Copper-catalyzed pyrrole synthesis from 3,6-dihydro-1,2-oxazines

Copper-catalyzed pyrrole synthesis from 3,6-dihydro-1,2-oxazines

 

Naoki Yasukawa,^a  Marina Kuwata,^a  Takuya Imai,^a  Yasunari Monguchi,^a  Hironao Sajiki*^a  and Yoshinari Sawama*^a 

 Author affiliations

*Corresponding authors

^aLaboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
E-mail: sajiki@gifu-pu.ac.jp, sawama@gifu-pu.ac.jp
Fax: +81-58-230-8109

Abstract

Highly-functionalized pyrroles could be effectively synthesized from 3,6-dihydro-1,2-oxazines using a heterogeneous copper on carbon (Cu/C) under neat heating conditions. Furthermore, the in situ formation of 3,6-dihydro-1,2-oxazines via the hetero Diels–Alder reaction between nitroso dienophiles and 1,3-dienes and the following Cu/C-catalyzed pyrrole synthesis also provided the corresponding pyrrole derivatives in a one-pot manner.

Brown solid; M. p. 107–108 o C;
IR (ATR) cm-1 : 3064, 2923, 2851, 1687, 1596, 1562, 1541, 1498, 1488, 1459, 1451, 1422, 1390, 1343, 1319, 1256, 1187, 1098, 1073, 1053, 1037, 1009;
1 H NMR (500 MHz, CDCl3): δ 7.37–7.28 (m, 5H), 7.17 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 6.95 (dd, J = 2.0, 3.0 Hz, 1H), 6.45 (dd, J = 2.0, 3.0 Hz, 1H), 6.37 (dd, J = 3.0, 3.0 Hz, 1H);
13C NMR (125 MHz, CDCl3): δ 140.19, 132.52, 131.85, 131.19, 129.65, 129.14, 126.84, 125.69, 124.83, 120.24, 110.97, 109.38;
ESI-HRMS m/z: 298.0231([M+H+ ]); Calcd for C16H13NBr: 298.0226.
 

//////////3,6-dihydro-1,2-oxazines

TAFENOQUINE, タフェノキン

1 H NMR (300 MHz, CDCl3, TMS) d (ppm): 7.32 (q, 1H, J ¼ 18 Hz), 7.21 (d, 1H, J ¼ 6 Hz), 7.07 (s, 1H), 6.94 (d, 1H, J ¼ 6 Hz), 6.64 (s, 1H), 6.50 (s, 1H), 5.84 (d, 1H, J ¼ 6 Hz), 4.00 (s, 3H), 3.79 (s, 3H), 3.66 (s, 1H), 2.78 (d, 2H, J ¼ 6 Hz), 2.55 (s, 3H), 1.69 (dd, 6H, J ¼ 6 Hz, J ¼ 9 Hz), 1.35 (d, 3H, J ¼ 6 Hz). 

13C NMR (100 MHz, CDCl3, TMS) d (ppm): 159.64, 148.961, 146.339, 142.010, 132.085, 131.760, 131.007, 129.968, 126.917, 125.344, 122.636, 120.681, 118.006, 115.256, 112.052, 94.996, 56.989, 52.870, 48.446, 42.248, 34.439, 30.130, 23.103, 20.833. 

MS (m/z): M+ calcd for C24H28F3N3O3: 463.2083; found (ESI): 464.17 (M + H)+ .

PAPER

http://pubs.rsc.org/en/Content/ArticleLanding/2017/RA/C7RA04867J#!divAbstract

1H NMR PREDICT

13C NMR PREDICT

Synthesis   https://newdrugapprovals.org/2018/07/25/tafenoquine-%E3%82%BF%E3%83%95%E3%82%A7%E3%83%8E%E3%82%AD%E3%83%B3/

2,6-Dihydroxy-4-methylbenzoic Acid

1H NMR

1H NMR (298.2 K, DMSO-d6, 300 MHz, δ in ppm): C 10.87 (br. s, 3 H, H17,12,11), B 6.21 (d, 2 H, J = 0.57 Hz, H14,13), A 2.17 (s, 3 H, H9).

13C NMR

13C NMR (298.2 K, DMSO-d6, 300 MHz, δ in ppm): 9 21.57(C9), 2 98.95 (C2), 1/3 107.98 (C1,3). ), 5 146.29 (C5), 4/6 160.68 (C4,6), 10 172.31 (C10).

In this case study the regioselective enzymatic carboxylation of 3,5-dihydroxytoluene (orcinol) using the nonoxidative 2,3-dihydroxybenzoic acid decarboxylase from Aspergillus oryzae (2,3-DHBD_Ao), followed by an adsorbent-based downstream approach, has been investigated. The product 2,6-dihydroxy-4-methylbenzoic acid (DHMBA) was herein purified by an adsorption–desorption cycle and subsequently obtained with purities >99% without a full elimination of the excess bicarbonate from its reaction solution. Ten adsorbent resins were studied in respect of their ability to recover the product from the reaction solution, whereas the strong anion exchange resin Dowex 1x2 in its chloride form showed affinities >99%, even at bicarbonate concentrations of >3 mol·L–1. Desorption from loaded resin was carried out by a 2 mol·L–1 HCl/acetone mixture, followed by product crystallization during acetone evaporation. This presented concept does not require a final column preparation step and improves the overall atom efficiency of the biocatalytic reaction system.

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00104

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.8b00104

//////////////

National award to Anthony Melvin Crasto for contribution to Pharma society from Times Network for Excellence in HEALTHCARE) | 5th July, 2018 | Taj Lands End, Mumbai, India

DR ANTHONY MEVIN CRASTO Conferred prestigious individual national award at function for contribution to Pharma society from Times Network, National Awards for Marketing Excellence ( For Excellence in HEALTHCARE) | 5th July, 2018 | Taj Lands End, Mumbai India

 

////////////National award,  contribution to Pharma society, Times Network, Excellence in HEALTHCARE,  5th July, 2018, Taj Lands End, Mumbai,  India, ANTHONY CRASTO

#hotpersoninawheelchair
#worlddrugtracker

A detailed study of literature-known and novel S-containing pincer-type ligands for ruthenium-catalyzed homogeneous hydrogenation and dehydrogenation reactions was carried out. The scope and limitations of these catalysts were carefully investigated, and it was shown that simple bench-stable SNS–Ru complexes can be used to facilitate the hydrogenation of a variety of different substrates at a maximum H₂ pressure of 20 bar under operationally simple, easy to scale up, glovebox-free conditions by using starting materials and reagents that do not require any special purification prior to use. It was also shown that such complexes can be used to catalyze the dehydrogenative coupling of alcohols and amines to get amides as well as for the dehydrogenative dimerization of alcohols to esters.

SNS-Ligands for Ru-Catalyzed Homogeneous Hydrogenation and Dehydrogenation Reactions

Johannes Schörgenhumer^†, Axel Zimmermann*^‡, and Mario Waser*^† 

^†Institute of Organic Chemistry, Johannes Kepler University Linz, Altenbergerstr. 69, 4040 Linz, Austria

^‡Patheon Austria, part of Thermo Fisher Scientific, St. Peterstr. 25, 4020 Linz, Austria

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00142

*E-mail: mario.waser@jku.at. Tel: +4373224685411. Fax: +437322468545402., *E-mail: axel.zimmermann@patheon.com.

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00142

 

Complex IIb:

Method A was applied, using 180 mg of ligand 11b (1.09 mmol) and 993 mg of 27 (1.04 mmol) to give the complex IIb as yellow powder in 83% yield. The complex was isolated as mixture of three isomers.

 

1 H-NMR (CDCl3, 300 MHz, 298 K), δ / ppm: 7.75-7.50 (m, 10H), 7.41-7.25 (m, 16H), 5.05 (bs, 1H), 3.73-2.9 (m, 9H), 2.71-2.41 (m, 3H), 1.89-1.71 (m, 1H), 1.64-1.54 (m, 12H);

 

31P-NMR (CDCl3, 121 MHz, 298 K), δ / ppm: 50.6 (59%), 49.0 (24%), 47.6 (17%);

 

13C NMR (75 MHz, CDCl3, 298 K): δ / ppm = 137.1 (d, J = 39.5 Hz), 134.6 (d, J = 10.0 Hz), 129.3, 127.8 (d, J = 8.9 Hz), 49.0, 42.2, 17.7;

HRMS (ESI+): m/z calcd for C24H30ClNPRuS2 [M - Cl]+: 564.0284; found: 564.0272.

1 H-NMR (CDCl3, 300 MHz, 298 K), δ / ppm: 7.75-7.50 (m, 10H), 7.41-7.25 (m, 16H), 5.05 (bs, 1H), 3.73-2.9 (m, 9H), 2.71-2.41 (m, 3H), 1.89-1.71 (m, 1H), 1.64-1.54 (m, 12H);

31P-NMR (CDCl3, 121 MHz, 298 K), δ / ppm: 50.6 (59%), 49.0 (24%), 47.6 (17%);

13C NMR (75 MHz, CDCl3, 298 K): δ / ppm = 137.1 (d, J = 39.5 Hz), 134.6 (d, J = 10.0 Hz), 129.3, 127.8 (d, J = 8.9 Hz), 49.0, 42.2, 17.7;

 

 

///////////////SNS-Ligands, Ru-Catalyzed,  Homogeneous Hydrogenation, Dehydrogenation Reactions

A borrowing hydrogen methodology: palladium-catalyzed dehydrative N-benzylation of 2-aminopyridines in water

A borrowing hydrogen methodology: palladium-catalyzed dehydrative N-benzylation of 2-aminopyridines in water

 

Hidemasa Hikawa,*^a  Hirokazu Imamura,^a  Shoko Kikkawa^a  and  Isao Azumaya*^a 

 Author affiliations

*Corresponding authors

^aFaculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Japan
E-mail: hidemasa.hikawa@phar.toho-u.ac.jp, isao.azumaya@phar.toho-u.ac.jp

Isao Azumaya

Abstract

We demonstrate a greener borrowing hydrogen methodology using the π-benzylpalladium system, which offers an efficient and environmentally friendly dehydrative N-monobenzylation of 2-aminopyridines with benzylic alcohols in the absence of base. The crossover experiment using benzyl-α,α-d₂ alcohol and 3-methylbenzyl alcohol afforded H/D scrambled products, suggesting that the dehydrative N-benzylation in our catalytic system involves a borrowing hydrogen pathway. KIE experiments show that C–H bond cleavage at the benzylic position of benzyl alcohol is involved in the rate-determining step (KIE = 2.9). This simple base-free protocol can be achieved under mild conditions in an atom-economic process, affording the desired products in moderate to excellent yields.
N-Benzylpyridin-2-amine 3a 1 Yield 165 mg (90%) as a white solid; mp 90-91 C; IR (KBr) (cm-1) 3226, 3029, 1600, 1575; 1H NMR (400 MHz, CDCl3):  4.50 (d, J=5.7 Hz, 2H), 4.95 (brs, 1H), 6.36 (dt, J=8.5, 0.9 Hz, 1H), 6.58 (ddd, J=7.1, 5.0, 0.9 Hz, 1H), 7.23-7.36 (m, 4H), 7.39 (dd, J=8.7, 7.1, 1.8 Hz, 1H), 8.09 (ddd, J=5.0, 1.8, 0.9 Hz, 2H); 13C-NMR (100 MHz, CDCl3): 46.3, 106.8, 113.1, 127.2, 127.4, 128.6, 137.5, 139.2, 148.2, 158.6; MS (FAB): m/z 185 [M+H]+ .

/////////////borrowing hydrogen methodology, palladium-catalyzed,  dehydrative N-benzylation, 2-aminopyridines,

CH4630808

CH4630808
syn   https://newdrugapprovals.org/2018/07/02/ch4630808/

Paper

Development of a Kilogram-Scale Synthesis of a Novel Anti-HCV Agent, CH4930808

CH4630808 corrected

Tsuyoshi Haneishi*† , Yoshiaki Kato‡, Hiroshi Fukuda†, Tomoyuki Shimamura‡, Takemi Tanokura‡, Akira Hiraide‡, Kaichiro Koyama‡, Masato Fudesaka‡, Kenji Maeda‡, Nobuyuki Nakata‡, Masahiro Nagase‡, Takahiko Yabuzaki‡, Hiroaki Takao‡, Masaharu Kigawa‡, Hitoshi Shimizu‡, and Makoto Shimizu§

† Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan

‡ Pharmaceutical Technology Division, Chugai Pharmaceutical Co., Ltd., 5-5-1 Ukima, Kita-ku, Tokyo 115-8543, Japan

§ Department of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu, Mie 514-8507, Japan

Org. Process Res. Dev., 2018, 22 (2), pp 236–240

DOI: 10.1021/acs.oprd.7b00383

*E-mail: haneishitys@chugai-pharm.co.jp. Tel.: +81-550-87-9102. Fax: +81-550-87-5326.

Abstract

Herein, we report the kilogram-scale synthesis of CH4930808 (1) CH 4630808 CORRECTED, a novel anti-hepatitis C virus agent. While pursuing improved productivity using many through-process strategies, we conducted scrupulous impurity control. Finally, we successfully developed a practical and scalable process for the synthesis of (1·1.5Na·2.5H2O), by which we prepared 3.28 kg of the active pharmaceutical ingredient for clinical studies

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.7b00383/suppl_file/op7b00383_si_001.pdf

1H-NMR and 13C-NMR spectra of compound 5·HCl S 3– S 4

1H-NMR spectra of compound 1·1.5 Na·2.5 H2O S 5

13C-NMR spectra compound 1·1.5 Na·2.5 H2O S 6

1H-COSY spectra of compound 1·1.5 Na·2.5 H2O S 7 – S 8

DEPT spectra of compound 1·1.5 Na·2.5 H2O S 9 – S 10

HMBC spectra of compound 1·1.5 Na·2.5 H2O S 11 – S 17

MASS

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