A novel strategy for the manufacture of idelalisib: Controlling the formation of an enantiomer

Article abstract of DOI:10.1039/c8ra00407b

A novel and scalable synthesis of 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-4(3H)-quinazolinone, idelalisib 1, has been developed. This strategy controls the desfluoro impurity of 13 during reduction of nitro intermediate 4, and also arrests the formation of the enantiomer during cyclisation of diamide 17, without affecting the neighbouring chiral centre. This process is demonstrated on a larger scale in the laboratory and achieved good chemical and chiral purities coupled with good yields.

Full text of DOI:10.1039/c8ra00407b

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A novel strategy for the manufacture of idelalisib:
controlling the formation of an enantiomer†
Cite this: RSC Adv., 2018, 8, 15863
Nagaraju Mekala,ab Srinivasa Rao Buddepu,ab Sanjay K. Dehury,a
a
Sunil Kumar V. Indukuri,a
*
Krishna Murthy V. R. Moturu,
Umamaheswara Rao Vasireddia and Atchuta R. Parimib
A
novel and scalable synthesis of 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-4(3H)-
Received 15th January 2018
Accepted 13th April 2018
quinazolinone, idelalisib 1, has been developed. This strategy controls the desfluoro impurity of 13 during
reduction of nitro intermediate 4, and also arrests the formation of the enantiomer during cyclisation of
diamide 17, without affecting the neighbouring chiral centre. This process is demonstrated on a larger
scale in the laboratory and achieved good chemical and chiral purities coupled with good yields.
DOI: 10.1039/c8ra00407b
rsc.li/rsc-advances
have received at least one prior therapy and as rst line treat-
ment in the presence of 17p depletion.
Introduction
As part of our research programme on the development of
a series of anticancer drugs, herein we disclose a novel strategy
for the synthesis of idelalisib, 1. Our approach has resulted not
only in achieving almost total control of undesired enantiomer
of 1, but also enhanced the yields tremendously during the
cyclisation step when compared to known related reports in the
literature.5–7
Quinazolinones are fused heterocyclic alkaloids and have
attracted many scientists working in organic and medicinal
chemistry due to their substantial and extensive range of ther-
apeutic activities. The remarkable therapeutic activities1 such as
antiinammatory, anticonvulsant, antidiabetic, anticancer,
antitussive, antibacterial, analgesic, hypnotic, and sedative
activities coupled with exotic structural features have impelled
a lot of activity in synthetic chemistry research groups towards
the development of new synthetic strategies and methodologies
for the synthesis of quinazolinone alkaloids. Till now approxi-
mately 200 naturally occurring quinazolinone alkaloids have
been isolated from various sources.2
Idelalisib 1, (trade name; Zydelig), 5-uoro-3-phenyl-2-[(1S)-
1-(9H-purin-6-ylamino)propyl]-4(3H)-quinazolinone is a quina-
zolinone drug used for the treatment of chronic lymphocytic
leukemia. The substance acts as a phosphoinositide 3-kinase
inhibitor; More specically, it blocks P110d, the delta isoform of
the enzyme phosphoinositide 3-kinase. The U.S. Food and Drug
Administration approved idelalisib,3 in 2014, for the treatment
of relapsed Follicular B-cell non-Hodgkin Lymphoma (FL),
relapsed Chronic Lymphocytic Leukemia (CLL) and relapsed
Small Lymphocytic Lymphoma (SLL). The European Medicines
Agency (EMA) granted idelalisib4 approval for the treatment of
adult patients with Chronic Lymphocytic Leukaemia (CLL) who
Results and discussion
Idelalisib was rst developed by Icos corporation.5 The
synthesis of idelalisib reported by Icos corporation was started
with 2-uoro-6-nitro benzoic acid (Scheme 1). Nitrobenzoic acid
on treatment with oxalylchloride followed by condensation with
aniline in DCM affords the corresponding 2-uoro-6-nitro-N-
phenylbenzamide 4. Coupling of this N-phenylbenzamide, 4
with N-Boc-L-2-amino butyric acid in presence of oxalylchloride
yields N-boc-2-amino butyrate intermediate 6 which on reduc-
tion with Zn/AcOH affords the corresponding quinazolinone
intermediate. Deprotection of Boc group followed by coupling
with 6-bromopurine affords idelalisib 1. In this route reaction of
N-Boc-L-2-amino butyric acid, 5 with nitro amide intermediate 4
is a tedious reaction. In this process only 50% conversion
observed with 60% purity, due to back ward reaction. Changing
the solvent medium from DCM to acetonitrile or toluene also
did not give any advantage in terms of conversion and purity. In
aOncology Division, Process Development Laboratories, Laurus Laboratories Limited, the subsequent stage, nitro group is reduced but further cycli-
ICICI Knowledge Park, Turkapally, Shameerpet, Hyderabad-500 078, Telangana,
sation is not completed to form the quinazolinone (Scheme 1).
India. E-mail: murthy.moturu@lauruslabs.com; Fax: +91 40 23480481; Tel: +91 40
In the second synthesis reported by Geng Fengluan et al.6 of
30413393
Shandong Kangmeile Pharmaceutical Technology Co Ltd.
avoided acid chloride reagent for the activation of 2-uoro-6-
nitro benzoic acid, 2 instead used CDI (Scheme 1). In the
reductive cyclisation of 6, Fe/AcOH was used in place of Zn/
bDepartment of Organic Chemistry, Food, Drugs & Water, School of Chemistry, Andhra
University, Visakhapatnam-530 003, Andhra Pradesh, India
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c8ra00407b
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Scheme 1 Synthesis of idelalisib, 1 reported by Icos Corporation& Shandong Kangmeile Pharmaceutical Technology Co Ltd.
AcOH. However, CDI is expensive to use and Fe/AcOH reagent the 2-amino-6-uoro-N-phenylbenzamide in 90% yield coupled
also not viable in commercial scale.
with 99% purity (Table 1; entry 4).
The third synthesis reported by Suzhou Mirac Pharma
In the next step for the formation of amide bond, we have
Technology Co. Ltd7 is started with coupling of adenine 10 with attempted different coupling reagents such as benzotriazol-1-yl-
2-hydroxy butyrate 9 to afford the corresponding adenine oxytripyrrolidinophosphonium hexauorophosphate (PyBOP),
derivative 11. Treatment of 11 with 2-amino-6-uoro benzoic N,N0-dicyclohexylcarbodiimide (DCC), carbonyldiimidazole
acid 2 in trimethylaluminium yields the corresponding acid (CDI), CDI/HOBt (1-hydroxybenzotriazole) and PyBOP/HOBt for
intermediate 12. This acid intermediate on treatment with the coupling reaction of N-Boc-L-2-amino butyric acid with 2-
aniline, 3 in presence ꢀof acetic anhydride and toluene at high amino-6-uoro-N-phenylbenzamide with different solvents to
temperatures (80–120 C) followed by cyclisation afforded ide- achieve good yield and purity (Table 2).
lalisib, 1. In this route coupling of aniline 3 with acid inter-
As shown in Table 2, the conversion of 13 was observed
mediate, 12 followed by cyclisation is a cumbersome reaction ꢁ50% by TLC when the reaction was carried out in DMF at room
forming many products. The removal of aniline from the reac- temperature using PyBOP as coupling agent. However, aer
tion mass to desired level as per ICH limit is also not achieved work up it was found that only 10% of the product was isolated
(Scheme 2).
with 99% purity along with control of other isomer formation
Hence, development of idelalisib, 1 process for the manu- (Table 2; entry 1). Changing the solvent to acetonitrile or
facture requires an alternate approach to achieve ICH purity toluene there was not much improvement in the yield but up to
and a scalable process. As part of our process development to 5% racemisation is observed (Table 2; entry 2) in acetonitrile
prepare 1 in desired cost, we have designed a novel route whereas the isomerisation was controlled to 0.10% in the latter
(Scheme 3). Unlike the innovator process (Scheme 1), N-Boc-L-2- solvent (Table 2; entry 3). Thus we decided to use toluene as
amino butyric acid, 5 was coupled with 2-amino-6-uoro-N- solvent in the further experiments. To our good fortune race-
phenylbenzamide at ambient temperature and achieved >98% misation is controlled completely with similar conversion and
purities with reasonably good yield (Table 1). The reduction of yield when 1.0 eq. of HOBt is added to PyBOP (Table 2; entry 4).
nitro group for the preparation of amino intermediate is carried Conversion is improved in both DCC (Table 2; entry 5) and CDI
out at ambient temperature with conventional catalysts like (Table 2; entry 6) with improved yield 44% in the same solvent
10% Pd–C (Table 1; entry 1), 5% Pd–C (Table 1; entry 2), Pt–C but up to 2% racemisation was observed with DCC and 0.5%
(Table 1; entry 3) in a 1 : 1 mixture of methanol and dichloro- with CDI. Complete conversion with reasonably good yield was
methane. With these catalysts desuoro impurity is formed up observed when 1.0 eq. of HOBt is added to CDI (2.0 eq.) and also
to 5% level which is very difficult to separate by means of any totally controlled the racemisation to 0.01% (Table 2; entry 7) at
crystallisation from the product once it is formed. Finally, this lower temperature (8–12 ꢀC). The same reaction at room
impurity is completely controlled in the reaction itself by temperature gives other isomer up to 0.15% level and at higher
changing the catalyst to zinc and ammonium formate8 to afford temperatures racemisation is observed up to 25%.
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Scheme 2 Synthesis of idelalisib, 1 reported by Suzhou Mirac Pharma Technology Co. Ltd.
Deprotection of the Boc group in DCM/triuoroacetic acid at amine, 15 when coupled with 6-chloropurine, 16 in acetonitrile
0–10 ꢀC is achieved smoothly to afford the corresponding with diisopropylethylamine (DIPEA; 1.5 eq.) and ZnCl2 (1.5 eq.)
amine, 15 in quantitative yield coupled with 99% purity. This at 80–90 ꢀC for 10–12 h afforded the corresponding diamide in
Scheme 3 Synthesis of idelalisib, 1 by Laurus Labs Ltd.
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Table 1 Reduction of 2-fluoro-6-nitro-N-phenylbenzamide, 4 with different catalysts
Purity by HPLC (% area)
S. No.
Catalyst
Input (g)
Output (g)
Yield (%)
Product
Desuoro impurity
1a
2a
3b
4c
10% Pd–C
5% Pd–C
Pt/C
110
100
10
84
82
8
87
93
91
90
93.5
98.0
—
5.6
0.28
0.2
Zn/HCOONH4
180
142
99.0
Not detected
a
Catalyst used: 50% wet. b Catalyst used: 0.2 w/w to the input. c Catalyst used: Zn: 6.0 eq. and HCOONH4 7.0 eq.
Table 2 Coupling of 2-amino-6-fluoro-N-phenylbenzamide, 13 with N-Boc-L-2-amino butyric acida
Purity by HPLC (% area)
Chemical
Chiral
Coupling
S. No. reagent
Input (g) Solvent
Output (g) Yield (%) Product
Product Enantiomer Remarks
1
PyBOp
10
DMF
5
10
99.0
99.95
0.05
Reaction not
completed (ꢁ50% conversion observed
by TLC)
2
3
4
5
PyBOp
PyBOp
PyBOp/HOBt 10
10
10
Acetonitrile
Toluene
Toluene
5
5
5
8
32
28
28
44
99.0
99.0
99.0
97.0
95.0
99.9
100
5.0
0.1
0.0
2.0
DCC
10
Toluene
98.0
Reaction not
completed (ꢁ70% conversion observed
by TLC)
6
7
CDI
CDI/HOBt
10
140
Toluene
Toluene
8
182
44
75
97.0
99.5
99.5
99.99
0.5
0.01
Reaction completed by TLC
a
Reagents used: 2.0 eq. of reagents used in all experiments except HOBt 1.0 eq.
58% yield with 60% purity (Table 3; entry 1). Conversion is
Cyclisation of 17 to form the quinazoline ring closing by
observed only 50% by TLC when the base is changed to trie- retaining the neighbouring chiral centre is a crucial step in the
thylamine but only 39% yield coupled with 98% purity with 5% preparation of idelalisib, 1. To accomplish the cyclisation of
of enantiomer is observed aer isolation (Table 3; entry 2). diamide, 17 various reagents such as HMDS, HMDS/I2 and
Reaction accelerates when zinc chloride loading is doubled (3.0 piperdine/I2 (Table 4) and solvents (Table 5) have been studied.
eq.) with DIPEA base and controlled the racemisation to below Cyclization of diamide attempted in Zn/AcOH as per innovator
0.5% (Table 3; entry 3). Reaction does not go to completion process5a at room temperature but did not result in any
without zinc chloride and up to 20% of other isomer is formed conversion (Table 4; entry 1). Reaction did not progress at all
(Table 3; entry 4). Reaction not moved at all in other bases, such with different reagent/solvent systems such as PTSA/toluene,
as pyridine and ammonia (Table 3; entries 5 & 6). Conversion is DMF, formamide and trimethyl aluminium/toluene (Table 4;
also observed in water but 50% racemisation is observed.
entries 2–5). Reaction also attempted with ZnCl2/acetonitrile9
Table 3 Alkylation of 2-{[(2S)-2-aminobutanoyl]amino}-6-fluoro-N-phenylbenzamide, 15 with 6-chloropurine
Chiral purity
by HPLC (% area)
Chemical purity
Conversion
by TLC (%)
S. No.
Base/reagent
Input (g)
Output (g)
Yield (%)
by HPLC (% area)
Product
Enantiomer
1
2
3
4
5
6
DIPEA/ZnCl2
TEA/ZnCl2
DIPEA/ZnCl2
DIPEA
Pyridine/ZnCl2
NH4OH/ZnCl2
10.0
5.0
10.0
10.0
3.0
6.0
2.0
6.0
3.0
—
58
39
58
29
—
—
60
98
78
60
—
—
98
95
99.5
80
—
2
5
0.5
20
—
—
70
50
75
30
No conversion
3.0
—
—
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Table 4 Cyclisation of diamide, 17 to idelalisib
Chiral purity
by HPLC (% area)
Chemical
purity (%)
S. No.
Base/reagent
Input (g)
Output (g)
Yield (%)
Product
Enantiomer
1
2
3
4
5
6
7
8
Zn/AcOH
pTSA/toluene
DMF
Formamide
Trimethyl aluminium/toluene
ZnCl2/acetonitrile
TPP/I2/piperidine
HMDS/I2/DCM
HMDS/I2/toluene
HMDS/ZnBr2/toluene
HMDS/I2
0.5
0.5
0.5
0.5
2.0
5.0
10.0
0.5
0.5
0.5
—
—
—
—
—
—
4.5
0.2
0.3
—
11.0
10.0
—
—
—
—
—
—
47
42
63
—
58
53
—
—
—
—
—
—
60
10
60
—
98.9
99.5
—
—
—
—
—
—
50
50
50
—
50
99.95
—
—
—
—
—
—
50
50
50
—
50
0.05
9
10
11
12
20.0
20.0
HMDS/ZnCl2/acetonitrile
Table 5 Selection of solvent for cyclisation of diamide, 17 to idelalisib
Chiral purity by HPLC (%)
Chemical
S. No.
Solvent
Input (g)
Output (g)
Yield (%)
purity (%)
Product
Enantiomer
1
2
3
4
5
Toluene
t-Butanol
n-Butanol
2-Methyl THF
Acetonitrile
40
20
3
300
30
20
10
2
208
20
48
48
64
66
64
78
90
80
75
50
50
50
98.0
99.95
50
50
50
2.0
0.05
99.5
but found no advantage (Table 4; entry 6). When the reagent purity was observed but racemisation could not be prevented.
system is changed to TPP/I2/piperidine in acetonitrile the Finally, racemisation is completely arrested by changing the
product was obtained in 60% purity but racemisation could not reagent to HMDS/ZnCl212 (Table 4; entry 12) in acetonitrile and
be controlled (Table 4; entry 7). When the reaction is carried out obtained the compound with good purity 99.5% in 53% yield.
in HMDS/I2 in DCM only 42% yield was observed with complete
Having this result in hand further efforts were directed
racemisation (Table 4; entry 8). Complete conversion is towards nding a suitable solvent to achieve ICH quality
observed but racemisation is not controlled when the DCM material coupled with good yield. Reaction in toluene afforded
replaced with toluene, though 60% purity of the product is the product in 48% yield and 78% purity but racemised
obtained (Table 4; entry 9). Reaction also attempted by replac- completely (Table 5; entry 1). Changing the solvent to t-butanol
ing iodine with ZnBr2 but product formation was not observed (Table 5; entry 2) or n-butanol (Table 5; entry 3) did not arrest
at all (Table 4; entry 10).10 When neat reaction was carried out in the racemisation but improved yield in n-butanol. Reaction in 2-
11
HMDS/I2 (Table 4; entry 11) 58% yield coupled with 98.9% methyl THF afforded the similar yield as observed in n-butanol,
Table 6 Yields and purities of scale up experiments in all stages
Theoretical yield
w/w
Observed yield
%
Chemical purity
by HPLC (%)
Stage
Input (g)
Output (g)
w/w
1
2
3
4
5
150
180
190
170
150
200
147
225
170
65
95
93
66
96
—
1.33
0.82
1.18
1.00
0.43
1.40
0.88
1.80
1.37
0.96
99.35
98.76
99.91
81.22
100a
a
Chiral purity also observed in 100%.
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however, racemisation controlled to 2% with reasonable purity
(Table 5; entry 4). No conversion was observed when the reac-
tion was carried out in water. Finally when reaction was carried
out in acetonitrile racemisation was controlled to 0.05% level
along with achieving high purity of 99.95% in 64% yield (Table
5; entry 5).
Finally, with all these results in hand the optimised process
was executed in 150–190 g scale in the Laboratory. We observed
good yield and purities in all the steps (Table 6).13
Preparation of 2-{[(2S)-2-amino(butoxycarbonyl)butanoyl]
amino}-6-uoro-N-phenylbenzamide, 14
To a toluene (500 mL) solution of N-Boc-L-2-amino butyric acid
(100 g; 493 mmol), was added 2-uoro-6-amino-N-
phenylbenzamide (100 g; 435 mmol) cooled to 8–15 ꢀC and
added carbonyldiimidazole (140.8 g, 869 mmol) followed by 1-
hydroxybenzotriazole (117.4 g, 868.6 mmol) and stirred for 30–
32 h. Aer completion of the reaction which was monitored by
TLC, the mass was quenched into water (500 mL). The obtained
precipitate was ltered, washed with water. The wet material
was leached with acetonitrile (300 mL), ltered and dried to
afford off-white coloured 2-{[(2S)-2-amino(butoxycarbonyl)
butanoyl]amino}-6-uoro-N-phenylbenzamide, 14 in 67% yield.
Mp by DSC: 167.48 ꢀC; 1HNMR (300 MHz, DMSO-d6) d 10.54 (s,
1H), 9.93 (s, 1H), 7.99 (d, 1H, J ¼ 8.4 Hz), 7.74 (m, 2H), 7.52 (m,
1H), 7.32 (m, 2H), 7.12 (m, 2H), 3.89 (broad s, 1H), 1.74 (m, 1H),
1.55 (m, 1H), 1.30 (s, 9H), 0.86 (t, J ¼ 7.2 Hz, 3H); 13CNMR (75
MHz, DMSO-d6) d 171.50, 161.41, 160.69, 157.43, 155.70, 138.60,
137.70, 131.75, 128.50, 124.07, 120.93, 119.96, 117.56, 115.75,
111.12, 78.33, 56.99, 28.00, 24.38, 10.54; MS: m/z 414(M+ ꢂ H).
Experimental procedures
Preparation of 2-uoro-6-nitro-N-phenylbenzamide, 4
To a DCM solution of 2-uoro-5-nitro benzoic acid (100 g; 540
mmol), was added catalytic amount of DMF (7.3 g, 100 mmol)
and oxalylchloride (102.8 g, 810 mmol) at ambient tempera-
ture and maintained for 3 h. Aer completion of the reaction
which was monitored by TLC, the solvent was stripped off
and the obtained residue was dissolved in 1,4-dioxane (80
mL) and kept a side. In another RBF having 250 mL 1,4-
dioxane was added aniline (50.3 g; 541 mmol) and aq. sodium
bicarbonate (90 g in 250 water) solution. To this aniline
solution was added the above 1,4-dioxane solution at 0–5 ꢀC,
maintained at ambient temperature for 90 min. Aer
completion of the reaction which was monitored by TLC, the
reaction mass was quenched into water (1500 mL) and stirred
for 2 h at ambient temperature. The obtained pale yellow
colour solids were ltered, washed with water to afford 2-
uoro-6-nitro-N-phenylbenzamide in 86% yield and 99.0%
purity which was proceed to next step without further puri-
Preparation of 2-{[(2S)-2-amino(7H-purin)butanoyl]amino}-6-
uoro-N-phenylbenzamide, 17
To a solution of 2-{[(2S)-2-amino(butoxycarbonyl)butanoyl]
amino}-6-uoro-N-phenylbenzamide (100 g; 241 mmol) in
dichloromethane (200 mL), was added triuoroacetic acid (200
mL) and stirred for 3 h at ambient temperature. Aer
completion of the reaction which was monitored by TLC,
added water (2000 mL) to the reaction mass and adjusted the
pH to neutral with saturated sodium bicarbonate solution.
The obtained precipitate was ltered, washed with water and
dried to afford 2-{[(2S)-2-aminobutanoyl]amino}-6-uoro-N-
phenylbenzamide, 15. Mp by DSC: 195.46 ꢀC; 1HNMR (300
MHz, DMSO-d6) d 10.64 (s, 1H), 8.13 (brs, 1H), 7.14 (d, J ¼
8.4 Hz, 2H), 7.56 (m, 2H), 7.50 (m, 2H), 7.32 (m, 1H), 7.13 (m,
1
cation. H NMR data were identical with those reported in
the literature.5a,b
Preparation of 2-amino-6-uoro-N-phenylbenzamide, 13
To a mixture of methanol (500 mL) and dichloromethane 1H), 3.96 (t, J ¼ 6 Hz, 1H), 1.74 (q, 2H), 0.89 (t, J ¼ 7.5 Hz, 3H);
(500 mL), was added 2-uoro-6-nitro-N-phenylbenzamide 13CNMR (75 MHz, DMSO-d6) d 168.43, 160.62, 158.42, 158.01,
(100 g; 385 mmol), zinc powder (140 g; 2154 mmol) and then 157.28, 139.01, 135.70, 131.10, 128.70, 123.81, 120.59, 119.40,
slowly added aq. ammonium formate solution (dissolved 115.29, 112.75, 53.66, 24.54, 8.82; MS: m/z 316(M+ + H). The
170 g ammonium formate in 300 mL water) and stirred the obtained compound was dissolved in acetonitrile (500 mL)
reaction at ambient temperature for 4–5 h. The progress of and added 6-chloro purine (39 g; 253 mmol), zinc chloride
the reaction was monitored by TLC. Aer completion of the (98.4 g, 722 mmol) followed by diisopropylamine (36.5 g, 361
reaction zinc salts were ltered, washed with dichloro- mmol) and maintained at 80–100 ꢀC for 10–12 h. Aer
methane (500 mL). The solvent from ltrate was stripped off completion of the reaction which was monitored by TLC, the
completely under vacuum and added water (1000 mL) to the reaction mass was quenched into water (2000 mL), stirred for
obtained residue. The emitted white-pale pink colour solids 3 h and ltered. The obtained crude product was puried by
were ltered washed with water to afford 2-amino-6-uoro-N- leaching with methanol (200 mL) and THF (200 mL), ltered
phenylbenzamide in 90% yield. The product used as such to and dried to afford 2-{[(2S)-2-amino(7H-purin)butanoyl]
next step without further purication. Mp by DSC: amino}-6-uoro-N-phenylbenzamide, 17 in 60% yield. Mp by
1
1
ꢀ
ꢀ
112.58 C; HNMR (300 MHz, DMSO-d6) d 10.27 (s, 1H), 7.63 DSC: 267.99 C; HNMR (300 MHz, DMSO-d6) d 12.96 (s, 1H),
(m, 2H), 7.33 (t, J ¼ 7.5 Hz, 2H), 7.14 (m, 2H), 6.75 (d, J ¼ 10.47 (s, 1H), 10.10 (s, 1H), 8.14 (t, J ¼ 10.2 Hz, 2H), 7.89 (d, J ¼
8.1 Hz, 1H), 6.42 (m, 2H), 5.7 (s, 2H); 13CNMR (75 MHz, 8.1 Hz, 2H), 7.82 (d, J ¼ 5.4 Hz, 1H), 7.48 (m, 2H), 7.24 (m, 2H),
DMSO-d6) d 167.87, 163.03, 161.80, 158.58, 149.36, 139.15, 4.79 (br s, 1H), 1.96 (m, 2H), 0.94 (t, J ¼ 7.2 Hz, 3H); 13CNMR
131.41, 128.50, 123.50, 120.25, 111.38, 108.60, 101.90; MS: m/ (75 MHz, DMSO-d6) d 171.41, 161.05, 160.46, 157.20, 154.02,
z 231(M+ + H).
151.96, 150.00, 139.18, 138.35, 137.34, 131.50, 131.37, 128.57,
15868 | RSC Adv., 2018, 8, 15863–15869
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123.93, 119.71, 118.30, 116.50, 111.37, 111.06, 56.34, 24.39,
Notes and references
10.70; MS: m/z 434(M+ + H).
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Preparation of 5-uoro-3-phenyl-2-[(1S)-1-(9H-purin-6-
ylamino)propyl]-4(3H)-quinazolinone, 1(idelalisib)
To a solution of 2-{[(2S)-2-amino(7H-purin)butanoyl]amino}-6-
uoro-N-phenylbenzamide, 50 g, 115 mmol), in acetonitrile (250
mL) was added zinc chloride (51 g, 374 mmol), hexamethyldi-
silazane (55.9 g, 347 mmol) and maintained the reaction mass
at reux for 4 h. Aer completion of the reaction which was
monitored by TLC, the reaction mass was quenched into water
(1250 mL), stirred for 2–3 h, ltered and washed with water. The
obtained crude product was dissolved in DCM (500 mL),
adjusted pH to 2.0–3.0 with 10% aq. HCl. The DCM phase
separated and fresh DCM (500 mL) was added to the aq. phase
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recrystallized from acetonitrile (500 mL) to afford a white col-
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4(3H)-quinazolinone, 1 in 60% yield and 99.9% purity. The
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Conclusion
In summary, we successfully developed a facile, novel and
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Conflicts of interest
There are no conicts to declare.
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Acknowledgements
The authors wish to thank Dr Satyanarayana Chava, CEO and Dr
Srihari Raju Kalidindi, Executive Director, Laurus Laboratories
Ltd for their continuous encouragement and support. We also
thank Mr. Narasimha Rao DVL and other Senior Management
for their helpful discussions in carrying out this work.
This journal is © The Royal Society of Chemistry 2018
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