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CAS No. : | 830-96-6 | MDL No. : | MFCD00005660 |
Formula : | C11H11NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GOLXRNDWAUTYKT-UHFFFAOYSA-N |
M.W : | 189.21 | Pubchem ID : | 3744 |
Synonyms : |
Indole-3-propionic acid;3-IPA;VP-20629;SHP-622;OX-1;IPA;NSC 47831;NSC 3252;Indolepropionic acid
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.18 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 54.65 |
TPSA : | 53.09 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.21 cm/s |
Log Po/w (iLOGP) : | 1.26 |
Log Po/w (XLOGP3) : | 1.75 |
Log Po/w (WLOGP) : | 2.19 |
Log Po/w (MLOGP) : | 1.4 |
Log Po/w (SILICOS-IT) : | 2.55 |
Consensus Log Po/w : | 1.83 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.39 |
Solubility : | 0.765 mg/ml ; 0.00404 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.48 |
Solubility : | 0.624 mg/ml ; 0.0033 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.47 |
Solubility : | 0.0644 mg/ml ; 0.00034 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.51 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302+H312+H332-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
96% | Stage #1: for 5 h; Reflux Stage #2: With sodium hydrogencarbonate In dichloromethane; water |
EXAMPLE 2; N'-(3,4-dimethoxybenzylidene)-3-(l-methyl-lH-indol-3- yl)propanehydrazide; [0488] (a) Methyl 3-(lH-indol-3-yl)propanoate: To a stirred solution of 3- indolepropionic acid (5 g, 26.4 mmol) in MeOH (80 mL) was added cone. H2SO4 (0.5 mL). The reaction mixture was heated at reflux for 5 hours. The reaction mixture was allowed to cool to room temperature and the reaction solution was reduced to 1/3 volume at reduced pressure. The remaining solution was diluted with water and extracted with CH2Cl2. The organic phase was washed with saturated aq. NaHCO3 and brine and dried (Na2SO4). The material was purified on silica gel using EtOAc-hexanes (0 to 30percent) and provided 5.16 g (96percent) of the desired compound as a pale yellow oil which solidified upon standing. |
95% | Stage #2: With hydrogenchloride In water |
Example 2: Preparation of δ-lactam library 14.; [00181] A second generation indoline library with an expanded D-ring was prepared exploiting the intramolecular inverse electron demand Diels-Alder chemistry beginning with five N- alkylated indolylpropionic acids 8a-e and triazine 2. The indolylpropionic acids were prepared by straightforward pathways as shown in Scheme 2. For N-methylindolylpropionic13161987.4 64 acid 8a, permethylation of indolylpropionic acid, followed by basic methyl ester hydrolysis with acid work-up gave 8a in 87percent yield over three steps. For the remaining acids 8b-e, methyl ester 9 formation, then N-alkylation, followed by ester hydrolysis all proceeded uneventfully in good yields. With the five indolylpropionic acids in hand, the second sublibrary again formed through an intramolecular inverse electron demand Diels-Alder reaction of an indolyl subunit with a tethered triazine, was pursued (Scheme 3). Conversion of the propionic acids to the acid chlorides lOa-e, then amidation of 10 with aminotriazines derived from 2 produced the tethered diene/dieno-phile pairs 13. Intramolecularcycloadditions by heating to 120°C in 1,2-dichlorobenzene yielded sublibrary 14quantitatively. Twenty-two primary amines (Figure 3) were employed in the S Ar displacements on the chlorotriazine, producing 22 aminotriazines 12. All amidations and cycloadditions were accomplished smoothly, resulting in a 110-membered, racemic sublibrary 14; all members were stable to storage in DMSO. Figure 4 shows some exemplary compounds from the library. Compound 15-17, from this library, were found to be the most active in vitro inhibitors of core dimerization.Scheme 2: Pre aration of indolylpropionic acids 8Scheme 3: Preparation of δ-lactam sublibrary 14 (racemic)13161987.4 65 |
85% | at 0℃; for 0.5 h; | 3-(1H-indol-3-yl)propionic acid (200 mg, 1.06 mmol) was dissolved in anhydrous methanol (3 mL), and thionyl chloride (249 mg, 2.12 mmol) was added at 0°C to react for 0.5 h. Water (10 mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by preparative TLC plate (3:1 petroleum ether / ethyl acetate, Rf = 0.5) to give methyl 3-(1H-indole-3)propionate (180 mg, as a green solid) with a yield of 85percent. MS-ESI [M + H]+ calcd. 204, found 204. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sulfuric acid In methanol at 0 - 20℃; | 2 g (10.57 mmol) of 3-indolepropionic acid were dissolved in 50 ml of methanol. The solution was cooled to 0°C and 5 ml of sulfuric acid 96percent were dropped under stirring. The solution was maintained at room temperature overnight and then poured onto ice-water, basified with 30 percent ammonium hydrate and finally extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to give 2.3 g of an oily product (93percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | 3-(1 /-/-lndol-3-yl)-propionic acid ethyl ester (Intermediate compound 1 )To a mixture of 3-indolepropionic acid (4.00 g, 1 eq) in ethanol (70 ml), 1 ml of sulphuric acid is added dropwise and the mixture is first refluxed overnight and then evaporated to dryness. The resulting crude residue is dissolved in ethyl acetate and the organic solution is washed with 5% aqueous sodium bicarbonate, water, dried over MgSO4, filtered and finally evaporated to dryness, to afford the title compound as a yellow solid (4.30 g, 95% yield), which is used as such for the next step. | |
95% | With sulfuric acid; for 3h;Reflux; | General procedure: The indole-3-carboxylic acids (1a-b) (10 mmol) were esterified in a classical manner with ethanol and catalytic amount of con. H2SO4 under reflux for 3 h. After completion, the reaction mixture was cooled and solvent ethanol was removed under reduce pressure,The residue was then poured onto crushed ice and treated with aq. NaOH solution (10%) drop wise till the reaction mixture became slightly basic in nature. The solid product obtained was filtered, washed with water and dried and characterized. |
74% | With sulfuric acid; at 0 - 80℃; | In an round bottom flask, 3-(lH-indol-3-yl)propanoic acid (8 g, 0.04 mol) was dissolved in EtOH (80 mL). The mixture was cooled to 0C and then sulphuric acid (1.6 mL) was added drop-wise over five minutes with stirring. After the addition was complete, the mixture was allowed to warm naturally to room temperature with stirring and was then refluxed at 80 C until completion (overnight). After the solvent was removed under reduced pressure, dichlorom ethane (10 mL) was added and the organic layer was washed with water (1x10 mL), followed by NaHC03 (1x10 mL) and finally brine (1x10 mL). The organic layers were then dried (MgS04) and concentrated to yield a crude brown oil which solidified on standing. The crude material was triturated with heptane (10 mL) and the solid was filtered under vacuum to yield the desired product as an off white solid (7.1 g, 74%). LC/MS (METCR1673 Generic 2 minutes) tr=l .28 min, 96%, m/z=217.95 [M+H] 1H NMR (250 MHz, Chloroform-d) d 7.98 (s, 1H), 7.69 - 7.52 (m, 1H), 7.43 - 7.30 (m, 1H), 7.29 - 7.07 (m, 2H), 7.05 - 6.92 (m, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.25 - 3.01 (m, 2H), 2.72 (dd, J = 8.4, 6.9 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H). |
With methanesulfonic acid; for 24h; | A mixture of 30 g of <strong>[830-96-6]indole-3-propionic acid</strong> and 10 ml of methanesulfonic acid in 200 ml of ethanol was stirred for 24 hours, poured into water, and extracted with ethylacetate. The ethylacetate solution was washed with NaHCO3 solution and water and dried over magnesium sulfate. A solution of 800 mg of the crude product (<strong>[830-96-6]indole-3-propionic acid</strong> ethyl ester) and 2 ml of hydrazine in 20 ml of ethanol was refluxed for 18 hours, and extracted with ethylacetate. The organic phase was washed with brine, dried over magnesium sulfate, and evaporated at reduced pressure to give with 93% yield the intermediate propanoic acid hydrazide as a solid. This material and 0.3 g of Raney nickel catalyst (W-4) in 25 ml of ethanol were refluxed for 2.5 hours. The solution was decanted and evaporated at reduced pressure and the residue chromatographed on silicia gel, eluting with ethylacetate, to give with 96% yield indole-3-propionamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | To a solution of 3-indole propionic acid (IPA) (1g, 4.93 mmol) in THF (15 mL) was added carbonyldiimidazole (1.1 g, 5.9 mmol) at room temperature. After stirring for 45 mm, a solution of 30% NH4OH (15 mL). The resulting reaction mixture was stirred for 16 h and was then evaporated. The residue was dissolved in DCM and washed with water and saturated aqueous NaC1. The organic layer was dried over Na2504 and evaporated. Compound 19 was isolated as a white solid, mp 125-127, in 70% yield. 1H-NMR (300 MHz, CDC13) ppm 9.99 (bs, 1H), 7.59-7.56 (m, 1H), 7.37- 7.35 (m, 1H), 7.13-6.68 (m, 3H), 6.79 (bs, 1H), 6.17(bs, 1H), 3.04 (t, J= 7.5 Hz, 2H),2.87 (bs, 1H), 2.56 (t, J= 7.5 Hz, 2H); 13C-NMR(75 MHz, CDC13) ppm 175.00, 137.74,128.43, 122.81, 122.01, 119.29, 115.61, 112.00, 37.06, 21.88. | |
65% | Example 33-(1H-Indol-3-yl)propylamide The title compound may be prepared from 3-(1H-indol-3-yl)propanoic acid according to Step 1 of Scheme B.3-(1H-Indol-3-yl)propylamide: 1H NMR (300 MHz, DMSO-d6): delta 10.73 (s, 1H), 7.52 (d, J=9 Hz, 1H), 7.32 (dt, J=7.8 Hz, 0.9 Hz, 1H), 7.29 (s, 1H), 7.09-6.94 (m, 3H), 6.73 (s, 1H), 2.90 (t, J=8.1 Hz, 2H), 2.41 (t, J=7.5 Hz, 2H); MS (ESI) m/z 189.0 (M+H+). Step 1: To a solution of 3-(1H-indol-3-yl)propanoic acid (6.06 g, 32.0 mmol) in tetrahydrofuran (100 mL) is added triethylamine (18 mL, 129 mmol) and ethyl chloroformate (4.65 mL, 48.8 mmol) in an ice cooled bath. The resulting mixture is allowed to stir for 0.5 hours at the same temperature followed by the addition of ammonia (2 N in methanol, 90 mL, 180 mmol). After stirring for a further one hour, the resulting precipitate is filtered off and the filtrate is concentrated in vacuo. The residue, after diluted with water (100 mL), is extracted with ethyl acetate (3×100 mL). The combined organic phases are washed with brine, dried with sodium sulfate and concentrated in vacuo to obtain 3-(1H-indol-3-yl)propylamide (3.85 g, 65%). | |
With triethylamine; In tetrahydrofuran; | Compounds 14 and 50 of Table 1 DEPC (98%, 1.28 mL) was added to a stirred solution of 3-(3-indolyl)propanoic acid [II: R1 =R3 =H, R2 =(CH2)2 COOH] (1.30 g) and triethylamine (1.15 mL) in THF (15 mL) at 0 C. After 5 minutes the solution was saturated with ammonia gas, then the mixture was stirred at 20 C. for 16 hours. The reaction was then quenched with water and extracted with EtOAc. Evaporation gave a solid, which was purified by chromatography on silica gel, eluding with EtOAc, to give 3-(3-indolyl) propanamide [II: R1 =R3 =H, R2 =(CH2)2 CONH2 ] (1.09 g, 84%); mp (MeOH/water) 134-136 C. (Crosby D. G., Boyd J. B., Johnson H. E., J. Org. Chem. 1960;25:1826 record mp 131.5-133 C.). 1 H NMR ((CD3)2 CO): delta9.95 (1H, s, NH), 7.58 (1H, dt, J=8.2, 0.7 Hz, ArH), 7.36 (1H, dr, J=8.1, 0.8 Hz, ArH), 7.13 (1H, m, H-2), 7.08 (1H, ddd, J=8.1, 7.0, 1.1 Hz, ArH), 7.00 (1H, ddd, J=8.0, 7.0, 1.0 Hz, ArH), 6.75, 6.12 (2xH, 2xbr s, CONH2), 3.04 (2H, m, 3-CH2), 2.05 (2H, m, 3-CH2 CH2). 13 C NMR: delta174.87 (s, CONH2), 137.75, 128.44 (2xs, Ar), 122.80, 122.02 (2xd, Ar), 119.30 (2xd, Ar), 115.67 (s, Ar), 112.08 (d, Ar), 37.05 (t, 3-CH2 CH2), 21.87 (t, 3-CH2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium periodate In ethanol | ||
With ferrous(II) sulfate heptahydrate; dihydrogen peroxide; ascorbic acid In water; dimethyl sulfoxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-hydroxybenzotriazol-hydrate; dicyclohexyl-carbodiimide In dichloromethane for 12h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With [ReOCl2(1,2-bis(diphenylphosphino)ethane)]; hydrogen; potassium tetraphenylborate; In tetrahydrofuran; at 160℃; under 30003.0 Torr; for 36h;Autoclave; Inert atmosphere; | General procedure: By the following method, it went 3-reduction of phenylpropionic acid (hydrogenation).Put a stir bar in a dry glass tube (25mL), further, 3-phenylpropionic acid (75.09mg, 0.5mmol), the rhenium complex 4 (7.07mg, 0.010mmol), potassium tetraphenylborate (17.92mg , accommodates 0.05 mmol), the tubes containing this mixture, was inserted into the autoclave. Then, after replacing the inside of the autoclave in an argon gas atmosphere was added while continuing flow of argon gas dehydration toluene (4.0mL). This autoclave through a stainless steel tube by introducing hydrogen gas from a hydrogen gas cylinder connected, the inside of the autoclave was replaced with hydrogen gas, then disconnect the hydrogen gas pressure from the leak valve. This operation - was repeated (substituted de substitution) five times. Finally, the hydrogen gas pressure in the autoclave was set to 4 MPa, using a constant temperature bath, and allowed to react for 12 hours at 180 C. After completion of the reaction, the autoclave was cooled by immersion in an ice bath, almost to room temperature. Then, carefully release the hydrogen gas that is inside in the draft. After removing the solvent, the reaction product was analyzed by 1H NMR using mesitylene (60.1 mg, 0.5 mmol) as an internal standard substance. As a result, 3-phenylpropyl alcohol, and 3-phenylpropionic acid 3-phenylpropyl The yield was 98% and 1%, respectively. In the above Examples 6-1,Substrate (carboxylic acid compounds), and hydrogenation conditions (hydrogen pressure),Except that to adopt the conditions described in Table 7-9,It has been reduced (hydrogenated) in the same manner as in Example 6-1.However,The entry 19-26 in Table 9,Using tetrahydrofuran (THF) as a solvent.The results are shown in Tables 7 to 9. |
41% | With sodium hydroxide; LiAlH4; In tetrahydrofuran; water; | EXAMPLE 9 3-(3-hydroxypropyl)-lH-indole To a stirred suspension of LiAlH4 (4.02 g) in THF (200 mL) at 0 C. and under N atmosphere was added dropwise a THF solution (100 mL) containing indole-3-propanoic acid (20.0 g). After the addition was complete, the reaction was heated at reflux for 16 h, after which time the mixture was cooled to 0 C. and water (4 mL) added, followed by 15% NaOH (4 mL), and finally additional water (12 mL). The reaction was filtered and the THF filtrate extracted with 5% NaOH (4 mL), and finally additional water (12 mL). The reaction was filtered and the THF filtrate extracted with 5% NaHCO3 followed by a sat. NaCl solution. The organic phase was dried with anhydrous K2 CO3, filtered, and concentrated under reduced pressure to yield 3-(3-hydroxypropyl)indole (VI; 7.5 g; 41%). |
With sodium hydroxide; LiAlH4; sulfuric acid; In tetrahydrofuran; water; | 3.103 3-(1H-Indol-3-yl)propan-1-ol (85LM16B). A suspension of LiAlH4 (2.48 g, 65 mmol) in dry THF (140 ml) was stirred in a 500 ml flask. 3-(1H-indol-3-yl)propionic acid (5.38 g, 28 mmol) was dissolved in dry THF (20 ml) and added slowly. The mixture was heated to 35 C. Stirring was continued for 2 hours at 35 C. and overnight at room temperature. Water (20 ml) was added drop wise and very slowly, followed by addition of H2O/H2SO4 (1:1) (50 ml). To the resulting mixture NaOH was added (until pH 7) and the two phases were separated. The organic phase was dried (Na2SO4) and evaporated to dryness to give the crude title compound (85LM16B) (5.0 g). The material was used for the next reaction step without further purification. 1H NMR (CD3OD) delta1.92 (qv, 2H), 2.80 (t, 2H), 3.61 (t, 2H), 7.00 (t, 1H), 7.05 (t, 1H), 7.33 (d, 1H), 7.55 (d, 1H). |
With sodium hydroxide; LiAlH4; sulfuric acid; In tetrahydrofuran; water; | 3.103 3-(1H-Indol-3-yl)propan-1-ol (85LM16B). A suspension of LiAlH4 (2.48 g, 65 mmol) in dry THF (140 ml) was stirred in a 500 ml flask. 3-(1H-indol-3-yl)propionic acid (5.38 g, 28 mmol) was dissolved in dry THF (20 ml) and added slowly. The mixture was heated to 35 C. Stirring was continued for 2 hours at 35 C. and overnight at room temperature. Water (20 ml) was added drop wise and very slowly, followed by addition of H2O/H2SO4 (1:1) (50 ml). To the resulting mixture NaOH was added (until pH 7) and the two phases were separated. The organic phase was dried (Na2SO4) and evaporated to dryness to give the crude title compound (85LM16B) (5.0 g). The material was used for the next reaction step without further purification. 1H NMR (CD3OD) delta 1.92 (qv, 2H), 2.80 (t, 2H), 3.61 (t, 2H), 7.00 (t, 1H), 7.05 (t, 1H), 7.33 (d, 1H), 7.55 (d, 1H). | |
3.103 3-(1H-Indol-3-yl)propan-1-ol (85LM16B). A suspension of LiAlH4 (2.48 g, 65 mmol) in dry THF (140 ml) was stirred in a 500 ml flask. 3-(1H-indol-3-yl)propionic acid (5.38 g, 28 mmol) was dissolved in dry THF (20 ml) and added slowly. The mixture was heated to 35 C. Stirring was continued for 2 hours at 35 C. and overnight at room temperature. Water (20 ml) was added drop wise and very slowly, followed by addition of H2O/H2SO4 (1:1) (50 ml). To the resulting mixture NaOH was added (until pH 7) and the two phases were separated. The organic phase was dried (Na2SO4) and evaporated to dryness to give the crude title compound (85LM16B) (5.0 g). The material was used for the next reaction step without further purification. 1H NMR (CD3OD) delta 1.92 (qv, 2H), 2.80 (t, 2H), 3.61 (t, 2H), 7.00 (t, 1H), 7.05 (t, 1H), 7.33 (d, 1H), 7.55 (d, 1H). | ||
1.34 g | With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 2.33333h; | Step A. Preparation of 3-(lH-indol-3-yl)propan-l-ol: To a solution of 3-(lH-indol-3- yl)propanoic acid (1.6g, 8.5 mmol) in THF (15 mL) was added BH3 in THF (1M, 17 mL, 17 mmol) dropwise at 0 C. The reaction mixture was stirred for 20 min at 0 C then warmed to 20 C and stirred for 2h. The reaction was quenched by slow addition of MeOH (20 mL). The reaction mixture was stirred for additional 30 min at 20 C. The reaction mixture was concentrated and purified by flash chromatography (Combi-flash Rf, hex/EtOAc 0-40% gradient) to give the title compound (1.34 g, 7.65 mmol) as a light yellow oil. MS (ES) 176.2 (M+H). |
1.2 g | With borane; In tetrahydrofuran; at 0℃; for 1h; | To a solution of 3-(lH-indol-3-yl)propanoic acid (1.5 g, 7.9 mmol) in THF (20 mL) was added 1M BH3 in THF (9 mL, 9 mmol) at 0 C. The reaction mixture was stirred for 1 h at 0 C and quenched by addition of MeOH then concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf Hexane/EtOAc gradient 0-25%) to give the title compound as a white solid in 1.2 g (7.1 mmol). MS (ES) 176.1 (M+H). |
With lithium aluminium tetrahydride; In diethyl ether;Reflux; | Adding to the reactor 3-indole propionic acid 8 (3.0g, 15 . 8mmol), anhydrous ether (100.0 ml), the reaction liquid reflux stirring, added in batches LiAlH4(1.5g, 39 . 5mmol), stir at reflux overnight. To the reaction solution is quenched by adding saturated ammonium chloride in the reaction. With ethyl ether (3×50.0 ml) extraction, the organic phase is dried with anhydrous magnesium sulfate, filtered by turns on lathe does 9-d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With dihydrogen peroxide; N,N,N-trimethyldodecan-1-ammonium iodide; In water; at 60℃; for 48h; | To a 10 ml reaction tube by sequentially adding a substrate (0.2 mmol, 37.8 mg), trimethyl twelve alkyl iodide (0.02 mmol, 7.2 mg), 2 ml of water, and finally adding hydrogen peroxide (0.12 mmol, 120 mul). The reaction mixture at 60 C under stirring 48 h after stopping the reaction, to the reaction system by adding ethyl acetate (5 ml * 4), the combined organic phase and drying with anhydrous sodium sulfate, filtered vacuum concentrated to obtain the crude product. The resulting crude product is purified by column chromatography separation, to obtain white solid product, separating the yield is 67% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With hydrogenchloride; acetic acid; phenol In dimethyl sulfoxide for 0.5h; | |
With hydrogenchloride; dimethyl sulfoxide for 0.5h; | ||
With MarE protein; ascorbate In aq. buffer at 28℃; for 6h; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 18-crown-6 ether In dimethyl sulfoxide for 8.3h; Ambient temperature; | ||
With 18-crown-6 ether In dimethyl sulfoxide for 4.7h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | General procedure: Method A (BuLi as base): To a stirred solution of the starting indole in dry THF (5 mL×mmol) under an argon atmosphere at -78 C was added a solution of BuLi 1.6 M in hexane (2 equiv). After stirring for 5 min, pivaloyl chloride (1 equiv) was added. The reaction mixture was stirred for 15 min at -78 C, followed by 15 min at -50 C and 15 min at -20 C. When the reaction finished, as judged by TLC, it was poured onto saturated aqueous NH4Cl solution (10 mL/mmol) and it was extracted with AcOEt (3×20 mL). The combined organic layers were dried over Na2SO4 and evaporated to yield the 1-pivaloylindole derivative. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 60% 2: 16% 3: 15% | With sodium methylate In methanol at 0℃; anodic oxidation at Pt/C electrode; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 56% 2: 14% 3: 19% | With sodium methylate In methanol at 0℃; anodic oxidation at Pt/C electrode; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Triethylamine (1.46 mL, 10.5 mmol) was added to a mixture of 1H-indole-3-propanoic acid (1.36 g, 7.2 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (1.5 g, 6.55 mmol) and 1-hydroxybenzotriazole (1.33g, 7.86 mmol) in tetrahydrofuran (20 mL) and the mixture was stirred at room temperature for 10 min. 1-(3-Dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (1.89 g, 9.8 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was poured into water and extracted with ethyl acetate. The combined organic fractions were washed with saturated aqueous sodium carbonate and water, dried (MgSO4), and the solvent was evaporated under reduced pressure . The residue was triturated with hexane to give the title compound as a colorless solid (2.1 g, 88%). H NMR (360 MHz, CDCl3) [delta]8.00 (1H, br s), 7.63 (1H, d, J 7.6 Hz), 7.36 (1H, d, J 8.0 Hz), 7.10-7.00 (2H, m), 6.94-6.80 (3H, m), 3.85 (3H, s), 3.80 (2H, t, J 5.0 Hz), 3.52 (2H, t, J 5.0 Hz), 3.14 (2H, m), 2.95 (2H, t, J 5.0 Hz), and 2.77 (4H, m). m/z (ES) 364 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | EXAMPLE 2; N'-(3,4-dimethoxybenzylidene)-3-(l-methyl-lH-indol-3- yl)propanehydrazide; [0488] (a) Methyl 3-(lH-indol-3-yl)propanoate: To a stirred solution of 3- indolepropionic acid (5 g, 26.4 mmol) in MeOH (80 mL) was added cone. H2SO4 (0.5 mL). The reaction mixture was heated at reflux for 5 hours. The reaction mixture was allowed to cool to room temperature and the reaction solution was reduced to 1/3 volume at reduced pressure. The remaining solution was diluted with water and extracted with CH2Cl2. The organic phase was washed with saturated aq. NaHCO3 and brine and dried (Na2SO4). The material was purified on silica gel using EtOAc-hexanes (0 to 30%) and provided 5.16 g (96%) of the desired compound as a pale yellow oil which solidified upon standing. | |
95% | Example 2: Preparation of delta-lactam library 14.; [00181] A second generation indoline library with an expanded D-ring was prepared exploiting the intramolecular inverse electron demand Diels-Alder chemistry beginning with five N- alkylated indolylpropionic acids 8a-e and triazine 2. The indolylpropionic acids were prepared by straightforward pathways as shown in Scheme 2. For N-methylindolylpropionic13161987.4 64 acid 8a, permethylation of indolylpropionic acid, followed by basic methyl ester hydrolysis with acid work-up gave 8a in 87% yield over three steps. For the remaining acids 8b-e, methyl ester 9 formation, then N-alkylation, followed by ester hydrolysis all proceeded uneventfully in good yields. With the five indolylpropionic acids in hand, the second sublibrary again formed through an intramolecular inverse electron demand Diels-Alder reaction of an indolyl subunit with a tethered triazine, was pursued (Scheme 3). Conversion of the propionic acids to the acid chlorides lOa-e, then amidation of 10 with aminotriazines derived from 2 produced the tethered diene/dieno-phile pairs 13. Intramolecularcycloadditions by heating to 120C in 1,2-dichlorobenzene yielded sublibrary 14quantitatively. Twenty-two primary amines (Figure 3) were employed in the S Ar displacements on the chlorotriazine, producing 22 aminotriazines 12. All amidations and cycloadditions were accomplished smoothly, resulting in a 110-membered, racemic sublibrary 14; all members were stable to storage in DMSO. Figure 4 shows some exemplary compounds from the library. Compound 15-17, from this library, were found to be the most active in vitro inhibitors of core dimerization.Scheme 2: Pre aration of indolylpropionic acids 8Scheme 3: Preparation of delta-lactam sublibrary 14 (racemic)13161987.4 65 | |
85% | With thionyl chloride; at 0℃; for 0.5h; | 3-(1H-indol-3-yl)propionic acid (200 mg, 1.06 mmol) was dissolved in anhydrous methanol (3 mL), and thionyl chloride (249 mg, 2.12 mmol) was added at 0C to react for 0.5 h. Water (10 mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by preparative TLC plate (3:1 petroleum ether / ethyl acetate, Rf = 0.5) to give methyl 3-(1H-indole-3)propionate (180 mg, as a green solid) with a yield of 85%. MS-ESI [M + H]+ calcd. 204, found 204. |
With thionyl chloride; at 20℃;Inert atmosphere; Reflux; | 3-indole propionic acid (3.78 g, 20 mmol) was dissolved in methanol (50 ml) in argon. Thionyl chloride (4.7 g, 2.9 ml, 40 mmol) was added very slowly to this solution in drops. During this, the temperature rose to 35 C. The mixture was then heated to reflux for 7 h and stirred overnight at room temperature. Complete conversion was evident in the DC. The LC/MS shows slight traces of a by-product. The batch was concentrated to low volume under the exhaust hood and co-distilled with methanol. The residue was a brown oil, which was thus used for the next reaction step. | |
hydrogenchloride; In diethyl ether; at 20℃; for 96h; | A mixture of 3-(1H-indol-3-yl)propionic acid (10 g), methanol (200 ml), and a saturated solution of HCl in ether (75 ml) was stirred at room temperature for 4 days. The solvents were removed in vacuo, and the residue was worked up in a conventional manner by the use of dilute ammonium hydroxide and ethyl acetate to yield an oil (10.6 g). The oil was dissolved in acetic acid (200 ml), and NaCNBH4 (12 g) was added in parts of 1 g. The mixture was stirred at room temperature for 48 h, and then poured into ice-cooled water. The pH of the solution was adjusted to 8 with ammonium hydroxide (25%), and the aqueous phase was extracted with ether. The combined organic phases were extracted with 1 M HCl solution. The pH of the aqueous phase was adjusted to 8 with ammonium hydroxide and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and the solvent was removed in vacuo. The residue was purified on silica gel eluted with ethyl acetate-heptane (1:1) to give an oil (6.1 g). The residue was dissolved in THF (50 ml) and added to a suspension of LiAlH4 (2.0 g) in THF (100 ml) at about 30 C. The mixture was stirred at room temperature for 15 min and then cooled to 5 C. By drop-wise addition, water (4.0 ml), 15% NaOH solution (2.0 ml), and water (10 ml) was added. The mixture was dried (MgSO4) and concentrated in vacuo. The oil was dissolved in THF (200 ml), added triethylamine (11 ml) and cooled to -20 C. To this mixture, a solution of acetyl chloride (2.1 ml) in THF (50 ml) was added, and the mixture was allowed to warm to 5 C. To this mixture, a solution of methanesulfonyl chloride (2.1 ml) in THF (50 ml) was added. Ether (200 ml) was added and the mixture was filtered. The mother liquid was concentrated in vacuo and subjected to purification on silica gel eluted with ethyl acetate-heptane (4:1) to give a crystalline compound (7.3 g). The compound was dissolved in acetone (500 ml), added lithium bromide (10.3 g), and the mixture was boiled under reflux for 1 h. The mixture was cooled, filtered and evaporated in vacuo to dryness to give the title compound. | |
With sulfuric acid; at 0 - 20℃; for 15h; | Step A. Preparation of methyl 3-(lH-indol-3-yl)propanoate: To a solution of 3-(lH- indol-3-yl)propanoic acid (2 g) in methanol (50 ml) at 0 C was added sulfuric acid (5 ml). The mixture was then warmed to rt. After 15h, the mixture was poured into ice water, basified with 30%NuEta4OmicronEta, extracted with CH2CI2, dried Na2S04, filtered and concentrated in vacuo to give the title compound. It was used without further purification. MS (ES) 204.3 (M+H). | |
With sulfuric acid; at 80℃; | General procedure: H2SO4 (98%) (0.5mL) was added to a stirred solution of raw material1 in CH3OH (10mL) at room temperature and the mixture was then stirred for 2-3 h at 80 C. TLC was used to monitor the reaction progress until it was complete. A large amount of ice water was then added to the mixture. A saturated solution of sodium carbonate was used to neutralise the mixture until white solid appeared. After filtering the mixed solution, compounds 2a-h (yield 91-99) were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; hexanes; at -78 - 45℃; for 2h;Inert atmosphere; | General procedure: Method A: To 1.6 M solution of butyllithium in hexanes (2 equiv) was added dropwise a stirred solution of diisopropylamine (2 equiv) in dry THF (2 mL×mmol) at 0 C, under an argon atmosphere. Stirring was continued for 10 min at 0 C, and the solution of LDA thus prepared was added via cannula to a stirred solution of the suitable 1-pivaloyl derivative (1 equiv) in THF (2 mL×mmol), under an argon atmosphere at -78 C. When addition was complete, the reaction mixture was heated in an oil bath at 40-45 C for 2 h, cooled and poured onto a saturated aqueous NH4Cl solution (30 mL), which was then extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried over Na2SO4 and evaporated, and the residue was chromatographed on silica gel, eluting with 9:1 EtOAc-petroleum ether. Evaporation of the mobile phase yielded the deprotected indole, which was identical in all respects to the commercially available sample employed as starting material for the protection reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | EXAMPLE 1: Preparation of 3- (3-lNo.-indol-3-yl-propionylamino) - benzamide; In 5.0 mL of dimethylformamide were dissolved 3-(1.H- indol-3-yl) -propionic acid (189 mg, 1.0 mmol) and 3-amino- benzamide (68.1 mg, 0.5 mmol), followed by the addition of benzotriazol-1-yl-oxitripyrrolidino phosphonium hexafluorophosphate (520.3 g, 1.0 mmol) and N, N- diisopropylethyl amine (0.17 ml, 1.0 mmol). The resulting solution was stirred at room temperature and mixed with ethyl acetate and an aqueous sodium salt solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified using silica gel column chromatography (n-hexane : <n="24"/>ethyl acetate : methanol = 6:3:1) to produce the subject compound 1 as a white solid (77.2 mg, 50%).1H-NMR (DMSOd6, 300Hz): 8.02 (IH, s, Aromatic), 7.75 (IH, d, J = 7.8 Hz, Aromatic), 7.50 (2H, m, Aromatic), 7.32 (2H, m, Aromatic), 6.93-7.09 (3H, m, Aromatic), 3.04 (2H, t, J = 7.8 Hz, Aliphatic), 2.68 (2H, t, J= 7.2 Hz, Aliphatic). |
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | 1-6. Synthesis of low-molecular-weight compound ID-134 (8e) Among the above-described low-molecular-weight compounds, ID-134 (3-[3-1H-indol-3-yl-propionylamino]benzamide (8e) was prepared in the following manner. 3-(1H-indol-3-yl)-propionic acid (7b, 189 mg, 1.0 mmol) and 3-amino-benzamide (6b, 68.1 mg, 0.5 mmol) were dissolved in DMF, and PyBOP and DIPEA were added to the solution to perform a coupling reaction. The reaction solution was stirred overnight at room temperature. Then, the resulting material was separated and purified to obtain 3-[3-1H-indol-3-yl-propionylamino]benzamide (ID-134) as a white solid. 1H NMR (DMSO-d6, 300 MHz) d = 8.02 (s, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.50 (m, 2H), 7.32 (m, 2H), 6.93-7.09 (m, 3H), 3.04 (t, J = 7.8 Hz, 2H), 2.68 (t, J = 7.2 Hz, 2H). | |
In N,N-dimethyl-formamide; | 1-6. Synthesis of Low-Molecular-Weight Compound ID-134 (8e) Among the above-described low-molecular-weight compounds, ID-134 (3-[3-1H-indol-3-yl-propionylamino]benzamide (8e) was prepared in the following manner. 3-(1H-indol-3-yl)-propionic acid (7b, 189 mg, 1.0 mmol) and 3-amino-benzamide (6b, 68.1 mg, 0.5 mmol) were dissolved in DMF, and PyBOP and DIPEA were added to the solution to perform a coupling reaction. The reaction solution was stirred overnight at room temperature. Then, the resulting material was separated and purified to obtain 3-[3-1H-indol-3-yl-propionylamino]benzamide (ID-134) as a white solid. 1H NMR (DMSO-d6, 300 MHz) d=8.02 (s, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.50 (m, 2H), 7.32 (m, 2H), 6.93-7.09 (m, 3H), 3.04 (t, J=7.8 Hz, 2H), 2.68 (t, J=7.2 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | EXAMPLE 3: Preparation of 3- (3-lH-indol-3-yl-propionylamino) - benzoic acid methyl ester; In 3.0 mL of dimethylformamide were dissolved 3-indole propionic acid (100 mg, 0.528 mmol) , 3-amino benzoic acid methyl ester (119 mg, 0.792 mmol), and N,N- diisopropylethylamine (102 mg, 0.792 mmol), followed by the addition of ethylenedichloride (151 mg, 0.792 mmol) and N- hydroxybenzotriazole (107 mg, 0.792 mmol) at room temperature. The resulting solution was stirred at room temperature before being mixed with 100 ml of water. The precipitate thus formed was extracted with ethyl acetate and washed with an aqueous sodium chloride solution, 5% citric acid and water. The organic layer thus formed was dried over anhydrous magnesium sulfate, filtered, and concentrated. The <n="26"/>residue was purified using silica gel column chromatography (ethyl acetate : n-hexane = 1:9~4:6) to yield the subject compound (3) as a colorless solid (0.16 g, 94% ).1H NMR (CDCl3, 300 MHz): 8.08 (IH, s, CONH), 7.88 (IH, s, indole NH), 7.73 (2H, d, J = 7.2 Hz, Aromatic), 7.60 (IH, d, J=7.2 Hz, Aromatic), 7.39-7.09 (5H, m, indole), 6.97 (IH, d, J=1.8 Hz, Aromatic), 3.86 (3H, s, OCH3), 3.18 (2H, t, J = 7.35Hz, CH2CONH), 2.74 (2H, t, J= 7.5 Hz, Of2CH2CONH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide; | 1(a) Methyl 3-(indol-3-yl)propionate 36.2 g of powdered potassium carbonate was added, with ice-cooling, to a solution of 24.8 g of 3-(indol-3-yl)propionic acid in 500 ml of N,N-dimethylformamide, followed by the addition of a solution of 10.2 ml methyl iodide in 50 ml of N,N-dimethylformamide. The reaction mixture was then warmed to room temperature and stirred for 3 hours. After this time, ice water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic extract was then washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 500 g of silica gel with a 4:1 v/v mixture of hexane and ethyl acetate as the eluent, to yield 25.8 g of the title compound as an amorphous solid. | |
With potassium carbonate; In acetonitrile; at 20℃; for 3h; | To a stirring solution of 3- (lH-indol-3-yl) propanoic acid (0.3 g) in MeCN (9 mL) was added K2CO3 (0.33 g) at ambient temperature followed by addition of iodomethane (0.15 mL) . After 3 hours, water was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified by column chromatography (n-hexane: EtOAc=3 : 1) to give methyl 3- (lH-indol-3- yl)propanoate (0.32 g) . 1H-NMR(CDCl3) delta:2.73(2H,t, J=8.0Hz) ,3.11 (2H, t , J=8. OHz) ,3.67 (3 H, s) ,6.96-7.02 ( IH, m) ,7.12 (IH, t , J=7.2Hz) , 7.19 (IH, t, J=7.2Hz) , <n="111"/>7 . 60 ( lH , d, J=7 . 2Hz ) , 7 . 99 ( IH , brs ) . |
Yield | Reaction Conditions | Operation in experiment |
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93% | With sulfuric acid; In methanol; at 0 - 20℃; | 2 g (10.57 mmol) of 3-indolepropionic acid were dissolved in 50 ml of methanol. The solution was cooled to 0C and 5 ml of sulfuric acid 96% were dropped under stirring. The solution was maintained at room temperature overnight and then poured onto ice-water, basified with 30 % ammonium hydrate and finally extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to give 2.3 g of an oily product (93% yield). |
Compounds 13 and 47 of Table 1 Esterification of 3-(3-indolyl)propanoic acid [II: R1 =R2 =H, R3 =(CH2)2 COOH] (1.50 g) with diazomethane as above gave methyl 3-(3-indolyl)propanoate [II: R1 =R2 =H, R3 =(CH2)2 COOMe] (1.62 g, 100%) as a light brown oil. |
Yield | Reaction Conditions | Operation in experiment |
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45.2% | With 1,1'-carbonyldiimidazole; In tetrahydrofuran; at 20℃; | General procedure: A solution of 3-(1H-indol-3-yl)propanoic acid (1 mmol) and 1,10-carbonyldiimidazole (1.1 mmol) in 12 mL of anhydrous THF was stirred at ambient temperature for 1 h. The 1-benzylpiperidin-4-amine (1 mmol) was added to the solution, and stirring was continued overnight. The reaction mixture was diluted with H2O and extracted with EtOAc. The organic extracts were combined, washed with brine, and dried with anhydrous Na2SO4, and the solvent was evaporated in vacuo to give the crude product, which was purified by chromatography (CH2Cl2-MeOH = 50:1) on silica gel. |
42% | With 1,1'-carbonyldiimidazole; In tetrahydrofuran; at 20℃; | (5) N-[2-(1-Benzyl-piperidin-4-yl)-ethyl]-3-(1H-indol-3-yl)-propionamide Reagents: 3-Indolepropionic acid (156mg, 0.82mmol), THF 3ml, 1,1'carbonyldiimidazol (141mg, 0.87mmol), and 2-(1-Benzyl-piperidin-4-yl)-ethylamine (188mg, 0.87mmol). Conditions: Room temperature, overnight. Purification: silica gel column chromatography using AcOEt/ MeOH (1:0.1). Yield:134.4mg (42%).1H-NMR (CDCl3, 400MHz, δ ppm): (8.85, s, 1H), (7.52, d, 1H, J=8 Hz), (7.25-7.20, m, 6H), (7.13-7.10, m, 1H), (7.06-7.02, s, 1H), (6.84, s, 1H), (5.67, m, 1H, NHCO), (3.45, s, 2H), (3.14-3.04, m, 4H), (2.81-2.78, m, 2H), (2.51-2.47, m, 2H), (1.87-1.81, m,2H), (1.50-1.47, m, 2H), (1.25-1.09, m,5H). 13C-NMR (CDCl3): 172.3, 137.9, 136.4, 129.4, 128.2, 127.0, 121.9, 121.8, 119.0, 118.6, 114.5, 111.4,, 63.4, 53.6, 37.5, 37.3, 36.2, 33.4, 32.0, 21.7. ESI-MS [M+H+]+389.25 |
General procedure: Under nitrogen protection was added to a solution of indole carboxilic/ethanolic acid derivates in THF, the 1,1' carbonyldiimidazol,and stirred for 4 h at room temperature. Then theamine was added and the resulting solution was stirred for 20 h, after this time the solvent was evaporated under reduced pressure and the residue purified by silica gel flash column chromatography using different gradients of solvents AcOEt/MeOH for each case. |
Yield | Reaction Conditions | Operation in experiment |
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57.3% | With dmap; dicyclohexyl-carbodiimide In chloroform; acetone at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
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80.9% | With dmap; dicyclohexyl-carbodiimide In chloroform; acetone at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
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In N,N-dimethyl-formamide at 60℃; for 3h; | 8 Example 8. Synthesis of Th95 (l-S):3-(1H-indol-3-yl)-N-p-tolyl-N-(p-tolylcarbamoyl)propanamide was synthesized as follows:; 111 mg (0.5 mmol) of 1 ,3-di-p-tolylcarbodiimide was dissolved in 1 ml DMF and activated by heating for 2 hours at 60 °C (oil bath). 94 mg (0.5 mmol) of 3- indolylacetic acid, dissolved in dry DMF was added to the solution and the mixture was heated and stirred for another 3 hours at 60 °C. The solvent was evaporated under high vacuum and the residue was recrystallized from ethyl acetate/petroleum ether. The melting point of the crystals was 162-164 °C. Rf=0.67 (CHCVMeOH 98/2). The main molecular peak was found at 412 (F.W. =411.5) with a second peak at 434 for the sodium salt. |
Yield | Reaction Conditions | Operation in experiment |
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9.5mg | Stage #1: Indole-3-propionic acid; methyl 2-azatricyclo[3.3.1.13,7]decane hydrochloride With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 0.5h; Stage #2: With triethylamine In dichloromethane at 20℃; for 15h; | 1 EXAMPLE 1 : 1-(2-azatricyclo[3.3.1.13,7]dec-2-yl)-3-(1H-indol-3-yl)propan-1-one (1 ) EXAMPLE 1 : 1-(2-azatricyclo[3.3.1.13,7]dec-2-yl)-3-(1H-indol-3-yl)propan-1-one (1 ) Starting Material-2 (0.2mmol) was added to lntermediate-5 (0.2mmol) in dichloromethane (DCM), followed by the addition of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochcloride (EDCI) (0.26mmol) and 1-Hydroxybenztriazole (HOBt) (0.23mmol). The reaction mixture was cooled to 0°C and was maintained at the same temperature for 30 minutes. Further, Triethylamine (0.93mmol) was added to the reaction mixture, and the resulting solution was stirred at room temperature for 15 hours. The reaction mass was then diluted with equal ratio of DCM and water, and was washed with 1 N HCI solution followed by NaHC03 and brine solution. The organic layer was separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the organic layer under reduced pressure and was purified by silica gel column using Petroleum ether: Ethyl acetate (1 :4) as eluent to obtain Compound (1) (9.5mg, gummy material). 1H NMR (300MHz,CDCI3): δ 7.91 (brs, 1 H), 7.54 (d, 1 H), 7.28 (d, 1 H), 7.12 (t, 1 H), 7.02 (t, 1 H), 6.98 (s, 1 H), 4.82 (s, 1 H), 3.92 (s, 1 H), 3.06 (t, 2H), 2.61 (t, 2H), 1.97-1.98 (m, 2H), 1.60 -1.75 (m, 10H). LC-MS (M+H)+ = 309.2; HPLC purity = 92.94% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41.2% | With benzotriazol-1-ol; 1,2-dichloro-ethane; triethylamine; In tetrahydrofuran; dichloromethane; at 20℃; | General procedure: To a mixture of 4-amino benzyl amine 6a (0.42 mmol) and indole-3-carboxylic acid (0.50 mmol) in 8 mL CH2Cl2 and 2 mL THF, was added HOBt (1.0 mmol), EDC (1.0 mmol) and triethyl amine (1.0 mmol). The mixture was stirred over night at room temperature and stopped by addition of 10 mL 5% NaHCO3 solution, then, the mixture was extracted with CH2Cl2 (15×3mL) and organic layers were combined, washed with brine, dried over Na2SO4. The solvent was evaporated under vacuum to give crude product, which was purified by silica gel column chromatography eluting with petroleum, ethyl acetate and triethylamine (20:20:1) to afford 1a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.3% | With dmap; dicyclohexyl-carbodiimide; In tetrahydrofuran; dichloromethane; at 20℃; | General procedure: To a solution of indole-3-carboxylic acid (1.55 mmol) in 10 mL dichloromethane and 2mL THF, was added DCC (1.71mmol), DMAP (1.55 mmol) and 4-piperidin-1-yl-methyl-phenol 7a (1.55 mmol). The mixture was stirred at room temperature over night and stopped by addition of 4.0 mL water, followed by extracting with dichloromethane (20 mL×3), the combined organic layer was washed with NaHCO3, saline, dried over anhydrous Na2SO4 and evaporated to dryness to get crude product, which was purified by silica gel column chromatography eluting with petroleum, ethyl acetate and triethylamine (20:20:1) to afford 3a |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.5% | With benzotriazol-1-ol; 1,2-dichloro-ethane; triethylamine; In tetrahydrofuran; dichloromethane; at 20℃; | General procedure: To a mixture of 4-amino benzyl amine 6a (0.42 mmol) and indole-3-carboxylic acid (0.50 mmol) in 8 mL CH2Cl2 and 2 mL THF, was added HOBt (1.0 mmol), EDC (1.0 mmol) and triethyl amine (1.0 mmol). The mixture was stirred over night at room temperature and stopped by addition of 10 mL 5% NaHCO3 solution, then, the mixture was extracted with CH2Cl2 (15×3mL) and organic layers were combined, washed with brine, dried over Na2SO4. The solvent was evaporated under vacuum to give crude product, which was purified by silica gel column chromatography eluting with petroleum, ethyl acetate and triethylamine (20:20:1) to afford 1a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 12h; | To solution containing 3-(1H-indol-3-yl)propanoic acid (200 mg, 1.06 mmol), N?-isopropylbenzohydrazide (283.4 mg, 1.59 mmol) and HATU (604.6 mg, 1.59 mmol) dissolved in DMF (7.0 ml), N,N-diisopropylethylamine (DIPEA)(0.277 ml, 1.59 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc:methanol=20:3:1) and dried so that white solid form of N?-(3-(1H-indol-3-yl)propanoyl)-N?-isopropylbenzohydrazide was obtained (350 mg, 95%). In 2-neck round bottom flask, NaH (5.5 mg, 0.23 mmol) dissolved in DMF at 0 C. was stirred, and solution containing N?-(3-(1H-indol-3-yl)propanoyl)-N?-isopropylbenzohydrazide (20 mg, 0.06 mmol) dissolved in DMF was transported and stirred at 0 C. for 30. The reaction mixture was drop-wise added with (bromomethyl)benzene (0.01634 ml, 0.14 mmol), and stirred at 80 C. for 1 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc=2:1) and dried so that ivory solid form of N?-(3-(1-benzyl-1H-indol-3-yl)propanoyl)-N?-isopropylbenzohydrazide was obtained (5 mg, 20%). [0281] 1H-NMR (DMSO, 500 MHz): delta 10.55 (brs, 1H, -NH), 7.91 (s, 1H, aromatic), 7.84 (d, J=6.84 Hz, 2H, aromatic), 7.56 (t, J=6.84 Hz, 1H, aromatic), 7.47 (t, J=7.82 Hz, 2H, aromatic), 7.40 (d, J=7.82 Hz, 2H, aromatic), 7.32 (d, J=8.31 Hz, 1H, aromatic), 7.20 (m, 5H, aromatic), 7.10 (d, J=7.82 Hz, 2H, aromatic), 6.99 (t, J=7.33 Hz, 1H, aromatic), 6.86 (t, J=7.33 Hz, 1H, aromatic), 5.26 (s, 2H, -N-CH2-Benzene), 4.67 (q, J=6.35 Hz, 1H, -N-CH-(CH3)2), 2.69 (m, 2H, -CH2-CH2-), 2.46 (m, 2H, -CH2-CH2-), 1.09 (d, J=6.35 Hz, 3H, -N-CH-(CH3)2), 1.02 (d, J=6.84 Hz, 3H, -N-CH-(CH3)2) |
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; for 12h; | General procedure: To a solution of the 4a (1g, 3.48 mmol), N'-isopropylbenzohydrazine (7a) (0.93g, 5.22 mmol) and HATU (1.98g,5.22 mmol) in DMF (15.0 mL) was added N,N-diisopropylethylamine (DIPEA) (0.90 ml, 5.22 mmol). The reaction mixture was then stirred at roomtemperature overnight, and then partitioned between ethyl acetate and water. Theorganic phase was washed with brine dried over MgSO4, andconcentrated. Purification by silica gel column chromatography using n-Hexane:EtOAc=3:1 as eluting solventsgave compound 8a as white solid.Compounds 8a-y, 14a-d, 15, 18, 20a and 20b were also preparedusing same procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: Indole-3-propionic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: 4-tert-Butylaniline In dichloromethane; N,N-dimethyl-formamide at 20℃; Inert atmosphere; | 4.1.2. General procedure for the coupling reaction for synthesis of compounds 2a-2f General procedure: The round-bottom flask was charged with trans-Indole-3-acrylic acid (1.0 equiv.) or 3-Indolepropionic acid (1.0 equiv.) and the resulting mixture of DMF in CH2Cl2 (v:v, 1:3). DIPEA (1.5 equiv.) followed by HBTU (1.5 equiv.) were added to the solution. After stirring at room temperature for 30 min, amine (1.0 equiv.) was added and stirred overnight at RT. The excess solvent was evaporated and then diluted with water and EtOAc, and the two layers were separated. The aqueous solution was extracted with EtOAc. The combined organic solution was washed with water and brine, dried over magnesium sulfate, and filtered. The residue was purified by column chromatography on silica gel using 0-60% EtOAc in Hexanes as eluant to give the desired products 2a-2f. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In methanol at 20℃; for 2h; Inert atmosphere; Schlenk technique; Dean-Stark; Reflux; | Me2Sn(IB)2 and Me2Sn(IP)2 Complexes (1 and 4) General procedure: Complexes 1 and 4 were prepared by heating a 1:2 molar mixture of dimethyltin(IV)oxide (0.49 g, 3 mmol) and indole-3-butyric acid (1.22 g, 6 mmol) or indole-3-propionic acid (1.13 g, 6 mmol) in methanol (50 mL) under a nitrogen atmosphere. The reaction mixture was refluxed for 2 h with a Dean-Stark apparatus, and then allowed to cool at room temperature. A clear light yellow (1) or brown (4) transparent solution was separated by filtration and kept in a bottle. After 4 days, pale yellow solid (1) or brown solid (4) was obtained. The products were then recrystallized from absolute ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.05% | With sodium hydroxide; In methanol; at 20℃; for 1h; | Sodium salt of 3-(1H-indol-3-yl)propanic acidwas prepared by 1 : 1 molar ratio reaction of 3-(1Hindol-3-yl)propanoic acid with aqueous solution ofNaOH in methanol with continuous stirring at room temperature for 1 h. The soluble in methanol productwas isolated by evaporating the solvent under vacuum.The ligand salt thus obtained was washed with diethylether and air dried. Yield 96.05 %, mp 277-279C. IRspectrum, nu, cm-1: 1618 (COO), 1387 (COO). 1H NMRspectrum, delta, ppm: 1.94 t (H2,3J = 7 Hz), 2.14 t (H3,3J = 7 Hz), 6.87 s (H12), 7.02-7.36 m (H5-10Ar), 10.65(N-H). 13C NMR spectrum, delta, ppm: 39.8 (C3), 42.1(C2), 108.3 (C4), 121.5 (C12), 125.4, 127.8, 128.8,130.8, 134.2 (CAr), 137.1, 203.1 (C1). |
With sodium hydroxide; In ethanol; for 2h;Reflux; Inert atmosphere; Schlenk technique; | The sodium salts of acids were synthesized by heating under reflux a 1:1 molar mixture of NaOH (0.12 g, 3 mmol) and indole-3-butyric acid (0.61 g, 3 mmol) or <strong>[830-96-6]indole-3-propionic acid</strong> (0.57 g, 3 mmol) in ethanol (50 mL) for 2 h. The resulting clear solution was filtered and evaporated to dryness. Recrystallization of the light yellow residue from alcohol gave a white solid. Yield: 86 %; IR (KBr, cm-1); IBH: nuas(COO) 1570 s, nus (COO)1420 s; IPH: nuas(COO) 1560 s, nus (COO) 1410 s. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; | Adding to the reactor 3-indole propionic acid 8 (0.945g, 5 . 0mmol), acetonitrile (15.0 ml), are sequentially added DBU (0.897 ml, 6 . 0mmol) and compound 3 (0.910g, 6 . 5mmol), stirring at room temperature overnight. After turns on lathe does column chromatography to obtain white solid product shown II-a 0.2202g, 17% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: Indole-3-propionic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.166667h; Inert atmosphere; Stage #2: cycloheptanamine With triethylamine In dichloromethane at 20℃; Inert atmosphere; | 4.1.1. General experimental procedure (A) for the synthesis of N-(1-adamantyl)-4-(1H-indol-3-yl) butanamide (3a) General procedure: To a solution of indole-3-butyric acid (0.5 g, 2.46 mmol) in anhydrous dichloromethane at room temperature were added 1-ethyl-3-(3-dimethylamino propyl) carbodiimide EDCI (0.38 g,2.46 mmol), 1-hydroxy benzotriazole HOBt (0.37 g, 2.46 mmol) under an argon atmosphere. After 10 min of stirring, 1-adamantylamine (0.37 g, 2.46 mmol) and triethylamine (0.51 mL,3.69 mmol) were added, and reaction mixture was stirred at same temperature until disappearance of starting materials (6-8 h). After completion of reaction by TLC, evaporated the solvent and extracted with dichloromethane and water. Organic layer was separated and washed with brine and sat. NaHCO3 soln, dried over anhydr. Na2SO4, evaporated and purified by 60-120No. silica gel column chromatography using ethyl acetate/hexane as eluent gavethe required compound in 92% yield (0.76 g) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: sulfuric acid / 2 h / Reflux; Inert atmosphere 2: dmap / tetrahydrofuran / 12 h / 20 °C / Inert atmosphere 3: lithium hydroxide monohydrate / water; tetrahydrofuran / 10 h / 20 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: sulfuric acid / 5 h / Reflux 2: dmap / tetrahydrofuran / 16 h / 20 °C 3: lithium hydroxide monohydrate / tetrahydrofuran; water / 16 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | General procedure: Compound A-1 (2000 mg, 2.67 mmol) was taken up in 10 mL dichloromethane and stirred. Separately 4.4eq of a carboxylic acid and 4.4eq of 1,1'- Carbonyldiimidazole were solved in dichloromethane (10 mL) and stirred over 20 min. Both solutions were unified and stirred continually at room temperature. The dichloromethane phase was washed with saturated NaHCO3 solution (2x) and dried with Na2SO4 (anhydrous). The solvent was evaporated in vacuo to produce a white foam containing products of reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | To a solution of 3-(1H-indol-3-yl)propanoic acid (8) (1.00 g, 5.29 mmol) in DMF (30 mL) was added EDC·HCl (1.52 g, 7.93 mmol) and HOBt·H2O (1.21 g, 7.93 mmol). The resulting mixture was stirred at room temperature for 30 minutes. A solution of the amine 21 (1.18 g, 5.82 mmol) in DMF (10 mL) and TEA (2.00 mL, 14.3 mmol) was added and the reaction was stirred for 16 hours at room temperature. The DMF was evaporated and the residue was partitioned with EtOAc (150 mL) and water (150 mL). The layers were separated and the organic solution was washed with 1N NaHSO4 (150 mL), saturated NaHCO3 (150 mL) and brine (150 mL). The organic layer was then dried (Na2SO4), filtered and concentrated to afford 1.99 g (100% yield) of compound 22 as a tan foam: 1H NMR (400 MHz, CDCl3) delta 9.06 (bs, 1H), 7.58 (d, J = 7.80 Hz, 1H), 7.38 (d, J = 7.80 Hz, 1H), 7.17 (dt, J = 6.90, 1.00 Hz, 1H), 7.09 (dt, J = 7.80, 0.90 Hz, 1H), 7.00 (d, J = 2.30 Hz, 1H), 5.34 (bs, 1H), 4.62 (bs, 1H), 3.07- 3.13 (m, 4H), 3.02 (apparent q, J ~ 6.75 Hz, 2H), 2.54 (t, J = 7.30 Hz, 2H), 1.46 (s, 9H), 1.33 (quint, J = 7.30 Hz, 2H), 1.20- 1.26 (m, 2H), 0.93- 1.01 (m, 2H). 13C NMR (100 MHz, CDCl3) delta 173.05, 156.49, 136.67, 127.02, 122.42, 121.86, 119.17, 118.60, 114.21, 111.57, 79.57, 40.50, 39.16, 37.59, 30.05, 29.15, 28.55, 23.70, 21.72. LCMS (40-95% acetonitrile in 0.05% TFA over 10 minutes) retention time = 4.12 minutes, ESI m/z = 374, [M+H]+ . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.8% | With dmap; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 25℃; for 10h; | 56 Example 56: [8,9-bis[3-(1 H-indol-3-yl)propanoyloxy]-6-oxo-benzo[c]chromen-3-yl] 3-(1 H-indol-3-yl)propanoate A mixture of 3,8,9-trihydroxybenzo[c]chromen-6-one (0.3 g) , 3-(1 H-indol-3-yl)propanoic acid (0.93 g), 4-dimethylaminopyridine (0.06) and N,Ndicyclohexylcarbodiimide (1 .02 g) in DMF (20 mL) was stirred at 25 00 for 10 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase prep-HPLC (018, water (0.1%trifluoroacetic acid)-acetonitrile gradient) to give [8,9-bis[3-1 H-indol-3-yl)propanoyloxy]-6-oxo- benzo[c]chromen-3-yl]3-(1H-indol-3-yl) propanoate (0.048 g, 4.8%) as a brown solid. 1H NMR (400 MHz, DMSO-d6): O 10.872(m, 3H), 8.250-8.233 (m, 2H), 8.087(s, 1H), 7.55-7.06 (m, 17H), 3.317-2.912 (m, 12H) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 25℃; for 12h; | 103 Example 103: [5-[3-(1 H-indol-3-yl)propanoyloxy]-4-[3-(1 H-indol-3-yl)propanoyloxymethyl]-6-methyl-3-pyridyl]methyl3-(1 H-indol-3-yl)propanoate To a mixture of 4,5-bis(hydroxymethyl)-2-methyl-pyridin-3-ol (0.5 g), N,N’dicyclohexylcarbodiimide (1 .28 g) and 4-dimethylaminopyridine (0.036 g) in 0H2012 (30 mL) was added 3- (1H-indol-3-yl) propanoic acid (1.17 g) at 25°C. The mixture was stirred at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by reverse phaseprep-HPLC (Cl 8, water (0.05%HCl)-acetonitrile gradient) to give [5-[3-(1 H-indol-3-yl)propanoyloxy]-4-[3-(1 H-indol-3-yl)propanoyloxymethyl]-6-methyl-3-pyridyl]methyl3-(1 H-indol-3-yl)propanoate (1 .2 g, 59%) asa colorless oil. LCMS: 683.2 (M÷H) 1H NMR (400 MHz, 0D013): O 8.306 (s, 1 H), 8.0 - 7.85 (br 2H),7.786 (br, 1 H), 7.65- 7.094 (m, 12H), 7.014 (s, 1 H), 6.836 (s,1 H), 6.793 (s, 1 H), 5.065 (s, 2H), 4.806 (s,2H), 3.238 (m, 2H), 3.033 (m, 6H), 2.726 (m, 2H), 2.604 (m, 2H), 2.274 (s, 3H) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With dmap; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 25℃; for 12.0h; | To a solution of (2R)-2,4-dihydroxy-N-(3-hydroxypropyl)-3,3-dimethyl-butanamide (0.2 g), N,N?dicyclohexylcarbodiimide (0.70 g) and 4-dimethylaminopyridine (0.060 g) in THE (4 mL) was added 3- (1 H-indol-3-yl) propanoic acid (0.645 g) and the mixture was stirred at 25 00 for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by reverse phase prep-HPLC (018, water (10 mM NH4HCO3)-acetonitrile gradient) to give 3-[[(2R)-2,4-bis[3-(1 Hindol-3-yl)propanoyloxy]-3,3-dimethyl-butanoyl]amino]propyl 3-(1 H-indol-3-yl)propanoate (0.307 g, 43%) as an off-white solid. LOMS: 719.2 (M÷H) 1H NMR (400 MHz, DMSO-d6): O 10.797(br s, 3H), 7.981 (m,1 H), 7.485 (m, 3H), 7.208 (m, 3H), 7.107 - 6.942 (m, 9H), 4.718 (s, 1 H), 4.005 - 3.837 (m, 3H), 2.950 (m,2H), 2.937 (m, 6H), 2.781 (m, 2H), 2.693 - 2.639 (m, 4H), 1 .687 (m, 2 H), 0.892 (m, 6H) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.9% | Stage #1: Indole-3-propionic acid With 1,1'-carbonyldiimidazole In acetonitrile at 20℃; for 1.5h; Inert atmosphere; Stage #2: 2-cyclohexylethylamine In acetonitrile at 20℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: Indole-3-propionic acid With Vilsmeier reagent In N,N-dimethyl-formamide at 20 - 40℃; for 2h; Stage #2: 3-(1H-imidazol-1-yl)propan-1-amine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 22h; | 5.5.3.5.3.1 .3.1. Synthesis of the ligand N-(3-(1H-imidazol-1-yl)propyl)-3-(1H-indol-3-yl)propanamide (ind-imi, L5) 3-(lf -Indol-3-yl)propanoic acid (398 mg, 2.0 mmol, 1.0 eq.) was dissolved in dry DMF (5 mL) and A'-(chloiomethylene)-/V-methylmethanaminium chloride (267 mg, 2.0 mmol, 1.0 eq.) was added at room temperature and stirred for 30 min at 40 °C. Then, after cooling to room temperature and stirring for 1.5 h, 3-( 1 //-imidazol- l -yl)propan- 1 -amine (243 pL, 2.0 mmol, 1.0 eq.) was added, followed by the addition of DIPEA (1.7 mL, 10.0 mmol, 5.0 eq.). After stirring at room temperature for 22 h, the mixture was diluted with water, extracted with DCM, and after removal of solvents under reduced pressure the residue was absorbed on Celite and purified chromatographically on silica (eluent: D C M/M e O H/ N H :, . = 100: 1 : 1 to 100:2: 1 to 100:3 : 1 to 100:4: 1) as an. After drying, a yellow oil (383 mg, 65% yield) was obtained. HRMS (ESL) C17H21N4O [M+H] 1 calc 297.1710, found 297.1697 NMR (400 MHz, DMSO-de): d 10.77 (s, 1 H, NH), 7.92-7.86 (m, 1 H, NH), 7.56 (s, 1 H), 7.55-7.51 (m, 1 H), 7.34-7.30 (m, 1 H), 7.12 (s, 1 H), 7.1 1-7.08 (m, 1 H), 7.08-7.02 (m, 1 H), 6.99-6.94 (m, 1 H), 6.87 (s, 1 H), 3.85 (t, J= 6.9 Hz, 2 H), 3.04-2.96 (m, 2 H), 2.93 (t, J= 7.6 Hz, 2 H), 2.45 (t, j= 7.6 Hz, 2 H), 1.77 (quint, j= 6.8 Hz, 2 H). HPLC (Grace Alltima C18 5 pm column, 25 x 4.6 mm) indicated that the product was 100% pure (retention time 14.5 min; gradient: 5 to 50% MeCN/0. l% TFA in water/0.1% TFA in 18 min measured at a wavelength of 273 nm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With dmap; triethylamine; dicyclohexyl-carbodiimide In dichloromethane at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: Indole-3-propionic acid; Vilsmeier reagent In N,N-dimethyl-formamide at 20 - 40℃; for 2h; Stage #2: 3-(1H-imidazol-1-yl)propan-1-amine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 22h; | 5.3.1 5.3.1. Synthesis of the ligand /V-(3-(lff-imidazol- l-yl)propyl)-3-(lf7-indol-3-yl)propanamide (ind-imi, L5) 3-(lff-Indol-3-yl)propanoic acid (398 mg, 2.0 mmol, 1.0 eq.) was dissolved in dry DMF (5 mL) and Ar-(chloroinethylene)-A'-methylmethanaminium chloride (267 mg, 2.0 mmol, 1.0 eq.) was added at room temperature and stirred for 30 min at 40 °C. Then, after cooling to room temperature and stirring for 1.5 h, 3-( 1 /7-imidazol-l -yOpropan- 1 -amine (243 pL, 2.0 mmol, 1.0 eq.) was added, followed by the addition of DIPEA (1.7 mL, 10.0 mmol, 5.0 eq.). After stirring at room temperature for 22 h, the mixture was diluted with water, extracted with DCM, and after removal of solvents under reduced pressure the residue was absorbed on Celite and purified chromatographically on silica (eluent: D C M / M e O H / N H ; q . = 100: 1 : 1 to 100:2: 1 to 100:3 : 1 to 100:4: 1) as an. After drying, a yellow oil (383 mg, 65% yield) was obtained. HRMS (ESI+) Ci7H2lN40 [M+H]+ calc 297.1710, found 297.1697 NMR (400 MHz, DMSO-do): d 10.77 (s, 1 H, NH), 7.92-7.86 (m, 1 H, NH), 7.56 (s, 1 H), 7.55-7.51 (m, 1 H), 7.34-7.30 (m, 1 H), 7.12 (s, 1 H), 7.1 1-7.08 (m, 1 H), 7.08-7.02 (m, 1 H), 6.99-6.94 (m, 1 H), 6.87 (s, 1 H), 3.85 (t, J= 6.9 Hz, 2 H), 3.04-2.96 (m, 2 H), 2.93 (t, J= 7.6 Hz, 2 H), 2.45 (t, J = 7.6 Hz, 2 H), 1.77 (quint, j= 6.8 Hz, 2 H). HPLC (Grace Alltima C18 5 pm column, 25 x 4.6 mm) indicated that the product was 100% pure (retention time 14.5 min; gradient: 5 to 50% MeCN/0.1% TFA in water/0.1% TFA in 18 min measured at a wavelength of 273 nm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With Rhizomucor miehei lipase; α,α,α-trifluorotoluene In aq. phosphate buffer at 30℃; for 24h; Enzymatic reaction; |
Tags: 830-96-6 synthesis path| 830-96-6 SDS| 830-96-6 COA| 830-96-6 purity| 830-96-6 application| 830-96-6 NMR| 830-96-6 COA| 830-96-6 structure
[ 1912-47-6 ]
2-(5-Methyl-1H-indol-3-yl)acetic acid
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P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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