| 94% |
In tetrahydrofuran; hexane; ethyl acetate; |
EXAMPLE 58 Preparation of 4-tert-butoxycarbonyl aminophenethyl alcohol To a solution of 4-aminophenethyl alcohol (1.0 g, 7.3 mmol) in THF (30 mL) was added di-tert-butyl dicarbonate (2.0 g, 9.5 mmol) and the resulting solution was stirred at 25 C. for 24 h; then the solution was concentrated under vacuum and purified by filtration on silica gel using ethyl acetate/n-hexane as eluant to afford the title compound as a white solid (1.63 g, 94%). m.p. 108 C. 1H NMR (CDCl3): 1.513 (s, 9H), 2.813 (t, J=6.6 Hz, 2H), 3.817 (d, J=5.1 Hz, 2H), 6.47 (bs, 1H), 7.145 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H). |
| 84% |
In tetrahydrofuran; at 20℃; |
Compound 1 l: tert-butyl N-[4-(2-hydroxyethyl)phenyl] carbamate Di-tert-butyl dicarbonate (16.7 g, 77 mmol, 1.05 eq.) was added to a solution of2-(4-aminophenyl)ethanol (10 g, 72.9 mmol, 1 eq.) in THF (200 mL), and the reactionstirred overnight at ambient temperature. The mixture was diluted with EtOAc (200 mL), washed with water (200 mL), then HC1 1M (100 mL), then saturated aqueous NaHCO3 solution (100 mL) then brine (100 mL). The organic phase was dried over MgSO4 then evaporated to dryness under reduced pressure. The crude product wastriturated twice with heptane (150 mL) and dried under vacuum to furnish compound hA as a white solid (14.7 g, 84 %). |
| 84% |
In tetrahydrofuran; at 20℃; |
Compound 11 A: tert-bvAy N-[4-(2-hydroxyethyl)phenyl] carbamate Di-tert-butyl dicarbonate (16.7 g, 77 mmol, 1.05 eq.) was added to a solution of 2-(4-aminophenyl)ethanol (10 g, 72.9 mmol, 1 eq.) in THF (200 mL), and the reaction stirred overnight at ambient temperature. The mixture was diluted with EtOAc (200 mL), washed with water (200 mL), then HCI 1M (100 mL), then saturated aqueous NaHCC"3 solution (100 mL) then brine (100 mL). The organic phase was dried over MgS04 then evaporated to dryness under reduced pressure. The crude product was triturated twice with heptane (150 mL) and dried under vacuum to furnish compound 11A as a white solid (14.7 g, 84 %). |
| 84% |
In tetrahydrofuran; at 20℃; |
Di-tert-butyl dicarbonate (16.7 g, 77 mmol, 1.05 eq.) was added to a solution of 2-(4-aminophenyl)ethanol (10 g, 72.9 mmol, 1 eq.) in THF (200 mL), and the reaction stirred overnight at ambient temperature. The mixture was diluted with EtOAc (200 mL), washed with water (200 mL), then HC1 1M (100 mL), then saturated aqueous NaHCC"3 solution (100 mL) then brine (100 mL). The organic phase was dried over MgS04 then evaporated to dryness under reduced pressure. The crude product was triturated twice with heptane (150 mL) and dried under vacuum to furnish compound 11A as a white solid (14.7 g, 84 %). |
| 84% |
In tetrahydrofuran; at 20℃; |
Compound 11A: tert-butyl N-[4-(2-hydroxyethyl)phenyl]carbamate Di-tert-butyl dicarbonate (16.7 g, 77 mmol, 1.05 eq.) was added to a solution of 2-(4-aminophenyl)ethanol (10 g, 72.9 mmol, 1 eq.) in THF (200 mL), and the reaction stirred overnight at ambient temperature. The mixture was diluted with EtOAc (200 mL), washed with water (200 mL), then HCl 1M (100 mL), then saturated aqueous NaHCO3 solution (100 mL) then brine (100 mL). The organic phase was dried over MgSO4 then evaporated to dryness under reduced pressure. The crude product was triturated twice with heptane (150 mL) and dried under vacuum to furnish compound 11A as a white solid (14.7 g, 84%). |
| 84% |
In tetrahydrofuran; at 20℃; |
Di-tert-butyl dicarbonate (16.7 g, 77 mmol, 1.05 eq.) was added to a solution of 2-(4-aminophenyl)ethanol (10 g, 72.9 mmol, 1 eq.) in THF (200 mL), and the reaction stirredovernight at ambient temperature. The mixture was diluted with EtOAc (200 mL), washed with water (200 mL), then HC1 1M (100 mL), then saturated aqueous NaHCO3 solution (100 mL) then brine (100 mL). The organic phase was dried over MgSO4 then evaporated to dryness under reduced pressure. The crude product was triturated twice with heptane (150mL) and dried under vacuum to furnish compound hA as a white solid (14.7 g, 84 %). |
| 83% |
With triethylamine; In tetrahydrofuran; at 20℃; for 16h; |
To a solution of 4-aminophenethyl alcohol (3.0 g, 21.8 mmol) in tetrahydrofuran (100 mL) at room temperature was added di-t°rt-butyldicarbonate (5.2 g, 23.6 mmol) and triethylamine (4.7 mL, 32.8 mmol). The reaction was stirred for 16 h at room temperature. The solution was diluted with water (100 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The organic layers were dried over sodium sulfate and filtered. The protected amine was obtained as a white solid (4.3 g, 83%). This compound (1.7 g, 7.4 mmol) and triphenylphosphine (1.9 g, 7.4 mmol) were added to a suspension of 6-chloropurine (761 mg, 4.9 mmol) in dry tetrahydrofuran (13 mL) at room temperature. The resulting mixture was evaporated to dryness. Dry tetrahydrofuran (13 mL) was added and the suspension was cooled to O0C followed by dropwise addition of diethylazo- dicarboxylate (891 muL, 5.7 mmol). After 16 h reaction at room temperature, the solution was concentrated under reduced pressure. The crude residue was purified on a EPO <DP n="26"/>Biotage 25M column (silica, hexane/AcOEt 95:5 to 65:35) to yield N-9 alkylated purine as a white solid (1.8 g, quantitative). |
| 80% |
With triethylamine; In 1,4-dioxane; at 20℃; for 1 - 8h;Product distribution / selectivity; |
Example 4; Preparation of Compounds According to the Invention; Diphenylphosphonylated compounds according to the invention (as e.g. in example 2) were prepared according to Scheme 1, by a fast and convenient synthetic route, affording the opportunity to obtain large and diverse series of compounds. The aminophosphonate building block was prepared from tert-butylcarbamate protected 4-aminophenylacetaldehyde (12), prepared from the corresponding alcohol (11) with Dess-Martin periodinane (Dess, D. B. and Martin, J. C. Readily Accessible 12-I-5 Oxidant for the Conversion of Primary and Secondary Alcohols to Aldehydes and Ketones. J. Org. Chem., 1983, 48, 4155-4156.). An amidoalkylation reaction with benzylcarbamate and triphenylphosphite using copper triflate as catalyst, afforded N-benzyloxycarbonyl protected diphenyl phosphonate 13 (Van der Veken, P.; El Sayed, I.; Joossens, J.; Stevens, C. V.; Augustyns, K. and Haemers, A.; Lewis Acid Catalyzed Synthesis of N-Protected Diphenyl 1-Aminoalkyl-Phosphonates. Synthesis, 2005, 4, 634-638). Acidolysis removed the tert-butyl carbamate protecting group. N,N'-bis(tert-butoxycarbonyl)-1-guanylpyrazole was used to introduce the protected guanidine group (Drake, B.; Patek, M.; Lebl, M., A Convenient Preparation of Monosubstituted N,N'-Di(Boc)-Protected Guanidines. Synthesis, 1994, 579-582.). Compound 14 was subsequently deprotected under hydrogenolytic conditions. Small non-peptide guanidyl compounds (7) were made by coupling compound (15) with selected sulfonyl chlorides or acylchlorides in pyridine. The p-acetylaminophenyl phosphonates (as e.g. in example 3) were prepared following scheme 1 using tri-p-acetylaminophenylphosphite (Belyaev et al. A. Structure-Activity Relationship of Diaryl Phosphonate Esters as Potent Irreversible Dipeptidyl Peptidase IV Inhibitors. J. Med. Chem., 1999, 42, 1041-1052) (22).; Boc-protection: To a solution of aminoalcohol or amino acid in 40 ml dioxane and 1 eq. triethylamine and 1 eq. di-tert-butyl dicarbonate (1.1 eq) were added and the mixture was stirred at room temperature for 1 h-8 h (reaction was followed by TLC). The solution was concentrated in vacuo and acidified with 2N HCl. The acidified aqueous layer was extracted 3 times with EtOAc. The organic solvent was evaporated and the obtained product was purified with flash chromatography.; tert-Butyl 4-(2-oxoethyl)phenylcarbamate (12); 2-(4-Aminophenyl)ethanol (13.7 g, 0.1 mol) was dissolved in dioxane (120 ml). Triethylamine (10.1 g, 0.1 mol) was added followed by addition of Boc2O (21.8 g, 0.1 mol). The reaction mixture was stirred overnight. After evaporation under vacuum, the residue was dissolved in ethylacetate and washed with HCl (2N) and brine. The organic layer was dried over Na2SO4 and evaporated. Purification by flash chromatography afforded the tert-butyl 4-(2-hydroxyethyl)phenylcarbamate as a white solid (19 g, 80 mmol, 80%). To a stirred solution of this alcohol (1 eq) in dichloromethane, a solution of Dess-Martin periodane (1.2 eq from 15% wt solution) was added. The suspension was stirred for 4 h at room temperature. The resulting solution was poured into a vigorously stirred saturated solution of NaHCO3 and Na2S2O3 (1: 1, 100 ml). The organic layer was separated and washed with brine and dried over anhydrous Na2SO4. This crude aldehyde 12 was used directly for further reaction. |
| 80% |
With triethylamine; In 1,4-dioxane; at 20℃; for 1h;Product distribution / selectivity; |
Example 4: Preparation of compounds according to the invention.Diphenylphosphonylated compounds according to the invention (as e.g. in example 2) were prepared according to Scheme 1 , by a fast and convenient synthetic route, affording the opportunity to obtain large and diverse series of compounds. The aminophosphonate building block was prepared from fe/t-butylcarbamate protected 4- aminophenylacetaldehyde (12), prepared from the corresponding alcohol (11) with Dess- Martin periodinane (Dess, D. B. and Martin, J. C. Readily Accessible 12-1-5 Oxidant for the Conversion of Primary and Secondary Alcohols to Aldehydes and Ketones. J. Org. Chem., 1983, 48, 4155-4156.). An amidoalkylation reaction with benzylcarbamate and triphenylphosphite using copper triflate as catalyst, afforded lambda/-benzyloxycarbonyl protected diphenyl phosphonate 13 (Van der Veken, P.; El Sayed, I.; Joossens, J.; Stevens, C. V.; Augustyns, K. and Haemers, A.; Lewis Acid Catalyzed Synthesis of N- Protected Diphenyl 1-Aminoalkyl-Phosphonates. Synthesis, 2005, 4, 634-638). Acidolysis removed the terf-butyl carbamate protecting group. lambda/,lambda/'-bis(te/-butoxycarbonyl)-1- guanylpyrazole was used to introduce the protected guanidine group (Drake, B.; Patek, M.; Lebl, M., A Convenient Preparation of Monosubstituted N,N'-Di(Boc)-Protected Guanidines. Synthesis, 1994, 579-582.). Compound 14 was subsequently deprotected under hydrogenolytic conditions. Small non-peptide guanidyl compounds (7) were made by coupling compound (15) with selected sulfonyl chlorides or acylchlorides in pyridine. EPO <DP n="69"/>The p-acetylaminophenyl phosphonates (as e.g. in example 3) were prepared following scheme 1 using tri-p-acetylaminophenylphosphite (Belyaev et al. A. Structure-Activity Relationship of Diaryl Phosphonate Esters as Potent Irreversible Dipeptidyl Peptidase IV Inhibitors. J.Med. Chem., 1999, 42, 1041-1052) (22).; Boc-protection: To a solution of aminoalcohol or amino acid in 40ml dioxane and 1 eq. triethylamine and 1eq. di-tert-butyl dicarbonate (1.1 eq) were added and the mixture was EPO <DP n="72"/>stirred at room temperature for 1 h-8h (reaction was followed by TLC). The solution was concentrated in vacuo and acidified with 2N HCI. The acidified aqueous layer was extracted 3 times with EtOAc. The organic solvent was evaporated and the obtained product was purified with flash chromatography.tert-Butyl 4-(2-oxoethyl)phenylcarbamate (12)2-(4-Aminophenyl)ethanol (13.7 g, 0.1 mol) was dissolved in dioxane (120 ml). Triethylamine (10.1 g, 0.1 mol) was added followed by addition of Boc2O (21.8 g, 0.1 mol). The reaction mixture was stirred overnight. After evaporation under vacuum, the residue EPO <DP n="84"/>was dissolved in ethylacetate and washed with HCI (2N) and brine. The organic layer was dried over Na2SO4 and evaporated. Purification by flash chromatography afforded the tert- butyl 4-(2-hydroxyethyl)phenylcarbamate as a white solid (19 g, 80 mmol, 80%). To a stirred solution of this alcohol (1eq) in dichloromethane, a solution of Dess-Martin periodane (1.2 eq from 15% wt solution) was added. The suspension was stirred for 4 h at room temperature. The resulting solution was poured into a vigorously stirred saturated solution of NaHCO3 and Na2S2O3 (1 : 1, 100 ml). The organic layer was separated and washed with brine and dried over anhydrous Na2SO4. This crude aldehyde 12 was used directly for further reaction. |
| 75% |
In tetrahydrofuran; at 20℃; |
Compound 11A was obtained with a yield of 75 % after reaction at ambienttemperature of 2-(4-aminophenyl)ethanol with BOC2O in THF. |
| 75% |
In tetrahydrofuran; at 20℃; |
Compound 11A was obtained with a yield of 75 % after reaction at ambienttemperature of 2-(4-aminophenyl)ethanol with BOC2O in THF. |
| 75% |
In tetrahydrofuran; at 20℃; |
Compound 11A was obtained with a yield of 75 % after reaction at ambienttemperature of 2-(4-aminophenyl)ethanol with BOC2O in THF. |
|
In 1,4-dioxane; |
[4-(2-Hydroxy-ethyl)-phenyl]-carbamic acid tert-butyl ester 5g (36.4 mmol) of 2-(4-Amino-phenyl)-ethanol was dissolved in 25 ml of dioxan and treated with 7.95 g (36.4 mmol) of di-tert-butyl pyrocarbonate. The solution was stirred for 16 h at RT. The solvent was removed under reduced pressure. |
|
In tetrahydrofuran; |
(C) Alternatively, for compounds in which Y is --NH-- or --NR2 --, one may begin with a hydroxyalkylaniline, protecting the amino group by reaction with di-t-butyldicarbonate. For example, 25 g of 4-(2-hydroxyethyl)aniline and 39.6 g of di-t-butyldicarbonate in 250 mL of THF was heated at reflux for 30 min. The solvent was evaporated and the residue dissolved in ether. The solution was washed with 5% HCl, water, and brine, and dried over Na2 SO4. Evaporation and recrystallization from ethyl acetatehexane yielded 25 g of N-(t-butoxycarbonyl)-4-(2-hydroxyethyl)aniline (8), m.p. 104-105 C. |
|
With triethylamine; In 1,4-dioxane; at 20 - 25℃;Inert atmosphere; |
Step A: Tert-Butyl r4-(2-hvdroxyethyl)phenyl1carbamateTriethylamine (30 mL, 220 mmol) was added to a solution of 2-(4- aminophenyl)ethanol (26.62 g, 194 mmol) in 1 ,4-dioxane (200 mL) followed by the addition of di-tert-butyl dicarbonate (50 g, 230 mmol). The reaction was stirred overnight at room temperature under nitrogen. The reaction was concentrated, dissolved in ethyl acetate (500 mL), washed with water (3x100 mL) and brine (100 mL), dried (MgS04), filtered and concentrated in vacuo to afford a crude white solid. A portion of the crude white solid (10.64 g) was purified via flash chromatography using an Analogix SF40-150g column and an eluant of ethyl acetate in heptane (30-60%) to afford the title compound as a white solid (6.45 g). 1H NMR (400 MHz, METHANOL-d4) delta ppm 1.52 (s, 9 H) 2.72 - 2.83 (m, 2 H) 3.68 - 3.77 (m, 2 H) 7.05 - 7.24 (m, 2 H) 7.25 - 7.44 (m, 2 H). |
| 7.85 g |
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 20℃; for 4h; |
5 g (35.36 mmol) of 2-(4-aminophenyl)ethanol and 6.17 mL (35.36 mmol) of Nu,Nu-diisopropylethylamine are added to a solution of 8.49 g (38.89 mmol) of di-tert-butyl dicarbonate in 10 mL of dioxane. After stirring for 4 hours at room temperature, the reaction mixture is evaporated to dryness. The residue is taken up in ethyl acetate and the solution is washed with 1 N hydrochloric acid solution and then with water. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 7.85 g of tert-butyl [4-(2-hydroxyethyl)phenyl]carbamate, the characteristics of which are as follows: 1H NMR spectrum (300 MHz, delta in ppm, DMSO-d6): 1.47 (s, 9H), 2.65 (t, 2H), 3.54 (q, 2H), 4.60 (t, 1 H), 7.07 (d, 2H), 7.33 (d, 2H), 9.13-9.3 (bs, 1 H). |
| 7.85 g |
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 20℃; for 4h; |
5 g (35.36 mmol) of 2-(4-aminophenyl)ethanol and 6.17 mL (35.36 mmol) of N,N-diisopropylethylamine are added to a solution of 8.49 g (38.89 mmol) of di-tert-butyl dicarbonate in 10 mL of dioxane. After stirring for 4 hours at room temperature, the reaction mixture is evaporated to dryness. The residue is taken up in ethyl acetate and the solution is washed with 1 N hydrochloric acid solution and then with water. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 7.85 g of tert-butyl [4-(2-hydroxyethyl)phenyl]carbamate, the characteristics of which are as follows: 1H NMR spectrum (300 MHz, delta in ppm, DMSO-d6): 1.47 (s, 9H), 2.65 (t, 2H), 3.54 (q, 2H), 4.60 (t, 1H), 7.07 (d, 2H), 7.33 (d, 2H), 9.13-9.3 (bs, 1H). |
| 1.65 g |
In ethyl acetate; at 20℃; for 16h; |
To a solution of 2-(4-aminophenyl)ethanol (1 g, 7.29 mmol) in EtOAc (15 mL) was added Boc-anhydride (1.862 mL, 8.02 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated under reduced pressure and triturated with hexane (30 mL) to afford the title compound (1.65 g) as a white solid. LC-MS retention time = 1.84 min; m/z = 238.2 [M+H]+ Column: KINETIX XB-C18, 75x3 mm, 2.6 muetaiota; Flow rate: 1 mL/min; Mobile Phase A: 10 mM HCOONHdn 98% Water/ 2% ACN; Mobile Phase B: 10 mM HCOONH4 in 2% Water/ 98% ACN; 20% B to 100% B over 4 min, then hold for 0.6 min at 100% B with flow rate of 1.5 mL/min; Detection: UV at 220 nm. 1H NMR (300 MHZ, CDCl3) delta 7.29 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.7 Hz, 2H), 6.46 (br. s., 1H), 3.84 (q, J=6.4 Hz, 2H), 2.84 (t, J=6.4 Hz, 2H), 1.53 (s, 9H). |
| 31 g |
With triethanolamine; In methanol; at 70℃; for 12h;Inert atmosphere; |
In the 500 ml reaction in the bottle, the 20g compound 2 (0.14 muM) dissolved in 200 ml in methanol, under the protection of nitrogen conditions, slowly add 50 ml triethanolamine and 40g (0.18 muM) mixed solution of di-tert-butyl dicarbonate, after adding after 70 C reflux reaction 12h, steaming and to remove the methanol, adding 100 ml dichloromethane, add a certain amount of water washing, separating the organic phase, boil off the organic phase to obtain 31g compound 3. |
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