(4S,6S)-4-(乙氨基)-6-甲基-5,6-二氢-4H-噻吩并[2,3-b]硫代吡喃-2-磺酰胺7,7-二氧化物盐酸盐

CAS号：130693-82-2

CAS号130693-82-2, 是Metabolic Enzyme类化合物, 分子量为360.90, 分子式C10H17ClN2O4S3, 标准纯度98%, 毕得医药(Bidepharm)提供130693-82-2批次质检（如NMR, HPLC, GC）等检测报告。

(4S,6S)-4-(乙氨基)-6-甲基-5,6-二氢-4H-噻吩并[2,3-b]硫代吡喃-2-磺酰胺7,7-二氧化物盐酸盐 (请以英文为准,中文仅做参考)

(4S,6S)-4-(Ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride , Dorzolamide HCl

货号：BD126858 (4S,6S)-4-(Ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride 标准纯度：, 98%

标准纯度	包装	价格	上海	深圳	天津	武汉	成都	VIP价格	数量

检测信息
批次：
纯度：批次查询可见
COA MS HPLC LC-MS Microanalysis

产品名称 :	(4S,6S)-4-(Ethylamino)-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride , Dorzolamide HCl
中文名称 :	(4S,6S)-4-(乙氨基)-6-甲基-5,6-二氢-4H-噻吩并[2,3-b]硫代吡喃-2-磺酰胺7,7-二氧化物盐酸盐(请以英文为准,中文仅做参考)
CAS号 :	130693-82-2
分子式 :	C₁₀H₁₇ClN₂O₄S₃
线性分子式 :	-
分子量 :	360.90
MDL NO :	MFCD00884659
沸点 :	-
Pubchem ID :	6918132
InChIKey :	OSRUSFPMRGDLAG-QMGYSKNISA-N

常用 :

SDS-BD126858

2D :

3D :

【用途一】

计算化学

Physicochemical Properties

Num. heavy atoms	20
Num. arom. heavy atoms	5
Fraction Csp3	0.6
Num. rotatable bonds	3
Num. H-bond acceptors	6.0
Num. H-bond donors	2.0
Molar Refractivity	80.25
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	151.33 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.0
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.21
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.25
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	-0.05
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.48
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.98

Water Solubility

Log S (ESOL)? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.83
Solubility	0.538 mg/ml ; 0.00149 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.98
Solubility	0.0374 mg/ml ; 0.000104 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.73
Solubility	0.664 mg/ml ; 0.00184 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	Low
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-7.64 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	1.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	1.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	4.28

合成路线：*资料仅供科研用途参考，更多细节请参阅原文出处。

1~20 ►

1. 合成：130693-82-2

N/A

130693-82-2

产率

合成条件

实验步骤

99.2%

Stage #1: With hydrogenchloride; sodium hydroxide In water at 52℃; Inert atmosphere
Stage #2: With hydrogenchloride In water; isopropyl alcohol at 20 - 75℃;

（4S，6S）-4-（乙基氨基）-5,6-二氢-6-甲基-4H-噻吩并[2,3-b]噻吩-2-磺酰胺-7,7-二氧化物，一氯化物多佐胺盐酸盐氢氧化钠（8.0g，30％）将水溶液加入到反式 - （6S）-4-乙氨基-5,6-二氢-6-甲基-7,7-二氧代-4R-噻吩并[2,3-b]噻喃-2-磺酰胺马来酸盐的悬浮液中在52℃，氮气氛下，将盐（12.0g，27.2mmol）的水（35mL）溶液加入水中。用盐酸（2.3g，31.5％水溶液）将pR调节至7.7，并将混合物用乙酸乙酯（36.1g）稀释。分离各相，水相用乙酸乙酯（24.8g）反萃取。分离各相，合并的有机相用水（10.2g）洗涤并浓缩至约30mL的体积。然后将混合物用异丙醇（26.5g）稀释，继续蒸馏过程。将残余物用异丙醇（33.0g）稀释，并在75℃下向混合物中加入盐酸（4.6g，31.5％水溶液）。将温度升至20℃，过滤固体，用异丙醇（14.6g，2份）洗涤，然后干燥，得到（4S，6S）-4-（乙基氨基）-5,6-二氢-6 - 甲基-4R-噻吩并[2,3-b]噻喃-2-磺酰胺-7,7-二氧化物，一氯化物（8.1g，滴定度99.2％，eelOOpercent）。

8.1 g

Stage #1: With sodium hydroxide In water at 52℃; Inert atmosphere
Stage #2: With hydrogenchloride In water; isopropyl alcohol at 75℃;

实施例10（4S，6S）-4-（乙基氨基）-5,6-二氢-6-甲基-4H-噻吩并[2,3-b]噻喃-2-磺酰胺-7,7-二氧化物，一氯化物多佐胺盐酸钠将氢氧化物（8.0g，30％水溶液）加入到反式 - （6S）-4-乙氨基-5,6-二氢-6-甲基-7,7-二氧代-4H-噻吩并[2,3-b]的悬浮液中。在52℃，氮气氛下，在水（35mL）中的噻喃-2-磺酰胺马来酸盐（12.0g，27.2mmol）。用盐酸（2.3g，31.5％水溶液）将pH调节至7.7，并将混合物用乙酸乙酯（36.1g）稀释。分离各相，水相用乙酸乙酯（24.8g）反萃取。分离各相，合并的有机相用水（10.2g）洗涤并浓缩至约30mL的体积。然后将混合物用异丙醇（26.5g）稀释，继续蒸馏过程。将残余物用异丙醇（33.0g）稀释，并在75℃下将盐酸（4.6g，31.5％水溶液）加入混合物中。将温度升至20℃，过滤并洗涤固体。用异丙醇（14.6g，分2份），然后干燥，得到（4S，6S）-4-（乙基氨基）-5,6-二氢-6-甲基-4H-噻吩并[2,3-b]噻喃 - 2-磺酰胺-7,7-二氧化物，一氯化物（8.1g，滴定度99.2％，ee 100％）。 1H NMR：δH（ppm）（400MHz，DMSO）9.9（bs，1H，-NH2 + Cl-），9.6（bs，1H，-NH2 + Cl-），8.2（s，2H，SO2NH2），8.0（ s，1H，CH），4.7（bs，1H，CH），4.35（m，1H，CH），3.2（bs，1H，NH-CH2），3.0（bs，1H，NH-CH2），2.8（m 1H，CH2），2.6-2.5（m，1H，CH2），1.4（d，3H，J = 6Hz，CH3），1.3（t，3H，J = 7Hz，CH3）。

参考文献：

[1] Patent: WO2014/5943, 2014, A1. Location in patent: Page/Page column 15; 16
[2] Patent: US2015/191485, 2015, A1. Location in patent: Paragraph 0066; 0067

2. 合成：130693-82-2

120279-96-1

130693-82-2

产率

合成条件

实验步骤

95%

With hydrogenchloride In ethyl acetate

实施例10（4S-反式）-4-（N-乙基氨基）-5,6-二氢-6-甲基-4H-噻吩 - （2,3-b） - 噻喃-2-磺酰胺-7,7-二氧化物盐酸盐 [CHEMMOL-00030] 0.55g（0.0017mol）（4S-反式）-4-（N-乙基氨基）-5,6-二氢-6-甲基-4H-噻吩 - （2,3）将-b） - 噻喃-2-磺酰胺-7,7-二氧化物溶于25ml乙酸乙酯中，用盐酸将pH调至1。将粗产物浓缩至干，得到0.62g（95％）标题产物，旋转能力为[α] D = -8.3°（c = 1，甲醇）。

参考文献：

[1] Patent: US2003/220509, 2003, A1. Location in patent: Page/Page column 12
[2] Patent: US2004/198805, 2004, A1. Location in patent: Page/Page column 1; 2

3. 合成：130693-82-2

N/A

130693-82-2

产率

合成条件

实验步骤

22.48%

Stage #1: Heating / reflux
Stage #2: With sodium hydrogencarbonate In water
Stage #3: With hydrogenchloride In ethanol

将实施例8的化合物（15gmψ.0462mol）和二对甲苯甲酰-D-酒石酸一水合物（4.55g，0.01125mol）在正丙醇（1600ml）中的混合物加热至沸腾并通过热溶液过滤。带有一层木炭的助滤垫。通过煮沸至约（400ml）的体积浓缩滤液，然后使其结晶。静置过夜后，滤出晶体，用正丙醇（400ml）将材料再结晶两次，得到游离碱与酸的2：1盐。将来自该重结晶的组合母液保存用于阶段B.然后用饱和碳酸氢钠溶液处理盐，并用乙酸乙酯萃取混合物。将有机萃取物干燥，过滤并浓缩至干，得到（3.2gm）游离碱。盐酸盐由5.6N HCl乙醇制备，并从甲醇 - 异丙醇中结晶，得到（2.83g）（+）异构体，SOR 8.23（C 0.9甲醇）M.P。 283-250℃。将合并的母液用饱和碳酸氢钠溶液处理，并将混合物用乙酸乙酯萃取。将有机萃取液干燥，过滤并浓缩至干。将残余物用二对甲苯甲酰-L-酒石酸一水合物（4.55克，0.01125摩尔）在正丙醇（1600毫升）中处理，通过前述方法分离异构体，得到标题化合物（I）（3.75克），22.48％）SOR = -8.34（C 1，甲醇）MP 283至285°C。

参考文献：

[1] Patent: WO2006/70387, 2006, A1. Location in patent: Page/Page column 14

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合成路线

1. 合成：130693-82-2

N/A

130693-82-2

产率

合成条件

实验参考步骤

99.2%

Stage #1: With hydrogenchloride; sodium hydroxide In water at 52℃; Inert atmosphere
Stage #2: With hydrogenchloride In water; isopropyl alcohol at 20 - 75℃;

8.1 g

Stage #1: With sodium hydroxide In water at 52℃; Inert atmosphere
Stage #2: With hydrogenchloride In water; isopropyl alcohol at 75℃;

参考文献：

[1] Patent: WO2014/5943, 2014, A1. Location in patent: Page/Page column 15; 16
[2] Patent: US2015/191485, 2015, A1. Location in patent: Paragraph 0066; 0067

2. 合成：130693-82-2

120279-96-1

130693-82-2

产率

合成条件

实验参考步骤

95%

With hydrogenchloride In ethyl acetate

参考文献：

[1] Patent: US2003/220509, 2003, A1. Location in patent: Page/Page column 12
[2] Patent: US2004/198805, 2004, A1. Location in patent: Page/Page column 1; 2

3. 合成：130693-82-2

N/A

130693-82-2

产率

合成条件

实验参考步骤

22.48%

Stage #1: Heating / reflux
Stage #2: With sodium hydrogencarbonate In water
Stage #3: With hydrogenchloride In ethanol

参考文献：

[1] Patent: WO2006/70387, 2006, A1. Location in patent: Page/Page column 14

4. 合成：130693-82-2

1227941-29-8

130693-82-2

产率

合成条件

实验参考步骤

100%

Stage #1: With sodium hydrogencarbonate In water; ethyl acetate at 25 - 30℃; for 0.25 h;
Stage #2: With hydrogenchloride In ethyl acetate; isopropyl alcohol at 25 - 85℃; for 12.50 h;

实施例7制备5,6-二氢-4H-4-乙基氨基-6-甲基噻吩并[2,3-b]噻喃-2-磺酰胺-7,7-二氧化物盐酸盐（a）多佐胺二对甲苯甲酰-L-将实施例6中制备的酒石酸盐（44.26克，0.085摩尔）加入乙酸乙酯（557.0毫升）中，用饱和碳酸氢钠溶液碱化。将反应物料在25℃至30℃下搅拌15分钟，并将水层用乙酸乙酯（278ml X 2）萃取。合并有机层，用盐水溶液洗涤，用硫酸钠干燥，并炭化。向澄清溶液中加入IPA + HCL（16.35ml，0.089摩尔），搅拌30分钟，通过在大气压下在85℃下蒸馏至约280ml体积除去乙酸乙酯，冷却至25-30℃，搅拌在相同温度下12小时并过滤得到26.0克盐酸多佐胺。反式（ - ）多佐胺盐酸盐> 99.5％反式（+）多佐胺盐酸盐<0.5％顺式异构体<0.1％（b）多佐胺盐酸盐以与来自实施例6（b）的盐的定量收率类似的方式获得。从实施例6（c）的盐以定量收率以类似方式获得多佐胺盐酸盐。

参考文献：

[1] Patent: WO2008/135770, 2008, A2. Location in patent: Page/Page column 21-22
[2] Patent: WO2008/135770, 2008, A2. Location in patent: Page/Page column 22
[3] Patent: WO2011/101704, 2011, A1. Location in patent: Page/Page column 15

5. 合成：130693-82-2

N/A

130693-82-2

参考文献：

[1] Patent: WO2006/38222, 2006, A1. Location in patent: Page/Page column 7

6. 合成：130693-82-2

N/A

130693-82-2

产率

合成条件

实验参考步骤

70%

Stage #1: at 20℃; for 2 - 3 h;
Stage #2: for 3 - 6 h; Heating / reflux

将胺IV的胺化中间体（20g）在惰性气氛下在室温下分批加入到40ml发烟硫酸中。将反应混合物在20°+/- 5℃下搅拌2至3小时。然后一次性加入160ml量的亚硫酰氯，并将所得混合物回流3至6小时。蒸发过量的亚硫酰氯，并将残余物在惰性气氛下分批搅拌成氨水和THF（300-300ml）的混合物，同时保持温度在-5°+/- 5℃。将反应混合物反应75 +/- 15分钟，过滤得到的硫酸铵。然后用两个80ml体积的THF洗涤滤饼，浓缩滤液以除去THF，并用四个300ml体积的乙酸乙酯萃取。合并有机层，浓缩至300ml，充分搅拌，缓慢加入16ml浓盐酸。将浆液搅拌40 +/- 15分钟，过滤，并用两个40ml体积的乙酸乙酯洗涤。将得到的白色固体在50℃下真空干燥。该方法显示出粗多佐胺HCl的产率为70-75％。粗盐从水或异丙醇 - 甲醇的混合物中重结晶。 4R，6S多佐胺的量（RRt 1.09）低于0.1％。

参考文献：

[1] Patent: US2006/155132, 2006, A1. Location in patent: Page/Page column 9; 10
[2] Patent: US2006/155132, 2006, A1. Location in patent: Page/Page column 9; 10

7. 合成：130693-82-2

N/A

130693-82-2

参考文献：

[1] Patent: US2006/142595, 2006, A1. Location in patent: Page/Page column 10

8. 合成：130693-82-2

N/A

130693-82-2

参考文献：