[ CAS No. 122181-85-5 ]

Name: 122181-85-5|Methyl 1-amino-1H-pyrrole-2-carboxylate|95%
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Product Details of [ 122181-85-5 ]

CAS No. :	122181-85-5	MDL No. :	MFCD11226170
Formula :	C₆H₈N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	N/A
M.W :	140.14 g/mol	Pubchem ID :	14104599
Synonyms :

Calculated chemistry of of [ 122181-85-5 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.17
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	35.85
TPSA :	57.25 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.66 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.52
Log Po/w (XLOGP3) :	2.1
Log Po/w (WLOGP) :	0.0
Log Po/w (MLOGP) :	0.25
Log Po/w (SILICOS-IT) :	-0.51
Consensus Log Po/w :	0.67

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.27
Solubility :	0.753 mg/ml ; 0.00537 mol/l
Class :	Soluble
Log S (Ali) :	-2.93
Solubility :	0.164 mg/ml ; 0.00117 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-0.47
Solubility :	47.2 mg/ml ; 0.337 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.75

Safety of [ 122181-85-5 ]

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

Application In Synthesis of [ 122181-85-5 ]

* 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 [ 122181-85-5 ]
Downstream synthetic route of [ 122181-85-5 ]

[ 122181-85-5 ] Synthesis Path-Upstream 1~3

1
[ 1193-62-0 ]
[ 122181-85-5 ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; Inert atmosphere Stage #2: With O-(2,4-dinitrophenyl)hydroxylamine In N,N-dimethyl-formamide; mineral oil at 0℃;	(Step 1) methy 1-amino-1H-pyrrolo-2-carboxylate; To a mixture of NaH (60percent, 4.1 g, 102.2 mmol) suspended in dimethylformamide (120 mL) at 0° C. under nitrogen atmosphere, methyl pyrrolo-1-H-2-carboxylate (8.0 g, 63.9 mmol) was slowly added over minutes. After stirring for 1 hour, a solution of 2,4-dinitrophenolamine (19.1 g, 95.9 mmol) in dimethylformamide (30 mL) was added dropwise for 30 minutes. The resulting reaction mixture was stirred at 0° C. for 2.5 hours. The reaction was completed by slowly adding saturated sodium thiosulfate aqueous solution. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with 10percent lithium chloride aqueous solution, dried with sodium sulfate, and then filtered. The filtrate was concentrated. The resulting brown residue was purified by silica gel chromatography (10percent ethyl acetate in hexane) to give the target compound as an oil (7.5 g, 53.5 mmol, 84percent yield).¹H NMR (400 MHz, CDCl₃): 6.96 (t, J=2.4 Hz, 1H), 6.83 (dd, J=4.4 Hz, 2.0 Hz, 1H), 6.02 (dd, J=4.4 Hz, 2.8 Hz, 1H) 5.54 (br s, 2H), 3.83 (s, 3H).
81.1%	Stage #1: With sodium hydride In hexanes; N,N-dimethyl-formamide at -5℃; Inert atmosphere Stage #2: With diphenyl aminooxyphosphonate In hexanes; N,N-dimethyl-formamide at 20℃; for 4 h; Stage #3: With sodium thiosulfate In hexanes; water; N,N-dimethyl-formamide at 80℃; for 1 h;	a) Methyl 1 -amino-1 W-pyrrole-2-carboxylateSodium hydride (4.40 g, 0.1 1 mol, 60percent in hexanes) was suspended in DMF (550 ml) under nitrogen atmosphere. Once cooled at - 5°C, methyl 1 H-pyrrole-2-carboxylate (1 1 .0 g, 0.09 mol) dissolved in DMF (182 ml) was dropwise added and vigorously stirred for 30. 277ml more of DMF was added and then O- (diphenylphosphoryl)hydroxylamine (32.8g, 0.14 mol) was introduced into the reaction mixture. The reaction mixture was stirred at room temperature for 4h. Once the reaction is over, 11 of saturated sodium thiosulfate solution (x5H₂0) was added and the mixture was warmed to 80°C for 1 h. Once at room temperature, 11 of ethyl ether was added and the phases separated. The aqueous phase was twice extracted with ethyl ether. The organic phase was washed with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. 10.41 g (81 .1 percent yield) of the final compound were obtained.LRMS (m/z): 141 (M+1 )⁺

Reference： [1] Patent: US2011/183983, 2011, A1, . Location in patent: Page/Page column 32
[2] Patent: WO2012/146666, 2012, A1, . Location in patent: Page/Page column 172
[3] Patent: US2010/47367, 2010, A1, . Location in patent: Page/Page column 22
[4] Patent: WO2010/71885, 2010, A1, . Location in patent: Page/Page column 335
[5] Patent: WO2016/144848, 2016, A1, . Location in patent: Page/Page column 33
[6] Patent: CN105524068, 2016, A, . Location in patent: Paragraph 0171; 0173

2
[ 122181-83-3 ]
[ 122181-85-5 ]

Reference： [1] Journal of Organic Chemistry, 1997, vol. 62, # 9, p. 2894 - 2906
[2] Tetrahedron Letters, 1988, vol. 29, # 38, p. 4823 - 4826

3
[ 122181-85-5 ]
[ 77287-34-4 ]
[ 159326-71-3 ]

Yield	Reaction Conditions	Operation in experiment
69%	at 170 - 190℃; for 3 h;	(Step 2) pyrrolo[1,2-f]1,2,4]triazin-4(3H)-one; Methyl 1H-pyrrole-2-carboxylate (7.5 g, 53.5 mmol) was dissolved in formamide (30 mL). After heating at 170° C. for 1 hour, the mixture was further heated at 190° C. for 2 hours. The resulting reaction mixture was cooled to room temperature. The produced solid was recrystallized with ethyl acetate to give the target compound as a white solid (5.0 g, 37.0 mmol, 69percent yield).¹H NMR (400 MHz, CDCl₃): 7.57 (s, 1H), 7.47 (dd, J=2.8 Hz, 1.6 Hz, 1H), 7.10 (dd, J=4.4 Hz, 1.6 Hz, 1H), 7.47 (dd, J=4.4 Hz, 2.8 Hz, 1H).

Reference： [1] Patent: US2011/183983, 2011, A1, . Location in patent: Page/Page column 32

[ 122181-85-5 ] Synthesis Path-Downstream 1~25

1
[ 122181-87-7 ]
[ 122181-85-5 ]
[ 122181-90-2 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 4823 - 4826
[2]Journal of Organic Chemistry,1997,vol. 62,p. 2894 - 2906

2
[ 122181-83-3 ]
[ 122181-85-5 ]

Reference： [1]Journal of Organic Chemistry,1997,vol. 62,p. 2894 - 2906
[2]Tetrahedron Letters,1988,vol. 29,p. 4823 - 4826

3
[ 122181-85-5 ]
5'-[1-Methoxycarbonyl-meth-(Z)-ylidene]-2'-oxo-2',3',4',5'-tetrahydro-[1,1']bipyrrolyl-2-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1997,vol. 62,p. 2894 - 2906

4
[ 122181-85-5 ]
5'-[1-Methoxycarbonyl-meth-(E)-ylidene]-2'-oxo-2',3',4',5'-tetrahydro-[1,1']bipyrrolyl-2-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1997,vol. 62,p. 2894 - 2906

5
[ 122181-85-5 ]
[ 122181-96-8 ]

Reference： [1]Tetrahedron Letters,1988,vol. 29,p. 4823 - 4826

Yield	Reaction Conditions	Operation in experiment
		(3) Synthesis of (1-amino-1H-pyrrol-2-yl)carboxylic acid methyl ester (II-29) The compound (II-29) was synthesised according to nearly the same manner as in (2) of the above-mentioned Synthesis Example 18. Light yellow oil; Yield 0.389 g (86.8%); HPLC purity 99.6% (254 nm) IR(NaCl cm-1): 3320 3210 2950 1694 1250 1100 1017 740 NMR(CDCl3, delta): 3.68(3H,S:COOCH3) 5.4(2H,bs:NH2) 5.85(1H,dd,J=3.0,4.0 Hz: pyrrole ring C4 H) 6.5~6.86(2H,m:pyrrole ring C3 H, C5 H)

7
[ 24424-99-5 ]
[ 122181-85-5 ]
[ 1208360-01-3 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,4-dioxane; for 12h;Reflux;	b) 1-tert-Butoxycarbonylamino-1H-pyrrole-2-carboxylic acid methyl ester A mixture of <strong>[122181-85-5]1-amino-1H-pyrrole-2-carboxylic acid methyl ester</strong> (309 mg, 2.20 mmol) and Boc2O (577 mg, 2.64 mmol) in dioxane (10 mL) was refluxed for 12 h; then cooled, concentrated, the residue was directly purified with silica gel column to give the desired product (448 mg) as white solid. 1H NMR (CDCl3, delta in ppm): 7.59 (s, br, 1H), 6.96-6.88 (m, 2H), 6.11 (dd, 1H, J=2.8 Hz, J=4.2 Hz), 3.80 (s, 3H), 1.49 (s, 9H).

Reference： [1]Patent: US2010/47367,2010,A1 .Location in patent: Page/Page column 22

8
[ 1193-62-0 ]
[ 122181-85-5 ]

Yield	Reaction Conditions	Operation in experiment
84%		(Step 1) methy 1-amino-1H-pyrrolo-2-carboxylate; To a mixture of NaH (60%, 4.1 g, 102.2 mmol) suspended in dimethylformamide (120 mL) at 0 C. under nitrogen atmosphere, methyl pyrrolo-1-H-2-carboxylate (8.0 g, 63.9 mmol) was slowly added over minutes. After stirring for 1 hour, a solution of 2,4-dinitrophenolamine (19.1 g, 95.9 mmol) in dimethylformamide (30 mL) was added dropwise for 30 minutes. The resulting reaction mixture was stirred at 0 C. for 2.5 hours. The reaction was completed by slowly adding saturated sodium thiosulfate aqueous solution. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with 10% lithium chloride aqueous solution, dried with sodium sulfate, and then filtered. The filtrate was concentrated. The resulting brown residue was purified by silica gel chromatography (10% ethyl acetate in hexane) to give the target compound as an oil (7.5 g, 53.5 mmol, 84% yield).1H NMR (400 MHz, CDCl3): 6.96 (t, J=2.4 Hz, 1H), 6.83 (dd, J=4.4 Hz, 2.0 Hz, 1H), 6.02 (dd, J=4.4 Hz, 2.8 Hz, 1H) 5.54 (br s, 2H), 3.83 (s, 3H).
81.1%		a) Methyl 1 -amino-1 W-pyrrole-2-carboxylateSodium hydride (4.40 g, 0.1 1 mol, 60% in hexanes) was suspended in DMF (550 ml) under nitrogen atmosphere. Once cooled at - 5C, methyl 1 H-pyrrole-2-carboxylate (1 1 .0 g, 0.09 mol) dissolved in DMF (182 ml) was dropwise added and vigorously stirred for 30. 277ml more of DMF was added and then O- (diphenylphosphoryl)hydroxylamine (32.8g, 0.14 mol) was introduced into the reaction mixture. The reaction mixture was stirred at room temperature for 4h. Once the reaction is over, 11 of saturated sodium thiosulfate solution (x5H20) was added and the mixture was warmed to 80C for 1 h. Once at room temperature, 11 of ethyl ether was added and the phases separated. The aqueous phase was twice extracted with ethyl ether. The organic phase was washed with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. 10.41 g (81 .1 % yield) of the final compound were obtained.LRMS (m/z): 141 (M+1 )+
		a) 1-Amino-1H-pyrrole-2-carboxylic acid methyl ester To a stirred, ice/water cooled mixture of 1H-pyrrole-2-carboxylic acid methyl ester (425 mg, 3.40 mmol) in NMP (10 mL) was added a solution of potassium tert-pentoxide in toluene (2.30 mL, 3.90 mmol, 25 wt % solution); then the solid of O-4-chlorobenzoyl hydroxyamine (670 mg, prepared according to the literature: Parlanti, L Discordia, R. P.; Hynes, J. Jr.; Miller, M. M.; O'Grady, H. R.; Shi, Z. Org. Lett. 2007, 9(19) 3821-3824) was added in one portion; the cold bath was removed after addition completed, and the slurry was stirred at rt for 30 min. Subsequently, the reaction was quenched by addition of saturate sodium bicarbonate solution, then extracted with EtOAc, washed with brine; organic layers was dried over anhydrous sodium sulfate, filtered, concentrated and the residue was column purified to give the desired product (309 mg). 1H NMR (CDCl3, delta in ppm): 6.94 (t, 1H, J=2.3 Hz), 6.81 (dd, 1H, J=2.0 Hz, 4.0 Hz), 6.00 (dd, J=2.7 Hz, 4.3 Hz), 5.53 (br, s, 2H), 3.82 (s, 3H).

		Chloramine was made according to J. Org. Chem., VoI 69 (4), 1368-1371. Into 4L Erlenmyer flask, lH-Pyrrole-2-carboxylic acid methyl ester (25.00 g, 0.1938 mol) and Tetrahydrofuran (1000 mL, 10 mol) were added and stirred at room temperature for 20 minutes under an atmosphere of Nitrogen . 1.00 M of Potassium tert-Butoxide in Tetrahydrofuran(500.0 mL, 0.5000 mol) was added and stirred for 30 minutes at room temperature. 0.15 M of Chloramine in Ether(2100 mL, 0.31 mol) was added to the reaction mixture at 10 0C over 20 minutes with nitrogen bubbling into the reaction mixture. The reaction was stirred at room temperature for 2 hours. HPLC suggested 72% conversion (18% SM remained). Saturated Na2S2O3 (500 mL) was added at 10 0C over 30 minutes. The mixture was stired for one hour. The organic was separated, washed with water, then subsequently with Brine, and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was concentrated to approximately 500 mL. Benzoyl isothiocyanate (22.75 g, 0.1394 mol) in Tetrahydrofuran (100 mL, 1 mol) was added dropwise to the residual organic. The reaction mixture was stired at room temperature overnight. The solvent was removed under vacuum. The solid was partitioned with Et2O (200 mL) and stirred for 30 minutes. The solid was filtered and washed with hexane/Et2O (9 to 1) to give l-(3-Benzoyl-thioureido)-lH-pyrrole-2-carboxylic acid ethyl ester (38.2Og) as an off white solid. NMR 1H (DSMO-d6) 12.89 (s, IH), 11.92 (s, IH), 7.99 (d, 2H, J= 7.46Hz), 7.68 (t, IH, J=7.37Hz), 7.55 (t, IH, J=7.81Hz ), 7.19 (dd, IH, JJ=2.04, 1.64 Hz), 6.89 (dd, IH, JJ=I.76, 1.60 Hz), 6.20 (dd, IH, J=3.00, 1.04 Hz),3.68 (s, 3H).
		Step 1: Into a 5 L round bottom flask containing a solution of 1H-pyrrole-2-carboxylic acidmethyl ester (15.0 g, 120 mmol) in tetrahydrofuran (500 mL) was added a solution of potassiumtert-butoxide (35 g, 310 mmol) in tetrahydrofuran (500 mL) and the reaction mixture was stirred at room temperature for 30 mm. A solution of monochloramine (0.15 M in diethyl ether, 2.1 L) was added at 10 C over 20 mm, while bubbling nitrogen into the reaction mixture and stirred at room temperature for 2 h. Aqueous Na25203 (500 mL) was added dropwise at 10 C over 30 mmand the reaction was stirred for 1 h. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 1 -amino- 1H-pyrrole-2-carboxylate.
		4L flask, 25.0 g of starting material 1-a-1 (0.19mol) was dissolved in 1L of tetrahydrofuran was stirred at room temperature under nitrogen for 20 minutes, the tetrahydrofuran solution of 1M potassium tert-butoxide (500.0ml, 0.50mol ) was added to this solution, stirred for 1 hour. Then 0.15M solution of chloramine in ether (2.1L, 0.31mol) in 20 minutes at 10 deg. C was added to the reaction mixture, while introducing nitrogen, after two hours, the saturated aqueous sodium thiosulfate solution (500ml) to the reaction solution was added dropwise, stirring was continued for one hour. The organic phase was separated, washed with water, saturated brine, dried over anhydrous sodium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure to give the oily compound 1-a-2.
		To a solution of methyl 1H-pyrrole-2-carboxylate (100 g, 799 mmol) indimethylformamide (DMF; 1.2 L) was added NaH (51.1 g, 1.28 mol, 60% purity) at 0 C. The mixture was stirred at 0 C for 1 hour, then O-(2,4-dinitrophenyl)hydroxylamine (238.71 g, 1.20 mol) in DMF (300 mL) was added dropwise. The mixture was stirred at 0 C for 3 hours. The reaction mixture of two batches was combined and poured into aqueous (aq.) sat. sodium thiosulfate solution (10 L). The resulting mixture was extracted with EtOAc (4 L x 3). The combined organic layers were washed with brine (2 L x 3), dried over Na2SO4, and then filtered. The filtrate was concentrated, then purified by silica gel chromatography to afford methyl 1- amino-1H-pyrrole-2-carboxylate (190 g, crude) as a yellow oil.

Reference： [1]Patent: US2011/183983,2011,A1 .Location in patent: Page/Page column 32
[2]Patent: WO2012/146666,2012,A1 .Location in patent: Page/Page column 172
[3]Patent: US2010/47367,2010,A1 .Location in patent: Page/Page column 22
[4]Patent: WO2010/71885,2010,A1 .Location in patent: Page/Page column 335
[5]Patent: WO2016/144848,2016,A1 .Location in patent: Page/Page column 33
[6]Patent: CN105524068,2016,A .Location in patent: Paragraph 0171; 0173
[7]Patent: WO2019/74962,2019,A1 .Location in patent: Paragraph 0160

9
[ 122181-85-5 ]
[ 532-55-8 ]
[ 1232815-48-3 ]

Yield	Reaction Conditions	Operation in experiment
65%	In tetrahydrofuran; at 20℃;	the crude compound 1-a-2 was dissolved in 500ml of tetrahydrofuran, and then tetrahydrofuran solution of benzoyl isothiocyanate at room temperature, then the reaction overnight. After completion of the reaction, concentrated under reduced pressure. The crude product was added to 200ml of diethyl ether and stirred for 30 minutes, filtered, washed with n-hexane / diethyl ether (9: 1) to give an off-white solid compound 1-a-3 (38.2g, 65%).
	In tetrahydrofuran; at 20℃;	Chloramine was made according to J. Org. Chem., VoI 69 (4), 1368-1371. Into 4L Erlenmyer flask, lH-Pyrrole-2-carboxylic acid methyl ester (25.00 g, 0.1938 mol) and Tetrahydrofuran (1000 mL, 10 mol) were added and stirred at room temperature for 20 minutes under an atmosphere of Nitrogen . 1.00 M of Potassium tert-Butoxide in Tetrahydrofuran(500.0 mL, 0.5000 mol) was added and stirred for 30 minutes at room temperature. 0.15 M of Chloramine in Ether(2100 mL, 0.31 mol) was added to the reaction mixture at 10 0C over 20 minutes with nitrogen bubbling into the reaction mixture. The reaction was stirred at room temperature for 2 hours. HPLC suggested 72% conversion (18% SM remained). Saturated Na2S2O3 (500 mL) was added at 10 0C over 30 minutes. The mixture was stired for one hour. The organic was separated, washed with water, then subsequently with Brine, and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was concentrated to approximately 500 mL. Benzoyl isothiocyanate (22.75 g, 0.1394 mol) in Tetrahydrofuran (100 mL, 1 mol) was added dropwise to the residual organic. The reaction mixture was stired at room temperature overnight. The solvent was removed under vacuum. The solid was partitioned with Et2O (200 mL) and stirred for 30 minutes. The solid was filtered and washed with hexane/Et2O (9 to 1) to give l-(3-Benzoyl-thioureido)-lH-pyrrole-2-carboxylic acid ethyl ester (38.2Og) as an off white solid. NMR 1H (DSMO-d6) 12.89 (s, IH), 11.92 (s, IH), 7.99 (d, 2H, J= 7.46Hz), 7.68 (t, IH, J=7.37Hz), 7.55 (t, IH, J=7.81Hz ), 7.19 (dd, IH, JJ=2.04, 1.64 Hz), 6.89 (dd, IH, JJ=I.76, 1.60 Hz), 6.20 (dd, IH, J=3.00, 1.04 Hz),3.68 (s, 3H).
	In tetrahydrofuran; at 25℃;	Step 2: Into a 2 L round bottom flask containing a solution of methyl 1-amino-1H-pyrrole-2- carboxylate (14 g, 97 mmol) in tetrahydrofuran (500 mL) was added benzoyl isothiocyanate (14g, 85 mmol) in tetrahydrofuran (100 mL) dropwise at room temperature and the reaction was stirred overnight. The solvent was evaporated under reduced pressure and the residue was triturated with diethyl ether (200 mL) and the solid obtained was collected by filtration and washed with hexane/diethyl ether (9:1 v/v, 500 mL) to afford methyl 1-(3-benzoylthioureido)- 1H-pyrrole-2-carboxylate as a solid. ?H NMR (DMSO-d6, 300 MHz): oe 7.99 (d, J 1.3 Hz, 2H),7.70-7.66 (m, 1H), 7.58-7.54 (m, 3H), 7.20-7.19 (m, 1H), 6.90-6.88 (m, 1H), 6.21-6.19 (m, 1H),3.69 (s, 3H). MS calc?d [M-Hj 302.1, found 302.0.

In tetrahydrofuran; at 25℃; for 2h;

To a solution of <strong>[122181-85-5]methyl 1-amino-1H-pyrrole-2-carboxylate</strong> (95.0 g, 647 mmol) in THF (tetrahydro furan; 2.0 L) was added a solution of benzoyl isothiocyanate (137 g, 842 mmol) in THF (500 mL) at 25 C. The mixture was stirred at 25 C for 2 hours. Two batches were combined and concentrated in vacuo. The residue was triturated with MTBE (methyl tert-butyl ether; 1.0 L) then filtered to afford the title compound (352 g, 696 mmol, 54% yield, 60% purity).

Reference： [1]Patent: CN105524068,2016,A .Location in patent: Paragraph 0171; 0174
[2]Patent: WO2010/71885,2010,A1 .Location in patent: Page/Page column 335
[3]Patent: WO2016/144848,2016,A1 .Location in patent: Page/Page column 33
[4]Patent: WO2019/74962,2019,A1 .Location in patent: Paragraph 0160-0161

10
[ 122181-85-5 ]
[ 77287-34-4 ]
[ 159326-71-3 ]

Yield	Reaction Conditions	Operation in experiment
69%	at 170 - 190℃; for 3h;	(Step 2) pyrrolo[1,2-f]1,2,4]triazin-4(3H)-one; Methyl 1H-pyrrole-2-carboxylate (7.5 g, 53.5 mmol) was dissolved in formamide (30 mL). After heating at 170 C. for 1 hour, the mixture was further heated at 190 C. for 2 hours. The resulting reaction mixture was cooled to room temperature. The produced solid was recrystallized with ethyl acetate to give the target compound as a white solid (5.0 g, 37.0 mmol, 69% yield).1H NMR (400 MHz, CDCl3): 7.57 (s, 1H), 7.47 (dd, J=2.8 Hz, 1.6 Hz, 1H), 7.10 (dd, J=4.4 Hz, 1.6 Hz, 1H), 7.47 (dd, J=4.4 Hz, 2.8 Hz, 1H).

Reference： [1]Patent: US2011/183983,2011,A1 .Location in patent: Page/Page column 32

11
[ 34840-23-8 ]
[ 122181-85-5 ]
[ 1350883-07-6 ]

Yield	Reaction Conditions	Operation in experiment
81%	With acetic acid; In methanol; at 20℃; for 16h;	To a solution of methyl 1 -amino- lH-pyrrole-2-carboxylate lib (0.29 g, 2.1 mmol) in methanol/AcOH (5 mL/0.6 mL) was added S-methyl bis(methoxycarbonyl)thiourea 26a (0.47 g, 2.28 mmol) and stirred at room temperature for 16 h. The reaction mixture was diluted with ether (5 mL) and hexane (15 mL). The solid obtained was collected by filtration, washed with hexane and dried under vacuum to furnish methyl l-(2,3-bis(methoxycarbonyl)guanidino)-lH- pyrrole-2-carboxylate 26b (0.5 g, 81%) as a white solid; mp 160.3 C. 1H NMR (300 MHz, DMSO) delta 11.17-10.23 (m, 1H), 10.16-9.48 (m, 1H), 7.10-6.86 (m, 1H), 6.79 (s, 1H), 6.1 1 (s, 1H), 3.70 (s, 3H), 3.66 (s, 3H), 3.49 (s, 3H). MS ES(+) 299.1 (M+l); ES(-) 296.9 (M-l); Analysis: Calcd for C?Hi4N406: C, 44.30; H, 4.73; N, 18.79; Found: C, 44.21 ; H, 4.76; N, 18.72.

Reference： [1]Patent: WO2011/150356,2011,A1 .Location in patent: Page/Page column 96

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[ 122181-85-5 ]
[ 1350883-09-8 ]

Reference： [1]Patent: WO2011/150356,2011,A1

13
[ 122181-85-5 ]
[ 1350882-32-4 ]

Reference： [1]Patent: WO2011/150356,2011,A1

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[ 122181-85-5 ]
[ 1350883-08-7 ]

Reference： [1]Patent: WO2011/150356,2011,A1

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[ 122181-85-5 ]
[ 1350882-33-5 ]

Reference： [1]Patent: WO2011/150356,2011,A1

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[ 122181-85-5 ]
[ 1350882-34-6 ]

Reference： [1]Patent: WO2011/150356,2011,A1

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[ 122181-85-5 ]
[ 1370007-53-6 ]