O-(1,1-Dimethylethyl)-L-threonine 1,1-dimethylethyl ester

Light yellowish liquid

(1) 250 L of double L-threonine and 1750 g of ethylene glycol dimethyl ether were added to 5000 mLThe flask was cooled to -10 to -5 ° C in a three-necked flask, and then 1000 g of trifluoromethanesulfonic acid was added dropwise at -5 to 5 ° C.(2) completed at -15 to -10 was added 1250 g of isobutylene, The reaction temperature was controlled at -15 ° C to -10 ° C for 48 hours;(3) is completed, at -5 to 5 water 2500 grams, The same temperature 20-25percent aqueous ammonia 1500 g to pH = 7.5-8.0, the phase, the water continued to add ethyl 1000ml, 500ml extracted twice, the combined organic phase and then 250ml, 250ml, 250ml washed three times, anhydrous 50 g of sodium sulfate was dried and concentrated to dryness under reduced pressure at 50 ° C to give 360 g of crude product with purity of 95percent (GC), yield of 70.44percent. The crude product can be purified by the following method: 360 g of crude product is added to 1500 g of n-hexane to dissolve with stirring, 5 g of activated carbon is added, decolorized at 25-35 ° C. for 1 hour, filtered, and washed with 150 g of n-hexane. 93.0 g of glacial acetic acid (360 × 95percent ÷ 231.33 × 1.05 × 60 = 88.0 g) was added thereto at 15-25 ° C, and the mixture was stirred at the same temperature for 2 hours and then slowly cooledThe mixture was stirred at 0 to 5 ° C for 2 hours, centrifuged, and crystallized by rinsing with a small amount of n-hexane. The wet crystals were vacuum dried at 45 ° CAfter the product was 415 g, purity 99.40percent, yield 67.87percent; 415 g of acetate product was added to 800 g of water, stirred and dissolved after adding n-hexane 500ml, sodium bicarbonate was added about 120 g to a pH = 7.5- 8.0, the phases are separated, the aqueous phase is continuously extracted twice with 500 ml of n-hexane, the aqueous phase is discarded, and the organic phases are combined. The organic phase is washed three times with 300 ml of water each, dried over anhydrous sodium sulphate and concentrated under reduced pressure Liquid 326.20 g, purity 99.69percent, yield 67.20percent.General procedure: 10 mmol of amino acid, 4 g of molecular sieves and 20 mL of MTBE was taken in a 50 mL round bottom flask fitted with a septum and cooled to 25 °C. To this solution 30 mmol of sulfuric acid was added very slowly using syringe. Reaction was carried out at 25 °C for given reaction time as shown in Table 5. Reaction was slowly quenched in to 25 mL of saturated aqueous solution of sodium bicarbonate. Organic layer was separated, and aqueous layer was extracted twice with hexane. Combined organic layer was washed with water, dried over sodium sulphate and the solvent was removed by distillation.Example 26 11-Dioxo-3, 3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-alpha-[N-((S)-1-carboxy-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2, 3, 4, 5-tetrahydro-1, 2, 5-benzothiadiazepine 1, 1-Dioxo-3, 3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-alpha-carboxy-4-hydroxybenzyl) carbamoylmethoxy]-2, 3, 4, 5-tetrahydro-1, 2, 5-benzothiadiazepine (Example 18; 100mg, 0.152mmol) was dissolved in 3ml DMF. o-tert-Butyl-(L)-threonine tert-butyl ester (50mg, 0.216mmol) and N-methylmorpholine (34mul, 0.309mmol) were added and the mixture was stirred for 5min. TBTU (60mg, 0.187mmol) was added and the solution was stirred for 30 min. Formic acid (1-2 drops) was added and the mixture was extracted between EtOAc and water. The aqueous phase was washed with EtOAc and the combined organic phases were washed with 2%NaHCO3, brine, dried and concentrated. The intermediate t-butyl ester of the title compound was confirmed; m/z: 869. DCM (3ml) and TFA (0.5ml) were added and the solution was stirred overnight. The mixture was concentrated and purified by preparative HPLC on a C8 column (50x250mm). A gradient (20/80 to 50/50) of MeCN/0.1M ammonium acetate buffer was used as eluent. Lyophilization gave the title compound in 61% yield (71mg). NMR (400MHz) 0.78 (t, 6H), 0.93 (d, 3H), 1.0-1.22 (m, 6H), 1.25-1.4 (m, 2H), 1.4-1.52 (m, 2H), 1.55-1.7 (m, 2H), 2.1 (s, 3H), 3.95 (brs, 2H), 4.18-4.25 (m, 1H), 4.35 (d, 1H), 4.63 (ABq, 2H), 5.53 (s, 1H), 6.57 (s, 1H), 6.75 (d, 2H), 7.03 (t, 1H), 7.2 (d, 2H), 7.23-7.37 (m, 5H); m/z: 757.1, 1-Dioxo-3, 3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-alpha-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoymethoxy)-2, 3, 4, 5-tetrahydro-1, 2, 5-benzothiadiazepine 1, 1-Dioxo-3, 3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-alpha-carboxybenzyl) carbamoylmethoxy]-2, 3, 4, 5-tetrahydro-1, 2, 5-benzothiadiazepine (Example 25; 50mg, 0.078mmol) was dissolved in 1ml DMF and 1ml DCM. o-tert-Butyl-(L)-threonine tert-butyl ester (22mg, 0.095mmol) and N-methylmorpholine (17mul, 0.154mmol) were added and the mixture was stirred for 20min. TBTU (30mg, 0.093mmol) was added and the solution was stirred for 2 hours and concentrated. DCM (20ml) was added and the solution was washed with 10ml brine, dried and concentrated to 3ml. The intermediate ester was confirmed; m/z: 853. TFA (0.5ml) was added and the solution was stirred overnight. Additionally 0.5ml TFA was added and after 3h the mixture was concentrated and purified by preparative HPLC on a C8 column (50x250mm). A gradient (20/80 to 60/40) of MeCN/0.1M ammonium acetate buffer was used as eluent. Lyophilization gave the title compound in 61 % yield (36mg). NMR (400MHz) 0.8 (t, 6H), 0.9 (d, 3H), 1.0-1.2 (m, 6H), 1.25-1.4 (m, 2H), 1.4-1.5 (m, 2H), 1.55-1.7 (m, 2H), 2.1 (s, 3H), 3.95 (brs, 2H), 4.15-4.25 (m, 1H), 4.35 (d, 1H), 4.6 (ABq, 2H), 5.65 (s, 1H), 6.6 (s, 1H), 7.05 (t, 1H), 7.1 (d, 2H), 7.15-7.4 (m, 6H), 7.5 (d, 2H); m/z: 741.

Molecular Weight:231.33
XLogP3:1.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:6
Exact Mass:231.18344366
Monoisotopic Mass:231.18344366
Topological Polar Surface Area:61.6
Heavy Atom Count:16
Complexity:238
Defined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes