29110-48-3

Basic information

• Product Name: GUANFACINE HCL
• Synonyms: bs100-141;estulic;lon798;n-(aminoiminomethyl)-2,6-dichlorobenzeneacetamidehydrochloride;n-(aminoiminomethyl)-2,6-dichloro-benzeneacetamidmonohydrochloride;n-amidino-2-(2,6-dichlorophenyl)acetamidehydrochloride;N (AMINOIMINOMETHYL)-2,6-DICHLOROBENZENEACETAMIDE HYDROCHLORIDE SALT;[(2,6-DICHLOROPHENYL)ACETYL]GUANIDINE HYDROCHLORIDE
• CAS NO: 29110-48-3
• Molecular Formula: C₉H₉Cl₂N₃O*ClH
• Molecular Weight: 282.55
• EINECS: 249-443-3
• Product Categories: Amines;Intermediates & Fine Chemicals;Pharmaceuticals;Adrenoceptor;API;Inhibitors
• Mol File: 29110-48-3.mol
• Article Data: 2

Chemical Properties

• Melting Point: 215-217℃
• Appearance: white/
• Storage Temp.: Store at RT
• Solubility: H2O: 12 mg/mL at 60 °C, soluble
• Merck: 14,4561
• CAS DataBase Reference: GUANFACINE HCL(CAS DataBase Reference)
• NIST Chemistry Reference: GUANFACINE HCL(29110-48-3)
• EPA Substance Registry System: GUANFACINE HCL(29110-48-3)

Safety Data

• RIDADR: 3249
• WGK Germany: 3
• RTECS: CY1481000
• HazardClass: 6.1(b)
• PackingGroup: III
• Hazardous Substances Data: 29110-48-3(Hazardous Substances Data)

Usage

Description

Guanfacine hydrochloride, also known as N-(aminoiminomethyl)-2,6-dichlorobenzeneacetamide (Tenex), is a centrally acting α2-adrenoceptor agonist. It is structurally related to clonidine hydrochloride and guanabenz acetate, sharing many of their pharmacological properties. The drug has a longer duration of action, lasting up to 24 hours, and requires a longer time (8-12 hours) for a peak effect to occur after administration.

Uses

Used in Pharmaceutical Industry:
Guanfacine HCL is used as a pharmaceutical reference standard for the determination of the analyte in bulk drug and pharmaceutical formulations by spectrophotometry and high-performance liquid chromatography.
Used in Medical Applications:
Guanfacine HCL is used as an antihypertensive agent for the treatment of high blood pressure. It functions as an alpha 2A agonist, which helps in lowering blood pressure by causing blood vessels to dilate and reducing the force of the heart's contractions.
Used in Central Nervous System:
Guanfacine HCL is used as a centrally acting α-adrenoceptor agonist, which means it works on the central nervous system to regulate blood pressure and other related conditions.

Therapeutic Function

Antihypertensive

Biological Activity

Selective α 2A -adrenoceptor agonist (K d = 31 nM). Displays 60-fold selectivity over α 2B -adrenoceptors. Also available as part of the α 2 -Adrenoceptor Tocriset? .

Biochem/physiol Actions

α-2 noradrenergic receptor agonist.

Pharmacokinetics

The pharmacokinetic properties for guanfacine differ from those of clonidine, guanabenz, and α-methyldopa. At pH 7.4, guanfacine is predominately (67%) in the nonionized, lipid-soluble base form, which accounts for its high oral bioavailability (>80%). Following an oral dose, peak plasma concentrations occur in 1 to 4 hours, with a relatively long elimination half-life of 14 to 23 hours. The maximum blood pressure response occurs in 8 to 12 hours after oral administration and is maintained up to 36 hours following its discontinuation. Following IV dosing, guanfacine achieves the highest concentrations in liver and kidney, with low concentrations in the brain. Guanfacine is 64% bound to plasma proteins. In patients with hepatic or renal impairment, its elimination half-life may be prolonged. Guanfacine is metabolized principally by hepatic hydroxylation to its inactive metabolite, 3-hydroxyguanfacine (20%), which is eliminated in the urine as its glucuronide (30%), sulfate (8%), or mercapturic acid conjugate (10%), and 24 to 37% is excreted as unchanged guanfacine. Its nearly complete bioavailability suggests no evidence of any first-pass effect. Guanfacine and its inactive metabolites are excreted principally in urine, with approximately 80% of its oral dose excreted in urine within 48 hours.

Clinical Use

Overall, the therapeutic applications for guanfacine are similar to those of the other centrally acting α2-adrenergic agonists and methyldopa. It has been effective as monotherapy in the treatment of patients with mild to moderate hypertension. One advantage for guanfacine is its once-a-day dosing schedule. The use of diuretics to prevent accumulation of fluid may allow a reduction in the dosage for guanfacine.

Side effects

Overall, although the frequency of troublesome adverse effects produced by guanfacine is similar to that produced by clonidine and the other centrally acting sympatholytics, their incidence and severity are lower with guanfacine. Unlike clonidine, abrupt discontinuation of guanfacine rarely results in rebound hypertension. When a withdrawal syndrome has occurred, its onset was slower and its symptoms less severe than the syndrome observed with clonidine.

InChI:InChI=1/C9H9Cl2N3O.ClH/c10-6-2-1-3-7(11)5(6)4-8(15)14-9(12)13;/h1-3H,4H2,(H4,12,13,14,15);1H

Synthetic route

methyl 2-(2,6-dichlorophenyl)acetate (54551-83-6) + guanidine hydrochloride (50-01-1) → guanfacine hydrochloride (29110-48-3)

Conditions	Yield
In ethanol at 20℃; for 30h;	15%

guanfacine (29110-47-2) → guanfacine hydrochloride (29110-48-3)

Conditions	Yield
With hydrogenchloride In ethanol; water for 0.5h; pH=1;	32.6 g

C21H30N4O9 (1364788-93-1) + guanfacine hydrochloride (29110-48-3) → C26H34Cl2N6O7 (1364788-95-3)

Conditions	Yield
With 4-methyl-morpholine In N,N-dimethyl-formamide at 22℃;	84%

di-tert-butyl dicarbonate (24424-99-5) + guanfacine hydrochloride (29110-48-3) → guanfacine tert-butyl carbamate (1364788-99-7)

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 22℃;	78%

C23H27NO6Si (1364788-77-1) + guanfacine hydrochloride (29110-48-3) → guanfacine [2-(tert-butyl-diphenyl-silanyloxy)-ethyl] carbamate (1364788-79-3)

Conditions	Yield
Stage #1: guanfacine hydrochloride With 4-methyl-morpholine In N,N-dimethyl-formamide at 22℃; for 0.166667h; Stage #2: C23H27NO6Si In N,N-dimethyl-formamide at 22℃;	75%

C24H29NO6Si (1364788-82-8) + guanfacine hydrochloride (29110-48-3) → guanfacine [3-(tert-butyl-diphenyl-silanyloxy)-propyl]carbamate (1364788-84-0)

Conditions	Yield
Stage #1: guanfacine hydrochloride With 4-methyl-morpholine In N,N-dimethyl-formamide at 22℃; for 0.166667h; Stage #2: C24H29NO6Si In N,N-dimethyl-formamide at 22℃;	61%

neopentyl chloroformate (20412-38-8) + guanfacine hydrochloride (29110-48-3) → 1-{N'-[2-(2,6-dichloro-phenyl)-acetyl]-guanidinocarbonyloxy}-2,2-dimethylpropane hydrochloride (1364788-31-7)

Conditions	Yield
With 4-methyl-morpholine In tetrahydrofuran at 22℃; Inert atmosphere;	34%

cyclopropylmethyl 2,5-dioxopyrrolidin-1-yl carbonate (959425-11-7) + guanfacine hydrochloride (29110-48-3) → {N'-[2-(2,6-dichloro-phenyl)acetyl]-guanidino-carbonyloxy}methylcyclopropane (1364788-87-3)

Conditions	Yield
Stage #1: guanfacine hydrochloride With 4-methyl-morpholine In N,N-dimethyl-formamide at 22℃; for 0.166667h; Stage #2: cyclopropylmethyl 2,5-dioxopyrrolidin-1-yl carbonate In N,N-dimethyl-formamide at 22℃;	33%

guanfacine hydrochloride (29110-48-3) + isobutyl chloroformate (543-27-1) → 1-{N'-[2-(2,6-dichloro-phenyl)-acetyl]-guanidinocarbonyloxy}-2-methylpropane hydrochloride (1364788-29-3)

Conditions	Yield
With 4-methyl-morpholine In tetrahydrofuran at 22℃; Inert atmosphere;	29%

(1R,2S,5R)-menthyl chloroformate (14602-86-9) + guanfacine hydrochloride (29110-48-3) → 1-(R)-{N'-[2-(2,6-dichloro-phenyl)-acetyl]-guanidinocarbonyloxy}-2-(S)-isopropyl-5-(R)-methyl-cyclohexane hydrochloride (1364788-66-8)

Conditions	Yield
With 4-methyl-morpholine In tetrahydrofuran at 22℃; Inert atmosphere;	28%

guanfacine hydrochloride (29110-48-3) + Ethyl chlorothioformate (2941-64-2) → guanfacine ethanthiol carbamate hydrochloride (1364788-68-0)

Conditions	Yield
With 4-methyl-morpholine In tetrahydrofuran at 22℃; Inert atmosphere;	27%

guanfacine hydrochloride (29110-48-3) + propoxycarbonyl chloride (109-61-5) → 1-{N'-[2-(2,6-Dichloro-phenyl)acetyl]-guanidinocarbonyloxy}propane Hydrochloride (1364788-20-4)

Conditions	Yield
With 4-methyl-morpholine In tetrahydrofuran at 22℃; Inert atmosphere;	26%

guanfacine hydrochloride (29110-48-3) + carbonochloridic acid, butyl ester (592-34-7) → 1-{N'-[2-(2,6-dichloro-phenyl)-acetyl]-guanidinocarbonyloxy}butane hydrochloride (1364788-25-9)

Conditions	Yield
With 4-methyl-morpholine In tetrahydrofuran at 22℃; Inert atmosphere;	22%

benzyl chloroformate (501-53-1) + guanfacine hydrochloride (29110-48-3) → α-{N'-[2-(2,6-dichloro-phenyl)-acetyl]guanidino-carbonyloxy}toluene hydrochloride (1364788-34-0)

Conditions	Yield
With 4-methyl-morpholine In tetrahydrofuran at 22℃; for 5h; Inert atmosphere;	13%

phosgene (75-44-5) + ethanol-d6 (1516-08-1) + guanfacine hydrochloride (29110-48-3) → {N'-[2-(2,6-dichloro-phenyl)acetyl]-guanidinocarbonyloxy}ethane-d5 (1364789-15-0)

Conditions	Yield
Stage #1: phosgene; ethanol-d6 With pyridine In toluene at 22℃; for 1.5h; Inert atmosphere; Cooling with ice; Stage #2: guanfacine hydrochloride In tetrahydrofuran; toluene at 22℃;	3%

C18H28N2O7 (1247867-13-5) + guanfacine hydrochloride (29110-48-3) + trifluoroacetic acid (76-05-1) → guanfacine-[glutaryl-(S)-valine]amide trifluoroacetate

Conditions	Yield
Stage #1: C18H28N2O7; guanfacine hydrochloride With 4-methyl-morpholine In N,N-dimethyl-formamide Stage #2: trifluoroacetic acid

C17H27N3O7 (1273016-95-7) + guanfacine hydrochloride (29110-48-3) + trifluoroacetic acid (76-05-1) → guanfacine-β-alanine-(S)-valine amide di-trifluoroacetate

Conditions	Yield
Stage #1: C17H27N3O7; guanfacine hydrochloride With 4-methyl-morpholine In N,N-dimethyl-formamide Stage #2: trifluoroacetic acid

C23H37N3O9 (1273017-00-7) + guanfacine hydrochloride (29110-48-3) + trifluoroacetic acid (76-05-1) → guanfacine-γ-(S)-glutamic acid-(R)-valine amide di-trifluoroacetate

Conditions	Yield
Stage #1: C23H37N3O9; guanfacine hydrochloride With 4-methyl-morpholine In N,N-dimethyl-formamide Stage #2: trifluoroacetic acid

C20H31N3O10 (1273017-05-2) + guanfacine hydrochloride (29110-48-3) + trifluoroacetic acid (76-05-1) → (S)-serine(guanfacine)-sarcosine carbamate di-trifluoroacetate

Conditions	Yield
Stage #1: C20H31N3O10; guanfacine hydrochloride With 4-methyl-morpholine In N,N-dimethyl-formamide Stage #2: trifluoroacetic acid

C21H33N3O10 (1273017-11-0) + guanfacine hydrochloride (29110-48-3) + trifluoroacetic acid (76-05-1) → sarcosine-(2S,3R)-threonine(guanfacine) carbamate di-trifluoroacetate

Conditions	Yield
Stage #1: C21H33N3O10; guanfacine hydrochloride With 4-methyl-morpholine In N,N-dimethyl-formamide Stage #2: trifluoroacetic acid

chloroformic acid ethyl ester (541-41-3) + guanfacine hydrochloride (29110-48-3) → {N'-[2-(2,6-Dichloro-phenyl)-acetyl]-guanidinocarbonyloxy}ethane Hydrochloride (1364788-17-9)

Conditions	Yield
With 4-methyl-morpholine In tetrahydrofuran

di-tert-butyl dicarbonate (24424-99-5) + guanfacine hydrochloride (29110-48-3) → guanfacine tert-butyl carbamate hydrochloride (1364788-97-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / N,N-dimethyl-formamide / 22 °C 2: hydrogenchloride / diethyl ether / 0.02 h View Scheme

1-[3-(benzyloxy)propoxycarbonyloxy]pyrrolidin-2,5-dione + guanfacine hydrochloride (29110-48-3) → C20H21Cl2N3O4

Conditions	Yield
With 4-methyl-morpholine

isobutyl chloroformate (17462-58-7) + guanfacine hydrochloride (29110-48-3) → 2-{N'-[2-(2,6-Dichloro-phenyl)-acetyl]-guanidinocarbonyloxy}-butane Hydrochloride (1364788-27-1)

Conditions	Yield
With 4-methyl-morpholine In tetrahydrofuran

C9H13NO5 (1246521-39-0) + guanfacine hydrochloride (29110-48-3) → 2-{N'-[2-(2,6-dichloro-phenyl)-acetyl]-guanidinocarbonyloxy}butane (1364788-73-7)

Conditions	Yield
Stage #1: guanfacine hydrochloride With 4-methyl-morpholine In N,N-dimethyl-formamide at 22℃; for 0.166667h; Stage #2: C9H13NO5 In N,N-dimethyl-formamide at 22℃;

C7H4(2)H5NO5 (1364788-38-4) + guanfacine hydrochloride (29110-48-3) → {N'-[2-(2,6-dichloro-phenyl)acetyl]-guanidinocarbonyloxy}ethane-d5 hydrochloride (1364788-40-8)

Conditions	Yield
Stage #1: C7H4(2)H5NO5; guanfacine hydrochloride With 4-methyl-morpholine Stage #2: With hydrogenchloride

guanfacine hydrochloride (29110-48-3) + Carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester (2R,3R,4S,5R,6S)-3,4,5-tris-benzyloxy-6-methoxy-tetrahydro-pyran-2-ylmethyl ester (228873-47-0) → C38H39Cl2N3O8

Conditions	Yield
With 4-methyl-morpholine

C14H15NO6 (1364788-48-6) + guanfacine hydrochloride (29110-48-3) → C19H19Cl2N3O4

Conditions	Yield
With 4-methyl-morpholine

C20H17NO7 (1364788-57-7) + guanfacine hydrochloride (29110-48-3) → C25H21Cl2N3O5

Conditions	Yield
With 4-methyl-morpholine

C19H15NO7 (1364788-62-4) + guanfacine hydrochloride (29110-48-3) → C24H19Cl2N3O5

Conditions	Yield
With 4-methyl-morpholine

Upstream product

• 54551-83-6 methyl 2-(2,6-dichlorophenyl)acetate 
• 50-01-1 guanidine hydrochloride 
• 29110-47-2 guanfacine 

Downstream Products

• 1364788-95-3 C₂₆H₃₄Cl₂N₆O₇ 
• 1364788-40-8 {N'-[2-(2,6-dichloro-phenyl)acetyl]-guanidinocarbonyloxy}ethane-d5 hydrochloride 
• 1364788-87-3 {N'-[2-(2,6-dichloro-phenyl)acetyl]-guanidino-carbonyloxy}methylcyclopropane 
• 1364788-84-0 guanfacine [3-(tert-butyl-diphenyl-silanyloxy)-propyl]carbamate 
• 1364788-79-3 guanfacine [2-(tert-butyl-diphenyl-silanyloxy)-ethyl] carbamate 
• 1364788-73-7 2-{N'-[2-(2,6-dichloro-phenyl)-acetyl]-guanidinocarbonyloxy}butane 
• 1364788-27-1 2-{N'-[2-(2,6-Dichloro-phenyl)-acetyl]-guanidinocarbonyloxy}-butane Hydrochloride 
• 1364788-68-0 guanfacine ethanthiol carbamate hydrochloride 
• 1364788-29-3 1-{N'-[2-(2,6-dichloro-phenyl)-acetyl]-guanidinocarbonyloxy}-2-methylpropane hydrochloride 
• 1364788-20-4 1-{N'-[2-(2,6-Dichloro-phenyl)acetyl]-guanidinocarbonyloxy}propane Hydrochloride 
• 1364788-34-0 α-{N'-[2-(2,6-dichloro-phenyl)-acetyl]guanidino-carbonyloxy}toluene hydrochloride 
• 1364789-15-0 {N'-[2-(2,6-dichloro-phenyl)acetyl]-guanidinocarbonyloxy}ethane-d5 
• 1364788-97-5 guanfacine tert-butyl carbamate hydrochloride 
• 1364788-99-7 guanfacine tert-butyl carbamate 

Relevant articles and documents

THERAPEUTIC COMPOUNDS

The invention provides compounds of formula Ia′, Ib′, Ic′, and Id′: and pharmaceutically acceptable salts thereof, wherein the variables A, R6, R7, R8, R9, Rx, L, X, Y, and Z have the meaning as described herein. The compounds are useful for reducing endoplasmic reticulum stress and for producing analgesia in an animal.