A novel process for the synthesis of substantially pure Letrozole

Article abstract of DOI:10.24820/ark.5550190.p010.891

This article demonstrates an improved novel and practical synthesis of oral non-steroidal aromatase inhibitor (AI) Letrozole in a five-stage synthetic process in excellent yields. Key steps of the synthesis involve the condensation of 4-(chloro(4-cyanophenyl)methyl)benzamide with 1H-1,2,4-triazole and further its dehydration to Letrozole by using trifluoroacetic anhydride at low temperature.

Full text of DOI:10.24820/ark.5550190.p010.891

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A novel process for the synthesis of substantially pure Letrozole
a
b
c
d
e
M. Suman, B. Vijayabhaskar, K. NageswaraRao, U. K. Syam Kumar,* and B. VenkateswaraRao
aResearch & Development, Dr. Reddy’s Laboratories Limited, API Plant, IDA, Pydibhimavaram,
RanasthalamMandal, Srikakulam District-532 409, India
GVK Biosciences PVT LTD, Survey no. 125 (part), 126, IDA, Mallapur, Hyderabad-500076, India.
b
C
Chemveda Life Sciences Pvt. Ltd, IDA Uppal, Hyderabad-500039, India
*
d
Integrated Product Development, Innovation Plaza, Dr. Reddy's Laboratories Ltd., Bachupalli, Qutubullapur,
R. R. Dist., 500072, Andhra Pradesh, India
e
Department of Engineering Chemistry, Andhra University, Visakhapatnam, 530003, India
Email: kalikinidi@gmail.com
Received 01-24-2019
Accepted 04-26-2019
Published on line 06-09-2019
Abstract
This article demonstrates an improved novel and practical synthesis of oral non-steroidal aromatase inhibitor
AI) Letrozole in a five-stage synthetic process in excellent yields. Key steps of the synthesis involve the
(
condensation of 4-(chloro(4-cyanophenyl)methyl)benzamide with 1H-1,2,4-triazole and further its dehydration
to Letrozole by using trifluoroacetic anhydride at low temperature.
Keywords: Letrozole, 1H-1, 2, 4-triazole, trifluoroacetic anhydride, 4-(chloro(4-
cyanophenyl)methyl)benzamide, 4,4-dibromobenzophenone
DOI: https://doi.org/10.24820/ark.5550190.p010.891
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Introduction
Letrozole 1 (Trade name: Femara) is an antineoplastic agent invented by Novartis Pharmaceuticals
Corporation and is used for the treatment of certain types of breast cancer (such as hormone-receptor-
1
positive breast cancer) in women. Letrozole is also used for the slow or reverse growth of breast cancer in
2,3
women by decreasing the production of estrogen in breast cancer patients.
Several reports are available in the literature for the synthesis of Letrozole 1. Most of these synthetic
protocols commenced with 4-((1H-1,2,4-triazol-1-yl)methyl)benzonitrile 6 as a key intermediate, which was
4-8
further converted into letrozole by reaction with 4-halocyanobenzene 7. The nucleophilic substitution on 4,
'-methylene-bis-benzonitrile 3 containing good leaving group at methylene bridge with triazole 4 is also
4
9,10
reportedly provided letrozole in excellent yields. Other notable synthesis of letrozole include the late stage
palladium catalysed cyanation on 1-[bis(4-bromophenyl)methyl]-1H-1,2,4-triazole 5 with Zn(CN)
11
2
.
Construction of 1H-1,2,4-triazole ring starting from 4,4'-(hydrazonomethylene)dibenzonitrile, removal of
12
amino functionality by diazotization reaction on amino substituted letrozole, late-stage dehydration of bis-
oxime 2 to biscyano functionality 13 (Scheme 1) are the other noticeable protocol adapted for the synthesis of
letrozole. Considering the high demand and commercial value of letrozole 1 as a drug substance in oncology
treatment, despite all these known synthetic procedures, search for an innovative and cost-effective protocol
for the synthesis of Letrozole 1 is always in demand. Here in we report an improved alternate synthesis of
Letrozole 1 in excellent yields, and this synthetic route has the freedom to operate from the existing patent
landscape.
Scheme 1. Various synthetic routes for the synthesis of Letrozole 1.
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Results and Discussion
The retrosynthetic design for the preparation of letrozole 1 is depicted in Scheme 2. Letrozole can be prepared
from 4-((4-cyanophenyl)(1H-1,2,4-triazol-1-yl)methyl)benzamide 11 by the amide dehydration in 1,4-dioxane
with a suitable dehydrating agent.1
4,15
The C-N bond formation between N-1 of 1,2,4-triazole 4 with 4-
(
chloro(4-cyanophenyl)methyl)benzamide 12 under nucleophilic substitution reaction conditions can yield
compound 11. The 4-(chloro(4-cyanophenyl)methyl)benzamide 12 in turn can be synthesized from bis(4-
1
6
17
bromophenyl)methanone 13 involving a series of reactions such as cyanation , in situ conversion to amide
18-20
14, reduction of keto functionality of 14
with sodium borohydride, and finally chlorination 12 using thionyl
chloride.
Scheme 2. Retrosynthetic analysis of Letrozole 1.
During the synthesis of Letrozole 1, initial attempts were focused on the preparation of 4-((4-
cyanophenyl)(hydroxy)methyl)benzamide 15. Compound 15 was prepared from 4-(4-cyanobenzoyl)benzamide
1
(
4 by reduction of keto functionality 14 with sodium borohydride in an alcoholic solvent (Scheme 3). The 4-(4-
cyanobenzoyl)benzamide 14 in turn prepared from 4,4-dibromo benzophenone 13 by cyanation with
potassium ferrocyanidetrihydrate in presence of palladium(II)chloride followed by the selective hydrolysis of
21
the cyano group to amide functionality at 100 °C under aerial oxidation in 86% of yield. Tosylation of 4-((4-
cyanophenyl)(hydroxy)methyl)benzamide 15 was attempted under various conditions using p-toluenesulfonyl
chloride in presence of base such as sodium hydroxide, sodium carbonate, triethylamine, sodium bicarbonate,
potassium carbonate, potassium bicarbonate, in various solvents like CH
2
Cl , THF, toluene, DMF, acetonitrile,
2
water; however these reactions were not successful and the required product was not observed under these
reaction conditions probably due to the increased steric repulsion of phenyl groups on the incoming tosyl
group. In all these attempts, 4-(4-cyanobenzoyl) benzamide 14 was isolated as one of the major product under
these conditions, and formation of this product can be attributed to the aerial oxidation of benzylic hydroxyl
group at elevated temperature in presence of air/oxygen as well as the less reactivity of 4-((4-
cyanophenyl)(hydroxy)methyl)benzamide 15 towards the tosylation reaction. Thus, we have decided to peruse
halogenations followed by 1H-1,2,4-triazole 4 introduction as the alternate strategy for the synthesis of
letrozole 1.
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Scheme 3. Attempt for the synthesis of tosylate 16.
Attributing to the increased strain may be a probable root cause for the failure of tosylation on compound 15,
we focused our attention for converting hydroxyl group in 15 to the chloro derivative 12 (Scheme 4). Thus the
alcohol 15 was treated with thionyl chloride in dichloromethane and the required compound 12 was isolated
in excellent yields. After the successful synthesis of 12, we focused our attention on the synthesis of the target
molecule Letrozole 1 by reacting it with 1H-1,2,4-triazole 4. Several attempts have been carried out for the
introduction of 1H-1,2,4-triazole 4 by the nucleophilic substitution on halo compound 12 in presence of a base
in polar protic as well as aprotic solvents. All these reactions resulted in poor conversion to the required
product. Reaction performed at higher temperatures in presence of polar protic solvents resulted in the
formation of 4-(4-cyanobenzoyl) benzamide 14 probably formed via aerial oxidation. However, when the
reaction was conducted under neat conditions at elevated temperature (110 °C-120 °C) over a period of 6 h,
the required product 11 was isolated in around 75% yield, along with the corresponding regioisomer 17 as
shown in Scheme 4.
Scheme 4. Completion of the synthesis of Letrozole 1.
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In the above process, formation of an appreciable amount of undesired regioisomer4,4'-(4H-1,2,4-triazol-
-ylmethylene)bisbenzonitrile 17 is observed. This product 11 was separated from its regioisomer 17 by silica
4
gel column chromatography (SiO
2
, 100-200 mesh, 4% Methanol/CH
2
Cl ). The amide 11 to nitrile 1 conversion
2
was then carried out by using trifluoroacetic anhydride in 1,4-dioxane, and Letrozole 1 was isolated in
excellent yields (Scheme 4). The crude letrozole was further recrystallized from a mixture of methanol and
water (1:5) to afford Letrozole 1 in overall 90% of isolated yield.
Conclusions
In summary, we have developed a novel and efficient synthetic route for the preparation of Letrozole 1 in
excellent yields, which is free from regioisomeric impurities. The developed process utilizes environmentally
benign reagents as well as milder reaction conditions.
Experimental Section
1
13
General. H and C NMR spectra were recorded in 500 MHz & 125 MHz. All chemical shifts were reported in
parts per million (δ) and were internally referenced to residual proton solvents, unless otherwise noted. All
spectral data were reported as follows: chemical shift multiplicity [singlet (s), doublet (d), triplet (t), quartet
(
q), and multiplet (m)], coupling constants [Hz]. Trifluoroacetic anhydride used in the reaction was distilled
from P and all other chemicals used were purchased from commercial suppliers and used without further
purification. All flash column purifications were performed by using silica gel (100-200) mesh.
O
2 5
4
-(4-cyanobenzoyl)benzamide (14). To a solution of compound 13 (25 g, 73.53mmol) in N,N-
dimethylacetamide (125mL) was added to potassium ferrocyanide.3H O (31 g, 73.53 mmol) followed by PdCl
0.65 g, 3.6 mmol), and Na CO (15.58 g, 147 mmol) at room temperature. The reaction mixture was heated to
00 °C and stirred for 6 h. Later water (2 mL) was added to the reaction mixture and air was purged into the
solution at 100°C for 5 h and stirring was continued at the same temperature for 30 h. Then TLC (Thin Layer
Chromatography) (10% MeOH/CH Cl ) showed complete conversion to compound 14. The reaction mixture
was cooled to room temperature and filtered through celite bed and washed with N, N-DMA (25 mL). To the
obtained filtrate added CH Cl (25 mL) and water (250 mL). Stirred the reaction mixture at ambient
temperature for 1h. The precipitated product was filtered and dried under vacuo at 60 °C for 8 h afforded 15.7
g (86%) of compound 14 as a pale yellow solid. R =0.4 (SiO , 5% MeOH/CH Cl ). mp 205-207, IR
Neat):νmax:3483.7, 3062.4, 2231.2 2036.3, 1943.8, 1693.1, 1650.7, 1615.0, 1500.3, 1280.5, 1187.9, 1124.3,
016.3, 990.2, 931.4, 864.9, 755.9, 691.3, 673.0, 638.3, 592.0, 539.9, 480.1 cm . H NMR (500MHz, DMSO-d6):
2
2
(
1
2
3
2
2
2
2
f
2
2
2
(
1
,
-
1 1
13
δ 8.20 (brs, 1H), 8.05 (m, 4H), 7.90 (d, J 6 Hz, 2H), 7.83 (d, J 6 Hz, 2H), 7.62 (brs, 1H) ppm. C NMR (125 MHz,
DMSO-D
6
): δ 194.9, 167.4, 141.0, 138.7, 138.5, 133.1, 130.6, 130.2, 128.2, 118.6, 115.3 ppm. HRMS (ESI):
251.0821, found 251.0822.
+
[
M+H] .calcd.for C15
H
11
N
O
2 2
4
-((4-cyanophenyl)(hydroxy)methyl)benzamide (15). A stirred solution of compound 14 (10 g, 39.9 mmol) in
(3.77 g, 99.75 mmol) in equal portions over a period of 15 minutes at
°C-5 °C and the resulting solution was warmed to room temperature and stirred for 2 h. After which time,
TLC (10% MeOH/CH Cl ) showed consumption of compound 14. Now, the reaction was quenched with
saturated aqueous NH Cl (20 mL) at 0°C and the volatile solvents were evaporated under pressure and diluted
MeOH (100 mL) was treated with NaBH
0
4
2
2
4
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with water (100 mL). The pH of the solution was adjusted to 6.5-7.0 by the addition of aqueous 1N HCl and
stirred at room temperature for 1 h. The solution was filtrated to obtain solid, which was washed with water
(
50 mL) and dried under vacuum to get 9.57 g (95%) of compound 15 as a pale yellow solid. R
f
= 0.5 (SiO
). mp 173-175. IR (Neat) νmax: 3396.9, 3307.3, 3185.8, 2932.2, 2859.9, 2364.3, 2236.0,
678.7, 1612.2, 1564.9, 1509.9, 1412.6, 1331.6, 1310.3, 1266.0, 1194.6, 1110.8, 1052.9, 865.8, 781.9, 620.9,
2
,
1
1
5
2
1
0%MeOH/CH
Cl
2 2
-
1 1
62.1 cm . H NMR (500MHz, DMSO-d6):δ7.92 (brs, 1H), 7.80 (m, 4H), 7.60 (d, J 6.4Hz, 2H), 7.46 (d, J 6.4 Hz,
13
H), 7.30 (brs, 1H), 6.26 (d, J 3.2 Hz, 1H), 5.86 (d, J 2.8 Hz, 1H) ppm. C NMR (125 MHz, DMSO-d6): δ 168.2,
+
51.2, 148.2, 133.7, 132.7, 128.0, 127.6, 126.5, 119.4, 110.1, 73.7 ppm. HRMS (ESI):[M+H] calcd. for
C
4
(
15
H
13
N
2
O
2
253.0977, found 253.0965.
-(chloro(4-cyanophenyl)methyl)benzamide (12). A solution of compound 15 (9.0 g, 35.67 mmol) in CH
90 mL) was added thionyl chloride (21.22g, 178.38mmol) at 0 °C and the solution was warmed to 40 °C and
stirred for 4 h. TLC (2% MeOH/CH Cl ) showed consumption of compound 15. The reaction mixture was
concentrated under reduced pressure at 50°C and diluted with CH Cl (30 mL). Reaction mixture was
neutralized with saturated 10% aqueous NaHCO (30 mL) at 0 °C. The layers were separated and aqueous layer
was extracted with CH CH (2 x 20 mL) twice. The combined organic extracts were washed with water (30 mL)
and aqueous NaCl solution (30 mL) and dried over anhydrous Na SO . The filtrate was concentrated under
reduced pressure to give a crude material, which was purified by silica gel flash column chromatography (SiO
00-200 mesh, 2% MeOH/CH Cl ) to afford 9.06 g (94%) of compound 12 as a white solid. R = 0.6 (SiO , ethyl
acetate); mp 152-156 °C. IR (Neat): νmax: 3399.8, 3342.0, 3604.3, 2944.7, 2749.0, 2223.5, 1810.8, 1728.2,
2
Cl
2
2
2
2
2
3
2
2
2
4
2
,
1
2
2
f
2
-
1
1
1
1
d
C
651.7, 1499.3, 1251.5, 1103.0, 1013.4, 816.7, 755.9, 633.5 cm . H NMR (500MHz, DMSO-d6): δ 8.0 (brs,
H), 7.88 (m, 4H), 7.69 (d, J 6.8 Hz, 2H), 7.48 (d, J 6.8 Hz, 2H), 6.70 (brs, 1H). C NMR (125 MHz, DMSO-
13
+
6
):δ167.4, 145.8, 143.0, 134.3, 132.7, 128.4, 128.0, 127.3, 118.4, 111.0, 61.8. HRMS (ESI): [M+H] calcd. for
15
H
12
N
2
OCl 271.0638, found 271.0629.
-((4-cyanophenyl)(1H-1,2,4-triazol-1-yl)methyl)benzamide (11) and Isomer 4,4'-(4H-1,2,4-triazol-4-
4
ylmethylene)bisbenzonitrile (17). A mixture of compound 12 (5.0 g, 18.46 mmol) and 1H-1,2 4-triazole 4 (3.18
g, 46.17 mmol) was heated under neat conditions at 110 °C-120 °C for 6h. After which time, TLC (10%
MeOH/CH
temperature and diluted with water (20 mL) and extracted with CH
organic extracts were washed with water (30 mL), aqueous NaCl solution (30 mL) and dried over anhydrous
Na SO . The filtrate was concentrated under reduced pressure to give a crude material which was purified by
silica gel column chromatography (SiO , 100-200 mesh, 1% MeOH/CH Cl ) to afford 4.20 g (75%) of compound
. mp: 130-134 °C. IR (Neat):νmax: 3429.7, 2923.0, 1629.0,
2
Cl
2
) showed complete consumption of compound 12. The reaction mixture was cooled to room
2
Cl (2 x 30 mL) twice. The combined
2
2
4
2
2
2
1
1
8
1 as a white solid. R
552.4, 1382.7, 1219.2, 1019.1, 772.3, 678, 6 cm . H NMR (500MHz, DMSO-d
.0 (brs, 1H), 7.88 (dd, J 6.4, 2.4 Hz, 4H), 7.41 (m, 3H), 7.32 (3, 3H), 7.34 (s, 1H), 7.31 (d, 2H). C NMR (125
f
= 0.4 (SiO
2
, 10% MeOH/CH
2
1
Cl
2
-
1
6
): δ 8.71 (brs, 1H), 8.11 (s, 1H),
13
MHz, DMSO-D
HRMS (ESI): [M+H] calcd. for C17
6
) δ: 167.3, 152.2, 144.9, 143.9, 140.9, 134.2, 132.7, 129.0, 128.0, 127.9, 118.4, 110.9, 64.3;
+
H
14
N O 304.1198, found 304.1213
5
Regioisomer 4,4'-(4H-1,2,4-triazol-4-ylmethylene)bisbenzonitrile (17). White solid (0.3 g), mp 138-142 °C, IR
(
7
(
1
Neat):νmax: 3356.2, 3189.4, 2229.8, 1669.4, 1613.5, 1569.1, 1507.4, 1416.7, 1390.7, 1167.9, 1066.6, 862.2,
-
1 1
48.4, 668.3, 622.0, 556.4 cm ; H NMR (500MHz, DMSO-D ):δ8.62 (s, 2H), 8.02 (brs, 1H), 7.91 (m, 4H), 7.41
6
1
3
m, 3H),7.29 (d, J 6.4 Hz,2H), 7.19 (s, 1H). C NMR (125 MHz, CDCl
3
):δ167.2, 143.7, 142.9, 140.7, 134.5, 133.0,
O 304.1198, found 304.1204.
+
28.8, 128.2,127.8, 118.4, 111.3, 61.1. HRMS (ESI): [M+H] calcd. for C17
H
N
14 5
Letrozole (1). A solution of compound 11 (3.0 g, 9.8 mmol) in 1,4-dioxane (3.0 mL) was treated with
trifluoroacetic anhydride (4.15 g, 19.7mmol) at 0 °C and the solution was warmed to room temperature and
stirred for 1h. After which time, TLC (10% MeOH/CH
2
Cl ) showed complete consumption of compound 11. The
2
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reaction was quenched with water (20 mL) and the aqueous layer was extracted with CH
Cl
2 2
(2 x 30 mL) twice.
The combined organic extracts were washed with a saturated aqueous NaHCO
3
solution (30 mL) and aqueous
NaCl solution (30 mL) and dried over anhydrous Na SO . The filtrate was concentrated under reduced pressure
2
4
to give the crude material which was crystallized in methanol (6 mL) and water (30 mL) to afford 2.55 g (90%)
of Letrozole 1 as a white solid. mp= 185-186 °C. IR (Neat) νmax: 3407.4, 3122.8, 2230.7, 1607.7, 1503.5, 1433.1,
-
1 1
1
7
1
412.9, 1378.2, 1275.0, 1199.7, 1138.0, 1009.7 cm . H NMR (500MHz,CDCl
3
) δppm: 8.09 (s, 1H), 8.06 (s, 1H),
13
.70 (m, 4H), 7.28 (m, 4H), 6.81 (s, 1H). C NMR (125 MHz,CDCl
3
):δ 153.0, 143.7, 141.8, 132.9, 128.9, 117.8,
+
13.3, 66.36. HRMS (ESI): [M+H] calcd. for C17
H
12
5
N 286.1093, found 286.1099.
Acknowledgements
The authors would like to thank Andhra University, Visakhapatnam for permitting the research work and for
constant encouragement.
Supplementary Material
Proton and carbon-13 NMR spectra of compounds and their synthetic intermediates are presented as
supporting information in Supplementary Material. Readers will be able to access this supporting information
using the link "Supplementary Material" in the journal issue contents page.
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