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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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Friday 6 January 2017

A catalyst-free 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines and 3-nitroindoles: an easy access to five-ring-fused tetrahydroisoquinolines




Graphical abstract: A catalyst-free 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines and 3-nitroindoles: an easy access to five-ring-fused tetrahydroisoquinolines

We have reported herein a catalyst-free 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines and 3-nitroindoles by which a series of five-ring-fused tetrahydroisoquinolines featuring an indoline scaffold were obtained as single diastereomers in moderate to high yields without any additives under mild conditions. Moreover, the current method provides a novel and convenient approach for the efficient incorporation of two biologically important scaffolds (tetrahydroisoquinoline and indoline).

A catalyst-free 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines and 3-nitroindoles: an easy access to five-ring-fused tetrahydroisoquinolines

Xihong Liu,a   Dongxu Yang,a   Kezhou Wang,a  Jinlong Zhanga and   Rui Wang*ab  
*Corresponding authors
aSchool of Life Sciences, Institute of Biochemistry and Molecular Biology, Lanzhou University, Lanzhou 730000, P. R. China
E-mail: wangrui@lzu.edu.cn
bState Key Laboratory of Chiroscience, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, P. R. China
E-mail: bcrwang@polyu.edu.hk
Green Chem., 2017,19, 82-87
DOI: 10.1039/C6GC02517J

 ethyl 13b-nitro-8-tosyl-8,8a,13b,13c-tetrahydro-5H-indolo[2',3':3,4]pyrazolo[5,1- a]isoquinoline-9(6H)-carboxylate: White solid, m.p. 153 – 154 oC; 94% yield;

1H NMR (300 MHz, CDCl3) δ 7.86 (d, J = 8.2 Hz, 2H), 7.78 (d, J = 7.9 Hz, 1H), 7.30 – 7.13 (m, 5H), 7.1 (s, 1H), 7.05 – 6.94 (m, 1H), 6.94 – 6.87 (m, 1H), 6.59 (t, J = 7.6 Hz, 3H), 6.28 (d, J = 7.6 Hz, 1H), 4.78 (s, 1H), 4.37 (q, J = 7.1 Hz, 2H), 2.80 – 2.58 (m, 2H), 2.33 (s, 3H), 2.31 – 2.11 (m, 2H), 1.41 (t, J = 7.1 Hz, 3H) ppm;

13C NMR (75 MHz, CDCl3) δ 152.1, 144.6, 142.6, 134.0, 132.1, 129.3, 129.0, 128.7, 128.3, 127.5, 127.3, 126.2, 122.8, 121.1, 115.5, 104.5, 84.9, 70.7, 62.8, 48.5, 29.1, 21. 6, 14.3 ppm;

HRMS (ESI): C27H26N4NaO6S [M + Na]+ calcd: 557.1465, found: 557.1476. 
“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent
 
/////////// catalyst-free,  1,3-dipolar cycloaddition, C,N-cyclic azomethine imines,  3-nitroindoles,  five-ring-fused tetrahydroisoquinolines

Methyl (Z)-11-[(3-Hydroxy)propylidene]-6,11-dihydrobenz[b,e]oxepin-2-acetate

Figure imgf000014_0002
E/Z
White solid; Ή NMR (200 MHz, CDC13 + CC14): δ 2.38-2.49 ( m,0.8H, E- Form), 2.63-2.73 ( m,1.2H, Z-Form), 3.53 (s, 2H), 3.68 (s, 3H), 3.75 (m, 0.8H, E-Form), 3.81 (t, J=6.3 Hz, 1.2H), 5.19 (brs, 2H), 5.73 (t, J=7.8 Hz, 0.6H, Z-Form), 6.06 (t, J=7.8 Hz, 0.4H, E-Form), 6.70 (d, J=8.2 Hz, 0.4 H, E-Form), 6.79 (d, J=8.2 Hz, 0.6 H, Z- Form), 7.00-7.34 (m, 6H), HRMS m/r. Calculated for C20H2,O4-325.1434, observed- 325.1437.

CLIP 2
SCHEMBL18101051.png
Methyl (Z)-11-[(3-Hydroxy)propylidene]-6,11-dihydrobenz[b,e]oxepin-2-acetate 
916243-39-5  cas
mf C20 H20 O4
Dibenz[b,​e]​oxepin-​2-​acetic acid, 6,​11-​dihydro-​11-​(3-​hydroxypropylidene)​-​, methyl ester, (11Z)​-
Molecular Weight, 324.37
 white colorless crystal;
 
1H NMR (CDCl3, 300 MHz) δ 7.34–7.23 (m, 4H), 7.17 (d, J = 2.2 Hz, 1H), 7.04 (dd, J = 8.4, 2.2 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.74 (t, J = 7.5 Hz, 1H), 5.18 (brs, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.69 (s, 3H), 3.53 (s, 2H), 2.68 (dt, J = 7.5, 6.1 Hz, 2H);
 
13C NMR (CDCl3, 75 MHz): δ 172.4, 154.6, 145.3, 141.4, 133.6, 132.1, 130.0, 129.1, 127.5, 126.2, 125.7, 124.0, 119.7, 70.5, 62.6, 52.1, 40.1, 33.3;
 
MS ESI (+) m/z 325 [M + H]+.
Org. Process Res. Dev.201216 (2), pp 225–231
DOI: 10.1021/op200312m
 
CLIP 3
Synthesis 2013; 45(24): 3399-3403
DOI: 10.1055/s-0033-1340008
 
 
 
str1
 
 
CLICK ON IMAGE
 
 
1H AND 13C NMR PREDICT
 
 
 
“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent
 
//////O=C(OC)Cc1ccc2OCc3ccccc3C(=C\CCO)\c2c1

Monday 2 January 2017

4-(2-Hydroxyethyl)-1,3-dihydro-2H-indol-2-one


str1
13C NMR (DMSO-d6, 100 MHz): δ = 35.2, 36.8, 61.5, 107.4, 122.5, 125.4, 127.8, 136.1, 143.8, 176.9;

1H NMR
str1
1H NMR (DMSO-d6, 400 MHz): δ = 2.64 (t, J = 6.8 Hz, 2H), 3.44 (s, 2H), 3.59 (q, J = 6.8 Hz, 2H), 4.62 (t, J = 5.2 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 10.30 (s, 1H);

4-(2-Hydroxyethyl)-1,3-dihydro-2H-indol-2-one (13)
..............as a white solid with 99% purity by HPLC (retention time: 19.0 min).
 
1H NMR (DMSO-d6, 400 MHz): δ = 2.64 (t, J = 6.8 Hz, 2H), 3.44 (s, 2H), 3.59 (q, J = 6.8 Hz, 2H), 4.62 (t, J = 5.2 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 10.30 (s, 1H);
 
13C NMR (DMSO-d6, 100 MHz): δ = 35.2, 36.8, 61.5, 107.4, 122.5, 125.4, 127.8, 136.1, 143.8, 176.9;
 
ESI-MS (m/z) 178 [M + H]+. Anal. Calcd for C10H11NO2: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.73; H, 6.20; N, 7.82.
 
 
Abstract Image

A new and efficient manufacturing technology is disclosed in the present work for the preparation of 4-(2-hydroxyethyl)-1,3-dihydro-2H-indol-2-one, which is a key intermediate for ropinirole hydrochloride. The whole process gives the target molecule in 71% overall yield with 99% purity. In the final step, a novel nitro reduction/ring-closing/debenzylation takes place in one pot. All the intermediates can be used directly for the next step without purification in this process.
Org. Process Res. Dev.201317 (4), pp 714–717
 
1H NMR PREDICT
DOI: 10.1021/op400024astr1 str2
 
13C NMR PREDICT
 
str1 str2
“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent
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Sunday 1 January 2017

Rhodium-catalyzed regiospecific C-H ortho-phenylation of benzoic acids with Cu/air as an oxidant





Rhodium-catalyzed regiospecific C-H ortho-phenylation of benzoic acids with Cu/air as an oxidant


Org. Chem. Front., 2017, Advance Article
DOI: 10.1039/C6QO00663A, Research Article
Shiguang Li, Guo-Jun Deng, Feifei Yin, Chao-Jun Li, Hang Gong
An efficient and practical synthetic approach for the regiospecific C-H ortho-phenylation of aromatic carboxylic acids in the absence of silver.

Rhodium-catalyzed regiospecific C–H ortho-phenylation of benzoic acids with Cu/air as an oxidant

Shiguang Li,a   Guo-Jun Deng,a   Feifei Yin,a  Chao-Jun Li*b and   Hang Gong*a  *
Corresponding authors
a
The Key Laboratory of Environmentally Friendly Chemistry and Application of the Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan 411105, China
 E-mail: hgong@xtu.edu.cn
b
Department of Chemistry and FQRNT Centre for Green Chemistry and Catalysis, McGill University, 801 Sherbrooke St. W., Montreal, Canada
 E-mail: cj.li@mcgill.ca
Org. Chem. Front., 2017, Advance Article

DOI: 10.1039/C6QO00663A
























http://pubs.rsc.org/en/Content/ArticleLanding/2017/QO/C6QO00663A#!divAbstract

The development of an efficient and practical synthetic approach for the regiospecific C–H ortho-phenylation of aromatic carboxylic acids without the use of silver or costly coupling partners is reported. The rhodium-catalyzed C–H phenylation proceeded in the presence of Cu/air as a terminal oxidant. In most cases, numerous inactivated benzoic acids could couple with low-cost NaBPh4 to obtain good to excellent yields.

A solution of aromatic acid 1a (27.2 mg, 0.2 mmol), NaBPh4 (0.27 g, 0.8 mmol), KF (46 mg, 0.8 mmol), [Rh(nbd)Cl]2 (9.2 mg, 0.02 mmol) and CuBr2 (4.5 mg, 0.02 mmol) in chlorobenzene (1.2 mL) was stirred in a sealed tube under air at 150 oC for 24 h. The reaction mixture was then cooled to room temperature and acidified by dilute aqueous HCl to pH<3, and then the solvent was evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (TLC) on silica gel with petroleum ether and ethyl acetate as eluent to give the pure product 2a.


2a White solid; Yield 86%; Mp 132-134 oC [lit1 mp 133-135oC];


IR (neat) νmax 3057, 2917, 2849, 2627, 1682, 1461, 1133, 1064, 1000, 759, 696 cm-1;

1H NMR (400 MHz, CDCl3): δ = 7.35-7.40 (m, 6H), 7.23 (m, 2H), 2.45 (s, 3H);

13C NMR (100 MHz, CDCl3) δ = 174.5, 140.7, 140.2, 135.5, 132.2, 129.7, 129.2, 128.4 (2C), 127.6, 127.5, 20.0;

HRMS (ESI) m/z calcd for C14H13O2 213.0910, found [M+H] + 213.0912.


1H NMR (400 MHz, CDCl3): δ = 7.35-7.40 (m, 6H), 7.23 (m, 2H), 2.45 (s, 3H);



13C NMR (100 MHz, CDCl3) δ = 174.5, 140.7, 140.2, 135.5, 132.2, 129.7, 129.2, 128.4 (2C), 127.6, 127.5, 20.0;

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