252742-72-6|3-(Chloromethyl)-1H-1,2,4-triazol-5(4H)-one| Ambeed

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Quality Control of [ 252742-72-6 ] Purity: 97% SDS Specification

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Product Details of [ 252742-72-6 ]

CAS No. :	252742-72-6
Formula :	C₃H₄ClN₃O
M.W :	133.54
SMILES Code :	ClCC1=NNC(=O)N1
MDL No. :	MFCD07776630
InChI Key :	ZLRBJVJEQXBAAI-UHFFFAOYSA-N
Pubchem ID :	135546685

Safety of [ 252742-72-6 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H302-H314
Precautionary Statements:	P260-P264-P270-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P405-P501
Class:	8
UN#:	3261
Packing Group:	Ⅱ

Computational Chemistry of [ 252742-72-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	8
Num. arom. heavy atoms	5
Fraction Csp3	0.33
Num. rotatable bonds	1
Num. H-bond acceptors	2.0
Num. H-bond donors	2.0
Molar Refractivity	28.97
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	61.54 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.49
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	-0.16
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	-0.32
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.	-0.26
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	1.92
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.33

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-0.96
Solubility	14.5 mg/ml ; 0.109 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-0.68
Solubility	28.1 mg/ml ; 0.21 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very 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	-1.76
Solubility	2.34 mg/ml ; 0.0175 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	No
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.	-7.23 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	2.0
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	1.0 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<1.0
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)	1.41

Application In Synthesis of [ 252742-72-6 ]

* 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.

Upstream synthesis route of [ 252742-72-6 ]
Downstream synthetic route of [ 252742-72-6 ]

[ 252742-72-6 ] Synthesis Path-Upstream 1~4

1
[ 24021-90-7 ]
[ 252742-72-6 ]

Yield	Reaction Conditions	Operation in experiment
90.7%	With thionyl chloride In acetonitrile at 5 - 20℃;	5-Hydroxymethyl-2,4-dihydro[1,2,4]triazol-3-one (100 g, 869 mmol) and anhydrous acetonitrile (1 L) were added to a 5 L four-necked flask, and the system was cooled to 5 ° C. Then, SOCl2 (150 g, 1261 mmol) was slowly added to the system under stirring. After the addition, the system was slowly warmed up to room temperature, and the TLC plate was traced until the reaction was complete. Then the system was decompressed under high vacuum conditions (including unreacted SOCl2). EtOAc (1 L) and H2 (EtOAc) (EtOAc) (EtOAc) The organic phase was combined, and the organic phase was washed with brine (2×500 mL), and the solvent was evaporated from the organic phase. The residue was added to the mixture of n-heptane (1 L) for 2 hours, filtered, and dried at 50 ° C. 5-Chloromethyl-2,4-dihydro[1,2,4]triazol-3-one (solid, 105.2 g, yield 90.7percent).
87.4%	With thionyl chloride In hexane; acetonitrile	EXAMPLE 3 Preparation of 3-Chloromethyl-1,2,4-triazolin-5-one Thionyl chloride (19.9 g) was added, over five minutes, to a slurry of 3-hydroxymethyl-1,2,4-triazolin-5-one (17 g) in acetonitrile (170 ml) at 20° C. under a nitrogen atmosphere. The reaction mixture as aged at 20° C. for 18 hours. [Note: after 30 minutes all the starting material had dissolved. At 1 hour the product began to crystallise]. TLC analysis (SiO₂; ethyl acetate/methanol(9/1); I₂) indicated that the reaction was complete. Hexane(510 ml) was added in one portion, the reaction cooled in an ice bath for 1 hour and the product collected by filtration. The solid was washed with hexane(100 ml) and dried in vacuo. 3-Chloromethyl-1,2,4-triazolin-5-one(17.2 g) was obtained as a white solid in 87.4% yield. mp 197-199° C.; ¹H NMR in d₆ DMSO δ=4.43(2H, s, CH₂), 11.48 (1H, s, NH) and 11.64(1H, s, NH)ppm and ¹³C NMR in d₆ DMSO, δ=37.0(ClCH₂), 144.4(CH₂C=N) and 156.8 (NHCONH) ppm.

References: [1] Patent: CN109485613, 2019, A, . Location in patent: Paragraph 0022.
[2] Tetrahedron Letters, 2000, vol. 41, # 44, p. 8661 - 8664.
[3] Patent: US6297376, 2001, B1, .
[4] Patent: WO2017/106062, 2017, A1, . Location in patent: Page/Page column 65.

2
[ 563-41-7 ]
[ 74974-54-2 ]
[ 252742-72-6 ]

Yield	Reaction Conditions	Operation in experiment
62%	at 20℃;	4.0 g Semicarbazide hydrochloride, 9.67 mL 2-chloro-1,1,1-trimethoxyethane and 40 mL methanol were combined and stirred at ambient temperature for 3 d. After this time additional 3.5 mL 2-chloro-1,1,1-trimethoxyethane was added to complete the reaction. The mixture was then concentrated under reduced pressure and the crude product was partitioned between ethyl acetate and 1N hydrochloric acid. The organic phase separated and it was washed with additional 1N hydrochloric acid (.x.2). The combined aqueous extracts were extracted with ethyl acetate (.x.5) and all of the organic fraction were then combined, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The solid that remained was triturated with ethyl acetate to give the title compound which was used without further purification.Yield: 2.97g (62percent of theory)Analysis: ¹H NMR (500 MHz, dimethyl sulfoxide-d6) in ppm 4.49 (2H, s), 11.55 (1H, br. s.), 11.70 (1H, br. s.)

References: [1] Tetrahedron Letters, 2000, vol. 41, # 44, p. 8661 - 8664.
[2] Patent: US2012/28939, 2012, A1, . Location in patent: Page/Page column 27.
[3] Patent: WO2011/92128, 2011, A1, . Location in patent: Page/Page column 51-52.
[4] Patent: WO2014/139328, 2014, A1, . Location in patent: Page/Page column 614.
[5] Patent: WO2006/133426, 2006, A2, . Location in patent: Page/Page column 276.

3
[ 74974-54-2 ]
[ 252742-72-6 ]

References: [1] Patent: US2003/187274, 2003, A1, .

4
[ 4426-72-6 ]
[ 74974-54-2 ]
[ 252742-72-6 ]

References: [1] Patent: WO2009/67233, 2009, A1, . Location in patent: Page/Page column 69.

[ 252742-72-6 ] Synthesis Path-Downstream 1~35

1
[ 100-53-8 ]
[ 252742-72-6 ]
[ 866602-60-0 ]

Yield	Reaction Conditions	Operation in experiment
61%	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 20.5h;	Benzylmercaptan (1.75 mL; 14.9 mmol) was dissolved in DMF (20 mL) and solid K2CO3 (2. 35 g; 17 mmol) was added. To the resulting slurry was added a solution of 5-(chloromethyl)-2,4-dihydro-3H-1, 2,4-triazol-3-one (2.0 g; 15 mmol) in DMF (12 mL), prepared by a literature procedure (C. J. Cowden et. al., Tetrahedron Letters 41 (2000) 8661-8664). The reaction mixture was stirred at room temperature for 20.5 h. Water (80 mL) was added and a thick slurry was formed. The solid product was collected by filtration and washed with water. The remaining filtrate and wash liquid still contained product and was extracted four times with EtOAc, and the organic phase was then washed with water (twice), brine (twice) and dried (Na2SO4). Evaporation of solvents gave another crop of crude product. The combined solid materials were suspended in toluene and evaporated to remove water residues. The crude product was then suspended in a boiling mixture of EtOAc/heptane (1: 4) and allowed to cool before the solid product was collected by filtration. The subtitle compound was obtained as a colourless solid (2.03 g; 61percent yield). APCI-MS m/z: 222.1 [MH+]. 'H-NMR (DMSO-D6): 8 11.35 (1H, vbrs), 11.26 (1H, brs), 7.37-7. 21 (5H, m), 3.72 (2H, s), 3.36 (2H, s) ppm. '3C-NMR (DMSO-D6): 8 156.09, 144.75, 137.66, 128.83, 128.23, 126.79, 34.75, 25.80 ppm.

References: [1]Patent: WO2005/95362,2005,A1 .Location in patent: Page/Page column 24.

2
[ 563-41-7 ]
[ 74974-54-2 ]
[ 252742-72-6 ]

Yield	Reaction Conditions	Operation in experiment
62%	In methanol; at 20℃;	4.0 g Semicarbazide hydrochloride, 9.67 mL 2-chloro-1,1,1-trimethoxyethane and 40 mL methanol were combined and stirred at ambient temperature for 3 d. After this time additional 3.5 mL 2-chloro-1,1,1-trimethoxyethane was added to complete the reaction. The mixture was then concentrated under reduced pressure and the crude product was partitioned between ethyl acetate and 1N hydrochloric acid. The organic phase separated and it was washed with additional 1N hydrochloric acid (.x.2). The combined aqueous extracts were extracted with ethyl acetate (.x.5) and all of the organic fraction were then combined, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The solid that remained was triturated with ethyl acetate to give the title compound which was used without further purification.Yield: 2.97g (62percent of theory)Analysis: 1H NMR (500 MHz, dimethyl sulfoxide-d6) in ppm 4.49 (2H, s), 11.55 (1H, br. s.), 11.70 (1H, br. s.)
	In methanol; at 20℃; for 72h;	Step 14.0 g Semicarbazide hydrochloride, 9.67 mL 2-chloro-1 ,1 ,1 -trimethoxyethane and 40 mL methanol were combined and stirred at ambient temperature for 3 d. After this time additional 3.5 mL 2-chloro-1 ,1 ,1 -trimethoxyethane was added to complete the reaction. The mixture was then concentrated under reduced pressure and the crude product was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic phase separated and it was washed with additional 1 N hydrochloric acid (x2). The combined aqueous extracts were extracted with ethyl acetate (x5) and all of the organic fraction were then combined, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The solid that remained was triturated with ethyl acetate to give the title compound which was used without further purification.Yield: 2.97g (62percent of theory)Analysis: 1H NMR (500 MHz, dimethyl sulfoxide-d6) in ppm 4.49 (2 H, s), 1 1.55 (1 H, br. s.), 1 1.70 (1 H, br. s.)
	In methanol; at 20℃; for 144h;	A mixture of semicarbazide hydrochloride (5 g, 44.8 mmol) and 2-chloro- 1, 1, 1- trimethoxyethane (13.29 ml, 99 mmol) in methanol (50 ml) was stirred at room temperature for 3 days at which time the reaction became a homogenous solution. Additional 2-chloro- 1, 1,1- trimethoxyethane (4.3 ml, 32.3 mmol) was added and the reaction was stirred for 3 days longer. The reaction mixture was concentrated and the residue was partitioned in ethyl acetate (500 mL) and IN aqueous HC1 (75 mL). The organic layer was washed with additional IN aqueous HC1 (2 x 75 mL). The combined aqueous layers were back-extracted with additional ethyl acetate (5 x 100 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound. MS (DCI+) m/z 150.9 (M+NH4)+.

In methanol; at 20℃; for 3h;

Example 325-chloromethyl-2,4-dihydro-l ,2,4-triazol~3-one (74); [0718] Semicarbazide.HCl (5 g, 89 mmol), 2-chloro-l,l,l-trimethoxyethane (12.07 mL, 179 mmol) and methanol (50 mL) were combined and stirred at room temperature for 3 days, with the reaction monitored by 1H NMR. Additional 2-chloro- 1,1,1 -trimethoxyethane (8.77 mL) was added to complete the reaction. Methanol was then removed under vacuum. The resulting residue was extracted with ethyl acetate (500 mL) and washed with IN HCl (2 x 100 mL). The aqueous phase was back extracted with ethyl acetate (5 X 100 mL). The organic layers were then combined, dried over anhydrous sodium sulfate, and solvent was removed under reduced pressure to give 3.1 g of 5-chloromethyl-2,4-dihydro-l,2,4-triazol-3- one (74) as a white powder. 1H NMR (DMSO-d6): delta 11.65 (s, 1H), 11.50 (s, 1H), 4.48 (s, 2H); LCMS (m/z): 133.90 (M+).

References: [1]Tetrahedron Letters,2000,vol. 41,p. 8661 - 8664.
[2]Patent: US2012/28939,2012,A1 .Location in patent: Page/Page column 27.
[3]Patent: WO2011/92128,2011,A1 .Location in patent: Page/Page column 51-52.
[4]Patent: WO2014/139328,2014,A1 .Location in patent: Page/Page column 614.
[5]Patent: WO2006/133426,2006,A2 .Location in patent: Page/Page column 276.

3
[ 24021-90-7 ]
[ 252742-72-6 ]

Yield	Reaction Conditions	Operation in experiment
90.7%	With thionyl chloride; In acetonitrile; at 5 - 20℃;	5-Hydroxymethyl-2,4-dihydro[1,2,4]triazol-3-one (100 g, 869 mmol) and anhydrous acetonitrile (1 L) were added to a 5 L four-necked flask, and the system was cooled to 5 ° C. Then, SOCl2 (150 g, 1261 mmol) was slowly added to the system under stirring. After the addition, the system was slowly warmed up to room temperature, and the TLC plate was traced until the reaction was complete. Then the system was decompressed under high vacuum conditions (including unreacted SOCl2). EtOAc (1 L) and H2 (EtOAc) (EtOAc) (EtOAc) The organic phase was combined, and the organic phase was washed with brine (2×500 mL), and the solvent was evaporated from the organic phase. The residue was added to the mixture of n-heptane (1 L) for 2 hours, filtered, and dried at 50 ° C. 5-Chloromethyl-2,4-dihydro[1,2,4]triazol-3-one (solid, 105.2 g, yield 90.7percent).
87.4%	With thionyl chloride; In hexane; acetonitrile;	EXAMPLE 3 Preparation of 3-Chloromethyl-1,2,4-triazolin-5-one Thionyl chloride (19.9 g) was added, over five minutes, to a slurry of 3-hydroxymethyl-1,2,4-triazolin-5-one (17 g) in acetonitrile (170 ml) at 20 C. under a nitrogen atmosphere. The reaction mixture as aged at 20 C. for 18 hours. [Note: after 30 minutes all the starting material had dissolved. At 1 hour the product began to crystallise]. TLC analysis (SiO2; ethyl acetate/methanol(9/1); I2) indicated that the reaction was complete. Hexane(510 ml) was added in one portion, the reaction cooled in an ice bath for 1 hour and the product collected by filtration. The solid was washed with hexane(100 ml) and dried in vacuo. 3-Chloromethyl-1,2,4-triazolin-5-one(17.2 g) was obtained as a white solid in 87.4% yield. mp 197-199 C.; 1H NMR in d6 DMSO delta=4.43(2H, s, CH2), 11.48 (1H, s, NH) and 11.64(1H, s, NH)ppm and 13C NMR in d6 DMSO, delta=37.0(ClCH2), 144.4(CH2C=N) and 156.8 (NHCONH) ppm.
	With thionyl chloride; at 20℃; for 18h;Inert atmosphere;	To a suspension of 3-(hydroxymethyl)-lH-l,2,4-triazol-5(4H)-one (850 mg, 7.39 mmol) in MeCN (10.0 mL) was added thionyl chloride (0.647 mL, 8.86 mmol) at 20 C under a nitrogen atmosphere. The reaction mixture was stirred at 20 C for 18 hours, and concentrated in vacuo. The residue was partitioned between ethyl acetate (20.0 mL) and water (10.0 mL). The organic layer was washed with saturated NaHCC (10.0 mL, aq) and brine (10.0 mL), and concentrated in vacuo. The residue was triturated with petroleum ether (20.0 mL), filtered, and washed with petroleum ether several times to give the crude title compound (900 mg) as a solid which was used in the next step without further purification. XH NMR (400 MHz, DMSO-c) delta 11.73 (br. s., 1 H), 11.49 - 11.62 (m, 1 H), 4.50 (s, 2 H). ESI MS m/z 134 [M+H]+

References: [1]Patent: CN109485613,2019,A .Location in patent: Paragraph 0022.
[2]Tetrahedron Letters,2000,vol. 41,p. 8661 - 8664.
[3]Patent: US6297376,2001,B1 .
[4]Patent: WO2017/106062,2017,A1 .Location in patent: Page/Page column 65.

4
[ 606929-58-2 ]
[ 252742-72-6 ]
[ 606929-61-7 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 3859 - 3863.

5
[ 252742-72-6 ]
[ 171338-27-5 ]
[ 172822-29-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In water; N,N-dimethyl-formamide; at 0℃; for 4h;	EXAMPLE 10: ALTERNATIVE PROCESS FOR THE PREPARATION OF APREPITANT (FORMULA I)10 g of the compound of Formula IIb obtained from Example 6 and 30 ml of N,N-dimethylformamide (DMF) were charged into a clean and dry 4 neck round bottom flask followed by stirring for about 10 minutes. The reaction solution was cooled to about 0 0C and a mixture of 3.5 g of potassium carbonate and 1 ml of water was charged. To the resultant reaction mixture a solution of 3.7 g of 3- chloromethyl-1 ,2,4-triazolin-5-one of Formula (IIe) dissolved in 10 ml of N1N- dimethylformamide (DMF) was charged followed by stirring at about 0 0C for about 4 hours. After the completion of the reaction, 100 ml of water was charged followed by stirring for about 30 minutes. The separated solid was filtered and the solid was washed with 20 ml of water. The solid obtained was dried at about 60 0C for about 3 hours to afford 8 g of aprepitant of Formula I. Specific optical rotation (SOR): [alpha]D25 = +61.18° (C = 0.68percent MeOH); Purity by RS HPLC: 94.36percent; Purity by chiral HPLC: (+)-cis isomer: 97.12percent; (-)-cis isomer: 2.87percent.

References: [1]Patent: WO2007/44829,2007,A2 .Location in patent: Page/Page column 37.

6
benzyl[(2S,3S)-2-phenyl-3-piperidinyl]carbamate [ No CAS ]
[ 252742-72-6 ]
benzyl[(2S,3S)-1-[(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2-phenyl-3-piperidinyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 1h;	To a solution of benzyl[(2S,3S)-2-phenyl-3-piperidinyl]carbamate (100 mg) in a mixture of N,N- dimethylformamide (0.66 ml) and water (0.01 ml) were added potassium carbonate (27 mg) and <strong>[252742-72-6]5-(chloromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one</strong> (45 mg), and the whole was stirred at room temperature for 1 hour. The mixture was poured into cold water (30 ml) and stirred for 10 minutes. The resulting precipitates was collected by filtration, washed with water, and dried to give the title compound (108 mg) . MASS (ES+): 408 (M+H)+

References: [1]Patent: WO2004/111000,2004,A2 .Location in patent: Page 45.

7
cis-4-[[3,5-bis(trifluoromethyl)benzyl]oxy]-3-phenylpiperidine hydrochloride [ No CAS ]
[ 252742-72-6 ]
5-[[cis-4-[[3,5-bis(trifluoromethyl)benzyl]oxy]-3-phenylpiperidinyl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%	With potassium carbonate; In DMF (N,N-dimethyl-formamide); water; at 0℃; for 3h;	To a mixed solution of the compound (0.15 g) obtained in Example 1 and potassium carbonate (0.047 g) in DMF (2 ml) and water (0.02 ml), <strong>[252742-72-6]5-(chloromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one</strong> (0.046 g) synthesized by the method described in the document (e.g., Tetrahedron Letters, Vol. 41, pages 8661-8664) was added at 0°C, and the reaction mixture was stirred at 0°C for 3 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was isolated and purified by silica gel column chromatography (ethyl acetate : methanol = 20 : 1) to obtain the title compound as colorless crystals (0.050 g, 29percent). Melting point: 89 - 91°C (recrystallized from ethyl acetate - IPE).

References: [1]Patent: EP1553084,2005,A1 .Location in patent: Page/Page column 57.

8
[ 874481-18-2 ]
[ 252742-72-6 ]
N-(2,4-dichlorobenzyl)-7-{(3RS,5SR)-3,5-dimethyl-4-[(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]piperazin-1-yl}-6-fluoro-8-methoxy-4-oxo-1-(2,2,2-trifluoroethyl)-1,4-dihydroquinoline-3-carboxamide [ No CAS ]

References: [1]Patent: WO2006/8046,2006,A1 .Location in patent: Page/Page column 92.

9
[ 74974-54-2 ]
[ 252742-72-6 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; toluene;	EXAMPLE 1 3-Chloromethyl-1,2,4-triazolin-5-one A mixture of semicarbzide hydrochloride (5.69 Kg, 51.0 mol), 2-chloro-1,1,1-trimethoxy ethane (94.0 mol) and methanol (54 L) was stirred at room temperature for 4 days. The solvent was then removed under reduced pressure and toluene (25 L) was added. The resulting slurry was cooled to 0° C. and filtered to afford 3-chloromethyl-1,2,4-triazolin-5-one (6.69 Kg, 98percent) as a white solid (mp 197-199° C.); 1H NMR (d6 DMSO) delta=4.43 (2H, s, CH2), 11.48 (1H, s, NH) and 11.64 (1H, s NH); 13C NMR (d6 DMSO) delta=36.9 (ClCH2), 144.6 (CH2C=N) and 156.9 (NHCONH). The difficulty in following the reaction of such water soluble compounds has been overcome using the following HPLC conditions:

References: [1]Patent: US2003/187274,2003,A1 .

10
C₂₃H₂₃F₇N₂O*ClH [ No CAS ]
[ 252742-72-6 ]
C₂₆H₂₇F₇N₅O₂⁽¹⁺⁾*Cl^(1-) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In water; N,N-dimethyl-formamide; at 0 - 20℃; for 14h;	Example 53 (3R,4R)-N-[3,5-bis(trifluoromethyl)benzyl]-3-(4-fluorophenyl)-N-methyl-1-[(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]piperidine-4-carboxamide hydrochloride To a solution of the compound (0.30 g) obtained in Example 11 and potassium carbonate (0.083 mg) in 1percent H2O-DMF (5.0 mL) was added <strong>[252742-72-6]5-(chloromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one</strong> (0.096 g) at 0°C, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the product was extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC. The obtained product was treated with 1 equivalent of 4N hydrogen chloride/ethyl acetate solution to give the title compound as a white powder (0.30 g, 89percent). MS(ESI+): 560(M-HCl+H)

References: [1]Patent: EP1705176,2006,A1 .Location in patent: Page/Page column 52.

11
C₂₄H₂₅F₇N₂O*ClH [ No CAS ]
[ 252742-72-6 ]
C₂₇H₂₉F₇N₅O₂⁽¹⁺⁾*Cl^(1-) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In water; N,N-dimethyl-formamide; at 0 - 20℃; for 14h;	Example 54 (3R,4R)-N-[3,5-bis(trifluoromethyl)benzyl]-3-(4-fluoro-2-methylphenyl)-N-methyl-1-[(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]piperidine-4-carboxamide hydrochloride To a solution of the compound (0.30 g) obtained in Example 12 and potassium carbonate (0.083 mg) in 1percent H2O-DMF (5.0 mL) was added <strong>[252742-72-6]5-(chloromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one</strong> (0.094 g) at 0°C, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the product was extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC. 1H-NMR(CDCl3)delta: 1.70-2.00 (1H, m), 2.05-2.40 (6H, m), 2.75-3.10 (6H, m), 3.45-3.49 (2H, m), 3.65-3.80 (1H, m), 4.16 (1H, d, J=15.0Hz), 4.88 (1H, d, J=15.0Hz), 6.70-6.80 (2H, m), 7.00-7.18 (1H, m), 7.33-7.40 (2H, m), 7.70-7.82 (1H, m), 10.21 (1H, br s), 10.3-11.0 (1H, br) The obtained product was treated with 1 equivalent of 4N hydrogen chloride/ethyl acetate solution to give the title compound as a white powder (0.28 g, 78percent). MS(ESI+): 574(M-HCl+H)

References: [1]Patent: EP1705176,2006,A1 .Location in patent: Page/Page column 52.

12
trans-1-{2-[(3,5-dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazine [ No CAS ]
[ 252742-72-6 ]
trans-5-[(4-{2-[(3,5-dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazin-1-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h;	Step A:; trans-5-[(4-{2-[(3,5-Dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazin-1-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one After reconversion to the base, the compound obtained in Step C of Example 1 (2.14 mmol) is dissolved in 30 ml of dimethylformamide. There are added 0.75 ml (4.28 mmol) of diisopropylethylamine and 314 mg (2.35 mmol) of <strong>[252742-72-6]5-(chloromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one</strong> prepared according to the method described in Tetrahedron Letters, 2000, 41, 8661. The mixture is stirred for 12 hours at ambient temperature and then evaporated to dryness. The residue obtained is taken up in dichloromethane, washed, dried, filtered and evaporated. The oil obtained is purified by flash chromatography on silica to yield the expected product.

References: [1]Patent: US2006/229318,2006,A1 .Location in patent: Page/Page column 14.

13
N₂-(3-aminosulfonyl-4-fluorophenyl)-5-fluoro-N₄-(4-hydroxyphenyl)-2,4-pyrimidinediamine [ No CAS ]
[ 252742-72-6 ]
N₂-(3-aminosulfonyl-4-fluorophenyl)-5-fluoro-N₄-[4-(2,4-dihydro-3-oxo-1,2,4-triazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In butanone; at 140℃; for 5h;Microwave irradiation;	1-200: N2-(3-Aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(254-dihydro-3-oxo-l,2,4- triazol-5-yl)methyleneoxyphenyI]-2,4-pyrimidinediamine (76); [0719] To a solution of 5-chloromethyl-2,4-dihydro-l ,2,4-triazol-3-one (35 mg, 0.26 mmol) in 2-butanone, were added N2-(3-aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-(4- hydroxyphenyl)-2,4-pyrimidmediamme (100 mg, 0.25 mmol) and potassium carbonate (35 mg, 0.25 mmol). The resulting mixture was micro waved at 140 0C for 5 hours, and then additional of 5-chloromethyl-2,4-dihydro-l,2,4-triazol-3-one was added as needed The reaction solvent was removed under a reduced pressure, and the residual was purified by column chromatography (silica gel, dichloromethane: methanol 8:2 v/v) to give 25 mg of N2- (3-aminosulfonyl-4-fluorophenyl)-5-fluoro-N4-[4-(2,4-dihydro-3-oxo-l,2,4-triazol-5- yl)methoxyphenyl]-2,4-pyrimidinediamine (76) as a light yellow solid. 1H NMR (D2O): delta 7.90-7.89 (d, J= 3 Hz, 1H), 7.60-7.58 (d, J= 6 Hz, 1H), 7.34 (bs, 2H), 7.24-7.18 (m, 2H), 7.05-7.02 (d, J= 9.0 Hz, 2H), 6.65-6.62 (d, J= 9.0 Hz, 2H), 5.11 (br s, 2H); LCMS (m/z): 491.05 (MH+).

References: [1]Patent: WO2006/133426,2006,A2 .Location in patent: Page/Page column 276-277.

14
[ 614729-48-5 ]
[ 252742-72-6 ]
[ 614729-09-8 ]

Yield	Reaction Conditions	Operation in experiment
7%	With potassium carbonate; In diethyl ether; water; ethyl acetate; acetonitrile;	Example 408 5-[4-(2-(2-Fluorophenyl)acetyl]piperidino]methyl-2,4-dihydro-[1,2,4]triazol-3-one After adding 150 mg of <strong>[252742-72-6]5-chloromethyl-2,4-dihydro-[1,2,4]triazol-3-one</strong>, 335 mg of 2-(2-fluorophenyl)-1-(piperidin-4-yl)ethanone hydrochloride and 180 mg of anhydrous potassium carbonate to acetonitrile, the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and the mixture was filtered to obtain the title compound (23 mg, 7percent yield). 1H-NMR (400 MHz, DMSO-d6); delta (ppm) 1.42-1.56 (2H, m), 1.79-1.87 (2H, m), 1.98-2.07 (2H, m), 2.45-2.55 (1H, m), 2.75-2.82 (2H, m), 3.25 (2H, s), 3.89 (2H, s), 7.09-7.16 (2H, m), 7.19-7.32 (2H, m), 11.20 (1H, s), 11.26 (1H, br s).

References: [1]Patent: US2004/167224,2004,A1 .

15
[ 614731-22-5 ]
[ 252742-72-6 ]
[ 614729-03-2 ]

Yield	Reaction Conditions	Operation in experiment
21%	With potassium carbonate; In water; ethyl acetate; acetonitrile;	Example 405 5-(4-(2-Fluorophenoxymethyl)piperidino]methyl-2,4-dihydro-[1,2,4]triazol-3-one After adding 150 mg of <strong>[252742-72-6]5-chloromethyl-2,4-dihydro-[1,2,4]triazol-3-one</strong>, 331 mg of 4-(2-fluorophenoxymethyl)piperidine hydrochloride and 180 mg of anhydrous potassium carbonate to acetonitrile, the mixture was stirred overnight at room temperature. Water and ethyl acetate were added to the reaction mixture and the insoluble portion was filtered out to obtain the title compound (70 mg, 21percent yield). 1H-NMR (400 MHz, DMSO-d6); delta (ppm) 1.26-1.38 (2H, m), 1.67-1.80 (3H, m), 1.95-2.04 (2H, m), 2.77-2.84 (2H, m), 3.24 (2H, s), 3.88 (2H, d, J=5.6 Hz), 6.87-6.94 (1H, m), 7.06-7.21 (3H, m), 11.19 (1H, s), 11.27 (1H, br s).

References: [1]Patent: US2004/167224,2004,A1 .

16
[ 22737-36-6 ]
[ 19552-10-4 ]
[ 252742-72-6 ]
[ 935760-75-1 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 12h;	Reference Example 108; 5-([(4-bromophenyl)methyl]thio}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; [Show Image] To a solution of 5-(chloromethyl) -2,4-dihydro-3H-1,2,4-triazol-3-one obtained according to the methods described in Tetrahedron Letter, 2000, 41, 8661 and the like (2.00 g, 15.0 mmol), (4-bromophenyl)methanethiol (3.04 g, 15.0 mmol) and potassium carbonate (2.48 g, 0.369 mmol) in THF (4 mL) was added a suspension of O-(trimethylsilyl)hydroxylamine (0.271 mL, 18.0 mmol) in DMF (40 mL) at room temperature, and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture, and the precipitated solid was collected by filtration. The solid was washed with water and diethyl ether to give the title compound as a white powder (3.97 g, 88percent). 1H-NMR (300MHz, DMSO-d6) delta: 3.36 (2H, s), 3.70 (2H, s), 7.28 (2H, d, J = 8.3 Hz), 7.52 (2H, d, J = 8.3 Hz), 11.29 (1H, br), 11.39 (1H, br).

References: [1]Patent: EP1953148,2008,A1 .Location in patent: Page/Page column 160.

17
[ 4426-72-6 ]
[ 74974-54-2 ]
[ 252742-72-6 ]

Yield	Reaction Conditions	Operation in experiment
		5- (chloromethyl)-2,4-dihydro-3H-l,2,4-triazol-3-one (21 mg, 0.156 mmol, 1.03 eq; prepared from semicarbazide and 2-chloro-l,l,l-trimethoxyethane as described by Cameron J. Cowden, Robert D. Wilson, Brian C. Bishop, Ian F. Cottrell, Antony J. Davies and Ulf-eta. Dolling; Tetrahedron Letters, 2000, 41, 8661-8664).

References: [1]Patent: WO2009/67233,2009,A1 .Location in patent: Page/Page column 69.

18
[ 327623-37-0 ]
[ 252742-72-6 ]
[ 172822-29-6 ]

References: [1]Synthetic Communications,2010,vol. 40,p. 2254 - 2268.
[2]Chinese Chemical Letters,2013,vol. 24,p. 1118 - 1122.

19
[ 170729-79-0 ]
[ 252742-72-6 ]
[ 170902-81-5 ]

References: [1]Synthetic Communications,2010,vol. 40,p. 2254 - 2268.

20
[ 1185503-48-3 ]
[ 252742-72-6 ]
[ 1185502-97-9 ]

References: [1]Synthetic Communications,2010,vol. 40,p. 2254 - 2268.
[2]Chinese Chemical Letters,2013,vol. 24,p. 1118 - 1122.

21
[ 1242175-38-7 ]
[ 252742-72-6 ]
[ 1242175-40-1 ]

References: [1]Synthetic Communications,2010,vol. 40,p. 2254 - 2268.

22
[ 1242175-36-5 ]
[ 252742-72-6 ]
[ 1242175-34-3 ]

References: [1]Synthetic Communications,2010,vol. 40,p. 2254 - 2268.

23
[ 170902-80-4 ]
[ 252742-72-6 ]
[ 172822-28-5 ]

References: [1]Synthetic Communications,2010,vol. 40,p. 2254 - 2268.

24
[ 252742-72-6 ]
[ 380499-06-9 ]
[ 1148113-53-4 ]

References: [1]Synthetic Communications,2010,vol. 40,p. 2254 - 2268.

25
[ 20348-23-6 ]
[ 252742-72-6 ]
C₁₀H₁₁N₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%		A solution of 33A (0.105 g 0.77 mmol) in DMF (5 mL) was treated with KN(SiMe3)2 (0.5 M/toluene, 1.8 mL, 0.93 mmol), stirred at 0° C. for 20 min, and then treated with 33B (0.155 g 1.16 mmol, Tetrahedron Letters 2000, 41, 8661). The reaction was warmed to 20° C., stirred 2 h, and concentrated. The residue was then treated with 0.5 N NaOH (10 mL) and washed with CH2Cl2 (3.x.). The aqueous layer was concentrated and subjected to chromatography (20-80percent EtOAc/hexanes) to provide 33 as a white solid (0.065 g, 36percent). LMCS m/z 234 (MH+).

References: [1]Patent: US2007/93477,2007,A1 .Location in patent: Page/Page column 41.

26
[ 252742-72-6 ]
[ 83160-78-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With ammonia; In methanol; at 20℃;	200 mg 5-Chloromethyl-2,4-dihydro-[1,2,4]triazol-3-one was placed in 25 mL of a 7N solution of ammonia in methanol at ambient temperature. The reaction was stirred overnight and then concentrated under reduced pressure. The product was used without further purification.Yield: 171 mg (100percent of theory)
	With ammonia; In methanol; at 20℃;	Step 2I-8 2.34200 mg 5-Chloromethyl-2,4-dihydro-[1 ,2,4]triazol-3-one was placed in 25 mL of a 7N solution of ammonia in methanol at ambient temperature. The reaction was stirred overnight and then concentrated under reduced pressure. The product was used without further purification. Yield: 171 mg (100percent of theory)

References: [1]Patent: US2012/28939,2012,A1 .Location in patent: Page/Page column 27.
[2]Patent: WO2011/92128,2011,A1 .Location in patent: Page/Page column 52.

27
[ 1155846-86-8 ]
[ 252742-72-6 ]
[ 1338226-05-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;	Step 1(e): 3-chloro-5-({2-oxo-1-[(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl}oxy)benzonitrile (1-6) A suspension of the 3-chloro-5-[2-hydroxy-4-(trifluoromethyl)pyridin-3-yl]oxy}benzonitrile (1-4; 2.00 g; 6.36 mmol), <strong>[252742-72-6]5-(chloromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one</strong> (1-5; 0.849 g; 6.36 mmol) and K2CO3 (0.878 g; 6.36 mmol) in DMF (32 mL) was stirred for 2 hours at room temperature, at which point LCMS analysis indicated complete conversion. The mixture was diluted with 200 mL Me-THF and washed with 150 mL 1:1:1 H2O:brine:saturated aqueous NH4Cl, then further washed with 2.x.150 mL 1:1 H2O:brine. The aqueous fractions were further extracted with 150 mL Me-THF, then the combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Purification by ISCO CombiFlash (80 g column; dry load; 100:0 to 90:10 EtOAc:EtOH over 25 minutes) provided the title compound (1-6) as a white solid. 1HNMR (400 MHz, DMSO): delta 11.46 (s, 1 H); 11.39 (s, 1 H); 7.93 (d, J=7.3 Hz, 1 H); 7.76 (s, 1 H); 7.58 (s, 1 H); 7.51 (s, 1 H); 6.67 (d, J=7.3 Hz, 1 H); 5.02 (s, 2 H).

References: [1]Patent: US2011/245296,2011,A1 .Location in patent: Page/Page column 19.
[2]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 917 - 922.

28
4-(5-fluoro-2-methoxyphenyl)-2-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride [ No CAS ]
[ 252742-72-6 ]
5-({4-[4-(5-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3,6-dihydropyridin-1(2H)-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 6h;	A mixture of Example 87D (0.05 g, 0.126 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.132 ml, 0.757 mmol) in Nu,Nu-dimethylformamide (1 mL) was treated with Example 637A (0.020 g, 0.151 mmol) and the reaction was stirred at room temperature for 3 hours. Additional N-ethyl-N- isopropylpropan-2-amine (0.05 mL) and additional Example 637A (0.010 g, 0.076 mmol) were added and the mixture was stirred 3 hours longer. The reaction mixture was directly purified by reverse phase HPLC on a Phenomenex Luna C8(2) 5 um IotaOmicronthetaAlpha AXIA column (30 mm x 75 mm) eluting with a gradient of 10-70percent acetonitrile in 0.1 percent ammonium acetate/water to afford the title compound. lH NMR (500 MHz, DMSO-d6) delta ppm 2.44 - 2.52 (m, 2H), 2.64 (t, J = 5.8 Hz, 2H), 3.14 (q, J = 2.7 Hz, 2H), 3.40 (s, 2H), 3.73 (s, 3H), 6.19 (d, J = 2.1 Hz, 1H), 6.44 - 6.51 (m, 1H), 7.02 (d, J = 4.9 Hz, 1H), 7.14 - 7.32 (m, 3H), 8.18 (d, J = 4.9 Hz, 1H), 1 1.24 (s, 1H), 1 1.30 - 1 1.39 (m, 1H), 1 1.77 (d, J = 2.2 Hz, 1H). MS (ESI+) m/z 421.1(M+H)+.

References: [1]Patent: WO2014/139328,2014,A1 .Location in patent: Page/Page column 614; 615.

29
[ 1155846-86-8 ]
[ 252742-72-6 ]
[ 1338226-05-3 ]

References: [1]Organic Process Research and Development,2016,vol. 20,p. 1476 - 1481.

30
[ 19552-10-4 ]
[ 252742-72-6 ]
[ 935760-75-1 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;	A mixture of <strong>[252742-72-6]5-(chloromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one</strong> (30, 2.00 g, 15.0 mmol, synthesized by the method of Cowden et al. 59), (4-bromophenyl)methanethiol (3.04 g, 15.0 mmol), and K2CO3 (2.48 g, 18.0 mmol) in DMF (40 mL) was stirred at room temperature for 12 h. After H2O was added to the reaction mixture, the precipitated solid was collected and washed with H2O and diethyl ether to give the title compound as a white powder (3.97 g, 13.2 mmol, 88percent). 1H NMR (300 MHz, DMSO-d6) d 3.36 (2H, s), 3.70 (2H, s), 7.28 (2H, d, J = 8.3 Hz), 7.52 (2H, d, J = 8.3 Hz), 11.29 (1H, br s), 11.39 (1H, br s).

References: [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 6149 - 6165.

31
N‐(3‐bromo‐4‐fluorophenyl)‐N'‐hydroxy‐4‐nitro‐1,2,5‐oxadiazole‐3‐carboximidamide [ No CAS ]
[ 252742-72-6 ]
N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-(((5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)thio)-1,2,5-oxadiazole-3-carboximidamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40 mg		To a solution of N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-nitro-l,2,5- oxadiazole-3-carboximidamide (100 mg, 0.289 mmol) in DMF (2.0 mL) at 25 C was added NaSH (25 mg, 0.446 mmol). The mixture was stirred at 25 C for 30 min. Then K2C03 (40 mg, 0.289 mmol) and 3-(chloromethyl)-lH-l,2,4-triazol-5(4H)-one (58 mg, 0.434 mmol) were added. The mixture was stirred at 25 C for 30 min, diluted with sat. NaHCC (10.0 mL, aq), and extracted with ethyl acetate (10.0 mL). The organic layer was washed with brine (5.0 mL), dried over MgSC>4, and concentrated. The residue was purified by reverse phase HPLC on a GILSON 281 instrument fitted with a Phenomenex Synergi C18 (25021.2 mm4 muiotaeta) using water (0.2% formic acid) and acetonitrile as eluents (Mobile phase A water(0.2% Formic acid), Mobile phase B acetonitrile, Detective wavelength: 220 nm) followed by freeze-drying to give the title compound (40 mg) as a solid. lH NMR (400 MHz, CD30D) delta 7.09 (dd, J=5.8, 2.5 Hz, 1 H), 7.04 (t, J=8.7 Hz, 1 H), 6.73 - 6.81 (m, 1 H), 4.27 (s, 2 H). ESI MS m/z 430 [M+H]+

References: [1]Patent: WO2017/106062,2017,A1 .Location in patent: Page/Page column 65; 66.

32
[ 538-37-4 ]
[ 252742-72-6 ]
C₁₇H₁₇ClN₃O₄P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium hexamethyldisilazane; In tetrahydrofuran; at -5℃;	13.35 g (100 mmol) of <strong>[252742-72-6]3-chloromethyl-1,2,4-triazolin-5-one</strong> and 50 ml of THF were added to the reaction flask, stirred well, 220ml of 1mol / L sodium hexamethyldisilazane in tetrahydrofuran solution was added, cooled to -5 ° C, a solution of dibenzylphosphoryl chloride in tetrahydrofuran (32.6 g of dibenzylphosphoryl chloride dissolved in 50 ml of tetrahydrofuran) was slowly added dropwise, after the drop wise addition, the reaction was continued to stir, TLC monitoring reaction endpoint. 300ml saturated sodium bicarbonate solution and 300 ml of isopropyl ether was added to the reaction solution, Stirred for 15min, liquid separation, organic phase was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, filtered , filtrate was concentrated to dryness , dried in vacuo to give a white solid of 35.84g, the yield was 91percent.

References: [1]Patent: CN104650143,2018,B .Location in patent: Paragraph 0031; 0032; 0043; 0044.

33
[ 990-91-0 ]
[ 252742-72-6 ]
C₁₇H₁₇ClN₃O₄P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium tert-butylate; In tetrahydrofuran; at -5℃;	13.35 g (100 mmol) of 3-chloromethyl-1, 2, 4-triazolin-5-one, 64.628 (120 mmol) tetrabenzyl pyrophosphate and 50 ml of THF were added to the reaction flask, stirred well, cooled down to -5 ° C, 24.69 g (220 mmol) of potassium t-butoxide was added, after the addition, continue to stir the reaction, TLC monitor the reaction end point. 300 ml of saturated sodium bicarbonate solution and 300 ml of isopropyl ether were added the reaction solution, stirred for 15 min, and dispense, the organic phase was washed with saturated brine until neutral, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness, dried in vacuo to give 33.86 g white solid, yield 86percent.

References: [1]Patent: CN104650143,2018,B .Location in patent: Paragraph 0037; 0038; 0040; 0041.

34
N<SUP>4</SUP>-semicarbazide hydrochloride [ No CAS ]
[ 70737-12-1 ]
[ 252742-72-6 ]

Yield	Reaction Conditions	Operation in experiment
60%	In methanol; for 70h;	Into a mechanically stirred reactor, 3.02 kg (40 mol) of chloroacetonitrile was introduced.Methanol (moisture content 0.05percent)1.28kg (40mol) and 33kg of methyl tert-butyl ether,Cool down to 2 ° C,Controlling a slow and uniform flow of 1.6 kg (44 mol) of dry HCl gas below this temperature,After the ventilation is completed,After stirring for 15 h, a large amount of white needle crystals were formed;The filter residue was filtered to obtain iminochloroethyl methyl ether hydrochloride.18kg of methanol was placed in the reaction kettle.Stirring to 50 ° C, then adding 6.1 kg of the iminochloroethyl methyl ether hydrochloride,And maintaining the reaction at 45 ° C for 2.5 hours;The reaction solution was stirred and cooled to 0 ° C.Filtered; the filtrate was stirred and warmed to 20 ° C.Adding 0.9 kg (8.07 mol) of semicarbazide hydrochloride,And maintaining the reaction at this temperature for 70 hours;The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure at 50 ° C to 50 ° C.The obtained solid was added with 6.5 kg of isopropanol.Heat and reflux for 30 min,The filtrate was filtered while hot, and the filtrate was cooled and crystallized at 5 ° C.Made of white fine needle crystals,Is 3-chloromethyl-1,2,4-triazolin-5-one, filtered,Drying at 50 ° C under vacuum to obtain a white powdery solid3-chloromethyl-1,2,4-triazolin-5-one 0.64kg,The total molar yield (based on semicarbazide hydrochloride) is 60percent,The HPLC purity was 99.3percent,

References: [1]Patent: CN109553585,2019,A .Location in patent: Paragraph 0017; 0018; 0021; 0022.

35
N<SUP>4</SUP>-semicarbazide hydrochloride [ No CAS ]
[ 36743-66-5 ]
[ 252742-72-6 ]

Yield	Reaction Conditions	Operation in experiment
62%	In ethanol; at 20℃; for 35h;	60.4 g (0.8 mol) of chloroacetonitrile and 36.8 g of ethanol (water content 0.06percent) were placed in a magnetic stirring reactor.(0.8 mol) and 400 g of dichloromethane, cooled to 5 ° C, controlled to slowly and uniformly pass 32 g (0.88 mol) of dry HCl gas below this temperature. After the completion of the aeration, the reaction was stirred for 10 h, and a large number of white needles were observed. Crystal formationThe filter residue was filtered to obtain iminochloroethyl ethyl ether hydrochloride.300 g of ethanol was placed in the reaction vessel, and the temperature was raised to 50 ° C with stirring.Then add the iminochloroethyl methyl ether hydrochloride 128g,And maintaining the reaction at 45 ° C for 6 hours; The reaction solution was stirred and cooled to -5 ° C, and suction filtered; the filtrate was stirred and heated to 40 ° C.Adding 19.5 g (0.14 mol) of semicarbazide hydrochloride,And stirring the reaction at this temperature for 35 hours; the reaction solution was filtered,The filtrate was concentrated to dryness under reduced pressure at 50 ° C to 50 ° C.The obtained solid was added to 150 g of acetone, and stirred under reflux for 30 min.The filtrate was filtered while hot, and the filtrate was cooled and crystallized at -5 ° C.Made of white fine needle crystals,Is 3-chloromethyl-1,2,4-triazolin-5-one, filtered,Drying at 55 ° C under vacuum to obtain a white powdery solid3-chloromethyl-1,2,4-triazolin-5-one 11.5g,The total molar yield (based on semicarbazide hydrochloride) was 62percent and the HPLC purity was 99.5percent.

References: [1]Patent: CN109553585,2019,A .Location in patent: Paragraph 0019; 0020.

Historical Records

Technical Information

• Acyl Group Substitution • Alkyl Halide Occurrence • Chan-Lam Coupling Reaction • Complex Metal Hydride Reductions • General Reactivity • Grignard Reaction • Hiyama Cross-Coupling Reaction • Hydride Reductions • Kinetics of Alkyl Halides • Kumada Cross-Coupling Reaction • Lawesson's Reagent • Preparation of Amines • Reactions of Alkyl Halides with Reducing Metals • Reactions of Amines • Specialized Acylation Reagents-Carbodiimides and Related Reagents • Specialized Acylation Reagents-Ketenes • Stille Coupling • Substitution and Elimination Reactions of Alkyl Halides • Suzuki Coupling

Related Functional Groups of
[ 252742-72-6 ]

Amides

A156441 [58910-25-1]

4-Ethyl-3-methyl-1H-1,2,4-triazol-5(4H)-one

Similarity: 0.75

A162219 [6969-71-7]

[1,2,4]Triazolo[4,3-a]pyridin-3(2H)-one

Similarity: 0.58

A524308 [425702-91-6]

6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Similarity: 0.51

Related Parent Nucleus of
[ 252742-72-6 ]

Triazoles

A156441 [58910-25-1]

4-Ethyl-3-methyl-1H-1,2,4-triazol-5(4H)-one

Similarity: 0.75

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CAS No.: 252742-72-6

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