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CAS No. : | 125414-41-7 |
Formula : | C8H17NO4 |
M.W : | 191.22 |
SMILES Code : | O=C(OC(C)(C)C)NC(CO)CO |
MDL No. : | MFCD00270213 |
InChI Key : | JHBKBRLRYPYBLP-UHFFFAOYSA-N |
Pubchem ID : | 10631565 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H319 |
Precautionary Statements: | P305+P351+P338 |
* 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 |
---|---|---|
100% | In ethanol; at 20℃; for 16h; | To a solution of 2-anunopropane-1 ,3-diol (1 0. 0 g, 0.1 mol) in EtOH ( 100 mL) wasadded di-tert-butyl dicarbonate (24.0 g, 0.1 mol). The reaction was stirred at room temperaturefor 16 hrs. The reaction solution was concentrated in vacuo to dryness to give tert-butyl (1,3-dihydroxypropan-2-yl)carbamate (21.0 g, yield: 1 00'%) as a white solid. |
97% | In dichloromethane; at 22 - 25℃; for 4h; | Serinol (2.00 g, 21.96 mmol) and (Boc)20 (4.80 g, 21.96 mmol) was dissolved in 20 mL of dichloromethane. The reaction mixture was stirred for 4 h at 22 to 25 C. The above mixture was washed with water (25 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum toyield tert-butyl (1 ,3-dihydroxypropan-2-yl)carbamate (4.1 g, 97% yield). |
95% | With hydrogenchloride; In 1,4-dioxane; water; at 20℃;Cooling with ice; | Serinol (10.1 mmol) (manufactured by Aldrich Chem. Co.) was dissolved in water-dioxane (1:1, 20 ml), andthen a dioxane solution (15 ml) of Boc2O (10.8 mmol) was added thereto under ice-cooling, followed by stirring overnightwhile returning to room temperature. The solvent was evaporated under reduced pressure. The residue was washedwith hexane and then dried under reduced pressure to give the titled compound (1847 mg, yield 95%).The structurewas identified by 1H-NMR.1H-NMR (500 MHz, CD3OD) delta (ppm) = 1.44 (9H, s, Boc), 3.57-3.58 (5H, m, Serinol) |
95% | With trimethylamine; In dichloromethane; for 4h; | Serinoi (2,00 g, 22,0 mmol) was dissolved in dichioromethane (40 mL) and trimethylamitie (10 mL). Di-tert-butyl dicarbonate (5.76 g, 26.4 mmol, 1.2 eq) was then added, and the reaction stirred for 4 hours. The mixture was evaporated and the residue portioned between ethyl acetate and water. The organic fraction was washed with water ( lx), 1M HC1 (2x), saturated sodium bicarbonate (lx), and brine (lx) before drying over sodium sulfate and evaporation to give compound 23 (3.99 g, 20.9 mmol) in 95% yield, which was used without purification in further steps. |
91% | In ethanol; at 20℃; for 6h; | 2-amino-1,3-propanediol (5 g) was dissolved in 150 mL of absolute ethanol, A solution of 100 mL of Boc anhydride (12 g) in absolute ethanol was added, Room temperature reaction 6h, Remove the solvent, Recrystallization from n-heptane gave a white solid 3 (9.6 g, 91%). |
72% | With N-ethyl-N,N-diisopropylamine; In methanol; for 0.25h;Product distribution / selectivity; | Example 2Lambda/-Boc-Serinol. Lambda/,Lambda/-diisopropylethylamine (DIEA; 10.3 ml_, 59 mmol, 1.1 equiv) was added to serinol (4.88 g, 54 mmol, 1 equiv) in 10 ml_ methanol. A solution of di-f-butyl dicarbonate (12.9 g, 59 mmol, 1.1 equiv.) in 5 mL methanol was then added to the original solution. The reaction was exothermic and evolved gas. The reaction appeared to be complete after 15 min. (as determined by TLC analysis in 9:1 CHCI3:CH3OH with ninhydrin stain). The solvent was then removed at reduced pressure, and the crude material was purified by flash chromatography, using CHCI3:CH3OH (first at a 9:1 ratio and then at a 85:15 ratio), to yield 7.18g (72% yield) of white, flaked crystals. [Rf: 0.35 (5:1 CHCI3:CH3OH); melting point 85-860C; 1H NMR (200 MHz, CDCI3) delta 5.25 (br d, J = 5.6, 1 H, NH), 3.9-3.65 (m, 5H, (-CH2)2CH-), 2.62 (t, J = 5.6, 2H, OH), 1.45 (s, 9H, C(CHa)3)]. EPO <DP n="30"/>Example 3[0107] To prepare the bis-phthalonitrile used in scheme 2, the nitrogen of serinol was Boc-protected, and the serinol was then reacted with 3-nitrophthalonitrile on a multi-gram scale, to give the desired tethered bis-phthalonitrile, in 70% yield |
62% | With potassium carbonate; In tetrahydrofuran; water; at 20℃; | 2-Amino-1,3-propanediol (1.62 g, 17.8 mmol, 1.0 eq) was dissolved in 60 mL of tetrahydrofuran/H2O (1/1). Di-tert-butyl dicarbonate (Boc2O) (5.82 g, 26.7 mmol, 1.5 eq) and K2CO3 (6.15 g, 44.5 mmol,2.5 eq) were added. The reaction was stirred at room temperature overnight. The reaction systemwas allowed to stand for stratification, and the aqueous phase was extracted three times withtetrahydrofuran. The organic phase was combined, dried over anhydrous Na2SO4, evaporatedin vacuo, and puried by column chromatography (silica gel:petroleum ether/ethyl acetate, 1:1) toproduce compound 4 as a white solid in a 62% yield (2.1 g, 11.0 mmol). 1H-NMR (400 MHz, CDCl3) 5.24 (s, 1H), 3.81 (qd, J = 11.1, 4.3 Hz, 4H), 3.69 (s, 1H), 2.50 (dd, J = 22.1, 14.7 Hz, 2H), 1.46 (s, 9H),which agrees with published data [39]. |
49% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; | 2-Amino-1 ,3-propanediol (5.Og, 54.9mmol) was dissolved in dry THF (175ml) and triethylamine (7.7ml) added. The solution was cooled in an ice-bath and di-fe/f- butylcarbonate (11.98g, 54.9mmol) added in portions over 15mins. The solution was allowed to warm to ambient temperature and stirred for 90mins. The solvent was evaporated and water (250ml) added and the product extracted into ethyl acetate (4 x 125ml). The combined organics were washed with brine, dried over magnesium sulphate, filtered and evaporated. The product was isolated by recrystallization from hot ethyl acetate-petrol (1 :3) to give shiny flakes 5.18g (49% yield). The structure was confirmed by 1H NMR (300MHz , CDCI3): 1.44 (s, 9H), 3.08-3.17 (m, 1 H), 3.61 - 3.84 (m, 4H). |
With triethylamine; In dichloromethane; at 20℃;Cooling with ice; | General procedure: Diols or diamine (0.048 mol) and triethylamine (4.81 g, 0.057 mol) were dissolved in anhydrous CH2Cl2 (50 mL). (Boc)2O (12.45 g, 0.057 mol) in anhydrous CH2Cl2 solution was added dropwise to the above stirred solution under the ice bath. The mixture was stirred overnight at room temperature, followed by evaporation of the organic solvents. The residue was purified with silica gel column chromatography (dichloromethane/methyl alcohol = 30: 1). The synthesis of naked two primary amine compound according to the literature [29]. Then, acryloyl chloride (6.95 g, 0.077 mol) in anhydrous dichloromethane (50 mL) was added dropwise to a stirred solution of diol or diamine (0.038 mol) and triethylamine (7.77 g, 0.077 mol) in anhydrous dichloromethane (50 mL) under the ice bath. The mixture was stirred overnight at room temperature and then filtered off generated salt, followed by evaporation of the volatile solvent. The residue was purified with silica gel column chromatography (PE: EA = 3: 1, v/v) to give LC1-LC6. | |
With triethylamine; In dichloromethane; at 0 - 20℃; | General procedure: Diethanolamine 3 (or threoninol 5, 3-amino-1,2-propanediol 6)(0.047 mol) was dissolved in CH2Cl2 and triethylamine (9.60 g,0.095 mol) was slowly added. The solution was cooled to 0 C,and (Boc)2O (12.45 g, 0.057 mol) was added dropwise. Then themixed solution was left for stirring at room temperature overnight.The solvent was removed under reduce pressure to afford crudeproduct, which was further purified by silica gel column chromatography(CH2Cl2/CH3OH = 10/1, v/v) to give compound 3a (or5a, 6a). | |
With triethylamine; In dichloromethane; | Referring to Scheme LLL, the amino group in diol 1-29 is protected with Boc2O to provide compound 1-30 which is mesylated (e.g., with MsC1 and TEA) to afford compound 1-31. Compound 1-31 is subjected to a double nucleophilic substitution with pyrazolone 1-9, providing1-32, which is brominated (e.g., with NBS) to afford compound 1-33. Sequential treatment of 1-33 with n-butyl lithium, zinc chloride, and TCPC provides compound 1-34. Intermediate 61 is obtained when 1-34 is reacted with aqueous ammonia. | |
In methanol; water; at 0 - 25℃; for 4.5h; | Add 6mL of deionized water and 14mL of methanol to the three-necked flask, stir and mix well, then add 0.02mol serinol to the mixed solution, stir and dissolve it completely, cool to 0 C with an ice bath, and then add the three mixed solutions Slowly add 0.022mol of di-tert-butyl dicarbonate. During the dropwise addition, the temperature was maintained at 0 C. After 30 minutes, the ice bath was removed and the reaction was performed at a constant 25 C for 4 hours. After the reaction was completed, extraction was performed three times with dichloromethane. The solvent methanol and water were distilled off under reduced pressure, and vacuum-dried at 45 C. for 24 h to obtain the product tert-butyl 1,3-dihydroxypropane-2-carbamate. | |
With triethylamine; In dichloromethane; for 4h; | Serinol (2.00 g, 22.0 mmol) was dissolved in dichloromethane (40 mL) and trimethyamine ( 10 mL). Di-tert-butyl dicarbonate (5.76 g, 26.4 mmol, 1 .2 eq) was then added, and the reaction stirred for 4 hours. The mixture was evaporated and the residue portioned between ethyl acetate and water. The organic fraction was washed with water ( l x), 1 M HCI (2x), saturated sodium bicarbonate ( l x), and brine ( l x) before drying over sodium sulfate and evaporation to give compound 23 (3.99 g, 20.9 mmol) in 95% yield, which was used without purification in further steps. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With triethylamine; In dichloromethane; at 0 - 20℃; for 2h; | To a solution of <strong>[125414-41-7]tert-butyl (1,3-dihydroxypropan-2-yl)carbamate</strong> (21.0 g, 0.1 mol) andTEA (23.0 g, 0.2 mol) in dry CI-bCb (200 mL) was added MsCl (26.0 g, 0.2 mol) at 0 C. Afterthe stirring at room temperature for 2 hrs, the reaction was filtered. The filtrate was concentratedto dryness to give crude 2-((tert-butoxycarbonyl)amino)propane-1,3-diyl dimethanesulfonate(37.0 g, yield: 97%) as a white solid which was used for next step directly without anypurification. |
With triethylamine; In dichloromethane; at 5 - 20℃; for 25h; | Methanesulfonyl chloride (130 mmol) was added at 5 C to a stirred solution of boc-serinol (40 mol) and triethylamine (25 ml) in dichloromethane (100 ml). The mixture was stirred at 5 C for 5 h and at 20 C for 20 h. Dichloromethane (200 ml) was added and the mixture was washed with an aqueous solution of sodium hydrogen carbonate (50 mM), dried (Na2SO4) and concentrated to dryness under vacuum. Chromatography of the residue on silicagel (1.2 L) eluting with hexane/ethyl acetate (50:50) gave bis-(methanesulfonic acid ester) of boc-serinol. | |
With triethylamine; In tetrahydrofuran; | Referring to Scheme LLL, the amino group in diol 1-29 is protected with Boc2O to provide compound 1-30 which is mesylated (e.g., with MsC1 and TEA) to afford compound 1-31. Compound 1-31 is subjected to a double nucleophilic substitution with pyrazolone 1-9, providing1-32, which is brominated (e.g., with NBS) to afford compound 1-33. Sequential treatment of 1-33 with n-butyl lithium, zinc chloride, and TCPC provides compound 1-34. Intermediate 61 is obtained when 1-34 is reacted with aqueous ammonia. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With potassium hydroxide; In N,N-dimethyl-formamide; for 2h; | tert-Butyl (l,3-dihydroxypropan-2-yl)carbamate (3.7 g, 19.35 mmol), potassium hydroxide (4.0 g, 71.59 mmol), and benzyl bromide (12.24 g, 71.59 mmol) were dissolved in 50 mL of DMF. The mixture was stirred for 2 h and concentrated under vacuum. The crude product was purified using column chromatography to yield tert-butyl (1 ,3-bis(benzyloxy)propan-2- yl)carbamate (3.25 g, 45% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; for 12h; | A solution of pentaacetylated gluconic acid (2.08 eq.) in anhydrous DCM is treated with EDC1 (2.2 eq.) and pyridine (3.4 eq.). <strong>[125414-41-7]N-Boc-serinol</strong> (1.0 eq.) is added into the reaction mixture followed by addition of DMAP (catalytic amount). The reaction mixture is stirred for 12 hours and is poured into saturated aq. ammonium chloride solution. The organic phase is separated and extracted with DCM, dried over MgS04 and concentrated under reduced pressure to give a sticky solid. Flash column chromatography on silica eluting with 2 % methanol/DCM gives N-Boc-protected bis-acetylated gluconate ester as a colorless dense oll. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | In tetrahydrofuran; | STEP B N-TERT-BUTOXYCARBONYL-DI(O-BENZYL)SERINOL The title compound was prepared in 49% yield from N-tert-butoxycarbonyl serinol using the procedure given in Example 4, Step B, but using tetrahydrofuran as solvent, 2.4 equivalents of benzyl bromide and 2.2 equivalents of potassium-tert-butoxide. RF: 0.17 (silica gel, petroleum ether/ethyl acetate: 90/10). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 72h;Product distribution / selectivity; | Example 3[0107] To prepare the bis-phthalonitrile used in scheme 2, the nitrogen of serinol was Boc-protected, and the serinol was then reacted with 3-nitrophthalonitrile on a multi-gram scale, to give the desired tethered bis-phthalonitrile, in 70% yieldExample 5[0109] Boc-serinol Bisphthalonitrile. Finely ground K2CO3 (4.32 g, 31.2 mmol,4 equiv.) was added to /V-Boc-serinol (1.45 g, 7.8 mmol, 1 equiv.) in 20 mL DMSO under argon; then 3-nitrophthalonitrile (3.38 g, 19.5 mmol, 2.5 equiv.) was added. The reaction mixture first turned pink, and then orange upon addition of the 3- nitrophthalonitrile. The reaction mixture was stirred at room temperature and monitored periodically by TLC (9:1 benzene:CH3CN). After 72 h, the reaction mixture was partitioned between EtOAc and water. The two layers were separated, and the aqueous layer was extracted 3 times with 50 mL EtOAc. The organic layer from the original partitioning was added to the organic extract. This mixture was then washed twice with 50 mL of saturated NaHCO3, and twice with 50 mL of water, and was then dried over Na2SO4. The solvent was removed at reduced pressure, and the resulting crude orange solid was recrystallized from methanol/water to give 2.43g (70% yield) of a slightly EPO <DP n="32"/>pink/tan solid. [ Rf: 0.25 (9:1 benzene:CH3CN); melting point 167-169C; 1H NMR (200 MHz, CD3CN) delta 7.85-7.4 (m, 6H, ArH), 5.76 (br s, 1 H, NH), 4.39 (s, 5H, (-CH2J2CH-), 1.42 (s, 9H, C(CH3)3).] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In pyridine; at 20℃; for 24h; | (2-Hydroxy-1-hydroxymethyl-ethyl)-carbamic acid tert-butyl ester (5.0g, 26.1 mmol) was dissolved in pyridine (50ml) and acetic anhydride (50ml) was added. The solution was stirred at ambient temperature for 24h when TLC showed no starting material remained. The solvent was evaporated and the residue dissolved in ethyl acetate (120ml) and washed with dilute hydrochloric acid (3 x 50ml), sodium bicarbonate solution (50ml), brine, dried over magnesium sulphate, filtered and evaporated to give a colourless oil (7.2g, 99% yield).The structure was confirmed by 1H NMR (300MHz, CDCI3): 1.42 (s, 9H), 2.05 (s, 6H), 4.00 - 4.20 (m, 4H), 4.76 - 4.88 (m, 1 H). |
99% | With pyridine; at 20℃; for 24h; | Preparation KAcetic acid 3-acetoxy-2-tert-butoxycarbonylamino-propyl ester(2-Hydroxy-1-hydroxymethyl-ethyl)-carbamic acid tert-butyl ester (5.Og, 26.1 mmol) was dissolved in pyridine (50ml) and acetic anhydride (50ml) was added. The solution was stirred at ambient temperature for 24h when TLC showed no starting material remained. The solvent was evaporated and the residue dissolved in ethyl acetate (120ml) and washed with dilute hydrochloric acid (3 x 50ml), sodium bicarbonate solution (50ml), brine, dried over magnesium sulphate, filtered and evaporated to give a colourless oil (7.2g, 99% yield).The structure was confirmed by 1H NMR (300MHz, CDCI3): 1.42 (s, 9H), 2.05 (s, 6H), 4.00 - 4.20 (m, 4H), 4.76 - 4.88 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 1.75h; | Preparation J(2-Hydroxy-1-hvdroxymethyl-ethyl)-carbamic acid tert-butyl esterO H ^OH <n="23"/>2-Amino-1 ,3-propanediol (5.Og, 54.9mmol) was dissolved in dry THF (175ml) and triethylamine (7.7ml) added. The solution was cooled in an ice-bath and di-te/f- butylcarbonate (11.98g, 54.9mmol) added in portions over 15mins. The solution was allowed to warm to ambient temperature and stirred for 90mins. The solvent was evaporated and water (250ml) added and the product extracted into ethyl acetate (4 x 125ml). The combined organics were washed with brine, dried over magnesium sulphate, filtered and evaporated. The product was isolated by recrystallization from hot ethyl acetate-petrol (1 :3) to give shiny flakes 5.18g (49% yield).The structure was confirmed by 1H NMR (300MHz , CDCI3): 1.44 (s, 9H), 3.08- 3.17 (m, 1 H), 3.61 - 3.84 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; | 2-(tert-butoxycarbonylamino)propane-l ,3-diyl ditetradecanoate To a solution of tetradecanoic acid (1.051 g) in dichloromethane (10 mL) at 00C were added tert-butyl l,3-dihydroxypropan-2-ylcarbamate (0.40 g), 4-(dimethylamino)pyridine (0.562 g), N-methylmorpholine (1.150 mL), and l-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (0.882 g). The mixture was stirred at room temperature overnight. The mixture was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane. The extract were dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash chromatography (1 :10 ethyl acetate/hexanes). MS (ESI) m/z 512.4 (M-CO2-tert-butyl+l)+. | |
With 4-methyl-morpholine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; | To a solution of tetradecanoic acid (1.051 g) in dichloromethane (10 mL) at 00C were added tert-butyl l,3-dihydroxypropan-2-ylcarbamate (0.40 g), 4-(dimethylamino)pyridine (0.562 g), N-methylmorpholine (1.150 mL), and l-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (0.882 g). The mixture was stirred at room temperature overnight. The mixture was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane. The extract were <n="127"/>dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash chromatography (1 :10 ethyl acetate/hexanes). MS (ESI) m/z 512.4 (M-CO2-tert-butyl+l)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In a 100 mL round-bottomed flask was added <strong>[125414-41-7]N-Boc-serinol</strong> (1,1-dimethylethyl (2- hydroxy-l-(hydroxymethyl)ethyl)carbamate) (2.0 g) and sodium hydride (1.255 g) in N5N- dimethylformamide (50 mL). The mixture was cooled using an ice/water bath, and 1- bromohexadecane (7.98 g) was added to it. The mixture was heated at 700C overnight, then cooled to room temperature. The mixture was cooled to 00C and quenched with a few drops of cold water. The mixture was diluted with saturated ammonium chloride (50 mL). The aqueous layer was extracted with ethyl acetate, and the extract was washed with brine, dried over Na2SO4, and concentrated. The concentrate was added to a silica gel column and was eluted with ethyl acetate/hexane (1 :9). The product, tert-butyl l,3-bis(hexadecyloxy) propan-2-ylcarbamate, was directly used for the next step.In a 100 mL round-bottomed flask was added tert-butyl l,3-bis(hexadecyloxy)propan- 2-ylcarbamate (5.0 g) and CH2Cl2 (40 mL). Trifluoroacetic acid (20 mL) was then added dropwise. The mixture was stirred under nitrogen for 3 hours and concentrated. The concentrate was added to a silica gel column and eluted with CH2Cl2/methanol (9:1). The product was dried under vacuum. 1H NMR (300 MHz, CDCl3) delta ppm 3.53-3.63 (m, 4H), 3.42-3.46 (t, 4H), 3.23 (m, IH), 2.92-2.97 (m, 2H), 1.53-1.64 (m, 4H), 1.18-1.40 (m, 52H), 0.86-0.90 (t, 6H). MS (ESI) m/z 540.6 (M+l)+. | ||
In a 100 mL round-bottomed flask was added <strong>[125414-41-7]N-Boc-serinol</strong> (1,1-dimethylethyl (2- hydroxy-l-(hydroxymethyl)ethyl)carbamate) (2.0 g) and sodium hydride (1.255 g) in N5N- dimethylformamide (50 mL). The mixture was cooled using an ice/water bath, and 1- bromohexadecane (7.98 g) was added to it. The mixture was heated at 700C overnight, then cooled to room temperature. The mixture was cooled to 00C and quenched with a few drops of cold water. The mixture was diluted with saturated ammonium chloride (50 mL). The aqueous layer was extracted with ethyl acetate, and the extract was washed with brine, dried over Na2SO4, and concentrated. The concentrate was added to a silica gel column and was eluted with ethyl acetate/hexane (1 :9). The product, tert-butyl 1,3 -bis(hexadecyloxy) propan-2-ylcarbamate, was directly used for the next step.In a 100 mL round-bottomed flask was added tert-butyl l,3-bis(hexadecyloxy)propan- 2-ylcarbamate (5.0 g) and CH2Cl2 (40 mL). Trifluoroacetic acid (20 mL) was then added dropwise. The mixture was stirred under nitrogen for 3 hours and concentrated. The concentrate was added to a silica gel column and eluted with CH2Cl2/methanol (9:1). The product was dried under vacuum. 1H NMR (300 MHz, CDCl3) delta ppm 3.53-3.63 (m, 4H), 3.42-3.46 (t, 4H), 3.23 (m, IH), 2.92-2.97 (m, 2H), 1.53-1.64 (m, 4H), 1.18-1.40 (m, 52H), 0.86-0.90 (t, 6H). MS (ESI) m/z 540.6 (M+l)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Preparation J (2-Hydroxy-1-hydroxymethyl-ethyl)-carbamic acid tert-butyl ester 2-Amino-1,3-propanediol (5.0 g, 54.9 mmol) was dissolved in dry THF (175 ml) and triethylamine (7.7 ml) added. The solution was cooled in an ice-bath and di-tert-butylcarbonate (11.98 g, 54.9 mmol) added in portions over 15 mins. The solution was allowed to warm to ambient temperature and stirred for 90 mins. The solvent was evaporated and water (250 ml) added and the product extracted into ethyl acetate (4*125 ml). The combined organics were washed with brine, dried over magnesium sulphate, filtered and evaporated. The product was isolated by recrystallization from hot ethyl acetate-petrol (1:3) to give shiny flakes 5.18 g (49% yield). The structure was confirmed by 1H NMR (300 MHz, CDCl3): 1.44 (s, 9H), 3.08-3.17 (m, 1H), 3.61-3.84 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With acetic anhydride; In pyridine; ethyl acetate; | Preparation K Acetic acid 3-acetoxy-2-tert-butoxycarbonylamino-propyl ester (2-Hydroxy-1-hydroxymethyl-ethyl)-carbamic acid tert-butyl ester (5.0 g, 26.1 mmol) was dissolved in pyridine (50 ml) and acetic anhydride (50 ml) was added. The solution was stirred at ambient temperature for 24 h when TLC showed no starting material remained. The solvent was evaporated and the residue dissolved in ethyl acetate (120 ml) and washed with dilute hydrochloric acid (3*50 ml), sodium bicarbonate solution (50 ml), brine, dried over magnesium sulphate, filtered and evaporated to give a colourless oil (7.2 g, 99% yield). The structure was confirmed by 1H NMR (300 MHz, CDCl3): 1.42 (s, 9H), 2.05 (s, 6H), 4.00-4.20 (m, 4H), 4.76-4.88 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With pyridine; In dichloromethane; at -78 - 20℃; for 3h; | <strong>[125414-41-7]N-Boc-serinol</strong> (2.00 g, 10.5 mmol, 1.0 equivalent) was suspended in anhydrous dichloromethane (15 mL) in a round bottom flask (50 mL) and pyridine (5.1 mL, 63.3 mmol, 6.0 equivalents) was added to the suspension. Immediately after the addition of pyridine, N-boc-serinol dissolved to form a homogeneous solution, which was cooled in a dry ice-acetone bath (-78 C). To this cooled reaction mixture, triphosgene (1.78 g, 6.0 mmol, 1.7 equivalents, based on functional equivalents of triphosgene) solution (dissolved in 10 mL of dichloromethane) was added dropwise over 15 minutes. After 1 hour at -78 C, the reaction mixture was allowed to warm to room temperature, and after 2 hours, the reaction was quenched by adding aqueous ammonium chloride solution (10 mL). The organic layer was washed twice with deionized (DI) water (50 mL) and once with 10% NaCl solution (50 mL), and dried using Na2S04. Removal of solvent by vacuum resulted in crude product as a yellow solid (1.82 g, 80%). The crude product was further purified by recrystallization from tetrahydrofuran: diethyl ether (10:90 to 20:80 v/v) (60 mL), resulting in a white crystalline solid (1.29 g, 57%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid; sodium sulfate; In chloroform; toluene; at 20℃; under 760.051 Torr;Inert atmosphere; | Step 3: p-Toluenesulfonic acid (30.6 g, 177.9 mmol) and Na2SO4 (2.528 kg, 17.8 mol) were added to a mixture of (9H-fluoren-9-yl)methyl(3-oxopropyl)carbamate (525 g, 1.778 mol) in toluene (6 L) and CHCl3 (1.8 L) at RT. To the mixture was added tert-butyl(1,3-dihydroxypropan-2-yl)carbamate (251.8 g, 2.133 mol). The reaction mixture was stirred overnight at RT and floccus solid formed. The pH of the reaction mixture was adjusted to 7 by adding anhydrous Na2CO3 and the suspension liquid was decanted from Na2SO4. The floccus solid in the suspension liquid was collected by filtration and washed with DCM (2 L). The solid obtained (100 g) was retrospectively identified as {(2R,5R)-2-[2-(9H-fluoren-9-ylmethoxycarbonylamino)-ethyl]-[1,3]dioxan-5-yl}-carbamic acid tert-butyl ester (anti isomer). LCMS (ESI): m/z=491 [M+23]+. The filtrates were combined and H2O (2 L) and DCM (2 L) were added. The organic phase was separated and the aqueous phase was extracted with DCM (3×500 mL). The combined organic layers were washed with brine (1 L) and dried (Na2SO4), filtered and evaporated. The residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (EA:hexane=1:8 to 1:4) to afford a second crop of product (390 g) as a brown oil. This crop was retrospectively identified as-9:1 mixture of {(2S,5S)-2-[2-(9H-fluoren-9-ylmethoxycarbonylamino)-ethyl]-[1,3]dioxan-5-yl}carbamic acid tert-butyl ester (syn isomer) and {(2R,5R)-2-[2-(9H-fluoren-9-ylmethoxycarbonylamino)-ethyl]-[1,3]dioxan-5-yl}-carbamic acid tert-butyl ester (anti isomer). LCMS (ESI): m/z=491 [M+23]+. | |
With toluene-4-sulfonic acid; sodium sulfate; In chloroform; toluene; at 20℃; under 760.051 Torr;Inert atmosphere; | Step 3: p-Toluenesulfonic acid (30.6 g, 177.9 mmol) and Na2SO4 (2.528 kg, 17.8 mol) were added to a mixture of (9H-fluoren-9-yl)methyl(3-oxopropyl)carbamate (525 g, 1.778 mol) in toluene (6 L) and CHCl3 (1.8 L) at RT. To the mixture was added <strong>[125414-41-7]tert-butyl (1,3-dihydroxypropan-2-yl)carbamate</strong> (251.8 g, 2.133 mol). The reaction mixture was stirred overnight at RT and floccus solid formed. The pH of the reaction mixture was adjusted to 7 by adding anhydrous Na2CO3 and the suspension liquid was decanted from Na2SO4. The floccus solid in the suspension liquid was collected by filtration and washed with DCM (2 L). The solid obtained (100 g) was retrospectively identified as {(2R,5R)-2-[2-(9H-fluoren-9-ylmethoxycarbonylamino)-ethyl]-[1,3]dioxan-5-yl}-carbamic acid tert-butyl ester (anti isomer). LCMS (ESI): m/z=491 [M+23]+. The filtrates were combined and H2O (2 L) and DCM (2 L) were added. The organic phase was separated and the aqueous phase was extracted with DCM (3×500 mL). The combined organic layers were washed with brine (1 L) and dried (Na2SO4), filtered and evaporated. The residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (EA:hexane=1:8 to 1:4) to afford a second crop of product (390 g) as a brown oil. This crop was retrospectively identified as 9:1 mixture of {(2S,5S)-2-[2-(9H-fluoren-9-ylmethoxycarbonylamino)-ethyl]-[1,3]dioxan-5-yl}carbamic acid tert-butyl ester (syn isomer) and {(2R,5R)-2-[2-(9H-fluoren-9-ylmethoxycarbonylamino)-ethyl]-[1,3]dioxan-5-yl}-carbamic acid tert-butyl ester (anti isomer). LCMS (ESI): m/z=491 [M+23]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 40 mg | With toluene-4-sulfonic acid; sodium sulfate; In chloroform; benzene; at 20℃; for 140h; | step 3: 2-[6-[2-Chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-methylsulfanyl-7-oxo-pyrido[2,3-d]pyrimidin-8-yl]acetaldehyde (648 mg, 1.480 mmol) was taken up in dry CHCl3 (20 mL) and PhMe (5 mL) and tert-butyl N-[2-hydroxy-1-(hydroxymethyl)ethyl]carbamate (10.0 equiv., 14.80 mmol, 2.83 g) was added, followed by anhydrous sodium sulfate (10 equiv., 2.10 g) and pTsOH monohydrate (0.1 equiv., 0.148 mmol, 25.7 mg). The resulting reaction mixture was stirred at RT for 44 h and only 25% of product was formed by that time. Additional p-TsOH monohydrate (0.1 equiv., 0.148 mmol, 25.7 mg) was added followed by stirring for 96 h. No appreciable change was noted and the reaction was quenched with sat. NaHCO3 and diluted further with DCM. The phases were separated and the aqueous layer was extracted with DCM (2×). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography (40 g Gold column) eluting with a MeOH/DCM gradient (0-10% MeOH) to afford ca. 40 mg of tert-butyl N-[2-[[6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-methylsulfanyl-7-oxo-pyrido[2,3-d]pyrimidin-8-yl]methyl]-1,3-dioxan-5-yl]carbamate which was used in the next step. LCMS (ESI): m/z=611.2 (M+) |