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Structure of 23357-46-2
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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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Engineering Heme Proteins for C(Sp³)–H Primary Amination
Shilong Gao ;
Abstract: Primary amine is one of the most prevalent moieties in synthetic intermediates and pharmaceutical compounds. The preparation of aliphatic primary amines via C−H functionalization would provide direct access to the nitrogen-containing compounds from hydrocarbon substrates. While the enzymatic oxyfunctionalization of C–H bonds is well established, the analogous strategy for nitrogen incorporation is unknown in Nature. Likewise, a synthetic method for selective primary amination of aliphatic C–H bonds remains elusive. Combining chemical intuition and inspiration from Nature, chemists and protein engineers have created new heme-containing enzymes for the C(sp³)–H primary amination via directed evolution. This thesis describes some of the efforts in the continued pursuit of these new-to-nature reactions. Chapter I discusses directed evolution in the context of biocatalysis, the strategies for introducing new-to-nature chemistry in enzymes, the discovery of nitrene transferases from the cytochrome P450 monooxygenase, and finally, the development of C(sp³)–H primary aminases. Chapter II details the discovery and engineering of serine-ligated cytochrome P411 enzymes that catalyze the first primary amination of C(sp³)–H bonds with excellent selectivity, affording a broad scope of enantioenriched primary amines. Chapter III demonstrates that these new-to-nature nitrene transferases were engineered to aminate and amidate unactivated, unbiased C(sp³)–H bonds with unprecedented selectivity. In Chapter IV, engineered protoglobins are shown to utilize hydroxylamine (NH₂OH) for nitrene transfer reactions, including benzylic C–H primary amination and styrene aminohydroxylation. Overall, these new-to-nature reactions can be considered the nitrogen analogs to the C–H oxidation chemistry performed by monooxygenases and peroxygenases. By offering a direct path from saturated precursors, these enzymes present a new biochemical logic for accessing nitrogen-containing compounds. Finally, this work hints at the possible future discovery of natural enzymes that use hydroxylamine precursors for amination chemistry.
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CAS No. : | 23357-46-2 |
Formula : | C10H13N |
M.W : | 147.22 |
SMILES Code : | N[C@@H]1CCCC2=C1C=CC=C2 |
MDL No. : | MFCD00671629 |
InChI Key : | JRZGPXSSNPTNMA-SNVBAGLBSA-N |
Pubchem ID : | 7058072 |
GHS Pictogram: |
![]() |
Signal Word: | Danger |
Hazard Statements: | H314 |
Precautionary Statements: | P301+P330+P331-P303+P361+P353-P363-P304+P340-P310-P321-P260-P264-P280-P305+P351+P338-P405-P501 |
Class: | 8 |
UN#: | 2735 |
Packing Group: | Ⅲ |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.4 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 46.58 |
TPSA ? Topological Polar Surface Area: Calculated from |
26.02 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.88 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.72 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.7 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.1 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.23 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.93 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.24 |
Solubility | 0.847 mg/ml ; 0.00575 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.88 |
Solubility | 1.93 mg/ml ; 0.0131 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.9 |
Solubility | 0.187 mg/ml ; 0.00127 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) |
No |
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 |
-5.98 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 |
2.0 |
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 |
0.0 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) |
1.84 |
* 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 |
---|---|---|
Boc-L-Pro-OH (41.7 g, 0.17 mol), R-tetrahydronapthylamine (31.8g, 0.22 mol), and hydroxybenzotriazole (28.4g, 0.18 mol) was dissolved in dimethylformamide (30OmL) and cooled to 00C. To this cooled reaction mixture was added EDC (41.7 g, 0.22 mol) followed by DiPEA (30.ImL, 0.17 mol). Reaction was allowed to slowly warm to room temperature and was stirred overnight. Reaction mixture was then partitioned between ethyl acetate and water. The aqueous layer was discarded and the organic layer was washed sequentially with sat. NaHCU3, 0.5 N HCl, and brine. Dried over Na2SO4. Reaction was clean by TLC (50 % ethyl acetate / hexanes). Took crude on to next step. Dissolved crude in CH2Cl2 (200 mL) and TFA (200 mL). Within 15 minutes, reaction was baseline by TLC (50% ethyl acetate / hexanes). Removed most of solvent via rotary evaporation. Upon addition of diethyl ether, a white solid crashes out. Filtered solid and washed with diethyl ether. Dried solid under vacuum. Obtained 63 g of desired compound (95% yield over 2 steps). 1H NMR (CD3OH): consistent with proposed structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | at 80℃; for 14h; | A mixture of(R)-(-)-1,2,3,4-tetrahydro-1-naphthylamine (10.0 g, 67.9 mmol, 1 equiv) and ethylformate (6.23 mL, 77.4 mmol, 1.14 equiv) was heated to 80 C for 14 h. Hexanes was added and themixture was triturated by sonication, then filtered and rinsed with hexanes to yield the product (7.44 g,63%) as atan solid. R1= 0.22 (3:1 hexanes/EtOAc). ‘HNMR(400 MHz, CDC13) 3: 8.23 (s, 1H), 7.29-7.25 (m, 1H), 7.23-7.16 (m, 2H), 7.13-7.08 (m, 1H), 5.82 (bs, 1H), 5.28 (dd, 1H, J= 5.2, 14.0 Hz), 2.85-2.73 (m, 2H), 2.15-2.03 (m, 1H), 1.88-1.81 (m, 3H); ‘3C NMR (100 MHz, CDC13) 3: 160.5, 137.7, 136.1,129.4, 128.8, 127.6, 126.5, 46.4, 30.3, 29.3, 20.0. HRMS calcd for C,,H,3NONa: 198.0889, found198.0890. |
at 60℃; | (l/?)-l,2,3,4-Tetrahydro-l-naphthalenamine (5.0 g, 34 mmol) was heated in 15 mL of ethyl formate at 60 C overnight, during which time a precipitate formed. The reaction mixture was added to 100 mL of hexanes with stirring, and the resulting solids were filtered, washed with hexanes and dried to give 4.63 g of the formamide as white needles. The resulting formamide (4.54 g, 26 mmol) was dissolved in 50 mL of tetrahydrofuran and added dropwise to a suspension of lithium aluminum hydride (1.1 g, 29 mmol) in 20 mL of tetrahydrofuran that had been cooled to 0 C. The reaction mixture was refluxed overnight, then cooled to 0 C and quenched by the sequential addition of 1.1 mL of water, 1.1 mL of15 % aqueous NaOH solution and 3.3 mL of water. The mixture was stirred at ambient temperature for 30 minutes and diluted with ethyl acetate. Several grams of MgSO4 were added, and the mixture was filtered through Celite diatomaceous filter aid and concentrated under reduced pressure to give 4.0 g of the title compound as a colorless oil.1H NMR (CDCl3) δ 1.17 (s, IH), 1.65-2.0 (m, 4H), 2.47 (s, 3H), 2.65-2.85 (m, 2H), 3.63 (m,IH), 7.0-7.35 (m, 4H). | |
at 60℃; | EXAMPLE 6 General preparation of 2-[1-[(substituted-phenyl)acetyl]-4-piperidinyl]-N-methyl-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-thiazolecarboxamide (Compound 144, Compound 145, Compound 146, Compound 147, Compound 148 and Compound 132) and N-methyl-2-[1-[[substituted-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-thiazolecarboxamide (Compound 149 and Compound 150) Step A: Preparation of (1R)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine. (1R)-1,2,3,4-tetrahydro-1-naphthalenamine (5.0 g, 34 mmol) was heated in 15 mL of ethyl formate at 60 0C overnight, during which time a precipitate formed. The reaction mixture was added to 100 mL of hexanes with stirring, and the resulting solids were filtered, washed with hexanes and dried to give 4.63 g of the formamide as white needles. The resulting formamide (4.54 g, 26 mmol) was dissolved in 50 mL of tetrahydrofuran and added dropwise to a suspension of lithium aluminum hydride (1.1 g, 29 mmol) in 20 mL of tetrahydrofuran that had been cooled to 0 C. The reaction mixture was refluxed overnight, then cooled to 0 0C and quenched by the sequential addition of 1.1 mL of water, 1.1 mL of 15 % aqueous NaOH solution and 3.3 mL of water. The mixture was stirred at ambient temperature for 30 minutes and diluted with ethyl acetate. Several grams of MgSO4 were added, and the mixture was filtered through Celite diatomaceous filter aid and concentrated under reduced pressure to give 4.0 g of the title compound as a colorless oil. 1HNMR (CDCl3) δ 1.17 (s, 1H), 1.65-2.0 (m, 4H), 2.47 (s, 3H), 2.65-2.85 (m, 2H), 3.63 (m, 1H), 7.0-7.35 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triethylamine; In dichloromethane; at 0 - 20℃; | (R)-2,2,2-Trifluoro-N-(l,2,3,4-tetrahydronaphthalen-l- yl)acetamide. A 250 ml round bottom flask was charged with of (R)- 1,2,3, 4- tetrahydronaphthalen-1 -amine (5 g, 34 mM), then purged with argon when DCM (50 ml) was added, and the solution was cooled to 0 0C. Triethylamine (9.5 mL) was added by syringe followed be trifluoroacetic anhydride (7.1 mL) of was added over 5 min by syringe. The solution was then stirred overnight, slowly warming to room temp. The mixture was diluted with DCM and washed with water, 1 N HCl, and brine. The organic layer was dried over MgSO4 and concentrated in vacuo, and purified by column chromatography (eluting with 1:1 DCM/Hex), to give 6.6g (80%) of the titled compound. IH-NMR (300 MHz, CDC13) δ 7.2 (m, 3H), 7.1 (t,lH), 6.5 (broad s, IH), 5.2 (q, IH), 2.8 (q, 2H), 2.1 (m IH), 1.9 (m, 3H) ppm. |
With triethylamine; In dichloromethane; at 0 - 20℃; | (R)-2,2,2-trifluoro-N-(1,2,3,4-tetrahydronaphthalen-1-yl)acetamide.; A 250 ml round bottom flask was charged with 5 g (34 mmol) of (R)-1,2,3,4-tetrahydronaphthalen-1-amine (Alfa Aesar). The flask was then purged with argon. 50 ml of DCM was then added, and the solution was cooled to 0 C. 9.48 ml (68 mmol) of TEA was added by syringe, then 7.09 ml (51 mmol) of trifluoroacetic anhydride was added slowly by syringe. The solution was then stirred overnight, slowly warming to room temp. The mixture was diluted with DCM and washed with water, 1 N HCl, and brine. The organic layer was dried over MgSO4 and concentrated in vacuo, and purified by column chromatography (eluting with 1:1 DCM:Hex), to give 6.63 g (80%) of the titled compound. 1H-NMR (CDCl3) δ 7.2 (m, 3H), 7.1 (t, 1H), 6.5 (br s, 1H), 5.2 (q, 1H), 2.8 (q, 2H), 2.1 (m 1H), 1.9 (m, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.5% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); dichloromethane; at 0 - 20℃; | To a solution of 3-Methyl-isoxazole-4-carboxylic acid (0.52 g, 4.06 mmol) in DCM (15 mL) and DMF (2 mL), was added HOBt (1.1 g, 8.14 mmol) and EDCI (0.896 g 4.67 mmol). The clear yellow solution was cooled to 0 C and allowed to stir under Ar for 15 minutes. To the solution was added (R)-1-Amino-1,2,3,4-tetrahydronaphthalene (0.73 mL, 5.04 mmol and the reaction mixture was allowed to slowly warm to ambient temperature and was stirred for overnight. Dilution with DCM (50 mL) was followed by aqueous extraction (NaHCO3 water, brine (50 mL), drying over MgSO4, filtration and removal of solvent in vacuo. Silica gel chromatography (0-25% Hexane:EtOAc) afforded the title compound (650 mg; 62.5%) as a sticky solid. 1H NMR (CDCl3) δ 1.88 (m, 3H), 2.12 (m, 1H), 2.51 (s, 3H), 2.81 (m, 2H), 5.32 (m, 1H), 5.99 (bd, 1H), 7.13 (m, 1H), 7.20 (m, 2H) 7.20 (m, 2H); 13C NMR (CDCl3) δ 11.22, 20.15, 29.41, 30.35, 47.93, 116.73, 126.72, 127.88, 128.88, 129.65, 136.25, 138.00, 158.45, 160.28. ESIMS: 257 (M+H) EA calc'd for C15H16N2O2: C, 70.29; H, 6.29; N, 10.93; found C, 70.61; H, 6.11; N, 11.09. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); dichloromethane; at 0 - 20℃; for 24h; | To a solution of furan-3-carboxylic acid (100 mg, 0.68 mmol), HOBt (240 mg, 1.78 mmol) and EDCI.HCl (196 mg, 1.03 mmol) in CH2Cl2 (8 mL) and DMF (1.5 mL) at 0 C., was added (R)-1,2,3,4-tetrahydronaphthalen-1-amine (160 μL, 1.06 mmol). The reaction was stirred at rt for 24 h, after which CH2Cl2 was added. The resulting solution was washed with saturated NaHCO3, H2O, brine, dried over MgSO4 and concentrated in vacuo. Recrystallization from EtOH/H2O afforded (R)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-2,5-dihydrofuran-3-carboxamide. 1H NMR (500 MHz, CDCl3): δ 1.89 (m, 3H), 2.12 (m, 1H), 2.84 (m, 2H), 5.35 (m, 1H), 5.96 (br d, 1H, J=7.75 Hz), 6.59 (dd, 1H, J=1.90, 0.86 Hz), 7.13 (m, 1H), 7.19 (m, 2H), 7.32 (m, 1H), 7.43 (t, 1H, J=1.73 Hz), 7.93 (m, 1H). MS(M+H, 242). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; at 0 - 70℃; | (i?)-2-(l,2,3,4-Tetrahydronaphthalen-l-yl)isoindoline-l,3-dione. To a solution of (i?)-l,2,3,4-tetrahydro-l-naphthylamine (6.0 g) in THF (150 mL) at 0 0C was added TEA (18.5 mL) and phthaloyl chloride (8.2 g), and the resultant mixture was stirred at room temperature overnight and 70 0C for 3 h. The mixture was diluted with CH2Cl2, washed with saturated NaHCO3, dried over MgSO4, and concentrated in vacuo. The resulting crude was chromatographed on silica gel (EtOAc/hexane, 5/95 to 30/70) to afford 8.2 g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | 4-Benzyl 1-tert-butyl (2S)-2-[(1 R)-1 ,2,3,4-tetrahydro-1-naphthalenyl- amino]carbonyl}-1 ,4-piperazinedicarboxylate (2);(2S)-4-[(benzyloxy)carbonyl]-1-(teAf-butoxycarbonyl)-2-piperazinecarboxylic acid (1, 17.33 g, 47.5 mmol) is dissolved in DMF (800 mL), to which is added diisopropylethylamine (DlEA, 41.5 mL, 0.24 mol). This mixture is stirred at RT for 1.5 h. R- f-j-1 ,2,3,4-tetrahydro-1-naphthylamine (7.00 g, 47.5 mmol) is added, and stirring continued for a further hour. O-(Benzotriazol-1-yl)-Λ/,/V,Λ/' /V-tetramethyluronium hexafluorophosphate (HBTU, 19.84 g, 52.3 mmol) and 1-hydroxybenzotriazole hydrate (HOBt, 7.07 g, 52.3 mmol) are also added and the entire mixture stirred overnight at RT. The reaction mixture is then diluted with EtOAc (1.2 L) and washed sequentially with 1 M citric acid, brine, sat. NaHCO3, brine, water and brine (1 L of each solution). The EtOAc layer is then dried with Na2SO4, filtered, and the solvent removed under reduced pressure to afford a crude off- white solid (23.34 g). This material is purified by flash chromatography on silica gel (CH2CI2 as eluent initially, followed by 5% Et2O/CH2CI2 to elute the desired product). The desired coupled product 6 is isolated as a white foam (20.37 g, 87% yield): 1H NMR δ (CDCI3) 7.27- 7.42 (m, 5 H), 7.06-7.19 (m, 4 H), 6.10 (br s, 1 H), 5.11-5.25 (br m, 3 H), 4.46-4.75 (br m, 2 H), 3.77-4.02 (br m, 2 H), 3.00-3.31 (br m, 3 H), 2.68-2.84 (m, 2 H), 1.97-2.07 (br m, 1 H), 1.69-1.84 (br m, 3 H), 1.43 (s, 9 H). LCMS (APCI+) 494.8 (MH+), 438.5 (MH+-tBu), 394.4 (MH+-BOC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | (S)-4-Benzyl-2-[(R)-(1 ,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyrj- piperazine-1-carboxylic acid tert-butyl ester (6): Anhydrous DMF ( 20 ml) is added to a 100 ml round bottom flask containing compound 4 ( 325 mg, 1.014 mmol) under N2. After ten minutes diisopropylamine ( 0.88 ml, 5.07 mmol) is added to the flask. It is then stirred at room temperature for 1.5 hrs. (R)- 1 ,2,3,4-Tetrahydro-1-napthylamine ( 149.3 mg, 1.014 mmol) is then added to the flask and stirred for 1 hr. HBTU ( 423.07 mg, 1.115 mmol) is added to the reaction followed by HOBT ( 152.1 mg, 1.126 mmol). The reaction mixture is then stirred at room temperature under N2 overnight at which point LCMS shows completion of the reaction. It is then diluted with EtOAc and washed subsequently with 1.0 M citric acid, brine, saturated sodiumbicarbonate, brine, water and brine. The organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure. The crude compound is flash column purified using hexane and ethylacetate gradient solvent system to yield 423 mg ( 93%) of the desired product 6. HPLC shows this compound to be greater than 99% pure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Boc-L-proline (9.36 g, 43.5 mmol), HOBt (8.0 g, 52.2 mmol), EDC (10 g, 52.2 mmol) and DIPEA (30 mL, 174 mmol) were dissolved in dry dichloromethane (200 mL) under N2 and stirred for 10 min at room temperature. 1,2,3,4-R-Tetrahydronaphtylamine (6.72 g, 45.6 mmol) was then added and the solution was left to stir for 24 h at RT. The contents were then added to a separatory funnel along with EtOAc and washed with 10% citric acid (2×), saturated NaHCO3 (2×) and brine. The organic layer was collected, dried and concentrated under reduced pressure to provide 6-1a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 10; /Vl-(1 ,2,3,4-Tetrahydronaphthalen-1 -yl)-λ^-(R)-(1 ,2,3,4-tetrahydronaphthalen-1 - yl)quinazoline-2,4-diamine; The title compound was prepared by Procedure B in two steps from 2,4-dichloro- quinazoline, 1 ,2,3,4-tetrahydro-1-naphtylamine and, in the second step, (R)-1 , 2,3,4- tetrahydro-1-naphtylamine. Upon aqueous work-up, the crude product was purified by column chromatography (EtOAc/heptane/TEA, 1 :2, 1 %) to give the title compound as the free base (solid, mp 96-97C). MS(ES+) m/z 421 ([M + I]+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 12; λ/4-(4-Chlorobenzyl)-λ^-(/:?)-(1 ,2,3,4-tetrahydronaphthalen-1 -yl)quinazoline-2,4- diamine; The title compound was prepared by Procedure B in two steps from 2,4-dichloro- quinazoline, 4-chlorobenzylamine and, in the second step, (fl)-1 , 2,3, 4-tetrahydro-1- naphtylamine. Upon aqueous work-up, the title product was isolated without further purification as the free base (solid, mp 85-86C). MS(ES+) m/z 415 (M+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; | (R)-2-Diphenylacetylamino-pentanedioic acid 5-methyl ester prepared above was dissolved in DMF (10 mL) and added to a solution of the (R)-l,2,3,4-tetrahydro-l- naphthylamine (1.41 g, 9.60 mmol), JPr2EtN (7.56 mL, 43.5 mmol) and HOBt (1.41 g, 10.4 mmol) in DMF (80 mL) at 0 0C under nitrogen. EDC (1.99 g, 10.4 mmol) was added to the reaction mixture and the reaction was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in EtOAc. The organic phase was washed with 5% KHSO4 in water, saturated NaHCOs and brine, dried over Na2SO4, <n="29"/>filtered, and concentrated in vacuo. The crude product was used directly in the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 95% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; 4-methyl-morpholine; 1-methyl-pyrrolidin-2-one; at 20℃; for 18h; | A solution of 2,5-dihydro-pyrrole-l,2-dicarboxylic acid 1-tert-butyl ester (392.4 mg, 1.84 mmol) and (R)-1, 2,3, 4-tetrahydro-naphthalen-l-ylamine (564.3 mg, 3.83 mmol) in teti-ahydrofuran (THF) (40 niL) was added l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrocliloride (EDCI) (860 mg, 4.48 mmol) and 1- hydroxybenzotriazole monohydrate (HOBt) (450 mg, 3.33 mmol), followed by JV-methyl- 2-pyrrolidinone (0.75 mL) and 4-methyl morpholine (0.75 mL). This mixture was stirred at room temperature for 18 hours. The reaction mixture was treated with water (20 mL), then partitioned between ethyl acetate/water. The organic phase was washed with IN HCl (2 x 25 mL), saturated sodium bicarbonate solution (50 mL) and brine solution (50 mL), dried over Na2SO4 and evaporated to dryness. The residue was purified by medium pressure column chromatography on silica gel eluting with ethyl acetate/hexane (0-100%) to give the title compound (630 mg, >95%) as a glassine solid. TLC (50% ethyl acetate/hexane) R7= 0.31; MS (ES) for C20H26N2O3 (MW=342.43): positive 343 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | To a solution of (3-tert-Butoxycarbonylamino-2-oxo-piperidin-l-yl)-acetic acid (305 mg, 1.12 mmol) in dimethylformamide (DMF, 5 mL) was added 1- hydroxybenzotriazole (HOBt, 242 mg, 1.79 mmol), l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDAC, 344 mg, 1.79 mmol), i?-l,2,3,4-tetrahydro-l- naphthylamine ( 231 mg, 1.57 mmol), and diisopropylethylamine (DIEA, 0.32 mL, 1.79 mmoL); the resulting mixture was stirred at room temperature for 18 hours. It was then diluted with ethyl acetate (50 mL) and washed successively with aq. 5% KHSO4, sat. NaHCO3, brine, and concentrated to give the crude product that was purified by flash column chromatography on silica gel eluting with 15% methanol/ methylene chloride to afford the title compound ( 387 mg, 86%). TLC (5% methanol/ methylene chloride) Rf = 0.39 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | To a solution of oxazolidine-3,4-dicarboxylic acid 3 -benzyl ester (3.12 g, 12.42 mmol) in diinethylformamide (DMF, 6 mL) was added 1-hydroxybenzotriazole (HOBt, 2.68 g, 19.9 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 3.8 g, 19.82 mmol), i?-l,2,3,4-tetrahydro-l-naρhthylamine ( 2.97 g , 19.91 mmol), and diisopropylethylamine (DIEA, 4.33 mL, 19.9 mmol) and the resulting mixture was stirred at room temperature for 18 hours. It was then diluted with ethyl acetate (100 mL), washed successively with aq. 5% KHSO4, saturated sodium bicarbonate solution, brine, dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel eluting with 35% ethyl acetate/hexane to furnish the title compound (4.6g, 97%). TLC (40% ethyl acetate/hexane) Rf = 0.29. MS (ES) for C22H24N2O4 (MW=380.44): positive 381(M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | To a solution of 4-hydroxy-pyrrolidine-l,2-dicarboxylic 1 -benzyl ester ( 2.07 g, 7.81 mmol) in dimethylformamide (DMF, 15 mL) was added 1-hydroxybenzotriazole (HOBt, 1.37 g, 10.15 mmol ), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.95 g, 10.15 mmol), i?-l,2,3,4-tetrahydro-l-naphthylamine (1.28 g, 8.95 mmol), and diisopropylethylamine (DIEA, 2 mL, 11.72 mmol). The resulting mixture was stirred at room temperature for 18 hours. It was then diluted with ethyl acetate (100 mL), and washed successively with aq. 5% KHSO4, saturated sodium bicarbonate solution, brine, dried (Na2SO4), and concentrated under reduced pressure. After removal of solvent , the residue was triturated with ether to give the pure title compound (0.7g, 88%).TLC (40% ethyl acetate/hexane) Rf = 0.18. MS (ES) for C23H38N2O4 (MW=394.46): positive 395(M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 95% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; 4-methyl-morpholine; 1-methyl-pyrrolidin-2-one; at 20℃; for 5h; | A solution of (2S,5R)-5-phenyl-pyrrolidine-l,2-dicarboxylic acid l-(9H-fluoren- 9-ylmethyl) ester (1001 mg, 2.42 mmol) and (R)- 1,2,3, 4-tetrahydro-naphthalen-l- ylamine (520 mg, 3.50 mmol) in tetrahydrofuran (TΗF) (40 mL) was added l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (950 mg, 4.95 mmol) and 1- hydroxybenzotriazole monohydrate (ΗOBt) (450 mg, 3.33 mmol), followed by iV-methyl- 2-pyrrolidinone (0.75 mL) and 4-methyl morpholine (0.75 mL). This mixture was stirred at room temperature for 5 hours. The reaction mixture was treated with water (20 mL), then partitioned between ethyl acetate/water. The organic phase was washed with IN HCl (2 x 25 mL), saturated sodium bicarbonate solution (50 mL) and brine solution (50 mL), dried over Na2SO4 and evaporated to dryness. The residue was purified by medium pressure column chromatography on silica gel eluting with ethyl acetate/hexane (0-100%) to give the title compound (1310 mg, >95%) as a glassine solid. TLC (25% ethyl acetate/hexane) R/= 0.12; MS (ES) for C36H34N2O3 (MW=542.67): positive 543 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; 4-methyl-morpholine; 1-methyl-pyrrolidin-2-one; at 20℃; for 18h; | A solution of 3- {2-[2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3- methyl-butyryl}-thiazolidine-2-carboxylic acid (424 mg, 1.01 mmol) and (R)- 1,2,3,4- tetrahydro-naphthalen-1-ylamine (306.9 mg, 2.08 mmol) in tetrahydrofuran (THF) (40 mL) was added l-ethyl-3-(3-dimemylaminopropyl)carbodiimide hydrochloride (EDCI) (510 mg, 2.66 mmol) and 1-hydroxybenzotriazole monohydrate (HOBt) (400 mg, 2.96 mmol), followed by N-methyl-2-pyrrolidinone (0.75 mL) and 4-methyl morpholine (0.75 mL). This mixture was stirred at room temperature for 18 hours. The reaction mixture was treated with water (20 mL), then partitioned between ethyl acetate/water. The organic phase was washed with IN HCl (2 x 25 mL), saturated sodium bicarbonate solution (50 mL) and saturated brine solution (50 mL), dried over Na2SO4 and evaporated to dryness. The residue was purified by medium pressure column chromatography on silica gel eluting with ethyl acetate/hexane (0-100%) to give the title compound (77 mg, 14%) as a tan solid. TLC (50% ethyl acetate/hexane) R/= 0.11; MS (ES) for C28H42N4O5S (MW=546.72): positive 547 (M+H), negative 545 (M-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 95% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; 4-methyl-morpholine; 1-methyl-pyrrolidin-2-one; at 20℃; for 5h; | A solution of 3-benzyloxy-2-[(9H-fluoren-9-ylmethoxycarbonyl)-methyl-amino]- propionic acid (976.2 mg, 2.26 mmol) and (R)-1, 2,3, 4-tetrahydro-naphthalen-l-ylamine (398.0 mg, 2.70 mmol) in tetrahydrofuran (TΗF) (60 mL) was added l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (840 mg, 4.38 mmol) and 1- hydroxybenzotriazole monohydrate (ΗOBt) (420 mg, 3.33 mmol), followed by iV-methyl- 2-pyrrolidinone (0.75 mL) and 4-methyl moφholine (0.75 mL). This mixture was stirred at room temperature for 5 hours. The reaction mixture was treated with water (20 mL), then partitioned between ethyl acetate/water. The organic phase was washed with IN HCl (2 x 25 mL), saturated sodium bicarbonate solution (50 mL) and brine solution (50 mL), dried over Na2SO4 and evaporated to dryness. The residue was purified by medium pressure column chromatography on silica gel eluting with ethyl acetate/hexane (0-100%) to give the title compound (1.27 g, >95%) as a colorless oil. TLC (50% ethyl acetate/hexane) R/= 0.48; MS (ES) for C36H36N2O4 (MW=560.68): positive 561 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 95% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; 4-methyl-morpholine; 1-methyl-pyrrolidin-2-one; at 20℃; for 18h; | A solution of 3-benzyloxy-2-(te7^-butoxycarbonyl-methyl-amino)-butyric acid (930 mg, 2.20 mmol) and (R)- 1 ,2,3 ,4-tetrahydro-naphthalen- 1 -ylamine (510 mg, 3.43 mmol) in tetrahydrofuran (THF) (40 mL) was added l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (1.00 g, 5.21 mmol) and 1- hydroxybenzotriazole monohydrate (HOBt) (500 mg, 3.70 mmol), followed by JV-methyl- 2-pyrrolidinone (0.75 mL) and 4-methyl moφholine (0.75 mL). This mixture was stirred at room temperature for 18 hours. The reaction mixture was treated with water (20 mL), then partitioned between ethyl acetate/water. The organic phase was washed with IN HCl (2 x 25 mL), saturated sodium bicarbonate solution (50 mL) and brine solution (50 mL), dried over Na2SO4 and evaporated to dryness. The residue was purified by medium pressure column chromatography on silica gel eluting with ethyl acetate/hexane (0-100%) to give the title compound (996 mg, >95%) as a colorless oil. TLC (50% ethyl acetate/hexane) R/= 0.26; MS (ES) for C27H36N2O4 (MW=452.59): positive 453 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 18h; | A solution 2-tert-Butoxycarbonylamino-6-(toluene-4-sulfonylamino)-hexanoic acid (1.462 g, 3.65 mmol) and (R)-l,2,3,4-tetrahydro-naphthalen-l-ylamine (645mg, 4.38 mmol) in Acetonitrile(MeCN) (14.6 niL) was added l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDCI) 1.049 g, 5.48 mmol) and 1- hydroxybenzotriazole monohydrate (HOBt) (.670 mg, 4.38 mmol), followed by diisopropylethylamine(0.3.12 mL, 18.25mmol). This mixture was stirred at room temperature for 18 hours. The reaction mixture was pumped down and re-suspended in 20OmL ethyl acetate (EtOAC). The organic phase was washed with IN HCl (2 x 20 mL), brine solution (20 mL), saturated sodium bicarbonate solution (2 x 2OmL) and brine solution (20 mL), dried over Na2SO4 and evaporated to dryness. The residue was purified by medium pressure column chromatography on silica gel eluting with ethyl acetate/hexane (1/1) to give the title compound (1.605 g,83%) as a pink foam. TLC (50% ethyl acetate/hexane) R/= 0.33; MS (ES) for C27H36N2O4 (MW=529.69): positive 530 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; 4-methyl-morpholine; 1-methyl-pyrrolidin-2-one; at 20℃; for 18h; | A solution of l-{2-[2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3- methyl-butyryl}-2-methyl-pyrrolidine-2-carboxylic acid (527.5 mg, 1.28 mmol) and (R)- 1,2,3,4-tetrahydro-naphthalen-l-ylamine (570.2 mg, 3.87 mmol) in tetrahydrofuran (THF) (40 mL) was added l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (700 mg, 3.65 mmol) and 1-hydroxybenzotriazole monohydrate (HOBt) (375 mg, 2.77 mmol), followed by iV-methyl-2-pyrrolidinone (1 mL) and 4- methyl morpholine (1 mL). This mixture was stirred at room temperature for 18 hours. The reaction mixture was treated with water (20 mL), then partitioned between ethyl acetate/water. The organic phase was washed with IN HCl (2 x 25 mL), saturated sodium bicarbonate solution (50 mL) and brine solution (50 mL), dried over Na2SO4 and evaporated to dryness. The residue was purified by medium pressure column chromatography on silica gel eluting with ethyl acetate/hexane (0-100%) to give the title compound (86.5 mg, 12%) as a glassine solid. TLC (50% ethyl acetate/hexane) R/= 0.08; MS (ES) for C30H46N4O5 (MW=542.71): positive 543 (M+H), negative 541 (M-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | To a solution of the acid A (Veale, C. A. et. al. J. Med. Chem. 1995,38, 98-108) (379 mg, 1 mmol), 1-hydroxybenzotriazole hydrate (203 mg, 1.5 mmol), and triethylamine (202 mg, 2 mmol) in DMF (5 mL) was added EDC (356 mg, 1.2 mmol), and the solution was stirred for 0.5 h. (R)-(1, 2,3,4-Tetrahydro-naphthalen-l-yl)amine (147 mg, 1 mmol) was added, and the solution was stirred for 16 h. Then the solution was diluted with H2O and extracted with ethyl acetate, washed with a saturated aqueous solution of ammonium chloride (2 x 25 mL). The solution was dried and the solvent removed. The resulting oil crystallized upon standing and was collected and dried to give the titled amide B (383 mg, 75%) as a white solid: 1H NMR (400 MHz, CDCl3): δ 8.75(1H, s), 7.62 (2H, m), 7.51 (4H, m), 7.37 (5H, m), 7.16 (4H, m), 6.08 (IH, d), 5.22 (2H, s), 5.20 (IH, m), 4.56 (2H, s), 2.74 (2H, t), 1.78 (4H, m); MS: 509 (M + H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1 :(S)-4-(Benzyloxycarbonyl)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (1.00 g, 2.70 mmol), HOBt (520 mg, 3.80 mmol), HBTU (1.35 g, 3.60 mmol) and DIPEA (955 uL, 5.50 mmol) were dissolved in dry DMF (10 ml) under N2 and stirred for 10 minutes at room temperature. R-1,2,3,4-Tetrahydro-1-naphtylamine (485 mg, 3.30 mmol) was added and <n="83"/>the solution was left to stir for 18 hours at room temperature. The contents were then added to a separatory funnel along with EtOAc and washed with 10% citric acid, saturated NaHCO3 and brine. The organic layer was collected, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to provide intermediate 5-a as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 4h; | 0.25 g (1.61 mmol) of 4-amino-2-chloropyrimidine-5-carbonitrile, 0.31 g (2.10 mmol) of (1R)-1,2,3,4-tetrahydronaphthalen-1-amine and 0.67 g (4.85 mmol) of potassium carbonate in 3 ml of N,N-dimethylformamide are heated at 120 C. for 4 hours, the crude mixture is concentrated by evaporation under a high vacuum, the remaining crude mixture is absorbed on silica gel and purified by means of column chromatography using heptane/ethyl acetate as eluent. Following concentration by evaporation, 0.22 g of 4-amino-2-[(1R)-1,2,3,4-tetrahydronaphthalen-1-ylamino]pyrimidine-5-carbonitrile (m.p. 167.6 C.) is obtained (yield 48% at 95% purity). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 160℃; for 1h;Irradiation with microwave; | Then, a mixture of 0.25 g of the solid obtained above and 0.224 g (1.47 mmol) of (R)-1,2,3,4-tetrahydro-1-naphthylamine and 0.35 g (2.53 mmol) of potassium carbonate in 1 ml of N-methylpyrrolidone as solvent is heated in a closed cell in a microwave appliance (Biotage initiator, http://www.biotage.com/DynPage.aspx?id=22001) at 160 C. for 60 min. The crude mixture is absorbed on silica gel and, following separation by means of column chromatography, 0.167 g of N2-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine with a melting point of 130-131 C., (95% purity) is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(24ert-Butoxycarbonylammo-4-memylsulfanyl-butyrylamino)-acetic acid methyl ester (2.15 g, 6.74 mmol) was dissolved in methyliodide (13 mL, excess) and the mixture was stirred at room temperature for 7 hours. The excess methyliodide was decanted and the crude product was dried to give the the sulfonium iodide that was dissolved in a 1 : 1 of mixture of dimethylformamide/methylene chloride (140 mL). To the resulting solution at O0C was added sodium hydride in one portion and then stirred for 2.5 hours. Methyl acetate (45 mL) and H2O (10 mL) were added and the resulting mixture was stirred for 18 hours at room temperature. The mixture was then concentrated under reduced pressure and partitioned between H2O (20 mL) and methylene chloride (20 mL). The aqueous layer was acidified to pH=3 with 0.5 M citric acid and extracted 3 times with methylene chloride. The combined organic layers were dried (Na2SO4) and concentrated to afford the acid product. This was directly coupled with i?-l,2,3,4-tetrahydro-l-naphthylamine (992mg, 6.74 mmol) using HOBt (1.18 g, 8.76 mmol), EDCI (1.68 g, 8.76 mmol), and DIEA (1.5 mL, 8.76 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The reaction was diluted with ethyl acetate (100 mL) and washed successively with aq. 5% KHSO4, saturated sodium bicarbonate solution, brine, dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel eluting with 5% methanol/ methylene chloride gave the desired product (1.3 g, 50%). MS (ES) for C21H29N3O4 (MW=387.47): positive 388(M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | To a solution of 6-tert-Butoxycarbonylamino-5-oxo-2,3,5,6,9,9a-hexahydro-lH- pyrrolo[l,2-a]azepine-3-carboxylic acid benzyl ester (64 mg, 0.16 mmol) in ethyl acetate (10 mL) at room temperature was added 10% Pd/C (30 mg). The reaction mixture was stirred under hydrogen (1 atm) for 1.5 hours. After removal of the catalyst by filtration and evaporation of the ethyl acetate, the residue was dissolved in DMF (3mL) followed by addition of HOBt (35 mg, 0.16 mmol ), EDCI (50 mg, 0.26 mmol), i?-l,2,3,4- tetrahydro-1-naphthylamine, and DIEA. The resulting mixture was stirred at room temperature for 18 hours, then diluted with ethyl acetate. The organic layer was washed with 5% KHSO4, saturated sodium bicarbonate solution, brine, dried (Na2SO4), then concentrated. The crude product was purified by flash column chromatography on silica gel eluting with 10-30% ethyl acetate/hexane to afford the title compound (63.58 mg, 90%). MS (ES) for C25H35N3O4 (MW=441.56): positive 442 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Compound 3Step i :(R)-3-Boc-amino-5-(carboxymethyl)-2,3-dihydro-1 ,5-benzothiazepin-4(5H)-one, 3-1 , (352 mg, 1.0 mmol) was dissolved in CH2CI2 (5 mL) and treated with EDC (232 mg, 1.5 mmol), HOBt (202 mg, 1.5 mmol) and DIPEA (520 μL, 3.0 mmol). The reaction was stirred for 5 minutes before (R)-1 , 2,3,4-tetrahydronaphthalamine (176 μL, 1.2 mmol) was added. The reaction was stirred for 16 hrs at room temperature before being partitioned between ethyl acetate (100 mL) and 10% citric acid (20 mL). The organic phase was washed with 10 % citric acid (2 x 20 mL), saturated aqueous NaHCO3 (3 x 20 mL), and brine (1 x 20 mL). <n="57"/>Attorney Docket No. L80003375WO The organic fraction was dried over anhydrous MgSO4, filtered, and the volatiles removed under reduced pressure. The resulting residue was purified by silica gel chromatography, eluting with a 10-100 % THF/hexanes gradient to provide 3-2a as a white solid (360 mg, 75 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Compound 1Step i :Boc-(3S)-3-amino-1-carboxymethylcaprolactam (286 mg, 1.0 mmol) was dissolved in DMF (5 mL) and treated with HBTU (564 mg, 1.5 mmol), HOBt (202 mg, 1.5 mmol) and DIPEA (520 μL, 3.0 mmol). The reaction was stirred for 5 minutes before (R)-1 , 2,3,4- tetrahydronaphthyl-1 -amine (176 μL, 1.2 mmol) was added. The reaction was stirred for 16 hrs at room temperature before being partitioned between ethyl acetate (100 mL) and 10% citric acid (20 mL). The organic phase was washed with 10 % citric acid (2 x 20 mL), saturated aqueous NaHCO3 (3 x 20 mL), and brine (1 x 20 mL). The organic fraction was dried over anhydrous MgSO4, filtered, and the volatiles removed under reduced pressure to provide 1-2a as a white solid, which was advanced to the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 18h; | A solution of 45 (563 mg, 1.21 mmol) in DCM (15 mL) was cooled to 0 0C and treated with i?-(-)-tetrahydronaphthylamine (0.17 mL, 1.21 mmol), EDC (279 mg, 1.46 mmol), HOBt (197 mg, 1.46 mmol) and DIPEA (0.66 mL, 3.76 mmol), respectively. After 18 h, the solution was diluted with DCM, washed successively with IM HCl, saturated aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered and concentrated. Purification by reverse phase HPLC (2" Dynamax C 18, 20-100% ACN in H2O with 0.1% HOAc over 30 min) afforded 46 (430 mg) as a white foam. 1H NMR (CDCl3, 300 MHz), -1 :1 mixture of rotomers: 58.36 (d, J = 8.4 Hz, 0.25H), 8.09 (d, J = 8.7 Hz, 0.25H), 7.35 (d, J = 9 Hz, 0.5H), 7.28-7.20 (m, 0.5H), 7.18-7.05 (m, 3.5H), 6.52 (d, J = 8.4 Hz, 0.25H) 5.25-5.02 (m, 2H), 4.91-4.84 (m, 0.5H), 4.72-4.44 (m, 2H), 4.33-4.19 (m, 1.5H), 4.05-3.93 (m, IH), 3.67-3.58 (m, 0.5H), 3.49-3.31 (m IH), 3.15-2.98 (m, IH), 2.86-2.71 (m, 2H), 2.44-2.35 (m, IH), 1.98-1.54 (m, 10H), 1.44 (s, 5.5H), 1.17-0.75 (m, 15H) ppm. Mass spectrum, m/z [593.8] (M+H)+. |
A686117 [2217-40-5]
1,2,3,4-Tetrahydronaphthalen-1-amine
Reason: Racemic-enantiomer
A673859 [1055321-35-1]
(R)-5-Methyl-1,2,3,4-tetrahydronaphthalen-1-amine
Similarity: 1.00
A169722 [3459-02-7]
1,2,3,4-Tetrahydronaphthalen-1-amine hydrochloride
Similarity: 0.97
A179783 [1810069-89-6]
7-Methyl-1,2,3,4-tetrahydronaphthalen-1-amine hydrochloride
Similarity: 0.97
A673859 [1055321-35-1]
(R)-5-Methyl-1,2,3,4-tetrahydronaphthalen-1-amine
Similarity: 1.00
A169722 [3459-02-7]
1,2,3,4-Tetrahydronaphthalen-1-amine hydrochloride
Similarity: 0.97
A179783 [1810069-89-6]
7-Methyl-1,2,3,4-tetrahydronaphthalen-1-amine hydrochloride
Similarity: 0.97