A scalable synthesis of biaryl unit of the HIV protease inhibitor atazanavir

Article abstract of DOI:10.2174/1570178616666190514080155

Atazanavir is one of the most prescribed HIV-1 protease inhibitors approved by the FDA. It was the first protease inhibitor approved for once-a-day dosing to treat AIDS due to good oral bioa-vailability and favorable pharmacokinetic profile. This research aims to develop a new synthetic cost effective process for biaryl-hydrazine unit {tert-butyl 2-[4-(2-pyridinyl)benzyl]hydrazinecarboxylate} of atazanavir on a large scale. The synthesis involved palladium catalyzed Suzuki-Miyaura coupling of 2-chloropyridine and (4-cyanophenyl)boronic acid followed by DIBAL-H reduction of cyano group to aldehyde which is then treated with tert-butyl carbazate to furnish hydrazone subsequently in situ reduction with NaBH₄. A large scale synthesis of biaryl-hydrazine unit of atazanavir was accomplished in three steps with 71% overall yield. We have developed a short and efficient synthesis of atazanavir key intermediate biaryl-hydrazine unit. The process does not require the usage of Grignard reagent, expensive catalyst, protection/deprotection of aldehyde moiety and catalytic hydrogenation.

Full text of DOI:10.2174/1570178616666190514080155

68
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Letters in Organic Chemistry, 2020, 17, 68-72
RESEARCH ARTICLE
ISSN: 1570-1786
eISSN: 1875-6255
A Scalable Synthesis of Biaryl Unit of the HIV Protease Inhibitor
Atazanavir
Impact
Factor:
0.723
BENTHAM
S
CIENCE
Chapala Vijayalakshmi1, Malavattu G. Prasad1, Naresh K. Katari1,* and Pedavenkatagari N. Reddy1,*
1Department of Chemistry, School of Technology, Gitam University, Hyderabad (T.S) 502329, India
Abstract: Atazanavir is one of the most prescribed HIV-1 protease inhibitors approved by the FDA. It
was the first protease inhibitor approved for once-a-day dosing to treat AIDS due to good oral bioa-
vailability and favorable pharmacokinetic profile. This research aims to develop a new synthetic cost
effective process for biaryl-hydrazine unit {tert-butyl 2-[4-(2-pyridinyl)benzyl]hydrazinecarboxylate}
A R T I C L E H I S T O R Y
of atazanavir on a large scale. The synthesis involved palladium catalyzed Suzuki-Miyaura coupling of
Received: January 29, 2019
2-chloropyridine and (4-cyanophenyl)boronic acid followed by DIBAL-H reduction of cyano group to
Revised: April 01, 2019
aldehyde which is then treated with tert-butyl carbazate to furnish hydrazone subsequently in situ re-
Accepted: April 19, 2019
duction with NaBH4. A large scale synthesis of biaryl-hydrazine unit of atazanavir was accomplished
DOI:
in three steps with 71% overall yield. We have developed a short and efficient synthesis of atazanavir
10.2174/1570178616666190514080155
key intermediate biaryl-hydrazine unit. The process does not require the usage of Grignard reagent, ex-
pensive catalyst, protection/deprotection of aldehyde moiety and catalytic hydrogenation.
Keywords: Atazanavir, HIV protease inhibitor, Suzuki-Miyaura coupling, In situ reduction, grignard reagent, catalytic hydro-
genation.
1. INTRODUCTION
4-formylphenylboronic acid in three steps [15-17]. However
several facets made it impractical for large scale production
such as use of Grignard reagent, expensive catalyst and pro-
tection and deprotection of aldehyde. Furthermore, isolation
of hydrazone intermediate and palladium catalyzed hydro-
genation would be unsuitable for scale up. Thus an efficient
and cost effective synthesis to biaryl-hydrazine unit 2 of
atazanavir (1) is of prime importance.
Human immunodeficiency virus (HIV), the causative
agent for acquired immunodeficiency syndrome (AIDS), is
the fifth most common cause of death among humans [1]. In
2016, about 36.7 million people were living with HIV and it
resulted in 1 million deaths [2]. AIDS was identified in the
early 1980s and from that time to 2017, the disease has
caused an estimated 35 million deaths worldwide [3]. HIV-1
protease inhibitors continue to play an important role in the
treatment of HIV/AIDS, transforming this deadly ailment
into a more manageable chronic infection [4]. Atazanavir (1)
is a type of anti-HIV protease inhibitor approved by the FDA
[5-10]. It was the first protease inhibitor approved for once-
a-day dosing to treat AIDS due to good oral bioavailability
and favorable pharmacokinetic profile [11-13]. Furthermore,
atazanavir (1) did not cause large increases in cholesterol,
triglycerides or blood sugar levels, which is a problem to
various degrees with other protease inhibitors [14]. Few
methods have been explored for the synthesis of atazanavir
(1) [15-17]. A series of inhibitors based on a modified sub-
structure of atazanavir (1) have been synthesized and evalu-
ated [18, 19].
2. RESULTS AND DISCUSSION
Owing to the challenges with the original approach to the
biaryl-hydrazine unit 2, a fundamentally different route was
devised. Our synthetic route is summarized in Scheme (1). Ac-
cordingly, inexpensive and readily available (4-cyanophenyl)-
boronic acid (4) was selected as the starting material. Suzuki-
Miyaura coupling of (4-cyanophenyl)boronic acid (4) and
2-chloropyridine (3) was investigated first. As indicated in
Table 1, the reaction conditions were optimized in terms of
the catalyst, ligand, base, solvent and temperature. Initially,
2-chloropyridine (3) (1 equiv) was treated with (4-
cyanophenyl)boronic acid (4) (1.2 equiv) in the presence of
tetrakis(triphenylphosphine)palladium(0) using ligand TPP
(triphenylphosphine) (0.2 equiv) and K2CO3 (2.2 equiv) as a
base in 1,4-dioxane at 100oC. The coupling product 5 was
obtained in 74% yield (Table 1, entry 1). To improve the
yield the reaction was screened in different solvents with
different bases. After an extensive screening process 0.2
equiv of tetrakis(triphenylphosphine)palladium(0) using lig-
and TPP (0.2 equiv), 2.2 equiv of K2CO3 in DMF at 100oC
The synthesis of atazanavir (1) required two chiral inter-
mediates and biaryl-hydrazine unit 2 (Fig. 1). Generally in-
termediate 2 was prepared from 4-bromobenzaldehyde or
*Address correspondence to this author at the Department of Chemistry,
GITAM University, Hyderabad, P.O. Box: 502329, India; Tel: +91-
9493499396; E-mails: iictpnreddy@gmail.com; dr.n.k.katari@gmail.com
1875-6255/20 $65.00+.00
© 2020 Bentham Science Publishers

A Scalable Synthesis of Biaryl Unit of the HIV Protease Inhibitor Atazanavir
Letters in Organic Chemistry, 2020, Vol. 17, No. 1 69
O
O
N
O
N
H
O
N
O
OH
O
H
N
H
N
+
N
OMe
O
N
H
N
H
HN
Boc
O
O
OH
N
H
H2N
Cl
Biaryl unit
2
Atazanavir
1
Fig. (1). Chemical structures concerning atazanavir (1).
O
H
N
N
H
CHO
CN
O
CN
10% Pd/C
DIPEA
N-Boc hydrazine
toluene, reflux, 4h
DIBAL-H
CH2Cl2
N
+
NaBH4, MeOH
45 0C, 4h
1,2-DME/MeOH
60 0C, 6h
Cl
-70 0C, 30 min
N
N
B
N
HO
OH
two stages
one-pot
6
5
2
3
4
Scheme (1). Synthetic route for biaryl-hydrazine unit 2 of atazanavir (1).
This procedure was successfully scaled up to 100 g large
were determined to be the most effective coupling condi-
tions (Table 1, entry 2). Second, the combination of
Pd(OAc)2 with different ligands such as TPP, dppe (1,2-
(bis(diphenylphosphino)ethane), dppf (1,1'-ferrocenediyl-
bis(diphenyphosphine) was tested for the reaction of 2-
chloropyridine (3) with (4-cyanophenyl)boronic acid (4).
The products were obtained in good yields ranging from 80
to 89%. As described above, the reaction worked equally
well for both tetrakis(triphenylphosphine)palladium(0) and
Pd(OAc)2. However, considering the cost of these palladium
catalysts, next we tested the reaction with Pd/C which is
cheap and commercially available. The reaction of 2-
chloropyridine (3) and (4-cyanophenyl)boronic acid (4) with
10% Pd/C in the presence of TEA (triethylamine) as a base
in 1,2-dimethoxyethane/methanol (1,2-DME/MeOH) at 60oC
gave 62% yield (Table 1, entry 12). Further reaction yield
was improved to 90% when the reaction was carried out in
the presence of DIPEA (diisopropylethylamine) as a base for
6 h (Table 1, entry 14). We also demonstrated that the reac-
tion could be scaled to 100 g level with similar yield (Table
1, entry 15). Compared to air-sensitive and expensive homo-
geneous palladium catalysts, palladium charcoal can be safe-
ly handled and removed from the reaction mixture by simple
filtration. The recovered palladium charcoal can be purified
and reused as palladium metal. These features are great ad-
vantages in an industrial process.
scale with similar yield (Table 2, entry 9).
The condensation of aldehyde 6 with tert-butyl carbazate
was initially carried out by heating in toluene. We then pre-
sumed that in situ reduction of imine could proceed by the
addition of reducing agent to the reaction mixture. Reduction
with sodium borohydride is being increasingly used as an
alternative for the classical catalytic hydrogenation of organ-
ic functional groups, as it offers convenient and simple ex-
perimental conditions. Accordingly, after completion of con-
densation reaction 1 equiv of sodium borohydride was added
and then MeOH was added slowly. This procedure afforded
a 78% yield of biaryl-hydrazine unit 2 of atazanavir (1)
(Table 3, entry 1). We investigated various reducing agents
and found that the use of 1.05 equiv of sodium borohydride
with the use of solvent mixture of 10:1 toluene/MeOH was
ideal for both the condensation and subsequent in situ reduc-
tion (Table 3, entry 2). This procedure was scaled up to 100
g of 2 in a single bath (Table 3, entry 10). The structures of
all the compounds were confirmed by spectral analysis. One
of the features of this method is that both the condensation
and reduction reactions were conducted in one-pot, while in
previously reported methods two steps were involved [15-
17]. It is worth to mention that this transformation minimizes
the side reactions and over reduction byproducts. Further, the
method does not require isolation and crystallization of hy-
drazone intermediate.
Next, attention was turned to a partial reduction of nitrile
group of 5 to aldehyde 6 with 1 equiv DIBAL-H in DCM at
0oC. The reduction provided 4-(2-pyridinyl)benzaldehyde (6)
in 58% yield (Table 2, entry 1). We investigated the reaction
at various temperatures and observed that reducing the tem-
perature significantly increases the yield. After some optimi-
zation, we found that 1.1 equiv of DIBAL-H at -70oC in DCM
was the optimum condition for this reaction (Table 2, entry 8).
3. EXPERIMENTAL SECTION
3.1. General
All chemicals were purchased from Lancaster (Alfa Aesar,
Johnson Matthey Co, Ward Hill, MA, USA), Sigma-Aldrich

70 Letters in Organic Chemistry, 2020, Vol. 17, No. 1
Vijayalakshmi et al.
Table 1. Optimization of reaction conditions for the preparation of 4-(2-pyridinyl)benzonitrile (5).
S. No.
Catalyst
Base
Ligand
Solvent
Temperature (oC)
Time (h)
Yielda (%)
1
2
Pd[(C6H5)3P]4
Pd[(C6H5)3P]4
Pd[(C6H5)3P]4
Pd[(C6H5)3P]4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd/C
K2CO3
K2CO3
TPP
TPP
TPP
TPP
TPP
TPP
dppe
dppe
dppf
dppf
-
1,4-dioxane
DMF
100
100
100
100
100
100
100
100
100
100
60
10
10
10
10
6
74
85
76
77
88
89
84
80
86
85
62
68
90
92b
3
Cs2CO3
Cs2CO3
K2CO3
1,4-dioxane
DMF
4
6
1,2-DME
7
Cs2CO3
DABCO
DABCO
DABCO
DABCO
TEA
1,2-DME
6
8
DMF
4
9
1,4-dioxane
DMF
4
10
11
12
13
14
4
1,4-dioxane
1,2-DME/MeOH
1,2-DME/MeOH
1,2-DME/MeOH
1,2-DME/MeOH
4
8
Pd/C
DIPEA
DIPEA
DIPEA
-
60
4
Pd/C
-
60
6
15
Pd/C
-
60
6
a Isolated yield.
b 2-chloropyridine (3) (0.88 mol), (4-cyanophenyl)boronic acid (4) (1.05 mol), 1,2-DME/MeOH (500:20 mL), 10% Pd/C (wet) (0.05 w/w) at 60oC,
Table 2. Optimization of reaction conditions for the preparation of 4-(2-pyridinyl)benzaldehyde (6).
S. No.
DIBAL-H (Equiv)
Temperature (oC)
Solvent
Time (min)
Yielda (%)
1
2
3
4
5
6
7
8
1
0
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
30
60
30
30
30
30
30
30
30
58
61
67
69
74
76
89
92b
92c
1.2
1.1
1.1
1.1
1.1
1.1
1.1
1.1
0
-10
-30
-40
-50
-60
-70
-70
9
a Isolated yield.
b 4-(2-Pyridinyl)benzonitrile (5) (1.00 mmol), DIBAL-H (1.2 mmol) at -70oC.
c 100 g scale.
3.2. Synthesis of 4-(2-pyridinyl)benzonitrile (5)
(St Louis, MO, USA) and Spectrochem Pvt Ltd (Mumbai,
India). Reactions were monitored by TLC, performed on
silica gel glass plates containing 60 F-254 and visualization
on TLC was achieved by UV light or iodine indicator. NMR
spectra were recorded on Avance (300 MHz) Bruker,
Fallanden, Switzerland instruments. Chemical shifts were
reported in ppm, downfield from internal TMS standard.
Spectral patterns were designated as s, singlet; d, doublet; m,
multiplet. ESI spectra were recorded on Micro mass, Quattro
LC using ESI+ software with a capillary voltage of 3.98 kV
and ESI mode positive ion trap detector.
To a solution of 2-chloropyridine (3) (0.97 mmol, 0.11 g)
and (4-cyanophenyl)boronic acid (4) (1.16 mmol, 0.17 g) in
1,2-DME (10 mL), DIPEA (2.37 mmol, 0.4 mL), MeOH
(1 mL), and 10% Pd/C (wet) (0.05 w/w based on 2-chloro-
pyridine) were added at room temperature. The reaction mix-
ture was heated at 60oC for 6 h. Then it was cooled to room
temperature, filtered through celite bed, and washed with
1,2-DME. The filtrate was poured into water and precipitated
solid was filtered, washed with water, and dried under vacu-
um at 40°C for 12 h to afford the pure product 5.

A Scalable Synthesis of Biaryl Unit of the HIV Protease Inhibitor Atazanavir
Letters in Organic Chemistry, 2020, Vol. 17, No. 1 71
Table 3. Preparation of tert-butyl 2-[4-(2-pyridinyl)benzyl]hydrazinecarboxylate (2).
S. No.
Reducing Reagent
Equiv
Temperature (oC)
Solvent
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
NaBH4
NaBH4
1
45
45
45
45
45
45
45
45
45
Toluene: Methanol
Toluene: Methanol
Toluene: Methanol
Toluene: Methanol
Toluene: Methanol
Toluene: Methanol
Toluene: Methanol
Toluene: Methanol
Toluene: Methanol
4
4
4
4
4
4
6
6
4
78
86
82
82
83
80
77
79
85a
1.05
1.1
NaBH4
NaBH4
1.2
NaBH(OAc)3
NaBH(OAc)3
NaBH3CN
NaBH3CN
NaBH4
1.05
1.1
1.05
1.1
10
1.05
a Isolated yield.
b 4-(2-Pyridinyl)benzaldehyde (6) (0.54 mol), tert-butyl carbazate (0.65 mol) at reflux in toluene (500 mL), sodium borohydride (0.56 mol) at 30oC.
White solid, m.p. 106-108oC; 1H NMR (300 MHz,
mmol, 0.04 g) was added followed by MeOH (5 mL). Then
the reaction mixture was heated to 45oC and stirred at the
same temperature. After 4 h, the reaction mixture was cooled
to room temperature and water (10 mL) was added. Organic
layer was separated, washed with brine (3 x 20 mL), dried
(Na2SO4), and solvent removed under vacuum. The crude
product was crystallized using mixture of ethanol-water,
filtered, washed, and dried to afford the product 2.
CDCl3): δ 8.76-8.71 (m, 1H, ArH), 8.18 (d, 2H, J = 8.4 Hz,
ArH), 7.82-7.63 (m, 4H, ArH), 7.36-7.28 (m, 1H, ArH); 13C
NMR (75 MHz, CDCl3): δ 155.0 (pyridine C-1'), 149.8 (C-
3'), 143.3 (C-4), 137.0 (C-5'), 132.3 (C-2,6), 127.3 (C-3,5),
123.2 (C-4'), 120.9 (C-6'), 118.6 (CN), 112.2 (C-1); ESIMS:
m/z 181 (M+H)+; HRMS: m/z (M+H)+ calcd for C12H9N2
181.1725, found 181.1729.
1
White solid, m.p. 78-80oC; H NMR (300 MHz, CDCl3):
3.3. Preparation of 4-(2-pyridinyl)benzaldehyde (6)
δ 8.72-8.63 (m, 1H, ArH), 7.96 (d, 2H, J = 8.0 Hz, ArH),
7.76-7.68 (m, 2H, ArH), 7.45 (d, 2H, J = 8.0 Hz, ArH), 7.22-
7.16 (m, 1H, ArH), 6.51 (s, 1H, NH), 4.32 (s, 1H, NH), 4.01
(s, 2H, CH2), 1.46 [s, 9H, (CH3)3]; 13C NMR (75 MHz,
CDCl3): δ 156.8, 156.5, 150.0, 139.1, 139.0, 137.2, 129.5,
127.3, 122.2, 120.1, 80.1, 55.1, 28.2; IR (KBr pellet, cm-1):
3293, 2982, 2938, 1699, 1457, 1284, 1151, 781; ESIMS: m/z
300 (M+H)+; HRMS: m/z (M+H)+ calcd for C17H22N3O2
300.2236, found 300.2241.
4-(2-Pyridinyl)benzonitrile (5) (1.00 mmol, 0.18 g) was
dissolved in dry DCM (10 mL), cooled to -70oC, and
DIBAL-H (1 M solution in DCM, 1.2 equiv, 1.2 mL) was
added slowly under nitrogen. The mixture was allowed to
stir for 30 min, warmed to 0oC and sodium potassium tartrate
solution (saturated) was added (5 mL). The resulting solution
was filtered through celite bed and washed with DCM. Or-
ganic layer was separated, washed with brine (3 x 20 mL),
dried (Na2SO4), and solvent removed under vacuum. The
resulted solid compound 6 was collected by filtration and
subjected to the next step without further purification.
CONCLUSION
We have developed a short and efficient synthesis of
atazanavir key intermediate biaryl-hydrazine unit 2. The
method is useful for large scale synthesis and gives excellent
yield. The process does not require the usage of Grignard
reagent, expensive catalyst, protection/deprotection of alde-
hyde moiety and catalytic hydrogenation.
1
White solid, m.p. 52-54oC; H NMR (300 MHz, CDCl3):
δ 10.01 (s, 1H, CHO), 8.78-8.68 (m, 1H, ArH), 8.18 (d, 2H,
J = 8.4 Hz, ArH), 8.00 (d, 2H, J = 8.4 Hz, ArH), 7.86-7.75
(m, 2H, ArH), 7.35-7.28 (m, 1H, ArH); 13C NMR (75 MHz,
CDCl3): δ 192.0 (CHO), 156.2 (pyridine C-1'), 150.0 (C-3'),
145.2 (C-4), 137.8 (C-5'), 136.5 (C-1), 130.2 (C-2,6), 127.5
(C-3,5), 123.4 (C-4'), 122.0 (C-6'); ESIMS: m/z 184 (M+H)+;
HRMS: m/z (M+H)+ calcd for C12H10NO 184.1913, found
184.1916.
CONSENT FOR PUBLICATION
Not applicable.
AVAILABILITY OF DATA AND MATERIALS
3.4. Preparation of tert-butyl 2-[4-(2-pyridinyl)benzyl]
hydrazinecarboxylate (2)
Not applicable.
Into a mixture of 4-(2-pyridinyl)benzaldehyde (6) (0.98
mmol, 0.18 g) and tert-butyl carbazate (1.13 mmol, 0.15 g)
toluene (10 mL) was added. The mixture was heated to re-
flux for 4 h, cooled to 30oC, and sodium borohydride (1.06
FUNDING
None.

72 Letters in Organic Chemistry, 2020, Vol. 17, No. 1
Vijayalakshmi et al.
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The authors declare no conflict of interest, financial or
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