30165-96-9

Basic information

• Product Name: 3-Chloro-4-morpholino-1,2,5-thiadiazole
• Synonyms: 3-MORPHOLINO-4-CHLORO-1,2,5-THIADIAZOLE;Timolol Related Compound F;4-(4-CHLORO-1,2,5-THIADIAZOL-3-YL)MORPHOLINE;3-Chloro-4-N-morpholine-1,2,5-thiadiazole;3-CHLORO-4-MORPHOLIN-4-YL-1,2,5-THIADIAZOLE;3-CHLORO-4-MORPHOLINO-1,2,5-THIADIAZOLE;3-CHLORO-4-MORPHOLINE-1,2,5-THIADIAZOLE;4-CHLORO-5-MORPHOLINO-2,1,3-THIADIAZOLE
• CAS NO: 30165-96-9
• Molecular Formula: C6H8ClN3OS
• Molecular Weight: 205.67
• EINECS: 250-077-1
• Product Categories: Aromatic Morpholines;Halides;Oxadiazoles & Thiadiazoles;API intermediates;Oxadiazoles & Thiadiazoles;Building Blocks;Halogenated Heterocycles;Heterocyclic Building Blocks;Thiadiazoles;ThiadiazolesHeterocyclic Building Blocks;Heterocycles;Sulfur & Selenium Compounds
• Mol File: 30165-96-9.mol
• Article Data: 7

Chemical Properties

• Melting Point: 44-47 °C(lit.)
• Boiling Point: 307.8 °C at 760 mmHg
• Flash Point: >230 °F
• Appearance: /
• Density: 1.462 g/cm³
• Vapor Pressure: 0.000711mmHg at 25°C
• Refractive Index: 1.591
• Storage Temp.: Refrigerator
• Solubility: Chloroform (Sparingly), DMSO (Slightly), Methanol (Slightly)
• PKA: -0.18±0.10(Predicted)
• CAS DataBase Reference: 3-Chloro-4-morpholino-1,2,5-thiadiazole(CAS DataBase Reference)
• NIST Chemistry Reference: 3-Chloro-4-morpholino-1,2,5-thiadiazole(30165-96-9)
• EPA Substance Registry System: 3-Chloro-4-morpholino-1,2,5-thiadiazole(30165-96-9)

Safety Data

• Hazard Codes: Xi
• Safety Statements: 22-24/25
• WGK Germany: 3
• HazardClass: IRRITANT
• Hazardous Substances Data: 30165-96-9(Hazardous Substances Data)

Usage

Chemical Properties

Brown Solid

Uses

Different sources of media describe the Uses of 30165-96-9 differently. You can refer to the following data:
1. An intermediate for the synthesis of Timolol
2. 3-Chloro-4-morpholino-1,2,5-thiadiazole (Timolol EP Impurity F; Timolol BP Impurity F; Timolol USP Related Compound F) is an intermediate for the synthesis of Timolol.

InChI:InChI=1/C6H8ClN3OS/c7-5-6(9-12-8-5)10-1-3-11-4-2-10/h1-4H2

Synthetic route

morpholine (110-91-8) + 3,4-dichloro-1,2,5-thiadiazole (5728-20-1) → 3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9)

Conditions	Yield
	98%
at 110℃; for 2.5h; Inert atmosphere;	95%
at 110 - 120℃;	90%

morpholineglyoxime (171852-92-9) → 3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9)

Conditions	Yield
With pyridine; disulfur dichloride In acetonitrile at -30 - 82℃; for 24h;	32%

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) + sodium methylate (124-41-4) → 3-methoxy-4-morpholinyl-1,2,5-thiadiazole

Conditions	Yield
In methanol for 12h; Inert atmosphere; Reflux;	95%

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) → 3-hydroxy-4-(N-morpholino)-1,2,5-thiadiazole (30165-97-0)

Conditions	Yield
With sodium hydroxide In dimethyl sulfoxide	93%
Stage #1: 3-Morpholino-4-chloro-1,2,5-thiadiazole With potassium hydroxide In water; dimethyl sulfoxide Reflux; Inert atmosphere; Stage #2: With hydrogenchloride In water; dimethyl sulfoxide at 0℃; Inert atmosphere;	93%
With potassium hydroxide In water; dimethyl sulfoxide Reflux;	89%

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) + 1-(4-trifluorophenyl)ethanol (1737-26-4) → 4-(4-(1-(4-(trifluoromethyl)phenyl)ethoxy)-1,2,5-thiadiazol-3-yl)morpholine

Conditions	Yield
With C52H70NO5PPdS; sodium t-butanolate In tetrahydrofuran at 20℃; for 18h; Sealed tube; Schlenk technique;	86%

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) + potassium p-cresolate (1192-96-7) → 3-(4-methylphenoxy)-4-morpholino-1,2,5-thiadiazole

Conditions	Yield
With copper at 180 - 190℃; for 2h;	80%

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) + (R,S)-5-(hydroxymethyl)-3-tert-butyloxazolidin-2-one (85665-60-7) → (S)-5-((4-morpholino-1,2,5-thiadiazol-3-yloxy)-methyl)-3-tert-butyloxazolidin-2-one (56526-15-9)

Conditions	Yield
With potassium tert-butylate In tert-butyl alcohol at 25℃; for 12h;	75%

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) + phenylmagnesium bromide (100-58-3) → 4-(4-phenyl-1,2,5-thiadiazol-3-yl)morpholine

Conditions	Yield
Stage #1: 3-Morpholino-4-chloro-1,2,5-thiadiazole With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate In tetrahydrofuran; toluene Kumada Cross-Coupling; Inert atmosphere; Sealed tube; Stage #2: phenylmagnesium bromide In tetrahydrofuran; toluene at 50℃; for 1h; Kumada Cross-Coupling; Inert atmosphere; Sealed tube; chemoselective reaction;	67%

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) + potassium p-methoxyphenolate (1122-93-6) → 4-[4-(4-methoxy-phenoxy)-[1,2,5]thiadiazol-3-yl]-morpholine

Conditions	Yield
With copper at 170 - 180℃; for 2h;	63%

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) + potassium o-cresolate (3235-09-4) → 4-(4-o-tolyloxy-[1,2,5]thiadiazol-3-yl)-morpholine

Conditions	Yield
With copper at 180 - 190℃; for 2h;	56%

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) + 3-(2-hydroxyphenyl)prop-1-ene potassium salt (79015-70-6) → 4-[4-(2-allyl-phenoxy)-[1,2,5]thiadiazol-3-yl]-morpholine

Conditions	Yield
With copper at 170 - 180℃; for 2h;	56%

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) + potassium phenolate (100-67-4) → 4-morpholino-3-phenoxy-1,2,5-thiadiazole

Conditions	Yield
With copper at 180 - 190℃; for 2h;	53%

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) + potassium 2,6-dimethylphenolate (58425-33-5) → 4-[4-(2,6-dimethyl-phenoxy)-[1,2,5]thiadiazol-3-yl]-morpholine

Conditions	Yield
With copper at 180 - 190℃; for 2h;	53%

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) + p-bromophenol, potassium salt (3046-26-2) → 4-[4-(4-bromo-phenoxy)-[1,2,5]thiadiazol-3-yl]-morpholine

Conditions	Yield
With copper at 180 - 190℃; for 2h;	53%

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) + potassium 3-methoxyphenolate (52688-74-1) → 4-[4-(3-methoxy-phenoxy)-[1,2,5]thiadiazol-3-yl]-morpholine

Conditions	Yield
With copper at 170 - 180℃; for 2h;	53%

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) → 2-imino-2-morpholinoacetonitrile (98197-10-5)

Conditions	Yield
With tetraethylammonium chloride In N,N-dimethyl-formamide at 24.85℃; Electrochemical reaction;	52%

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) + potassium 3-bromophenoxide (2550-74-5) → 4-[4-(3-bromo-phenoxy)-[1,2,5]thiadiazol-3-yl]-morpholine

Conditions	Yield
With copper at 180 - 190℃; for 2h;	50%

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) + 3-hydroxy-2,2,5,5-tetramethylpyrrolidine-1-oxyl (2154-37-2) → 4-(4-(2,2,5,5-tetramethylpyrrolidin-1-oxyl-3-yloxy)-1,2,5-thiadiazol-3-yl)morpholine

Conditions	Yield
Stage #1: 3-hydroxy-2,2,5,5-tetramethylpyrrolidine-1-oxyl With potassium tert-butylate In tert-butyl alcohol for 0.5h; Stage #2: 3-Morpholino-4-chloro-1,2,5-thiadiazole In tert-butyl alcohol at 40℃; for 48h;	20%
Stage #1: 3-hydroxy-2,2,5,5-tetramethylpyrrolidine-1-oxyl With potassium tert-butylate In tert-butyl alcohol for 0.5h; Stage #2: 3-Morpholino-4-chloro-1,2,5-thiadiazole In tert-butyl alcohol at 40℃; for 48h;	20%

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) + (R,S)-2,2-dimethyl-1,3-dioxolane-4-methanol (100-79-8) → 4-[4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-morpholine (66492-30-6)

Conditions	Yield
With potassium tert-butylate In N,N-dimethyl-formamide

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) + ((2Ξ,5S)-3-tert-butyl-2-phenyl-oxazolidin-5-yl)-methanol (194861-99-9) → 3-tert-butylamino-2-(4-morpholin-4-yl-[1,2,5]thiadiazol-3-yloxy)-propan-1-ol (59697-06-2) + timolol (26839-75-8)

Conditions	Yield
With potassium tert-butylate In tert-butyl alcohol at 25℃; for 16h;

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) + ((2Ξ,5S)-3-tert-butyl-2-phenyl-oxazolidin-5-yl)-methanol (194861-99-9) → timolol (26839-75-8)

Conditions	Yield
With potassium tert-butylate In tert-butyl alcohol at 25℃; for 16h;

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) + oxiranyl-methanol (556-52-5) → 4-{4-[(2R/S)-oxiran-2-ylmethoxy]-1,2,5-thiadiazol-3-yl}morpholine (58827-68-2)

Conditions	Yield
With sodium hydride In N,N-dimethyl-formamide

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) + (R)-oxiranemethanol (57044-25-4) → 4-{4-[(2S)-oxiran-2-ylmethoxy]-1,2,5-thiadiazol-3-yl}morpholine (69500-53-4)

Conditions	Yield
With sodium hydride In N,N-dimethyl-formamide

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) → timolol (26839-75-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 75 percent / potassium tert-butoxide / 2-methyl-propan-2-ol / 12 h / 25 °C 2: 90 percent / aq. NaOH / methanol / 8 h View Scheme
Multi-step reaction with 2 steps 1: aq. NaOH / dimethylsulfoxide / 3 h / Heating 2: dimethylsulfoxide / 96 h / Ambient temperature View Scheme

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) → timolol maleate (26921-17-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 75 percent / potassium tert-butoxide / 2-methyl-propan-2-ol / 12 h / 25 °C 2: 90 percent / aq. NaOH / methanol / 8 h 3: tetrahydrofuran / 1 h / 25 °C View Scheme
Multi-step reaction with 3 steps 1: 75 percent / potassium tert-butoxide / 2-methyl-propan-2-ol / 12 h / 25 °C 2: 90 percent / aq. NaOH / methanol / 8 h 3: tetrahydrofuran / 1 h / 25 °C View Scheme

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) → timolol maleate

Conditions	Yield
Multi-step reaction with 3 steps 1: 75 percent / potassium tert-butoxide / 2-methyl-propan-2-ol / 12 h / 25 °C 2: 90 percent / aq. NaOH / methanol / 8 h 3: tetrahydrofuran / 1 h / 25 °C View Scheme

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) → 3-chloro-1-<(4-morpholino-1,2,5-thidiazol-3-yl)oxy>-2-propanone (110638-01-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 93 percent / aq. NaOH / dimethylsulfoxide 2: 80 percent / NaHCO3 / dimethylformamide / 23 h / 0 - 20 °C View Scheme

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) → 3-(4-morpholino-1,2,5-thiadiazol-3-yloxy)-propane-1,2-diol (66492-31-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: KOtBu / dimethylformamide 2: aq. HCl View Scheme

3-Morpholino-4-chloro-1,2,5-thiadiazole (30165-96-9) → 2-hydroxy-3-(4-morpholin-4-yl-[1,2,5]thiadiazol-3-yloxy)-propionitrile (66950-05-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: KOtBu / dimethylformamide 2: aq. HCl 3: Pb(OAc)4 / benzene 4: aq. NaHSO3 View Scheme

Upstream product

• 171852-92-9 morpholineglyoxime 
• 110-91-8 morpholine 
• 5728-20-1 3,4-dichloro-1,2,5-thiadiazole 

Downstream Products

• 741719-53-9 4-{4-[(2R)-oxiran-2-ylmethoxy]-1,2,5-thiadiazol-3-yl}morpholine 
• 69500-53-4 4-{4-[(2S)-oxiran-2-ylmethoxy]-1,2,5-thiadiazol-3-yl}morpholine 
• 7716-66-7 3-chloro-1,2-benzisothiazole 
• 22801-59-8 3-(morpholin-4-yl)-1,2-benzoisothiazole 
• 26921-17-5 timolol maleate 
• 26839-75-8 timolol 
• 30165-97-0 3-hydroxy-4-(N-morpholino)-1,2,5-thiadiazole 
• 59697-06-2 3-tert-butylamino-2-(4-morpholin-4-yl-[1,2,5]thiadiazol-3-yloxy)-propan-1-ol 

Relevant articles and documents

Synthesis of 4-substituted 3-chloro-1,2,5-thiadiazoles from monosubstituted glyoximes

One-pot synthesis of 3-chloro-1,2,5-thiadiazoles from monosubstituted glyoximes and sulfur monochloride was developed.

Optimization of 1,2,5-thiadiazole carbamates as potent and selective ABHD6 inhibitors

At present, inhibitors of α/β-hydrolase domain 6 (ABHD6) are viewed as a promising approach to treat inflammation and metabolic disorders. This article describes the development of 1,2,5-thiadiazole carbamates as ABHD6 inhibitors. Altogether, 34 compounds were synthesized, and their inhibitory activity was tested using lysates of HEK293 cells transiently expressing human ABHD6 (hABHD6). Among the compound series, 4-morpholino-1,2,5-thiadiazol-3-yl cyclooctyl(methyl)carbamate (JZP-430) potently and irreversibly inhibited hABHD6 (IC50 = 44 nM) and showed ～ 230-fold selectivity over fatty acid amide hydrolase (FAAH) and lysosomal acid lipase (LAL), the main off-targets of related compounds. Additionally, activity-based protein profiling indicated that JZP-430 displays good selectivity among the serine hydrolases of the mouse brain membrane proteome. JZP-430 has been identified as a highly selective, irreversible inhibitor of hABHD6, which may provide a novel approach in the treatment of obesity and type II diabetes.

Thiadiazole carbamates: Potent inhibitors of lysosomal acid lipase and potential niemann-pick type C disease therapeutics

Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized at the cellular level by abnormal accumulation of cholesterol and other lipids in lysosomal storage organelles. Lysosomal acid lipase (LAL) has been recently identified as a potential therapeutic target for NPC. LAL can be specifically inhibited by a variety of 3,4-disubstituted thiadiazole carbamates. An efficient synthesis of the C(3) oxygenated/C(4) aminated analogues has been developed that furnishes the products in high yields and high degrees of purity. Common intermediates can also be used for the synthesis of the C(3) carbon substituted derivatives. Herein we tested various thiadiazole carbamates, amides, esters, and ketones for inhibition of LAL. In addition, we tested a diverse selection of commercially available non-thiadiazole carbamates. Our studies show that, among the compounds examined herein, only thiadiazole carbamates are effective inhibitors of LAL. We present a mechanism for LAL inhibition by these compounds whereby LAL transiently carbamoylates the enzyme similarly to previously described inhibition of acetylcholinesterase by rivastigmine and other carbamates as well as acylation of various lipases by orlistat.