718632-46-3|5-tert-Butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate| Ambeed

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Quality Control of [ 718632-46-3 ] Purity: 95% SDS Specification

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Product Details of [ 718632-46-3 ]

CAS No. :	718632-46-3
Formula :	C₁₅H₂₄N₄O₄
M.W :	324.38
SMILES Code :	O=C(N1N=C(C(C)(C)N(C(OC(C)(C)C)=O)C2)C2=C1N)OCC
MDL No. :	MFCD20134032
InChI Key :	ULJAXXIYTXRCKL-UHFFFAOYSA-N
Pubchem ID :	57523245

Safety of [ 718632-46-3 ]

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

Application In Synthesis of [ 718632-46-3 ]

* 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 [ 718632-46-3 ]

[ 718632-46-3 ] Synthesis Path-Downstream 1~35

1
[ 401495-67-8 ]
[ 718632-46-3 ]
6,6-dimethyl-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; for 6h;Heating / reflux;	Example 1; 6,6-Dimethyl-3-[4-(4-methyl-piperazin-l-yl)-benzoylamino]-4,6-dihydro-lH- pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester [Formula (IV), R = 4-(4-methyl-piperazin)-phenyl]; To a solution of 3-Amino-6,6-dimethyl-4H,6H-pyrrolo[3,4-c]pyrazole-2,5- dicarboxylic acid 5-tert-butyl ester 2-ethyl ester (2.50 g, 7.70 mmol) prepared as reported in WO2004/056827, N,N-diispropylethylamine (14.6ml, 33.6mmol) in anhydrous Dioxane (100 ml), 4-(4-Methyl-piperazin-l-yl)-benzoyl chloride (0.24 g ,1.00 mmol) was added. The reaction was heated to reflux and stirred for 6h. The solvent was removed under vacuum, the residue dissolved in CH2Cl2 (150 mL) and washed with brine (I X 10OmL). The organic phase was dried over sodium sulphate, the solvent evaporated in vacuo and the residue purified by flash chromatography (Acetone/DCM 80/20) affording 2.1O g (yield 52%) of the title compound. ESI MS: m/z 527 (MH+); 1H NMR (400 MHz, DMSO-d6): delta 10.69 (s, IH), 7.76 (m, 2H), 7.09 (m, 2H), 4.55 (d, 2H, J = 9.8 Hz), 4.48 (q, 2H, J = 7.1 Hz), 3.34 (m, 4H), 2.52 (m, 4H), 2.27 (s, 3H ), 1.64 (s, 3H ), 1.62 (s, 3H ), 1.47 (s, 9H), 1.38 (t, 3H, J= 7.1 Hz).

References: [1]Patent: WO2008/43745,2008,A1 .Location in patent: Page/Page column 43.

2
tert-butyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]-pyrazole-5(2H)-carboxylate [ No CAS ]
[ 541-41-3 ]
[ 718632-47-4 ]
[ 718632-46-3 ]

Yield	Reaction Conditions	Operation in experiment
30%; 38%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0℃; for 1.5h;	15 g of tert-Butyl 3-AMINO-6, 6-dimethyl-2, 6-DIHYDROPYRROLO [3, 4-c] pyrazole-5 (4H) - carboxylate (59.4 mmol) were dissolved in anhydrous THF (150 ml) and treated, at 0C under Ar atmosphere, first with N, N-diisopropylethylamine (50 ml) and then with CICOET (4.65 ml, 1 eq. ) dropwise. 90 minutes later, the solvent was diluted with EtOAc (1 1), washed with water and then with brine, dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography (HEXANE/ETOAC 2/8) to afford 7.3 g of 5-TERT-BUTYL 2-ethyl 3-amino-6,6-dimethylpyrrolo [3,4-c] pyrazole-2,5 (4H, 6H)-DICARBOXYLATE as the major compound in 38% yield, together with 5.7 g of 5-tert-butyl 1-ethyl 3-amino- 6,6-dimethyl-4, 6-dihydropyrrolo [3, 4-C] PYRAZOLE-1, 5-dicarboxylate in 30% yield. 5-tert-Butyl 2-ethyl 3-AMINO-6, 6-dimethylpyrrolo [3, 4-C] PYRAZOLE-2, 5 (4H, 6H)- dicarboxylate ESI MS : m/z 325 (MH+); 1H NMR (400 MHz, DMSO-D6) : 6 4.35 (q, 2H), 4.10 (2s, 2H, conformers), 1.50-1. 51 (m, 6H), 1.41-1. 43 (2s, 9H, conformers), 1.29 (t, 3H). 5-TERT-BUTYL 1-ETHYL 3-amino-6,6-dimethyl-4, 6-dihydropyrrolo [3,4-c] pyrazole-1, 5- dicarboxylate ESI MS : M/Z 325 (MH+) ; 1H NMR (400 MHz, DMSO-D6) : 8 4.28 (q, 2H, J = 7.1 Hz), 4.09-4. 14 (2s, 2H, conformers), 1.66-1. 67 (m, 6H), 1.41-1. 44 (2s, 9H, conformers), 1.27 (t, 3H, J = 7.1 Hz).

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 4728 - 4739.
[2]Patent: WO2004/56827,2004,A2 .Location in patent: Page 50.
[3]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 584 - 587.

4
[ 718632-46-3 ]
3-amino-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With hydrogenchloride; In 1,4-dioxane; ethanol; at 20℃;	Example 68(1S)-2-(dimethylamino)-1-phenylethyl 6,6-dimethyl-3-[(1,3-thiazol-4-ylcarbonyl)amino]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate Preparation of Compound I(l): ethyl 3-amino-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate dihydrochloride; To a stirred slurry of I(g) (40.00 g, 123.3 mmol) in ethanol (270 mL) was added 4 M HCl solution in dioxane (155 mL) dropwise. The resulting clear solution was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the residue was stirred with hexanes (300 mL) for 30 min. The solid product was collected by filtration, washed with hexanes (2×100 mL) and dried under vacuum at 40 C. to afford dihydrochloride salt I(L) (35.80 g, 98%) as white solid. 1H NMR (300 MHz, dmso-d6) delta: 1.31 (t, J=7.2 Hz, 3H), 1.59 (s, 6H), 4.09 (t, J=4.7 Hz, 2H), 4.36 (q, J=7.1 Hz, 2H), 10.14 (s, 2H).
	With hydrogenchloride; ethanol; In hexanes; at 20℃; for 12h;	Example 54: W-[(1S)-2-(Dimethylamino)-1-phenylethyl]-3-[(6-ethylpyrimidin-4-yl)amino]-6,6- dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide. EPO <DP n="69"/>Preparation of I(H): 5-tert-butyl 2-ethyl 3-amino-6,6-dimethylpyrroIo[3,4-c]pyrazoIe-2,5(4H,6H)- dicarboxylate.The synthetic route of compound I(H) can be found in Scheme 1 under the "Detailed Description" of this application. The detailed synthetic condition of for the preparation of I(H) can be found in U.S. Patent Application Publication No. 2003/0171357 and PCT Publication WO 02/12242, the disclosure of which are incorporated herein by reference.Preparation of compound 54a: ethyl 3-amino-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)- carboxylate dihydrochloride. EPO <DP n="70"/>To a stirred slurry of 5-tert-butyl 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazoIe-1,5- dicarboxylate (l(H),~30.0 g, 92.5 mmol) in ethanol (200 mL)was drop wise added HCI 4 M solution in hexanes (116 mL) drop wise. The resulting clear solution was stirred at room temperature for 12 h. The reaction mixture was concentrated under vacuum to a residue and stirred with hexane (250 mL) for 10 min. The solid product was collected by filtration, washed with hexane (100 mL) and dried under vacuum at 40 0C for 15 h to get ethyl 3-amino-6,6-dimethyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate dihydrochloride (54a, 27.0 g, 98.5 %) as white solid. 1H NMR (300MHz, dmso-d6): delta 1.31 (td, J=7, 1.3Hz, 3H), 1.59 (s, 6H), 4.09 (t, J=3.7Hz, 2H), 4.36 (qd, J=7.2, 1.2Hz, 2H), 10.12 (br s, 2H). Preparation of compound 54c: benzyl [(1S)-2-(dimethylamino)-2-oxo-1-phenylethyl]-carbamate. To a mixture of (2S)-[(benzy.oxy)carbonyljamino}(phenyl)acetic acid (54b, 196 g, 688 mmol), HBTU (261 g, 688 mmol), and dichloromethane (2.8 L) were added sequentially potassium carbonate (285 g, 2.06 mol) and dimethylamine hydrochloride (84.1 g, 1031 mmol). The reaction mixture was heated at 40 C overnight. After cooling to room temperature, the solids were filtered, washed with ethyl acetate (2x500 mL) and the filtrate concentrated to a residue. Water (1L) was added to the residue and the solution kept in an ultrasonic cleanser for 2 hours. The precipitated solids were collected and washed with water (4*300 mL), hexane (2x500 mL), and dried under vacuum for 24 hours. The solid crude product was dissolved in chloroform (300 mL) and un-dissolved solids were filtered off. The filtrate was concentrated to dryness and the residue dissolved in hexane/ethyl acetate (2:1) (250 mL) and allowed to stand at room temperature overnight. The resulting crystals were collected by filtration, washed with hexane/ethyl acetate (3:1) (100 mL) and dried in high vacuum at 40 C for 24 hours to give compound 54c (100.0 g, 47 %) as a white crystalline solid. 1H NMR (CDCI3) delta: 2.88 (s, 3H), 2.98 (s, 3H), 5.01 (d, J = 12.2 Hz, 1H), 5.11 (d, J = 12.2 Hz, 1 H), 5.58 (d, J = 7.5 Hz, 1 H), 6.37 (d, J = 7.2 Hz, 1 H), 7.32 (m, 10H). Preparation of Compound 54d: (2S)-2-amino-Lambda/,Lambda/-dimethyl-2-phenylacetamide. To a solution of 54c (80.0 g, 256 mmol) in ethanol (1.2 L) was added a slurry of Pd/C (10%, 9.0 g) in ethyl acetate (50 mL). The reaction mixture was shaken in Parr-apparatus under hydrogen (40 psi) overnight. The catalyst was removed by filtration through celite. The filter pad was washed with ethanol (2x200 mL) and the combined filtrate was concentrated to give 54d (40.2 g, 88%) as a white solid. 1H NMR (CDCI3) delta: 2.85 (s, 3H), 2.99 (s, 3H), 4.72 (s, 1 H), 7.33 (m, 5H). Preparation of Compound 54e: N-[(2S)-2-amino-2-phenylethyl]-N,N-dimethylamine.A flask containing dry THF (2300 mL) under a nitrogen atmosphere was chilled by an ice-water bath. Lithium aluminum hydride pellets (59.0 g, 1555 mmol) were added. To this LAH suspension, a solution of amide 54d (123.0 g, 691 mmol) in dry THF (800 mL) was slowly added over approximately 1 hour. The resulting reaction mixture was heated at reflux for 5 hours, then cooled to 10 C. The cooled reaction mixture was slowly quenched with saturated sodium sulfate solution (380 mL) and stirred overnight. The precipitated solids were filtered off and washed with ethyl acetate (4x500 mL). The filtrate was concentrated to a residue that was purified on silica gel column (10% methanol, 5% triethylamine in chloroform) to afford 54e (66.7 g, 59%) as a light yellow liquid. 1H NMR (CDCI3) delta: 2.24 (dd, J = 3.6, 12.1 Hz, 1 H), 2.29 (s, 6H), 2.47 (dd, J = 10.6, 12.1 Hz, 1H), 4.07 (dd, J = 3.6, 10.4 Hz, 1H), 7.24 (m, 1 H), 7.37 (m, 4H). Preparation of Compound 54f: N-[(2S)-2-isocyanato-2-phenylethyl]-N,N-dimethylamine hydrochloride. EPO <DP n="71"/>To a cooled (0 C) and stirred solution of triphosgene (27.1 g, 91.32 mmol) in DCM (250 ml.) was drop wise added a solution of diisopropylethyl amine (23.6 g, 182.26 mmol) in DCM (50 ml_) over a period of 20 min. A solution of N-[(2S)-2-amino-2-phenylethyl]-N,N-dimethylamine (54e, 15.0 g, 91.32 mmol) in DCM (10...

References: [1]Patent: US2009/318440,2009,A1 .Location in patent: Page/Page column 74-75.
[2]Patent: WO2006/72831,2006,A1 .Location in patent: Page/Page column 68-71.

5
[ 718632-46-3 ]
C₁₀H₁₆N₄O₂*ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,4-dioxane; dichloromethane; at 20℃; for 2h;Product distribution / selectivity;	Example 3 : N-(5-[(2S)-2-benzyl-4-methylpiperazin-1 -yl]carbonyl}-6,6-dimethyl-1 ,4,5,6 tetrahydropyrrolofS^-clpyrazol-S-yO^-chlorotriienotS^-dJpyrimidin^-amine. EPO <DP n="46"/>3b 3Preparation of 3a: ethyl 3-amino-5-(chlorocarbonyl)-6,6-dimethyl-5,6-dihydropyrrolo[3,4- c]pyrazole-2(4H)-carboxylate.; To a stirring mixture of 5-terf-butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4W,6W)- dicarboxylate (5.65g, 17.4mmol) in CH2CI2 (20ml) was added 4.0M HCI in dioxane (30ml). The resulting mixture was stirred at room temperature for 2h. After the reaction mixture was concentrated in vacuo, a portion of residue (1.53g, 5.15mmol) was dissolved into a solution of DIPEA (3.6ml, 4eq) in CH2CI2 (10ml). The resulting solution was slowly added to a solution of triphosgene (628mg, 0.41 eq) in CH2CI2 (10ml) at O0C and the resulting mixture was stirred at O0C for 1h. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3, dried over sodium sulfate. The organic layer was filtered and evaporated in vacuo to give a residue, compound 3a. Compound 3a was directly carried onto the next reaction without further purification. Preparation of 3b: 5-[(2S)-2-benzyl-4-methylpiperazin-1-yl]carbonyl}-6,6-dimethyl-1 ,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3-amine.A portion of above residue (525mg) was added into a solution of (3S)-3-benzyl-1-methylpiperazine (552mg, 1.5eq) in CH2CI2 (4ml). The resulting mixture was stirred at reflux for 4h. The reaction mixture was then cooled to room temperature, and the solvent was removed in vaccuo. To the residue was added 2N LiOH (3ml) and methanol (2ml). The resulting mixture was stirred at reflux for 4 hours. The reaction mixture was purified by prep-HPLC to provide compound 3b as a white solid (150mg). To a stirring solution of compound 3b (0.15, 0.41 mmol) in NMP (1mL) was added 2,4-dichlorothieno[3,2- phiyrimidine(0.084g, 1eq) and triethylamine (0.11ml, 2eq). The resulting mixture was heated to 1400C for 5 minutes in microwave reactor. The reaction mixture was purified by prep-HPLC to provide compound 3 as a white solid (0.014g, 15%). 1H NMR (CD3OD) delta: 1.58 (s, 3 H), 1.66 (s, 3 H), 2.22 (s, 3 H), 2.38 (m, 2 H), 2.45 (m, 1 H), 2.60 (m, 1 H), 2.78 (dd, J=13.26, 8.21 Hz, 1 H), 2.99 (dd, J=13.52, 6.44 Hz, 1 H), 3.15 (s, 1 H), 3.35 (m, 1 H), 3.75 (m, 1 H), 4.28 (d, J=11.12, 1 H), 4.65 (m, 1 H), 6.99 (t, J=7.01, 1 H), 7.08 (t, J=7.58 Hz, 2 H) 7.10-7.13 (m, 2 H) 7.27 (d, J=5.31 Hz, 1 H) 8.07 (d, J=5.31 Hz, 1 H). Anal. (C26H29N8OSCLO-SHOACO-SH2O) C, H, N. HPLC: >95% purity.; Example 4: 3-[(2,6-dichloropyrimidin-4-yl)amino]-6,6-dimethyl-Lambda/-[trans-2-phenyl cyclopropyl]-4,6- dihydropyrrolo[3,4-c]pyrazole-5(1W)-carboxamide.Preparation of compound 4a: ethyl-3-amino-6,6-dimethyl-5-([trans-2-phenyl cyclo propyl] amino}carbonyl)-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4W)-carboxylate.To a stirring mixture of 5-terf-butyl 2-ethyl 3-amino-6,6-dimethylpyrrolof3,4-c]pyrazo.e-215(4H,6H)- dicarboxylate (5.65g, 17.4mmol) in CH2CI2 (20ml) was added 4.0M HCI in dioxane (30ml). After the reaction mixture was concentrated in vacuo, a portion of residue (3.45g, 11.6mmol) was dissolved into a solution of DIPEA (8.1 ml, 4eq) in CH2CI2 (50ml). To the resulting solution was slowly added to trans-2- phenylcyclopropyl isocyanate at O0C and the resulting mixture was stirred at O0C for 30 minutes then warmed up and stirred at room temperature for 1 h. The reaction mixture was diluted with CH2CI2, and washed with saturated NaHCO3, dried over sodium sulfate, concentrated in vacuo, purified by flash chromatography. Elution with 60-80% EtOAc/hexane provided the compound 4a as a white solid (4.24 g, 95%). 1H NMR (CD3OD) delta: 1.03 - 1.16 (m, 2 H) 1.60 (d, J=3.79 Hz, 6 H) 1.98 (s, 1 H) 2.71 (s, 1 H) 4.12 (s, 1 H) 7.01 - 7.10 (m, 3 H) 7.13 - 7.21 (m, 2 H)Preparation of compound 4b: 3-amino-6,6-dimethyl-Lambda/-[trans-2-phenylcyclopropyl]-4,6- dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide. To a stirring solution of ethyl 3-amino-6,6-dimethyl-5-([trans-2-phenylcyclopropyl] amino} carbonyl)-5,6- dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate (613mg, 1.60mmol) in MeOH (3mL) was added 2N LiOH (1ml, 1.25eq). The resulting mixture was stirred under reflux for 4 hours, cooled, and concentrated. The residue was partitioned between ethyl acetate and saturated NaHCO3, dried, and concentrated to give compound 4b as a white solid (0.42g, 79%). 1H NMR (CD3OD) delta: 1.03 - 1.16 (m, 2 H) 1.60 (d, J=3.79 Hz, 6 H) 1.98 (s, 1 H) 2.71 (s, 1 H) 4.12 (s, 2 H) 7.01 - 7.10 (m, 3 H) 7.13 - 7.21 (m, 2 H).To a stirring solution of compound 4b (0.1Og, 0.32mmol) in DMA (0.5mL) was added 2,4,6- trichloropyrimidine(0.041 ml, 1.1eq) and triethylamine (0.089ml, 2eq). The resulting mixture was heated to a temperature of 800C for 5 minutes in microwave reactor. The reaction mixture was purified by prep- EPO <DP n="48"/>HPLC to provide the compound 4 as a white solid (0.025g, 171H NMR (CD3OD) delta: 1.05 - 1.11 (m, ...

References: [1]Patent: WO2006/72831,2006,A1 .Location in patent: Page/Page column 44-47; 81-82.

6
[ 718632-46-3 ]
[ 345927-99-3 ]
[ 942273-10-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 48h;	To a suspension of 2-(l,3-dioxo-l,3-dihydro-isoindol-2-ylmethyl)-benzoic acid (1.35 g, 4.8 mmol) in dry dichloromethane (30 mL), at 0 C, under stirring, was added oxalyl chloride (2.1 mL, 24 mmol) and dry N,N-dimethylformamide (35 microL). The mixture was allowed to warm to room temperature, stirred for 1.5 hours then evaporated to dryness. The residue was diluted with dry toluene and evaporated again. The crude acyl chloride thus obtained (yellow solid) was dissolved in dry tetrahydrofuran (20 mL) and treated with N,N-diisopropylethylamine (2.5 mL, 15 mmol) and with a solution of 3- amino-6,6-dimethyl-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester (1.3 g, 4 mmol) in 15 mL of dry tetrahydrofuran. The mixture was stirred at room temperature for 2 days then evaporated to dryness. The residue was dissolved in dichloromethane, washed with IN HCl, water, saturated solution of NaHCC>3, brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using dichloromethane/methanol 98.5:1.5 as the eluant affording the title compound as white solid (1.5 g).IH-NMR (400 MHz), delta (ppm, DMSOtZ6): 10.63 (bs, IH), 7.91-7.83 (m, 4H), 7.71 (m, IH), 7.58-7.46 (m, 2H), 7.37 (m, IH), 5.07 (s, 2H), 4.53 (bs, 2H), 4.43 (m, 2H), 1.63 (bs, 6H), 1.50 (s, 9H), 1.37 (m, 3H).

References: [1]Patent: WO2007/68637,2007,A1 .Location in patent: Page/Page column 108.

7
[ 718632-46-3 ]
[ 1108746-59-3 ]
[ 942271-66-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 80℃; for 6h;	4-(4-methylpiperazin-l-yl)-2-nitrobenzoic acid (15 g, 49.7 mmol) in dry tetrahydrofuran (100 mL) was treated with thionyl chloride (5 eq., 18.1 mL, 248.7 mmol) and few drops of N,N-dimethylformamide at 800C for 14 hours. After removal of the solvent under vacuum, the crude material was added portion-wise to a solution of 3-amino-6,6- dimethyl-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester (16.1 g, 49.7 mmol) and diisopropylethylamine (5 eq., 43.4 mL, 248.7 mmol) in 1,4-dioxane (200 mL) maintained under magnetic stirring at 800C. The reaction mixture was stirred for about 6 hours at 800C. After removal of the solvent, the crude material was diluted with dichloromethane (200 mL), saturated sodium hydrogenocarbonate (200 mL), dried over sodium sulfate, evaporated to dryness and purified by flash chromatography on silica gel, using acetone as eluant. The title compound was obtained as light yellow powder (13.5 g, 47% yield).IH-NMR (400 MHz), delta (ppm, DMSOtZ6): 10.70, 10.67 (s, IH), 7.68, 7.66 (d, Jl=8.78 Hz, IH), 7.48 (bs, IH), 7.30 (dd, Jl=8.78 Hz, J2=2.56 Hz, IH), 4.47-4.39 (m, 4H), 3.41 (m, 4H), 2.52 (m, 4H), 2.27 (s, 3H), 1.63,1.62 (s, 6H), 1.49, 1.46 (s, 9H), 1.37, 1.36 (t, J=7.07 Hz,3H), mixture of rotamers

References: [1]Patent: WO2007/68637,2007,A1 .Location in patent: Page/Page column 50-51.

8
[ 718632-46-3 ]
[ 942271-66-1 ]

Yield	Reaction Conditions	Operation in experiment
47%		Example 5; Preparation of 6,6-dimethyi-3-[4-(4-methyl-piperazin-1-yl)-2-nitro-benzoylamino]- 4H,6H-pyrrolo\|;3,4-c]pyrazole-2,5-d.carboxylic acid 5-tert-butyl ester 2-thetathyl ester; 4-(4-rnethyip1perazin-1-yl)-2-nitro-ben;-oic acid (15 g, 49,7 mmol) in dry tetrahydrofuran (100 mL) was stirred with thionyl chloride (5 eq ., 18,1 mL, 2487 mmol) and a few drops of N,N-dimethyiformamide at 8QC for about 14 hours . After removal of the solvent <n="60"/>under vacuum, the crude material was added portion-wise to a solution of 3-amino-6,6- dimethy.-4H,6H-pyrro.o[3,4~c]pyrazo.e-2,5-d.carboxytic acid 5-tert-butyl ester 2-ethyl ester (16 t g, 49 7 mmol) and IM.N-diethyiisopropylatnine (5 eq , 43 4 mL, 248 7 mmol} in 1 ,4- dioxane (200 mL) maintained under magnetic stirring at 80C The reaction mixture was stirred for about 6 hours at 80C After removal of the solvent, the crude material was diluted with dichloromethane (200 mL), washed with saturated sodium hydrogen carbonate solution (200 mL), dried over sodium sulphate, evaporated to dryness and purified by flash chromatography on sittca gel using acetone as the efuant. The titfe compound was obtained as light yellow powder (13 5 g, 47% yield). 1 H-NMR (400 MHz), 3. (ppm, DMSOd6): 10 70, 10 67{s, 1 H)1 7 68, 7 66 (d, J1 =8 78Hz, 1 H), 7 48(bs, I H), 7.30 (dd, J 1=8 78 Hz, J2=2.56 Hz, 1 H)1 4 47-4.39 (m, 4H), 3,41 (m, 4H), 2.52 (m, 4H), 2 27 (s, 3H), 1,63, 1 62 (s, 6H), 1.49, 1 46 (s, 9H)1 137, 1 36 (t, J=7 07 Hz1 3H); mixture of rotamers

References: [1]Patent: WO2007/99171,2007,A2 .Location in patent: Page/Page column 57-58.

9
[ 718632-46-3 ]
[ 98-88-4 ]
[ 1041015-44-4 ]

Yield	Reaction Conditions	Operation in experiment
95.0%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;	Example 1(1S)-2-(dimethylamino)-1-phenylethyl 3-(benzoylamino)-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate Preparation of Compound 1a: 5-tert-butyl 2-ethyl 3-(benzoylamino)-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate; To a cooled (0 C.) and stirred solution of I(g) (12.0 g, 37.0 mmol) and DIPEA (13.0 mL, 74.0 mmol) in dichloromethane (100 mL) was drop wise added a solution of benzoyl chloride (5.75 g, 40.7 mmol) in dichloromethane (50 mL). The resulting clear solution was stirred at room temperature for 12 h. The reaction mixture was washed with water (2×75 mL), dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel column chromatography (40% ethyl acetate in hexane) to give amide 1a (15.0 g, 95.0%) as an off-white solid. 1H NMR (300 MHz, CDCl3) delta: 1.44-1.56 (m, 12H) 1.69 (s, 3H) 1.75 (s, 3H) 4.58 (q, J=7.10 Hz, 2H) 4.74 (s, 1H) 4.79 (s, 1H) 7.44-7.64 (m, 3H) 7.87-7.96 (m, 2H) 10.97-11.11 (m, 1H).

References: [1]Patent: US2009/318440,2009,A1 .Location in patent: Page/Page column 28.
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 4728 - 4739.
[3]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 1844 - 1853.

10
[ 718632-46-3 ]
[ 87392-05-0 ]
[ 1041017-26-8 ]

Yield	Reaction Conditions	Operation in experiment
86%		Preparation of compound 89a: (R)-5-tert-butyl 2-ethyl 6,6-dimethyl-3-(tetrahydrofuran-2-carboxamido)pyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate (R)-tetrahydrofuran-2-carboxylic acid (1.39 g, 12.0 mmol) was dissolved in dichloromethane (24 mL) and cooled to 0 C. Oxalyl chloride (4.57 g, 36.0 mmol) was added dropwise, followed by DMF (25 uL). After stirring for 3 hours at 0 C., the solution was concentrated to dryness then rotavop over DME (2×5 mL) to remove residual oxalyl chloride, then redissolved in DME (8.0 mL). In another flask, <strong>[718632-46-3]5-tert-butyl 2-ethyl 3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate</strong> I(G) (1.95 g, 6.0 mmol) and diisopropyl ethyl amine (2.09 mL, 12.0 mmol) were dissolved in dichloromethane (8.0 mL) and cooled to 0 C. The acid chloride solution was added dropwise, causing fuming and raising the internal temperature to 15 C. Reaction was at 0 C. for 5 hours. Aqueous workup using NaHCO3 and DME followed by silica gel column provided 89a (2.2572 g, 86%) as a white foam. 1HNMR (300 MHz, dmso-d6) delta: 1.35 (t, J=7.1 Hz, 3H), [1.42 (s), 1.45 (s), 9H together], 1.57 (dd, J=2.8, 6.6 Hz, 6H), 1.86 (m, 2H), 1.96 (m, 1H), 2.23 (m, 1H), 3.91 (m, 2H), 4.47 (m, 5H), 10.80 (s, 1H). LCMS (APCI, M+H+): 423. Anal. (C20H30N4O6.0.15 EtOAc) C, H, N.

References: [1]Patent: US2009/318440,2009,A1 .Location in patent: Page/Page column 86.

11
[ 41507-35-1 ]
[ 718632-46-3 ]
C₂₀H₂₆N₄O₅S [ No CAS ]