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Synthesis and Spectral Characterization of 4,7-Dichloro-6-nitroquinazoline

Synthesis and Spectral Characterization of 4,7-Dichloro-6-nitroquinazoline molbank Communication Synthesis and Spectral Characterization of 4,7-Dichloro-6-nitroquinazoline 1 , 2 2 2 2 Thi Ngoc Nguyen , Thi Huong Tran , Nguyet Suong Huyen Dao , Van Giang Nguyen , 2 3 2 , Dinh Luyen Nguyen , Nguyen Trieu Trinh and Van Hai Nguyen * Department of Pharmaceutical Technology, Thainguyen University of Medicine and Pharmacy, Thainguyen 24117, Vietnam; ngock3a@gmail.com Department of Pharmaceutical Industry, Hanoi University of Pharmacy, Hanoi 110403, Vietnam; huongve2910@gmail.com (T.H.T.); huyendns@hup.edu.vn (N.S.H.D.); giangnv@hup.edu.vn (V.G.N.); ngdluyen@hotmail.com (D.L.N.) School of Environmental and Life Sciences, Faculty of Science, University of Newcastle, Newcastle (Callaghan) 2308, Australia; nguyentrieu@gmail.com * Correspondence: hainv@hup.edu.vn or nguyenvanhaicnd@gmail.com; Tel.: +84-918-971-109 Received: 5 April 2020; Accepted: 9 May 2020; Published: 11 May 2020 Abstract: Afatinib is a 4-anilinoquinazoline tyrosine kinase inhibitor (TKI) in the form of a dimaleate salt which is indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). The most scalable route for the synthesis of this drug was reported in two Boehringer Ingelheim patents, in which the title compound, 4,7-dichloro-6-nitroquinazoline (IV), is an important intermediate. Compound IV is also present in a number of synthetic pathways for various 4,7-disubstituted quinazoline derivatives displaying high therapeutic potential. However, no detailed characterization of this popular compound has been reported, possibly due to its high instability. In this paper, IV was prepared in an overall yield of 56.1% by a 3-step process (condensation, nitration, and chlorination) from 2-amino-4-chlorobenzoic acid (I). The target compound has been for the first time fully characterized by melting point, mass-spectrometry, FT-IR, H-NMR and C-NMR spectroscopies. Keywords: afatinib; 2-amino-4-chlorobenzoic acid; 4,7-dichloro-6-nitroquinazoline; quinazoline 1. Introduction Quinazoline and quinazolinones sca olds are present in a diverse range of biologically active compounds with huge therapeutic potential, including anticancer, antimicrobial, antiviral, antituberculosis, antifungal, antimalarial, anti-inflammatory, analgesic, and antidiabetic properties [1–4]. Many quinazoline derivatives, in particular the 4-anilinoquinazolines such as gefitinib, erlotinib, lapatinib, vandetanib, icotinib, afatinib and dacomitinib are approved as tyrosine kinase inhibitors (TKI) for the treatment of di erent cancers in targeted therapies [5,6]. Among those, afatinib dimaleate is a powerful second-generation TKI, irreversibly binding to both EGFR (epidermal growth factor receptor) and HER2 (human epidermal growth factor receptor 2). It is an approved anticancer drug ® ® marketed under the brand names Giotrif (EU, Japan, Taiwan and Canada) and Gilotrif (USA). It is indicated for patients with specific types EGFR mutation-positive non-small cell lung cancer [7,8]. The synthetic route to afatinib dimaleate can be derived from two Boehringer Ingelheim patents, comprising 10 reactions [9–14]. In that synthetic procedure, the compound 4,7-dichloro-6-nitroquinazoline (IV, CAS Registry number 162012-71-7) is a highly reactive intermediate. However, it was used in situ and thus no characterization was available. Similarly, in other synthetic routes of other bioactive quinazoline derivatives reported by SciFinder and Reaxys, compound IV Molbank 2020, 2020, M1134; doi:10.3390/M1134 www.mdpi.com/journal/molbank Molbank 2020, 2020, x  5 of 5  Molbank 2020, 2020, M1134 2 of 7 other bioactive quinazoline derivatives reported by SciFinder and Reaxys, compound IV was also  was also synthesized and used directly in the next step without characterization [15–36], or only synthesized and  used  directly  in  the  next  step  without  characterization  [15–36],  or  only  partially  partially characterized by H-NMR [37]. The most detailed characterization of IV includes a melting characterized by  H‐NMR [37]. The most detailed characterization of IV includes a melting point  1 13 1 13 point analysis, H-NMR and C-NMR spectroscopies, and an elemental analysis [38]. However, analysis,  H‐NMR and  C‐NMR spectroscopies, and an elemental analysis [38]. However, it appears  it tha appears t the reported that the NM reported R dataNMR  for IV data  in this for pa IVper in this are close paper to ar those e close ofto the those  start of ing the ma starting terial (7 material ‐chloro‐ (7-chloro-6-nitroquinazolin-4(3H)-one, III), indicating the possibility of a hydrolysis reaction which 6‐nitroquinazolin‐4(3H)‐one, III), indicating the possibility of a hydrolysis reaction which converts  converts IV  back IV to back the  starting to the starting   materia material. l.  In  add Initaddition, ion,  the  given the given   eleme elemental ntal  ananalysis alysis  did did  not not  present present  the the  per percenta centage ge of of each each element, element, which which oo ffer erss no no clarification clarification over over the the identity identity of of this this compound. compound. In In this this  paper paper, , compound   compound IV  IV has  has been  been for the   for first   the time   first fully   time characterized   fully  charact by e melting rized  by point,   melt mass-spectr ing  point,ometry   mass‐, 1 13 1 13 FT spectrometry, -IR, H-NMR FT and ‐IR,  H C-NMR ‐NMR and spectr   C oscopies. ‐NMR spectroscopies.  2. Results and Discussion 2. Results and Discussion  The target compound IV was prepared in three steps from 2-amino-4-chlorobenzoic acid (I) in an The target compound IV was prepared in three steps from 2‐amino‐4‐chlorobenzoic acid (I) in  overall yield of 56.1% (Scheme 1). The synthetic procedures were based on references [30,33,39] with an overall yield of 56.1% (Scheme 1). The synthetic procedures were based on references [30,33,39]  some changes. with some changes.  Scheme 1. Synthesis of 4,7-dichloro-6-nitroquinazoline (IV). Reagents and conditions (yield): Scheme 1. Synthesis of 4,7‐dichloro‐6‐nitroquinazoline (IV). Reagents and conditions (yield): (a) HCO‐ (a) HCO-NH , reflux at 160 C (82.3%); (b) HNO /H SO (84.7%); (c) SOCl /DMF at 100 C (91.3%). NH2, reflux at 160 °C (82.3%); (b) HNO3/H2SO4 (84.7%); (c) SOCl2/DMF at 100 °C (91.3%).  2 3 2 4 2 Compound IV is an imidoyl halide (also known as imidyl or iminochlorides), a group of highly Compound IV is an imidoyl halide (also known as imidyl or iminochlorides), a group of highly  reactive organic compounds widely used as synthetic tools to produce a variety of compounds. It is reactive organic compounds widely used as synthetic tools to produce a variety of compounds. It is  often not necessary to isolate imidoyl halides because in situ generation and subsequent reactions can often not necessary to isolate imidoyl halides because in situ generation and subsequent reactions  a ord the desired derivatives in high yields [40–42]. In fact, our experimental observations demonstrate can  afford  the  desired  derivatives  in  high  yields  [40–42].  In  fact,  our  experimental  observations  that IV is extremely sensitive to moisture and can be readily hydrolyzed giving back the starting demonstrate that IV is extremely sensitive to moisture and can be readily hydrolyzed giving back the  material III. This phenomenon could explain the reason why the NMR-data in the aforementioned starting  material  III.  This  phenomenon  could  explain  the  reason  why  the  NMR‐data  in  the  article [38] are so close to those of the starting material III. These data are presented in Tables 1 and 2. aforementioned article [38] are so close to those of the starting material III. These data are presented  in Tables 1 and 2.  Table 1. Reported and our data for H-NMR spectroscopies of III and IV. Table 1. Reported and our data for  H‐NMR spectroscopies of III and IV.  (ppm) for Compound III  (ppm) for Compound IV Signals Ref [30] (in Ref [43] (in Ref [39] (in Our Data (in Ref [38] (in Ref [37] (in Our Data (in δ (ppm) for Compound III  δ (ppm) for Compound IV  DMSO-d ) DMSO-d ) DMSO-d ) DMSO-d ) DMSO-d ) DMSO-d ) CDCl ) 6 6 6 6 6 6 3 Our data  Our data  OH or NH 3.30 * (br.s, 1H, 12.79 (br.s, 1H, 12.79 (br.s, 1H, 12.73 (br.s, 1H, Signals  NA ** NA NA Ref [30] (in  Ref [43] (in  Ref [39] (in  Ref [38] (in  Ref [37] (in  forms NH form) OH form) OH form) OH form) (in DMSO‐ (in  H-5 8.53 DMSO (s, 1H)‐d6)  8.69 DMSO (s, 1H)‐d6)  8.67 DMSO (s, 1H)‐d6)  8.64 (s, 1H) 8.60DMSO (s, 1H)‐d6)  9.56 DMSO (s, 1H)‐d6)  9.18 (s, 1H) d6)  CDCl3)  H-2 8.28 (s, 1H) 8.32 (s, 1H) 8.31 (s, 1H) 8.27 (s, 1H) 8.27 (s, 1H) 8.71 (s, 1H) 8.76 (s, 1H) H-8 7.97 (s, 1H) 8.03 (s, 1H) 8.01 (s, 1H) 7.97 (s, 1H) 7.85 (s, 1H) 8.28 (s, 1H) 8.30 (s, 1H) OH or  3.30 * (br.s,  12.79 (br.s,  12.79 (br.s,  12.73 (br.s,  NH  *:1H, The NH signal  is overlapped 1H, OH with water 1H,  signal OH  at 3.331H, ppm OH in DMSO-dNA . ** ** NA:   not available. NA  NA  forms  form)  form)  form)  form)  8.60 (s,  9.56 (s,  9.18 (s,  H‐5  8.53 (s, 1H)  8.69 (s, 1H)  8.67 (s, 1H)  8.64 (s, 1H)  1H)  1H)  1H)  8.27 (s,  8.71 (s,  8.76 (s,  H‐2  8.28 (s, 1H)  8.32 (s, 1H)  8.31 (s, 1H)  8.27 (s, 1H)  1H)  1H)  1H)  Molbank 2020, 2020, x  5 of 5  7.85 (s,  8.28 (s,  8.30 (s,  H‐8  7.97 (s, 1H)  8.03 (s, 1H)  8.01 (s, 1H)  7.97 (s, 1H)  1H)  1H)  1H)  *: The signal is overlapped with water signal at 3.33 ppm in DMSO‐d6. ** NA: not available.  Molbank 2020, 2020, M1134 3 of 7 Table 2. Reported and our data for  C‐NMR spectroscopies of III and IV.  δ (ppm) for Compound III  δ (ppm) for Ccompound IV  Signals  Table 2. Reported and our data for C-NMR spectroscopies of III and IV. Literature  Our data (in DMSO‐d6)  Ref [38] (in DMSO‐d6)  Our data (in CDCl3)  C‐4  NA  159.3  159.0  163.6  (ppm) for Compound III  (ppm) for Compound IV Signals C‐2  NA Literature   Our Data 151.5 (in  DMSO-d ) Ref [38] (in DMSO- 150.3  d ) Our Data (in CDCl 156.9 )   6 6 3 C‐8a  NA  149.6  149.2  151.6  C-4 NA 159.3 159.0 163.6 C-2 NA 151.5 150.3 156.9 C‐6  NA  144.7  144.8  147.5  C-8a NA 149.6 149.2 151.6 C‐7  NA  130.4  131.1  132.8  C-6 NA 144.7 144.8 147.5 C‐8  NA  129.4  129.4  132.2  C-7 NA 130.4 131.1 132.8 C-8 NA 129.4 129.4 132.2 C‐5  NA  124.2  124.2  123.5  C-5 NA 124.2 124.2 123.5 C‐4a  NA  121.7  121.4  122.1  C-4a NA 121.7 121.4 122.1 The data in Table 1 indicate that III is capable of tautomerism between the lactim (‐C(OH)=N‐)  The data in Table 1 indicate that III is capable of tautomerism between the lactim (-C(OH)=N-) and lactam (‐C(=O)‐NH‐) forms, displaying a huge difference in chemical shifts between the ‐OH and  and lactam (-C(=O)-NH-) forms, displaying a huge di erence in chemical shifts between the -OH and the ‐NH groups (12.79 ppm vs. 3.30 ppm). In the latter form, the ‐NH‐ signal is actually overlapped  the -NH groups (12.79 ppm vs. 3.30 ppm). In the latter form, the -NH- signal is actually overlapped with the water signal if DMSO‐d6 is used and may not be seen in a proton spectrum. As the reported  with the water signal if DMSO-d is used and may not be seen in a proton spectrum. As the reported proton chemical shifts for compound IV in [38] are similar to those of compound III in [30], we  proton chemical shifts for compound IV in [38] are similar to those of compound III in [30], we suspect suspect  that  they  are  of  the  same  chemical  compound  (Table  1).  Indeed,  the  H‐NMR  values  for  that they are of the same chemical compound (Table 1). Indeed, the H-NMR values for compound IV compound IV in [38] do not match up with those of either our data or another paper [37], displaying  in [38] do not match up with those of either our data or another paper [37], displaying large chemical large chemical shifts’ differences of 0.96 ppm, 0.44 ppm, and 0.43 ppm, respectively, for the aromatic  shifts’ di erences of 0.96 ppm, 0.44 ppm, and 0.43 ppm, respectively, for the aromatic hydrogens hydrogens in DMSO‐d6 [37,38]. We would not expect such large discrepancies in chemical shifts for  in DMSO-d [37,38]. We would not expect such large discrepancies in chemical shifts for the same the same compound using the same NMR solvent (DMSO‐d6). When comparing our  H‐NMR data  compound using the same NMR solvent (DMSO-d ). When comparing our H-NMR data with those with those of [37], the differences are −0.38 ppm, 0.05 ppm, and 0.02 ppm, respectively, which indicate  of [37], the di erences are 0.38 ppm, 0.05 ppm, and 0.02 ppm, respectively, which indicate a high a high level of spectral similarities. These slight deviations could potentially originate from the fact  level of spectral similarities. These slight deviations could potentially originate from the fact that two that two different NMR solvents (DMSO‐d6 vs. CDCl3) were used [44]. On the other hand, when  di erent NMR solvents (DMSO-d vs. CDCl ) were used [44]. On the other hand, when examining 6 3 examining the  C‐NMR data, we found strikingly similar values between IV of reference [38] and  the C-NMR data, we found strikingly similar values between IV of reference [38] and the starting 13 the starting material III (∆δ = 0–0.4 ppm, Table 2). These reported values are different from our  C‐ material III (D = 0–0.4 ppm, Table 2). These reported values are di erent from our C-NMR data of IV 1 13 NMR  data  of  IV  (∆δ  =  0.4–5.4  ppm,  Table  2).  Altogether,  both  the  H‐NMR  and  C‐NMR  data  1 13 (D = 0.4–5.4 ppm, Table 2). Altogether, both the H-NMR and C-NMR data combined indicate that combined indicate that the reported NMR data in [38] could potentially be that of the starting material  the reported NMR data in [38] could potentially be that of the starting material III, and not the desired III, and not the desired compound IV. One possible explanation could be the hydrolysis of the highly  compound IV. One possible explanation could be the hydrolysis of the highly reactive compound IV reactive compound IV back into the starting material III, a phenomenon we have observed in our  back into the starting material III, a phenomenon we have observed in our laboratory. laboratory.  Another interesting fact is that, when measuring mass spectrometry, we not only detected the peak Another interesting fact is that, when measuring mass spectrometry, we not only detected the  of compound IV, but also its methoxy form (compound V), which possibly occurs due to alcoholysis peak  of  compound  IV,  but  also  its  methoxy  form  (compound  V),  which  possibly  occurs  due  to  by methanol (the solvent in MS). We show this in Scheme 2. alcoholysis by methanol (the solvent in MS). We show this in Scheme 2.  Scheme Scheme 2. 2. The The formation formation of of 7 7-chlor ‐chloro o-4-methoxy-6-nitr ‐4‐methoxy‐6‐nitroquinazoline oquinazoline ((V V)) by by alcoholysis alcoholysis with with methanol methanol  in MS. in MS.  On the whole, in the synthesis of IV, our control of anhydrous reaction conditions and the On  the  whole,  in  the  synthesis  of  IV,  our  control  of  anhydrous  reaction  conditions  and  the  appropriate work-up procedures have made it feasible to synthesize and characterize this highly appropriate work‐up procedures have made it feasible to synthesize and characterize this highly  reactive compound for the first time. These data may be useful for further investigations in the reactive  compound  for  the  first  time.  These  data  may  be  useful  for  further  investigations  in  the  synthesis process improvement of afatinib, its analogs and other biologically active quinazoline based synthesis process improvement of afatinib, its analogs and other biologically active quinazoline based  1 13 compounds. All the mass, FT-IR, H-NMR and C-NMR spectra are presented in the Supplementary Material File. Molbank 2020, 2020, M1134 4 of 7 3. Materials and Methods 3.1. General Information The 2-amino-4-chlorobenzoic acid was purchased from Energy Chemical (Zhejiang, China) and used as received. Formamide (99.5%) was purchased from Scharlau Chemie (Barcelona, Spain). Thionyl chloride (99.5%) was purchased from Merck Schuchardt (Hohenbrunn, Germany). Dichloromethane (DCM, 99.5%), sufuric acid (98%) and N,N-dimethylformamide (DMF, 99.5%) was purchased from Xilong Scientific Co., Ltd. (Shantou, China). Fuming nitric acid (d 1.50 g/mL) was prepared by reaction of solid sodium nitrate and liquid sulfuric acid (98%), following distillation at b.p 82 C. The melting point was determined using a SRS EZ-Melt apparatus (Stanford Research Systems, Sunnyvale, CA, USA) and is uncorrected. MS was performed at a EVOQ Qube— (Bruker, Billerica, MA, USA) or an LTQ Orbitrap XL— (Thermo Scientific, Waltham, MA, USA) system. FT-IR spectra were recorded by a Perkin Elmer (Waltham, MA, USA) or Shimadzu (Kyoto, Japan) spectrometer. H- and C-NMR spectra were acquired with a 500 MHz Ascent spectrometer (Bruker, Billerica, MA, USA) using acetone-d , DMSO-d , or CDCl as the solvent. The reaction mixtures were monitored, and the 6 6 3 purity of all products was checked by thin-layer chromatography (TLC) on silica gel 60 F plates (Merck, Darmstadt, Germany). 3.2. Synthetic Procedure 3.2.1. Preparation of 7-Chloroquinazolin-4(3H)-one (II) The synthetic procedure for compound II was based on the method described in [39] with some modifications. A mixture of 2-amino-4-chlorobenzoic acid (I, 34.30 g, 0.20 mol, 1 equiv.), formamide (125.0 mL, 2.77 mol, 14 equiv.) was aerated with nitrogen, then stirred and refluxed for 1.5 h at 160 C (the reaction was monitored by TLC with a 9:1 DCM/methanol mixture as eluent). The reaction mixture was cooled to 80 C, then 500 mL of water was added. The mixture was cooled to 5 C in 1 h and filtered. The precipitate was washed with water and dried at 60 C to a ord 7-chloroquinazolin-4(3H)-one (II) as a light brown solid (29.71 g, 82.3%), which was used for the next step without further purification. M.p 251.0–253.0 C. R 0.60 (DCM/methanol, 9:1). MS (ESI , MeOH), m/z: found 181.2 and 183.2 + + 1 [M + H] , C H ON Cl requires [M + H] 181.0 and 183.0. FT-IR (KBr),  (cm ): 3031 (C-H); 2964, 8 5 2 max 2919 (N-H); 1714 (C=O); 1693 (C=N); 1655, 1606 (C=C). H-NMR (acetone-d ),  (ppm): 11.82 (br.s, 1H, H-3, NH); 8.17 (d, J = 8,5 Hz, 1H, H-5); 8.09 (s, 1H, H-2); 7.67 (d, J = 2.0 Hz, 1H, H-8); 7.51 (dd, J = 8.5 Hz, J = 2.0 Hz, 1H, H-6). C-NMR (acetone-d ),  (ppm): 160.6 (C-4); 151.2 (C-8a); 147.3 (C-2); 1 2 6 140.2 (C-7); 128.8 (C-5); 127.7 (C-6); 127.6 (C-8); 122.8 (C-4a). 3.2.2. Preparation of 7-Chloro-6-nitroquinazolin-4(3H)-one (7-Chloro-4-hydroxy-6-nitroquinazoline, III) The synthetic procedure for compound III was based on [30] with some modifications. Compound II (10.83 g, 0.060 mol) and sulfuric acid (120 mL) were added into a 500 mL two-neck round bottom flask. The mixture was cooled to 0 C on ice and stirred until dissolution. Fuming nitric acid (120 mL) was slowly added to the mixture at 0 C, and the mixture was stirred for 1.5 h at 30 C. After completion of reaction as indicated by TLC, 10% NaOH solution was slowly added to the reaction mixture until a precipitate was formed (pH ~7). The mixture was then filtered to furnish a light yellow solid (III). The compound was purified by redissolving in HCl (5M) and then neutralizing this solution with NaOH (10%) to pH 6–7 to furnish the pure precipitate which was then filtered, washed with water and dried at 60 C to furnish 7-chloro-6-nitroquinazolin-4(3H)-one (III) as a light yellow solid (11.46 g, 84.7%). M.p 263.5–265.0 C. R 0.34 (DCM/methanol, 20:1). MS (ESI , MeOH), m/z: found 225.9 + + 1 [M + H] , C H O N Cl requires [M + H] 225.9. FT-IR (KBr),  (cm ): 3452, 3215 (O-H); 3091, 8 4 3 3 max 3012 (C-H); 1696 (C=O); 1666, 1612 (C=N); 1523 (C=C); 1336 (NO ). H-NMR (DMSO-d ),  (ppm): 2 6 Molbank 2020, 2020, M1134 5 of 7 12.73 (br.s, 1H, OH); 8.64 (s, 1H, H-5); 8.27 (s, 1H, H-2); 7.97 (s, 1H, H-8). C-NMR (DMSO-d ),  (ppm): 159.3 (C-4); 151.5 (C-8a); 149.6 (C-2); 144.7 (C-6); 130.4 (C-7); 129.9 (C-5); 124.2 (C-8); 121.7 (C-4a). 3.2.3. Preparation of 4,7-Dichloro-6-nitroquinazoline (IV) The synthetic procedure for compound IV was based on [33] with some modifications. A mixture of compound III (6.09 g, 0.027 mol), thionyl chloride (48.0 mL, 0.661 mol) and N,N-dimethyl-formamide (0.25 mL) was melted and stirred at 100 C for 2 h. The reaction mixture was allowed to cool down and excess thionyl chloride was removed by rotary evaporation under reduced pressure. Toluene (40 mL) was added to the residue and the mixture was evaporated again to completely remove volatile matter. The precipitate was washed with diethyl ether and dried in the desiccator to obtain 4,7-dichloro-6-nitroquinazoline (IV) as a yellow solid (6.02 g, 91.3%). M.p: 269.0–270.5 C. R : 0.87 + + (DCM/methanol, 20:1). MS (ESI , MeOH), m/z: found 244.4 [M + H] , 240.00 and 241.99 [methoxy + 1 form]; C H O N Cl requires [M + H] 244.0 and 246.0. FT-IR (KBr),  (cm ): 3089 (C-H); 1726, max 8 3 2 3 2 1645, 1610 (C=N); 1546 (C=C); 1527, 1323 (NO ). H-NMR (CDCl ),  (ppm): 9.18 (s, 1H, H-2); 8.76 (s, 2 3 1H, H-5); 8.30 (s, 1H, H-8). C-NMR (CDCl ),  (ppm): 163.6 (C-4); 156.9 (C-2); 151.6 (C-8a); 147.5 (C-6); 132.8 (C-7); 132.2 (C-8); 123.5 (C-5); 122.1 (C-4a). Supplementary Materials: Spectral data of starting material I, intermediates II, III and title compound IV are available online, Figure S1: FT-IR spectrum of compound 2-amino-4-chlorobenzoic acid (I), Figure S2: 1 13 H-NMR spectrum of compound 2-amino-4-chlorobenzoic acid (I), Figure S3: C-NMR spectrum of compound 2-amino-4-chlorobenzoic acid (I), Figure S4: MS spectrum of compound 7-chloroquinazolin-4(3H)-one (II), Figure S5: FT-IR spectrum of compound 7-chloroquinazolin-4(3H)-one (II), Figure S6: H-NMR spectrum of compound 7-chloroquinazolin-4(3H)-one (II), Figure S7: C-NMR spectrum of compound 7-chloroquinazolin-4(3H)-one (II), Figure S8: MS spectrum of compound 7-chloro-6-nitroquinazolin-4(3H)-one (III), Figure S9: FT-IR spectrum of compound 7-chloro-6-nitroquinazolin-4(3H)-one (III), Figure S10: H-NMR spectrum of compound 7-chloro-6-nitroquinazolin-4(3H)-one (III), Figure S11: C-NMR spectrum of compound 7-chloro-6-nitroquinazolin-4(3H)-one (III), Figure S12: MS spectrum of compound 4,7-dichloro-6-nitroquinazoline (IV), Figure S13: FT-IR spectrum of compound 4,7-dichloro-6-nitroquinazoline (IV), Figure S14: H-NMR spectrum of compound 4,7-dichloro-6-nitroquinazoline (IV), Figure S15: C-NMR spectrum of compound 4,7-dichloro-6-nitroquinazoline (IV). Author Contributions: T.N.N. and T.H.T. synthesized the compounds. T.N.N. wrote the manuscript. N.S.H.D., V.G.N. and D.L.N. designed the experiments. V.H.N. analyzed spectroscopic data. V.H.N. and N.T.T. edited the manuscript. All authors read and approved the final version of the manuscript. Funding: This research received no external funding. Acknowledgments: The authors would like to thank Hanoi University of Pharmacy and Thainguyen University of Medicine and Pharmacy for financial support and research facilities. Conflicts of Interest: The authors declare no conflict of interest. References 1. Khan, I.; Zaib, S.; Batool, S.; Abbas, N.; Ashraf, Z.; Iqbal, J.; Saeed, A. Quinazolines and quinazolinones as ubiquitous structural fragments in medicinal chemistry: An update on the development of synthetic methods and pharmacological diversification. Bioorg. Med. Chem. 2016, 24, 2361–2381. [CrossRef] [PubMed] 2. 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H chemical shifts in NMR: Part 23, the e ect of dimethyl sulphoxide versus chloroform solvent on H chemical shifts. Magn. Reson. Chem. 2006, 44, 491–509. [CrossRef] [PubMed] © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Molbank Multidisciplinary Digital Publishing Institute

Synthesis and Spectral Characterization of 4,7-Dichloro-6-nitroquinazoline

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Abstract

molbank Communication Synthesis and Spectral Characterization of 4,7-Dichloro-6-nitroquinazoline 1 , 2 2 2 2 Thi Ngoc Nguyen , Thi Huong Tran , Nguyet Suong Huyen Dao , Van Giang Nguyen , 2 3 2 , Dinh Luyen Nguyen , Nguyen Trieu Trinh and Van Hai Nguyen * Department of Pharmaceutical Technology, Thainguyen University of Medicine and Pharmacy, Thainguyen 24117, Vietnam; ngock3a@gmail.com Department of Pharmaceutical Industry, Hanoi University of Pharmacy, Hanoi 110403, Vietnam; huongve2910@gmail.com (T.H.T.); huyendns@hup.edu.vn (N.S.H.D.); giangnv@hup.edu.vn (V.G.N.); ngdluyen@hotmail.com (D.L.N.) School of Environmental and Life Sciences, Faculty of Science, University of Newcastle, Newcastle (Callaghan) 2308, Australia; nguyentrieu@gmail.com * Correspondence: hainv@hup.edu.vn or nguyenvanhaicnd@gmail.com; Tel.: +84-918-971-109 Received: 5 April 2020; Accepted: 9 May 2020; Published: 11 May 2020 Abstract: Afatinib is a 4-anilinoquinazoline tyrosine kinase inhibitor (TKI) in the form of a dimaleate salt which is indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). The most scalable route for the synthesis of this drug was reported in two Boehringer Ingelheim patents, in which the title compound, 4,7-dichloro-6-nitroquinazoline (IV), is an important intermediate. Compound IV is also present in a number of synthetic pathways for various 4,7-disubstituted quinazoline derivatives displaying high therapeutic potential. However, no detailed characterization of this popular compound has been reported, possibly due to its high instability. In this paper, IV was prepared in an overall yield of 56.1% by a 3-step process (condensation, nitration, and chlorination) from 2-amino-4-chlorobenzoic acid (I). The target compound has been for the first time fully characterized by melting point, mass-spectrometry, FT-IR, H-NMR and C-NMR spectroscopies. Keywords: afatinib; 2-amino-4-chlorobenzoic acid; 4,7-dichloro-6-nitroquinazoline; quinazoline 1. Introduction Quinazoline and quinazolinones sca olds are present in a diverse range of biologically active compounds with huge therapeutic potential, including anticancer, antimicrobial, antiviral, antituberculosis, antifungal, antimalarial, anti-inflammatory, analgesic, and antidiabetic properties [1–4]. Many quinazoline derivatives, in particular the 4-anilinoquinazolines such as gefitinib, erlotinib, lapatinib, vandetanib, icotinib, afatinib and dacomitinib are approved as tyrosine kinase inhibitors (TKI) for the treatment of di erent cancers in targeted therapies [5,6]. Among those, afatinib dimaleate is a powerful second-generation TKI, irreversibly binding to both EGFR (epidermal growth factor receptor) and HER2 (human epidermal growth factor receptor 2). It is an approved anticancer drug ® ® marketed under the brand names Giotrif (EU, Japan, Taiwan and Canada) and Gilotrif (USA). It is indicated for patients with specific types EGFR mutation-positive non-small cell lung cancer [7,8]. The synthetic route to afatinib dimaleate can be derived from two Boehringer Ingelheim patents, comprising 10 reactions [9–14]. In that synthetic procedure, the compound 4,7-dichloro-6-nitroquinazoline (IV, CAS Registry number 162012-71-7) is a highly reactive intermediate. However, it was used in situ and thus no characterization was available. Similarly, in other synthetic routes of other bioactive quinazoline derivatives reported by SciFinder and Reaxys, compound IV Molbank 2020, 2020, M1134; doi:10.3390/M1134 www.mdpi.com/journal/molbank Molbank 2020, 2020, x  5 of 5  Molbank 2020, 2020, M1134 2 of 7 other bioactive quinazoline derivatives reported by SciFinder and Reaxys, compound IV was also  was also synthesized and used directly in the next step without characterization [15–36], or only synthesized and  used  directly  in  the  next  step  without  characterization  [15–36],  or  only  partially  partially characterized by H-NMR [37]. The most detailed characterization of IV includes a melting characterized by  H‐NMR [37]. The most detailed characterization of IV includes a melting point  1 13 1 13 point analysis, H-NMR and C-NMR spectroscopies, and an elemental analysis [38]. However, analysis,  H‐NMR and  C‐NMR spectroscopies, and an elemental analysis [38]. However, it appears  it tha appears t the reported that the NM reported R dataNMR  for IV data  in this for pa IVper in this are close paper to ar those e close ofto the those  start of ing the ma starting terial (7 material ‐chloro‐ (7-chloro-6-nitroquinazolin-4(3H)-one, III), indicating the possibility of a hydrolysis reaction which 6‐nitroquinazolin‐4(3H)‐one, III), indicating the possibility of a hydrolysis reaction which converts  converts IV  back IV to back the  starting to the starting   materia material. l.  In  add Initaddition, ion,  the  given the given   eleme elemental ntal  ananalysis alysis  did did  not not  present present  the the  per percenta centage ge of of each each element, element, which which oo ffer erss no no clarification clarification over over the the identity identity of of this this compound. compound. In In this this  paper paper, , compound   compound IV  IV has  has been  been for the   for first   the time   first fully   time characterized   fully  charact by e melting rized  by point,   melt mass-spectr ing  point,ometry   mass‐, 1 13 1 13 FT spectrometry, -IR, H-NMR FT and ‐IR,  H C-NMR ‐NMR and spectr   C oscopies. ‐NMR spectroscopies.  2. Results and Discussion 2. Results and Discussion  The target compound IV was prepared in three steps from 2-amino-4-chlorobenzoic acid (I) in an The target compound IV was prepared in three steps from 2‐amino‐4‐chlorobenzoic acid (I) in  overall yield of 56.1% (Scheme 1). The synthetic procedures were based on references [30,33,39] with an overall yield of 56.1% (Scheme 1). The synthetic procedures were based on references [30,33,39]  some changes. with some changes.  Scheme 1. Synthesis of 4,7-dichloro-6-nitroquinazoline (IV). Reagents and conditions (yield): Scheme 1. Synthesis of 4,7‐dichloro‐6‐nitroquinazoline (IV). Reagents and conditions (yield): (a) HCO‐ (a) HCO-NH , reflux at 160 C (82.3%); (b) HNO /H SO (84.7%); (c) SOCl /DMF at 100 C (91.3%). NH2, reflux at 160 °C (82.3%); (b) HNO3/H2SO4 (84.7%); (c) SOCl2/DMF at 100 °C (91.3%).  2 3 2 4 2 Compound IV is an imidoyl halide (also known as imidyl or iminochlorides), a group of highly Compound IV is an imidoyl halide (also known as imidyl or iminochlorides), a group of highly  reactive organic compounds widely used as synthetic tools to produce a variety of compounds. It is reactive organic compounds widely used as synthetic tools to produce a variety of compounds. It is  often not necessary to isolate imidoyl halides because in situ generation and subsequent reactions can often not necessary to isolate imidoyl halides because in situ generation and subsequent reactions  a ord the desired derivatives in high yields [40–42]. In fact, our experimental observations demonstrate can  afford  the  desired  derivatives  in  high  yields  [40–42].  In  fact,  our  experimental  observations  that IV is extremely sensitive to moisture and can be readily hydrolyzed giving back the starting demonstrate that IV is extremely sensitive to moisture and can be readily hydrolyzed giving back the  material III. This phenomenon could explain the reason why the NMR-data in the aforementioned starting  material  III.  This  phenomenon  could  explain  the  reason  why  the  NMR‐data  in  the  article [38] are so close to those of the starting material III. These data are presented in Tables 1 and 2. aforementioned article [38] are so close to those of the starting material III. These data are presented  in Tables 1 and 2.  Table 1. Reported and our data for H-NMR spectroscopies of III and IV. Table 1. Reported and our data for  H‐NMR spectroscopies of III and IV.  (ppm) for Compound III  (ppm) for Compound IV Signals Ref [30] (in Ref [43] (in Ref [39] (in Our Data (in Ref [38] (in Ref [37] (in Our Data (in δ (ppm) for Compound III  δ (ppm) for Compound IV  DMSO-d ) DMSO-d ) DMSO-d ) DMSO-d ) DMSO-d ) DMSO-d ) CDCl ) 6 6 6 6 6 6 3 Our data  Our data  OH or NH 3.30 * (br.s, 1H, 12.79 (br.s, 1H, 12.79 (br.s, 1H, 12.73 (br.s, 1H, Signals  NA ** NA NA Ref [30] (in  Ref [43] (in  Ref [39] (in  Ref [38] (in  Ref [37] (in  forms NH form) OH form) OH form) OH form) (in DMSO‐ (in  H-5 8.53 DMSO (s, 1H)‐d6)  8.69 DMSO (s, 1H)‐d6)  8.67 DMSO (s, 1H)‐d6)  8.64 (s, 1H) 8.60DMSO (s, 1H)‐d6)  9.56 DMSO (s, 1H)‐d6)  9.18 (s, 1H) d6)  CDCl3)  H-2 8.28 (s, 1H) 8.32 (s, 1H) 8.31 (s, 1H) 8.27 (s, 1H) 8.27 (s, 1H) 8.71 (s, 1H) 8.76 (s, 1H) H-8 7.97 (s, 1H) 8.03 (s, 1H) 8.01 (s, 1H) 7.97 (s, 1H) 7.85 (s, 1H) 8.28 (s, 1H) 8.30 (s, 1H) OH or  3.30 * (br.s,  12.79 (br.s,  12.79 (br.s,  12.73 (br.s,  NH  *:1H, The NH signal  is overlapped 1H, OH with water 1H,  signal OH  at 3.331H, ppm OH in DMSO-dNA . ** ** NA:   not available. NA  NA  forms  form)  form)  form)  form)  8.60 (s,  9.56 (s,  9.18 (s,  H‐5  8.53 (s, 1H)  8.69 (s, 1H)  8.67 (s, 1H)  8.64 (s, 1H)  1H)  1H)  1H)  8.27 (s,  8.71 (s,  8.76 (s,  H‐2  8.28 (s, 1H)  8.32 (s, 1H)  8.31 (s, 1H)  8.27 (s, 1H)  1H)  1H)  1H)  Molbank 2020, 2020, x  5 of 5  7.85 (s,  8.28 (s,  8.30 (s,  H‐8  7.97 (s, 1H)  8.03 (s, 1H)  8.01 (s, 1H)  7.97 (s, 1H)  1H)  1H)  1H)  *: The signal is overlapped with water signal at 3.33 ppm in DMSO‐d6. ** NA: not available.  Molbank 2020, 2020, M1134 3 of 7 Table 2. Reported and our data for  C‐NMR spectroscopies of III and IV.  δ (ppm) for Compound III  δ (ppm) for Ccompound IV  Signals  Table 2. Reported and our data for C-NMR spectroscopies of III and IV. Literature  Our data (in DMSO‐d6)  Ref [38] (in DMSO‐d6)  Our data (in CDCl3)  C‐4  NA  159.3  159.0  163.6  (ppm) for Compound III  (ppm) for Compound IV Signals C‐2  NA Literature   Our Data 151.5 (in  DMSO-d ) Ref [38] (in DMSO- 150.3  d ) Our Data (in CDCl 156.9 )   6 6 3 C‐8a  NA  149.6  149.2  151.6  C-4 NA 159.3 159.0 163.6 C-2 NA 151.5 150.3 156.9 C‐6  NA  144.7  144.8  147.5  C-8a NA 149.6 149.2 151.6 C‐7  NA  130.4  131.1  132.8  C-6 NA 144.7 144.8 147.5 C‐8  NA  129.4  129.4  132.2  C-7 NA 130.4 131.1 132.8 C-8 NA 129.4 129.4 132.2 C‐5  NA  124.2  124.2  123.5  C-5 NA 124.2 124.2 123.5 C‐4a  NA  121.7  121.4  122.1  C-4a NA 121.7 121.4 122.1 The data in Table 1 indicate that III is capable of tautomerism between the lactim (‐C(OH)=N‐)  The data in Table 1 indicate that III is capable of tautomerism between the lactim (-C(OH)=N-) and lactam (‐C(=O)‐NH‐) forms, displaying a huge difference in chemical shifts between the ‐OH and  and lactam (-C(=O)-NH-) forms, displaying a huge di erence in chemical shifts between the -OH and the ‐NH groups (12.79 ppm vs. 3.30 ppm). In the latter form, the ‐NH‐ signal is actually overlapped  the -NH groups (12.79 ppm vs. 3.30 ppm). In the latter form, the -NH- signal is actually overlapped with the water signal if DMSO‐d6 is used and may not be seen in a proton spectrum. As the reported  with the water signal if DMSO-d is used and may not be seen in a proton spectrum. As the reported proton chemical shifts for compound IV in [38] are similar to those of compound III in [30], we  proton chemical shifts for compound IV in [38] are similar to those of compound III in [30], we suspect suspect  that  they  are  of  the  same  chemical  compound  (Table  1).  Indeed,  the  H‐NMR  values  for  that they are of the same chemical compound (Table 1). Indeed, the H-NMR values for compound IV compound IV in [38] do not match up with those of either our data or another paper [37], displaying  in [38] do not match up with those of either our data or another paper [37], displaying large chemical large chemical shifts’ differences of 0.96 ppm, 0.44 ppm, and 0.43 ppm, respectively, for the aromatic  shifts’ di erences of 0.96 ppm, 0.44 ppm, and 0.43 ppm, respectively, for the aromatic hydrogens hydrogens in DMSO‐d6 [37,38]. We would not expect such large discrepancies in chemical shifts for  in DMSO-d [37,38]. We would not expect such large discrepancies in chemical shifts for the same the same compound using the same NMR solvent (DMSO‐d6). When comparing our  H‐NMR data  compound using the same NMR solvent (DMSO-d ). When comparing our H-NMR data with those with those of [37], the differences are −0.38 ppm, 0.05 ppm, and 0.02 ppm, respectively, which indicate  of [37], the di erences are 0.38 ppm, 0.05 ppm, and 0.02 ppm, respectively, which indicate a high a high level of spectral similarities. These slight deviations could potentially originate from the fact  level of spectral similarities. These slight deviations could potentially originate from the fact that two that two different NMR solvents (DMSO‐d6 vs. CDCl3) were used [44]. On the other hand, when  di erent NMR solvents (DMSO-d vs. CDCl ) were used [44]. On the other hand, when examining 6 3 examining the  C‐NMR data, we found strikingly similar values between IV of reference [38] and  the C-NMR data, we found strikingly similar values between IV of reference [38] and the starting 13 the starting material III (∆δ = 0–0.4 ppm, Table 2). These reported values are different from our  C‐ material III (D = 0–0.4 ppm, Table 2). These reported values are di erent from our C-NMR data of IV 1 13 NMR  data  of  IV  (∆δ  =  0.4–5.4  ppm,  Table  2).  Altogether,  both  the  H‐NMR  and  C‐NMR  data  1 13 (D = 0.4–5.4 ppm, Table 2). Altogether, both the H-NMR and C-NMR data combined indicate that combined indicate that the reported NMR data in [38] could potentially be that of the starting material  the reported NMR data in [38] could potentially be that of the starting material III, and not the desired III, and not the desired compound IV. One possible explanation could be the hydrolysis of the highly  compound IV. One possible explanation could be the hydrolysis of the highly reactive compound IV reactive compound IV back into the starting material III, a phenomenon we have observed in our  back into the starting material III, a phenomenon we have observed in our laboratory. laboratory.  Another interesting fact is that, when measuring mass spectrometry, we not only detected the peak Another interesting fact is that, when measuring mass spectrometry, we not only detected the  of compound IV, but also its methoxy form (compound V), which possibly occurs due to alcoholysis peak  of  compound  IV,  but  also  its  methoxy  form  (compound  V),  which  possibly  occurs  due  to  by methanol (the solvent in MS). We show this in Scheme 2. alcoholysis by methanol (the solvent in MS). We show this in Scheme 2.  Scheme Scheme 2. 2. The The formation formation of of 7 7-chlor ‐chloro o-4-methoxy-6-nitr ‐4‐methoxy‐6‐nitroquinazoline oquinazoline ((V V)) by by alcoholysis alcoholysis with with methanol methanol  in MS. in MS.  On the whole, in the synthesis of IV, our control of anhydrous reaction conditions and the On  the  whole,  in  the  synthesis  of  IV,  our  control  of  anhydrous  reaction  conditions  and  the  appropriate work-up procedures have made it feasible to synthesize and characterize this highly appropriate work‐up procedures have made it feasible to synthesize and characterize this highly  reactive compound for the first time. These data may be useful for further investigations in the reactive  compound  for  the  first  time.  These  data  may  be  useful  for  further  investigations  in  the  synthesis process improvement of afatinib, its analogs and other biologically active quinazoline based synthesis process improvement of afatinib, its analogs and other biologically active quinazoline based  1 13 compounds. All the mass, FT-IR, H-NMR and C-NMR spectra are presented in the Supplementary Material File. Molbank 2020, 2020, M1134 4 of 7 3. Materials and Methods 3.1. General Information The 2-amino-4-chlorobenzoic acid was purchased from Energy Chemical (Zhejiang, China) and used as received. Formamide (99.5%) was purchased from Scharlau Chemie (Barcelona, Spain). Thionyl chloride (99.5%) was purchased from Merck Schuchardt (Hohenbrunn, Germany). Dichloromethane (DCM, 99.5%), sufuric acid (98%) and N,N-dimethylformamide (DMF, 99.5%) was purchased from Xilong Scientific Co., Ltd. (Shantou, China). Fuming nitric acid (d 1.50 g/mL) was prepared by reaction of solid sodium nitrate and liquid sulfuric acid (98%), following distillation at b.p 82 C. The melting point was determined using a SRS EZ-Melt apparatus (Stanford Research Systems, Sunnyvale, CA, USA) and is uncorrected. MS was performed at a EVOQ Qube— (Bruker, Billerica, MA, USA) or an LTQ Orbitrap XL— (Thermo Scientific, Waltham, MA, USA) system. FT-IR spectra were recorded by a Perkin Elmer (Waltham, MA, USA) or Shimadzu (Kyoto, Japan) spectrometer. H- and C-NMR spectra were acquired with a 500 MHz Ascent spectrometer (Bruker, Billerica, MA, USA) using acetone-d , DMSO-d , or CDCl as the solvent. The reaction mixtures were monitored, and the 6 6 3 purity of all products was checked by thin-layer chromatography (TLC) on silica gel 60 F plates (Merck, Darmstadt, Germany). 3.2. Synthetic Procedure 3.2.1. Preparation of 7-Chloroquinazolin-4(3H)-one (II) The synthetic procedure for compound II was based on the method described in [39] with some modifications. A mixture of 2-amino-4-chlorobenzoic acid (I, 34.30 g, 0.20 mol, 1 equiv.), formamide (125.0 mL, 2.77 mol, 14 equiv.) was aerated with nitrogen, then stirred and refluxed for 1.5 h at 160 C (the reaction was monitored by TLC with a 9:1 DCM/methanol mixture as eluent). The reaction mixture was cooled to 80 C, then 500 mL of water was added. The mixture was cooled to 5 C in 1 h and filtered. The precipitate was washed with water and dried at 60 C to a ord 7-chloroquinazolin-4(3H)-one (II) as a light brown solid (29.71 g, 82.3%), which was used for the next step without further purification. M.p 251.0–253.0 C. R 0.60 (DCM/methanol, 9:1). MS (ESI , MeOH), m/z: found 181.2 and 183.2 + + 1 [M + H] , C H ON Cl requires [M + H] 181.0 and 183.0. FT-IR (KBr),  (cm ): 3031 (C-H); 2964, 8 5 2 max 2919 (N-H); 1714 (C=O); 1693 (C=N); 1655, 1606 (C=C). H-NMR (acetone-d ),  (ppm): 11.82 (br.s, 1H, H-3, NH); 8.17 (d, J = 8,5 Hz, 1H, H-5); 8.09 (s, 1H, H-2); 7.67 (d, J = 2.0 Hz, 1H, H-8); 7.51 (dd, J = 8.5 Hz, J = 2.0 Hz, 1H, H-6). C-NMR (acetone-d ),  (ppm): 160.6 (C-4); 151.2 (C-8a); 147.3 (C-2); 1 2 6 140.2 (C-7); 128.8 (C-5); 127.7 (C-6); 127.6 (C-8); 122.8 (C-4a). 3.2.2. Preparation of 7-Chloro-6-nitroquinazolin-4(3H)-one (7-Chloro-4-hydroxy-6-nitroquinazoline, III) The synthetic procedure for compound III was based on [30] with some modifications. Compound II (10.83 g, 0.060 mol) and sulfuric acid (120 mL) were added into a 500 mL two-neck round bottom flask. The mixture was cooled to 0 C on ice and stirred until dissolution. Fuming nitric acid (120 mL) was slowly added to the mixture at 0 C, and the mixture was stirred for 1.5 h at 30 C. After completion of reaction as indicated by TLC, 10% NaOH solution was slowly added to the reaction mixture until a precipitate was formed (pH ~7). The mixture was then filtered to furnish a light yellow solid (III). The compound was purified by redissolving in HCl (5M) and then neutralizing this solution with NaOH (10%) to pH 6–7 to furnish the pure precipitate which was then filtered, washed with water and dried at 60 C to furnish 7-chloro-6-nitroquinazolin-4(3H)-one (III) as a light yellow solid (11.46 g, 84.7%). M.p 263.5–265.0 C. R 0.34 (DCM/methanol, 20:1). MS (ESI , MeOH), m/z: found 225.9 + + 1 [M + H] , C H O N Cl requires [M + H] 225.9. FT-IR (KBr),  (cm ): 3452, 3215 (O-H); 3091, 8 4 3 3 max 3012 (C-H); 1696 (C=O); 1666, 1612 (C=N); 1523 (C=C); 1336 (NO ). H-NMR (DMSO-d ),  (ppm): 2 6 Molbank 2020, 2020, M1134 5 of 7 12.73 (br.s, 1H, OH); 8.64 (s, 1H, H-5); 8.27 (s, 1H, H-2); 7.97 (s, 1H, H-8). C-NMR (DMSO-d ),  (ppm): 159.3 (C-4); 151.5 (C-8a); 149.6 (C-2); 144.7 (C-6); 130.4 (C-7); 129.9 (C-5); 124.2 (C-8); 121.7 (C-4a). 3.2.3. Preparation of 4,7-Dichloro-6-nitroquinazoline (IV) The synthetic procedure for compound IV was based on [33] with some modifications. A mixture of compound III (6.09 g, 0.027 mol), thionyl chloride (48.0 mL, 0.661 mol) and N,N-dimethyl-formamide (0.25 mL) was melted and stirred at 100 C for 2 h. The reaction mixture was allowed to cool down and excess thionyl chloride was removed by rotary evaporation under reduced pressure. Toluene (40 mL) was added to the residue and the mixture was evaporated again to completely remove volatile matter. The precipitate was washed with diethyl ether and dried in the desiccator to obtain 4,7-dichloro-6-nitroquinazoline (IV) as a yellow solid (6.02 g, 91.3%). M.p: 269.0–270.5 C. R : 0.87 + + (DCM/methanol, 20:1). MS (ESI , MeOH), m/z: found 244.4 [M + H] , 240.00 and 241.99 [methoxy + 1 form]; C H O N Cl requires [M + H] 244.0 and 246.0. FT-IR (KBr),  (cm ): 3089 (C-H); 1726, max 8 3 2 3 2 1645, 1610 (C=N); 1546 (C=C); 1527, 1323 (NO ). H-NMR (CDCl ),  (ppm): 9.18 (s, 1H, H-2); 8.76 (s, 2 3 1H, H-5); 8.30 (s, 1H, H-8). C-NMR (CDCl ),  (ppm): 163.6 (C-4); 156.9 (C-2); 151.6 (C-8a); 147.5 (C-6); 132.8 (C-7); 132.2 (C-8); 123.5 (C-5); 122.1 (C-4a). Supplementary Materials: Spectral data of starting material I, intermediates II, III and title compound IV are available online, Figure S1: FT-IR spectrum of compound 2-amino-4-chlorobenzoic acid (I), Figure S2: 1 13 H-NMR spectrum of compound 2-amino-4-chlorobenzoic acid (I), Figure S3: C-NMR spectrum of compound 2-amino-4-chlorobenzoic acid (I), Figure S4: MS spectrum of compound 7-chloroquinazolin-4(3H)-one (II), Figure S5: FT-IR spectrum of compound 7-chloroquinazolin-4(3H)-one (II), Figure S6: H-NMR spectrum of compound 7-chloroquinazolin-4(3H)-one (II), Figure S7: C-NMR spectrum of compound 7-chloroquinazolin-4(3H)-one (II), Figure S8: MS spectrum of compound 7-chloro-6-nitroquinazolin-4(3H)-one (III), Figure S9: FT-IR spectrum of compound 7-chloro-6-nitroquinazolin-4(3H)-one (III), Figure S10: H-NMR spectrum of compound 7-chloro-6-nitroquinazolin-4(3H)-one (III), Figure S11: C-NMR spectrum of compound 7-chloro-6-nitroquinazolin-4(3H)-one (III), Figure S12: MS spectrum of compound 4,7-dichloro-6-nitroquinazoline (IV), Figure S13: FT-IR spectrum of compound 4,7-dichloro-6-nitroquinazoline (IV), Figure S14: H-NMR spectrum of compound 4,7-dichloro-6-nitroquinazoline (IV), Figure S15: C-NMR spectrum of compound 4,7-dichloro-6-nitroquinazoline (IV). 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Molbank – Multidisciplinary Digital Publishing Institute

Published: May 11, 2020

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