CHAPTER I

INTRODUCTION

A. Background
Ephedrine is an alkaloid found in the Ma Huang plant that originates from
China has been used for 5000 years, it has been recorded in the Pentsao Kang Mu.
written by Shih-Cheng li in the year 1596 AD has been used as a circulation stimulant,
antipyretic, sedative for cough treatment.
Ephedra plants found in Russia have been used since the early 19th century.
E. vulgaris. The infusion of this plant is mixed with butter milk for the treatment of rheumatism.

(reported by Bectin in 1891), syphilis and respiratory tract diseases.

In America, some ephedra plants have been used by Indian tribes for
several purposes. [Link], [Link], and [Link] are used for
treatment of syphilis and gonorrhea.
In 1885, the ma huang plant was first isolated by G. Yamanashi and
finding materials in the form of pure crystals, next isolated by Nagai and
Y. Hori discovered a pure alkaloid in 1887, the alkaloid was
it was then named ephedrine by Nagai.
In 1917, Japanese researchers Amatsu and Kubota discovered the effect
sympathomimetic from ephedrine used for the treatment of asthma. This result is supported
by Hirose and To who draw the same conclusion. This publication attracts attention
Europe and America to use ephedrine as an anti-asthma. Then on
In 1923, it was used in tablet form by Western countries.

1 Drug Synthesis| Efedrine Paper

 CHAPTER II

DISCUSSION
A. Definition of Ephedrine

According to FI IV Ephedrine (Ephedrinum) is an anhydrous compound or contains

no more than half of the hydrated water molecules, containing not less than 98.5% and
no more than 100.5% C10H15NO, calculate against the anhydrous substance.
Ephedrine is a sympathomimetic obtained from plants of the genus
Ephedra (for example, ephedra vulgaris) has been widely used in China and East India.
since 5000 years ago. Traditional Chinese medicine referred to ephedrine by the name
Ma huang. Ephedrine has the molecular formula C10H15NO and the other name is alpha-
hydroxy-beta-methylaminopropylbenzene. With a Molecular Weight of 165.23.
Structure of ephedrine

Ephedrine is an alkaloid compound found in several plants of the genus

ephedra. Alkaloids are a class of basic compounds that contain one or more.
Nitrogen atom which is heterocyclic and found in plants. Alkaloids are present.
on leaves, roots, seeds, branches, and bark. Its function is not yet known,
however, experts estimate as a protector of plants from pest attacks and
disease, growth regulator, or as a mineral base to maintain
ion balance. Chemically, ephedrine shows optical isomerism and has 2
chiral center, resulting in 4 pairs of stereoisomersenantiomer with stereochemistry
(1R, 2R and 1S 2R).
Ephedrine has been widely used in medical practice including in the field of
anesthesia. Ephedrine works on alpha and beta receptors, alpha1, alpha2, beta1, and beta2, well
working directly or indirectly. Ephedrine 25 mg to 50 mg
Intramuscular or subcutaneous can be used to address hypotensive conditions, 25 mg.
per oral once a day to manage orthostatic hypotension, also bronchodilator and
decongestant. Other allergic disorders such as bronchial asthma, nasal congestion
due to acute rhinitis, rhinitis, and sinusitis.

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 For pregnant women undergoing a cesarean section procedure with spinal anesthesia,
Ephedrine is a choice for addressing hypotension caused by spinal anesthesia.
Ephedrine not only increases blood pressure but also improves blood flow to the placenta.
Ephedrine can be administered orally, topically, or parenterally, and can be absorbed.
completely and quickly in oral, subcutaneous, and intramuscular administration.
Bronchodilation occurs within 15-60 minutes after oral administration and lasts for 2-4.
The absorption of ephedrine given through the intramuscular route is faster (10-20 minutes)
compared to subcutaneous administration. In intravenous administration, the clinical effect can be

directly observed. The duration of work on blood pressure effects can last up to 1
it lasts for 4 hours when given orally.
Ephedrine can also cross the placenta and be distributed in breast milk.
Ephedrine is metabolized by the liver in small amounts through oxidative deamination,
demethylation, aromatic hydroxylation, and conjugation. Its metabolite is p-hydroxyephedrine,
p-hydroxy norephedrine, norephedrine and its conjugates. Ephedrine and its metabolites in
excretion primarily through urine and in unchanged form. Elimination of ephedrine and
its metabolites are influenced by urine acidity.
B. Ephedrine Synthesis
Ephedrine can be obtained in two ways, the first being extraction from plants,
the second one with synthesis using chemical materials.
Extraction from plants
Extraction is the process of obtaining active substances from parts of medicinal plants. The purpose is

namely to extract the chemical components contained in the simplicia.

Samples of medicinal plants that have been pollinated are extracted with alcohol.

60%
The extract obtained is added with strong ammonium hydroxide.
or sodium carbonate and precipitation will occur, but there is still
ephedrine that remains in the filtrate.
Next, the sediment and the filtrate are added with ether or chloroform.
to extract the alkaloid ephedrine.

To neutralize the remaining solvent, HCl or H2SO4 is added.

then alkaloid salt is formed.
To purify the alkaloid ephedrine, recrystallization is carried out with
adding absolute alcohol.

3 MEDICATION SYNTHESIS| Epinephrine Paper

 Then metal content testing was carried out but unfortunately there was none.
bioassays developed to achieve satisfactory results.
The isolation result of ephedrine from plants obtained from China is around 80%, while
The isolation results of plants from America are fewer in number.
2. Synthesis of chemical substances

The first attempt to synthesize ephedrine was made by Fourneau in 1904.

followed by Schmidt in 1905. Nagai in 1911 carried out the synthesis
racemic ephedrine, but has not yet been recorded in the literature. Eberhard discovered

racemic ephedrine and pseudoephedrine in 1917 through alpha-hydrogenation

methylaminopropiophenone. In 1920, Späth and Göhring had
synthesizing ephedrine, pseudoephedrine and racemic substances.
Here are some examples of ephedrine synthesis:

a. Synthesis of ephedrine by Neuberg and Hirsch (year 1921)

Using stereoselective synthesis techniques (asymmetric).
Phenylacetylcarbinol is obtained from the reaction between benzaldehyde and
added carbohydrate solution (glucose) and fermented by
yeast. Optical activity occurs at C1which is a natural configuration
from L-ephedrine.

Then hydrogenation catalysis with the aid of methylamine, platinum.

and H2, thus forming L-ephedrine directly and forming
asymmetric configuration in C2.

4 SYNTHESIS OF MEDICINE| Ephidrine Paper

 b. Synthesis of ephedrine by Manske, Johnson, and Skita (year 1929)
This synthesis uses propionic acid derivatives in Friedel- alkylation.
Crafts with side chains contain 3 carbon atoms.

The synthesis process begins by reacting phenyl with propionyl.

chloride. With the help of Aluminum chloride, compounds will be formed
propiophenone.

Propiophenone is converted by isoamyl nitrite (isonitroso ketone), then

dihydrolysis.

Next, ephedrine is obtained through catalytic hydrogenation with

the presence of methylamine and platinum catalyst as well as H2

5 DRUG SYNTHESIS| Efedrine Paper

 c. Synthesis of ephedrine by Nagai and Kanao (1929)
Synthesis of ephedrine from benzaldehyde and nitro ethane can be seen in the reaction

following:

C. IDENTIFICATION OF EPHEDRINE

a. Description
A solid that resembles fat, colorless, or granular or white crystalline. decomposes
gradually when exposed to light, melts at a temperature between 33oand 40o,
the variation in melting temperature due to differences in water molecule content, anhydrous ephedrine

has a lower melting point than ephedrine with one and a half molecules of water
hydrate.
b. Solubility
Dissolves in water, ethanol, chloroform, and ether, and dissolves slightly more slowly in oil.

Mineral solution becomes cloudy when ephedrine contains more than 1% water.
c. Comparison Sheet
Ephedrine Sulfate BPFI; Dry at a temperature of 105ofor 3 hours before
used.
d. Identification
Carefully weigh about 100 mg, then add a volume of 0.1 N sulfuric acid.
with a burette to neutralize until stated in the determination of content. dilute
with water in a measuring flask up to 25 ml. mix 2 ml of the solution with 10 ml
ethanol, evaporate in steam with an air flow until dry. against the residue
the obtained is set as follows: infrared absorption spectrum
the substance that has been crushed with several drops of methanol and has been dried
at a temperature of 105ofor 3 hours and dispersed in potassium bromide,

6 SYNTHESIS OF MEDICINE| Ephidrine Paper

 shows a maximum only at the same wavelength as at
Ephedrine Sulfate BPFI.
e. Determination of Content

Weigh carefully about 500 mg, dissolve in 10 ml of neutral ethanol,

Add 5 drops of red metal and 40.0 ml of 0.1 N hydrochloric acid. Titrate the excess.
sour with sodium hydroxide 0.1. Carry out the blank determination as follows.
stated in Residual Titration in titrimetry.
D. OTHER TESTING
1. Qualitative Analysis
Qualitative analysis is used to detect compounds, elements, or substances.
others in a solution visually, both dry and wet.
The parameters are the precipitate, the color change in the solution, and the color.

the deposit that is formed.

a. Tools and materials:

The tools used are:

1 hotplate
1 piece of 10 ml pipette

1 piece of filler

5 test tubes
1 piece of 500 ml beaker
Tissue
Dropper
b. The materials used are:
Ephedrine HCL
Aquades
Sodium hydroxide
Copper(II) sulfate
K4Fe(CN)6

7 DRUG SYNTHESIS| Ephredrine Paper

 Material Treatment Result
Ephedrine + Water + NaOH + K4Fe(CN)6 Construction
HCl 50 benzaldehyde
mg + Water + 2 heads CuSO4+ NaOH + Color
Butanol is shaken and compared yang
with a standard solution produced
the same
with
color
reactant
that is color
green
In this experiment, 50 mg of ephedrine HCl is dissolved in a quantity of

water, then 2 drops of CuSO4 are added and NaOH and butanol are added.
into the tube and shake for a few minutes. Shaking helps
the process of combining several reagents with a drug. The result of the chemical reaction that

there is a color change to green. Then a standard solution is made

from the mixture of its reagents, and the two colors are the same.

2. Quantitative Analysis
The reagent commonly used in argentometry is potassium.
chrome, ferric ammonium sulfate, absorption indicator or acid dye or
the base that changes color due to adsorption by the precipitate at the endpoint.
Included in acidic dyes are fluorescein, dichlorofluorescein, and eosin.
whereas rodamin B is classified as an acid-base color.
The reaction that occurs:

C10H15NO,HCl + AgNO3 → C10H15NO,HNO3 + AgCl

How it works:
Weigh 250 mg of ephedrine HCl
Diluted with distilled water to a total volume of 250 ml

Pipette 20 ml of ephedrine HCl solution

Add 3 drops of K2CrO4 indicator.

Titrated with AgNO3 solution until a color change occurs from
red brick sediment is formed

8 DRUG SYNTHESIS| Ephidrine Paper

E. BENEFITS OF EPHEDRINE

a. Ephedrine is used as an asthma medication, as a bronchodilator (relieving the airway)

breathing) because it can activate the beta adrenergic receptors found in the airway
breath. Traditional or ancient asthma treatment still uses
ephedrine in its formulation, but is increasingly being abandoned because it has
side effects that are quite significant. It is non-selective in nature where it can

activating alpha-adrenergic receptors in peripheral blood vessels can

causes vasoconstriction effects or narrowing of blood vessels, which can
resulting in increased blood pressure.
b. Vasoconstrictor effects are also used as decongestant medications (relieving
nasal congestion). When the nose is congested, there is dilation of blood vessels.
in the capillaries around the nose. Therefore, ephedrine, which is characterized by
Constricting blood vessels can relieve a stuffy nose.
c. Ephedrine is also used as a slimming agent because it has thermogenic effects.
The effect can enhance the speed related to lipolysis (breakdown
fat).
d. Ephedrine is an appetite suppressant, making it ideal for those on a diet.
The stimulatory effect on the nerves causes people to feel more energetic.
so that even though calorie intake is low or there is a lot of exercise, they do not
feeling tired.

9 SYNTHESIS OF MEDICINE| Epinephrine Paper

 CHAPTER III

CLOSING

A. Conclusion
Ephedrine is an alkaloid compound found in several plants.
genus ephedra. Alkaloids are a group of basic compounds that
contains one or more nitrogen atoms that are heterocyclic and
found in plants.
Ephedrine can be obtained in two ways, the first is by extraction from
plants, the second with synthesis using chemical materials.
Ephedrine is used as an asthma medication, as a bronchodilator (relieves the airway)
breath) because it can activate the beta adrenergic receptors present in the airways
breath. Traditional asthma treatment or ancient times still uses
ephedrine in its formulation, but is increasingly being abandoned because it has
quite significant side effects. It is not selective where it can
activating alpha-adrenergic receptors in peripheral blood vessels can
causes vasoconstriction or the narrowing of blood vessels, which can
resulting in an increase in blood pressure.

10 Drug Synthesis| Efedrine Paper

 BIBLIOGRAPHY
Department of Health of the Republic of Indonesia. Indonesian Pharmacopoeia Edition IV. 1995

Bavadekar A. Supriya, Davis M. Yolande, Feller R. Dennis, Khan A. Ikhlas

Lalchandani G. Shilpa, Ma Guoyi, Nagmani Rangaswamy, Schaneberg T. Brian
2007, 'Pharmacological Effects of Ephedrine Alkaloids on Human alfa1- and alfa2-'
Adrenergic Receptor Subtypes, The American Society for Pharmacology and
Experimental Therapeutics, Vol. 322 No. 1
[Link] accessed on date 14
October 2015.
Unable to access the content of the provided link., accessed on the day
Tuesday, October 13, 2015 at 9:30 PM
[Link]
compound-yang_20.htmlyou areon Wednesday, October 14, 2015 at 1:30 PM
Pharmaceutical Chemistry
English. Pages 39 - 49

11 MEDICINE SYNTHESIS| Paper on Ephedrine