionsOperation in experiment
88% To a solution of (R)-3-((R)-l-phenylethylamino)-4-(2,4,5-trifluorophenyl)-N-phenyl butanamide (Formula IV) (50 g, 0.12 moles) was subjected to hydrogenolysis in methanol (500 ml) employing 5% Palladium on charcoal (6 g) as catalyst at 70 C at a hydrogen pressure of 8 kg/cm . After completion on reaction, the catalyst was removed by filtration and reaction mixture was concentrated under vacuum. Hydrochloric acid (100 ml) was added to the obtained reaction mixture and heated at 90 C until the reaction was complete. The resulting reaction mixture was cooled to room temperature and 50% sodium hydroxide was added to the solution at below 35 C. Then methylene dichloride (100 ml) was added under stirring for 10 min and organic layer was separated. The aqueous layer was cooled to 10 C and tetrahydrofuran (100 ml) was added followed by DIBOC (21 g, 0.09 moles).The reaction mass stirred at 10-15 C for 2 hrs and then the temperature was allowed to reach room temperature and further stirring was continued for 18 hrs. After completion of the reaction, tetrahydrofuran was distilled off under vacuum and the crude product was extracted with ethyl acetate (100 ml). The pH of the reaction mixture was adjusted to 2-3 with hydrochloric acid at 0-5 C. The organic layer was separated and aq. layer was washed with another 100 ml of ethyl acetate. Combined organic layers were washed with water (100 ml) and distilled off completely under vacuum. n-Hexane (150 ml) was added to the crude product and stirred for 30 min at room temperature. The obtained solid was filtered to obtain the title compound (23 g, 88%). (0195) HPLC: 99.2% and Chiral purity by HPLC: >99%.
  • 67
  • [ 883267-70-7 ]
  • [ 486460-00-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: potassium bromide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hypochlorite; sodium hydrogencarbonate / dichloromethane; water / 1 h / 0 °C 2.1: pyridinium p-toluenesulfonate; magnesium sulfate / dichloromethane / 4 h / 20 °C 3.1: potassium carbonate; sodium iodide / 4 h / 20 °C 4.1: hydrogenchloride; water / 9 h / Reflux 4.2: 20 °C
Multi-step reaction with 4 steps 1.1: potassium bromide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hypochlorite; sodium hydrogencarbonate / dichloromethane; water / 1 h / 0 °C 2.1: pyridinium p-toluenesulfonate; magnesium sulfate / dichloromethane / 4 h / 20 °C 3.1: potassium carbonate; sodium iodide / 6 h / 0 °C 4.1: hydrogenchloride; water / 18 h / Reflux 4.2: 20 °C / pH 8
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