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Structure of 4-Nitrophenyl chloroformate
CAS No.: 7693-46-1
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Folate-conjugated organic CO prodrugs: Synthesis and CO release kinetic studies
Shameer M. Kondengadan ; Shubham Bansal ; Xiaoxiao Yang ; Binghe Wang ;
Abstract: Carbon monoxide (CO) is an endogenous produced molecule and has shown efficacy in animal models of inflammation, organ injury, colitis and cancer metastasis. Because of its gaseous nature, there is a need for developing efficient CO delivery approaches, especially those capable of targeted delivery. In this study, we aim to take advantage of a previously reported approach of enrichment-triggered prodrug activation to achieve targeted delivery by targeting the folate receptor. The general idea is to exploit folate receptor-mediated enrichment as a way to accelerate a biomolecular Diels-Alder reaction for prodrug activation. In doing so, we first need to find ways to tune the reaction kinetics in order to ensure minimal rection without enrichment and optimal activation upon enrichment. In this feasibility study, we synthesized two diene-dienophile pairs and studied their reaction kinetics and ability to target the folate receptor. We found that folate conjugation significantly affects the reaction kinetics of the original diene-dienophile pairs. Such information will be very useful in future designs of similar targeted approaches of CO delivery.
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Keywords: Enrichment triggered delivery ; Carbon Monoxide ; Folate conjugate ; Reaction kinetics ; Diels-Alder reaction
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Raithatha, Sheetal A. ; Hagel, Jillian M. ; Matinkhoo, Kaveh ; Yu, Lisa ; Press, David ; Cook, Sarah G. , et al.
Abstract: The psychedelic prodrug psilocybin has shown therapeutic benefits for the treatment of numerous psychiatric conditions. Despite pos. clin. end points targeting depression and anxiety, concerns regarding the duration of the psychedelic experience produced by psilocybin, associated with enduring systemic exposure to the active metabolite psilocin, pose a barrier to its therapeutic application. Our objective was to create a novel prodrug of psilocin with similar therapeutic benefits but a reduced duration of psychedelic effects compared with psilocybin. Here, we report the synthesis and functional screening of 28 new chem. entities. Our strategy was to introduce a diversity of cleavable groups at the 4-hydroxy position of the core indole moiety to modulate metabolic processing. We identified several novel prodrugs of psilocin with altered pharmacokinetic profiles and reduced pharmacol. exposure compared with psilocybin. These candidate prodrugs have the potential to maintain the long term benefits of psilocybin therapy while attenuating the duration of psychedelic effects.
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Purchased from AmBeed: 77877-94-2 ; 7693-46-1 ; 33657-49-7 ; 38871-41-9 ; 20289-26-3 ; 7693-46-1 ; 2251-50-5 ; 35180-01-9 ; 4090-55-5 ; 54322-65-5 ; 52061-51-5 ; 63881-16-3 ; 5402-53-9
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CAS No. : | 7693-46-1 |
Formula : | C7H4ClNO4 |
M.W : | 201.56 |
SMILES Code : | O=C(Cl)OC1=CC=C([N+]([O-])=O)C=C1 |
MDL No. : | MFCD00007321 |
InChI Key : | NXLNNXIXOYSCMB-UHFFFAOYSA-N |
Pubchem ID : | 82129 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H314-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338-P310 |
Class: | 8 |
UN#: | 3261 |
Packing Group: | Ⅱ |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 47.14 |
TPSA ? Topological Polar Surface Area: Calculated from |
72.12 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.36 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.56 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.33 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.84 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.24 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.37 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.85 |
Solubility | 0.287 mg/ml ; 0.00143 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.72 |
Solubility | 0.0382 mg/ml ; 0.00019 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.09 |
Solubility | 1.64 mg/ml ; 0.00815 mol/l |
Class? Solubility class: Log S scale |
Soluble |
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 |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.71 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
3.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.82 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With sodium bicarbonate; triethylamine; In dichloromethane; acetonitrile; | Example 33 Methyl 3-(4-((2,6-dichlorophenyl)carbonylamino)-2-oxohydropyrimidinyl)-2-((4-(3-methyl-2-oxo-3-azaindolinyl)piperidyl)carbonylamino) propionate (33) Under argon atmosphere, 55 mg of methyl 2-amino-3-(4-((2,6-dichlorophenyl)carbonylamino)-2-oxohydropyrimidinyl) propionate was dissolved in 2 ml of acetonitrile and 3 ml of dichloromethane, and 18.5 mg of saturated sodium hydrogen carbonate and 30.2 mg of chloroformic acid p-nitrophenyl ester were added while cooling the mixture in ice, followed by stirring the resulting mixture at room temperature for 4 hours. To the reaction mixture, 39.3 mg of <strong>[53786-10-0]1-methyl-3-(4-piperidyl)-3-hydrobenzimidazol-2-one</strong> and 49 ael of triethylamine were added, and the resulting mixture was stirred at room temperature for 14 hours. After concentrating the reaction mixture, saturated aqueous sodium hydrogen carbonate solution was added and the resulting mixture was extracted with ethyl acetate. Organic phases were combined, washed with 1N hydrochloric acid and with saturated saline, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (dichloromethane/methanol = 30:1) to obtain 65 mg of methyl 3-(4-((2,6-dichlorophenyl)carbonylamino)-2-oxohydropyrimidinyl)-2-((4-(3 -methyl-2-oxo-3-azaindolinyl)piperidyl)carbonylamino) propionate (yield: 68%). LR-MS(m/z):641(M+) IR(KBr):3423,3071,2952,1660,1562,1495,1434,1368,1305,1247,1197,1132,1053, 986,903,791,753,743,700cm-1 NMR(300MHz,CDCl3, delta ppm): 1.72-1.84(2H,m),2.26-2.48(2H,m),2.80-2.97(2H,m),3.31(3H,s),3.76(3H,m),4.06-4.20(2H,m),4.31-4.49(3H,m),4.80-4.88(1H,m),6.40-6.55(1H,m),6.93-7.20(5H,m),7.22-7.40(4H,m),7.58(1H,brs),7.81-7.88(1H.m),9.56(1H,brs) [alpha]D20: -139.4Ø (C=0.11, MeOH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With pyridine; In ISOPROPYLAMIDE; at 90℃; for 18h; | To a solution of <strong>[25475-67-6]3-aminoisoquinoline</strong> (210 mg, 1.5 mmol), EPO <DP n="223"/>pyridine (236 muL, 2.9 mmol) and 4-nitrophenyl chlorocarbonate (294 mg, 1.5 mmol) in N,N-dimethylacetamide (6 mL) was added 2-chloro-4- [ (5-methyl-5H-pyrrolo [3, 2-d] pyrimidin-4- yl) oxy]"aniline (200 mg, 0.73 mmol), and the mixture was stirred at 900C for 18 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate (chil) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (53 mg, 16percent) as a colorless solid.1H-NMR (DMSO-de, 300 MHz) delta 4.11 (3H, s) , 6.61 (IH, d, J = 3.0 Hz), 7.30 - 8.40 (1OH, m) , 9.19 (IH, -s) , 10.08 (IH, s) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 4A^-rcyig^^-Chloro-S-oxo-P^^^-trifluoroethylVS.J.S^.lO-hexahvdroazepinofSLambda-elindazol-?- yl]-2'-oxo-r.2'-dihydro-lH-spiro[piperidine-4,4'-pyrido[2,3-][l,3]oxa2ine]-l-carboxamideTo a solution of (7i?)-7-amino-4-chloro-9-(2,2,2-trifluoroethyl)-6,7,9,10- tetrahydroazepino[3,4-e]indazol-8(3H)-one (100 mg, 0.3 mmol) [Chaturvedula et al. WO 2006/052378],and triethylamine (120 uL, 0.9 mmole) is added ^-nitrophenyl chloroformate (60 mg, 0.3 mmmol) and stirred at 0 0C for 1 hr. Spiro[piperidine-4,4'-pyrido[2,3-c/][l,3]oxazin]- 2'(l'H)-one hydrochloride [Burgey et al. WO 2006/044504], (77'mg, 0.3mmole is then added with triethylamine (120 uL, 0.675 mmol) and the reaction mixture is stirred at ambient temperature for 16 hrs. Saturated aqueous sodium carbonate (50 mL) is added and the mixture is extracted with dichloromethane (3 * 25 mL). The organic layer is washed with saturated aqueous sodium bicarbonate (3 x), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography, eluting with a gradient of CHCl3 :MeOEta - 100:0 to 90:10, provides the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | A solution [OF 3, 5-BISTRIFLUOROMETHYLBENZYL ALCOHOL] (15.0 g, 61.4 mmole) and pyridine (4.86 g, 61.4 mmole) in 100 ml of dry [CH2C12] was added over a 15 minute period to a stirred solution [OF 4-NITROPHENYL CHLOROFORMATE (12. 38] g, 61.4 mmole) in 150 mi dry [CH2CI2] under an atm. of argon in an ice water bath. The mixture was allowed to warm to rt over a period of 2 hrs at which time beta-alanine-t-butylester [HC1] (13.94 g, 76.7 mmole) was added followed by triethylamine (12.97 g, 128.2 mmole). The mixture was stirred to rt overnight at which time it was evaporated to near dryness. Then 500 ml of ethyl acetate was added and extracted with 2 x 200 ml IN HCI, 3 X 200 ml 2N NaOH, dried over [NA2SO4] and evaporated to dryness. This was redissolved in 200 ml hexanes with sonication and placed in the freezer for [1] hr. The product was collected by filtration and washed with 100 ml cold hexanes and dried as a white solid, 22.57g [(88%). 1H-NMR] (500 MHz, [CDC13,] rt, ppm): [8] 1.45 (s, 9H), 2.42-2. 48 [(M,] 2H), [3.] 40-3.46 [(M,] 2H), 5.20 (s, 2H), 5.42 (bs, [1H),] 7.79 (s, 2H), 7.82 (s, [1H).] MS (ES+): m/z 416.5 [M+H] [+.] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | To a solution of 4-nitrophenyl chloroformate (264 mg, 1.26 mmol) in 3 mL of DCM at 0 C was added dropwise Et3N (177 muL, 1.26 mmol). The mixture was stirred during 20 min under argon then a solution of 6a (100 mg, 0.42 mmol) in 4 mL of DCM was added dropwise to the first solution and the mixture was stirred during 3 h at r.t. The reaction was quenched with brine, extracted with DCM (3×20 mL), the organic layers were combined, dried with MgSO4 and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography over silica gel with cyclohexane-EtOAc: 90- 10 to 60-40 to give the expected product (135 mg, yield: 80%). 1H NMR (300 MHz, CDCl3) delta 7.88-7.82 (m, 2H), 7.46-7.41 (m, 2H), 7.40-7.35 (m, 2H), 5.31 (m, 2H), 1.35 (s, 12H). 13C NMR (75 MHz, CDCl3) delta 155.47, 152.38, 145.36, 137.02, 135.15, 127.58, 127.23, 125.25, 121.74, 83.95, 70.75, 24.82. HRMS (ESI): m/z Calcd for C20H22BNO7Na, [M+Na]+:422.1387, found: 422.1367. | |
60% | With triethylamine; In tetrahydrofuran; at 20℃; for 1h;Product distribution / selectivity; | 4-(Hydroxymethyl)phenylboronic acid pinacol ester (0.5 g, 2.1 mmol) was dissolved in 20 mL of dry THF. Triethylamine (0.6 mL, 4.3 mmol) was added followed by 4-nitrophenyl chloroformate (0.47 g, 2.3 mmol) and the reaction was allowed to stir at room temperature for 1 h. The reaction was diluted with EtOAc and washed with 1.0 M HCl followed by saturated NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated. Compound B2a was purified on a silica gel column eluting with 5% EtOAc in hexanes to give 0.51 g (1.3 mmol, 60% yield) as a white solid. 1H NMR (400 MHz, CDCl3) delta=8.25 (d, J=9.2 Hz, 2H), 7.85 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 7.36 (d, J=9.2 Hz, 2H), 5.31 (s, 2H), 1.35 (s, 12H). 13C NMR (100 MHz, CDCl3) delta=155.7, 152.7, 145.6, 137.2, 135.4, 127.9, 125.5, 122.0, 84.2, 71.0, 25.1. ESI-MS(+): m/z 417.19 [M+NH4]+, 422.20 [M+Na]+. |
In dichloromethane; at 0℃; | 1) Preparation of active small molecules:Mixing 4-(hydroxymethyl)phenylboronic acid pinacol ester and p-nitrophenoxycarbonyl chloride as a molar ratio of 1:1The solution was dissolved in dichloromethane in that order, and the reaction was stirred well at 0 C.Synthesizing a small molecule capable of reversibly binding to methotrexate; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Procedure: 4-Nitrophenyl chloroformate (43 mg, 0.216 mmol) was added to DIEA (18 mg, 0.135 mmol), DMAP (26 mg, 0.216 mmol) and carbamate 433 (15 mg, 0.027 mmol) in dry CH2C12 (1 mL) under N2 and allowed to stir for 12 hours. Tetrahydro-pyran-4-ylamine hydrochloride salt (11 mg, 0.081 mmol) was added. Then the mixture was stirred at room temperature for another 2 hours. TLC showed the reaction was completed. Water (15 mL) was added and the mixture was extracted with DCM (3 x 15 mL). The combined organic layers were dried over Na2S04, filtered and concentrated to give SW-127 which was purified by preparative HPLC (9.07 mg, 49percent). LCMS (m/z): [M+H]+ 685 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -15 - 0℃; for 2h; | Step 5.1. 4-Nitrophenyl tetrahydro-2ff-pyran-4-ylcarbamateTo a solution of 5.00 g (36.3 mmol) of tetrahydro-2H-pyran- 4-yl-amine hydrochloride (CAS 38041-19-9) in 300 ml of dichloromethane, cooled to -15°C are added portionwise 13.2 g (65.4 mmol) of 4-nitrophenyl chloroformate (CAS 7693- 46-1) and then 12.7 ml (72.7 mmol) of diisopropylethylamine. Stirring is continued at -0°C for 2 hours, and 20 ml of saturated aqueous sodium hydrogen carbonate solution are then added. The organic phase is separated out by settling and dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a column 80 g of silica gel, eluting with a mixture of 20percent acetone in dichloromethane, to give 8.26 g of 4-nitrophenyl tetrahydro-2H-pyran-4-ylcarbamate in the form of a white powder,m.p.: 174-176°CXH NMR (CDC13) delta : 8.25 (d, 2H) ; 7.35 (d, 2H) ; 5.10 (broad d, 1H) ; 4.05 (m d, 2H) ; 3.85 (m, 1H) ; 3.50 (t d, 2H) ; 2.0 (m, 2H) ; 1.60 (m, 2H) ppm. | |
8.26 g | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 2h; | To a solution of 5.00 g (36.3 mmol) of tetrahydro-2H-pyran-4-yl-amine hydrochloride (CAS 38041-19-9) in 300 ml of dichloromethane, cooled to -15° C. are added portionwise 13.2 g (65.4 mmol) of 4-nitrophenyl chloroformate (CAS 7693-46-1) and then 12.7 ml (72.7 mmol) of diisopropylethylamine. Stirring is continued at -0° C. for 2 hours, and 20 ml of saturated aqueous sodium hydrogen carbonate solution are then added. The organic phase is separated out by settling and dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a column 80 g of silica gel, eluting with a mixture of 20percent acetone in dichloromethane, to give 8.26 g of 4-nitrophenyl tetrahydro-2H-pyran-4-ylcarbamate in the form of a white powder. m.p.: 174-176° C. 1H NMR (CDCl3) delta: 8.25 (d, 2H); 7.35 (d, 2H); 5.10 (broad d, 1H); 4.05 (m d, 2H); 3.85 (m, 1H); 3.50 (t d, 2H); 2.0 (m, 2H); 1.60 (m, 2H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With triethylamine; In tetrahydrofuran; at 30℃; for 4h; | Preparation of 4-nitrophenyl 4-(pyridin-3-yl)-l //-imidazole- 1-carboxylateThis example illustrates the synthesis of the nitrophenyl carbamate intermediate for preparing urea compounds by the process of the invention (i.e. intermediates in which J of Formula Gamma or IotaGamma is nitro).In a 250ml reactor to a mixture of 3-(l//-imidazol-4-yl)pyridine (5 g, 34.4 mmol) and tetrahydrofuran (100 ml) was charged triethylamine (5.76 ml, 41.3 mmol) and then a solution of 4-nitrophenyl chloroformate (7.29 g, 36.2 mmol) in tetrahydrofuran (25 ml) maintaining the temperature below 30C. After the addition finished, the reaction mixture was left stirring for 4 hours. The suspension was filtered and washed with water (V= 150ml) and THF (25ml) to afford a light yellow solid 8.0g (61%).NMR spectra of this nitrophenyl carbamate intermediate were recorded at 20C, on a Bruker 400 MHz DPX spectrometer with solvent used as internal standard. Data are reported in the following order: approximate chemical shift (ppm), number of protons, multiplicity (d, doublet; d d, doublet of doublet; d d d, doublet of doublet of doublet; t d, triplet of doublet; m d, multiplet of doublet) and coupling constant (Hz).H NMR (400 MHz, DMSO, 20C) delta: 9.18 (1H, d, J = 2.3 Hz), 8.67 (1H, d, J = 2.3 Hz), 8.57 (1H, d, J = 1.3 Hz), 8.55 (1 H, d d, J = 1.6, 5.0 Hz), 8.42 (2H, m d, J = 9.3 Hz), 8.36 (1H, t d, J = 1.8, 8.0 Hz), 7.79 (2H, m d, J = 9.3 Hz), 7.53 (1H, d d d, J = 0.8, 4.9, 8.0 Hz).13C NMR (100 MHz, DMSO, 20C) delta: 154.3, 147.9, 146.1 , 145.8, 145.7, 139.2, 139.0, 133.1, 128.7, 125.6, 124.2, 123.2, 1 14.8Mp (C) : 202 - 204 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of (7lambda)-4-chloro-10-[l-(trifluoromethyl)cyclopropyl]-3,6,7,12- tetrahydroimidazo[r,2':l,7]azepino[3,4-e]indazol-7-amine (100 mg, 0.3 mmol)],and triethylamine (120 uL, 0.9 mmole) is added p-nitrophenyl chloroformate (60 mg, 0.3 mmmol) and stirred at 0C for 1 hr. Spiro[piperidine-4,4'-pyrido[2,3-d][l,3]oxazin]-2'(1'H)-one hydrochloride [Burgey et ah WO 2006/044504], (77 mg, 0.3mmole is then added with triethylamine (120 uL, 0.675 mmol) and the reaction mixture is stirred at ambient temperature for 16 hrs. Saturated aqueous sodium carbonate (50 mL) is added and the mixture is extracted with dichloromethane (3 * 25 mL). The organic layer is washed with saturated aqueous sodium bicarbonate (3 x), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane ? 93% dichloromethane/ methanol] gives the title compound |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | [001038] Procedure: 4-Nitrophenyl chloro formate (43 mg, 0.216 mmol) was added to DIEA (18 mg, 0.135 mmol), DMAP (26 mg, 0.216 mmol) and carbamate 433 (15 mg, 0.027 mmol) in dry CH2C12 (1 mL) under N2 and allowed to stir for 12 hours. Tetrahydro-pyran-4-ylamine hydrochloride salt (11 mg, 0.081 mmol) was added. Then the mixture was stirred at room temperature for another 2 hours. TLC showed the reaction was completed. Water (15 mL) was added and the mixture was extracted with DCM (3 x 15 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated to give SW-127 which was purified by preparative HPLC (9.07 mg, 49percent). LCMS (m z): [M+H]+ 685 | |
49% | [001038] Procedure: 4-Nitrophenyl chloro formate (43 mg, 0.216 mmol) was added to DIEA (18 mg, 0.135 mmol), DMAP (26 mg, 0.216 mmol) and carbamate 433 (15 mg, 0.027 mmol) in dry CH2C12 (1 mL) under N2 and allowed to stir for 12 hours. Tetrahydro-pyran-4-ylamine hydrochloride salt (11 mg, 0.081 mmol) was added. Then the mixture was stirred at room temperature for another 2 hours. TLC showed the reaction was completed. Water (15 mL) was added and the mixture was extracted with DCM (3 x 15 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated to give SW-127 which was purified by preparative HPLC (9.07 mg, 49percent). LCMS (m z): [M+H]+ 685 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.3 g | Step 8. tert-Butyl S)-1-[^[1H.2H.3H-pyrrolof3.4-c]pyridin-2- yl]carbonyl)amino]methyl]-6-azaspiro[2.51octane-6-carboxylate. A solution of tert- butyl (1 S)-l -(aminomethyl)-6-azaspiro[2.5]octane-6-carboxylate (5 g, 20.80 mmol, 1.00 equiv), 4-nitrophenyl chloroformate (4.4 g, 21.83 mmol, 105 equiv) and D1PEA (10 mL) in THF (200 mL) was stirred overnight at rt. 1 H,2H,3H-Pyrrolof3,4- c]pyndine dihydrochloride (44 g, 2279 mmol, 9.24 equiv) was then added and the reaction mixture was stirred overnight at rt The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column eluted with DCM/MeOH (20/1 ) to give 2.3 g of tert-butyl (lS)-l-[[([lH,2H,3H-pyrrolo[3,4- c]pyndin-2-yl]carbonyl)amino]methyl]-6-azaspiro[2.5]octane-6-carboxylate as a light yellow solid TLC: DCM MeOH =10:1, R, = 0.4. |
Yield | Reaction Conditions | Operation in experiment |
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80% | Example 5: l-(4-((lH-Indo -3-yl)methyl)-3-ethylphenyl)-3-(2-(piperazin-l-yl)ethyl)urea [00109] Step 1. To a solution of 4-((lH-indol-3-yl)methyl)-3-ethylaniline (0.8 g, 3.2 mmol) and 4-nitrophenyl carbonochloridate (0.64 g, 3.2 mmol) in THF was added diisopropylethylamine (0.4 g, 16 mL, 3.2 mmol) at 25 °C and the resulting solution was stirred for 30 min. Then iert-butyl 4-(2-aminoethyl)piperazine-l-carboxylate (1.5 g, 6.4 mmol) was added to the above solution. The resulting mixture was stirred at 25 °C for 12 h. The mixture was concentrated and purified by preparative HPLC to give iert-butyl 4-(2-(3-(4-((lH-indol-3- yl)methyl)-3-ethylphenyl)ureido)ethyl)piperazine-l-carboxylate (1.3 g, 80percent) as a white solid. 1H NMR (400 MHz, CDC13) delta: 1.16-1.18 (t, 3H), 1.46 (s, 9H), 2.36-2.38 (m, 4H), 2.49-2.52 (t, 2H), 2.64-2.69 (q, 2H), 3.31-3.37 (m, 6H), 4.06 (s, 2H), 5.36 (s, IH), 6.66 (s, IH), 7.01-7.08 (m, IH), 7.12-7.35 (m, 3H), 7.35-7.37 (d, J = 8.0 Hz, IH), 7.54-7.56 (d, J = 8.0 Hz, IH), 8.11 (s, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of <strong>[302348-51-2][4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanol</strong> (2.34 g,10 mmol) and pyridine (890 ul, 11 mmol) in THF (50 ml) at rt was added dropwise a solution of 4-nitrophenyl chloroformate (2.22 g, 11 mmol) in THF (10 ml). The reaction mixture was stirred at rt for overnight. The precipitate was removed by filtration. The filtrate was concentrated to give thedesired compound (4.2 g, may contain some pyridine HCI salt).To a solution of above product (400 mg, 1 mmol) in THF (3 ml) was added isopropyl amine(1.5 ml). The mixture was stirred at rt for 3h then concentrated to give the titled compound. LRMS5 (ESI) mjz 320.2 [(M+H)]+, calc'd for C17H26BN04: 319.21 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | In diethyl ether; at 20℃; for 2h; | To a solution of 4-nitrophenyl chloroformate (596 mg, 2.84 mmol) in diethyl ether (10 mL), a solution of 3-(pyrrolidin-1-yl)propan-1-ol (manufactured by ABCR, Inc., 386 mg, 2.84 mmol) in diethyl ether (10 mL) was added, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was crystallized from ethanol, followed by filtration, whereby Compound VI-3 (498 mg, 53percent) was obtained. 1H-NMR (DMSO-d6) delta: 1.76-1.84 (m, 2H), 1.85-2.00 (m, 4H), 3.11-3.16 (m, 2H), 3.30-3.44 (m, 4H), 3.47 (t, J=6.0 Hz, 2H), 4.77 (br s, 1H), 6.95 (d, J=9.2 Hz, 2H), 8.11 (d, J=9.2 Hz, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With pyridine; dmap; In dichloromethane; at 0 - 20℃; for 2.0h; | To a stirred solution of (4-(pyridin-2-yldisulfanyl)phenyl)methanol (0.40 g, 1.60 mmol) in CH2CI2 (10 mL) were added 4-nitrophenyl chloroformate (0.65 g, 3.2 mmol), pyridine (0.25 mL, 3.20 mmol), catalytic amount of DMAP (0.005 g ) at 0C. The mixture was allowed to stir for 2 h at room temperature. The reaction mixture was quenched with 1.5 N HC1 solution. The organic layer was separated and washed with brine, dried over anhydrous Na2SCri and concentrated. The crude product was purified by columnchromatography (S1O2, 20-30% of EtO Ac/hexanes) to afford (4-nitrophenyl) [4-(2- pyridyldisulfanyl)phenyl] methyl carbonate as a colourless liquid (600 mg, 91% yield); MS m/z 415.0 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; In dichloromethane; at 20℃; for 1.5h; | A solution of 4-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-lH-indazol-l-yl)-2-(((lr,4r)-4- hydroxycyclohexyl)amino)benzamide (464 mg, 1.0 mmol), 4-nitrophenylchloroformate (240 mg, 1.2 mmol) and DMAP (366 mg, 3.0 mmol) in DCM was stirred at room temperature for 1.5 hrs. The reaction mixture was diluted with DCM, washed with 0.1 N HCl and dried with Na2S04. Solvent was evaporated under reduced pressure to give (lr,4r)-4-((2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-lH-ind azol-l-yl)phenyl)amino)cyclohexyl (4-nitrophenyl) carbonate (702 mg, 90% purity) as a yellow solid. ESMS calculated for C30H30F3N5O7: 629.2; found: 630.5 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 1h; | Step 1:The mixture of methyl (±)-4-Boc-piperazine-2-carboxylate (CAS: 129799-08-2, 2.44 g, 0.01 mol), TEA (1.52 g, 0.015 mol) in DCM (10 mL) was added to a solution of (4-nitrophenyl) carbonochloridate (2.42 g, 0.012 mol) in DCM (10 mL). After 1 hour at rt, the organic layer was washed with water and saturated sodium bicarbonate solution, dried over sodium sulfate. After removal of solvent, the crude product 67-B was obtained and used in the next step without purification. MS: calc'd 410 (MH+), measured 410 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 18h;Inert atmosphere; | To a solution of maleimidoethanol (0.655 mg, 4.64 mM) in dry DCM (5 ml) under Argon wasadded p-nitrophenylchloroformate (1.12 g, 5.56 mM) and DIPEA (1.13 ml, 6.50 mM)respectively. The reaction was allowed to stir at RT for 18 h. TLC analysis (5 percent methanol inmethylene chloride) indicated that the reaction was complete. The reaction mixture was concentrated and purified using combiflash (Si02) column and eluted with 0-100percent EtOAc in petroleum ether to yield pure EC2474 (0.78 g, 55percent). ?H NMR (500 MHz, CDC13): (5 8.28 (d, J,= 9.0 Hz, 2H), 7.41 ((d, J,= 9.0 Hz, 2H)), 6.77 (s, 2H), 4.41 (t, J,= 4.5 Hz, J2= 5.5 Hz, 2H), 3.95 (t, J,= 4.5 Hz, J2= 5.5 Hz, 2H); ?3C NMR (500 MHz, CDC13): (5170.37, 155.40, 152.40,145.59, 134.36, 125.32, 121.99, 66.15, 36.35 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | A vial was charged with (4-nitrophenyl) carbonochloridate (37 mg, 183 umol) and dichloromethane (0.5 mL). <strong>[166737-85-5]S-trityl-L-cysteine amide</strong> (53 mg, 147 umol) was charged in a vial and dissolved in dichloromethane (0.5 mL). S-trityl-L- cysteine amide solution was added to (4-nitrophenyl) carbonochloridate solution. After 20 mins, solvent was evaporated, then 0.5 mL DMF was added. 3D (25 mg, 61 umol) was charged in a vial and suspended in DMF (1 mL). Carbamate solution was added, followed by diisopropylethylamine (24 mg, 183 umol, 32 uL). Solution was stirred at room temperature overnight. Crude was purified by preparative HPLC (40- 95% MeCN/water, 0.1% acetic acid). Pure fractions were pooled, frozen and lyophilized. 21 mg (43%) of white lyophilized powder was obtained (3.86 mins, M+H = |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | A vial was charged with (4-nitrophenyl) carbonochloridate (65.5 mg, 325 umol) and dichloromethane (0.5 mL). <strong>[166737-85-5]S-trityl-L-cysteine amide</strong> (94 mg, 260 umol) was charged in a vial and dissolved in dichloromethane (0.5 mL). S-trityl-L- cysteine amide solution was added to (4-nitrophenyl) carbonochloridate solution. After 20 mins, solvent was evaporated, then 0.5 mL DMF was added. 1A (made according to procedures in WO2015038649) (100 mg, 217 umol) was charged in a vial and suspended in DMF (2 mL). Carbamate solution was added, followed by diisopropylethylamine (84 mg, 650 umol, 113 uL). Solution was stirred at room temperature overnight. Crude was purified by preparative FIPLC (40-95% MeCN/water, 0.1% acetic acid). Pure fractions were pooled, frozen and lyophilized. 61 mg (33%)) of white lyophilized powder was obtained (4.89 mins, M+H = 851). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of Intermediate 97 (289 mg, 1.01 minol, 1 .00 eq) in DCM (12 mL) was treated with 8 mL of an aqueous buffer solution (pH 7). The 2-phase system was stirred for 10 min at roomtemperature. Subsequently 4-nitrophenyl chloroformate (243 mg, 1.21 minol, 1.20 eq) was added and the mixture was stirred at 40 00 for 12 h. The organic layer was separated, dried over Na2504 and the volume was reduced. To this solution a mixture of 2,3-dihydro-I H-pyrrolo[3,4- c]pyridine dihydrochloride (233 mg, 1.21 minol, 1.20 eq) and 3.00 eq DIPEA in DCM II4Owas added. The reaction mixture was stirred over night at room temperature. The reaction mixturewas diluted with DCM and three times extracted with IM aqueous NaOH. The organic layer was dried over Na2504 and the solvent was removed under reduced pressure. After trituration with diethyl ether 275 mg of the desired product were obtained (63percent).1H-NMR (500MHz, DMSO-d6): 6 [ppm] = 1.05 (d, 3H), 1.47 - 1.59 (m, 2H), 1.86 (qd, IH), 2.09(qd, I H), 2.33 (d, I H), 2.72 (dd, I H), 3.35 - 3.48 (m, 3H), 3.86 - 4.02 (m, 2H), 4.75 (tt, I H), 4.83(br d, 4H), 7.44 (d, I H), 7.68 (d, 2H), 7.74 - 7.80 (m, 2H), 8.51 (d, I H), 8.58 - 8.68 (m, 2H).UPLC-MS (Method 2): R = 0.70 min. MS (ESipos): mz [M÷H] 434.Optical rotation (Method 5): [a] = 3Q50 (c = 1.00, DMSO). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of Intermediate 103 (4.07 g, 10.5 minol) in THE (45 mL) was added at r.t. 4- nitrophenylchloroformate (2.11 g, 10.5 minol). After heating to 6000 for 3 h the reaction mixture was concentrated under reduced pressure and the residue taken up in dichloromethane(40 mL). To the solution was added at r.t. N,N-diisopropylamine (4.28 mL, 24.6 minol) and 2,3- dihydro-IH-pyrrolo[3,4-c]pyridine dihydrochloride (1.53 g, 7.93 minol). After stirring for 20 h at this temperature further N,N-diisopropylamine (1 .50 mL) and THE (25 mL) was added. After 30 min stirring at r.t. the reaction mixture was heated to 60°C. After cooling to r.t. the reaction mixture was poured on water and aq. I N NaOH was added. After separation of the organicphase the aqueous phase was extracted 2 x with dichloromethane and the combined organic extracts were washed with brine and filtered through a phase separator filter. After removal of the solvent the crude product was purified by comumn chromatography (silica gel, ethyl acetate/ethanol gradient) to give the title compound (1.72 g, 75percent purity, 2.54 minol, 32percent).LC-MS (Method 6): Rt = 1.27 min; MS (ESIpos): m/z = 508 [M÷H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | To a solution Intermediate 106 (500 mg, 1.34 minol) in THE (15 mL) was added at r.t. 4- nitrophenylchloroformate (270 mg, 1.34 minol) and the mixture stirred for 14 h at that temperature. After concentrating the mixture under reduced pressure the residue was taken upin dichloromethane (40 mL) and N,N-diisopropylethyl amine (0.78 mL, 4.4 minol) and 2,3- dihydro-1 H-pyrrolo[3,4-c]pyridine dihydrochloride (274 mg, 1 .42 minol) were added. The reaction mixture was heated to 6000 for 4h and then poured on water. After basification of the mixture with I N aqueous sodium hydroxide solution the mixture was extracted with dichloromethane (2x). The combined organic extracts were washed with brine and filtered through a phaseseparator filter. The residue on the filter was dried at 50°C under vacuum to give the titlecompound (446 mg, 1.03 minol, 72percent).1H-NMR (400 MHz, DMSO-d6): 6 [ppm] = 8.77 (s, IH), 8.71 (s, IH), 8.65 (d, IH), 7.76-7.64 (m,5H), 4.95-4.86 (m, 4H), 3.80 (br t, 2H), 3.60 (t, 2H), 2.84 (s, 2H), 1.09 (s, 6H).LC-MS (Method 6): Rt = 0.79 min; MS (ESIpos): mz = 408 [M÷H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | To a solution of Intermediate 108 (200 mg, 0.51 minol) in THE (5 mL) was added at r.t. 4- nitrophenylchloroformate (103 mg, 0.51 minol) and the mixture was heated to 6000 for 3 h. After cooling to r.t. the mixture was concentrated under reduced pressure and taken up indichloromethane (5 mL). To this mixture was added at r.t. N,N-diisopropylethylamine (0.27 mL,1.56 minol) and 2,3-dihydro-IH-pyrrolo[3,4-c]pyridine dihydrochloride (97.0 mg, 0.50 minol) and the mixture stirred for 20 h at that temperature. After that more N,N-diisopropylethylamine (1.5 mL) and THE (25 mL) was added and the mixture was stirred for 30 min at r.t. and then heated to 60°C. After cooling to r.t. the mixture was poured on water, basified with aqueous I N NaOHand extracted with dichloromethane (2 x). The combined organic extracts were washed with brine and filtered through a silicone filter. Removal of the solvent gave the crude product which was purified by column chromatography (silica gel, hexane/ethyl acetate gradient) to give the title compound (183 mg, 0.34 minol, 68percent).1H-NMR (400 MHz, DMSO-d6): 6 [ppm] = 8.62 (s, IH), 8.59 (s, IH), 8.51 (d, IH), 7.82 (ddd, 4H),7.54-7.48 (m, 2H), 7.45 (d, I H), 7.41-7.37 (m, 2H), 4.82 (br d, 4H), 4.04-3.98 (m, 2H), 3.91-3.86 (m, 2H), 2.73 (s, 2H), 0.98 (s, 6H).LC-MS (Method 1): R = 0.90 min; MS (ESIpos): mz = 537 [M÷H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | To a solution of Intermediate 47 (400 mg, 1.73 minol, 1.00 eq) in THE (10 mL) was added 4- nitrophenyl chloroformiate (418 mg, 2.08 minol, 1.20 eq) and the mixture was stirred over night at 60 00. The solution was taken to dryness, the residue was resolved in DCM (12 mL) andtreated with DIPEA (0.90 mL, 5.19 minol, 3.00 eq) and 2,3-dihydro-IH-pyrrolo[3,4-C]pyridine dihydrochloride (401 mg, 2.08 minol, 1.20 eq). The resulting mixture was stirred over night at room temperature. The mixture was extracted three times with I M aqueous sodium hydroxide solution, the organic layer was washed with water and dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was triturated with MeOHdiethyl ether toyield the desired product (630 mg, 97percent).1H-NMR (400MHz, DMSO-d6): oe [ppm] = 1.07- 1.09 (m, 6H), 2.85 (s, 2H), 3.31 (s, 3H), 4.82 (d,4H), 7.44 (d, I H), 7.63 - 7.75 (m, 4H), 8.50 (d, I H), 8.63 (d, 2H).UPLC-MS (Method 2): Rt= 0.69 min; MS (ESIpos): mz [M÷H] 378. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | A vial was charged with (4-nitrophenyl) carbonochloridate (37 mg, 183 umol) and dichloromethane (0.5 mL). <strong>[166737-85-5]S-trityl-L-cysteine amide</strong> (53 mg, 147 umol) was charged in a vial and dissolved in dichloromethane (0.5 mL). S-trityl-L- cysteine amide solution was added to (4-nitrophenyl) carbonochloridate solution.After 20 mins, solvent was evaporated, then 0.5 mL DMF was added. T-1817 (25 mg, 61 umol) was charged in a vial and suspended in DMF (1 mL). Carbamate solution was added, followed by diisopropylethylamine (24 mg, 183 umol, 32 uL). Solution was stirred at room temperature overnight. Crude was purified by preparative HPLC (40-95% MeCN/water, 0.1% acetic acid). Pure fractions were pooled, frozen and lyophilized. 21 mg (43%) of white lyophilized powder was obtained (3.86 mins, M+H = 799). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 6-(4-aminophenyl)-4-{1-[oxan-2-yl]-1H-indazol-4-yl}pyridazin-3(2H)-one (360 mg, 0.929 mmol) in dichloromethane (34.3 mL) under argon was added pyridine (150 muL, 1.86 mmol), followed by portion wise addition of 4-nitrophenyl carbonochloridate (225 mg 1.12 mmol) over 1 minute, and the reaction mixture stirred at r.t. for 5 hours. To this crude reaction mixture was added N,N-diisopropylethylamine (809 muL, 4.65 mmol), followed by 2,3- dihydro-1H-pyrrolo[3,4-c]pyridine dihydrochloride (359 mg, 1.86 mmol) under argon and the reaction mixture stirred at r.t. for 5 hours. The reaction mixture was combined with another batch starting from 4-nitrophenyl (4-{6-oxo-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]- 1,6-dihydropyridazin-3-yl}phenyl)carbamate (0.852 mmol), and concentrated to give a residue. The crude residue was triturated with water-ethanol and the precipitate collected by filtration, washed with ethyl acetate, diethyl ether and dried to give the desired product, 580 mg (61% combined yield over two steps, 88% purity). (0950) LC-MS (Method 3): Rt = 0.46 min; MS (ESIneg): m/z = 532 [M-H]- 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.57 (s, 2H), 1.75 (s, 1H), 1.94-2.01 (m, 2H), 2.40- 2.42 (m, 1H), 3.70-3.77 (m, 1H), 3.85-3.88 (m, 1H), 4.80 (d, 4H), 5.87-5.89 (m, 1H), 7.41- 7.42 (m, 1H), 7.47-7.52 (m, 2H),7.66- 7.74 (m, 2H),7.80- 7.83 (m, 3H),8.08- 8.10 (m, 2H), 8.48 (d, 1H), 8.59-8.62 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 6-(4-aminophenyl)-4-{1-[(4-methylphenyl)sulfonyl]-1H-indol-5-yl}pyridazin- 3(2H)-one (200 mg, 0.438 mmol) in dichloromethane (16.2 mL) and N,N-dimethylformamide (4.00 mL) was added pyridine (71.0 muL, 0.876 mmol) followed by portion wise addition of 4- nitrophenyl carbonochloridate (106 mg, 0.526 mmol) over 1 minute, and the reaction mixture stirred at r.t. for1 hour. To this reaction mixture was added N,N-diisopropylethylamine (381 muL, 2.19 mmol) followed by <strong>[6000-50-6]2,3-dihydro-1H-pyrrolo[3,4-c]pyridine dihydrochloride</strong> (169 mg, 0.876 mmol) under argon and the reaction mixture stirred at r.t. for 16 hours. The reaction mixture was combined with another batch (0.219 mmol), and concentrated to give a residue. The crude residue was triturated with water-ethanol and the resulting precipitate collected by filtration, washed with ethyl acetate, diethyl ether and dried to give 246 mg (90% purity,63% combined yield over two steps) of the desired product as pale yellow solid. (0981) LC-MS (Method 5): Rt = 0.85 min; MS (ESIpos): m/z = 603 [M+H]+ (0982) 1H-NMR (400 MHz, DMSO-D6) delta (ppm): 2.29 (s, 3H), 4.80 (d, 4H), 6.90 (s, 1H), 7.37 (d, 2H), 7.53-7.54 (m, 1H), 7.60-7.66 (m, 2H), 7.83-7.97 (m, 5H), 8.10 (s, 2H), 8.24 (s, 1H), 8.53- 8.55 (m, 1H), 8.63-8.65 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
850 mg | To a solution of 6-(4-aminophenyl)-4-(quinolin-7-yl)pyridazin-3(2H)-one, (800 mg, 2.54 mmol), in tetrahydrofuran, 160 mL, was added 4-nitrophenyl carbonochloridate (615 mg, 3.05 mmol). The reaction mixture was heated at 60 C for 5 hours and concentrated under vacuum. The residue was dissolved in N,N-dimethylformamide, 20 mL and added to 2,3- dihydro-1H-pyrrolo[3,4-c]pyridine dihydrochloride (588 mg, 2.54 mmol) and N,N- diisopropylethylamine, (2.21 mL, 12.7 mmol) in dichloromethane (60 mL) and stirred at r.t. for 16 hours. The precipitate was collected by filtration, washed with water and dried to give the desired product, 850 mg (98% purity, 65% yield over two steps).PRODUCTS: (1029) LC-MS (Method 3): Rt = 0.32 min; MS (ESIpos): m/z = 461 [M+H]+ 1H-NMR (400 MHz, DMSO-D6) delta [ppm]: 4.79-4.81 (m, 4H), 7.41 (d, 1H), 7.54-7.57 (m, 1H), 7.68-7.71 (m, 2H), 7.91-7.93 (m, 2H), 8.03-8.05 (m, 1H), 8.15-8.17 (m, 1H), 8.31 (s, 1H), 8.38-8.40 (m, 1H), 8.46-8.48 (m, 1H), 8.58-8.60 (m, 2H), 8.74 (s, 1H), 8.93-8.94 (m, 1H). |