124832-27-5

Basic information

• Product Name: Valacyclovir hydrochloride
• Synonyms: 2-[(2-azanyl-6-oxo-3H-purin-9-yl)methoxy]ethyl (2S)-2-azanyl-3-methyl-butanoate hydrochloride;L-Valacyclovir Hydrochloride;Valacyclovir Hydrochloride (200 mg);L-Valine 2-[(2-AMino-1,6-dihydro-6-oxo-9H-purin-9yl)Methoxy]ethyl Ester Hydrochlroride Salt;Zelitrex;L-Valine 2-(2-Amino-1,6-dihydro-6-oxo-9H-purin-9-ylmethoxy)ethyl Ester Hydrochloride;L-Valine-2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester, hydrochloride (1:1);Valaciclovir hydrochloride (anhydrous)
• CAS NO: 124832-27-5
• Molecular Formula: C13H21ClN6O4
• Molecular Weight: 360.8
• EINECS: 1308068-626-2
• Product Categories: API;Active Pharmaceutical Ingredients;Nucleotides and Nucleosides;Bases & Related Reagents;Intermediates & Fine Chemicals;Nucleotides;Pharmaceuticals;API's;Valacyclovir
• Mol File: 124832-27-5.mol

Chemical Properties

• Melting Point: 170-172°C
• Boiling Point: 588.4 °C at 760 mmHg
• Flash Point: 309.7 °C
• Appearance: white/
• Density: 1.55g/cm3
• Vapor Pressure: 7.95E-14mmHg at 25°C
• Refractive Index: 1.673
• Storage Temp.: Refrigerator
• Solubility: H2O: >20mg/mL
• Stability: Hygroscopic
• Merck: 14,9899
• CAS DataBase Reference: Valacyclovir hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: Valacyclovir hydrochloride(124832-27-5)
• EPA Substance Registry System: Valacyclovir hydrochloride(124832-27-5)

Safety Data

• Hazard Codes: Xi,Xn
• Statements: 36/37/38-22
• Safety Statements: 26-36-24/25
• RIDADR: 3077
• WGK Germany: 3
• Hazardous Substances Data: 124832-27-5(Hazardous Substances Data)

Usage

Uses

Used in Antiviral Treatment:
Valacyclovir hydrochloride is used as an antiviral drug for the management of herpes simplex, herpes zoster, and herpes B infections. It is employed as a prodrug to improve the pharmacokinetic profile of acyclovir, allowing for rapid absorption and conversion to the active compound acyclovir in virus-infected cells.
Used in Herpes Simplex Virus Infections:
Valacyclovir hydrochloride is used as a treatment for herpes simplex virus (HSV) infections of the skin and mucous membranes, including initial and recurrent genital herpes. It is used for its improved pharmacokinetic profile compared to acyclovir, providing effective management of these infections.
Used in Herpes Zoster (Shingles) Treatment:
Valacyclovir hydrochloride is used as a treatment for herpes zoster (shingles) in immunocompromised patients. It has been approved for this use due to its effectiveness in managing the condition and its comparable side effect profile with bioequivalent doses of acyclovir.
Used in Cytomegalovirus Infection Suppression:
Valacyclovir hydrochloride is reportedly in clinical trials for the suppression of cytomegalovirus infection and disease in renal transplant patients, demonstrating its potential use in managing viral infections in immunocompromised populations.

Originator

Glaxo Wellcome (United Kingdom)

Pharmacokinetics

The binding of valacyclovir to human plasma proteins ranges between 13.5 to 17.9%. The plasma elimination half-life of acyclovir is 2.5 to 3.3 hours. The bioavailability of valacyclovir hydrochloride is 54%, compared to approximately 20% for oral acyclovir, and it is as effective as acyclovir in decreasing the duration of pain associated with posttherapeutic neuralgia and episodes of genital lesion healing.

Side effects

The adverse effects are similar to acyclovir, which include nausea, headache, vomiting, constipation, and anorexia.

InChI:InChI=1/C13H20N6O4/c1-7(2)8(14)12(21)23-4-3-22-6-19-5-16-9-10(19)17-13(15)18-11(9)20/h5,7-8H,3-4,6,14H2,1-2H3,(H3,15,17,18,20)/t8-/m0/s1

Synthetic route

2-[(2-amino-1,6-dihydro-6-oxo-9H-purine-9-yl)methoxy]ethyl N-[(benzyloxy)carbonyl]-L-valinate (124832-31-1) → valacyclovir Hydrochloride (124832-27-5)

Conditions	Yield
Stage #1: 2-[(2-amino-1,6-dihydro-6-oxo-9H-purine-9-yl)methoxy]ethyl N-[(benzyloxy)carbonyl]-L-valinate With 5 % alumina-supported palladium; hydrogen In N,N-dimethyl-formamide at 30℃; under 2942.29 Torr; Stage #2: With hydrogenchloride In water at 10℃; pH=3 - 4;	98.5%
With hydrogenchloride; 5%-palladium/activated carbon; hydrogen In water at 25 - 30℃; under 2250.23 - 6000.6 Torr; Concentration;	92%
With hydrogenchloride; 5%-palladium/activated carbon; hydrogen In water at 25 - 30℃; under 2250.23 - 6000.6 Torr;	92%

acycloguanosine (59277-89-3) → valacyclovir Hydrochloride (124832-27-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 3.5 g / 4-dimethylaminopyridine; DCC / dimethylformamide / 66 h / 20 °C 2: aq. HCl; hydrogen / palladium on charcoal / methanol; tetrahydrofuran / 18 h / 20 °C View Scheme

9-[(acetoxyethoxy)methyl]guanine (102728-64-3) → valacyclovir Hydrochloride (124832-27-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: SIRC cell lysate; Dulbecco's Modified Phosphite-Buffer Saline / 34 °C / pH 7.4 2: 3.5 g / 4-dimethylaminopyridine; DCC / dimethylformamide / 66 h / 20 °C 3: aq. HCl; hydrogen / palladium on charcoal / methanol; tetrahydrofuran / 18 h / 20 °C View Scheme

2-[(2-amino-1,6-dihydro-6-oxo-9H-purine-9-yl)methoxy]ethyl N-[(benzyloxy)carbonyl]-L-valinate (124832-31-1) → 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl) methoxy]ethyl-L-valinate hydrochloride + valacyclovir Hydrochloride (124832-27-5)

Conditions	Yield
With hydrogenchloride; formic acid; palladium In water; acetone

Valacyclovir (124832-26-4) → valacyclovir Hydrochloride (124832-27-5)

Conditions	Yield
With hydrogenchloride In water; N,N-dimethyl-formamide; acetonitrile at 0 - 5℃; for 0.5h; pH=2; Product distribution / selectivity;
With hydrogenchloride In water; ethyl acetate; N,N-dimethyl-formamide at 5 - 50℃; for 0.5h; pH=2; Product distribution / selectivity;
With hydrogenchloride In water; N,N-dimethyl-formamide; isopropyl alcohol at 3 - 5℃; for 0.5h; pH=2; Product distribution / selectivity;
With hydrogenchloride In tetrahydrofuran; water; N,N-dimethyl-formamide at 15℃; for 0.5h; pH=2; Product distribution / selectivity;
With hydrogenchloride In water; N,N-dimethyl-formamide; acetone at 5 - 50℃; for 0.5h; pH=2; Product distribution / selectivity;

Boc-L-valacyclovir (502421-44-5) → valacyclovir Hydrochloride (124832-27-5)

Conditions	Yield
With hydrogenchloride In methanol; dichloromethane; water at 80℃; Solvent; Temperature; Flow reactor;	31 g

valacyclovir Hydrochloride (124832-27-5) → 2-[(2-Amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl L-valinate hydrochloride monohydrate

Conditions	Yield
With water In ethanol at 20 - 75℃; Product distribution / selectivity; Heating / reflux;

valacyclovir Hydrochloride (124832-27-5) → Valacyclovir hydrochloride dihydrate

Conditions	Yield
With water In ethanol at 20℃;
With water In N,N-dimethyl-formamide at 51℃; for 0.166667h;

valacyclovir Hydrochloride (124832-27-5) → valacyclovir hydrochloride sesquihydrate

Conditions	Yield
With water In ethanol at 20℃;

valacyclovir Hydrochloride (124832-27-5) → acycloguanosine (59277-89-3)

Conditions	Yield
With ammonia In methanol; chloroform at 20℃; for 0.25h;

NBD chloride (10199-89-0) + valacyclovir Hydrochloride (124832-27-5) → C19H21N9O7

Conditions	Yield
In methanol at 70℃; for 0.333333h; pH=8.5; pH-value; Concentration; Temperature;

Upstream product

• 59277-89-3 acycloguanosine 
• 102728-64-3 9-[(acetoxyethoxy)methyl]guanine 
• 124832-31-1 2-[(2-amino-1,6-dihydro-6-oxo-9H-purine-9-yl)methoxy]ethyl N-[(benzyloxy)carbonyl]-L-valinate 
• 124832-26-4 Valacyclovir 
• 502421-44-5 Boc-L-valacyclovir 
• 124832-32-2 CBZ-L-valineacyclovir 

Downstream Products

• 59277-89-3 acycloguanosine 

Relevant articles and documents

Preparation method of valaciclovir hydrochloride

The invention relates to a preparation method of valaciclovir hydrochloride. The preparation method comprises following steps: (1) CBZ-L-valine-acyclovir synthesis: adding N,N-dimethyl formamide, N-carbobenzyloxy-L-valine, 4-dimethylamino pyridine, and ac

PROCESS FOR THE PREPARATION OF VALACYCLOVIR

The present invention relates to an improved process for the preparation of Valacyclovir or pharmaceutically acceptable salts thereof, which comprises reaction of amine -protected Valacyclovir or its salt with deprotecting agent in a continuous flow reactor.

PROCESS FOR THE PREPARATION OF VALACYCLOVIR HYDROCHLORIDE

The present invention provides a process for the preparation of 2-[(2-amino-1,6-dihydro-6-oxo-9H-yl)]ethyl L-valine ester hydrochloride (valacyclovir hydrochloride) of formula I comprising deprotection of N-[(benzyloxy)carbonyl]-L-valine-2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester, of formula II using 5% palladium on carbon as a catalyst and mineral acid in the presence of water, avoiding use of organic solvents under hydrogen pressure to yield valacyclovir hydrochloride having yield of ≧90% and purity of ≧99.5%, pharmaceutically acceptable grade. The valacyclovir hydrochloride obtained using the process of the present invention is valacyclovir hydrochloride polymorphic Form I.

A PROCESS FOR THE PREPARATION OF VALACYCLOVIR HYDROCHLORIDE

The present invention provides a process for the preparation of 2-[(2-amino-1,6-dihydro- 6-oxo-9H-purin-9-yl)methoxy]ethyl L-valine ester hydrochloride (valacyclovir hydrochloride) of formula I comprising deprotection of N-[(benzyloxy)carbonyl]-L- valine-2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl) methoxy]ethyl ester, of formula II using 5% palladium on carbon as a catalyst and mineral acid in the presence of water, avoiding use of organic solvents under hydrogen pressure to yield valacyclovir hydrochloride having yield of ≥90% and purity of ≥99.5%, pharmaceutically acceptable grade. The valacyclovir hydrochloride obtained using the process of the present invention is valacyclovir hydrochloride polymorphic Form I.

An efficient and large scale process for synthesis of valacyclovir

A facile, commercially viable and large scale process is developed for an antiviral drug substance, valacyclovir hydrochloride. Several process related critical factors including organic and heavy metal impurities are efficiently addressed in this process.

VALACYCLOVIR PROCESS

A process for preparing valacyclovir or a salt thereof.

Valacyclovir polymorphs and a process for the preparation thereof

A process for the preparation of valacyclovir hydrochloride in monohydrate form, as well as of several other hydrate and anhydrous forms, and novel hydrate polymorphic forms obtainable by said process.

METHOD FOR REDUCING RESIDUAL ALCOHOLS IN CRYSTALLINE VALACYCLOVIR HYDROCHLORIDE

Provided is valacyclovir hydrochloride stable against formation of N’-formylvalacyclovir upon storage at elevated humidity and pharmaceutical compositions including such valacyclovir hydrochloride.

NOVEL PSEUDOMORPH OF VALACICLOVIR HYDROCHLORIDE

The present invention relates to a stable novel pseudomorph of Valaciclovir hydrochloride and the process for its preparation by the debenzylation of 2-[(2-Amino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl N- [(benzyloxy)carbonyl]L-valinate by bubbling hydrogen gas in presence of HCl, isolating the product in a mixture of ethanol and water followed by crystallization in aq.ethanol, drying under vacuum and allowing to adsorb moisture at ambient conditions.

Crystalline forms of valacyclovir hydrochloride

Provided are novel crystalline forms of valacyclovir hydrochloride, in particular a novel hydrated form of valacyclovir hydrochloride having about 6% to about 10% by weight water. Also provided are methods for making the novel crystalline forms.