3-Chloromethyl-1,2,4-triazolin-5-one

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: EXAMPLE 3 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).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 (SiO4.0 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: Example 8: Synthesis of I5-Chloromethyl-2, 4-dihydro-[1 , 2, 4]triazol-3-one-variant:To a solution of 0.6Og (1.48mmol, 1 equivalent) of III in 3.1 mL of DMF were added 226mg (1.64mmol, 1.1 equivalents) of potassium carbonate at ambient temperature. The mixture was stirred at 209C and a solution of 238mg (1.78mmol, 1.2 equivalents) of 5-Chloromethyl-2, 4-dihydro-[1 , 2, 4]triazol-3-one in 1.5ml_ of DMF was added dropwise within 15min. The reaction was stirred for 15min at 209C before 1 OmL of water were added dropwise while the product started to crystallize. The resulting suspension was stirred for 10min at 259C before it is cooled to 00C and stirred for 1 h. The crystals was collected by filtration and washed with cold water to give 416mg (68percent) of the title compound after drying under reduced pressure (400C, 10mbar) as a white crystalline product.Example 8a: Synthesis of I lambda^I -Amino^-chloro-eth-^-ylideneJ-hydrazinecarboxylic acid methyl ester-variant: To a solution of 500mg (1.14mmol, 1 equivalent) of III in 4.2mL of acetonitrile were added 546muL (3.29mmol, 2.9 equivalents) of lambda/, lambda/-diisopropylethylamine and 244mg (1.48mmol, 1.29 equivalents) of /V- [1 -Amino-2-chloro-eth-(Z)-ylidene]-hydrazinecarboxylic acid methyl ester. The resulting suspension was stirred at ambient temperature for 3h while a clear solution was formed. The reaction mixture was concentrated under reduced pressure (450C, 100mbar) and the residue was dissolved in 1 OmL of dichloromethane and washed with 1 OmL of a 26.5percent aqueous sodium chloride solution. The organic layer was concentrated under reduced pressure (459C, 100mbar). Then 4.2mL of acetonitrile were added to the residue and the mixture was transferred to a reactor where it was stirred for 55h at 1109C and 1.5bar. Then the reaction mixture was concentrated under reduced pressure (450C, 10 mbar) and the residue was dissolved in 5.6mL of methanol. The reaction mixture was heated to reflux and charcoal was added. 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).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.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]+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.)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.)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)+.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+).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.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 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 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.13.35 g (100 mmol) of

Aretetan intermediate