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Tuesday 31 January 2017

Dimethyl 4,4′-(Benzylazanediyl)(2E,2′E)-bis(but-2-enoate)

str5


Dimethyl 4,4′-(Benzylazanediyl)(2E,2′E)-bis(but-2-enoate)
STR1
IR (CHCl3): ν = 758, 1215, 1278, 1437, 1660, 1720, 2806, 2953, 3020, 3421 cm–1;

STR2
13C NMR (CDCl3, 100 MHz) δ: 51.53, 53.42, 58.37, 122.66, 127.28, 128.41, 128.55, 128.76, 138.24, 145.84, 166.58;

STR3
1H NMR (CDCl3, 400 MHz) δ: 3.23 (dd, J1 = 1.6 Hz, J2 = 6.0 Hz, 4H), 3.62 (s, 2H), 3.75 (s, 6H), 6.07 (dt, J1 = 1.6 Hz, J2 = 16.0 Hz, 2H), 6.97 (dt, J1 = 6.0 Hz, J2 = 16.0 Hz, 2H), 7.25–7.34 (m, 5H-merged with CDCl3 proton);

str4
TOFMS: [C17H21NO4 + H+]: calculated 304.1543, found 304.1703(100%).
str5

UPLC conditions were as follows for compound 11; Acquity Waters, column: BEH C18 (2.1 mm X 100 mm) 1.7 µm with mobile phases A (0.05% TFA in water) and B (acetonitrile). Detection was at 220 nm, flow was set at 0.4 mL/min, and the temperature was 30 °C (Run time: 9 min). Gradient: 0 min, A = 90%, B = 10%; 0.5 min, A = 90%, B = 10%; 6.0 min, A = 0%, B = 100%; 7.5 min, A = 0%, B = 100%; 7.6 min, A = 90%, B = 10%; 9.0 min, A = 90%, B = 10%.

Dimethyl 4,4′-(Benzylazanediyl)(2E,2′E)-bis(but-2-enoate) (11)
as a yellow oil. % purity: 93.4% (UPLC);
 
1H NMR (CDCl3, 400 MHz) δ: 3.23 (dd, J1 = 1.6 Hz, J2 = 6.0 Hz, 4H), 3.62 (s, 2H), 3.75 (s, 6H), 6.07 (dt, J1 = 1.6 Hz, J2 = 16.0 Hz, 2H), 6.97 (dt, J1 = 6.0 Hz, J2 = 16.0 Hz, 2H), 7.25–7.34 (m, 5H-merged with CDCl3 proton);
 
13C NMR (CDCl3, 100 MHz) δ: 51.53, 53.42, 58.37, 122.66, 127.28, 128.41, 128.55, 128.76, 138.24, 145.84, 166.58;
 
IR (CHCl3): ν = 758, 1215, 1278, 1437, 1660, 1720, 2806, 2953, 3020, 3421 cm–1;
 
TOFMS: [C17H21NO4 + H+]: calculated 304.1543, found 304.1703(100%).
 
 
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00399
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Sunday 29 January 2017

3,6−bis([1,1'−biphenyl]−4−ylmethyl)−1,2,4,5−tetra zine








3,6−bis([1,1'−biphenyl]−4−ylmethyl)−1,2,4,5−tetra zine




Synthesis of tetrazines from gem-difluoroalkenes under aerobic conditions at room temperature

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC03494B, Paper
Zheng Fang, Wen-Li Hu, De-Yong Liu, Chu-Yi Yu, Xiang-Guo Hu
A procedure for the synthesis of tetrazines from gem-difluoroalkenes under aerobic conditions has been developed.
An efficient and green procedure for the synthesis of tetrazines has been developed based on an old chemistry reported by Carboni in 1958. Both symmetric and asymmetric 3,6-disubstituted 1,2,4,5-tetrazines can be obtained in moderate to high yields from the corresponding gem-difluoroalkenes under aerobic conditions at room temperature. This work represents a rare example that ambient air is utilized as an oxidant for the synthesis of tetrazines.

Synthesis of tetrazines from gem-difluoroalkenes under aerobic conditions at room temperature

Zheng Fang,a   Wen-Li Hu,a   De-Yong Liu,a  Chu-Yi Yuab and   Xiang-Guo Hu*a  
*
Corresponding authors
a
National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, P. R. China
 E-mail: huxiangg@iccas.ac.cn
b
Beijing National Laboratory for Molecular Science (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC03494B

























http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC03494B?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract





3,6−bis([1,1'−biphenyl]−4−ylmethyl)−1,2,4,5−tetra zine (3a). (41 mg, 83%). purple solid;

m.p. 200−202°C;

IR(KBr) nmax/cm−1 2924, 2850, 1488, 1451, 1432, 1388, 851, 750;

1 H NMR (400 MHz, CDCl3) 7.55−7.33 (m, 18H), 4.65 (s, 4H).

 13C NMR (100 MHz, CDCl3) δ 169.2, 140.6, 140.4, 134.8, 129.7, 128.8, 127.6, 127.4, 127.1, 40.9;

HRMS (ESI): calcd. for C28H22N4 [M+H]+ 415.19172, found 415.19124.



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Monday 23 January 2017

1-Bromo-4-fluoro-2-((2-iodobenzyl)oxy)benzene

STR1
1-Bromo-4-fluoro-2-((2-iodobenzyl)oxy)benzene
CAS 1161931-51-6
STR1 STR2
Mp 89.8–92.3 °C.
IR (neat, ATR): 3072 (w), 1482 (s), 1451 (s), 1294 (s), 1294 (s) cm–1.
1H NMR (399 MHz, DMSO-d6) δ 5.12 (s, 2H), 6.81 (td, J = 8.49, 2.77 Hz, 1H), 7.14 (td, J = 7.64, 1.65 Hz, 1H), 7.18 (dd, J = 10.90, 2.82 Hz, 1H), 7.46 (td, J = 7.52, 0.92 Hz, 1H), 7.60 (dd, J = 7.64, 1.41 Hz, 1H), 7.62 (dd, J = 8.66, 6.23 Hz, 1H), 7.92 (dd, J = 7.83, 0.83 Hz, 1H).
13C NMR (100 MHz, DMSO-d6) δ 74.5, 99.2, 102.4 (d, J = 27.1 Hz), 105.8 (d, J = 3.4 Hz), 108.9 (d, J = 22.5 Hz), 128.5, 129.8, 130.3, 133.6 (d, J = 9.9 Hz), 138.0, 139.2, 155.4 (d, J = 10.7 Hz), 162.2 (d, J = 244.3 Hz).
GCMS: m/z [M]+ calcd for C13H9BrFIO: 405.88600; found: 405.88620.
1H AND 13C NMR PREDICT
STR1 STR2 STR3 str4

Org. Process Res. Dev., Article ASAP
 
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Brc2ccc(F)cc2OCc1ccccc1I

Friday 20 January 2017

2,6-diphenyl-5-methylpyrimidinone






Metal-free radical C-H methylation of pyrimidinones and pyridinones with dicumyl peroxide


Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC03355E, Communication
Pei-Zhi Zhang, Jian-An Li, Ling Zhang, Adedamola Shoberu, Jian-Ping Zou, Wei Zhang
A method for free radical methylation of pyrimidinones and pyridinones with dicumyl peroxide under metal-free conditions is introduced. A 50 g-scale reaction could be performed safely. The product was separated by crystallization and the byproducts were recovery by distillation

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC03355E?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

Metal-free radical C–H methylation of pyrimidinones and pyridinones with dicumyl peroxide

Pei-Zhi Zhang,a   Jian-An Li,a   Ling Zhang,a  Adedamola Shoberu,a   Jian-Ping Zou*a and  Wei Zhang*b  
*
Corresponding authors
a
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Soochow University, 199 Renai Street, Suzhou, China
 E-mail: jpzou@suda.edu.cn
b
Centre for Green Chemistry and Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, USA
 E-mail: wei2.zhang@umb.edu
Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC03355E


























A new method for free radical methylation of pyrimidinones and pyridinones with dicumyl peroxide (DCP) under metal-free conditions is introduced. A 50 g-scale reaction could be performed safely at the desired concentration. The reaction solvent and DCP derivative were readily recovered by distillation. The product was purified by crystallization to minimize the amount of waste.


2,6-diphenyl-5-methylpyrimidinone







Colorless solid, mp 258−260 °C, 73% yield (191 mg).

1H NMR (400 MHz, DMSO-d6): δ 12.85 (s, 1H), 8.17 (d, J = 7.1 Hz, 2H), 7.68 (d, J = 6.6 Hz, 2H), 7.53 (dd, J = 14.3, 6.8 Hz, 6H), 2.10 (s, 3H).

13C NMR (101 MHz, CDCl3): δ 161.15, 152.97, 138.68, 132.26, 131.62, 129.11, 129.02, 128.86, 128.15, 127.45, 119.09, 12.65.

 HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C17H15N2O 263.1184, found 263.1194.





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Thursday 19 January 2017

(3R)-4-[2-chloro-6-[[(R)-methylsulfinyl]methyl]pyrimidin-4-yl]-3-methyl-morpholine

STR1

(3R)-4-[2-chloro-6-[[(R)-methylsulfinyl]methyl]pyrimidin-4-yl]-3-methyl-morpholine
STR1 STR2
Synthesis of (3R)-4-[2-chloro-6-[[(R)-methylsulfinyl]methyl]pyrimidin-4-yl]-3-methyl-morpholine (10)
off-white solid (53.9 kg, 68.3% yield). 1H NMR (400 MHz, DMSO-d6, δ): 1.20 (d, J = 6.8 Hz, 3 H), 2.52 (m, 1 H), 2.63 (s, 3 H), 3.21 (m, 1 H), 3.44 (m, 1 H), 3.58 (dd, J = 11.6, 3.1 Hz, 1 H), 3.72 (d, J = 11.5 Hz, 1 H), 3.92 (m, 3 H), 4.07 (d, J = 12.4 Hz, 1 H), 6.80 (s, 1 H); Assay (HPLC) 99%; Assay (QNMR) 100%; Chiral purity (HPLC) (R,R)-diastereoisomer 99.6%, (R,S)-diastereoisomer 0.4%.

Abstract Image
A Baeyer–Villiger monooxygenase enzyme has been used to manufacture a chiral sulfoxide drug intermediate on a kilogram scale. This paper describes the evolution of the biocatalytic manufacturing process from the initial enzyme screen, development of a kilo lab process, to further optimization for plant scale manufacture. Efficient gas–liquid mass transfer of oxygen is key to obtaining a high yield.

Development and Scale-up of a Biocatalytic Process To Form a Chiral Sulfoxide

The Departments of Pharmaceutical Sciences and Pharmaceutical Technology and Development, AstraZeneca, Silk Road Business Park, Macclesfield, Cheshire SK10 2NA, United Kingdom
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00391
Publication Date (Web): January 4, 2017
Copyright © 2017 American Chemical Society
*Tel: +44 (0)1625-519149. E-mail: william.goundry@astrazeneca.com.
 
 
Figure
Examples of biologically active molecules containing a sulfoxide or sulfoximine: esomeprazole (3), aprikalim (4), oxisurane (5), OPC-29030 (6), ZD3638 (7), buthionine sulfoximine (8), and AZD6738 (9).

(±)-trans-ethyl 2-(3,4-difluorophenyl)Cyclopropanecarboxylate

STR1 STR2 STR3
(±)-trans-ethyl 2-(3,4-difluorophenyl)Cyclopropanecarboxylate
C12H12F2O2
GC-MS (EI) m/z: [M]+ calc. for C12H12F2O2 + : 226.08; found: 226.08.
δH (400 MHz, CDCl3): 1.25 (1H, ddd, 3 J 8.4 Hz, 3 J 6.4 Hz, 2 J 4.5 Hz , 3-H); 1.28 (3H, t 3 J 6.4 Hz CH3Ethyl) 1.57-1.62 (2H, m, 3 J 9.2 Hz, 3 J 5.2 Hz, 2 J 4.5 Hz, 3-H + H2O), 1.84 (1H, ddd, 3 J 8.5 Hz, 3 J 5.3 Hz, 3 J 4.3 Hz , 2-H), 2.47 (1H, ddd, 3 J 9.5 Hz, 3 J 6.4 Hz, 3 J 4.2 Hz , 1-H), 4.17 (2H, q, 3 J 6.3 Hz, CH2Ethyl) 6.81-6.87 (1H, m, 3 J 8.5 Hz, 4 J 7.6 Hz, 4 J 2.4 Hz, 6-H’ ), 6.88 (1H, ddd, 3 J 11.5 Hz, 4 J 7.6 Hz, 4 J 2.2 Hz, 2-H’) 7.06 (1H, dt, 3 J 10.3 Hz, 3 J 8.2 Hz. 5-H’).
δc (400 MHz, CDCl3): 14.27 (CH3Ethyl), 16.84 (3-C) 24.04 (1-C), 25.14 (d, 4 J 1.4, 2-C), 60.71 (CH2Ethyl), 114.74 (d, 2 J 19 Hz, 2-C’), 117.09 (d, 2 J 18 Hz, 5-C’), 122.25 (dd, 3 J 6.1 Hz, 4 J 3.4 Hz, 6- C’), 137.06 (dd, 3 J 6.1 Hz, 4 J 3.4 Hz, 1- C’), 149.2 (dd, 1 J 248 Hz, 2 J 13 Hz, 4-C’) 151.32 (dd, 1 J 249 Hz, 2 J 12.5 Hz, 3-C’) 172.87 (Ccarbonyl).
[ ] 20 a D = -381.9 (c 1.0 in EtOH) for (1R,2R)-3, ee = 95%
Abstract Image
In this study a batch reactor process is compared to a flow chemistry approach for lipase-catalyzed resolution of the cyclopropanecarboxylate ester (±)-3. (1R,2R)-3 is a precursor of the amine (1R,2S)-2 which is a key building block of the API ticagrelor. For both flow and batch operation, the biocatalyst could be recycled several times, whereas in the case of the flow process the reaction time was significantly reduced.

Comparison of a Batch and Flow Approach for the Lipase-Catalyzed Resolution of a Cyclopropanecarboxylate Ester, A Key Building Block for the Synthesis of Ticagrelor

 School of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, Manchester M1 7DN, United Kingdom
 Chemessentia, SRL - Via G. Bovio, 6-28100 Novara, Italy
§ Institute of Process Research and Development, School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, United Kingdom
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00346
Publication Date (Web): December 22, 2016
Copyright © 2016 American Chemical Society

Sunday 8 January 2017

(S,S,S)-2-aza-bicyclo-[3.3.0]- octane-3-carboxylic acid benzyl ester, Ramipril intermediate

Image result for (S,S,S)-2-azabicyclo-[3.3.0]- octane-3-carboxylic acid benzyl ester

93779-31-8 cas


Formula:C15H20ClNO2
Molecular Weight:281.78
cas 93779-29-4


(S,S,S)-2-aza-bicyclo-[3.3.0]- octane-3-carboxylic acid benzyl ester

(S,S,S)-2-aza-bicyclo-[3.3.0]- octane-3-carboxylic acid benzyl ester, white solid. Yield 33.7 g (95%); mp 178–180 8C (lit.[6c] mp 180 8C); [a]D 20 ¼ 240.0 (c ¼ 1, H2O) [lit.[6c] [a]D 30 ¼ 238.4 (c ¼ 1, H2O)];

 1H NMR (400 MHz, CDCl3) d 1.36–1.42 (m, 1H), 1.58–1.75 (m, 2H), 1.82–2.01 (m, 3H), 2.32–2.37 (m, 1H), 2.58 (dt, J ¼ 13.2, 8.4 Hz, 1H), 2.83–2.88 (m, 1H), 4.31 (td, J ¼ 8.0, 3.6 Hz, 1H), 4.43 (t, J ¼ 8.4 Hz, 1H), 5.20 (AB q,J ¼ 12.0 Hz, 2H), 7.33–7.37 (m, 5H); 13C NMR (50 MHz, DMSO) d 24.07, 29.60, 31.02, 33.45, 41.37, 60.11, 63.81, 66.99, 128.11, 128.28, 128.43, 135.14, 167.32; FT IR (KBr disc) 1758 cm21; MS: m/e 246 (Mþ).

(c) Teetz, V.;
Geiger, R.; Gaul, H. Synthesis of unnatural amino acids: (S,S,S)-2-azabicyclo-
[3.3.0]-octane-3-carboxylic acid. Tetrahedron Lett. 1984, 25, 4479.












Saturday 7 January 2017

Copper-catalyzed S-methylation of sulfonyl hydrazides with TBHP for the synthesis of methyl sulfones in water, 1-methyl-4-(methylsulfonyl)benzene

Copper-catalyzed S-methylation of sulfonyl hydrazides with TBHP for the synthesis of methyl sulfones in water

Green Chem., 2017, 19,112-116
DOI: 10.1039/C6GC03142K, Communication
Yu Yang, Yajie Bao, Qianqian Guan, Qi Sun, Zhenggen Zha, Zhiyong Wang
A copper-catalyzed S-methylation of sulfonyl hydrazides with TBHP for the synthesis of methyl sulfones in water.

A copper-catalyzed S-methylation of sulfonyl hydrazides with TBHP was efficiently developed, providing a variety of methyl sulfones with good to excellent yields. The reaction can be carried out in water smoothly without any ligand or additive under mild conditions and this catalyst-in-water can be recycled several times.

Copper-catalyzed S-methylation of sulfonyl hydrazides with TBHP for the synthesis of methyl sulfones in water

Yu Yang,a   Yajie Bao,a   Qianqian Guan,a   Qi Sun,a  Zhenggen Zhaa and   Zhiyong Wang*a  
*
Corresponding authors
a
Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Soft Matter Chemistry and Department of Chemistry & Collaborative Innovation Center of Suzhou Nano Science and Technology, University of Science and Technology of China, Hefei, P. R. China
 E-mail: zwang3@ustc.edu.cn
Fax: (+86) 551-360-3185
Green Chem., 2017,19, 112-116

DOI: 10.1039/C6GC03142K
























General procedures for the synthesis of Arylsulfonyl Hydrazides Arylsulfonyl hydrazides 2b-2s were prepared according to the literature procedure.[1] To a solution of an arylsulfonyl chloride (3.0 mmol) in tetrahyrdofuran (15 mL), was added hydrazine monohydrate (375 mg, 7.5 mmol) dropwise under nitrogen at 0 °C. After vigorous stirring for 30 min at 0 °C, the reaction mixture was added ethyl acetate (60 mL), and washed with saturated brine (3 x 10 mL). The organic layer was dried over sodium sulfate, filtered, concentrated and added to hexane (12 mL) over 5 min. The mixture was filtered, and the collected solid was dried in vacuum.


1-methyl-4-(methylsulfonyl)benzene (3aa).[1] The title compound was prepared according to the general procedure and purified by column chromatography (Petroleum Ether: EtOAc = 3:1) to give a white solid (88 % yield).

1H NMR (400 MHz, CDCl3): 7.84-7.82 (d, 2H, J = 8.0 Hz), 7.38- 7.36 (d, 2H, J = 8.0 Hz ), 3.04 (s, 3H), 2.46 ( s, 3H );

13C NMR (100 MHz, CDCl3): 144.7, 137.7, 130.0, 127.3, 44.6, 21.6

Reference [1] G. Yuan, J. Zheng, X. Gao, X. Li, L. Huang, H. Chen and H. Jiang, Chem. Commun., 2012, 48, 7513.


1H NMR (400 MHz, CDCl3): 7.84-7.82 (d, 2H, J = 8.0 Hz), 7.38- 7.36 (d, 2H, J = 8.0 Hz ), 3.04 (s, 3H), 2.46 ( s, 3H );



13C NMR (100 MHz, CDCl3): 144.7, 137.7, 130.0, 127.3, 44.6, 21.6




Image result for 1-methyl-4-(methylsulfonyl)benzene nmr















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