2-Propylpentanoic acid CAS 99-66-1

Introduction：Basic information about 2-Propylpentanoic acid CAS 99-66-1, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.

2-Propylpentanoic acid Basic information

• Product Name: 2-Propylpentanoic acid
• Synonyms: (n-C3H7)2CHCOOH;2 PP (base);2-n-Propylpentanoicacid;2-n-Propylvalericacid;2-Propylpentansαure;depakote;Di-n-propylessigsaure;dipropyl-aceticaci
• CAS: 99-66-1
• MF: C8H16O2
• MW: 144.21
• EINECS: 202-777-3
• Product Categories: Aliphatics;Intermediates & Fine Chemicals;Pharmaceuticals;Organic acids;Antiepileptic;Valproic acid Series;All Aliphatics;Pharmaceutical Raw Materials;K00001
• Mol File: 99-66-1.mol

2-Propylpentanoic acid Chemical Properties

• Melting point: -21.25°C (estimate)
• Boiling point: 220 °C (lit.)
• density: 0.9 g/mL at 25 °C (lit.)
• vapor pressure: 0.01 hPa (20 °C)
• refractive index: n20/D 1.425(lit.)
• Fp: 232 °F
• storage temp.: Store below +30°C.
• solubility: H₂O: slightly soluble
• form: Liquid
• pka: 4.6(at 25℃)
• color: Clear colorless to pale yellow
• explosive limit: 1%(V)
• Odor Threshold: 0.0033ppm
• Water Solubility: slightly soluble
• Merck: 14,9913
• BRN: 1750447
• BCS Class: 1,2
• Major Application: pharmaceutical (small molecule)
• Cosmetics Ingredients Functions: SKIN CONDITIONING
• InChI: 1S/C8H16O2/c1-3-5-7(6-4-2)8(9)10/h7H,3-6H2,1-2H3,(H,9,10)
• InChIKey: NIJJYAXOARWZEE-UHFFFAOYSA-N
• SMILES: CCCC(C(O)=O)CCC
• LogP: 1.59 at 22.1℃ and pH5
• CAS DataBase Reference: 99-66-1(CAS DataBase Reference)
• NIST Chemistry Reference: Valproic Acid(99-66-1)
• EPA Substance Registry System: Valproic acid (99-66-1)

Safety Information

• Hazard Codes: Xn,T,F
• Risk Statements: 22-36/37/38-39/23/24/25-23/24/25-11-34-61
• Safety Statements: 26-45-36/37-16-7-36/37/39-53
• RIDADR: UN 1230 3/PG 2
• WGK Germany: 3
• RTECS: YV7875000
• HazardClass: 8
• PackingGroup: III
• HS Code: 29159080
• Storage Class: 6.1C - Combustible acute toxic Cat.3 toxic compounds or compounds which causing chronic effects
• Hazard Classifications: Acute Tox. 4 Oral Eye Dam. 1 Repr. 1A Skin Irrit. 2
• Hazardous Substances Data: 99-66-1(Hazardous Substances Data)
• Toxicity: LD50 orally in rats: 670 mg/kg (Jenner)

2-Propylpentanoic acid Usage And Synthesis

Description

Valproate is a first- generation antiepileptic drug (AED) known with the proprietary brand names of Epilim® (Sanofi, Paris) and Episenta® (Desitin, Hamburg) in the UK and Depakote® (Sanofi, Paris) in the USA.

Generic formulation

MHRA/ CHM advice to minimize risk when switching patients with epilepsy between different manufacturers’ products (including generic products):

• The need for continued supply of a particular manufacturer’s product should be based on clinical judgment and consultation with the patient and/ or carer, taking into account factors such as seizure frequency and treatment history.

Indications

Epilepsy
Monotherapy and adjunctive therapy of focal and generalized seizures.

Recommendations summarized from NICE (2012)

• Seizure types: first line (generalized tonic- clonic seizures, tonic/ atonic seizures, absence seizures, myoclonic seizures, focal seizures), adjunctive (generalized tonic- clonic seizures, absence seizures, myoclonic seizures, focal seizures).
• Epilepsy types: first line (absence syndromes, juvenile myoclonic epilepsy, epilepsy with generalized tonic- clonic seizures only, idiopathic generalized epilepsy, benign epilepsy with centrotemporal spikes, Panayiotopoulos syndrome, late- onset childhood occipital epilepsy, Dravet syndrome, Lennox– Gastaut syndrome), adjunctive (absence syndromes, juvenile myoclonic epilepsy, epilepsy with generalized tonic- clonic seizures only, idiopathic generalized epilepsy, benign epilepsy with centrotemporal spikes, panayiotopoulos syndrome, late- onset childhood occipital epilepsy).

Psychiatry
Treatment of acute mania associated with bipolar disorder.

Neurology
Migraine prophylaxis (unlicensed).

Dose titration

Epilepsy
600 mg daily divided into 1 or 2 doses, then increased by 150– 300 mg every 3 days; usual maintenance 1000– 2000 mg (or 20–30 mg/ kg) daily divided into 1 or 2 doses (max 2500 mg daily).

Mania
750 mg daily divided into 1 or 2 doses, adjusted according to response; usual maintenance 000– 2000 mg daily divided into 1 or 2 doses (doses greater than 45 mg/ kg daily require careful monitoring).

Plasma levels monitoring

Although plasma levels can be measured, and a therapeutic range has been postulated (40– 100 mg/ L), plasma valproate concentrations are not a useful index of efficacy. Therefore, routine monitoring is unhelpful.

Cautions

• Patients with systemic lupus erythematosus.
• Patients with a personal or family history of severe hepatic dysfunction (contraindication).
• Patients with known metabolic disorders (contraindication).
• • Patients with suspected metabolic disorders (contraindication).
• • Patients with porphyria (contraindication).

Adverse effects

Valproate can be associated with adverse effects at the level the nervous system and other systems.

Interactions

With AEDs

• AEDs with enzyme inducing effect (including carbamazepine, phenobarbital, phenytoin) decrease valproate plasma concentrations.
• Valproate reduces the metabolism of lamotrigine and increases the lamotrigine mean half- life by nearly two fold. This interaction may lead to increased lamotrigine toxicity, in particular serious skin rashes.
• Valproate increases phenobarbital and primidone plasma concentrations with exacerbation of its adverse effects (sedation may occur).
• Valproate may potentiate toxic effects of carbamazepine.
• Valproate decreases phenytoin total plasma concentration, but displaces phenytoin from its plasma protein binding sites and reduces its hepatic catabolism, thereby increasing phenytoin free form with possible overdose symptoms.
• Concomitant administration of valproate and topiramate has been associated with encephalopathy and/ or hyperammonaemia. In patients taking these two AEDs, careful monitoring of signs and symptoms is advised (especially in patients with pre- existing encephalopathy).

With other drugs

• Mefloquine and chloroquine increase valproate metabolism and may lower the seizure threshold (therefore, epileptic seizures may occur in cases of combined therapy).
• Decreases in blood levels of valproate have been reported when it is coadministered with carbapenem antibiotics (such as imipenem, panipenem, meropenem), resulting in a 60– 00% decrease in valproate levels within 2 days, sometimes associated with convulsions.
• Colestyramine may decrease the absorption of valproate.
• Rifampicin may decrease valproate blood levels, resulting in a lack of therapeutic effect.
• In case of concomitant use of valproate and highly protein bound agents (e.g. aspirin), free valproate plasma levels may be increased.
• Valproic acid plasma levels may be increased (as a result of reduced hepatic metabolism) in case of concomitant use with cimetidine or erythromycin.
• Valproate may potentiate the effect of other psychotropics such as antipsychotics (especially olanzapine), MAO inhibitors, antidepressants, and benzodiazepines.
• Valproate may raise zidovudine plasma concentration, possibly leading to increased zidovudine toxicity.
• The anticoagulant effect of warfarin and other coumarin anticoagulants may be increased following displacement from plasma protein binding sites by valproate.

With alcohol/food
There are no specific foods that must be excluded from diet when taking valproate. Alcohol intake is not recommended during treatment with valproate.

Special populations

Hepatic impairment
Avoid if possible: hepatotoxicity and hepatic failure may occasionally occur (usually in first 6 months). Avoid in active liver disease.

Renal impairment
In patients with renal insufficiency, it may be necessary to decrease dosage of valproate. As monitoring of plasma concentrations may be misleading, dosage should be adjusted according to clinical monitoring.

Pregnancy

• Valproate is associated with the highest risk of major and minor congenital malformations (in particular neural tube defects) and neurodevelopmental effects among AEDs.
• Therefore, valproate should not be used during pregnancy or in women of child- bearing age unless there is no safer alternative and only after a careful discussion of the risks.
• If valproate is to be used during pregnancy, the lowest effective dose should be prescribed in divided doses or as modified- release tablets to avoid peaks in plasma valproate concentrations (doses greater than 000 mg daily are associated with an increased risk of teratogenicity). The dose should be monitored carefully during pregnancy and after birth, and adjustments made on a clinical basis.
• Avoid use in the treatment of epilepsy and bipolar disorder unless there is no safer alternative and only after a careful discussion of the risks (effective contraception advised in women of child- bearing potential).
• Neonatal bleeding (related to hypofibrinaemia) and hepatotoxicity have been reported, and specialist prenatal monitoring should be instigated when valproate has been taken in pregnancy.
• Valproate is excreted in human milk with a concentration ranging from 1 to 10% of maternal serum levels. Haematological disorders have been shown in breastfed newborns/ infants of treated women. A decision must be made whether to discontinue breastfeeding or to discontinue/ abstain from valproate therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Behavioural and cognitive effects in patients with epilepsy

The incidence of adverse psychiatric effects associated with valproate in patients with epilepsy is overall negligible (apart from reports of depression, irritability, and other behavioural symptoms in the context of encephalopathy). Cognitive difficulties have occasionally been reported in patients with epilepsy treated with valproate, especially affecting attention and memory functions.

Psychiatric use

Valproate is an effective mood stabilizer, licensed for the treatment of acute mania in patients with bipolar disorder. Although it has no formal indication, it is also considered a first- line agent for maintenance treatment in bipolar disorder. There is evidence suggesting efficacy of valproate in the treatment of hostility among patients with acute alcohol- associated hallucinosis or schizophrenia, and in impulsive/ aggressive behaviours, either in isolation or in the context of comorbid bipolar disorder or personality disorder. Available data show a limited efficacy of valproate in depressive disorders, schizophrenia, pathological gambling, as well as benzodiazepine/ cannabis/ cocaine dependence and acute alcohol withdrawal.

Description

Valproic acid and its salts are a new group of antiepileptic drugs that differs from theknown drugs both structurally and in terms of its mechanism of action. It is believed thatit acts on the metabolism of the GABA system. Valproic acid has been shown to elevatethe level of GABA in the brain by means of competitive inhibition of GABA transaminaseand the dehydrogenase of succinic semialdehyde.
This drug not only exhibits anticonvulsant action, but also betters the mental conditionof the patient.

Chemical Properties

Colorless Liquid

Originator

Depakote,Abbott

Uses

Antiepileptic; increases levels of -aminobutyric acid(GABA) in the brain. Anticonvulsant that also has efficacy as a mood stabilizer in bipolar disorder

Uses

Antiepileptic; Anticonvulsant that also acts as a mood stabilizer for those with bipolar disorder.

Uses

For treatment and management of seizure disorders, mania, and prophylactic treatment of migraine headache. In epileptics, valproic acid is used to control absence seizures, tonic-clonic seizures (grand mal), complex partial seizures, and the seizures asso

Uses

2-Propylpentanoic acid has been used as a supplement in mouse embryonic fibroblast - conditioned medium (MEF-CM)?to feed the cells.

Definition

ChEBI: A branched-chain saturated fatty acid that comprises of a propyl substituent on a pentanoic acid stem.

Manufacturing Process

Dipropyl acetic acid or valproic acid may be prepared the next way.Propylbromide is mixed with cyanacetic acid in the presence of sodiumethylate, made from absolute ethanol and sodium. By that prepared α,α-dipropylcyanacetic acid ethyl ester is saponified with equimolecular amountsof NaOH to give dipropylacetonitril. The desired dipropylacetic acid is producedby saponification of dipropylacetonitryl with aquatic NaOH. It is colorlessliquid. BP 219°-220°C.
Sodium salt of this acid may be prepared by adding of equivalent of NaOH.

Brand name

Depakene (Abbott);Valproine;Vederon.

Therapeutic Function

Anticonvulsant

Biological Functions

Although it is marketed as both valproic acid(Depakene) and as sodium valproate (Depakote), it isthe valproate ion that is absorbed from the gastrointestinaltract and is the active form.
As with several other AEDs, it is difficult to ascribea single mechanism of action to valproic acid.This compoundhas broad anticonvulsant activity, both in experimentalstudies and in the therapeutic management ofhuman epilepsy.Valproic acid has been shown to blockvoltage-dependent sodium channels at therapeuticallyrelevant concentrations. In several experimental studies,valproate caused an increase in brain GABA; themechanism was unclear.There is evidence that valproate may also inhibit T-calcium channels and that this maybe important in its mechanism of action in patients withabsence epilepsy.

General Description

VPA is an established AED with a simple chemical structurebut an unusually broad spectrum of action. It is generallywell tolerated, but its use is limited by two rare but significanttoxic side effects (hepatotoxicity and teratogenicity) thatcan be dose-dependent or idiosyncratic in nature.Thesedrawbacks are apparently shared by its equipotent activemetabolite, (E)-2-propyl-2-pentenoic acid (2-ene-VPA).
VPA is also an important inhibitor of the cytochrome P450isozymes, mainly of CYP2C9 and also of uridine diphosphate(UDP)-glucuronyl transferase and epoxide hydrolase.

General Description

Clear colorless liquid.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

2-Propylpentanoic acid is a carboxylic acid. Carboxylic acids donate hydrogen ions if a base is present to accept them. They react in this way with all bases, both organic (for example, the amines) and inorganic. Their reactions with bases, called "neutralizations", are accompanied by the evolution of substantial amounts of heat. Neutralization between an acid and a base produces water plus a salt. Carboxylic acids with six or fewer carbon atoms are freely or moderately soluble in water; those with more than six carbons are slightly soluble in water. Soluble carboxylic acid dissociate to an extent in water to yield hydrogen ions. The pH of solutions of carboxylic acids is therefore less than 7.0. Many insoluble carboxylic acids react rapidly with aqueous solutions containing a chemical base and dissolve as the neutralization generates a soluble salt. Carboxylic acids in aqueous solution and liquid or molten carboxylic acids can react with active metals to form gaseous hydrogen and a metal salt. Such reactions occur in principle for solid carboxylic acids as well, but are slow if the solid acid remains dry. Even "insoluble" carboxylic acids may absorb enough water from the air and dissolve sufficiently in 2-Propylpentanoic acid to corrode or dissolve iron, steel, and aluminum parts and containers. Carboxylic acids, like other acids, react with cyanide salts to generate gaseous hydrogen cyanide. The reaction is slower for dry, solid carboxylic acids. Insoluble carboxylic acids react with solutions of cyanides to cause the release of gaseous hydrogen cyanide. Flammable and/or toxic gases and heat are generated by the reaction of carboxylic acids with diazo compounds, dithiocarbamates, isocyanates, mercaptans, nitrides, and sulfides. Carboxylic acids, especially in aqueous solution, also react with sulfites, nitrites, thiosulfates (to give H2S and SO3), dithionites (SO2), to generate flammable and/or toxic gases and heat. Their reaction with carbonates and bicarbonates generates a harmless gas (carbon dioxide) but still heat. Like other organic compounds, carboxylic acids can be oxidized by strong oxidizing agents and reduced by strong reducing agents. These reactions generate heat. A wide variety of products is possible. Like other acids, carboxylic acids may initiate polymerization reactions; like other acids, they often catalyze (increase the rate of) chemical reactions. 2-Propylpentanoic acid is incompatible with bases, oxidizing agents and reducing agents. 2-Propylpentanoic acid is corrosive. .

Fire Hazard

2-Propylpentanoic acid is combustible.

Biochem/physiol Actions

Anticonvulsant that also has efficacy as a mood stabilizer in bipolar disorder

Mechanism of action

Although its mechanism of action is not clearly established, valproate appears to increase the inhibitory effect of GABA,possibly by activation of glutamic acid decarboxylase or inhibition of GABA-transaminase). The high drugconcentrations required, however, cast doubt on the clinical relevance of this effect. Furthermore, valproate recently has beenshown to decrease the uptake of GABA into cultured astrocytes; this action may contribute to the AED efficacy. Valproateis known to produce a blockade of high-frequency repetitive firing by slowing the rate of Na+ recovery from inactivation, amechanism consistent with the actions of phenytoin and CBZ. Valproate blocks the low-threshold T-type Ca2+ channel.Consequently, the overall therapeutic utility of valproate is likely caused by multiple effects.
Valproate is indicated for initial or adjunct treatment of absence seizures or as an adjunct when absence seizures occur incombination with either tonic-clonic seizures, myoclonic seizures, or both. For patients with unambiguous idiopathic generalizedepilepsy, valproate often is the drug of choice, because it controls absence, myoclonic, and generalized tonic-clonic seizureswell. It also is approved by U.S. FDA for use in complex partial seizures, occurring with or without other seizure types inadults or children 10 years of age or older. In new patients with typical absence seizures, ethosuximide is preferred tovalproate because of the latter drug's risk of producing hepatotoxicity. In a comparative trial, sodium valproate andethosuximide were equally effective when either drug was given alone or in combination with other AEDs in children with typicalabsence seizures. In atypical absence seizures (Lennox-Gastaut syndrome), sodium valproate is more effective, whereas inmyoclonic seizures, it is less effective than clonazepam. Valproate is approved by the U.S. FDA for use in bipolar disorder andagainst migraine headaches.

Pharmacokinetics

Valproate undergoes rapid and complete absorption, which is only slightly slowed by food. It is 90% protein bound, and itsclearance is dose-dependent because of an increase in the free fraction of the drug at higher doses. It is metabolized almostentirely by the liver, with 30 to 50% of an orally administered dose being eliminated in the urine as its acyl glucuronideconjugate, 40% from mitochondrial β-oxidation, approximately 15 to 20% by ω-oxidation, and less than 3% is excretedunchanged in urine. Its major active metabolite is (E)-2-ene valproate (trans 2-ene valproate). Its 4-ene metabolite has beenproposed to be a reactive metabolite responsible for the hepatotoxicity of valproate. Other metabolites foundin the urine include 3-oxo- and 4-hydroxyvalproate. The elimination half-life for valproate ranged from 9 to 16 hours followingoral dosing regimens of 250 to 1,000 mg. Patients who are not taking enzyme-inducing AEDs (carbamazepine, phenytoin, andphenobarbital) will clear valproate more rapidly; therefore, monitoring of AED plasma concentrations should be intensifiedwhenever concurrent AEDs are introduced or withdrawn.

Clinical Use

Valproic acid is well absorbed from the gastrointestinaltract and is highly bound (~90%) to plasma protein,and most of the compound is therefore retainedwithin the vascular compartment.Valproate rapidly entersthe brain from the circulation; the subsequent declinein brain concentration parallels that in plasma, indicatingequilibration between brain and capillaryblood. A large number of metabolites have been identified,but it is not known whether they play a role in theanticonvulsant effect of the parent drug. Valproic acidinhibits the metabolism of several drugs, including phenobarbital,primidone, carbamazepine, and phenytoin,leading to an increased blood level of these compounds.At high doses, valproic acid can inhibit its own metabolism.It can also displace phenytoin from binding siteson plasma proteins, with a resultant increase in unboundphenytoin and increased phenytoin toxicity. Inthis instance, the dosage of phenytoin should be adjustedas required. These examples reinforce the needto determine serum anticonvulsant levels in epilepticpatients when polytherapy is employed.
Valproic acid has become a major AED against severalseizure types. It is highly effective against absenceseizures and myoclonic seizures. In addition, valproicacid can be used either alone or in combination withother drugs for the treatment of generalized tonic–clonic epilepsy and for partial seizures with complexsymptoms.

Side effects

The most serious adverse effect associated with valproicacid is fatal hepatic failure. Fatal hepatotoxicity ismost likely to occur in children under age 2 years, especiallyin those with severe seizures who are given multipleanticonvulsant drug therapy. The hepatotoxicity isnot dose related and is considered an idiosyncratic reaction;it can occur in individuals in other age groups,and therefore, valproic acid should not be administeredto patients with hepatic disease or significant hepaticdysfunction or to those who are hypersensitive to it.Valproic acid administration has been linked to an increasedincidence of neural tube defects in the fetus ofmothers who received valproate during the firsttrimester of pregnancy. Patients taking valproate maydevelop clotting abnormalities.
Valproic acid causes hair loss in about 5% of patients,but this effect is reversible. Transient gastrointestinaleffects are common, and some mild behavioraleffects have been reported. Metabolic effects, includinghyperglycemia, hyperglycinuria, and hyperammonemia,have been reported. An increase in body weight alsohas been noted. Valproic acid is not a CNS depressant,but its administration may lead to increased depressionif it is used in combination with phenobarbital, primidone,benzodiazepines, or other CNS depressant agents.

Synthesis

Valproic acid, 2-propylvaleric acid (9.4.3), is synthesized by the alkylation of cyanoaceticester with two moles of propylbromide, to give dipropylcyanoacetic ester (9.4.1).Hydrolysis and decarboxylation of the carbethyoxy group gives dipropylacetonitrile(9.4.2), which is hydrolyzed into valproic acid (9.4.3) [12¨C15].

Solubility in organics

soluble in most organic solvents, including methanol, chloroform, and ether, solubility in water: 1.27 mg/mL.

references

[1] phiel c j, zhang f, huang e y, et al. histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. journal of biological chemistry, 2001, 276(39): 36734-36741.
[2] chateauvieux s, morceau f, dicato m, et al. molecular and therapeutic potential and toxicity of valproic acid. biomed research international, 2010, 2010.

2-Propylpentanoic acid Preparation Products And Raw materials

• Raw materials: 2,2-Dipropylmalonic acid-->Sodium-->1-Bromopropane
• Preparation Products: 2-PROPYL-1-PENTANOL