- Email: [email protected]
Synthesis and Crystal structure studies of some new derivatives of thiazolopyrimidines
Available online at www.sciencedirect.com
ScienceDirect Materials Today: Proceedings 5 (2018) 20932–20938
www.materialstoday.com/proceedings
ICSEM 2016
Synthesis and Crystal structure studies of some new derivatives of thiazolopyrimidines Narasimhaiah Lakshmi Prasad, Noor Shahina Begum* Department of Chemistry, Bangalore University, Dr.B.R.Ambedkar Veedhi, Central College Campus, Bangalore 560001, India e-mail: [email protected] ; [email protected]
Abstract Thiazolopyrimidine derivatives are important class of compounds which display number of pharmacological properties including antiviral, antitumor, antibacterial and antihypertensive effects. The compounds, ethyl 2-acetyl-5-(2-fluorophenyl)-3,7-dimethyl-5H-thiazolo[3,2a]pyrimidine-6-carboxylate (1), ethyl 2-acetyl-5-(3-fluorophenyl)-3,7-dimethyl-5H-thiazolo[3,2a]pyrimidine-6-carboxylate (2), ethyl 2-acetyl-5-(4-fluorophenyl)-3,7-dimethyl-5H-thiazolo[3,2a]pyrimidine-6-carboxylate (3), methyl 2-acetyl-5-(3-fluorophenyl)-3,7-dimethyl-5Hthiazolo[3,2-a]pyrimidine-6-carboxylate (4) have been synthesized and their structures evaluated crystallographically. The crystal structures of the compounds are stabilized by different intermolecular interaction such as C-H‧‧‧O, N-H‧‧‧N, C-H‧‧‧O, C-H‧‧‧N, π - π, CH‧‧‧π, etc. These weak interactions and their effect on packing features will be discussed in detail on the basis of their strength and orientations in the lattice. These interactions lead to interesting supramolecular architecture in the solid state. These compounds have also shown promising pharmacological activity against various microbes. © 2018 Elsevier Ltd. All rights reserved. Selection and Peer-review under responsibility of INTERNATIONAL CONFERENCE ON SMART ENGINEERING MATERIALS (ICSEM 2016).
Keywords: Thiazolo[3,2−a]pyrimidines; Crystal structure; Intermolecular interactions;
Pharmacological properties. * Corresponding author. Tel.: +919845528348; Fax: ++918022961331 E-mail address:[email protected]:
2214-7853 © 2018 Elsevier Ltd. All rights reserved. Selection and Peer-review under responsibility of INTERNATIONAL CONFERENCE ON SMART ENGINEERING MATERIALS (ICSEM 2016).
N. L. Prasad et. al. /Materials Today: Proceedings 5 (2018) 20932–20938
20933
1. Introduction Heterocyclic compounds containing thiazole rings represent a very significant group of organic compounds [1]. In recent years, interest has also been focused on aza-analogs of 1,4dihydropyridines such as dihydropyrimidines (DHPMs), which exhibit a pharmacological profile similar to classical dihydropyridine calcium channel modulators. Pyrimidine derivatives have been reported to possess a broad spectrum of pharmacological properties including antiviral, antiumor, antibacterial and antihypertensive effects [2]. Thiazolo [3, 2-a] pyrimidines are pharmacological interest due to their anti-inflammatory psychopharmacological bactericidal and antiviral activity as inhibitors of HIV-1 reverse transcriptase[3-7]. Chemistry and promising biological activities of these derivatives prompted us to synthesize and characterize the compound (4). 2. Experimental A mixture of ethyl 4-(2-fluorophenyl)-1,2,3,4-tetrahydro-6-methyl-2-thioxopyrimidine-5carboxylic acid ethyl ester (10 mmol) and 3-chloro-2,4-pentanedione (10 mmol) was refluxed in dry ethanol (20 mmol) for 12 h. The excess of solvent was distilled off and the solid hydrochloride salt that separated was collected by filtration, suspended in water and neutralized by aqueous sodium carbonate solution to yield the free base. The solution was filtered, the solid washed with water, dried and recrystallized from ethyl acetate to give the title compound (79% yield, mp 380 K). The compound was recrystallized by slow evaporation from 1:1 mixture of ethyl acetate and methanol, yielding pale-yellow single crystals suitable for X-ray diffraction studies. O R1
Ar
O
O NH
N H
+
C5H7ClO2
S
R1=Et,Me.
EtOH R Na2CO3 1
Ar
O
N
N
S
O
Ar= 2-FC6H5, 3-FC6H5, 4-FC6H5.
Scheme 1: Synthesis of methyl 2-acetyl-5-(3-fluorophenyl)-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidine6-carboxylate.
3. Results and Discussion 3.1. Single Crystal-XRD analysis Data collection: SMART (Bruker, 1998); cell refinement: SAINT (Bruker, 1998); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s)
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used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012) and PLATON (Spek, 2009); software used to prepare material for publication: WinGX (Farrugia, 2012). Herein, we report the crystal structure of Compound (4), C18H17FN2O3S, crystallizes with two molecules in the asymmetric unit. The molecular structure of the title compound is shown in Fig. 1. The pyrimidine ring is in a sofa conformation and the 3-fluro substituent is in an axial arrangement. The thiazole ring forms a dihedral angle of 86.3 (1)o with the phenyl ring.The mean-plane of the 3-fluro phenyl group adopts a syn periplanar conformation with respect to the C5-H5 bond of the pyrimidine ring. The 3-fluro phenyl substituent bonded to atom C5 is in an axial position. The methyl group was refined as disordered over two sets of sites with an occupancy ratio of 0.52 (3):0.48 (2). The bond lengths and angles in the title compound are in good agreement with the corresponding bond distances and angles reported in closely related structures (N. L. Prasad et al., 2014). The crystal data has been shown in Table-1 for compound(4). In the crystal, weak C-H...O and C-H...F interactions link molecules into chains along [010] (Fig. 2).
Fig 1 : ORTEP diagram of compound (4)
N. L. Prasad et. al. /Materials Today: Proceedings 5 (2018) 20932–20938
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Figure 2: Part of the crystal structure with weak C-H...O and C-H...F interactions shown as dashed lines. H atoms not involved in hydrogen bonding have been excluded. Table 1. Crystal data and structure refinement for compound(4). Empirical formula C18 H17 F N2 O3 S Formula weight 360.40 Temperature 100(2) K Wavelength 0.71073 Å Crystal system, space group triclinic, P-1 Unit cell dimensions a = 10.2605(5) A alpha = 67.1230(10) deg. b = 12.9347(7) A beta = 89.395(2) deg. c = 14.5606(8) A gamma = 78.420(2) deg. Volume 1739.31(16) A3 Z, Calculated density 4, 1.376 Mg/m3 Absorption coefficient 0.216 mm-1 F(000) 752 Crystal size 0.14 x 0.14 x 0.12 mm Theta range for data collection 2.03 to 25.00 deg. Limiting indices -12<=h<=12, -15<=k<=15, -17<=l<=17 Reflections collected / unique 21213 / 6123 [R(int) = 0.0397] Completeness to theta = 25.00 99.8 % Max. and min. transmission 0.9746 and 0.9704 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 6123 / 0 / 459 Goodness-of-fit on F2 1.042 Final R indices [I>2sigma(I)] R1 = 0.0809, wR2 = 0.2197 R indices (all data) R1 = 0.1067, wR2 = 0.2357 Largest diff. peak and hole 2.480 and -1.584 e.A-3
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N. L. Prasad et. al. /Materials Today: Proceedings 5 (2018) 20932–20938
3.2. Powder X-Ray Diffraction The phase composition of the synthesized powder was analyzed by powder X-ray diffraction (PXRD) using PANalytical X’pert PRO MPD instrument with graphite filtered CuKα radiation source ( λ=1.541 Å). Figure 3 shows the PXRD pattern of as synthesized compound (4). Well
Intensity (a.u)
defined diffraction peaks indicate the crystalline nature of the as synthesized compound.
0
10
20
30
40
50
60
70
80
90
2 (degree)
Fig. 3. Powder X-ray diffraction pattern of compound(4).
4. Conclusions In this work, we have reported the synthesis of compound (4). The formation of the thiazolopyrimidine moiety was confirmed by X-ray diffraction studies. The bond lengths and angles of the compound are in good agreement with the corresponding bond distances and angles reported in closely related structures. Crystal structure of compound showed the pyrimidine ring is in a sofa conformation. Crystal structure with weak C-H...O and C-H...F interactions control the architecture of organic solids. Acknowledgements NLP thanks the UGC for UGC–JRF fellowship.
N. L. Prasad et. al. /Materials Today: Proceedings 5 (2018) 20932–20938
20937
Supplementary Information The CIF files are deposited at the Cambridge Crystallographic Data Centre, The deposition numbers for Compound (4) is CCDC-1510332. These data can be obtained free of charge at www.ccdc.cam.ac.ul/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223-336033; email: [email protected]]. References [1] A Shawkat Abdelmohsen,S Mohammed Abaddy, Int J Pharm Pharm Sci, Vol 6, 5 , 696-703 (2014). [2] Shivapura Viveka, Dinesha, Sandeep Sadananda Laxmeshwar and Gundibasappa Karikannar Nagaraja, Molbank, M776, (2012). [3]. Tozkoparan B, Ertan M, Krebs B, Lage M, Kelicen P, Demirdamar R.Arch Pharm Pharm Med Chem, 1998; 331: 201. [4]. Tozkoparan B, Ertan M, Kelicen P, Demirdamar R. Farmaco, 1999; 54:588. [5]. Van Laar M, Volkerts E, Verbaten M. Psychopharmacology, 2001; 154:189. [6]. Parmar JM, Parikh AR. Heterocycl Commun. 1998; 4: 463. [7]. Danel K, Pedersen EB, Nielsen C. J Med Chem. 1998; 41: 191. [8]. N. L. Prasad, M. S. Krishnamurthy, H. Nagarajaiah and Noor Shahina Begum Acta Cryst. (2014). E70, o1204.
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N. L. Prasad et. al. /Materials Today: Proceedings 5 (2018) 20932–20938
[9]. H. Eranjaneya & G. T. Chandrappa, Transactions of the Indian Ceramic Society, 75:2, 133137. [10]. Gujjarahalli Thimmanna Chandrappa, Gangaiah Vijayakumar, Jacques Livage, J Sol-Gel Sci Technol. 2014.
ScienceDirect Materials Today: Proceedings 5 (2018) 20932–20938
www.materialstoday.com/proceedings
ICSEM 2016
Synthesis and Crystal structure studies of some new derivatives of thiazolopyrimidines Narasimhaiah Lakshmi Prasad, Noor Shahina Begum* Department of Chemistry, Bangalore University, Dr.B.R.Ambedkar Veedhi, Central College Campus, Bangalore 560001, India e-mail: [email protected] ; [email protected]
Abstract Thiazolopyrimidine derivatives are important class of compounds which display number of pharmacological properties including antiviral, antitumor, antibacterial and antihypertensive effects. The compounds, ethyl 2-acetyl-5-(2-fluorophenyl)-3,7-dimethyl-5H-thiazolo[3,2a]pyrimidine-6-carboxylate (1), ethyl 2-acetyl-5-(3-fluorophenyl)-3,7-dimethyl-5H-thiazolo[3,2a]pyrimidine-6-carboxylate (2), ethyl 2-acetyl-5-(4-fluorophenyl)-3,7-dimethyl-5H-thiazolo[3,2a]pyrimidine-6-carboxylate (3), methyl 2-acetyl-5-(3-fluorophenyl)-3,7-dimethyl-5Hthiazolo[3,2-a]pyrimidine-6-carboxylate (4) have been synthesized and their structures evaluated crystallographically. The crystal structures of the compounds are stabilized by different intermolecular interaction such as C-H‧‧‧O, N-H‧‧‧N, C-H‧‧‧O, C-H‧‧‧N, π - π, CH‧‧‧π, etc. These weak interactions and their effect on packing features will be discussed in detail on the basis of their strength and orientations in the lattice. These interactions lead to interesting supramolecular architecture in the solid state. These compounds have also shown promising pharmacological activity against various microbes. © 2018 Elsevier Ltd. All rights reserved. Selection and Peer-review under responsibility of INTERNATIONAL CONFERENCE ON SMART ENGINEERING MATERIALS (ICSEM 2016).
Keywords: Thiazolo[3,2−a]pyrimidines; Crystal structure; Intermolecular interactions;
Pharmacological properties. * Corresponding author. Tel.: +919845528348; Fax: ++918022961331 E-mail address:[email protected]:
2214-7853 © 2018 Elsevier Ltd. All rights reserved. Selection and Peer-review under responsibility of INTERNATIONAL CONFERENCE ON SMART ENGINEERING MATERIALS (ICSEM 2016).
N. L. Prasad et. al. /Materials Today: Proceedings 5 (2018) 20932–20938
20933
1. Introduction Heterocyclic compounds containing thiazole rings represent a very significant group of organic compounds [1]. In recent years, interest has also been focused on aza-analogs of 1,4dihydropyridines such as dihydropyrimidines (DHPMs), which exhibit a pharmacological profile similar to classical dihydropyridine calcium channel modulators. Pyrimidine derivatives have been reported to possess a broad spectrum of pharmacological properties including antiviral, antiumor, antibacterial and antihypertensive effects [2]. Thiazolo [3, 2-a] pyrimidines are pharmacological interest due to their anti-inflammatory psychopharmacological bactericidal and antiviral activity as inhibitors of HIV-1 reverse transcriptase[3-7]. Chemistry and promising biological activities of these derivatives prompted us to synthesize and characterize the compound (4). 2. Experimental A mixture of ethyl 4-(2-fluorophenyl)-1,2,3,4-tetrahydro-6-methyl-2-thioxopyrimidine-5carboxylic acid ethyl ester (10 mmol) and 3-chloro-2,4-pentanedione (10 mmol) was refluxed in dry ethanol (20 mmol) for 12 h. The excess of solvent was distilled off and the solid hydrochloride salt that separated was collected by filtration, suspended in water and neutralized by aqueous sodium carbonate solution to yield the free base. The solution was filtered, the solid washed with water, dried and recrystallized from ethyl acetate to give the title compound (79% yield, mp 380 K). The compound was recrystallized by slow evaporation from 1:1 mixture of ethyl acetate and methanol, yielding pale-yellow single crystals suitable for X-ray diffraction studies. O R1
Ar
O
O NH
N H
+
C5H7ClO2
S
R1=Et,Me.
EtOH R Na2CO3 1
Ar
O
N
N
S
O
Ar= 2-FC6H5, 3-FC6H5, 4-FC6H5.
Scheme 1: Synthesis of methyl 2-acetyl-5-(3-fluorophenyl)-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidine6-carboxylate.
3. Results and Discussion 3.1. Single Crystal-XRD analysis Data collection: SMART (Bruker, 1998); cell refinement: SAINT (Bruker, 1998); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s)
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N. L. Prasad et. al. /Materials Today: Proceedings 5 (2018) 20932–20938
used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012) and PLATON (Spek, 2009); software used to prepare material for publication: WinGX (Farrugia, 2012). Herein, we report the crystal structure of Compound (4), C18H17FN2O3S, crystallizes with two molecules in the asymmetric unit. The molecular structure of the title compound is shown in Fig. 1. The pyrimidine ring is in a sofa conformation and the 3-fluro substituent is in an axial arrangement. The thiazole ring forms a dihedral angle of 86.3 (1)o with the phenyl ring.The mean-plane of the 3-fluro phenyl group adopts a syn periplanar conformation with respect to the C5-H5 bond of the pyrimidine ring. The 3-fluro phenyl substituent bonded to atom C5 is in an axial position. The methyl group was refined as disordered over two sets of sites with an occupancy ratio of 0.52 (3):0.48 (2). The bond lengths and angles in the title compound are in good agreement with the corresponding bond distances and angles reported in closely related structures (N. L. Prasad et al., 2014). The crystal data has been shown in Table-1 for compound(4). In the crystal, weak C-H...O and C-H...F interactions link molecules into chains along [010] (Fig. 2).
Fig 1 : ORTEP diagram of compound (4)
N. L. Prasad et. al. /Materials Today: Proceedings 5 (2018) 20932–20938
20935
Figure 2: Part of the crystal structure with weak C-H...O and C-H...F interactions shown as dashed lines. H atoms not involved in hydrogen bonding have been excluded. Table 1. Crystal data and structure refinement for compound(4). Empirical formula C18 H17 F N2 O3 S Formula weight 360.40 Temperature 100(2) K Wavelength 0.71073 Å Crystal system, space group triclinic, P-1 Unit cell dimensions a = 10.2605(5) A alpha = 67.1230(10) deg. b = 12.9347(7) A beta = 89.395(2) deg. c = 14.5606(8) A gamma = 78.420(2) deg. Volume 1739.31(16) A3 Z, Calculated density 4, 1.376 Mg/m3 Absorption coefficient 0.216 mm-1 F(000) 752 Crystal size 0.14 x 0.14 x 0.12 mm Theta range for data collection 2.03 to 25.00 deg. Limiting indices -12<=h<=12, -15<=k<=15, -17<=l<=17 Reflections collected / unique 21213 / 6123 [R(int) = 0.0397] Completeness to theta = 25.00 99.8 % Max. and min. transmission 0.9746 and 0.9704 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 6123 / 0 / 459 Goodness-of-fit on F2 1.042 Final R indices [I>2sigma(I)] R1 = 0.0809, wR2 = 0.2197 R indices (all data) R1 = 0.1067, wR2 = 0.2357 Largest diff. peak and hole 2.480 and -1.584 e.A-3
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N. L. Prasad et. al. /Materials Today: Proceedings 5 (2018) 20932–20938
3.2. Powder X-Ray Diffraction The phase composition of the synthesized powder was analyzed by powder X-ray diffraction (PXRD) using PANalytical X’pert PRO MPD instrument with graphite filtered CuKα radiation source ( λ=1.541 Å). Figure 3 shows the PXRD pattern of as synthesized compound (4). Well
Intensity (a.u)
defined diffraction peaks indicate the crystalline nature of the as synthesized compound.
0
10
20
30
40
50
60
70
80
90
2 (degree)
Fig. 3. Powder X-ray diffraction pattern of compound(4).
4. Conclusions In this work, we have reported the synthesis of compound (4). The formation of the thiazolopyrimidine moiety was confirmed by X-ray diffraction studies. The bond lengths and angles of the compound are in good agreement with the corresponding bond distances and angles reported in closely related structures. Crystal structure of compound showed the pyrimidine ring is in a sofa conformation. Crystal structure with weak C-H...O and C-H...F interactions control the architecture of organic solids. Acknowledgements NLP thanks the UGC for UGC–JRF fellowship.
N. L. Prasad et. al. /Materials Today: Proceedings 5 (2018) 20932–20938
20937
Supplementary Information The CIF files are deposited at the Cambridge Crystallographic Data Centre, The deposition numbers for Compound (4) is CCDC-1510332. These data can be obtained free of charge at www.ccdc.cam.ac.ul/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223-336033; email: [email protected]]. References [1] A Shawkat Abdelmohsen,S Mohammed Abaddy, Int J Pharm Pharm Sci, Vol 6, 5 , 696-703 (2014). [2] Shivapura Viveka, Dinesha, Sandeep Sadananda Laxmeshwar and Gundibasappa Karikannar Nagaraja, Molbank, M776, (2012). [3]. Tozkoparan B, Ertan M, Krebs B, Lage M, Kelicen P, Demirdamar R.Arch Pharm Pharm Med Chem, 1998; 331: 201. [4]. Tozkoparan B, Ertan M, Kelicen P, Demirdamar R. Farmaco, 1999; 54:588. [5]. Van Laar M, Volkerts E, Verbaten M. Psychopharmacology, 2001; 154:189. [6]. Parmar JM, Parikh AR. Heterocycl Commun. 1998; 4: 463. [7]. Danel K, Pedersen EB, Nielsen C. J Med Chem. 1998; 41: 191. [8]. N. L. Prasad, M. S. Krishnamurthy, H. Nagarajaiah and Noor Shahina Begum Acta Cryst. (2014). E70, o1204.
20938
N. L. Prasad et. al. /Materials Today: Proceedings 5 (2018) 20932–20938
[9]. H. Eranjaneya & G. T. Chandrappa, Transactions of the Indian Ceramic Society, 75:2, 133137. [10]. Gujjarahalli Thimmanna Chandrappa, Gangaiah Vijayakumar, Jacques Livage, J Sol-Gel Sci Technol. 2014.