Dilthiazem hydrochloride

Iupac Name：[(2S,3S)-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl] acetate;hydrochloride

CAS No.: 33286-22-5

Molecular Weight：450.97878

Modify Date.: 2022-11-22 16:09

Introduction: 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. View more+

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1. Names and Identifiers

1.1 Name: Dilthiazem hydrochloride
1.2 Synonyms: (+)-cis-3-(Acetyloxy)-5-(2-(dimethylamino)ethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one Monohydrochloride (+)-cis-Diltiazem Hydrochloride (2S,3S)-(+)-cis-3-Acetoxy-5-(2-dimethylaminoethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one hydrochloride (2S,3S)-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl acetate hydrochloride (2S,3S)-5-[2-(Dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl acetate hydrochloride (1:1) (2S,3S)-5-[2-(Dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-ylacetathydrochlorid (2S-cis)-3-acetoxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one monohydrochloride 1,5-Benzothiazepin-4(5H)-one, 3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-, (2S,3S)-, hydrochloride (1:1) 1,5-benzothiazepin-4(5H)-one, 3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-, (2S,3S)-, monohydrochloride 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 acétate de (2S,3S)-5-[2-(diméthylamino)éthyl]-2-(4-méthoxyphényl)-4-oxo-2,3,4,5-tétrahydro-1,5-benzothiazépin-3-yle chlorhydrate Adizem altiazem anginyl angiotrofin angizem bruzem Cohlen Cormax Diltiazem (hydrochloride) Diltiazem d-cis-form hydrochloride Diltiazem HCl Diltiazem hydrochloride Diltiazem hydrochloride s dilzem Dodexen A.P. EINECS 251-443-3 Kardil masdil MFCD00069252 monohydrochloride,cis-(+)-yl)-2-(4-methoxyphenyl) Presokin A. P. Tiazac Zilde Zilden

1.3 CAS No.: 33286-22-5

1.4 CID: 62920

1.5 EINECS(EC#): 251-443-3

1.6 Molecular Formula: C22H27ClN2O4S (isomer)

1.7 Inchi: InChI=1S/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

1.8 InChkey: HDRXZJPWHTXQRI-BHDTVMLSSA-N

1.9 Canonical Smiles: CC(=O)OC1C(SC2=CC=CC=C2N(C1=O)CCN(C)C)C3=CC=C(C=C3)OC.Cl

1.10 Isomers Smiles: CC(=O)O[C@@H]1[C@@H](SC2=CC=CC=C2N(C1=O)CCN(C)C)C3=CC=C(C=C3)OC.Cl

2. Properties

2.1 Density: 1.26

2.1 Melting point: 210-215℃

2.1 Boiling point: 594.4°Cat760mmHg

2.1 Refractive index: 118 ° (C=1, H2O)

2.1 Flash Point: 313.3°C

2.1 Precise Quality: 450.13800

2.1 PSA: 84.38000

2.1 logP: 4.23550

2.1 Appearance: White to off-white Powder

2.2 Storage: Ambient temperatures.

2.3 Chemical Properties: Fine Needles

2.4 Color/Form: White to off-white

2.5 PH: pH (10g/l, 25℃) : 4.3～5.3

2.6 Water Solubility: soluble

2.7 StorageTemp: 2-8°C

3. Use and Manufacturing

3.1 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.

3.2 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.

3.3 Methods of Manufacturing: The N-alkylated lactam (0.317 mmol), Ac2O (1 mmol), Et3N (2 mmol) and DMAP (0.03 mmol) taken in CH2Cl2 (5 mL) were heated at reflux under N2 for 3 h. The mixture was poured into ice water and brine was added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (10 mL). The combined organic layers were washed with 5percent NH4OH (5 mL) solution, dried (Na2SO4) and evaporated. The residue was dissolved in MeOH (2 mL) and treated with anhydrous HCl gas till pH was 2. Ether (3 mL) was added to the resulting solution. The precipitated solids were collected by filtration and washed with 10percent MeOH-ether to afford diltiazem hydrochloride (92percent yield).The N-alkylated lactam (0.317 mmol), Ac2O (1 mmol), Et3N (2 mmol) and DMAP (0.03 mmol) taken in CH2Cl2 (5 mL) were heated at reflux under N2 for 3 h. The mixture was poured into ice water and brine was added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (10 mL). The combined organic layers were washed with 5percent NH4OH (5 mL) solution, dried (Na2SO4) and evaporated. The residue was dissolved in MeOH (2 mL) and treated with anhydrous HCl gas till pH was 2. Ether (3 mL) was added to the resulting solution. The precipitated solids were collected by filtration and washed with 10percent MeOH-ether to afford diltiazem hydrochloride (92percent yield).

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

4. Safety and Handling

4.1 Symbol: GHS02, GHS07

4.1 Hazard Codes: Xn

4.1 Signal Word: Danger

4.1 Risk Statements: R22;R40

4.1 Safety Statements: S36/37;S45

4.1 Packing Group: III

4.1 Hazard Class: 6.1(b)

4.1 Hazard Declaration: H225-H302 + H312 + H332-H319

4.1 RIDADR: 3249

4.1 Caution Statement: P210-P261-P302 + P352 + P312-P304 + P340 + P312-P337 + P313-P403 + P235

4.1 WGK Germany: 3

4.1 RTECS: DL0310000

4.1 Safety: Hazard Codes:?Xn,?Xi
Risk Statements: 22-40-36/37/38
R22: Harmful if swallowed?
R40: Limited evidence of a carcinogenic effect?
R36/37/38: Irritating to eyes, respiratory system and skin
Safety Statements: 36-45-36/37-26
S36: Wear suitable protective clothing?
S45: In case of accident or if you feel unwell, seek medical advice immediately (show the label whenever possible)?
S36/37: Wear suitable protective clothing and gloves?
S26: In case of contact with eyes, rinse immediately with plenty of water and seek medical advice
RIDADR: 3249
WGK Germany: 3
RTECS: DL0310000
F: 8-10
HazardClass: 6.1(b)
PackingGroup: III

4.2 Specification: ?Diltiazem HCl (CAS NO.33286-22-5)?is also called (2s-cis)-3-(Acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5h)-one hydrochloride ; (2s,3s)-(+)-cis-3-(Acetoxy)-5-(2-dimethylaminoethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one hydrochloride ; l-cis-Diltiazem HCl ; cis-(+)-3-(Acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxy-phenyl)-1,5-benzothiazepin-4(5h)-one hydrochloride .?Diltiazem HCl (CAS NO.33286-22-5) is soluble in water, methanol and chloroform, insoluble in ethanol and not soluble in benzene.?Diltiazem HCl (CAS NO.33286-22-5) is ddorless and bitter taste.

4.3 Toxicity: LD50 in male, female mice, male, female rats (mg/kg): 61, 58, 38, 39 i.v.; 260, 280, 520, 550 s.c.; 740, 640, 560, 610 orally (Nagao, 1972)

5. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

Acute toxicity - Oral, Category 4

2.2 GHS label elements, including precautionary statements

Pictogram(s)
Signal word	Warning
Hazard statement(s)	H302 Harmful if swallowed
Precautionary statement(s)
Prevention	P264 Wash ... thoroughly after handling. P270 Do not eat, drink or smoke when using this product.
Response	P301+P312 IF SWALLOWED: Call a POISON CENTER/doctor/\u2026if you feel unwell. P330 Rinse mouth.
Storage	none
Disposal	P501 Dispose of contents/container to ...

2.3 Other hazards which do not result in classification

none

View all

6. Synthesis Route

33286-22-5Total: 10 Synthesis Route

123-11-5 469 Suppliers

33286-22-5 242 Suppliers

Literatures:
Journal of the Chemical Society - Perkin Transactions 1, , # 23 p. 3501 - 3507
Yield: null

2419-67-2

33286-22-5 242 Suppliers

Literatures:
Journal of the Chemical Society - Perkin Transactions 1, , # 23 p. 3501 - 3507
Yield: null

42399-48-4 1 Suppliers

33286-22-5 242 Suppliers

Literatures:
Journal of Organic Chemistry, , vol. 57, # 3 p. 851 - 856
Yield: null

View all

7. Precursor and Product

precursor:

42399-40-6

201804-22-0

75472-91-2

138382-02-2

201804-19-5

108-22-5

201804-23-1

2419-67-2

123-11-5

42399-48-4

product :

42399-41-7

42399-40-6

8. Other Information

8.0 Usage: An L-type calcium channel blocker

8.1 Merck: 13,3226

8.2 BRN: 4228706

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

8.4 Chemical Properties: Fine Needles

8.5 Originator: Herbesser,TANABE SEIYAKU,Japan,1974

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

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

8.8 Uses: antihypertensive, sedative, antibacterial

8.9 Uses: Peripheral Vasodilator

8.10 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.

8.11 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.

8.12 Brand name: Cardizem (Biovail); Cartia (Andrx); Dilacor (Watson); Diltzac (Apotex); Taztia (Andrx); Tiazac (Biovail).

8.13 Therapeutic Function: Coronary vasodilator

8.14 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.

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

8.16 Biochem/physiol Actions: Product does not compete with ATP.

8.17 Storage Conditions: The N-alkylated lactam (0.317 mmol), Ac2O (1 mmol), Et3N (2 mmol) and DMAP (0.03 mmol) taken in CH2Cl2 (5 mL) were heated at reflux under N2 for 3 h. The mixture was poured into ice water and brine was added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (10 mL). The combined organic layers were washed with 5percent NH4OH (5 mL) solution, dried (Na2SO4) and evaporated. The residue was dissolved in MeOH (2 mL) and treated with anhydrous HCl gas till pH was 2. Ether (3 mL) was added to the resulting solution. The precipitated solids were collected by filtration and washed with 10percent MeOH-ether to afford diltiazem hydrochloride (92percent yield).The N-alkylated lactam (0.317 mmol), Ac2O (1 mmol), Et3N (2 mmol) and DMAP (0.03 mmol) taken in CH2Cl2 (5 mL) were heated at reflux under N2 for 3 h. The mixture was poured into ice water and brine was added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (10 mL). The combined organic layers were washed with 5percent NH4OH (5 mL) solution, dried (Na2SO4) and evaporated. The residue was dissolved in MeOH (2 mL) and treated with anhydrous HCl gas till pH was 2. Ether (3 mL) was added to the resulting solution. The precipitated solids were collected by filtration and washed with 10percent MeOH-ether to afford diltiazem hydrochloride (92percent yield).

8.18 Collision Cross Section: 196.1 ?2 [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

8.19 Mesh: Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS. (See all compounds classified as Antihypertensive Agents.)|A class of drugs that act by selective inhibition of calcium influx through cellular membranes. (See all compounds classified as Calcium Channel Blockers.)|Drugs used to cause dilation of the blood vessels. (See all compounds classified as Vasodilator Agents.)|Agents that affect the rate or intensity of cardiac contraction, blood vessel diameter, or blood volume. (See all compounds classified as Cardiovascular Agents.)

8.20 Mesh Entry Terms: Aldizem

8.21 Use Classification: Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

9. Computational chemical data

Molecular Weight: 450.97878g/mol
Molecular Formula: C₂₂H₂₇ClN₂O₄S
Compound Is Canonicalized: True
XLogP3-AA: null
Exact Mass: 450.1380062
Monoisotopic Mass: 450.1380062
Complexity: 565
Rotatable Bond Count: 7
Hydrogen Bond Donor Count: 1
Hydrogen Bond Acceptor Count: 6
Topological Polar Surface Area: 84.4
Heavy Atom Count: 30
Defined Atom Stereocenter Count: 2
Undefined Atom Stereocenter Count: 0
Defined Bond Stereocenter Count: 0
Undefined Bond Stereocenter Count: 0
Isotope Atom Count: 0
Covalently-Bonded Unit Count: 2
CACTVS Substructure Key Fingerprint: AAADceB7OABEAAAAAAAAAAAAAAAAAAAAAAAwYAAABYAAAAABQAAAHgQAAAAADBzl2Aayz4MABAiIAiXSWAKCCAAhKhAIiB1ObIgOZjLksZ+XMChkxhH46AeYyKCOIAAAAAAAAQBAAAAAAAACAAAAAAAAAA==

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