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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.
NH2-C2-NH-Boc is a protected amine group compound, commonly used in peptide synthesis and as a building block for further modifications.
Synonyms: PROTAC Linker 22
4.5
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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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Discovery of Inhibitory Fragments That Selectively Target Spire2-FMN2 Interaction
Kitel, Radoslaw ; Surmiak, Ewa ; Borggrafe, Jan ; Kalinowska-Tluscik, Justyna ; Golik, Przemyslaw ; Czub, Miroslawa , et al.
Abstract: Here, we report the fragment-based drug discovery of potent and selective fragments that disrupt the Spire2-FMN2 but not the Spire1-FMN2 interaction. Hit fragments were identified in a differential scanning fluorimetry-based screen of an inhouse library of 755 compounds and subsequently validated in multiple orthogonal biophys. assays, including fluorescence polarization, microscale thermophoresis, and 1H-15N HSQC NMR. Extensive structure-activity relationships combined with mol. docking followed by chem. optimization led to the discovery of compound 13, which exhibits micromolar potency and high ligand efficiency (LE = 0.38). Therefore, this fragment represents a validated starting point for the future development of selective chem. probes targeting the Spire2-FMN2 interaction.
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Purchased from AmBeed: 63010-72-0 ; 391-82-2 ; 188111-79-7 ; 23432-40-8 ; 75090-52-7 ; 178984-56-0 ; 57260-73-8 ; 21617-12-9 ; 611-35-8 ; 68500-37-8 ; 346-55-4 ; 181950-57-2 ; 216854-23-8 ; 86-98-6 ; 309956-78-3 ; 5407-57-8 ; 625471-18-3 ; 63136-61-8 ; 82121-05-9 ; 259731-83-4 ; 82121-08-2 ; 1557337-03-7 ; 41460-18-8 ; 766544-91-6 ; 256923-25-8 ; 91066-18-1
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CAS No. : | 57260-73-8 |
Formula : | C7H16N2O2 |
M.W : | 160.21 |
SMILES Code : | O=C(OC(C)(C)C)NCCN |
Synonyms : |
PROTAC Linker 22
|
MDL No. : | MFCD00191871 |
InChI Key : | AOCSUUGBCMTKJH-UHFFFAOYSA-N |
Pubchem ID : | 187201 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H314 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Class: | 8 |
UN#: | 2735 |
Packing Group: | Ⅲ |
* 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 |
---|---|---|
92% | Stage #1: at 20℃; Molecular sieve Stage #2: at -10 - 20℃; for 16 h; |
Preparation 63 Synthesis of tert-butyl 2-(benzylamino)ethylcarbamate (A) To a solution of tert-butyl 2-aminoethylcarbamate (6.4 g, 40.0 mmol) in methanol (60 mL) was added benzaldehyde (4.7 g, 44.0 mmol) and molecular sieve 3 Å. After stirring at ambient temperature overnight, the mixture was cooled down to ca. -10° C. (ice/salt bath) and treated portion wise with NaBH4 (9.1 g, 240.0 mmol) over 30 min. After complete addition, the bath was removed and the reaction mixture stirred at ambient temperature for 16 h. The solvent was evaporated and the residue taken into EtOAc (150 mL) and poured into water (100 mL). The organic layer was extracted with 0.5 N HCl (3*100 mL). The combined aqueous solution was cooled to 0° C., basified with sat. NaHCO3 and extracted with CHCl3 (3*100 mL). The combined organic layers were washed with brine (200 mL). After drying over MgSO4 and filtering, the solvent was evaporated in vacuo to give compound A (9.2 g, 36.8 mmol, 92percent) as a colorless oil. LC-MS [M+H] 251.2 (C14H22N2O2+H, calc: 251.3). TLC Rf (DCM/MeOH 9:1): 0.30. |
92% | Stage #1: at 20℃; molecular sieve 3Å Stage #2: at -10 - 20℃; for 16.5 h; |
Example 34: Synthesis of N-((S)-l-{2-[(Dihydrocodein-6-enyloxycarbonyl)-methylamino]- ethylcarbamoyl-4-guanidino}-butyl)-malonamic acid (Compound KC-4)Preparation 63: Synthesis of tert-butyl 2-(benzylamino)ethylcarbamate (A)To a solution of tert-butyl 2-aminoethylcarbamate (6.4 g, 40.0 mmol) in methanol (60 mL) was added benzaldehyde (4.7 g, 44.0 mmol) and molecular sieve 3A. After stirring at ambient temperature overnight, the mixture was cooled down to ca. -10 °C (ice/salt bath) and treated portion wise with NaBH4 (9.1 g, 240.0 mmol) over 30 min. After complete addition, the bath was removed and the reaction mixture stirred at ambient temperature for 16 h. The solvent was evaporated and the residue taken into EtOAc (150 mL) and poured into water (100 mL). The organic layer was extracted with 0.5 N HC1 (3 x 100 mL). The combined aqueous solution was cooled to 0 °C, basified with sat. NaHC03 and extracted with CHC13 (3 x 100 mL). The combined organic layers were washed with brine (200 mL). After drying over MgS04 and filtering, the solvent was evaporated in vacuo to give compound A (9.2 g, 36.8 mmol, 92percent) as a colorless oil. LC-MS [M+H] 251.2 (C14H22N2O2 +H, calc: 251.3). TLC Rf (DCM/MeOH 9:1): 0.30. Compound A was used without further purification. |
92% | Stage #1: at 20℃; Molecular sieve 3 Å Stage #2: With sodium tetrahydroborate In methanol at -10 - 20℃; for 16.5 h; Cooling with ice |
Preparation 63: Synthesis of tert-butyl 2-(benzylamino)ethylcarbamate (A)To a solution of tert-butyl 2-aminoethylcarbamate (6.4 g, 40.0 mmol) in methanol (60 mL) was added benzaldehyde (4.7 g, 44.0 mmol) and molecular sieve 3A. After stirring at ambient temperature overnight, the mixture was cooled down to ca. -10 °C (ice/salt bath) and treated portion wise with NaBH4 (9.1 g, 240.0 mmol) over 30 min. After complete addition, the bath was removed and the reaction mixture stirred at ambient temperature for 16 h. The solvent was evaporated and the residue taken into EtOAc (150 mL) and poured into water (100 mL). The organic layer was extracted with 0.5 N HC1 (3 x 100 mL). The combined aqueous solution was cooled to 0 °C, basified with sat. NaHC03 and extracted with CHC13 (3 x 100 mL). The combined organic layers were washed with brine (200 mL). After drying over MgS04 and filtering, the solvent was evaporated in vacuo to give compound A (9.2 g, 36.8 mmol, 92percent) as a colorless oil. LC-MS [M+H] 251.2 (C14H22N2O2 +H, calc: 251.3). TLC Rf (DCM/MeOH 9:1): 0.30. Compound A was used without further purification. |
92% | Stage #1: at 20℃; Molecular sieve Stage #2: at -10 - 20℃; for 16.5 h; |
To a solution of tert-butyl 2-aminoethylcarbamate (6.4 g, 40.0 mmol) in methanol (60 mL), Benzaldehyde (4.7 g, 44.0 mmol)And molecular sieves 3 Å were added.After stirring overnight at ambient temperature, the mixture was cooled to about -10 ° C. (ice / salt bath) and treated in portions with NaBH 4 (9.1 g, 240.0 mmol) for 30 minutes. After all addition, the bathtub was removed and the reaction mixture was stirred at ambient temperature for 16 hours. The solvent was evaporated and the residue was taken up in EtOAc (150 mL) and poured into water (100 mL). The organic layer was extracted with 0.5 N HCl (3 × 100 mL). The combined aqueous solution was cooled to 0 ° C., basified with saturated NaHCO 3 and extracted with CHCl 3 (3 × 100 mL). The combined organic layers were washed with brine (200 mL). After drying and filtering over MgSO 4, the solvent was evaporated under reduced pressure to give compound A (9.2 g, 36.8 mmol, 92percent) as a colorless oil. |
51% | Stage #1: at 20℃; for 2 h; Stage #2: at 0 - 20℃; |
Example 3Atert-butyl [2-(benzylamino)ethyl]carbamate; 2.0 g (18.4 mmol) benzaldehyde and 3.32 g (20.7 mmol) N-Boc-ethylendiamine are dissolved in 25 ml methanol. The mixture is stirred 2 h at rt before cooled to 00C and 3.57 g (94.2 mmol) sodium borohydride and water are added to generate a solution, which is stirred over night at rt. Solvents are removed in vacuo and the residue is dissolved in dichloromethane and washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by reverse phase HPLC (water / acetonitrile) to afford 2.4 g (51percent of th.) of the title compound.HPLC (method 1): R, = 3.70 min; MS (ESIpos): m/z = 251 (M+H)+1H-NMR (400 MHz, DMSOd6): δ = 7.30 (m, 4H), 7.21 (m, IH), 6.72 (m, IH), 3.68 (s, 2H), 3.02 (m, 2H), 2.53 (m, 2H), 2.08 (bs, IH), 1.37 (s, 9H). |
23% | Stage #1: With sodium tris(acetoxy)borohydride; magnesium sulfate; triethylamine In 1,2-dichloro-ethane at 20℃; for 16 h; Stage #2: With water; sodium hydrogencarbonate In 1,2-dichloro-ethane |
To a solution of tert-butyl 2-aminoethylcarbamate (3.7 g, 22.3 mmol), benzaldehyde (2.36 g, 22.3 mmol) and MgSO4 (1.33 g) in 1,2-dicholoroethane (300 mL) and Et3N (3.1 mL, 22.3 mmol) at RT was added NaHB(AcO)3. The mixture was stirred (RT, 16 h) and filtered. The solution was washed with saturated NaHCO3 (200 ml), dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with MeOH-DCM (0-10percent) to afford tert-butyl 2-(benzylamino)ethylcarbamate (1.4 g, 23percent). Mass calculated for C14H22N2O2=250.34; found: [M+H]+=251.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With pyridine; at 120℃; for 16h; | The corresponding amine (2.07 mmol, 1.1 eq) was added to a suspension of <strong>[93107-30-3]1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid</strong> (Q1b) (500 mg, 1.89 mmol, 1 eq) in pyridine (10 mL). The resulting mixture was heated at reflux at 120 C for 16 h. The resultant mixture was concentrated under reduced pressure. The crude product was isolated by vacuum filtration and washed with EtOAc, water and Et2O to afford the Boc-protected aminated quinolone |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 6h; | Tert-butyl 2-AMINOETHYLCARBAMATE (0.32 g, 2 mmol) was dissolved in dichloromethane with DIEA (0.6 mL, 3.4 mmol). To this solution, 2-BROMO-N- (3- (TRIFLUOROMETHYL)- phenyl) acetamide was added and the reaction mixture stirred for 6 hours at room temperature. The reaction mixture was concentrated to an oil and purified by column chromatography (eluent: ETOAC) to give the product 0.37 g, 1.02 mmol, 50% YIELD.1H NMR (500 MHz, CDCl3) 5 9.39 (s, 1H), 7.82 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 4.68 (s, 1H), 3.36 (s, 2H), 3.22 (dd, J = 11. 2,5. 5 Hz, 2H), 2.74 (t, J= 5. 7 HZ, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tetrahydroborate; In methanol; at 20℃; | A mixture of 4-methoxy-3-nitro- benzaldehyde (0.00625 mol) and (2-aminoethyl)- carbamic acid, 1,1 -dimethylethyl ester (0.00625 mol) in MeOH (30 ml) was reacted for 2 hours at room temperature, then sodium tetrahydroborate (0.0069 mol) was added and the reaction mixture was stirred overnight. Water was added and the resulting mixture was extracted 3 times with toluene. The organic layer was separated, dried (MgSO4) and the solvent was evaporated, yielding intermediate 58. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In propan-1-ol; | Preparation of N-(2-Pyrimidinyl)ethylenediamine a)N-Boc-N'-(2-Pyrimidinyl)ethylenediamine N-(Boc)ethylenediamine (0.80 g, 5.0 mmol) (Syn. Commun. 1990, 20, 255-264) was dissolved in 1-propanol (12 mL) and treated with K2 CO3 (1.2 g, 9.0 mmol), followed by 2-chloropyrimidine (0.91 g, 8.0 mmol), and the mixture was heated to reflux for 24 h. The reaction mixture was poured into H2 O (30 mL) and extracted with EtOAc (3*30 mL). The combined organic fractions were dried (MgSO4) and concentrated to give the title compound as a yellow solid (1.6 g): MS (ES) m/e 238.9 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; dichloromethane; water; | EXAMPLE 7 4.0 g of <strong>[103878-09-7]3-ethoxy-2-pyridinecarboxylic acid</strong> and 4.1 g of 1,1'-carbonyldiimidazole were stirred at 70 for 2 hours in 250 ml of tetrahydrofuran. To this solution were then added dropwise 4.1 g of N-(t-butoxycarbonyl)ethylenediamine in 20 ml of tetrahydrofuran and the mixture was left to stir at 70 for a further 2 hours. The reaction mixture was subsequently cooled to room temperature and concentrated to about 1/4 of the volume on a rotary evaporator under reduced pressure, taken up in water and extracted three times with chloroform. The chloroform extracts, dried over magnesium sulfate, were evaporated completely, and the residue was chromatographed on silica gel with 2-5% methanol in methylene chloride as the elution agent and crystallized from methylene chloride/n-hexane, whereby there was obtained t-butyl [2-(3-ethoxypyridine-2-carboxamido)ethyl]carbamate, m.p. 125-126. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; water; | EXAMPLE 20 9.8 g of <strong>[14190-59-1]thiazole-2-carboxylic acid</strong> and 12.3 g of 1,1'-carbonyldiimidazole were stirred at 70° for 1 hour in 35 ml of tetrahydrofuran. To this solution were then added dropwise 12.2 g of N-(t-butoxycarbonyl)ethylenediamine in 20 ml of tetrahydrofuran and the mixture was left to stir at 70° for a further 1/2 hour. The reaction mixture was subsequently cooled to room temperature and concentrated to about 1/4 of the volume on a rotary evaporator under reduced pressure, taken up in water and extracted three times with ethyl acetate. The ethyl acetate extracts, dried over magnesium sulfate, were evaporated completely, whereby t-butyl [2-(thiazole-2-carboxamido)ethyl]carbamate was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h; | 4-fluoro-phenylacetyl chloride (500 μL, 3.65 mmol) and diisopropylethylamine (1.30 mL, 7.30 mmol) was added to a solution of tert-butyl 2- aminoethylcarbamate (584 mg, 3.65 mmol) dissolved in anhydrous DCM (15 mL). After stirring at room temperature for 1 hour, formation of a precipitate was observed and the reaction mixture was diluted with ethyl acetate. The organic layer was separated and washed with 5% Na2CO3 (2x), H2O (2x), and brine (Ix), dried over Na2SO4, and concentrated to obtain a yellow solid (998 mg, 92 % yield). The solid was taken directly to the next step without further purification. 1H NMR (DMSO-fi?<USD, 600 MHz): δ 8.02 (br s, IH), 7.27 (m, 2H), 7.10 (m, 2H), 6.78 (br s, IH), 3.38 (s, 2H), 3.06 (m, 2H), 2.97 (m, 2H), 1.37 (s, 9H); 19F NMR (OMSO-d6, 565 MHz): δ - 117.16-117.21 (m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In water; at 0 - 20℃; for 1.5h; | (11) Synthesis of the following IL- Ira conjugate:JV-(ethoxycarbonyl) maleimide (0.53 g, 3.1 mmol) was added to N-(tert- butoxycarbonyl)-ethylenediamine (0.40 g, 2.5 mmol) in saturated aqueous bicarbonate solution (15 mL) at 00C. The reaction mixture was stirred for 30 min at 00C, and then stirred for an additional 1.0 hour at room temperature. The aqueous layer was extracted with methylene chloride (30 mL) three times. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Example 4 Preparation of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanamido)ethyl)docosa-4,7,10,13,16,19-hexaenamide In a typical run, <strong>[42017-89-0]2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoic acid</strong>, (<strong>[42017-89-0]fenofibric acid</strong>, 5.2 g, 16.3 mmol) was taken up in CH2Cl2 (80 mL) along with oxalyl chloride (1.4 mL, 16.3 mmol). After 20 muL of DMF was added, the resulting reaction mixture was stirred at room temperature for 3 h, until all gas evolution had ceased, and then concentrated under reduced pressure. The resulting acid chloride was taken up in 100 mL of CH2Cl2 and cooled to 0 C. A solution containing tert-butyl 2-aminoethylcarbamate (2.60 g, 16.3 mmol) and triethylamine (3.4 mL) in 15 mL of CH2Cl2 was added dropwise at 0 C. over a period of 20 min. The resulting reaction mixture was warmed to room temperature and stirred for 18 h. It was then quenched with brine and the two layers were separated. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (95% CH2Cl2, 5% MeOH) afforded tert-butyl 2-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanamido)ethylcarbamate (3.00 g, 40%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.9% | [00351] Step 2: To a solution of tert-butyl 2-aminoethylcarbamate (4.86 g, 30.3 mmol) in THF (500 mL) was added <strong>[357405-75-5]4-bromo-2,5-difluorobenzaldehyde</strong> (6.7 g, 30.3 mmol) followed by acetic acid (1.93 mL, 33.3 mmol) and the reaction was stirred for 30 minutes. Sodium triacetoxyhydroborate (9.64 g, 45.5 mmol) was added and the reaction was stirred overnight at ambient temperature. To the reaction was added sodium hydrogen carbonate (121 mL, 121 mmol, a saturated aqueous solution) and the reaction was stirred for 30 minutes followed by addition of benzyl carbonochloridate (4.31 mL, 30.3 mmol). The reaction was stirred at ambient temperature for 4 hours. The reaction was partitioned between EtOAc (500 mL) and water (500 mL) and the organic layer was separated. The organic layer was washed with brine (100 mL), dried over MgS04, filtered and concentrated in vacuo. The crude material was chromatographed eluting with DCM to give benzyl 4-bromo-2,5-difluorobenzyl(2-((tert- butoxycarbonyl)amino)ethyl)carbamate (13 g, 26.0 mmol, 85.9percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | With triethylamine; In dimethyl sulfoxide; at 40℃; for 16.0h;Inert atmosphere; | Preparational Example 1 Preparation of Cyclized Neutral Phthalimide Derivative (8) [0110] [0111] To a solution of Compound 6 (4,5,6,7-tetraiodobenzofuran-1,3-dione (TIPN), 2.40 g, 3.68 mmol) and Compound 7 (N-tert-Boc-ethylenediamine, 200 mg, 1.22 mmol) in dimethyl sulfoxide (DMSO) (5 mL) was added triethylamine (0.50 mL, 3.59 mmol). The reaction was heated at 40 C. and stirred for 16 hours under a dry argon atmosphere. The reaction mixture was passed through a size-exclusion chromatography (SEC) column (model: Bio-Beads S-X1, H 36 cm×O.D. 4.5 cm, manufacturer: Bio-Rad) in N,N-dimethylformamide (DMF) to remove DMSO, concentrated under reduced pressure, and the crude product was chromatographed on silica gel (20:1 methylene chloride (CH2Cl2)/acetone) to give 60.1 mg of Compound 8 (75.7 mol, 6%) as a yellow powder. [0112] Rf: 0.63 [silica gel, 10:1 CH2Cl2/acetone]; [0113] 1H NMR (600 MHz, DMSO-d6) δ 6.89 (t, 1H, J=6.4 Hz, H3), 3.60 (t, 2H, J=5.6 Hz, H1), 3.14 (q, 2H, J=5.8 Hz, H2), 1.29 (s, 9H, H4); [0114] 13C NMR (150 MHz, DMSO-d6) δ 164.1, 155.7, 135.4, 134.4, 104.0, 77.7, 38.9, 37.5, 28.1; [0115] HRMS (ESI) Calcd for C15H14N2O4I4Na (M+Na)+: 816.7030, Found: 816.7028. |
6% | With triethylamine; In dimethyl sulfoxide; at 40℃; for 16.0h;Inert atmosphere; | To a solution of Compound 6 (4,5,6,7-tetraiodobenzofuran-1,3-dione (TIPN), 2.40 g, 3.68 mmol) and Compound 7 (N-tert-Boc-ethylenediamine, 200 mg, 1.22 mmol) in dimethyl sulfoxide (DMSO) (5 mL) was added triethylamine (0.50 mL, 3.59 mmol). The reaction was heated at 40 C. and stirred for 16 hours under a dry argon atmosphere. The reaction mixture was passed through a size-exclusion chromatography (SEC) column (model: Bio-Beads S-X1, H 36 cm×O.D. 4.5 cm, manufacturer: Bio-Rad) in N,N-dimethylformamide (DMF) to remove DMSO, concentrated under reduced pressure, and the crude product was chromatographed on silica gel (20:1 methylene chloride (CH2Cl2)/acetone) to give 60.1 mg of Compound 8 (75.7 mol, 6%) as a yellow powder. Rf: 0.63 [silica gel, 10:1 CH2Cl2/acetone]; 1H NMR (600 MHz, DMSO-d6) δ 6.89 (t, 1H, J=6.4 Hz, H3), 3.60 (t, 2H, J=5.6 Hz, H1), 3.14 (q, 2H, J=5.8 Hz, H2), 1.29 (s, 9H, H4); 13C NMR (150 MHz, DMSO-d6) δ 164.1, 155.7, 135.4, 134.4, 104.0, 77.7, 38.9, 37.5, 28.1; HRMS (ESI) Calcd for C15H14N2O4I4Na (M+Na)+: 816.7030. Found: 816.7028. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 1h; | N-Boc-ethylenediamine (0.77 g, 4.8 mmol) was dissolved in DCM (15 mL) and 6- tritylmercaptohexanoic acid (2.25 g, 5.76 mmol) and PyBOP (3.0 g 5.76 mmol) were added with stirring. DIPEA (2.52 ml, 14.4 mmol) was added and the reaction stirred for 1 h. Thereaction was diluted with diethyl ether (150 mL) and washed with slightly basic brine (3x30 mL, prepared from 100 mL brine and 3 mL 0.1 M aq. NaOH). The organic phase was washed once more with brine (30 mL), dried over Na2SO4 and concentrated in vacuo and purifiedusing flash chromatography to give 18a as a white foam. Yield: 2.55 g (4.79 mmol, 99%) MS:m/z 555.24 = [M+Na], (calculated = 555.27). |
99% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 1h; | N-Boc-ethylenediamine (0.77 g, 4.8 mmol) was dissolved in DCM (15 mL) and <strong>[80441-55-0]6-tritylmercaptohexanoic acid</strong> (2.25 g, 5.76 mmol) and PyBOP (3.0 g 5.76 mmol) were added with stirring. DIPEA (2.52 ml, 14.4 mmol) was added and the reaction stirred for 1 h. The reaction was diluted with diethyl ether (150 mL) and washed with slightly basic brine (3x30 mL, prepared from 100 mL brine and 3 mL 0.1 M aq. NaOH). The organic phase was washed once more with brine (30 mL), dried over Na2S04 and concentrated in vacuo and purified using flash chromatography to give la as a white foam. Yield: 2.55 g (4.79 mmol, 99%) MS: m/z 555.24 = [M+Na]+, (calculated = 555.27). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With 4-methyl-morpholine; In tetrahydrofuran; at 20℃; | 2-Chloro-4,6-dimethoxy-1,3,5-triazole (0.88 g, 5 mmol) and N-methyl morpholine (1.1 mL, 10 mmol) were stirred in anhydrous THF (20 mL) for 20 minutes. <strong>[23351-91-9]5-Bromoisophthalic acid</strong> (0.5 g, 2 mmol) and tert-butyl-N-(2-aminoethyl)carbamate (0.8 g, 5 mmol) were added. Theresulting mixture was stirred at room temperature over night. The reaction mixture was pouredinto a mixture of ethyl acetate and water. The organic layer was washed with brine and driedover Na2SO4. A white solid (0.8 g, 76percent) was obtained as product. LC-MS and HNMR agreed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With sodium hydrogencarbonate; In tetrahydrofuran; at 0 - 20℃; for 1h;Inert atmosphere; | To a solution of 1-((tert-butoxycarbonyl)amino)-2-aminoethane (42)23 26, 27 (1.13 g, 7.1 minol) in saturated NaHCO3 (35 mL) at 0 C was added <strong>[55750-49-7]N-(ethoxycarbonyl)maleimide</strong>22 (45) (1.1 g, 7.1 minol). The reaction mixture was warmed to rt and stirred for 15 min.THF (55 mL) was then added and the reaction mixture stirred for a further 45 mi H20 (50 mL) was added and the aqueous phase extracted with EtOAc (3 x 75 mL). The combined organic extracts were washed with saturated NaCI (100 mL) and dried over Mg504. Removal of the solvent in vacuo gave an off-white solid that was purified by flash chromatography (0%, then 5%, then 10% EtOAc in CH2CI2) to yleld the title compound 46(1.1 g 58%) as a white solid. Mp. 126-128 C; Rf(10% EtOAc in CH2CI2) 0.28; IR (ATR)vmaxjcm1 3350 (C-H), 3089 (C-H), 2977, 1701 (C=O), 1678 (C=O), 1516, 1434, 1288,1256, 1167, 944, 844, 692, 623; 1H NMR (400 MHz, CDCI3) oe 1.40 (9H, 5), 3.30-3.35 (2H,m), 3.66 (2H, t, J = 6.0 Hz), 4.74 (1H, br 5), 6.71 (2H, 5); 13C NMR (100 MHz, CDCI3) oe28.3, 38.0, 39.4, 79.5, 131.1, 155.9, 170.8. The 1H and 13C NMR data obtained was in agreement with that reported from literature.23 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.3% | In ethanol; for 5h;Reflux; | A mixture of 4-amino- , 8-naphthalene dicarboxylic anhydride (0.30 g, 1.4 mmol) and tert-butyl-2-aminoethylcarbamate (1.88 g, 10 mmol) were suspended in 20 mL of absolute ethanol,The reaction was refluxed for 5 hours, concentrated to 5 mL, filtered,Wash the cake with ether,After drying, the yellow powder was obtained in 65.3% yield. No purification is required for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Will 200mg (0.70mmol) rhein,148 mg (0.77 mmol) of EDC was added to 100 mL of dichloromethane and stirred for 30 min at room temperature.Then add 88mg (0.77mmol) NHS,Reaction at room temperature for 24h until the reaction system is clear100 muL of N-Boc-ethylenediamine was added dropwise to the reaction solution.Stir at room temperature for 24h,Filtered to give a yellow solid,Wash with methanol to give pure Intermediate 1. 200 mg (0.47 mmol) of Intermediate 1 was added to 15 ml of dichloromethane/trifluoroacetic acid (10:1) and reacted at room temperature for 12 h. The solvent was evaporated under reduced pressure to give Intermediate 2.421 mg (0.74 mmol) of DOTA-tris(tBu)ester,280 mg (0.74 mmol) HBTU was added to 50 mL acetonitrile,Then add 100muL DIPEA,Room temperature reaction for 30min,Then, 241 mg (0.74 mmol) of Intermediate 2 was added to the reaction system.Room temperature reaction 24h.The solvent was removed under reduced pressure to give crude product.Purification by silica gel column gave Intermediate 3.200 mg (0.23 mmol) of intermediate 3 was added to 20 mL of dichloromethane/trifluoroacetic acid (1:1) and reacted at room temperature for 24 h.The solvent was removed under reduced pressure to give ligand 1.200 mg (0.28 mmol) of Ligand 1,104mg (0.28mmol)GADOLINIUM(III) CHLORIDE HEXAHYDRATE IN5mL water,Adjust pH to 6-7 with 1M NaOH and react at room temperature for 24h.Evaporate the solvent under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Trifluoroacetic Acid/N-(2-aminoethyl)-4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)cyclohexanecarboxamide (1:1) The title compound was prepared by classical methods of peptide chemistry from commercially available 1-[(4-[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}cyclohexyl)methyl]-1H-pyrrole-2,5-dione and tert-butyl (2-aminoethyl)carbamate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | To a solution of benzyl 3,3-dimethyl-4-oxo-piperidine-l-carboxylate (5.8 g, 22.2 mmol) in MeOH (50 mL) was added tert-butyl (2-aminoethyl)carbamate (3.5 g, 22.2 mmol) and AcOH (66.6 mg, 1.11 mmol, 63 muEpsilon). The mixture was stirred at 25 C for 1 h. Then to the mixture was added NaBH3CN (4.19 g, 66.6 mmol) and was stirred at RT for 3 h. The residue was poured into water (100 mL), extracted with EtOAc (50 mL x2). The combined organic layer was concentrated and purified by column chromatography on silica (Petroleum Ether:EtOAc=l : l) and concentrated in vacuo to give benzyl 4-[2-(tert-butoxycarbonylamino)ethylamino]-3,3- dimethyl-piperidine-l-carboxylate (3.5 g, 6.04 mmol, 27 % yield) as a yellow oil. MS (ES+) C22H35N304 requires: 405, found: 406 [M+H]+. 1H MR (400 MHz, MeOH-d4) delta: 7.42-7.30 (m, 5H), 5.13 (s, 2H), 3.72 (d, J= 13.3, 1H), 3.41 - 3.29 (m, 1H), 3.27 - 3.10 (m, 2H), 2.97 - 2.56 (m, 4H), 2.40 - 2.22 (m, 1H), 1.81 (d, J = 11.7, 1H), 1.45 (s, 9H), 1.38 (dd, J = 4.1, 12.2, 1H), 0.98 (d, J= 6.4, 3H), 0.84 (d, J= 6.4, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With sodium cyanoborohydride; acetic acid; In ethanol; at 60℃; | 6-Bromo-2,3 ,4,9-tetrahydro- 1H-carbazol - 1-one (1.0 g, 3.79 mmol), N-bocethylenediamine (1.80 mL, 11.37 mmol) and sodium cyanoborohydride (1.19 g, 18.95 mmol)were dissolved in ethanol (20 mL). Catalytic amount of acetic acid was added. The reactionmixture was stirred for overnight at 60 C. After removal of solvent, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with 10% sodium hydroxide and brine, and it was dried over sodium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified on an ISCO chromatograph (0-10%methanol/dichloromethane + 0.1% NH4OH) to give the product as a yellow solid (952 mg,6 1%); LC/IVIS RT = 3.01 (M-H: 406/408). |
To a solution of 1,2-cyclohexanedione (2243?mg, 20?mmol) and concentrated hydrochloric acid (13?mL) in acetic acid (40?mL), p-tolylhydrazine hydrochloride (1586?mg, 10?mmol) in methanol (25?mL) was added dropwise slowly over 10?min. After the addition, the resulting mixture was heated to 60?C, and stirred overnight. The solvent was evaporated, and the residue was pH adjusted to weak alkaline with saturated NaHCO3. The mixture was extracted with AcOEt (3?*?20?mL). The combined organic extract was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel chromatography (petroleum ether/AcOEt, 12/1 v/v) to give intermediate 7 (1235?mg, 62%) as a brown powder. The mixture of intermediate 7 (102?mg, 0.5?mmol), 4-phenylbutylamine (0.12?mL, 0.8?mmol) and catalytic p-TsOH in toluene (10?mL) was refluxed at 140?C for 16?h with a Dean-Stark trap in place. The solvent was evaporated and the residue was dissolved in methanol. NaBH4 (177?mg) was then added at 0?C. The solution was heated to 80?C until TLC indicated the reaction was complete. The reaction was quenched with water and concentrated. Subsequently, the mixture was extracted with AcOEt twice and the combined organic layers were dried over anhydrous Na2SO4. After evaporation of the solvent, the resulting residue was purified by column chromatography on silica gel (petroleum ether/AcOEt, 4/1 v/v) to give compound 5 (123?mg, Yield: 72%). |
Tags: NH2-C2-NH-Boc | PROTAC Linker 22 | Carbamates | Esters | Aliphatic Linkers | Organic Building Blocks | Bifunctional Linkers | PROTAC Linkers | 57260-73-8
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