2H-Thieno[3,2-e]-1,2-thiazine-6-sulfonamide, 3,4-dihydro-4-hydroxy-2-(3-methoxypropyl)-, 1,1-dioxide, (4S)-

The cyclisation of compound (Vl) may be carried out using a chiral reducing agent such as (+)-diisopinocamphenylborane (DIPCI) in order to obtain the desired isomer of compound (VII) by a stereoselective reduction. Compound (Vl) (21Og, 0.484 moles) was suspended in t-butyl methyl ether (15 vol) and stirred under nitrogen atmosphere. The stirred suspension was cooled to -40Method 2 Prepare a 1L three-vial bottle equipped with a mechanical stirrer, a constant pressure dropping funnel, and an ice water bath.Added compound of formula A (50 g, 0.14 mol) and acetonitrile (250 mL), Under N2 protection, stirring and cooling to 5 ~ 10 C, Then DMF-DMA (17.5 g, 0.147 mol) was added dropwise thereto.The rate of addition is such that the stability of the system does not exceed 15C.After the addition, cooling was removed and the reaction was continued for 1 hour. TLC detected the disappearance of the starting material.Concentrate at normal pressure, recover the solvent and add the residue to DCM.Rotary evaporation is replaced by desolvation, and the mixture is finally dried under high vacuum for 1 hour. The residue is the compound of formula B-2.Can be directly after the subsequent reaction without purificationThe crude product B-2 was obtained in equivalent yield.Compound B (50.0 g, 140.7 mmol) was added to 450 mL of acetonitrile, trimethyl orthoacetate (27.0 g, 225.1 mmol) and triethylamine (1.4 g, 14.0 mmol) were added with stirring, and the mixture was heated to 78C. , stirring for 5h, HPLC monitoring showed complete reaction and the HPLC monitoring results are shown in Table 1 (see FIG. 1).Cool to 40C, distill off under reduced pressure, and concentrate to a minimum volume.Compound C crude product was obtained.The crude compound C was dissolved in 180 mL of tetrahydrofuran, cooled to -10 DEG C, triethylamine (31.3 g, 309.5 mmol) was slowly added dropwise at a drip rate of 1 d/s, and the addition was completed at a drip rate of 3 d/s. 4- A solution of tosyl chloride (53.5 g, 280.6 mmol) in 70 mL of tetrahydrofuran. After the addition, the temperature was controlled at -4C, and the reaction was complete after about 3 hours.At a controlled temperature of 10 C. or less, a 70% aqueous solution of ethylamine (361.0 g, 5.6 M) was slowly added dropwise at a rate of 5 d/s. After the addition, the temperature was kept stirring at 12C and the reaction was complete after about 15 hours.The mixture was concentrated under reduced pressure to 70-80 mL, and the temperature was lowered to 0C. The temperature was controlled below 30C, and concentrated hydrochloric acid (12 mol/L) was added dropwise to adjust the pH to 1 to 2, and then about 14 mL of concentrated hydrochloric acid (12 mol/L) was added. The mixture was stirred at room temperature for 1 hour. The reaction was extracted twice with methyl tert-butyl ether (2*250 mL). The organic phases were combined and extracted once with dilute hydrochloric acid (1 mol/L, 100 mL). Combine the aqueous phases, slowly add sodium bicarbonate solids, adjust the pH to 5-6, add 150 mL of water, and adjust the pH to 7-8 with 7% sodium bicarbonate solution. After adjustment, stir at room temperature for 15 h and slowly crystallize. After filtration, the filter cake was rinsed with 30 mL of water and the cake was dried to obtain 35.4 g of product with a purity of 98.3%.Add 250 mL of dichloromethane, 25 mL of methanol to the filter mother liquor, stir, extract, separate, and concentrate the organic phase to dryness4.6 g of yellow viscous material was added and 10 mL of ethyl acetate was added. Heat to 70 ~ 75 C dissolved, slowly dropped to 0 ~ 10 C, stirring 1 ~ 2h, precipitation of a white solid, continue stirring 3 ~ 4h, filtration, with 3mL water filter cake, filter cake drying, Obtained product 2.4g, purity 97.3%.Combined, the purity was 98.1%, the total yield was 65.3%, the ignition residue was 0.08%, and the chiral purity was 99.7%.Prepare a 1L three-vial bottle equipped with a mechanical stirrer, a constant pressure low liquid funnel, and an ice water bath.Add compound of formula A (100 g, 0.28 mol) and acetonitrile (400 mL), Under N2 protection, stirring and cooling to 5 ~ 10 C, Then drop itTrimethyl orthoacetate(77.3g, 0.64mol), The rate of addition is such that the stability of the system does not exceed 15C.After the addition, remove the cooling and continue the reaction for 1 hour.TLC detected the disappearance of the starting material, creating a slightly more polar new point.Concentrate at normal pressure, recover the solvent and add the residue to DCM.Swirling to replace desolvation, and finally high vacuum drying for 1 hour, The residue is a compound of formula B-1Can be directly used in subsequent reactions without purificationThe reaction gave the crude product B-1 in equivalent yield.

Molecular Weight:356.4
XLogP3:-0.9
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:9
Rotatable Bond Count:5
Exact Mass:356.01704976
Monoisotopic Mass:356.01704976
Topological Polar Surface Area:172
Heavy Atom Count:21
Complexity:567
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes