33286-22-5

Basic information

• Product Name: Dilthiazem hydrochloride
• Synonyms: 1,5-benzothiazepin-4(5h)-one,2,3-dihydro-3-(acetyloxy)-5-(2-(dimethylamino)eth;2,3-dihydro-3-(acetyloxy)-5-(2-(dimethylamino)ethyl)-2-(4-methoxyphenyl)-5-benzothiazepin-4(5h)-one;altiazem;anginyl;angizem;britiazim;bruzem;calcicard
• CAS NO: 33286-22-5
• Molecular Formula: C₂₂H₂₆N₂O₄S*ClH
• Molecular Weight: 450.98
• EINECS: 251-443-3
• Product Categories: Active Pharmaceutical Ingredients;Intermediates & Fine Chemicals;Pharmaceuticals;Calcium channel;Ion Channels;Aromatics;Chiral Reagents;Sulfur & Selenium Compounds;Cardiovascular APIs
• Mol File: 33286-22-5.mol
• Article Data: 11

Chemical Properties

• Melting Point: 212-214 °C
• Boiling Point: 594.4 ºC at 760 mmHg
• Flash Point: 2℃
• Appearance: White to off-white/Powder
• Density: 1.26g/cm3
• Vapor Pressure: 4.27E-14mmHg at 25°C
• Refractive Index: 118 ° (C=1, H2O)
• Storage Temp.: 2-8°C
• Solubility: Freely soluble in water, in methanol and in methylene chloride, slightly soluble in anhydrous ethanol.
• Water Solubility: soluble
• Merck: 13,3226
• BRN: 4228706
• CAS DataBase Reference: Dilthiazem hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: Dilthiazem hydrochloride(33286-22-5)
• EPA Substance Registry System: Dilthiazem hydrochloride(33286-22-5)

Safety Data

• Hazard Codes: Xn,Xi,F
• Statements: 22-40-36/37/38-36-20/21/22-11
• Safety Statements: 36-45-36/37-26-16
• RIDADR: 3249
• WGK Germany: 3
• RTECS: DL0310000
• F: 8-10
• HazardClass: 6.1(b)
• PackingGroup: III
• Hazardous Substances Data: 33286-22-5(Hazardous Substances Data)

Usage

Biological Activity

Antihypertensive and cardioprotective agent; an inhibitor of L-type Ca 2+ channels.

Uses

Diltiazem Hydrochloride is a calcium channel blocker with vasodilating activity. Anti-anginal; anti-hypertensive; anti-arrhythmic (class IV).

Manufacturing Process

β-Diethylaminoethyl chloride is condensed with 2-(4-methoxyphenyl)-3- hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one in a first step. Then a mixture of 1.5 grams of 2-(4-methoxyphenyl)-3-hydroxy-5-(βdimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 20 ml of acetic anhydride was heated on a water bath for 5 hours. The reaction mixture was evaporated under reduced pressure to remove acetic anhydride and the concentrated product was poured into ice water. The resulting mixture was made alkaline with sodium bicarbonate and extracted with chloroform. The chloroform layer was dried and evaporated to remove the solvent. The residue was dissolved in acetone, and an ethanol solution containing hydrogen chloride was added thereto producing 1.53 grams of 2-(4-methoxyphenyl)3- acetoxy-5-(β-dimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride having a melting point from 187° to 188°C.The starting material is made by reacting 4-methoxybenzaldehyde with ethyl chloroacetate; that product with sodium ethoxide; and that product with 2- aminothiophenol.

Originator

Herbesser,TANABE SEIYAKU,Japan,1974

Uses

Peripheral Vasodilator

Uses

A calcium channel blocher with vasodilating activity. Antianginal; antihypertensive; antiarrhythmic (class IV).

Chemical Properties

Fine Needles

General Description

Diltiazem hydrochloride,(+)-cis-3-(acetoxy)-5-[2(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)1,5-benzothiazepin-4(5H)one hydrochloride(Cardizem), was developed and introduced inJapan as a cardiovascular agent to treat angina pectoris. Itwas observed to dilate peripheral arteries and arterioles. Thedrug increases myocardial oxygen supply by relieving coronaryartery spasm and reduces myocardial oxygen demandby decreasing heart rate and reducing overload. Diltiazemhydrochloride is used in patients with variant angina. Thedrug has electrophysiological properties similar to those ofverapamil and is used in clinically similar treatment conditionsas an antiarrhythmic agent, but it is less potent.The drug is absorbed rapidly and almost completely fromthe digestive tract. It reaches peak plasma levels within 1hour after administration in gelatin capsules. Oral formulationson the market are sustained-release preparations providingpeak plasma levels 3 to 4 hours after administration.

Uses

An antianginal, antihypertensive. Regulates Calcium release from intracellular stores in neutrophils

Brand name

Cardizem (Biovail); Cartia (Andrx); Dilacor (Watson); Diltzac (Apotex); Taztia (Andrx); Tiazac (Biovail).

Definition

ChEBI: A hydrochloride salt resulting from the reaction of equimolar amounts of diltiazem and hydrogen chloride. A calcium-channel blocker and vasodilator, it is used in the management of angina pectoris and hypertension.

Therapeutic Function

Coronary vasodilator

Uses

antihypertensive, sedative, antibacterial

InChI:InChI=1/C22H26N2O4S.ClH/c1-15(25)28-20-21(16-9-11-17(27-4)12-10-16)29-19-8-6-5-7-18(19)24(22(20)26)14-13-23(2)3;/h5-12,20-21H,13-14H2,1-4H3;1H/t20-,21+;/m1./s1

Synthetic route

O-desacetyldiltiazem (42399-40-6) + acetic anhydride (108-24-7) → diltiazem hydrochloride (33286-22-5)

Conditions	Yield
Stage #1: O-desacetyldiltiazem; acetic anhydride With dmap; triethylamine In dichloromethane for 3h; Heating / reflux; Stage #2: With hydrogenchloride In methanol pH=2;	92%
With hydrogenchloride In ethanol; butanone at 90℃; for 1h;	80%
With dmap In dichloromethane for 3h; Heating; Yield given;

(2S,3S)-5-(2-dimethylaminoethyl)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride (75472-91-2) + acetic anhydride (108-24-7) → diltiazem hydrochloride (33286-22-5)

Conditions	Yield
Stage #1: (2S,3S)-5-(2-dimethylaminoethyl)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride; acetic anhydride With dmap; triethylamine In dichloromethane Stage #2: With hydrogenchloride In methanol pH=2;	92%
With pyridine; dmap

Isopropenyl acetate (108-22-5) + (2S,3S)-5-(2-dimethylaminoethyl)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride (75472-91-2) → diltiazem hydrochloride (33286-22-5)

Conditions	Yield
With methanesulfonic acid In chloroform for 0.75h; Heating;	88.8%

(E)-1-(4-methoxyphenyl)-4,4-dimethylpent-1-en-3-one (2419-67-2, 24470-83-5, 41564-61-8) → diltiazem hydrochloride (33286-22-5)

Conditions	Yield
Multi-step reaction with 6 steps 1: 70 percent / urea hydrogen peroxide, DBU, immobilised poly-L-leucine / tetrahydrofuran / 28 h 2: 84 percent / MCPBA, KF / CH2Cl2 / 24 h 3: 90 percent / toluene / 17 h / Heating 4: 94 percent / xylene / 216 h / Heating 5: K2CO3 / ethyl acetate 6: pyridine, DMAP View Scheme

(2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (42399-49-5) → diltiazem hydrochloride (33286-22-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: K2CO3 / ethyl acetate 2: pyridine, DMAP View Scheme
Multi-step reaction with 2 steps 1: 67 percent / NaH / dimethylformamide; paraffin; diethyl ether / 3 h / 70 °C 2: 80 percent / 2.) HCl / butan-2-one; ethanol / 1 h / 90 °C View Scheme
Multi-step reaction with 2 steps 1: 88.2 percent / K2CO3 / H2O; ethyl acetate / 5 h / Heating 2: DMAP / CH2Cl2 / 3 h / Heating View Scheme

4-methoxy-benzaldehyde (123-11-5) + (+-)-2-cyano-3-m-tolyl-propionic acid hydrazide → diltiazem hydrochloride (33286-22-5)

Conditions	Yield
Multi-step reaction with 7 steps 1: 87 percent / NaOMe / methanol / 40 h / Heating 2: 70 percent / urea hydrogen peroxide, DBU, immobilised poly-L-leucine / tetrahydrofuran / 28 h 3: 84 percent / MCPBA, KF / CH2Cl2 / 24 h 4: 90 percent / toluene / 17 h / Heating 5: 94 percent / xylene / 216 h / Heating 6: K2CO3 / ethyl acetate 7: pyridine, DMAP View Scheme

tert-butyl (2R,3S)-3-(4-methoxyphenyl)glycidate (201804-22-0) → diltiazem hydrochloride (33286-22-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: 90 percent / toluene / 17 h / Heating 2: 94 percent / xylene / 216 h / Heating 3: K2CO3 / ethyl acetate 4: pyridine, DMAP View Scheme

(2S,3S)-3-(2-Amino-phenylsulfanyl)-2-hydroxy-3-(4-methoxy-phenyl)-propionic acid tert-butyl ester (201804-23-1) → diltiazem hydrochloride (33286-22-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 94 percent / xylene / 216 h / Heating 2: K2CO3 / ethyl acetate 3: pyridine, DMAP View Scheme

1-((2R,3S)-4-methoxyphenyloxiranyl)-2,2-dimethylpropan-1-one (201804-19-5) → diltiazem hydrochloride (33286-22-5)

Conditions	Yield
Multi-step reaction with 5 steps 1: 84 percent / MCPBA, KF / CH2Cl2 / 24 h 2: 90 percent / toluene / 17 h / Heating 3: 94 percent / xylene / 216 h / Heating 4: K2CO3 / ethyl acetate 5: pyridine, DMAP View Scheme

(2S,3S)-threo-2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)-propionic acid (42399-48-4) → diltiazem hydrochloride (33286-22-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 88 percent / PTSA / xylene / 16 h / Heating 2: 88.2 percent / K2CO3 / H2O; ethyl acetate / 5 h / Heating 3: DMAP / CH2Cl2 / 3 h / Heating View Scheme

(αS,βS,1R,2S)-β-<(2-aminophenyl)thio>-α-hydroxy-β-(4-methoxyphenyl)propanoic acid 2-phenylcyclohexyl ester hydrochloride (138382-02-2) → diltiazem hydrochloride (33286-22-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: 81 percent / 2 N NaOH / ethanol; H2O / 2 h / Heating 2: 88 percent / PTSA / xylene / 16 h / Heating 3: 88.2 percent / K2CO3 / H2O; ethyl acetate / 5 h / Heating 4: DMAP / CH2Cl2 / 3 h / Heating View Scheme
Multi-step reaction with 3 steps 1: 73.2 percent / PTSA / xylene / 16 h / Heating 2: 88.2 percent / K2CO3 / H2O; ethyl acetate / 5 h / Heating 3: DMAP / CH2Cl2 / 3 h / Heating View Scheme

diltiazem hydrochloride (33286-22-5) → 5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-hydroxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one

Conditions	Yield
With water; hydrogen bromide at 100℃; for 0.5h;	96%

diltiazem hydrochloride (33286-22-5) → cis(+)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (23515-44-8)

Conditions	Yield
With lithium hydroxide; water In tetrahydrofuran at 160℃; for 0.0833333h; Microwave irradiation;	94%

diltiazem hydrochloride (33286-22-5) → O-desacetyldiltiazem (42399-40-6)

Conditions	Yield
In water Ambient temperature; Irradiation; decomposition of diltiazem in various solvents;
With sodium chloride at 79.85℃; Kinetics; Thermodynamic data; Activation energy; Further Variations:; Temperatures; relative humidity;
With hydrogenchloride at 39.85℃; pH=0.43; Kinetics; Further Variations:; pH-values; Reagents; Temperatures;

diltiazem hydrochloride (33286-22-5) → diltiazem (42399-41-7)

Conditions	Yield
With sodium hydrogencarbonate In water; ethyl acetate
With sodium carbonate In water pH=7.5;
With sodium hydrogencarbonate In water for 0.25h;

C62H68N16O24S4(4-)*4Na(1+) + diltiazem hydrochloride (33286-22-5) → C22H26N2O4S*ClH*C62H68N16O24S4(4-)*4Na(1+)

Conditions	Yield
In aq. phosphate buffer pH=7.4; UV-irradiation;

diltiazem hydrochloride (33286-22-5) → diltiazem acetylsalicylate hydrate

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium carbonate / water / pH 7.5 2: diethyl ether / 20 °C View Scheme

diltiazem hydrochloride (33286-22-5) → diltiazem nicotinate

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium carbonate / water / pH 7.5 2: acetonitrile / 20 °C View Scheme

Upstream product

• 105-37-3 Ethyl propionate 
• 107-99-3 2-Chloroethyldimethylamine 
• 137-07-5 2-Aminobenzenethiol 

Downstream Products

• 332862-36-9 ethyl 4-{3-(2-thienyl)-2-[(2-thienylcarbonyl)amino]acryloyl}-1-piperazinecarboxylate 
• 332862-42-7  
• 332862-45-0 N-[1-(1-azepanylcarbonyl)-2-(2-thienyl)vinyl]-2-thiophenecarboxamide 
• 33286-27-0 rac N,N-DiMethyl AMphetaMine Hydrochloride 
• 33286-30-5 dipotassium dihydrogen 15alpha-hydroxy-2beta-[[2-O-isovaleryl-3,4-di-O-sulphonato-beta-D-glucopyranosyl]oxy]kaur-16-ene-18,19-dioate 
• 332-86-5 1,1,1,7,7,7-Hexafluoro-4-heptanone 
• 33286-57-6 sodium 4-[(dimethylcarbamothioyl)disulfanyl]butane-1-sulfinate 
• 33286-65-6 (~203~Hg)mercury dichloride 
• 332867-69-3 4-[5-(3-NITROPHENYL)-3-PHENYL-4,5-DIHYDRO-1H-PYRAZOL-1-YL]-4-OXOBUTANOIC ACID 
• 332867-72-8 BUTTPARK 101\41-85 
• 332867-75-1 methyl 2-[2-[(5-furan-2-yl-4-phenyl-1,2,4-triazol-3-yl)sulfanyl] 
• 332867-78-4 [3-amino-4-(4-methoxyphenyl)-6-phenylthieno[2,3-b]pyridin-2-yl](4-methoxyphenyl)methanone 
• 332867-79-5 2-AMINO-5-(2-METHOXY-PHENYLCARBAMOYL)-4-METHYL-THIOPHENE-3-CARBOXYLIC ACID ETHYL ESTER 
• 332868-27-6 Acetic acid, [[(dimethylamino)carbonyl]hydrazono]- (9CI) 

Recommend Products

• 75472-91-2  (2S,3S)-5-(2-dimethylaminoethyl)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride 
• 108-24-7  acetic anhydride 
• 23515-44-8  cis(+)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one 
• 42399-41-7  diltiazem 
• 138382-02-2  (αS,βS,1R,2S)-β-<(2-aminophenyl)thio>-α-hydroxy-β-(4-methoxyphenyl)propanoic acid 2-phenylcyclohexyl ester hydrochloride 
• 42399-48-4  (2S,3S)-threo-2-hydroxy-3-(2-aminophenylthio)-3-(4-methoxyphenyl)-propionic acid 
• 201804-19-5  1-((2R,3S)-4-methoxyphenyloxiranyl)-2,2-dimethylpropan-1-one 
• 201804-23-1  (2S,3S)-3-(2-Amino-phenylsulfanyl)-2-hydroxy-3-(4-methoxy-phenyl)-propionic acid tert-butyl ester 
• 201804-22-0  tert-butyl (2R,3S)-3-(4-methoxyphenyl)glycidate 
• 123-11-5  4-methoxy-benzaldehyde 
• 42399-49-5  (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 
• 2419-67-2  (E)-1-(4-methoxyphenyl)-4,4-dimethylpent-1-en-3-one 
• 42399-40-6  O-desacetyldiltiazem 
• 108-22-5  Isopropenyl acetate