Originator
Calcium D-Pantothenate,Arocor Holdings Inc.
History
Pantothenic acid (PA), also known as vitamin B5, is essential to all forms of life. Its name is derived from the Greek word pantos that means “everywhere”, which is appropriate for this widely, distributed vitamin.
Definition
ChEBI: Calcium pantothenate is a polymer.
Manufacturing Process
A mixture of 288 g (4 mols) of isobutyraldehyde, 288 g of methanol was
cooled to 10°C and 170 g (2 mols) of 36.6% formalin containing 8.5 g (3%
based on isobutyraldehyde) of sodium hydroxide was added dropwise over a
55 minute period to produce alpha,alpha-dimethyl-beta-hydroxy-propionaldehyde. The mixture was stirred for an additional 2 hours at 10-15°C
and then contacted with acetic acid to neutralize the catalyst. The excess
isobutyraldehyde and methanol were stripped off at a kettle temperature of
50°C at 25 mm. To the residual α,α-dimethyl-beta-hydroxypropionaldehyde a
mixture of 260 ml of methanol and 2 g (0.75%) sodium cyanide was added
and the solution cooled to 10°C before adding 59.4 g (2.2 mols) of hydrogen
cyanide dropwise over a 35 minute period to produce α,γ-dihydroxy-β,β-
dimethylbutyronitrile. The mixture was stirred at 10°C for one hour period and
then contacted with acetic acid to neutralize the catalyst before stripping off
the excess methanol to a kettle temperature of 45°C at 18 mm. The crude
cyanohydrin was then hydrolysed by heating with 4 mols of concentrated
hydrochloric acid at 80°C for 2 hours, then diluting with an equal volume of
water and heating at 100°C for an additional 8 hours. The aqueous mixture
was extracted continuously with ethylene dichloride. The solvent was removed, and pantolactone (B. P. 131°C/19 mm, M.P. 61-77°C, 96.5% purity
by saponification) was obtained by distillation in 71.5% yield based on
formaldehyde and 55% efficiency based on isobutyraldehyde.
26 grams of racemic pantolactone (0.2 mol) and 1.1 grams of sodium
methoxide (0.02 mol) contained in 30 ml of methanol, were added to 78.8
grams of 1-brucine (0.2 mol) contained in 156 ml of methanol. The resulting
mixture was refluxed for 1.5 hours and allowed to stand at room temperature
overnight. After centrifuging, washing with methanol and drying, 65.4 grams
of D-(-)-pantolactone 1-brucine (62% of theory based upon all of the racemic
pantolactone) melting at 203° to 206°C were obtained. Upon chilling the
mother liquor, 13.46 grams of additional complex melting at 175° to 177°C
were obtained.
D-(-)-Pantolactone was obtained from the complex in the following manner.
The 65.4 grams of complex obtained above were treated with 65 ml of
chloroform and 5.35 grams of sodium hydroxide contained in 35 ml of water
for one hour at room temperature. The aqueous layer was extracted 6 times
with 20 ml portions of chloroform in order to remove the brucine. The sodium
pantoate contained in the aqueous layer was relactonized by treatment with
11 ml of concentrated hydrochloric acid. Extraction of the crude D-(-)-
pantolactone yielded 15.29 grams. This material was then recrystallized from
7 ml of methyl isobutyl ketone and 7 ml hexane thereby yielding 9.77 grams
of D-(-)-pantolactone (37% of theory). The αD25 was -44.8°.
Into a vessel equipped with an agitator and reflux condenser are placed
approximately 52 parts by weight of α-hydroxy-β,β-di-methyl-γ-butyrolactone,
approximately 36 parts by weight of β-alanine, about 40 parts by weight of
diethylamine and about 100 parts by weight of anhydrous methanol. The
mixture is stirred and refluxed for about 12 hours until the reaction is
complete as evidenced by the dissolution of the β-alanine. To this resulting
mass is gradually added 8 parts by weight of calcium metal nodules or pellets
and refluxing continued until the metal is dissolved. The diethylamine and
alcohol are distilled off until the residue becomes viscous. The viscous residue
is dried under vacuum at 100°C. The solid residue recovered, as biologically
assayed, indicated a 91% yield of calcium pantothenate.
Reactions
Pantothenic acid is a constituent of coenzyme A, which participates in numerous enzyme reactions. CoA was discovered as an essential cofactor for the acetylation of sulfanilamide in the liver and of choline in the brain.
Brand name
Calpan (BASF); Pantholin
(Lilly).
Therapeutic Function
Vitamin
Biological Functions
Calcium D-Pantothenate accelerates the wound healing process by increasing the number of migrating cells, their distance and hence their speed. In addition, cell division is increased and the protein synthesis changed. Hence, higher quantities of pantothenate are locally required to enhance wound healing.
General Description
The first suggestion for the existance of vitamin B5 came from Carter et al. in 1930; although it was never characterized or isolated. This vitamin is synthesized by most green plants and microorganisms. Excellent sources of the vitamin are liver, egg yolk, whole grains, and fortified ready-to-eat cereals. However, as the original name implies, many foods contain sufficient pantothenic acid to supply dietary needs.
Chemically, pantothenic acid is considered to be aβ-alanine derivative of the asymmetric pantoic acid and thus shows asymmetry. Only the naturally occurring D(+)- stereoisomer (with R configuration) is biologically active and the L(-)-stereoisomer (with S configuration) is inactive. When its carboxylate functional group is attached through an amide linkage with β-mercaptoethylamine, it is known as pantetheine (also spelled pantotheine). The biologically active form of pantothenic acid, CoA, is formed when the terminal alcoholic function of pantetheine is attached to ADP 3'-phosphate.
Biochem/physiol Actions
The calcium salts of panthenol are commonly used for pharmaceutical preparations. Pantothenate is a component of coenzyme A and is useful in its synthesis. Pantothenic acid is also involved in the synthesis of heme, cholesterol and fatty acids. Since vitamin B5 is found in all foods, its deficiency is not commonly observed.
Clinical Use
The only therapeutic indication for pantothenic acid is intreatment of a known or suspected deficiency of this vitamin.Because of the ubiquitous nature of pantothenic acid, deficiencystates of this vitamin are only seen experimentally byuse of synthetic diets devoid of the vitamin, by use of thevitamin antagonist, ω-methylpantothenic, or both. In a 1991review, Tahiliani and Beinlich described that the mostcommon symptoms associated with pantothenic acid deficiencywere headache, fatigue, and a sensation of weakness.Sleep disturbances and gastrointestinal disturbances, amongothers, were also noted. The most likely setting for pantothenicacid deficiency is in the setting of alcoholism wherea multiple vitamin deficiency exists confounding the exactrole of the pantothenic acid deficiency as compared to theother vitamins. Because a deficiency of a single B vitamin israre, pantothenic acid is commonly formulated in multivitaminor B-complex preparations.
Purification Methods
The salt crystallises as needles from MeOH, EtOH or isoPrOH (with 0.5mol of isoPrOH). It is moderately hygroscopic. The S-benzylisothiuronium salt has m 151-152o (149o when crystallised from Me2CO). [Kagan et al. J Am Chem Soc 79 3545 1957, Wilson et al. J Am Chem Soc 76 5177 1954, Stiller & Wiley J Am Chem Soc 63 1239 1941, Beilstein 4 IV 2569.]
