[ CAS No. 154127-42-1 ] {[proInfo.proName]}

Name: 154127-42-1|(S)-4-Hydroxy-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide 1,1-dioxide|97%
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Quality Control of [ 154127-42-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 154127-42-1 ]

SDS Specification

Alternatived Products of [ 154127-42-1 ]

Product Details of [ 154127-42-1 ]

CAS No. :	154127-42-1	MDL No. :	MFCD09033313
Formula :	C₁₀H₁₆N₂O₆S₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UHIWBQIWXWWDKT-MRVPVSSYSA-N
M.W :	356.44	Pubchem ID :	15225314
Synonyms :

Calculated chemistry of [ 154127-42-1 ]

Physicochemical Properties

Num. heavy atoms :	21
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.6
Num. rotatable bonds :	5
Num. H-bond acceptors :	8.0
Num. H-bond donors :	2.0
Molar Refractivity :	79.55
TPSA :	172.0 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-9.11 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.61
Log Po/w (XLOGP3) :	-0.89
Log Po/w (WLOGP) :	0.93
Log Po/w (MLOGP) :	-1.93
Log Po/w (SILICOS-IT) :	-0.47
Consensus Log Po/w :	-0.35

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	1.0
Egan :	1.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.34
Solubility :	16.5 mg/ml ; 0.0462 mol/l
Class :	Very soluble
Log S (Ali) :	-2.24
Solubility :	2.05 mg/ml ; 0.00576 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.54
Solubility :	10.3 mg/ml ; 0.0289 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	4.12

Safety of [ 154127-42-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 154127-42-1 ]

* 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.

Upstream synthesis route of [ 154127-42-1 ]
Downstream synthetic route of [ 154127-42-1 ]

[ 154127-42-1 ] Synthesis Path-Upstream 1~6

1
[ 1245550-91-7 ]
[ 154127-42-1 ]

Yield	Reaction Conditions	Operation in experiment
65.2%	Stage #1: With (-)-chlorodiisopinocampheylborane In hexane; tert-butyl methyl ether at -40 - -20℃; Inert atmosphere Stage #2: With sodium hydroxide In hexane; tert-butyl methyl ether; water at 25 - 30℃;	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 -40⁰C and (+)-diisopinocamphenylborane (DIPCI) (762g (60-65percent in hexane solution), 1.063 moles) was added via a cannula over a period of 30 minutes. A rise in temperature (upto -30⁰C) was observed. The reaction mixture was maintained at -25 to -2O⁰C for 3.0 to 4.0 h and monitored by TLC [mobile phase ethyl acetate: hexane, 3:7].After completion of the reduction, 1 M aqueous sodium hydroxide solution (20 vol) was added from an addition funnel over a period of 15-20 minutes, The reaction mixture was stirred at 25-30°C overnight and monitored by TLC[Mobile phase Ethyl acetate: hexane, 1 :1] for completion. After completion, the aqueous and organic phases were separated and the aqueous phase was extracted with t-butyl methyl ether (4.0 vol), acidified to pH 1 using 5N hydrochloric acid solution and extracted with ethyl acetate (3 x 6.0 vol). The combined ethyl acetate extracts were washed with saturated brine solution(2 x 2.5 vol), dried over sodium sulphate and filtered. The organic layer was distilled completely (below 50⁰C) under reduced pressure. The crude product obtained was a pale yellow colored syrup.Yield of compound (VIl): 112 g (65.2percent)Alternatively, step (f) may also be carried out using a non-chiral reducing agent such as sodium tetrahydroborane. In this case, subsequent optical resolution steps, i.e. removal of undesired isomer, have to be carried out.

Reference： [1] Patent: WO2010/103115, 2010, A1, . Location in patent: Page/Page column 15-16

2
[ 1029324-91-1 ]
[ 154127-42-1 ]

Yield	Reaction Conditions	Operation in experiment
60%	Stage #1: With sec.-butyllithium In tetrahydrofuran; cyclohexane at -5 - 0℃; for 8.75 h; Inert atmosphere Stage #2: With sulfur dioxide In tetrahydrofuran; cyclohexane at -65 - 20℃; Inert atmosphere Stage #3: With sodium acetate trihydrate; hydroxylamine-O-sulfonic acid In water at 0 - 20℃;	Method 2 3,4-Dihydro-4(S)-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide (IX) A solution of the compound from step F (58 g, 0.21 moles) in tetrahydrofuran (1000 ml) was cooled to -5 to 0° C. under nitrogen atmosphere. Sec-butyl lithium (464 ml of 1.4 M solution in cyclohexane) was added to the above solution over 45 min while maintaining the temperature at -5 to 0° C. The mixture was stirred for 8 hours at the temperature less than 0° C. and cooled to -65° C. and sulfur dioxide gas was bubbled through reaction mass at -65° C. till the reaction mixture is acidic. The reaction mixture was stirred overnight while warming it to ambient temperature. The reaction mixture was concentrated to dryness on rotary evaporator to get the lithium sulfinate salt, which was further dissolved in cold water (1160 ml) and washed with ethyl acetate (580 ml). Sodium acetate trihydrate (142.8 g, 1.05 moles) was added and the solution was cooled to 0 to 5° C. Hydroxylamine-O-sulfonic acid (101 g, 0.89 mol) was added slowly to reaction mass below 5° C. The reaction mass was stirred at ambient temperature overnight. The reaction mixture was extracted with ethyl acetate (2*1200 ml)) and the combined extracts were washed with sodium carbonate solution, brine and dried over sodium sulfate. Evaporation to dryness gave a viscous oily compound which was further stirred with dichloromethane (250 ml) to get solid. The product was isolated by filtration. The product was further washed with Dichloromethane, dried in air to yield compound of the formula compound IX (45 g, 60percent).

Reference： [1] Patent: US2010/9977, 2010, A1, . Location in patent: Page/Page column 11

3
[ 160982-13-8 ]
[ 154127-42-1 ]

Reference： [1] Organic Process Research and Development, 1999, vol. 3, # 2, p. 114 - 120

4
[ 154127-41-0 ]
[ 111-42-2 ]
[ 154127-42-1 ]

Reference： [1] Patent: US5378703, 1995, A,

5
[ 36157-40-1 ]
[ 154127-42-1 ]

Reference： [1] Organic Process Research and Development, 1999, vol. 3, # 2, p. 114 - 120

6
[ 160982-09-2 ]
[ 154127-42-1 ]

Reference： [1] Organic Process Research and Development, 1999, vol. 3, # 2, p. 114 - 120

[ 154127-42-1 ] Synthesis Path-Downstream 1~21

1
[ 154127-42-1 ]
[ 75-04-7 ]
[ 154127-05-6 ]

Yield	Reaction Conditions	Operation in experiment
950 mg (34%)	With hydrogenchloride; sodium hydrogencarbonate; triethylamine; In ethanol; p-toluenesulfonyl chloride;	Step J: (+)-4-Ethylamino-3,4-dihydro-2-(3-methoxy)propyl-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide hydrochloride To a solution of the product from Step I (2.4 g, 6.74 mmol) and triethylamine (3.8 mL, 27 mmol) in anhydrous tetrahydrofuran (20 mL) cooled to -20 C. was added tosyl chloride (2.6 g, 13.5 mmol); this mixture was allowed to warm to room temperature and stirred for 18 hr. The reaction mixture was cooled to -60 C. and ethylamine (10 mL) was added and the mixture was again allowed to warm to room temperature. After 18 hr the reaction mixture was diluted with ethyl acetate (200 mL), washed with a saturated aqueous solution of sodium bicarbonate (3*50 mL), dried (MgSO4), and evaporated to give the crude product which was purified by column chromatography [silica; CH3 OH/CH2 Cl2 (20:1)] to give 1.3 g (52%) of the desired amine. The free base was dissolved in ethanol (5 mL) and treated with a 2M solution of hydrochloric acid in ethanol (4 mL) at room temperature. Evaporation of the solvent provided a solid which was recrystallized from methanol: methylene chloride to give 950 mg (34%) of the desired product; mp 175-177 C.; [~]D +10.35 (C=1.00, H2 O). Analysis. Calculated for C12 H22 ClN3 O5 S3: C, 34.32; H, 5.28; N, 10.00 Found: C, 34.26; H, 5.23; N, 9.92.

Reference： [1]Patent: US5378703,1995,A

2
[ 154127-41-0 ]
[ 111-42-2 ]
[ 154127-42-1 ]

Yield	Reaction Conditions	Operation in experiment
2.4 g (92%)	In tetrahydrofuran;	Step I: (S)-3,4-Dihydro-4-hydroxy-2-(3-methoxy)propyl-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-di oxide To a solution of the product of Step H (2.6 g, 7.34 mmol) in THF (30 mL) at -78 C. was added a solution of (+)-beta-chlorodiisopinocampheylborane (11.8 g, 36.7 mmol) in THF (10 mL). The reaction mixture was allowed to warm to -20 C. and kept at this temperature for 4 days. Diethanolamine (4.2 mL, 44 mmol) was added to the reaction mixture and the solution stirred for 30 min, diluted with EtOAc (150 mL), washed with water (250 mL) and brine (250 mL), dried (MgSO4), and evaporated to a syrup which was purified by column chromatography [silica; CH30 OH/CH2 Cl2 (20:1)] to give 2.4 g (92%) of the desired compound as a colorless foam.

Reference： [1]Patent: US5378703,1995,A

3
[ 154127-42-1 ]
[ 75-04-7 ]
[ 138890-62-7 ]

Yield	Reaction Conditions	Operation in experiment
		Step H: 4(R)-ethylamino-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-l,2- thiazine-6-sulfonamide- 1,1 -dioxide (I); To a solution of IX (41 g, 0.12 moles) and triethylamine (33 ml. 0.24 moles) in anhydrous tetrahydrofuran (615 ml) cooled to 0 to 5 C was added a solution of tosyl chloride (44 g, 0.24 moles) in tetrahydrofuran (205 ml). The mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was cooled to 0 to 50C and ethylamine gas was purged from its 70% aqueous solution (365 ml) below 10C. Reaction mixture was allowed to attain ambient temperature and stirred for 36 hours. The reaction <n="28"/>mixture was concentrated and ethyl acetate (615 ml) was added to it. Further the organic layer was washed with water (410 ml). The concentrated ethyl acetate layer and MDC (615 ml) was added followed by cooling to temperature 0 to 50C and 6M hydrochloric acid (600 ml) was added. The reaction mixture was stirred for 1 h at 15 to 20C. Aqueous layer was washed with MDC (205 ml). pH of the aqueous solution was adjusted to 8 using sodium bicarbonate solution causing white solid to precipitate which was extracted with ethyl acetate (2 x 410 ml). The ethyl acetate layer was evaporated to dryness to yield crude Brinzolamide (29g, 66%). Material was recrystallized from ethanol. [Purity: greater than 99.5%, m.p. 125-1270C]
		To a solution of IX (41 g, 0.12 moles) and triethylamine (33 ml. 0.24 moles) in anhydrous tetrahydrofuran (615 ml) cooled to 0 to 5 C. was added a solution of tosyl chloride (44 g, 0.24 moles) in tetrahydrofuran (205 ml). The mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was cooled to 0 to 5 C. and ethylamine gas was purged from its 70% aqueous solution (365 ml) below 10 C. Reaction mixture was allowed to attain ambient temperature and stirred for 36 hours. The reaction mixture was concentrated and ethyl acetate (615 ml) was added to it. Further the organic layer was washed with water (410 ml). The concentrated ethyl acetate layer and MDC (615 ml) was added followed by cooling to temperature 0 to 5 C. and 6M hydrochloric acid (600 ml) was added. The reaction mixture was stirred for 1 h at 15 to 20 C. Aqueous layer was washed with MDC (205 ml). pH of the aqueous solution was adjusted to 8 using sodium bicarbonate solution causing white solid to precipitate which was extracted with ethyl acetate (2*410 ml). The ethyl acetate layer was evaporated to dryness to yield crude Brinzolamide (29 g, 66%). Material was recrystallized from ethanol. [Purity: greater than 99.5%, m.p. 125-127 C.]

Reference： [1]Patent: WO2008/62463,2008,A2 .Location in patent: Page/Page column 26-27
[2]Patent: US2010/9977,2010,A1 .Location in patent: Page/Page column 11-12

4
C₁₀H₁₄NO₆S₃^(1-)*Li⁽¹⁺⁾ [ No CAS ]
[ 154127-42-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium acetate; hydroxylamine-O-sulfonic acid; In water; at 0 - 20℃;	Step G: 3,4-dihydro-4(S)-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e]- 1 ,2-thiazine-6- sulfonamide- 1,1 -dioxide (IX); Method 1; A solution of the compound from step F (58 g, 0.21 moles) in tetrahydrofuran (1500ml) was cooled to -60C under nitrogen atmosphere. n-Butyl lithium (1160 ml of 1.6 M hexane solution) was added to the above solution over 45 min while maintaining the temperature below -60C. The mixture was stirred for 8 hours at the same temperature and sulfur dioxide gas was bubbled through reaction mass at -65C till the reaction mixture is acidic. The reaction mixture was stirred overnight while warming it to ambient temperature. The reaction mixture was concentrated to dryness on rotary evaporator to get the lithium sulfinate salt, which was further dissolved in cold water (1160 ml) and washed with ethyl acetate (580 ml). Sodium acetate trihydrate (285 g, 2.1 moles) was added and the solution was cooled to 0 to 5C. Hydroxylamine-O-sulfonic acid (189 g, 1.67mol) was added slowly to reaction mass below 50C. The reaction mass was stirred at ambient temperature overnight. The reaction mixture was extracted with ethyl acetate (2 x 1200 ml) and the combined extracts were washed with sodium bicarbonate solution, brine and dried over sodium sulfate. Evaporation to dryness gave a viscous oily compound which was purified by column chromatography to yield compound of formula IX (41 g, <n="27"/>%).; Method 2; 3 ,4-Dihydro-4(S)-hydroxy-2-(3-methoxypropyl)-2H-thieno [3 ,2-e] - 1 ,2-thiazine-6- sulfonamide- 1,1 -dioxide (IX); A solution of the compound from step F (58 g, 0.21 moles) in tetrahydrofuran (1000ml) was cooled to -5 to 0C under nitrogen atmosphere. Sec-butyl lithium (464 ml of 1.4 M solution in cyclohexane) was added to the above solution over 45 min while maintaining the temperature at -5 to O0C. The mixture was stirred for 8 hours at the temperature less than 00C and cooled to -650C and sulfur dioxide gas was bubbled through reaction mass at -65C till the reaction mixture is acidic. The reaction mixture was stirred overnight while warming it to ambient temperature. The reaction mixture was concentrated to dryness on rotary evaporator to get the lithium sulfinate salt, which was further dissolved in cold water (1160 ml) and washed with ethyl acetate (580 ml). Sodium acetate trihydrate (142.8 g, 1.05 moles) was added and the solution was cooled to 0 to 5 "C. Hydroxylamine-O- sulfonic acid (101 g, 0.89mol) was added slowly to reaction mass below 50C. The reaction mass was stirred at ambient temperature overnight. The reaction mixture was extracted with ethyl acetate (2 x 1200 ml)) and the combined extracts were washed with sodium carbonate solution, brine and dried over sodium sulfate. Evaporation to dryness gave a viscous oily compound which was further stirred with dichloromethane (250ml) to get solid. The product was isolated by filtration. The product was further washed with Dichloromethane, dried in air to yield compound of the formula compound IX (45 g, 60%).

Reference： [1]Patent: WO2008/62463,2008,A2 .Location in patent: Page/Page column 25-26

5
[ 1029324-91-1 ]
[ 154127-42-1 ]

Yield	Reaction Conditions	Operation in experiment
60%		Method 2 3,4-Dihydro-4(S)-hydroxy-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide (IX) A solution of the compound from step F (58 g, 0.21 moles) in tetrahydrofuran (1000 ml) was cooled to -5 to 0 C. under nitrogen atmosphere. Sec-butyl lithium (464 ml of 1.4 M solution in cyclohexane) was added to the above solution over 45 min while maintaining the temperature at -5 to 0 C. The mixture was stirred for 8 hours at the temperature less than 0 C. and cooled to -65 C. and sulfur dioxide gas was bubbled through reaction mass at -65 C. till the reaction mixture is acidic. The reaction mixture was stirred overnight while warming it to ambient temperature. The reaction mixture was concentrated to dryness on rotary evaporator to get the lithium sulfinate salt, which was further dissolved in cold water (1160 ml) and washed with ethyl acetate (580 ml). Sodium acetate trihydrate (142.8 g, 1.05 moles) was added and the solution was cooled to 0 to 5 C. Hydroxylamine-O-sulfonic acid (101 g, 0.89 mol) was added slowly to reaction mass below 5 C. The reaction mass was stirred at ambient temperature overnight. The reaction mixture was extracted with ethyl acetate (2*1200 ml)) and the combined extracts were washed with sodium carbonate solution, brine and dried over sodium sulfate. Evaporation to dryness gave a viscous oily compound which was further stirred with dichloromethane (250 ml) to get solid. The product was isolated by filtration. The product was further washed with Dichloromethane, dried in air to yield compound of the formula compound IX (45 g, 60%).

Reference： [1]Patent: US2010/9977,2010,A1 .Location in patent: Page/Page column 11

6
[ 154127-42-1 ]
[ 7143-01-3 ]
C₁₁H₁₈N₂O₈S₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In tetrahydrofuran; at 0 - 5℃;	Compound (VII) (112g, 0.313 mol) was suspended in tetrahydrofuran (10 vol). Methanesulfonic anhydride (65.7g, 0.374 moles) was added in one lot and stirred. The reaction mixture was cooled to 0-50C and pyridine (2.5 vol) was added slowly over a period of 45 minutes. The reaction was monitored by TLC [Mobile phase dichloromethane: methanol, 9.5:0.5] for completion. As reaction product the intermediate compound (Vila) was obtained.To the above reaction mixture 70% aqueous ethylamine solution (400 ml, 10 vol) was added slowly at 0-5C. After the complete addition, the reaction mixture was stirred at 25-300C for 12.0 h. The reaction is monitored by TLC [Mobile phase dichloromethane: methanol, 9.5:0.5] for completion. The organic layer (ethylamine and tetrahydrofuran mixture) was distilled off completely below 500C under reduced pressure. The aqueous phase was acidified with concentrated hydrochloric acid and the pH adjusted to 3.0 at 15-25C. The aqueous phase was extracted with t-butyl methyl ether twice (2 x 2.0 vol) to remove any organic impurities if present. The t-butyl methyl ether layer was extracted with 1 N HCI solution and the layers separated.The aqueous layers were combined, treated with activated charcoal and heated at 65-700C. The contents were stirred at 65-700C for 30 minutes, filtered through hyflo supercel at 65-700C and washed with preheated water(65-700C). The filtrate was cooled to 25-30C and the pH was adjusted to 8 with solid sodium bicarbonate. The reaction mixture was stirred for 12 h for crystallization. If the crystallization did not occur, the reaction mass was filtered through a Bchner funnel, extracted with ethyl acetate (3 x 5.0 vol), dried over sodium sulphate and filtered. The organic layer was distilled completely (below 500C) under reduced pressure. The crude product was obtained as a pale yellow syrup, which was washed with hexane (4 x 1.0 vol) to yield a residue which crystallized to a solid on standing.Yield of crude compound (VIIl): 8Og (66.3%)

Reference： [1]Patent: WO2010/103115,2010,A1 .Location in patent: Page/Page column 16-17

7
[ 1245550-91-7 ]
[ 154127-42-1 ]

Yield	Reaction Conditions	Operation in experiment
65.2%		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 -400C and (+)-diisopinocamphenylborane (DIPCI) (762g (60-65% in hexane solution), 1.063 moles) was added via a cannula over a period of 30 minutes. A rise in temperature (upto -300C) was observed. The reaction mixture was maintained at -25 to -2O0C for 3.0 to 4.0 h and monitored by TLC [mobile phase ethyl acetate: hexane, 3:7].After completion of the reduction, 1 M aqueous sodium hydroxide solution (20 vol) was added from an addition funnel over a period of 15-20 minutes, The reaction mixture was stirred at 25-30C overnight and monitored by TLC[Mobile phase Ethyl acetate: hexane, 1 :1] for completion. After completion, the aqueous and organic phases were separated and the aqueous phase was extracted with t-butyl methyl ether (4.0 vol), acidified to pH 1 using 5N hydrochloric acid solution and extracted with ethyl acetate (3 x 6.0 vol). The combined ethyl acetate extracts were washed with saturated brine solution(2 x 2.5 vol), dried over sodium sulphate and filtered. The organic layer was distilled completely (below 500C) under reduced pressure. The crude product obtained was a pale yellow colored syrup.Yield of compound (VIl): 112 g (65.2%)Alternatively, step (f) may also be carried out using a non-chiral reducing agent such as sodium tetrahydroborane. In this case, subsequent optical resolution steps, i.e. removal of undesired isomer, have to be carried out.

Reference： [1]Patent: WO2010/103115,2010,A1 .Location in patent: Page/Page column 15-16

8
3-acetyl-5-chloro-2-thiophenesulfenamide [ No CAS ]
[ 154127-42-1 ]

Reference： [1]Organic Process Research and Development,1999,vol. 3,p. 114 - 120

9
3-acetyl-5-chloro-2-thiophenesulfonamide [ No CAS ]
[ 154127-42-1 ]

Reference： [1]Organic Process Research and Development,1999,vol. 3,p. 114 - 120

10
3-(2-Bromoacetyl)-5-chloro-thiophene-2-sulfonamide [ No CAS ]
[ 154127-42-1 ]

Reference： [1]Organic Process Research and Development,1999,vol. 3,p. 114 - 120

11
[ 36157-40-1 ]
[ 154127-42-1 ]

Reference： [1]Organic Process Research and Development,1999,vol. 3,p. 114 - 120

12
(S)-3,4-dihydro-6-chloro-4-hydroxy-4H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide [ No CAS ]
[ 154127-42-1 ]

Reference： [1]Organic Process Research and Development,1999,vol. 3,p. 114 - 120

13
[ 160982-09-2 ]
[ 154127-42-1 ]

Reference： [1]Organic Process Research and Development,1999,vol. 3,p. 114 - 120

14
[ 160982-13-8 ]
[ 154127-42-1 ]

Reference： [1]Organic Process Research and Development,1999,vol. 3,p. 114 - 120

15
[ 154127-42-1 ]
[ 138890-62-7 ]

Reference： [1]Organic Process Research and Development,1999,vol. 3,p. 114 - 120
[2]Patent: CN107759618,2018,A
[3]Patent: CN107722043,2018,A
[4]Patent: CN107722043,2018,A

16
[ 154127-42-1 ]
C₂₀H₂₆N₂O₉S₄ [ No CAS ]

Reference： [1]Organic Process Research and Development,1999,vol. 3,p. 114 - 120
[2]Patent: CN107759618,2018,A

17
[ 1445-45-0 ]
[ 154127-42-1 ]
C₁₃H₂₀N₂O₇S₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In acetonitrile; at 78℃; for 5h;	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%.
	In acetonitrile; at 5 - 15℃; for 1h;Inert atmosphere;	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.

Reference： [1]Organic Process Research and Development,1999,vol. 3,p. 114 - 120
[2]Patent: CN107759618,2018,A .Location in patent: Paragraph 0111-0139; 0140-0167; 0168-0192
[3]Patent: CN107722043,2018,A .Location in patent: Paragraph 0082-0084

18
3-acetyl-5-chloro-2-thiophenesulfenyl chloride [ No CAS ]
[ 154127-42-1 ]

Reference： [1]Organic Process Research and Development,1999,vol. 3,p. 114 - 120

19
[ 154127-42-1 ]
[ 4637-24-5 ]
C₁₃H₂₁N₃O₆S₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile; at 5 - 15℃; for 1h;Inert atmosphere;	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.

Reference： [1]Patent: CN107722043,2018,A .Location in patent: Paragraph 0085-0087

20
[ 154127-42-1 ]
C₂₁H₂₉N₃O₈S₄ [ No CAS ]

Reference： [1]Patent: CN107722043,2018,A

21
[ 154127-42-1 ]
C₂₁H₂₉N₅O₉S₄ [ No CAS ]

Reference： [1]Patent: CN107722043,2018,A

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P378
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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.
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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
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H231	May react explosively even in the absence of air at elevated pressure and/or temperature
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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
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H351	Suspected of causing cancer
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H361d	Suspected of damaging the unborn child
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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

[ CAS No. 154127-42-1 ] {[proInfo.proName]}

Quality Control of [ 154127-42-1 ]

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[ 154127-42-1 ] Synthesis Path-Upstream 1~6

[ 154127-42-1 ] Synthesis Path-Downstream 1~21

Related Functional Groups of [ 154127-42-1 ]

Ethers

Alcohols

Amines

Sulfamides

Related Parent Nucleus of [ 154127-42-1 ]

Other Aromatic Heterocycles

Precautionary Statements-General

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Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

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Related Functional Groups of
[ 154127-42-1 ]

Related Parent Nucleus of
[ 154127-42-1 ]