Multi-step Organic Synthesis of Naphazoline Hydrochloride Vasoconstrictor from Naphthalene

Gianella Aguilar, Martin Alvero, Franco Bayle, Hannah Caga, Bea Javier, Orlando Mirando III,

Alexandra Sarmiento, Alexis Sia, Angelica Tan, Paula Tuazon

Department of Pharmaceutical Chemistry

College of Pharmacy

University of the Philippines Manila

Taft Ave. cor. Pedro Gil St., Ermita, Manila, Philippines 1000
 Abstract

Naphazoline Hydrochloride is a sympathomimetic drug that functions as a nasal and ophthalmic

decongestant. To synthesize the Naphazoline hydrochloride, naphthalene will be used as the

starting material. Naphthalene will undergo the process of chloromethylation, wherein

formaldehyde will react with HCl catalyzed by Zinc chloride to form 1-naphthylmethyl chloride.

1-naphthylmethyl chloride will go through Kolbe nitrile synthesis to yield 1-naphthyl-

acetonitrile, with sodium cyanide as the reagent. This product will undergo the Pinner reaction

with ethanolamine to yield Naphazoline Hydrochloride, the desired compound. Ethanolic Silver

Nitrate test, Hydroxamic acid test, and Hinsberg’s test will be done as confirmatory tests;

Ethanolic Silver Nitrate test will confirm the presence of 1-naphthyl-methyl chloride,

Hydroxamic acid test will confirm the presence of 1-naphthyl-acetonitrile, and Hinsberg’s test

will confirm that Naphazoline hydrochloride is the final product in the synthesis.
 I. Introduction

Naphazoline hydrochloride is an imidazoline derivative that acts as a sympathomimetic

drug. Sympathomimetic drugs usually mimic stimulation of the peripheral endings of the

sympathetic or ‘adrenergic’ nerves (McCorry, 2007). It has a strong effect on contraction of

blood vessels and on blood pressure elevation. It is used to provide relief to nasal congestion and

is also administered ophthalmically to provide relief to conjunctival congestion (Kar, 2007).

Upon administration of naphazoline hydrochloride, swollen blood vessels are narrowed down

thus providing temporary relief to discomforts such as itching, irritations and redness in the

specific site of action of the drug (National Cancer Institute, 2019).

II. Reactions Involved

The overall reaction mechanism of the multi-step synthesis of Naphazoline

Hydrochloride from Naphthalene is as follows:

​ verall Reaction Mechanism of the Multi-step Synthesis of Naphazoline hydrochloride

Figure 1. O

from Naphthalene (Kar, 2007)

 Based on Ashutosh Kar’s (2007) reaction mechanism, the reagents involved were

modified to fit the resources available in the laboratory, as well other practical considerations.

The revised overall reaction mechanism is as follows:

​ odified version of Kar’s (2007) Overall Reaction Mechanism

Figure 2. M

Modifications in the reaction mechanism include the use of NaCN instead of KCN as the

source of cyanide in the reaction, as NaCN provides a faster reaction (Friedman & Shechter,

1960) and the use of ethanolamine in place of ethylenediamine due to the unavailability of the

latter (Kubiczek & Neugebauer, 1949).

The overall equation of this reaction is as follows:

C 10 H 8 (naphthalene) + HCl + HCHO + N aCN + C 2 H 7 N O + H + → C 14 H 14 N 2 (naphazoline) • H Cl + 2H 2 O + N a+ .

 ​ hloromethylation reaction of naphthalene to 1-naphthyl-methyl chloride (Organic
Figure 3. C

Chemistry Portal, 2019). Phosphoric acid is also a viable catalyst, assumed to perform similar to

ZnCl​2 (Grummitt
​ & Buck, 1944).
 ​ olbe nitrile reaction of 1-naphthyl-methyl chloride to 1-naphthyl-acetonitrile
Figure 4. K

(Organic Chemistry Portal, 2019).

​ inner​ ​reaction of 1-naphthyl-acetonitrile to Naphazoline hydrochloride (Organic

Figure 5. P

Chemistry Portal, 2019).

III. Methodology

Alternative Blanc chloromethylation of naphthalene

A mixture of 226 g (2 moles) of naphthalene, 297.3 g (3 moles) of 37 wt.%

formaldehyde, 260 mL glacial acetic acid, 362 mL of concentrated hydrochloric acid, and 165

mL of 85 wt.% phosphoric acid, will be heated at about 80-85°C for 6 hours with vigorous

stirring.

The crude mixture will be washed with 2 L of cold water (5-15°C), followed by 500 mL

cold 10% K​2​CO​3​, and then with 500 mL cold water, always keeping the oily layer​1​. 200 mL of

ether will be added and the ethereal solution will be dried with 10 g anhydrous K​2​CO​3 ​with

agitation for 1 hour. The ethereal layer will be separated, and dried over 20 g K​2​CO​3 for 8-10

hours. Once the ethereal layer is separated, 50 mL dry benzene will be added​2​.

First, the ether, benzene, and benzene-water azeotrope will be distilled off by heating the

mixture to above 80.1°C. Unreacted naphthalene will then be separated from the mixture by

filtering the mixture while it is below 80°C, but above 32°C​3 (NCBI, n.d.). The remaining

mixture will then be cooled, and the solid 1-napthyl-methyl chloride will be collected. The

expected yield is 74-77%, 195-204 g (Grummitt & Buck, 1944).

​ ilver Nitrate Test and Sodium Iodide in Acetone Test (Shriner et al.,
Confirmatory test(s): S

2004, pp. 320-325)

​ lkyl halides, 1-naphthyl-methyl chloride

Detects: A

Melting point: 3​ 2°C (NCBI, n.d.)

RFIS:
1​
The water and K​2​CO​3 washings should be done carefully to wash away water-soluble impurities

and acids (Grummitt & Buck, 1944).

2
K​2​CO​3 is
​ a drying agent. Dry benzene will form an azeotrope with water. Drying is essential to

avoid resinification of the product (Grummitt & Buck, 1944).

3 ​
Naphthalene and 1-naphthyl-methyl chloride have different melting temperatures (80°C vs

32°C), allowing for separation (NCBI, n.d.).

Kolbe nitrile synthesis of 1-naphthyl-acetonitrile

(Assuming yield of 195 g, 1.10 mol), 58.22 g of NaCN will be weighed and suspended in

250 mL DMSO with rapid stirring maintained at 80°C. When the temperature quickly rises, it

will be maintained at 140 +/- 5°C by cooling when necessary. After the addition of

1-naphthyl-methyl chloride, the temperature will drop, and the reaction will be completed.

This reaction mixture will be diluted to 1000 mL with distilled water, and will be extracted thrice

with 150 mL ether per extraction, and the extract will be tested for cyanide before proceeding to

the next step​4​. The extract will be washed with 6M HCl​5​, then with water. The washed ethereal

solution will then be dried over calcium chloride​6​. The dried ethereal solution will then be

distilled to remove the ether and separate 1-napthyl-acetonitrile. The expected yield is 93%,

171.06 g (Friedman & Shechter, 1960).

​ itrile Hydrolysis to Carboxylic Acid (Shriner et al., 2004, pp. 427-428)

Confirmatory test(s): N

​ itriles, 1-napthyl-acetonitrile
Detects: N

Melting point: 3​ 2.5°C (NCBI, n.d.)

RFIS:
4​
Allows the product to be separated from water-soluble impurities, especially NaCN. Increasing

the volume lowers the concentration of these impurities, and allows the product to be

concentrated in ether. A small portion of the extract will be tested for the formation of Prussian

blue indicative of the presence of cyanide (Hyde, 1975). If positive, more ether extractions will

be performed.
5​
HCl is used to hydrolyze the isocyanide byproducts (Friedman & Shechter, 1960).
6​
Prevents loss of product through hydrolysis during the distillation step.

Condensation with ethanolamine and formation of HCl salt

(Assuming yield is 171.06 g, 1.02 mol), 1-naphthyl-acetonitrile and 143.1 g (1.05 mol) of

ZnCl​2 will
​ be mixed in a sand bath at 190-200°C. To this, 65.36 g (1.07 mol) of

monoethanolamine will be added slowly, over an hour, and with constant stirring. The reaction

product will then be broken up, which will be followed with the addition of 85.6 g (2.14 mol)

NaOH and absolute ethanol​7​. The precipitated zinc hydroxide will be separated, and the ethanol

will be distilled off. The remaining mixture will then be filtered, followed by 1-2 cold water

washes, to separate the solid naphazoline​8​. The expected yield is 9%, 12.88 g (Kubiczek &

Neugebauer, 1949).

The solid product will then be dissolved in sufficient ether. An HCl gas generator will

then be set-up, which is simply a 3 or 2-necked flask with 50 mL concentrated H​2​SO​4​, with one

of the necks hosed to bubble gas through the ethereal amine solution. 30 mL concentrated HCl

will then be added to the H​2​SO​4 flask dropwise, until no more precipitate forms. The naphazoline
HCl precipitate will be separated through filtration, and washed with more ether (Shriner et al.,

2004, p. 389).

​ insberg Test (for secondary amines) and Quaternary Ammonium Salt

Confirmatory test(s): H

Formation with Methyl Iodide (for tertiary amines) (Shriner et al., 2004, pp. 386-388).

Detects:​ The secondary and tertiary amines in the imidazole group, naphazoline

Melting point: 2​ 55-260°C (NCBI, n.d.)

Spectra:

IR:
Figure 6. IR spectrum of naphazoline (NIST, 2018)

NMR:

​ MR spectrum of naphazoline HCl (Chemical Book, 2017).

Figure 7. N

RFIS:
7
NaOH is used to precipitate Zn(OH)​2​, which is insoluble in ethanol. The product is soluble in

ethanol.
8 ​
Ethanolamine is a liquid beyond 10.5 °C, while naphazoline remains a solid up to 260°C.

Furthermore, ethanolamine is more soluble in water than naphazoline (NCBI, n.d.)

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