518048-03-8|2-(2-Aminopropan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide| Ambeed

Structure of 518048-03-8

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Quality Control of [ 518048-03-8 ] Purity: 97% SDS Specification

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Product Details of [ 518048-03-8 ]

CAS No. :	518048-03-8
Formula :	C₁₆H₁₉FN₄O₃
M.W :	334.35
SMILES Code :	O=C(C(N=C(C(C)(N)C)N1C)=C(O)C1=O)NCC2=CC=C(F)C=C2
MDL No. :	MFCD10698741
InChI Key :	AQLZTHZLYFFVIJ-UHFFFAOYSA-N
Pubchem ID :	54721880

Safety of [ 518048-03-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 518048-03-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	24
Num. arom. heavy atoms	12
Fraction Csp3	0.31
Num. rotatable bonds	5
Num. H-bond acceptors	6.0
Num. H-bond donors	3.0
Molar Refractivity	86.39
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	110.24 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.9
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.63
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.91
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.75
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.51
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.14

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.35
Solubility	1.49 mg/ml ; 0.00447 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.52
Solubility	1.01 mg/ml ; 0.00302 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-4.18
Solubility	0.0219 mg/ml ; 0.0000656 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	Yes
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-7.89 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<0.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.97

Application In Synthesis of [ 518048-03-8 ]

* 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 [ 518048-03-8 ]

[ 518048-03-8 ] Synthesis Path-Downstream 1~34

1
{1-[4-(4-fluoro-benzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidin-2-yl]-1-methyl-ethyl}carbamic acid benzyl ester [ No CAS ]
[ 518048-03-8 ]

Yield	Reaction Conditions	Operation in experiment
98%		To a 3L, three-necked flask equipped with a mechanical stirrer and thermometer, was added the compound RLT-8 (200g), methanol (2000 ml), formic acid (24.2 ml), Pd/C 10% (50% water wet, 5.5g) and potassium formate (5.5g) (dissolved in 300 ml of water). The resulting mixture was heated to 50C and stirred for 2.5 hours. Water (300 ml) and sulfuric acid (26 ml) were added and the palladium was filtered off. The filter cake was washed with methanol 80% solution (250 ml).The combined filtrate was then added to a 5 L flask and the pH was adjusted to 8.5 with aqueous sodium hydroxide (940 ml, IN). The resulting mixture was stirred at room temperature for 19 hours and then was cooled to 5C. After 2 hours of stirring at 5C, a solid precipitate formed and was separated by filtering. The filter cake was washed with water (200 ml). The solid was then dried overnight at 45C to provide the compound RLT-9 as a white solid. (143.4g, 98% yield, purity 98.75%).
96%	With methanesulfonic acid; hydrogen;5%-palladium/activated carbon; In methanol; at 20 - 50℃; under 2828.7 Torr; for 3 - 4h;	A stainless steel hydrogenation vessel was preconditioned with MeOH, Pd/C catalyst and MSA under the reaction conditions described below. Cbz-amide g (1 Og) was then slurried in MeOH (80 mL) in the preconditioned vessel. MSA (1.45 mL) was added to the slurry in one portion at room temperature. 5% Pd/C (0.15g, 50% wet) was also added to the hydrogenation vessel. Hydrogen was charged to the vessel in three successive vacuum/hydrogen purge cycles, after which the mixture was hydrogenated at 40 psig for 3-4 hour at 500C. Following hydrogenation, water (8 mL) was added to the reaction mixture, the mixture was stirred, and the catalyst was filtered and washed with 4:1 MeOHrwater (20 mL). The pH of combined filtrates was adjusted to pH 7 to 8.0 by slow addition of 1 N NaOH (22.4 mL), which precipitated a solid. The slurry was stirred at 0-5 0C for 4 hours and the solid filtered, <n="37"/>washed with water (30 mL), collected and dried in vacuo at 500C. The product amine (as hydrate) was obtained as a white crystalline solid (7.7g) in 96% yield (corrected for KF), 89%LCWP, 99.8% LCAP, KF=Il wt.%HPLC Method A (product assay): column: 25 cm x 4.6 mm Zorbax RX-C8; mobile phase: A =0.1% H3PO4, B = CH3CN, 0 minutes (80% A/ 20% B), 20 minutes (20% AJ 80% B), 25 minutes (20% AJ80% B); flow. 1.0 mL/minute; wavelength: 210 nm; column temperature: 40 0C; retention times: des- fluoroamine byproduct - 5.5 min, amine product - 5.85 minutes, toluene - 16.5 minutes, Cbz-amide - 16.82 minutes.HPLC Method B (product purity): column: 25 cm x 4.6 mm YMC-basic; mobile phase: A =25 mmol KH2PO4 adjusted to pH=6.1, B = CH3CN, 0 minutes (90% A/ 10% B)5 30 minutes (30% A/ 70% B), 35 minutes (30% A/ 70% B); flow: 1 mL/minute; wavelength: 210nm; column temperature: 30 0C; retention times: des-fluoroamne - 9.1 minutes, amine - ] 0.1 minutes, toluene - 24.2 minutes, Cbz amide - 25.7 minutes.
96%	With methanesulfonic acid; hydrogen;5% palladium over charcoal; In methanol; at 20 - 50℃; under 2828.7 Torr; for 3 - 4h;	Material MW mmoles Mass Volume CBz amide (g) 468.48 21.33 10 g MeOH 80 mL 5% Pd/C (50% wet) 0.15 g MSA 96.1 22.4 1.45 mL water 8 mLcake wash (4:1 MeOH:H20 20 mL 1 N NaOH 22.4 22.4 mL final cake wash (water) 30 mL A stainless steel hydrogenation vessel was preconditioned with MeOH, Pd/C catalyst and MSA under the reaction conditions described below. Cbz-amide g (10 g) was then slurried in MeOH (80 mL) in the preconditioned vessel. MSA (1.45 mL) was added to the slurry in one portion at room temperature. 5% Pd/C (0.15 g, 50% wet) was also added to the hydrogenation vessel. Hydrogen was charged to the vessel in three successive vacuum/hydrogen purge cycles, after which the mixture was hydrogenated at 40 psig for 3-4 hour at 50 C. Following hydrogenation, water (8 mL) was added to the reaction mixture, the mixture was stirred, and the catalyst was filtered and washed with 4:1 MeOH:water (20 mL). The pH of combined filtrates was adjusted to pH 7 to 8.0 by slow addition of 1 N NaOH (22.4 mL), which precipitated a solid. The slurry was stirred at 0-5 C. for 4 hours and the solid filtered, washed with water (30 mL), collected and dried in vacuo at 50 C. The product amine (as hydrate) was obtained as a white crystalline solid (7.7 g) in 96% yield (corrected for KF), 89% LCWP, 99.8% LCAP, KF=11 wt. % HPLC Method A (product assay): column: 25 cm×4.6 mm Zorbax RX-C8; mobile phase: A=0.1% H3PO4, B=CH3CN, 0 minutes (80% A/20% B), 20 minutes (20% A/80% B), 25 minutes (20% A/80% B); flow: 1.0 mL/minute; wavelength: 210 nm; column temperature: 40 C.; retention times: des-fluoroamine byproduct-5.5 min, amine product-5.85 minutes, toluene-16.5 minutes, Cbz-amide-16.82 minutes. HPLC Method B (product purity): column: 25 cm×4.6 mm YMC-basic; mobile phase: A=25 mmol KH2PO4 adjusted to pH=6.1, B=CH3CN, 0 minutes (90% A/10% B), 30 minutes (30% A/70% B), 35 minutes (30% A/70% B); flow: 1 mL/minute; wavelength: 210 nm; column temperature: 30 C.; retention times: des-fluoroamine-9.1 minutes, amine-10.1 minutes, toluene-24.2 minutes, Cbz amide-25.7 minutes.

96%	With methanesulfonic acid; hydrogen;5% palladium over charcoal; In methanol; at 50℃; under 2068.65 Torr; for 3 - 4h;	Hvdrogenation of Cbz-amide[MW = 468.48] [MW = 334.35]Material MW mmoles Mass VolumeCBz amide (g) 468.48 21.33 1O gMeOH 8O mL5% Pd/C (50% wet) 0.15 gMSA 96.1 22.4 1.45 mL water 8 mL cake wash (4: 1 MeOH:H2theta 2O mL1 N NaOH 22.4 22.4 mL final cake wash (water) 3O mLA stainless steel hydrogenation vessel was preconditioned with MeOH, Pd/C catalyst and MSA under the reaction conditions described below. Cbz-amide g (IOg) was then slurried in MeOH (80 mL) in the preconditioned vessel. MSA (1.45 mL) was added to the slurry in one portion at room temperature. 5% Pd/C (0.15g, 50% wet) was also added to the hydrogenation vessel. Hydrogen was charged to the vessel in three successive vacuum/hydrogen purge cycles, after which the mixture was hydrogenated at 40 psig for 3-4 hour at 500C. Following hydrogenation, water (8 mL) was added to the reaction mixture, the mixture was stirred, and the catalyst was filtered and washed with 4:1 MeOH:water (20 mL). The pH of combined filtrates was adjusted to pH 7 to 8.0 by slow addition of 1 N NaOH (22.4 mL), which precipitated a solid. The slurry was stirred at 0-5 0C for 4 hours and the solid filtered, washed with water (30 mL), collected and dried in vacuo at 500C. The product amine (as hydrate) was obtained as a white crystalline solid (7.7g) in 96% yield (corrected for KF), 89%LCWP, 99.8% LCAP, JCF=I l wt.%HPLC Method A (product assay): column: 25 cm x 4.6 mm Zorbax RX-C8; mobile phase: A =0.1% H3PO4, B = CH3CN, 0 minutes (80% A/ 20% B), 20 minutes (20% A/ 80% B), 25 minutes (20% AJ EPO <DP n="35"/>80% B); flow: 1.0 mL/minute; wavelength: 210 nm; column temperature: 40 0C; retention times: des- fluoroamine byproduct - 5.5 min, amine product - 5.85 minutes, toluene - 16.5 minutes, Cbz-amide - 16.82 minutes.HPLC Method B (product purity): column: 25 cm x 4.6 mm YMC-basic; mobile phase: A =25 mmol KH2PO4 adjusted to pH=6.1, B = CH3CN, 0 minutes (90% A/ 10% B), 30 minutes (30% A/ 70% B), 35 minutes (30% A/ 70% B); flow: 1 mL/minute; wavelength: 210nm; column temperature: 30 0C; retention times: des-fluoroamine - 9.1 minutes, amine - 10.1 minutes, toluene - 24.2 minutes, Cbz amide - 25.7 minutes
96% - 99.8%Chromat.	With methanesulfonic acid; hydrogen;5% palladium over charcoal; In methanol; at 20 - 50℃; under 2828.7 Torr; for 3 - 4h;	A stainless steel hydrogenation vessel was preconditioned with MeOH, Pd/C catalyst and MSA under the reaction conditions described below. Cbz-amide g (1Og) was then slurried in MeOH (80 mL) in the preconditioned vessel. MSA (1.45 mL) was added to the slurry in one portion at room temperature. 5% Pd/C (0.15g, 50% wet) was also added to the hydrogenation vessel. Hydrogen was charged to the vessel in three successive vacuum/hydrogen purge cycles, after which the mixture was hydrogenated at 40 psig for 3-4 hour at 50C. Following hydrogenation, water (8 mL) was added to the reaction mixture, the mixture was stirred, and the catalyst was filtered and washed with 4: 1 MeOHrwater (20 mL). The pH of combined filtrates was adjusted to pH 7 to 8.0 by slow addition of 1 N NaOH (22.4 mL), which precipitated a solid. The slurry was stirred at 0-5 0C for 4 hours and the solid filtered, washed with water (30 mL), collected and dried in vacuo at 500C. The product amine (as hydrate) was obtained as a white crystalline solid (J. Ig) in 96% yield (corrected for KF), 89%LCWP, 99.8% LCAP, KF=Il wt.%.
96%		A stainless steel hydrogenation vessel was preconditioned with MeOH, Pd/C catalyst and MSA under the reaction conditions described below. Cbz-amide g (1Og) was then slurried in MeOH (80 mL) in the preconditioned vessel. MSA (1.45 mL) was added to the slurry in one portion at room temperature. 5% Pd/C (0.15g, 50% wet) was also added to the hydrogenation vessel. Hydrogen was charged to the vessel in three successive vacuum/hydrogen purge cycles, after which the mixture was hydrogenated at 40 psig for 3-4 hour at 500C. Following hydrogenation, water (8 mL) was added to the reaction mixture, the mixture was stirred, and the catalyst was filtered and washed with 4:1 MeOH:water (20 mL). The pH of combined filtrates was adjusted to pH 7 to 8.0 by slow addition of 1 N NaOH (22.4 mL), which precipitated a solid. The slurry was stirred at 0-5 0C for 4 hours and the solid filtered, washed with water (30 mL), collected and dried in vacuo at 500C. The product amine (as hydrate) was obtained as a white crystalline solid (7.7g) in 96% yield (corrected for KJ), 89%LCWP, 99.8% LCAP, KF=I 1 wt.%HPLC Method A (product assay): column: 25 cm x 4.6 mm Zorbax RX-C8; mobile phase: A =0.1% H3PO4, B = CH3CN, 0 minutes (80% A/ 20% B), 20 minutes (20% A/ 80% B)5 25 minutes (20% A/80% B); flow: 1.0 mL/minute; wavelength: 210 nm; column temperature: 40 0C; retention times: des- fluoroamine byproduct - 5.5 min, amine product - 5.85 minutes, toluene - 16.5 minutes, Cbz-amide - 16.82 minutes.HPLC Method B (product purity): column: 25 cm x 4.6 mm YMC-basic; mobile phase: A =25 mmol KH2PO4 adjusted to pH=6.1, B = CH3CN, 0 minutes (90% AJ 10% B), 30 minutes (30% A/ 70% B), 35 EPO <DP n="36"/>minutes (30% AJ 70% B); flow: 1 mL/minute; wavelength: 210nm; column temperature: 30 0C; retention times: des-fluoroamine - 9.1 minutes, amine - 10.1 minutes, toluene - 24.2 minutes, Cbz amide - 25.7 minutes.
	With hydrogen bromide; In water; at 28 - 62℃; for 2.5h;	A mass of 730 g of aqueous hydrobromic acid was added to 100 g of benzyl (2- { 4-ft4-fluorobenzyl) carbamoyl]-5 -hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidin-2-yl}propan-2-yl)-carbamate at 28 + 3 C and stirred for 30 minutes. The reaction mixture temperature was raised to 62 + 3 C and stirring continued for 2 hours. After completion of the reaction, the reaction mixture was cooled to 28 ± 3 C and 300 mL of purified water was added. The reaction mixture was stirred and cooled to 12 + 3C. The pH of the reaction mixture was adjusted to 7.0 - 8.0 with a sodium hydroxide solution and further cooled to 3 ± 2 C. The reaction mixture was stirred for about 3- 4 hrs. The product was filtered then washed with water. Methanol (500 mL) was added to the wet material at 28 ±3 C and stirred for 1 hour to obtain a solid. The solid was filtered then washed with methanol. The product was dried under vacuumat 55 ± 3 C to get 2-(2-amino propan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo- 1, 6-dihydro pyrimidine-4-carboxamide (Formula III).
65 g	With glycolic Acid; 5%-palladium/activated carbon; hydrogen; In methanol; under 6723.1 Torr;	A slurry suspension of 100 g (0.213 mol) Benzyl (2-(4-((4-fluorobenzyl)carbamoyl)- 5-hydroxy-l-methyl-6-oxo-l,6-dihydropyrimidin-2-yl)propan-2yl)carbamate IVa, 38 ml (0.426 mol) glycolic acid (67% w/w) and 5g 5% Pd/C (50% w/w) in 3L methanol was hydrogenated at 130 psi for 3-4 h (>99.6% purity). The reaction mixture was filtered through celite bed and washed with 100 ml methanol. The combined filtrate was concentrated to a total volume of 1.1L at 25-28 C and neutralized by 65 ml triethylamine to pH= 9-10 at 25-28 C. The formed crystalline solid is collected by filtration, rinsed with 100ml methanol and dried under vacuum to afford 65 g (0.194 mol) of free amine (lib). (0147) 1H-NMR (500 MHz, DMSO-d6) delta 10.16 (br, 1 H), 7.33-7.30 (m, 2H), 7.14-7.10 (m, 2 H), 4.45 (d, J = 6.0 Hz, 2 H), 3.68 (s, 3 H), 1.56 (s, 6 H). (0148) 13C-NMR (125 MHz, DMSO-d6) delta 168.1, 162.1, 160.2, 135.6, 129.3, 123.2, 115.0, 55.9, 48.6, 41.3, 33.1, 28.2.
3 g	With sodium hydroxide; In ethanol; butan-1-ol;Reflux;	In a 250 mL four necked round bottom flask added 5 g of compound 6 portion-wise to a alcoholic solution of sodium hydroxide (2 g) in n-butanol (20 mL) at room temperature under vigorous stirring. The slurry solution was slowly heated to reflux and maintain for 3-4 h until it TLC complies. The resulting brown colored precipitated solution was cooled to 20-25 C diluted with 50 mL of water to get clear solution. The obtained off-white coloured solid was filtered and dried after reaction mass pH was adjusted to 7.5 with conc. HCl (5 mL) to afford 3 g of compound 5 with HPLC purity 99.4 %. 1H NMR (DMSO-d6): delta 10.55 (s, 1H), 7.27-7.30 (m, 2H), 7.10(t, 2H), 4.43 (d, 2H), 3.60 (s, 3H), 1.58 (s, 6H); 13C NMR(DMSO-d6):167.87, 162.50, 159.95, 152.15, 145.17, 135.77,129.23, 122.92, 115.10, 56.02, 41.33, 33.01, 27.24. Mass: M+:334.35 , M+H: 435.1 (+ve Scan), M-H: 333.1 (-ve scan).

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[ 889131-28-6 ]
[ 518048-03-8 ]
[ 518048-05-0 ]

Yield	Reaction Conditions	Operation in experiment
95%		(Note: An alternative procedure is included parenthetically. Except as noted therein, the alternative procedure is essentially the same as the main procedure.) A 500 mL round bottom flask was charged with oxadiazole K salt i (33.8 g) followed byACN (280 mL) and DMF (0.33 mL) with strong stirring. The resulting slurry was then cooled down to 0-50C and oxalyl chloride (23.7 g) was added over the course of 20 minutes in order to maintain the internal temperature at less than 50C. The resulting acyl chloride-containing slurry was then aged for 1 hour. To a 2 L round bottom flask the free amine h (30 g) was added followed by THF (821 mL). The resulting slurry was cooled down to 0-50C, after which NMM (21.56 g) was added and the slurry so obtained was stirred for 10 minutes at the cold temperature. The previously prepared acyl chloride-containing slurry was added slowly to the free amine slurry over the course of 20 minutes such that the temperature did not exceed 5 0C. The slurry was then aged for 1.5 hours at 0-50C. At this time HPLC showed no more amine Jh (<0.5 % LCAP, 100% conversion). The reaction mixture was then quenched with NH4OH (30 % in water) (69 mL) which was added over the course of 3 minutes (in the alternative procedure, aqueous KOH was employed in place of NH4OH). The resulting yellow slurry was then stirred for an additional hour at temperatures less than 1O0C. The yellow slurry was then EPO <DP n="39"/>acidified to pH 2-3 with HCl (2N) (500 mL). To the resulting red wine colored solution, IPA (920 mL) was added. The low boiling point organic solvents were then evaporated under reduced pressure (40 torr) at room temperature to a final solution volume of 1100 mL, at which volume crystalline Compound A began to precipitate. Water (400 mL) was then added to this new slurry over the course of 10 minutes, and the slurry aged overnight at room temperature (in the alternative procedure, the slurry was cooled to 0-100C and then aged for 2 hours). The aged slurry was filtered and the solid obtained was washed with water (170 mL), followed by a swish wash with cold MeOH (300 mL, previously cooled in an ice bath), and finally by a swish wash with water (700 mL). (In the alternative procedure, the solid obtained by filtering the aged slurry was washed twice with water; i.e., MeOH was not employed.) The solid so obtained was dried overnight under vacuum and nitrogen stream to give 35.5 g of Compound A (91% yield). (The alternative procedure provided Compound A in 95% yield.)
91%		Part B: Oxadiazole CouplingCompound AMoI. Wt.: 444.42Reagent Mass mL Moles Eq oxadiazole K salt ] 33.8 g (96.1 wt%) 0.20 2.2ACN 28O mLDMP 0.33 oxalyl chloride 23.7 g 16.3 mL 0.19 2.1 free amine h 30 g (99 wt%) 0.089 1THF 82I mLNMM 21.56 g 23.4 mL 0.21 2.4NH4OH (30% in H2O) 62.3 g 69 mL 0.53 6HCl (2N) 50O mLIPA 92O mL water 40O mLMeOH 30O mLA 500 mL round bottom flask was charged with oxadiazole K salt i (33.8 g) followed by ACN (280 mL) and DMF (0.33 mL) with strong stirring. The resulting slurry was then cooled down to EPO <DP n="38"/>0-50C and oxalyl chloride (23.7 g) was added over the course of 20 minutes in order to maintain the internal temperature at less than 50C. The resulting acyl chloride-containing slurry was then aged for 1 hour.To a 2 L round bottom flask the free amine h (30 g) was added followed by THF (821 mL). The resulting slurry was cooled down to 0-50C, after which NMM (21.56 g) was added and the slurry so obtained was stirred for 10 minutes at the cold temperature. The previously prepared acyl chloride-containing slurry was added slowly to the free amine slurry over the course of 20 minutes such that the temperature did not exceed 5 0C. The slurry was then aged for 1.5 hours at 0-50C. At this time HPLC showed no more amine h (<0.5 % LCAP, 100% conversion). The reaction mixture was then quenched with NEta4OH (30 % in water) (69 mL) which was added over the course of 3 minutes. The resulting yellow slurry was then stirred for an additional hour at temperatures less than 1O0C. The yellow slurry was then acidified to pH 2-3 with HCl (2N) (500 mL). To the resulting red wine colored solution, IPA (920 mL) was added. The low boiling point organic solvents were then evaporated under reduced pressure (40 torr) at room temperature to a final solution volume of 1100 mL, at which volume crystalline Compound A began to precipitate. Water (400 mL) was then added to this new slurry over the course of 10 minutes, and the slurry aged overnight at room temperature. The aged slurry was filtered and the solid obtained was washed with water (170 mL), followed by a swish wash with cold MeOH (300 mL, previously cooled in an ice bath), and finally by a swish wash with water (700 mL). The solid so obtained was dried overnight under vacuum and nitrogen stream to give 35.5 g of Compound A (91% yield).
91%		(Note: An alternative procedure is included parenthetically. Except as noted therein, the alternative procedure is essentially the same as the main procedure.) A 500 mL round bottom flask was charged with oxadiazole K salt i (33.8 g) followed byACN (280 mL) and DMF (0.33 mL) with strong stirring. The resulting slurry was then cooled down to 0-50C and oxalyl chloride (23.7 g) was added over the course of 20 minutes in order to maintain the internal temperature at less than 50C. The resulting acyl chloride-containing slurry was then aged for 1 hour. To a 2 L round bottom flask the free amine h (30 g) was added followed by THF (821 mL). The resulting slurry was cooled down to 0-50C, after which NMM (21.56 g) was added and the slurry so obtained was stirred for 10 minutes at the cold temperature. The previously prepared acyl chloride-containing slurry was added slowly to the free amine slurry over the course of 20 minutes such that the temperature did not exceed 5 0C. The slurry was then aged for 1.5 hours at 0-50C. At this time HPLC showed no more amine Jh (<0.5 % LCAP, 100% conversion). The reaction mixture was then quenched with NH4OH (30 % in water) (69 mL) which was added over the course of 3 minutes (in the alternative procedure, aqueous KOH was employed in place of NH4OH). The resulting yellow slurry was then stirred for an additional hour at temperatures less than 1O0C. The yellow slurry was then EPO <DP n="39"/>acidified to pH 2-3 with HCl (2N) (500 mL). To the resulting red wine colored solution, IPA (920 mL) was added. The low boiling point organic solvents were then evaporated under reduced pressure (40 torr) at room temperature to a final solution volume of 1100 mL, at which volume crystalline Compound A began to precipitate. Water (400 mL) was then added to this new slurry over the course of 10 minutes, and the slurry aged overnight at room temperature (in the alternative procedure, the slurry was cooled to 0-100C and then aged for 2 hours). The aged slurry was filtered and the solid obtained was washed with water (170 mL), followed by a swish wash with cold MeOH (300 mL, previously cooled in an ice bath), and finally by a swish wash with water (700 mL). (In the alternative procedure, the solid obtained by filtering the aged slurry was washed twice with water; i.e., MeOH was not employed.) The solid so obtained was dried overnight under vacuum and nitrogen stream to give 35.5 g of Compound A (91% yield). (The alternative procedure provided Compound A in 95% yield.)

90%	With triethylamine; In acetonitrile; at 50 - 60℃;Inert atmosphere;	Operating as described in Example 1, but after the catalyst was filtered, NaOH 2M was slowly dripped to reach pH ~ 8 maintaining a temperature lower than 20C, to the solution cooled to about 20C. At completed addition, the product of formula (II) was precipitated in the form of free base, the suspension was maintained at 0-5C for 1 hour, filtered and the solid washed with cold water (2 c 45 ml), dried in vacuum at 60C for at least 6 hours to give the compound of formula (II) free base in hydrated form (26.6 g, KF 4.74%) in 93.4% yield on anhydrous base. A suspension hydrated form of the compound of formula (II) free base (21.3 g, 60.7 mmol) in in toluene (100 ml) was dried by complete distillation up to KF 72.7 mmol) was dripped under nitrogen. The mixture was maintained at 50-60C until completion of the reaction and subsequently cooled to room temperature. Water (45 ml), ethyl acetate(l50 ml) and glacial acetic acid to pH 4-4.5 were added to the suspension. The organic phase recovered by decanting was washed again with water (45 ml) and subsequently concentrated. The suspension was then diluted with EtOH (130 ml), heated to 60-70C for 1 h, cooled to 0-5C and, after 1 h, filtered and washed with cold EtOH. The solid was dried under vacuum at 60C for at least 6 h to give Raltegravir (24.3 g, 54.6 mmol) in 90% yield and 99.8% HPLC purity.
79.2%	With 4-methyl-morpholine; In acetonitrile; at -5 - 5℃; for 1.5h;	Compound (Xa) (20 g, 0.057 mole MC: -5%) was suspended in toluene (200 ml), azeotropically dried at reflux temperature and the toluene was completely removed by co-distillation with acetonitrile (20 ml). Acetonitrile (80 ml) and N-methylmorpholine (16.5 g, 0.163 mole) were added to the concentrated mass and the resulting slurry was cooled to -5 to 5C. Oxadiazole-5-methyl-2-carbonylchloride slurry was added to the above slurry at -5 to 5C in -30 min and stirred for lhr at 0-5C. After completion of reaction, acetonitrile was distilled at 50-55C under reduced pressure till total volume of reaction mass became to four volume. After that water (80 ml) was added and the pH of the reaction mass was adjusted to -9.0 with aqueous potassium hydroxide solution. The mass was stirred for 1 hr at 25-30C. Then the pH of reaction mass was adjusted to 4.0- 4.5 with 5N aqueous hydrochloric acid and stirred the mass for 15-min. DM water (120 ml) was added slowly and the resulting slurry was stirred for ~3hrs at 20-25C The product was filtered and washed with mixture of water and acetonitrile (2.5: 1.0, 40 ml) and dried at 45- 50C under reduced pressure to obtain the title compound (I) 20 g. Yield: 79.2%, Purity (By HPLC, by area normalization): -96%.
		Reagent Mass mL Moles Eq. oxadiazole K salt i 33.8 g (96.1 wt %) 0.20 2.2 MeCN 280 mL DMF 0.33 oxalyl chloride 23.7 g 16.3 mL 0.19 2.1 free amine h 30 g (99 Wt %) 0.089 1 THF 821 mL NMM 21.56 g 23.4 mL 0.21 2.4NH4OH (30% in H2O) 62.3 g 69 mL 0.53 6 HCl (2N) 500 mL IPA 920 mL water 400 mL MeOH 300 mL A 500 mL round bottom flask was charged with oxadiazole K salt i (33.8 g) followed by MeCN (280 mL) and DMF (0.33 mL) with strong stirring. The resulting slurry was then cooled down to 0-5 C. and oxalyl chloride (23.7 g) was added over the course of 20 minutes in order to maintain the internal temperature at less than 5 C. The resulting acyl chloride-containing slurry was then aged for 1 hour. To a 2 L round bottom flask the free amine h (30 g) was added followed by THF (821 mL). The resulting slurry was cooled down to 0-5 C., after which NMM (21.56 g) was added and the slurry so obtained was stirred for 10 minutes at the cold temperature. The previously prepared acyl chloride-containing slurry was added slowly to the free amine slurry over the course of 20 minutes such that the temperature did not exceed 5 C. The slurry was then aged for 1.5 hours at 0-5 C. At this time HPLC showed no more amine h (<0.5% LCAP, 100% conversion). The reaction mixture was then quenched with NH4OH (30% in water) (69 mL) which was added over the course of 3 minutes. The resulting yellow slurry was then stirred for an additional hour at temperatures less than 10 C. The yellow slurry was then acidified to pH 2-3 with HCl (2N) (500 mL). To the resulting red wine colored solution, IPA (920 mL) was added. The low boiling point organic solvents were then evaporated under reduced pressure (40 torr) at room temperature to a final solution volume of 1100 mL, at which volume crystalline Compound A began to precipitate. Water (400 mL) was then added to this new slurry over the course of 10 minutes, and the slurry aged overnight at room temperature. The aged slurry was filtered and the solid obtained was washed with water (170 mL), followed by a swish wash with cold MeOH (300 mL, previously cooled in an ice bath), and finally by a swish wash with water (700 mL). The solid so obtained was dried overnight under vacuum and nitrogen stream to give 35.5 g of Compound A (91% yield).
		A 500 mL round bottom flask was charged with oxadiazole K salt i (33.8 g) followed by ACN (280 mL) and DMF (0.33 mL) with strong stirring. The resulting slurry was then cooled down to 0-50C and oxalyl chloride (23.7 g) was added over the course of 20 minutes in order to maintain the internal temperature at less than 50C. The resulting acyl chloride-containing slurry was then aged for 1 hour.To a 2 L round bottom flask the free amine h (30 g) was added followed by THF (821 mL). The resulting slurry was cooled down to 0-50C, after which NMM (21.56 g) was added and the slurry so obtained was stirred for 10 minutes at the cold temperature. The previously prepared acyl chloride-containing slurry was added slowly to the free amine slurry over the course of 20 minutes such that the temperature did not exceed 5 0C. The slurry was then aged for 1.5 hours at 0-50C. At this time HPLC showed no more amine h (<0.5 % LCAP, 100% conversion). The reaction mixture was then quenched with NH4OH (30 % in water) (69 mL) which was added over the course of 3 minutes. The resulting yellow slurry was then stirred for an additional hour at temperatures less than 1O0C. The yellow slurry was then acidified to pH 2-3 with HCl (2N) (500 mL). To the resulting red wine colored solution, IPA (920 mL) was added. The low boiling point organic solvents were then evaporated under reduced pressure (40 torr) at room temperature to a final solution volume of 1100 mL, at which volume EPO <DP n="35"/>crystalline Compound A began to precipitate. Water (400 mL) was then added to this new slurry over the course of 10 minutes, and the slurry aged overnight at room temperature. The aged slurry was filtered and the solid obtained was washed with water (170 mL), followed by a swish wash with cold MeOH (300 mL, previously cooled in an ice bath), and finally by a swish wash with water (700 mL). The solid so obtained was dried overnight under vacuum and nitrogen stream to give 35.5 g of Compound A (91% yield).
115 g		A mixture of oxadiazole K-salt Va (79.5 g, 0.478 mol), acetonitrile (400 ml), and DMF (2.47 ml) was cooled to -5 C and oxalyl chloride (38.4 ml, 0.448 mol) is added over a course of 30 min. The resulting slurry was aged at 0-5 C for lh, then cooled to -10 C. (0151) A slurry of amine lib (100 g, 0.299 mol) and THF (1L) was stirred at room temperature and HMDS (49.5 ml, 0.239 mol) is added dropwise over a period of 5 min. To the resulting suspension 1.71g p-TsOH (8.9 mmol) were added in one portion. The reaction mixture was heated at 60-65 C for 2h, then cooled down at -5- (0152) 0 C and N-methylmorpholine (98.8 ml, 0.898 mol) was added. The resulting solution was aged at -5 C for 20 min. The oxadiazole acid chloride Va was added dropwise to the amine containing slurry reaction mixture at -5 C over a course of 45 min. Reaction is monitored with HPLC and after completion 20% aq. potassium hydroxide (500 ml) was added and the reaction mixture is stirred at 5 C for lh. HC1 2N (370 ml) was added over 10 min to adjust pH at 3-4 and reaction mass is warmed at 15 C. 3.75 L ml water were added slowly over a course of lh. The resulting white suspension was aged at 15 C for 1 h and filtered. The cake was washed with 300 ml water/acetonitrile (2.5: 1) and 300 ml water. White solid is dried to afford Raltegravir (0153) 1 (115 g, 0.258 mol). (0154) 1H-NMR (500 MHz, DMSO-d6) delta 12.21 (s, 1 H), 9.86 (s, 1H), 9.08 (t, J = 6.4 Hz, 1 H), 7.41-7.38 (m, 2 H), 7.19-7.15 (m, 2 H), 4.52 (d, J = 6.4 Hz, 2 H), 3.49 (s, 3 H), 2.56 (s, 3 H), 1.74 (s, 6 H). (0155) 13C-NMR (125 MHz, DMSO-d6) delta 168.4, 165.7, 162.2, 160.3, 158.5, 158.1, 152.6, 151.8, 145.7, 134.9, 129.5, 124.4, 115.2, 57.6, 41.6, 32.9, 27.0, 10.7.

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