[ CAS No. 200575-16-2 ] {[proInfo.proName]}

Name: 200575-16-2|5-(Chlorosulfonyl)-2-ethoxybenzoic acid|95%
Brand: Ambeed
SKU: A212513
Price: 10.0 USD
Availability: InStock
Rating: 96 (26 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

HazMat Fee +

There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

DV 2D 3D

3d Animation Molecule Structure of 200575-16-2

Structure of 200575-16-2 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 200575-16-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 200575-16-2 ]

SDS Specification

Alternatived Products of [ 200575-16-2 ]

Product Details of [ 200575-16-2 ]

CAS No. :	200575-16-2	MDL No. :	MFCD09701452
Formula :	C₉H₉ClO₅S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UHNRCKXZRULNSC-UHFFFAOYSA-N
M.W :	264.68	Pubchem ID :	11380071
Synonyms :

Calculated chemistry of [ 200575-16-2 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	4
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	57.78
TPSA :	89.05 Å²

Pharmacokinetics

GI absorption :	High
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) :	-6.71 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.44
Log Po/w (XLOGP3) :	1.69
Log Po/w (WLOGP) :	2.79
Log Po/w (MLOGP) :	1.17
Log Po/w (SILICOS-IT) :	1.12
Consensus Log Po/w :	1.64

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-2.56
Solubility :	0.73 mg/ml ; 0.00276 mol/l
Class :	Soluble
Log S (Ali) :	-3.17
Solubility :	0.177 mg/ml ; 0.000668 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.85
Solubility :	0.376 mg/ml ; 0.00142 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.12

Safety of [ 200575-16-2 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	3261
Hazard Statements:	H302-H314	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 200575-16-2 ]

* 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 [ 200575-16-2 ]
Downstream synthetic route of [ 200575-16-2 ]

[ 200575-16-2 ] Synthesis Path-Upstream 1~1

1
[ 134-11-2 ]
[ 200575-16-2 ]

Yield	Reaction Conditions	Operation in experiment
81%	at 0 - 25℃; for 18 h;	Example 1 Preparation of 5-chlorosulphonyl-2-ethoxy benzoic acid (II) In a 250ml three-neck flack, 2-ethoxy benzoic acid (50g, 0.30mol) was added dropwise to an ice-cooled mixtures of sulfoxide dichloride (22 ml, 0.30mol)and chlorosulfonic acid (82.6ml, 1.24mol) under stirring.. At the same time, the temperature of the reacting mixture was kept below 25°C. The resulting mixture was stirred at room temperature for 18 hours and then poured into ice water with stirring, and white deposit appeared.. The reaction mixture was stirred for another 1 hour and filtered, washed with water and dried in vacuum, gave 64.4g of crude product as white solid (II) (yield 81percent).. m.p. 108-110°C.
30 g	at 20 - 25℃; for 16 h;	2-ethoxybenzoic acid (25 g) at 25°C was added to a mixture of thionyl chloride (11 mL), and chlorosulfonic acid (41.3 mL) and the resultant reaction mixture was stirred at RT for 16 h. An off white solid was separated out which is stirred for 1 h. And the reaction mixture was quenched - - with ice (270 g) and water (60 mL). The obtained solid was separated by filtration and solid was washed with water (2xl00mL) and dried under vacuum to afford the title compound as a solid (30 g). 1H NMR (400MHz, CDC1₃) δ = 8.83 (s, 1H), 8.20 (br d, J=8.8 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 4.45 (q, J=6.6 Hz, 2H), 1.64 (t, J=6.6 Hz, 3H), LCMS (M-H) =263.1, purity=95percent.

Reference： [1] Organic Process Research and Development, 2000, vol. 4, # 1, p. 17 - 22
[2] Patent: EP1400522, 2004, A1, . Location in patent: Page 5
[3] Patent: US5955611, 1999, A,
[4] Patent: US6723719, 2004, B1, . Location in patent: Page column 63
[5] Patent: WO2017/85056, 2017, A1, . Location in patent: Page/Page column 54; 55

[ 200575-16-2 ] Synthesis Path-Downstream 1~88

1
[ 103-76-4 ]
[ 200575-16-2 ]
2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 20℃; for 72.0h;	Preparation 39 2-Ethoxy-5-[4-(2-hydroxymethyl)piperazin-1-ylsulphonyl]benzoic Acid N-(2-hydroxyethyl)piperazine (3.40 ml, 28.0 mmol) was added to a solution of <strong>[200575-16-2]2-ethoxy-5-chlorosulphonyl-benzoic acid</strong> (EP 812845 A1) (3.67 g, 14.0 mmol) in ethanol (25 ml) and the reaction mixture stirred at room temperature for 72 hours.. The reaction mixture was concentrated under reduced pressure, the residue suspended in water, acidified to PH 6, and extracted with dichloromethane (3*50 ml).. The combined organic extracts were dried (Na2SO4) and evaporated under reduced pressure.. The residual brown oil was purified by column chromatography on reverse phase polystyrene resin using an elution gradient of water:acetonitrile (100:0 to 80:20) then triturated with acetonitrile to afford the title compound as a white solid, (1.10 g). delta (DMSOd6): 1.37 (3H, t), 2.38 (2H, t), 2.48 (4H, m), 2.84 (4H, m), 3.42 (2H, t), 4.20 (2H, q), 7.35 (1H, d), 7.80 (1H, d), 7.88 (1H, s). LRMS: m/z 359 (M+1)+.
2 g	With triethylamine; In dichloromethane; at 0 - 20℃; for 16.0h;Inert atmosphere;	To a stirred solution of 2-(piperazin-l-yl)ethan-l-ol (740 mg, 5.67 mmol) in CH2CI2 (9 mL) was added triethylamine (4 mL, 28.35 mmol) at 0 C under inert atmosphere. To this, a solution of 5-(chlorosulfonyl)-2-ethoxybenzoic acid (1.5 g, 5.67 mmol) in CH2CI2 (9 mL) was added drop wise at 0 C under inert atmosphere. The reaction mixture was allowed to stir at room temperature for 16 h. After completion of reaction (monitored by LCMS analysis), the reaction mixture was purified by (without work-up) reverse phase column chromatography (C- 18 column, Grace System) by eluting with 0-15% acetonitrile with water to afford the title compound 18 (2.0 g) as an off-white semi solid. 1H NMR (300 MHz, DMSO- ) delta ppm 7.72 - 7.63 (m, 2 H), 7.24 (d, J = 8.4 Hz, 1 H), 4.16 (q, J = 6.9 Hz, 2 H), 3.44 - 3.29 (m, 3 H), 2.83 - 2.78 (m, 4 H), 2.51 - 2.47 (m, 4 H), 2.36 - 2.33 (m, 2 H), 1.34 (t, J = 6.9 Hz, 3 H); LCMS (ESI): m/z 359.0 [M+H+]; purity~95.9%.

Reference： [1]Patent: US6407114,2002,B1 .Location in patent: Page column 28-29
[2]Patent: WO2018/215433,2018,A1 .Location in patent: Page/Page column 79

2
[ 109-01-3 ]
[ 200575-16-2 ]
[ 194602-23-8 ]

Yield	Reaction Conditions	Operation in experiment
	In water; at 10 - 20℃; for 2.0h;	[00343] (a): One-step Procedure [00344] 1-Methylpiperazine (33.6 ml, 0.303 mol) was added to a stirred suspension of the title compound of Preparation 84 (34.4 g, 0.130 mol) in water (124 ml) at about 10 C. whilst maintaining the temperature of the reaction mixture below 20 C. The resulting solution was cooled to about 10 C. and, after 5 minutes, crystallisation of a solid commenced. After a further 2 hours, the solid was collected by filtration, washed with ice-water and dried under vacuum to furnish the crude product (36.7 g). A sample (15.0 g) was purified by stirring it in refluxing acetone for 1 hour; the resulting suspension was allowed to cool to room temperature and the crystalline solid collected by filtration and dried under vacuum to afford the title compound (11.7 g), m.p. 198-199 C. whose 1H nmr spectrum is identical with that obtained for the product of procedure (b) below. [00345] (b): Two-step Procedure [00346] A solution of the title compound of Preparation 84 (50.0 g, 0.189 mol) in acetone (150 ml) was added dropwise to a stirred mixture of 1-methylpiperazine (20.81 g, 0.208 mol) and triethylamine (28.9 ml, 0.207 mol), whilst maintaining the temperature of the reaction mixture below 20 C. A white crystalline solid formed during the addition and stirring was continued for a further 1.5 hours. Filtration, followed by washing with acetone and drying under vacuum of the product, provided the hydrochloride-triethylamine double salt of the title compound (78.97 g), m.p. 166-169 C. Found: C, 51.33; H, 8.14; N, 9.06; Cl, 8.02. C14H20N2O5S; C6H15N; HCl requires C, 51.55; H, 7.79; N, 9.02; Cl, 7.61%. delta (DMSOd6): 1.17 (9H, t), 1.32 (3H, t), 2.15 (3H, s), 2.47 (6H, br s), 2.86 (2H, br s), 3.02 (6H, q), 4.18 (2H, q), 7.32 (1H, d), 7.78 (1H, dd), 7.85 (1H, d). [00347] The double salt (30.0 g) was stirred in water (120 ml) to produce an almost clear solution, from which crystallisation of a solid rapidly occurred. After 2 hours, the solid was collected by filtration, washed with water and dried under vacuum to give the title compound (14.61 g) as a white solid. A reference sample, m.p. 201 C., was obtained by recrystallisation from aqueous ethanol. Found: C, 51.09; H, 6.16; N, 8.43. C14H20N2O5S requires C, 51.21; H, 6.14; N, 8.53%. delta (DMSOd6): 1.31 (3H, t), 2.12 (3H, s), 2.34 (4H, br s), 2.84 (4H, br s), 4.20 (2H, q), 7.32 (1H, d), 7.80 (1H, dd), 7.86 (1H, d).
	In water; at 10 - 20℃; for 2.0h;	To a stirring solution of 5-(chlorosulfonyl)-2-ethoxybenzoic acid (9) (30 g) in water (124 mL) at 10 C, was added N-methyl piperazine (33.6 mL) at 15-20 C. The resultant reaction mixture was stirred at 10 C. After 5 min the title compound started to crystallize and the reaction mixture was stirred for 2 h. The solid was separated by filtration; the solid was washed with water and dried under vacuum. Purification was done by heating in acetone (100 mL) for 1 h. The suspension was cooled to RT, crystallized solid was separated by filtration and dried under vacuum to afford the title compound as a white solid (23 g). 1H NMR (400MHz, DMSO-d6) delta = 7.89 (br d, J=1.9 Hz, 1H), 7.81 (br dd, J=1.9, 8.8 Hz, 1H), 7.35 (br d, J=8.8 Hz, 1H), 4.21 (q, J=6.8 Hz, 2H), 2.87 (br s, 4H), 2.37 (br s, 4H), 2.14 (s, 3H), 1.36 (t, J=7.0 Hz, 3H), LCMS (M+H) =329.1, purity=88%.

Reference： [1]Organic Process Research and Development,2000,vol. 4,p. 17 - 22
[2]Patent: US6723719,2004,B1 .Location in patent: Page column 63
[3]Patent: WO2017/85056,2017,A1 .Location in patent: Page/Page column 55
[4]Science,2019,vol. 363

3
[ 109-01-3 ]
[ 200575-16-2 ]
[ 215299-33-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In acetone; at 20℃; for 1.5h;	[00343] (a): One-step Procedure [00344] 1-Methylpiperazine (33.6 ml, 0.303 mol) was added to a stirred suspension of the title compound of Preparation 84 (34.4 g, 0.130 mol) in water (124 ml) at about 10 C. whilst maintaining the temperature of the reaction mixture below 20 C. The resulting solution was cooled to about 10 C. and, after 5 minutes, crystallisation of a solid commenced. After a further 2 hours, the solid was collected by filtration, washed with ice-water and dried under vacuum to furnish the crude product (36.7 g). A sample (15.0 g) was purified by stirring it in refluxing acetone for 1 hour; the resulting suspension was allowed to cool to room temperature and the crystalline solid collected by filtration and dried under vacuum to afford the title compound (11.7 g), m.p. 198-199 C. whose 1H nmr spectrum is identical with that obtained for the product of procedure (b) below. [00345] (b): Two-step Procedure [00346] A solution of the title compound of Preparation 84 (50.0 g, 0.189 mol) in acetone (150 ml) was added dropwise to a stirred mixture of 1-methylpiperazine (20.81 g, 0.208 mol) and triethylamine (28.9 ml, 0.207 mol), whilst maintaining the temperature of the reaction mixture below 20 C. A white crystalline solid formed during the addition and stirring was continued for a further 1.5 hours. Filtration, followed by washing with acetone and drying under vacuum of the product, provided the hydrochloride-triethylamine double salt of the title compound (78.97 g), m.p. 166-169 C. Found: C, 51.33; H, 8.14; N, 9.06; Cl, 8.02. C14H20N2O5S; C6H15N; HCl requires C, 51.55; H, 7.79; N, 9.02; Cl, 7.61%. delta (DMSOd6): 1.17 (9H, t), 1.32 (3H, t), 2.15 (3H, s), 2.47 (6H, br s), 2.86 (2H, br s), 3.02 (6H, q), 4.18 (2H, q), 7.32 (1H, d), 7.78 (1H, dd), 7.85 (1H, d). [00347] The double salt (30.0 g) was stirred in water (120 ml) to produce an almost clear solution, from which crystallisation of a solid rapidly occurred. After 2 hours, the solid was collected by filtration, washed with water and dried under vacuum to give the title compound (14.61 g) as a white solid. A reference sample, m.p. 201 C., was obtained by recrystallisation from aqueous ethanol. Found: C, 51.09; H, 6.16; N, 8.43. C14H20N2O5S requires C, 51.21; H, 6.14; N, 8.53%. delta (DMSOd6): 1.31 (3H, t), 2.12 (3H, s), 2.34 (4H, br s), 2.84 (4H, br s), 4.20 (2H, q), 7.32 (1H, d), 7.80 (1H, dd), 7.86 (1H, d).

Reference： [1]Patent: US6723719,2004,B1 .Location in patent: Page column 63-64

4
[ 200575-16-2 ]
cis-2,6-dimethylpiperazine [ No CAS ]
2-ethoxy-5-(cis-2,6-dimethypiperazin-4-ylsulphonyl) benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	In water; at 10 - 20℃; for 2.0h;	Example 2 Preparation of 2-ethoxy-5-(cis-2,6-dimethypiperazin-4-ylsulphonyl) benzoic acid (III) In 250ml three-neck flask, 52.6g(0.23mol)of cis-2, 6-dimethylpiperazine was added to the suspension of compound (II) (53g, 0.20mol)in water (170ml) at about 10 C with stirring, at the same time the temperature of reacting mixture was kept below 20C. The reaction was then stirred at 10C for another 2 hours.. The precipitate was filtered, ice-water washed, dried, and refluxed in acetone for 1 hour, and purified, gave 48g compound (III)(yield 70%) as white crystalline, m.p. 260.5-273.0 C (Dec.). HNMR(DMSO) delta: 7.72-7.75(2H, H-4 and H-6 on benzene ring), 7.26-7.28(1H, H-3 on benzene ring),4.12-4.17(2H, -CH2- on -OCH2CH3), 3.5-3.53(2H, -CH2-on piperazine ring), 2.89-2.92(2H, -CH- on piperazine ring), 1.80-1.86(2H, -CH2-on piperazine ring), 1.31-1.34(3H, -CH3 on -OCH2CH3), 1.0-1.04(6H, -CH3 on piperazine ring).

Reference： [1]Patent: EP1400522,2004,A1 .Location in patent: Page 5

5
[ 134-11-2 ]
[ 200575-16-2 ]

Yield	Reaction Conditions	Operation in experiment
81%	With chlorosulfonic acid; thionyl chloride; at 0 - 25℃; for 18.0h;	Example 1 Preparation of 5-chlorosulphonyl-2-ethoxy benzoic acid (II) In a 250ml three-neck flack, 2-ethoxy benzoic acid (50g, 0.30mol) was added dropwise to an ice-cooled mixtures of sulfoxide dichloride (22 ml, 0.30mol)and chlorosulfonic acid (82.6ml, 1.24mol) under stirring.. At the same time, the temperature of the reacting mixture was kept below 25C. The resulting mixture was stirred at room temperature for 18 hours and then poured into ice water with stirring, and white deposit appeared.. The reaction mixture was stirred for another 1 hour and filtered, washed with water and dried in vacuum, gave 64.4g of crude product as white solid (II) (yield 81%).. m.p. 108-110C.
	With chlorosulfonic acid; thionyl chloride; In water;	PREPARATION 1 5-Chlorosulphonyl-2-ethoxybenzoic acid Molten 2-ethoxybenzoic acid (25.0 g, 0.150 mol) was added to a stirred, ice-cooled mixture of thionyl chloride (11 ml, 0.151 mol) and chlorosulphonic acid (41.3 ml, 0.621 mol), whilst maintaining the temperature of the reaction mixture below 25 C. The resulting mixture was stirred at room temperature for 18 hours and then poured into a stirred mixture of ice (270 g) and water (60 ml) to give an off-white precipitate. Stirring was continued for 1 hour, then the product was collected by filtration, washed with water and dried under vacuum to provide the title compound (36.08 g). A reference sample, m.p. 115-116 C., was obtained by crystallisation from hexane:toluene. Found: C,41.02; H,3.27. C9 H9 ClO5 S requires C,40.84; H,3.43%. delta (CDCl3): 1.64(3H,t), 4.45(2H,q), 7.26(1H,d), 8.20(1H,dd), 8.80(1H,d).
	With chlorosulfonic acid; thionyl chloride; at 0 - 25℃; for 18.0h;	[00342] Molten 2-ethoxybenzoic acid (25.0 g, 0.150 mol) was added to a stirred, ice-cooled mixture of thionyl chloride (11 ml, 0.151 mol) and chlorosulphonic acid (41.3 ml, 0.621 mol), whilst maintaining the temperature of the reaction mixture below 25 C. The resulting mixture was stirred at room temperature for 18 hours and then poured into a stirred mixture of ice (270 g) and water (60 ml) to give an off-white precipitate. Stirring was continued for 1 hour, then the product was collected by filtration, washed with water and dried under vacuum to provide the title compound (36.08 g). A reference sample, m.p. 115-116 C. was obtained by crystallisation from hexane:toluene. Found: C, 41.02; H, 3.27. C9H9ClO5S requires C, 40.84; H, 3.43%. delta (CDCl3): 1.64 (3H, t), 4.45 (2H, q), 7.26 (1H, d), 8.20 (1H, dd), 8.80 (1H, d).

30 g

With chlorosulfonic acid; thionyl chloride; at 20 - 25℃; for 16.0h;

2-ethoxybenzoic acid (25 g) at 25C was added to a mixture of thionyl chloride (11 mL), and chlorosulfonic acid (41.3 mL) and the resultant reaction mixture was stirred at RT for 16 h. An off white solid was separated out which is stirred for 1 h. And the reaction mixture was quenched - - with ice (270 g) and water (60 mL). The obtained solid was separated by filtration and solid was washed with water (2xl00mL) and dried under vacuum to afford the title compound as a solid (30 g). 1H NMR (400MHz, CDC13) delta = 8.83 (s, 1H), 8.20 (br d, J=8.8 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 4.45 (q, J=6.6 Hz, 2H), 1.64 (t, J=6.6 Hz, 3H), LCMS (M-H) =263.1, purity=95%.

Reference： [1]Organic Process Research and Development,2000,vol. 4,p. 17 - 22
[2]Patent: EP1400522,2004,A1 .Location in patent: Page 5
[3]Patent: US5955611,1999,A
[4]Patent: US6723719,2004,B1 .Location in patent: Page column 63
[5]Patent: WO2017/85056,2017,A1 .Location in patent: Page/Page column 54; 55
[6]Science,2019,vol. 363

Yield	Reaction Conditions	Operation in experiment
		Active-site-directed modification of subtilisin. J. Am. Chem. Soc. (1991), 113(6), 2259-63. CODEN: JACSAT; ISSN: 0002-7863. CAN 114:123036 CAPLUS. [2] 5-Chlorosulfonyl-2-ethoxy-benzoic acid:
		(a): One-step Procedure 1-Methylpiperazine (33.6 ml, 0.303 mol) was added to a stirred suspension of the title compound of Preparation 1 (34.4 g, 0.130 mol) in water (124 ml) at about 10 C., whilst maintaining the temperature of the reaction mixture below 20 C.
		The double salt (30.0 g) was stirred in water (120 ml) to produce an almost clear solution, from which crystallisation of a solid rapidly occurred. After 2 hours, the solid was collected by filtration, washed with water and dried under vacuum to give the title compound (14.61 g) as a white solid. A reference sample, m.p. 201 C., was obtained by recrystallisation from aqueous ethanol. Found: C,51.09; H,6.16; N,8.43. C14 H20 N2 O5 S requires C,51.21; H,6.14; N,8.53%. delta (CD3 SOCD3): 1.31(3H,t), 2.12(3H,s), 2.34(4H,br s), 2.84(4H, br s), 4.20(2H,q), 7.32(1H,d), 7.80(1H,dd), 7.86(1H,d).

7
[ 200575-16-2 ]
[ 100-46-9 ]
2-ethoxy-5-(benzylamidosulfonyl)benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In acetone;	(Step 1) Preparation of 2-ethoxy-5-(benzylamidosulfonyl)benzoic Acid To 7.4 ml of benzylamine was added 6 g of <strong>[200575-16-2]2-ethoxy-5-chlorosulfonylbenzoic acid</strong> in acetone at 0 C., and the mixture was stirred below 20 C. for 3 hours. Acetone was removed by evaporation, the residue was diluted with dichloromethane and extracted with saturated sodium bicarbonate solution. The product was re-extracted with dichloromethane after acidifying the extracted aqueous bicarbonate layer with HCl. The saturated brine, dried over anhydrous MgSO4, and concentrated to give 5.76 g of the desired compound. NMR(CDCl3): 1.58(t, 3H), 4.16(d, 2H), 4.37(q, 2H), 5.01(t, 1H), 7.07(d, 1H), 7.20(m, 5H), 8.00(dd, 1H), 8.60(d, 1H)

Reference： [1]Patent: US6583147,2003,B1

8
[ 109-01-3 ]
[ 200575-16-2 ]
[ 121-44-8 ]
[ 215299-33-5 ]

Reference： [1]Organic Process Research and Development,2000,vol. 4,p. 17 - 22

9
[ 200575-16-2 ]
C₁₇H₂₂N₄O₄S [ No CAS ]

Reference： [1]Organic Process Research and Development,2000,vol. 4,p. 17 - 22

10
[ 200575-16-2 ]
[ 200575-15-1 ]

Reference： [1]Organic Process Research and Development,2000,vol. 4,p. 17 - 22
[2]Science,2019,vol. 363

11
[ 200575-16-2 ]
1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenylsulphoyl]-4-methylpiperazine [ No CAS ]

Reference： [1]Organic Process Research and Development,2000,vol. 4,p. 17 - 22

12
[ 200575-16-2 ]
2-(piperidin-4-yl)ethyl benzoate trifluoroacetic acid salt [ No CAS ]
5-((4-(2-(benzoyloxy)ethyl)piperidin-1-yl)sulfonyl)-2-ethoxybenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With triethylamine; In dichloromethane; at 0 - 20℃; for 12.0h;Inert atmosphere;	To a stirred solution of 35 (4.07 g, 17.49 mmol) in CH2CI2 (40 mL) was added triethylamine (11.10 mL, 79.54 mmol) at room temperature. After addition, a solution of 9 (4.2 g, 15.90 mmol) in CH2CI2 (20 mL) was added dropwise at 0 C under inert atmosphere. The resultant reaction mixture was stirred at room temperature for 12 h. After completion of reaction (monitored by TLC), the reaction mixture was concentrated and diluted with saturated NaHC03 solution (50 mL). The resultant solution was then neutralized with saturated citric acid solution (50 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford Compound 36 (5.78 g, 78%) as a brown solid. *Eta NMR (300 MHz, DMSO-rf6): delta 13.02 (br s, 1H; D20 exchangeable), 7.97 - 7.88 (m, 3H), 7.81 (ddj = 2.4, 8.8 Hz, 1H), 7.68 - 7.60 (m, 1H), 7.55 - 7.46 (m, 2H), 7.33 (dj = 8.8 Hz, 1H), 4.27 (tj = 6.4 Hz, 2H), 4.20 (q, / = 7.0 Hz, 2H), 3.61 (br d, / = 11.7 Hz, 2H), 2.20 (br t, / = 10.8 Hz, 2H), 1.79 (br dj = 11.7 Hz, 2H), 1.63 (qj = 6.4 Hz, 2H), 1.46 -1 41 (m, 1H), 1.35 (tj = 7.0 Hz, 3H), 1.30 - 1.17 (m, 2H); LCMS (ES): m/z 462.2 [M+H+]; purity~95%.
52%	With triethylamine; In dichloromethane; at 0 - 20℃; for 16.0h;Inert atmosphere;	To a stirred solution of 2-(piperidin-4-yl)ethyl benzoate as a TFA salt (980 mg, 2.83 mmol) in CH2CI2 (5 mL) was added triethylamine (1.96 mL, 14.1 mmol) at 0C under inert atmosphere. To this, a solution of 5-(chlorosulfonyl)-2-ethoxybenzoic acid (750 mg, 2.83 mmol) in CH2CI2 (10 mL) was added drop wise at 0 C under inert atmosphere. The reaction mixture was allowed to stir at room temperature for 16 h. After completion of reaction (monitored by TLC & LCMS), the reaction mixture was diluted in CH2CI2 (50 mL), washed with chilled water (10 mL), chilled 10% aqueous citric acid solution (2 X 10 mL), brine (10 mL), dried over Na2S04 and concentrated under reduced pressure to afford the title compound 12 (710 mg, 52% yield) as a white solid. 1H NMR (300 MHz, CDC13) delta ppm 8.49 (d, J= 2.2 Hz, 1 H), 8.08 - 7.83 (m, 3 H), 7.59 - 7.51 (m, 1 H), 7.47 - 7.38 (m, 2 H), 7.14 (d, J = 8.8 Hz, 1 H), 4.49 - 4.25 (m, 4 H), 3.83 - 3.80 (m, 2 H), 2.30 - 2.26 (m, 2 H), 1.84 - 1.82 (m, 2 H), 1.73 - 1.71 (m, 2 H), 1.60 (t, J = 7.1 Hz, 3 H), 1.45 - 1.33 (m, 3 H); LCMS (ESI): m/z 462.4 [M+H+]; purity~96.4%.

Reference： [1]Patent: WO2017/85056,2017,A1 .Location in patent: Page/Page column 92
[2]Patent: WO2018/215433,2018,A1 .Location in patent: Page/Page column 72; 73

13
[ 200575-16-2 ]
3-(piperazin-1-yl)propyl benzoate trifluoroacetate [ No CAS ]
5-(4-(3-(benzoyloxy)propyl)piperazin-1-ylsulfonyl)-2-ethoxybenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With triethylamine; In dichloromethane; at 0 - 20℃; for 16.0h;Inert atmosphere;	To a stirred solution of Compound 44 (8.3 g, 31.43 mmol) in CH2CI2 (60 mL) was added triethylamine (26.5 mL, 188.63 mmol) at room temperature. After addition, a solution of 9 (8.57 g, 34.58 mmol) in CH2CI2 (40 mL) was added dropwise at 0 Cunder inert atmosphere. The resultant reaction mixture was stirred at room temperature for 16 h. After completion of reaction (monitored by TLC), the reaction mixture was concentrated and diluted with saturated NaHC03 solution (50 mL). The resultant solution was washed with ethyl acetate (100 mL). The aqueous solution was then neutralized with saturated - - citric acid solution (100 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title 45 (9.1 g, 60%) as a white solid. *H NMR (400 MHz, CDC13): delta 12. 17 (br s, 1H), 8.35 (d , } = 2.4 Hz, 1H), 7.99 (dj = 7.3 Hz, 2H), 7.86 (dd, / = 2.4, 8.8 Hz, 1H), 7.61 - 7.51 (m, 1H), 7.47 - 7.36 (m, 2H), 7.12 (dj = 8.8 Hz, 1H), 4.43 - 4.26 (m, 4H), 3.21 (br s, 4H), 2.92 (br s, 4H), 2.86 - 2.78 (m, 2H), 2.15 - 2.05 (m, 2H), 1.55 (t, / = 6.8 Hz, 3H); LCMS (ES): m/z 477.2 [M+H+]; purity~97%.

Reference： [1]Patent: WO2017/85056,2017,A1 .Location in patent: Page/Page column 99; 100

14
[ 200575-16-2 ]
1-(2-ethoxy-5-((4-(2-hydroxyethyl)piperazin-1-yl)sulfonyl)benzamido)-4-formyl-3-methyl-5-propyl-1H-pyrrole-2-carboxylic acid [ No CAS ]