ADAPALENE

GROUP 4
Lương Ngọc Mai 20211604
Trần Hoàng Duy 20211590
Lê Thị Mai 20211603
Trịnh Thị Phương Thảo 20211617
 Table of Contents

Part 1 Part 2

Overview Synthesis

Part 3

Production
 PART 1

1 Name & Structure

2 Physiochemical & Pharmacological Properties

Overview

3 Spectrum

4 Pharmacopeia Standards
 Name and Structure
O

OH

● Generic Name: Adapalene

O

● IUPAC Name: 6-[3-(1-adamantyl)-4

methoxyphenyl]naphthalene-2-carboxylic acid

● Brand Names: Differin, Epiduo

● Synonyms: 6-(3-(1-adamantyl)-4
methoxyphenyl)-2-naphthoic acid, Adaferin,
Differin

● CAS number registry: 106685-40-9

Structure–Activity Relationships
 Physiochemical Properties

● Molecular formula:
C28H28O3
● ● Density: 1.2 g/cm3
Appearance: White or almost
● Refractive index: 1.66
white powder
● ● pKa: 4.23; 3.99 (strongest
Solubility: Soluble in dimethyl
sulfoxide (DMSO) (>10 acidic), −4.8 (strongest basic)
● Lipophilic parameters:
mg/mL at 25 ◦C),
● log P: 8.04, 8.6; 6.06, 6.47
dimethylformamide (DMF) (5
● AlogP: 6.68
mg/mL at 25 ◦C) and
● XlogP: 7.7
tetrahydrofuran; sparingly
● Storage temperature 2–8 ◦C
soluble in ethanol (<1 mg/mL
at 25 ◦C), and practically
insoluble in water
● Melting point: 319–322 ◦C
● Boiling point: 606.3 ◦C at 760
mmHg
 Pharmacological Propperties

Anti-Inflammatory
Immunomodulatory Antiproliferative
and Comedolytic Keratolytic Effect
Effect Effect
Effects

Neuroprotector
Antibacterial Activity Other Effects
Effect
 Pharmacological Propperties
Pharmacokinetic
s
Absorption Distribution

Metabolism Excretion
Pharmacopoeia standards
 Spectrum

UV Spectrum IR Spectrum
 Spectrum
HNMR Spectrum
Spectrum
MS Spectrum
Spectrum
HPLC Spectrum
PART 2: SYNTHETIC METHODS OF ADAPALENE

Method 1 Method 2 Method 3

(2009) (2006) (2020)
Mercury is the smallest planet Venus has a beautiful name
in the Solar System and it’s hotter than Mercury
Process for the
A High Yield and
Preparation of
Pilot-Scale Process Preparation method
Adapalene and
for the Preparation of adapalene
Related
of Adapalene
Compounds

Zhichang Liu and

US20090131713A1 CN111333496A
Jiannan Xiang
PART 2: SYNTHETIC METHODS OF ADAPALENE
2.1. Method 1 (2009)

Mg ZnCl2

O Br O MgBr O ZnBr

II

O-

Br
III

O O
- K+
O KOH O

O O
V HCl IV
O

HO

O
I
 2 3 Br 4 room temperature, 2 days
OH

PART 2: SYNTHETIC METHODS OF ADAPALENE 2 3

dimethyl sulfate, K2CO3, acetone, Mg/ THF, 40 °C, 1 h
H2SO4 (5:1,v/v) 2.2. Method
reflux, 8 h2 (2006) dimethyl sulfate, K2CO3, acetone,
O Br Mg/ THF, 40 °C, 1 h

mperature, 2 days reflux, 8 h

OH Br O Br
5
AcOH/ H2SO4 (5:1,v/v) dimethyl sulfate, K2CO3, acetone, Mg/
OH
+
4 room temperature, 2 days 5 reflux, 8 h
OH
Br
OH Br
O Br

2 3 O 4
5
PdCl2(PPh3)2 (2% mol)
+ O O
ZnCl2 (5% mol), 55 °C, 45 min PdCl2(PPh3)2 (2% mol)
O 40 °C, MgBr
Mg/ THF, 1h Br + O

dimethyl sulfate, K2CO3, acetone, O MgBrMg/ THF, 40 °C, 1Brh ZnCl2 (5% mol), 55 °C, 45 min O
Br PdCl2
reflux, 8 h + O
O Br
Grignard reagent 6
O MgBr Br ZnCl2 (5
5
Grignard
5 reagent 6
O O

O (i) NaOH, MeOH, reflux, 8 hO GrignardOH

reagent O6
O O
PdCl2(PPh3)2 (2% mol) O (2% mol)
PdCl2(PPh3)2
(i) NaOH, MeOH, reflux, 8 h OH
O + (ii) aqueous HCl,
O
O Br Omin
ZnCl2 (5% mol), 55 °C, 45 O
ZnCl2 (5% mol),
O 55 °C, 45 min
MgBr
(ii) aqueous HCl,
O O O (i) NaOH, MeOH, reflux, 8 h
7 1

Grignard reagent 6 7 1 (ii) aqueous HCl,

6 O
PART 2: SYNTHETIC METHODS OF ADAPALENE
2.3. Method 3 (2020)
O O
O OH
O B
O O OH
S
O NiCl₂[P (C₆H₅)₃] ₂
O
2-methoxycarbonyl-6-naphthol p- O
toluenesulfonate 6- (4-methoxyphenyl) -2-methyl
O O naphthoate

OH

O
6- [3- (1-adamantyl) -4-methoxyphenyl ] -2-methyl naphthoate

NaOH OH
THF

O
adapalene
PART 3: TECHNOLOGICAL SCHEME
OF ADPALENE PRODUCTION
Block
3.1
Diagram

Piping and Instrumentation

3.2 Diagram
3.1. Block Diagram
3.2. P&ID