Chiral pharmaceuticals are generally synthesized as racemates or single enantiomers.
The bronchodilators were developed from the modification of norepinephrine (adrenaline), a natural neuro transmitter and an arylethanolamine. Adrenaline was used in treating asthma just after World War II. Because norepinephrine stimulates both α and β adrenoceptors in the body, a more specific drug was needed, to target only the β adrenoceptors.
The replacement of two hydrogens on the amine with two methyl groups yielded a isopropyl group, instead of a methyl group and produced isoproterenol (isoprenaline), the next compound introduced in the treatment of acute asthma, after adrenaline. This compound, introduced since 1940, has a duration of action of only 20 minutes. It increases the stimulation of β adrenoceptors while having a reduced stimulation of β adrenoceptors. However, isoproterenol is not metabolically stable and is inactivated by the enzyme catechol O-methyltransferase too quickly to be usefully used in the treatment of asthma. One major disadvantage is that the activation of β adrenoceptors in the cardiovascular system gives rise to side effects such as palpitations and cardiac arrhythmia.
By 1960, it was known that the maximum potency of bronchodilators was always associated with the presence of a catechol function, as in isoprenaline, but these compounds quickly loose activity due to the action of the enzyme catechol O-methyl transferase (COMT), which catalysed the rapid conversion of the meta-OH group of the catechol ring to an ether. Chemists tried to prevent the action of COMT by changing the catechol without affecting the drug's ability to interact at the receptor. By replacing the catechol ring with another aromatic ring, called resorcinol, orciprenaline was synthetised and introduced since 1961. Compared to isoprenaline, it was longer acting, albeit less potent, with some selectivity on the bronchial muscle.
Designing the Perfect β2-adrenergic agonist ----> MAJOR RESEARCH EFFORT into studies on aromatic ring substitution ----> to try to overcome effects of COMT 4 approaches -----> successful First approach . move an -OH group from position 4 to 5 -----> orciprenaline [Alupent] more at
The action of orciprenaline showed that a catechol structure was not essential for β-adrenoceptor stimulant activity and that selective actions in different organs of the body were also possible when using other aromatic rings. In 1964, A. M. Lands and coworkers, demonstrated that certain catecholamines with bulky N-alkyl substituents in the side chain were more active on bronchial smooth muscle than on cardiac muscle. They concluded that the optimal structural requirements for bronchodilator activity were different from those for cardiac stimulation. In a subsequent work they concluded in 1967 that the β-receptors in these tissues must be different; now, these receptors are named β1- and β2-receptors. It turns out that β1-receptors are more common in the powerful myocardial muscle in the heart, while β2 are prevalent in the smooth muscle of the lungs. (Lands AM, Arnold A, McAuliff JP, Luduena FP, Brown TG Jr. Differentiation of receptor systems activated by sympathomimetic amines. Nature (London) 1967;214:597–598.)
Researchers from Allen & Hanbury's focused their attention on the possible beta-adrenergic stimulant potencies of arylethanolamines with different aromatic rings. As the researchers believed that the most important function of this meta-OH group was in hydrogen bonding at the receptor, they needed to replace the OH group with another group that could still hydrogen bond, in order to lengthen the new drug's duration of action without loss of that activity. After several attempts, Lunts had the idea to add an extra carbon on the benzene ring by replacing the meta-OH with a hydroxymethyl group, which is not sensitive to COMT and is still able to hydrogen bond. The resultant compounds possess an aromatic ring, called saligenin. Saligenin is a salicyl alcohol (synonyms : 2-Hydroxybenzyl alcohol; Salicyl Alcohol).
A screening of the library of aryletanolamines synthetised by the Allen & Hanburys chemistry researchers showed that the saligenin moiety has the capacity to subserve as a cathechol, the structural requirements of the ethanolamine side chain for potent beta-stimulant activity for the saligenin compounds broadly follow the requirements for the catecholamine compounds and that the saligenin derivatives have a lower efficacy in promoting α stimulation in animal models. (Hartley)
A further screening of the library of aryletanolamines synthetised at Allen & Hanbury's yielded AH.3365 as the most typical saligenin compound, with a potent and long-lasting selective stimulant action on the β-adrenergic receptors in bronchial smooth muscle, and in contrast to the catecholamines, with little effect on cardiac muscle. It has a (Hartley) bulky lateral chain, containing a tert-butyl group, obtained through the addition of a supplemental methyl function to the terminal isopropyl, which further enhances its β2-selectivity and makes the drug longer-acting. AH.3365 was one of the earliest drug types developed by the now familiar process of rational design by Allen & Hanburys' chemistry research leader Larry Lunts, being launched on the market by Glaxo in the late 1960's under the name salbutamol. It is known in the United States as albuterol.
Initially, Lunts and his team used the widely available acetyl salicyclic acid (aspirin) as a starting point for the synthesis of racemic albuterol, but, currently, there are better methods of manufacturing in use. study organic chemistry: need to protect Click here Mainly, types of synthetic preparations are utilized
As an introductory part, we present below some characteristics of the chemical reactions involving aromatic (phenolic) compounds that were used in different syntheses of salbutamol.
An ester has the general structure R-CO-O-R' Acyl group - any group or radical of the form RCO- where R is an organic group Acyl halide - organic compounds containing the group -COX where X is a halogen atom Acylation - the process of introducing an acyl group into a compound.
The generic name "ketone" is given to compounds containing an oxygen atom doubly bound to a single carbon atom with the carbonyl group >C=O joined to two carbon atoms. (IUPAC) Alkane - a non-aromatic saturated hydrocarbon with the general formula CnH(2n+2) Alkyl halide - organic compound in which halogen atoms have been substituted for hydrogen atoms in an alkane
Friedel-Crafts Reaction Definition: The alkylation or acylation of aromatic compounds catalyzed by aluminum chloride or other Lewis acids original reference: C. Friedel, J. M. Crafts, Compt. Rend. 84, 1392, 1450 (1877).
AlCl3 acts as a Lewis acid (electron pair acceptor) to promote ionization of the alkyl halide and it permits primary alkyl groups to be attached to an aromatic ring. However, the Lewis acid catalyst AlCl3 often complexes to aryl amines making them very unreactive. more
tert-butyl amine correct name
Friedel-Crafts step-by-step: alkylation: t-butil is the electrophile and it acts as a lewis acid to promote the ionization of the alkyl halide
An aromatic molecule or compound is one that has special stability and properties due to a closed loop of electrons. If a molecule contains an aromatic sub-unit, this is often called an aryl group.
Phenols (and also their derivatives such as Salicylic and Acetylsalicylic acids) contain aryl groups and they are also examples of bidentate nucleophiles, meaning that they can react at two positions:
on the aromatic ring by an electrophilic aromatic substitution, giving an aryl ketone via C-acylation--a Friedel-Crafts reaction or,
on the phenolic oxygen by a nucleophilic acyl substitution, giving an ester via O-acylation--an esterification
Reagents : C-acylation : the acylating agent (acyl chloride or anhydride) and AlCl3 . O-acylation : acylating agent (acyl chloride or anhydride)
The product of C-acylation is more stable and predominates under conditions of thermodynamic control (i.e. when AlCl3 is present).
The product of O-acylation forms faster and predominates under conditions of kinetic control
Both reactions can compete, with the O-acylation being faster; C-acylation occurs only when the catalyst is included.
O-acylation can be promoted by either:
acid catalysis via protonation of the acylating agent, increasing its' electrophilicity or
base catalysis via deprotonation of the phenol, increasing its' nucleophilicity.
OH groups on benzene rings are ortho, para-directing and strongly activating
It is also known that aryl esters readily rearrange to aryl ketones in the presence of AlCl3, a reaction known as the Fries rearrangement of phenolic esters (Fries, K. Liebigs. Ann. Chem. 1907, 353, 339) : paste here Fries.rearrangement.bmp(delete after use)
I. Syntheses without protecting groups
I.1. (Warren): The key compound in the synthesis of aspirin, salicylic acid, is prepared from phenol by a process involving an electrophilic aromatic substitution, discovered over 100 years ago by the German chemist Hermann Kolbe. The mechanism involve hydrogen-bonded complexes that direct the substitution to take place entirely at the ortho position. Salicylate is less basic than para isomer and predominates under conditions of thermodynamic control.
paste here Kolbe.Synthesis.bris.ac.uk.gif (delete after use)
The next step is to prepare its acetyl ester derivative, named acetylsalicilic acid (aspirin), through a process of O-acylation: paste here aspirin.bris.ak.uk.jpg (delete after use)
If treated with the AlCl3 as catalyst, the acetyl salicylic acid undergoes a rearranging process, known as the Fries rearrangement of phenolic esters, from this conversion resulting a key aromatic acid ketone derivative, which is further brominated in laboratory in a neutral solution. The aromatic ketone reacts with tert-butyl amine C(CH3)NH2, resulting an aromatic aminoketone. Reductions with lithium aluminum hydride. The last step in the synthesis of Salbutamol involves the reduction of the ketone functional group of the precursor aminoketone with excess LiAlH4. LiAlH4 is a donor of the hydride ion H, which is a strong nucleophile. The hydride, being a nucleophile, does not normally attack a C=C double bond (which is reactive towards electrophiles). Consequently, molecules containing both a C=C and a C=O functional group will only react at the carbonyl group when treated with hydride ion. LiAlH4 must be used in dry solutions, as it is decomposed violently by water. http://firstyear.chem.usyd.edu.au/LabManual/E27.pdf. paste here simple.synthesis.jpg (delete after use)
I.2. In 1973, Lunts and Toon patented a method for preparing several 1-phenyl-2-aminoethanol derivatives, which constitutes another route to the synthesis of salbutamol. (Aboul-Enein) paste here lunts2.jpg (delete after use)
They started with a reduction of methyl-5-(2-amino-1-hydroxymethyl)-salicylate, using a LiAlH4 catalyst to give the corresponding alcohol-the first saligenin derivative in the chain of reactions. This was converted to salbutamol by reacting with tertiary butyl-chloride. It appears that no protecting was used in this synthesis. I.3. The route to salbutamol synthesis devised by Okumura and his coworkwers starts from a saligenin derivative (4-hydroxy-3-hydroxy methyl benzoyl chloride) and does not use protecting groups. paste here okumura.jpg (delete after use)
This compound reacts with tertiary butyl isonitrile in benzene to give an aromatic ketone, which is reduced with LiAlH4 catalyst to salbutamol.
I.4. Acetaldehyde
II. Syntheses using a protecting group: The need for using a protecting group: The aminoketone formed through the reaction between an alkyl halide and an amine still has an amine moiety. The hydride ion from the amine moiety of the aromatic aminoketone structure needs to be less reactive than its equivalent from the starting t-butyl amine. If it is more reactive, it can react further with its alkyl halide precursor, giving a more branched product. Multiple alkylations can be a problem if the product is more reactive than the starting material and protecting groups need to be added during synthesis. The use of protecting groups may be strategically poor, because of the need to use unproductive steps to add and remove them. Adding a protecting group sometimes looks like a failure for the chemist, but is essential in salbutamol synthesis. Protecting benzyl groups, used in many syntheses of salbutamol, can be removed in one step by hydrogenolysis. This hydrogenolysis step may be low yielding sometimes.
II.1. The second synthesis published by Warren uses a benzyl as a protecting group, removable by hydrogenation. This group is added after the bromination of the aminoketone in a neutral solution of CHCl3. The benzyl is removed through hydrogenation
with a palladium catalyst on a carbon support, a step concomitant with another two hydrogenations, catalyzed by LiAlH4, that reduce both the ketone and the acidic functions of the aminoketone precursor. The percentage of palladium on its support generally varies between 0.5 % and 20 %. A more detailed scheme of the same synthesis is shown below:
paste here warren2.jpg (delete after use) This synthesis is short and high yielding.
II.2. According to Aboul-Enein, Lunts et al started their patented first synthesis of salbutamol (A-E+ S Afr. 67, .....) from a methylated acetophenone (methylated phenyl-methyl-ketone) derivative, which first underwent a chlorination. This aromatic ketone gave compound II after condensation with benzyl tert-butyl amine. The resultant aromatic ketonic ester II was reduced with LiAlH4 in THF under nitrogen to yield compound III. This compound is subsequently debenzylated with hydrogen in the presence of a palladium catalyst on carbon support to give salbutamol. paste here lunts1.jpg (delete after use)
This synthesis shows very clear that the aromatic saligenin ring, so characteristic to salbutamol, appears for the first time during the synthesis after reduction with LiAlH4. Each reaction requires that 2 hydrides (H-) be added to the carbonyl of esters, resulting an alcohol:
paste here hydride+ester.gif (delete after use)
This reaction usually occurs in Et2O or THF. http://www.chem.ucalgary.ca/courses/351/Carey5th/Ch15/ch15-2-8.html At the same time, LiAlH4 is a hydrogen ion donor only for the methyl ester, but the protecting group is not removed. This group accepts hydrogen ions only in the presence of the palladium catalyst.
II.3. Kyotani et al () devised a route to synthesis of several 1-(-3-hydroxymethyl-4-hydroxyphenyl)-2-alkylaminoethanol derivatives, including salbutamol. They started from O-protected benzaldehyde, which reacted with tert-butyl isonitrile in the presence of acetic acid to give a tert-butyl derivative.
paste here kyotani.jpg (delete after use) After hydrolysis and reduction with either diborane or LiAlH4, resulted compound III, which still had attached the benzyl protection group on a lateral group located in a meta position. Further, this compound underwent kydrogenolysis and gave salbutamol in a yield of about 49 %.
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