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A Greener Approach for the Large Scale Synthesis of 1,4,5-trisubstituted Pyrazole, AZD8329 Paramashivappa Rangappa, Avipsa Ghosh, Smitha Chitrapadi, Gajanan Kantikar, Vinod Kumar CH, Sureshkumar Sythana, Sulur G. Manjunatha, Sudhir Nambiar, and Sridharan R Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 02 Jul 2014 Downloaded from http://pubs.acs.org on July 3, 2014
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A Greener Approach for the Large Scale Synthesis of 1,4,5trisubstituted Pyrazole, AZD8329 Paramashivappa Rangappa,* Avipsa Ghosh, Smitha Chitrapadi, Gajanan Kantikar, Vinod Kumar C H , Sythana Sureshkumar, Sulur Manjunath, Sudhir Nambiar and Sridharan R Pharmaceutical Development, AstraZeneca India Pvt. Ltd, Hebbal, Off Bellary Road, Bangalore 560024, India. Supporting Information Placeholder ABSTRACT: The development of a convenient, safe and scalable process for AZD8329 manufacturing is reported here. Synthesis was achieved in two step telescopic process with an excellent overall yield of 75%. In the first step enamine (6) was synthesized with 90% yield through three chemical transformations. In the next step AZD8329 was synthesized from the reactions of 6 and 4hydrazinobenzoic acid hydrochloride 7 through two chemical transformations. The process is very efficient and economical and AZD8329 was manufactured in multi-kilogram scale. Greener approach is demonstrated through usage of minimum number of solvents, energy and with process mass intensity (PMI) 24 h and ketoamide 4 was isolated in about 85% yield by distillation of xylene to dryness. In the next stage, 4 was treated with DMF-DMA (5) by refluxing in 1,4-Dioxane and then reaction mixture was concentrated to dryness to afford 6 in about 85% yield. In order to address the process challenges such as dry distillation and high temperature reactions, we have explored multiple opportunities to improve the process wrt safety, scalability and yield. Toluene was identified as the single solvent for free base (2) generation and reaction purposes in place of xylene and DCM. In the initial phase of development, reaction of 2 with 3 was very slow in toluene and took more than 30 h for the reaction completion. This was due to lowering of reaction temperature due to the formation of byproduct ethanol. To overcome this problem, removal of ethanol from the reaction was very essential, and hence azeotropic distillation was employed. This assisted in maintaining the reaction temperature at about 110112oC thereby driving the reaction to completion in 3-4 h. 4-5 rel vol of toluene was distilled out from the reaction to facilitate the next step of reaction and easy isolation. A solution of 4 in toluene was used as such for the next step. In the synthesis of 6, DMF-DMA (5) was replaced with dimethylformamide di-isopropyl acetal (DMF-DIA) (11) to improve safety of the process. We then investigated reaction in different solvents viz DMSO, DME, IPA, butanol, THF, acetonitrile, toluene, heptane and iso-octane (Table-1). As seen in the Table-1, reaction was relatively slow and conversion to product was not satisfactory in THF, 2Me-THF and alcoholic solvents. Reaction in toluene and n-heptane or iso-octane was very good (>95%). In the case of toluene, reaction mixture was homogeneous, it was necessary to distill out the solvent and add n-heptane or iso-octane to precipitate 6. The reaction mass was heterogeneous in n-heptane or iso-octane and hence reaction monitoring was challenging during scale up.
Figure-1: Structure of AZD8329 RESULTS AND DISCUSSION Synthesis of enamine (6): In the medicinal chemistry approach, key intermediate 6 was synthesized in three stages starting from adamantylamine.HCl 1 as shown in Scheme-1. In the first step, adamantylamine free base 2 was generated by the addition of aqueous sodium hydroxide to a solution of 1 in Scheme-1: Medicinal chemistry route of synthesis
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iii
ii
i .HCl
85%
1
85% 3
2
4
6
5
vi
6
iv
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85%
vii
v 80% 7
8
80%
9
90%
10
AZD8329
Reaction conditions: i)DCM- H2O, Aq NaOH (1.25 eq); ii)Xylene, heat to 145-150oC for >24 h; iii) 1,4-Dioxane, heat to 95-100 oC for 2 h; iv)MeOH, HCl, heat to 65-70 oC for 4 h; v)MeOH, RT 1 h; vi)MeOH, HCl, heat to 65-70 oC 4 h; vii)Aq NaOH, MeOH.
Scheme-2: Large scale route of synthesis
i
2
ii
iii
4 3
.HCl
90% 6
11 1
v
iv 6 12
7
AZD8329
85%
Reaction conditions: i)Toluene- H2O, Aq NaOH (1.25 eq); ii)Heat to 110-112 oC for 4 h; iii) iso-octane, Et3N (0.5 eq), heat to 95-98 oC for 2 h; iv)10% H2O in IPA, 1 h RT; v) heat to 75-78 oC for 2 h
Table-1: % of Enamine (6) conversion in different solvents S No
Solvents
TempoC /time (h)
%Conversion*
1
THF
60/5
85
2
DMSO
85/4
89
3
DME
80/3
95
4
IPA
75/5
70
5
Acetonitrile
75/5
82
6
Butanol
80 /4
80
7
Toluene
95/2
97
8
n-Heptane/
95/3
96
9
iso-octane
95/3
>96
10
Toluene/isooctane (1:2), Et3N
95/2
>98
*% Conversion is by relative % area by HPLC with RI detector.
To address this issue, mixtures of toluene and iso-octane (1:1, 1:2 and 2:1) were screened. 1:2 ratio of toluene and iso-octane was found to be the most suitable in terms of reaction profile and product isolation. It was also observed that use of organic base (triethylamine) not only facilitated faster reaction by increasing the nucleophilicity of acidic carbon, but also reduced the formation of unknown byproducts. Thus, in the optimized conditions, iso-octane was added to solution of 4 in toluene5 followed by DMF-DIA and triethylamine (0.5 eq) and heated at 95-98 oC for 2 h to complete the reaction. The reaction mixture was cooled to ambient temperature and precipitated product 6 was isolated by filtration in 90% yield. It is worthy to note that generated byproduct iso-propyl alcohol was distilled off by azeotropic distillation to complete the reaction in 2-3 h. Yield of 6 was comparable with DMF-DMA in the similar experimental conditions.6 These key developments made remarkable improvement in reaction profile, operations time, solvent reduction, yield and quality of 6. Synthesis of AZD8329: In the medicinal chemistry procedure, 4-Hydrazino-benzoic acid.HCl 7 was converted to corresponding methyl ester 8 and subsequently reacted with 6 in methanol (200 rel vol) to get cyclized product 10 in 80% yield. Later, methylester 10 was hydrolyzed to AZD8329 and purified
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to get desired quality of compound. Esterfication of 7 to 8 and further hydrolysis of 10 to AZD8329 seemed to be additional steps. Initially, the synthesis of AZD8329 was evaluated on small scale with acid 7 in place of corresponding ester 8.7 The reaction was found to be smooth and there was no impact on the quality of the product. Encouraged by the result, synthesis of AZD8329 using 7 was studied in various solvents like, THF, toluene, acetonitrile, BuOH, DMSO, MeOH and IPA. Results are summarized in Table-2.
reacts with 7 to give undesirable products 13 and 14 as shown in Scheme-3.10 Temperature also plays a critical role in the formation of eneacid (12). This is because at elevated temperatures (>30 oC), hydrolysis of 6 will be faster than its reaction with 7. Scheme-3: Degradation product of enamine (6) N
SNo
Solvents
TempoC/ time (h)a
1
IPA
75/2
95
85/98
2
DMSO
75/2
90
80/98
3
ACN
75/24
83
75/90 c
% Conversionb
Hydrolysis
O
O
Table-2: Results of AZD8329 synthesis in different solvents.
H N
H N O
O
4
6
%Yield/ purity
H N N HH + N Cl – N H
O N H
N
4
Butanol
80/3
80
5
THF
65/4
89
75/90
6
Toluene
80/6
52
c
7
MeOH
68/2
95
83/95
8
MeOHH2O (5%)
68/2
95
85/96
9
MeOHH2O (10%)
68/2
96
85/97
10
IPA- H2O (5%)
78/2
96
84/99
11
IPA-H2O (10%)
78/2
97
85/99
12
IPA- H2O (20%)
78/2
97
85/99
a time for cyclization after eneacid (12) formation, bconversion by relative area% by HPLC, cproduct not isolated.
As seen in Table-2, in the majority of cases, good conversion to desired product was observed except in toluene. Beter conversion was observed in DMSO, MeOH and IPA. DMSO was found to be good in terms of solvent volume. However large volume of water (100 rel vol) was required for product precipitation and to get filterable solid. Moreover, residual DMSO was quite higher than desirable limit in the product. Methanol was the preferred solvent in terms of low cost, but product quality was inferior with the formation of ester impurity 10 upto 4-5%. IPA was the next choice of reaction solvent. It was further studied in combination with water to facilitate the dissolution of 7 in the reaction mass, cleaner reaction profile and easy isolation of the product. After screening with different proportions of water in IPA (5, 10 and 20% v/v), 10% water in IPA was found to be the most suitable. Thus in the developed process, 6 was added to a solution of 7 in IPA-water and stirred at ambient temperature for about 1 h to ensure the formation of eneacid (12).8,9 Then the reaction mass was warmed to 75-80 oC for about 2 h to facilitate the cyclization. The mass was cooled to 50-60 oC and water (6 rel vol) was added to precipitate AZD8329. It was isolated by filtration and dried to obtain pure product in 8085% yield with purity >99%. It is worthy to notice that sequence of addition was very critical in the formation of eneacid (12). In the absence of 7, enamine (6) undergoes hydrolysis to ketoamide (4) which then
7
15
14
13
16
N H
COOH
COOH COOH
N
17
Figure-2: Impurities During the process development, formation of impurities (Figure-2) 15, 16, and 17 were observed in traces. 15 generates from the contaminated starting material 711 and 16 by the esterfication of AZD8329 with IPA and 17 from the reaction conditions.12 Appropriate control strategies were made to ensure that their formation was very low. It is worthy to note that, we had carried out a significant developmental work on the Medchem approach with minimal changes to the route of synthesis. These key changes in the process made significant impact on scalability, yield, time and environmental aspects. Process mass intensity (PMI) of the final process is in line with industrial guidelines on tonnage scale.13 Process efficiency index using Boehringer Ingelheim model14 is calculated for the large scale process and is very efficient for both stages.15 Attributes of the large scale synthesis vs medchem are summarized in Table-4. Mass composition data for the large scale manufacturing of AZD8329 is shown in Figure-3, which accounted only 31.6 % of water based effluent generated in the process.
Figure-3: Process mass composition Table-4. Large scale vs Medchem synthesis
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Entry
Medchem
Large scale
% Overall yield
35%
75%
No stages
6
2 telescopic
a
Time ( in days)
7-8
3
PMI
NA
63.7
Process efficiency
NA
95%
a
time required to complete the cycle In summary, we have developed an efficient process for large scale manufacturing of AZD8329 through a greener approach using class -2 and 3 solvents and less hazardous reagents. The advantage of the processes is that, five chemical transformations achieved in two pots through telescopic approach. This made huge impact on manufacturability, occupancy time in plant, operations, yield, PMI and cost of goods. EXPERIMENTAL SECTION General. All reactions were performed under a nitrogen atmosphere unless otherwise specified. All reagents and solvents were of commercial grade and used without purifications. NMR spectra were recorded in a 400 MHz Bruker instrument; coupling constant (J) are averaged where necessary. Compound 3 and 4 were analyzed by GC. 6 was analyzed by HPLC with RI detector. HPLC analyses were performed using Agilent 1200 series. LC-MS analyses were done using an Agilent 1200 series LC instrument and LC/MSD SL detector with +ve atmospheric pressure electrospray ionization (APESI) (2)-N-(2-adamantyl)-2-(dimethylaminomethylidene)-4,4dimethyl-3-oxo-pentanamide (6): Aqueous NaOH solution (1.33 kg, 33.3 mol in 10 0 L) was added to a suspension of 2adamantanamine hydrochloride (5.0 kg, 26.63 mol) in a mixture of water (15.0 L) and toluene (20.0 L). After stirring for 15-30 min organic layer was separated and the aqueous layer was re-extracted with toluene (20.0 L). The combined organic layers was washed with saturated brine solution (10.0 L) and separated. Ethyl pivaloylacetate 3 (5.04 kg, 29.3 mol) was added to toluene solution and heated to reflux at 110-112 oC. Toluene (4-5 rel.vol.) was collected azeotropically over 4 h and progress reaction was monitored by GC. The reaction mass was cooled to 40-45 oC and iso-octane (40.0 L) followed by DMF-DIA (7.0 kg, 40.0 mol) and triethylamine (1.35 kg, 13.3 mol) were added. The reaction mass was heated to 95-98 o C for 2 h and progress of the reaction was monitored by HPLC equipped with RI detector. The reaction mass was cooled to ambient temperature and precipitated product was filtered, then washed with iso-octane (10.0 L). Product was dried under vacuum at 35-40 oC for 4 h to give title compound (7.30 kg, 90.3% yield), purity 99.7%, mp:158-160 oC.1H NMR (DMSO-d6): δ 1.13 (s, 9H), 1.47 (d, J = 18.6, 2H), 1.691.83 (m,10H), 2.03 (d, J = 17.2, 2H), 2.92 (s, 6H), 3.90 (d, 1H), 7.23 (s,1H), 7.94 (d,1H). 13CNMR: δ 27.2, 27.3, 28.7 (3C), 31.6 (2C), 31.8 (2C), 37.5(2C), 37.7 (2C), 42.8, 44.0, 54.3, 107.4, 152.1 169.0, 202.3. LRMS ESI m/z: calcd for C20H32N2O2 (M+H)+ 333.49, found 333.3. 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl] benzoic acid (AZD8329): Compound 6 (7.20 kg, 21.66 mol) and 7 (4.02 kg, 22.11 mol) were added into a 500 L jacketed reactor followed by isopropyl alcohol (90.7 L) and water (10.0 L). The reaction mass was stirred at 20- 25 oC for about 1 h to complete formation of intermediate 12. Then the reaction mass was heated to reflux at 78-80 oC for 1.5 h and progress of reac-
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tion was monitored by HPLC. It was cooled to 50 -55 oC and then water (43.0 L) was added slowly while maintaining at the same temperature. Further it was cooled to ambient temperature (20-25 oC) and stirred for 1.0 h. Precipitated product was filtered and then washed with a mixture of 1:1 ratio of isopropyl alcohol:water (72.0 L). Product was dried under vacuum at 50-55 oC to yield title compound (7.75 kg, 85% yield), mp:308-309 oC. 1H NMR (DMSO-d6): δ 1.20 (s, 9H), 1.50 (d, J = 16.4, Hz, 2H), 1.84-1.94 (m, 10H), 2.10 (d, J = 16.8 Hz, 2H), 4.00 (d, 9.6 Hz, 1H), 7.50 (d, J = 11.2 Hz, 2H), 7.61 (s,1H), 8.07 (d, J = 11.6 Hz, 2H), 8.10 (d, J = 9.6 Hz, NH), 13.30 (bs, COOH). 13CNMR: δ 27.3, 27.34, 31.0(3C), 31.5 (2C), 31.7(2C), 33.5, 37.4(2C), 37.7, 54.3, 119.1, 128.8 (2C), 130.4 (2C), 131.9, 139.7, 146.4, 149.9, 165.4, 166.9. DEPT: 27.3 (CH), 31.0 (CH3), 31.5 (CH2), 31.7 (CH), 37.5 (CH2), 37.7 (CH2), 54.3 (CH). 128.8 (CH), 130.4 (CH), 139.7 (CH). LRMS ESI m/z: calcd for C25 H31N3O3 (M+H)+ 422.54, found 422.2. Methyl4-{2-[(1Z)-4,4-dimethyl-3-oxo-2-(2adamantylcarbmoyl)pent-1-en-1-yl]hydrazinyl}benzoate (9). Charged 7 (3.05 g, 0.015 mol), to a precold solution of 6 (5.0g, 0.015 mmol) in methanol (20 mL) and water (1 mL). Reaction mass was stirred at 0-5 oC for 30-45 min. Precipitated white solid was filtered and then washed with cold methanol to yield off- white solid. This was slurried in methanol (20 mL) and filtered to give pure compound (2.25g, 32% yield). 1 H NMR (DMSO-d6): δ 1.15 (s, 9H), 1.51 (d, J=12.4, Hz, 2H), 1.70-1.80 (m,10H), 1.98 (d, J=12.8 Hz, 2H), 3.77 (s,3H), 3.81 (d, J = 7.2 Hz, 1H), 5.12 (d, J = 7.2 Hz,1H), 6.93 (d, J = 8.8Hz, 2H), 7.41 (d, J = 7.2 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 8.21 (d, J = 7.2 Hz, NH), 10.60 (s, NH). 13CNMR: 26.3, 27.15, 27.18, 31.5, 31.75, 31.77, 37.1, 37.3, 37.5, 45.4, 51.8, 54.0, 57.6, 111.3, 119.4, 131.5, 140.4, 149.7, 165.4, 166.6, 208.8. LRMS ESI m/z: calcd for C26 H35N3O3, (M+H)+ 454.59, found 454.3. Methyl-4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol1-yl] benzoate (10). Compound 8 (3.05 g, 0.015 mol) was added in one portion to a solution of 6 (5.0 g, 15 mol) in methanol (100 mL) and stirred for an h. Solution was hated to reflux at 65-70 °C for 3 h. The reaction mixture was concentrated, diluted with EtOAc (100 mL), and washed with water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified chromatography to yield off-white solid (4.6 g, 71 %) . 1H NMR (DMSO-d6) δ 1.19 (s, 9H), 1.49 (d, J = 12.4, Hz, 2H), 1.70-1.85 (m, 10H), 2.09 (d, J = 12.8 Hz, 2H), 3.91 (s,3H), 3.99 (d, J = 6.8 Hz, 1H), 7.54 (d, J = 11.2 Hz, 2H), 7.62 (s, 1H), 8.10 (d, J = 11.2 Hz, 2H), 8.20 (d, J = 6.5Hz, NH). 13CNMR: δ 27.3, 27.33, 31.0, 31.5, 31.7, 33.5, 37.4, 37.7, 52.9, 54.3. 119.2, 129.0, 130.3, 130.7, 139.8, 146.7, 150.0, 165.4, 165.9. LRMS ESI m/z: calcd for C26 H33N3O3, (M+H)+ 436.56, found 436.2. 4-{2-[(1Z)-4,4-dimethyl-3-oxo-2-(2adamantylcarbamoyl)pent-1-en-1-yl]hydrazinyl}benzoic acid (12): Compound 7 (2.85 g, 0.015 mol) was added to a precold solution 6 (5.0 g, 0.015 mol) in methanol (20 mL) and water (1 mL). Reaction mass was stirred at 0-5oC for 30-45 min. Precipitated white solid was filtered and then washed with cold methanol (10 mL) to yield off white solid. This was slurried in methanol (20 mL) and filtered to give pure compound (1.75g, 26% yield).1H NMR (DMSO-d6): δ 1.15 (s, 9H), 1.51 (d, J = 12.4, Hz, 2H), 1.71-1.80 (m, 10H), 1.94-1.97
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(m, 2H), 3.82 (d, J = 7.2 Hz, 1H), 5.12 (d, J = 6.8Hz, 1H), 6.91 (d, J = 8.8Hz, 2H), 7.40 (d, J = 7.2 Hz, 1H), 7.77 (d, J = 8.8 Hz, 2H), 8.21 (d, J = 7.6 Hz, NH), 10.54 (s, NH), 12.29 (bs, COOH). 13CNMR: δ 25.8, 25.9, 31.2, 31.3, 37.3, 37.5, 44.9, 53.5, 57.1, 110.7, 120.0, 131.1, 139.5, 148.9, 165.0, 167.2, 208.4. DEPT: 25.8 (CH3), 25.9 (CH), 31.2 (CH2), 31.3 (CH), 37.5 (CH2), 37.7 (CH2), 57.1 (CH), 53.5 (CH), 110.7 (CH), 131.1 (CH), 139.5 (CH). LRMS ESI m/z: calcd for C25H33N3O4 (M+H)+ 440.56, found 440.3 4. {(2E)-2-[4,4-dimethyl-1-oxo-1-(2adamantylcarbamoyl)pentan-3-ylidene]hydrazinyl}benzoic acid(13): Compound 7 (3.4 g, 0.018 mol) was added in one portion to a solution of 4 (5.0 g, 0.018 mol) in methanol (100 mL) at ambient temperature and stirred for an h. Precipitated solid was filtered and washed with cold methanol (10 mL) and dried under vacuum at 50 oC for 5-6 h to yield (1.5 g, 20%) pure compound. 1HNMR (DMSO-d6): δ 1.15 (s, 9H), 1.53 (d, J = 17.2, Hz, 2H), 1.70-1.80 (m, 10H), 1.98 (d, J = 17.2 Hz, 2H), 3.52 (s, 2H), 3.87 (d, J = 9.6 Hz, 1H), 7.00 (d, J = 9.6 Hz, 2H), 7.76 (d, J = 11.6 Hz, 2H), 8.16 (d, J = 10.4 Hz, 1H), 10.45 (s, NH), 12.25 (s, COOH). 13CNMR: 21.3, 26.3, 27.14, 27.18, 28.1, 31.4, 31.9, 34.6, 37.2, 37.5, 53.9, 112.1, 120.5, 126.0, 131.5, 150.9, 153.1, 167.8, 169.8. DEPT: 27.14 (CH), 28.1 (CH3), 31.4 (CH2), 31.9 (CH), 34.6 (CH2), 37.2 (CH2), 37.5 (CH2), 53.8 (CH), 112.1 (CH), 131.4 (CH). LRMS ESI m/z: calcd for C24H33N3O3 (M+H)+ 412.54, found 412.2. 4-[3-tert-butyl-5-(2-adamantylcarbamoyl)-1H-pyrazol-1yl]benzoic acid (14): Compound 7 (3.40 g, 0.018 mol) to a solution of 4 (5.0 g, 0.018 mol) in a mixture of IPA and water (8:2) ambient temperature and stirred for an h. Later it was heated to reflux for an h to undergo cyclization in the presence of catalytic amount HCl gas in IPA (0.1 mL). It was cooled to ambient temperature and precipitated solid was filtered and washed with cold methanol (10 mL). Obtained compound was dried under vacuum at 50 oC for 5-6 h to yield title compound (0.55 g, 7.7% yield). 1HNMR (DMSO-d6): δ 1.25 (s, 9H), 1.55 (d, J = 18.4, Hz, 2H), 1.70-1.84 (m, 10H), 2.05 (d, 2H, J = 18.4 Hz), 3.29 (s,1H), 7.90 (dd, J = 2.2Hz and J = 11.2 Hz, 2H), 7.97 (s, 1H), 7.99 (dd, J=2.5Hz and J=8.8 Hz, 2H), 8.16 (s, NH). LRMS ESI m/z: calcd for C24H31N3O2 (M+H)+ 394.52, found 394.2. 5-tert-butyl-1-phenyl-N-(2-adamantyl)-1H-pyrazole-4carboxamide (15). Phenylhydrazine hydrochloride (4.4g 0.030 mol) was added in one portion to a solution of 6 (10 g, 0.030 mol) in a mixture of IPA-water (8:2, 140 mL). After stirring for an h solution was heated to 75-80 °C for 2 h. Work
up was done similar to process of AZD8329 and purified by chromatography to yield pure compound (2.25g, 24% yield). 1 H NMR (DMSO-d6) δ 1.25 (s, 9H), 1.49 (d, J = 12.4, Hz, 2H), 1.70-1.92 (m, 10H), 2.09 (d, J = 12.5 Hz, 2H), 4.00 (s, 1H), 7.35-7.38 (m, 2H), 7.50-7.52 (m, 3H), 7.55 ( s, 1H), 8.18 (d, J = 7.0 Hz, NH). 13CNMR: 26.8, 30.4, 31.1, 31.2, 32.9, 36.9, 37.1, 53.7, 118.2, 128.1, 128.8, 129.2, 138.6, 142.3, 149.0, 165.1. LRMS ESI m/z: calcd for C24H32N3O (M+H)+ 378.49, found 378.3. Propan-2-yl4-[5-tert-butyl-4-(2-adamantylcarbamoyl)-1Hpyrazol-1-yl]benzoate (16): To a solution of AZD8329 (2 g, 0.047 mol) in IPA (20 mL) was added solution of HCl gas in IPA (6.5 mL, 0.67 m mol). This was heated to reflux for 5-6 h. Reaction mass was cooled and neutralized with aq sodium hydroxide and precipitated compound was filtered. It was purified by chromatography to yield titled compound (0.55 g, 22%). 1H NMR (DMSO-d6) δ 1.25 (s, 9H), 1.36 (d, 8.0, J = Hz, 6H), 1.55, (d, J = 12.5Hz, 2H), 1.70-1.90 (m, 10H), 2.03 (d, J = 12.8 Hz, 2H), 3.95 (d, J = 7.0Hz, 1H), 5.25 (sept, J = 7.5 Hz, 1H), 7.54 (d, J=8.8 Hz, 2H), 7.62 ( s, 1H), 8.06 (d, J = 8.4 Hz, 2H), 8.25 (d, J = 6.5Hz, NH). 13CNMR: 21.6, 26.8, 30.4, 31.1, 31.2, 33.0, 36.9, 37.1, 53.7, 68.6. 118.7, 128.5, 129.8, 130.7, 139.2, 146.1, 149.3, 164.4, 165.0. LRMS ESI m/z: calcd for C28H36N3O3 (M+H)+ 464.56, found 464.3.
REFRENCES Seckl, J. R. Walker, B. R. Endocrinology, 2001, 142, 1371–6. Menozzi, G.; Mosti, L.; Shenone, P. J. Heterocyclic. Chem. 1987, 24, 1669-1674. Heightman, T. D.;Gaster, L.; Pardoe, S. L.; Pilleux, J. P.; Hadely, M. S.; Middlemiss, D.N.;Price, G. W.; Roberts, C.; Scott, C. M. ; Watson, J. M. ; Gordon, L. J. ; Holland, V. A. ; Powels, J.; Riley, G. J.; Stean, T. O.; Trail, B. K.; Upton, N.; Austin, N. E.; Ayrton, A. D.; Coleman, T.; Cutler, L. Bio-org Med. Chem. Lett. 2005, 15, 4370-4374. Dyckman, A; Das, J; Leetheris, K.; Liu, C.; Zhao, R.; Chen, B.-C.; Wrobleski, S. T., WO 2004/099156 A1. Ketoamide (4) was isolated in 90% yield and characterized: 1 H NMR (CDCl3): δ 1.24(s, 9H), 1.71-1.95(m, 14H), 3.55 (s, 2H), 4.20 (bs, 1H), 7.8 (bs, NH). 13CNMR: 26.0, 27.1,
27.2, 27.5, 31.9, 32.0, 37.1, 37.6, 43.3, 45.3, 53.3, 164.7, 213.4 m/z (ESI+) (M+H)+ = 278.33. Isolation of 4 leads to decrement in the overall yield and increases solvent volumes and operations. Suresh, S.; Vinodkumar, C. H.; Paramashivappa, R. WO21010/087770A1. Investigation and assessment indicated that synthesis of 8 and 10 were not necessary. 7 can be used in place of corresponding ester 8, which avoids hydrolysis of 10 to AZ8329. Intermediates 9 and 12 are identified as potential genotoxic impurities; they have synthesized separately and characterized to control their limit in the final compound. Compound 9 and 12 may exist as tatuomers, detailed investigation work is under evaluation and it will be communicated separately in due course.
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4. 5.
ACKNOWLEDGMENT We thank analytical, LSL and Process safety team for their support. We also thank senior management team of Pharmaceutical development Bangalore and Phil Cornwall for their constant encouragement and support throughout the project and discussions.
ASSOCIATED CONTENT SUPPORTING INOFORMATION Copies of 1H 13C and Mass spectra for all compounds and DEPT for key intermediates listed in the experimental section. This material is available free of charge via Internet at http://pubs.acs.org
AUTHOR INFORMATION Corresponding Author *E-mail:
[email protected] [email protected] 6. 7.
8.
9.
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10. Compounds 13 and 14 are synthesized and identified for process understanding and their control strategy made in the final process. 11. Commercial product of 7 has 0.2-0.5% of phenyl hydrazine which generates 15 in the synthetic process and it has been controlled by control strategy in the RM specification. 12. Regio-isomer 17 has been observed in extremely low concentration in the reaction mass and identified by mass that
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can be formed by condensation with carbonyl function at first and then cyclization. 13. R. A. Sheldon, Chem. Ind. 1997, 12-15. 14. Dach, R.; Song, J. J.; Roschngar, F.; Samstag, W.; Senanayake, C. H. Org. Process. Res. Dev. 2012, 16, 16971706. 15. Process efficiency index is calculated using Boehringer Ingelheim model for the large scale process and data is available in the supporting information.
Table of Content.
A Greener Approach for the Large Scale Synthesis of 1,4,5-trisubstituted Pyrazole, AZD8329 Paramashivappa Rangappa, Avipsa Ghosh, Smitha Chitrapadi, Gajanan Kantikar, Vinod CH, Sureshkumar Sythana, Sulur Manjunatha, Sudhir Nambiar and Sridharan R
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