BOSENTAN PRECURSOR

Molecular Formula:	C57H60N10O12S2
Molecular Weight:	1141.285 g/mol

4-tert-butyl-N-[6-[[5-[[6-[(4-tert-butylphenyl)sulfonylamino]-5-(2-methoxyphenoxy)-2-pyrimidin-2-ylpyrimidin-4-yl]oxymethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]-5-(2-methoxyphenoxy)-2-pyrimidin-2-ylpyrimidin-4-yl]benzenesulfonamide

N,N′-(6,6′-(2,2-Dimethyl-1,3-dioxolane-4,5-diyl)bis- (methylene)bis(oxy)bis(5-(2-methoxy phenoxy)-2,2′-bipyrimidine-6,4-diyl))bis(4-tert-butylbenzenesulfonamide)

Mp: 72−74 °C. 

1 H NMR (400 MHz, CDCl3): δ 1.25 (6H, s), 1.29 (18H, s), 3.84−3.90 (4H, m), 4.27−4.31 (2H, m), 6.84−6.87 (3H, t), 6.97−7.00 (2H, dd), 7.09−7.13 (3H, t), 7.43−7.45 (10H, m), 9.0−9.01 (4H, d), 8.43 (2H, br s); 

13C NMR (100 MHz, CDCl3): δ 25.88, 30.02, 34.10, 55.01, 61.53, 77.36, 108.43, 111.4, 118.73, 120.4, 124.09, 124.34, 126.67, 127.38, 128.35, 135.30, 138.25, 144.74, 148.62, 150.99, 156.07, 156.71, 160.56; 

MS: m/z 1142.2 (M + H); 

Elem. Anal: Found: C 59.87, H 5.20, N 12.38; Calcd for C57H60N10O12S2: C 59.99, H 5.30, N 12.27

A new and efficient synthetic process for the synthesis of an endothelin receptor antagonist, bosentan monohydrate, involves the coupling of p-tert-butyl-N-(6-chloro-5-(2-methoxy phenoxy)-2,2′-bipyrimidin-4-yl)benzenesulfonamide (7) with (2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethanol (14) as a key step. This new process provides desired bosentan monohydrate (1) with better quality and yields. Our new methodology consists of technical innovations/improvements which totally eliminate the probability for the formation of critical impurities such as pyrimidinone 8, dimer impurity 9, and N-alkylated impurity 13 in the final drug substance.

1H NMR PREDICT

13 C NMR PREDICT

Org. Process Res. Dev., 2013, 17 (8), pp 1021–1026

DOI: 10.1021/op400100s

http://pubs.acs.org/doi/suppl/10.1021/op400100s

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CC1(OC(C(O1)COC2=NC(=NC(=C2OC3=CC=CC=C3OC)NS(=O)(=O)C4=CC=C(C=C4)C(C)(C)C)C5=NC=CC=N5)COC6=NC(=NC(=C6OC7=CC=CC=C7OC)NS(=O)(=O)C8=CC=C(C=C8)C(C)(C)C)C9=NC=CC=N9)C

Heck–Matsuda Reaction in Flow

Product 3 was obtained as a mixture of diastereomers (58:42). The NMR data are consistent with literature precedent.20a

Major diastereomer: 1H NMR (300 MHz, CDCl3) δ (ppm) 7.25-7.28 (m, 2H), 7.14-7.17 (m, 2H), 5.14 (dd, 1H, J = 2.5, 5.8 Hz), 4.29 (t, 1H, J = 8.3 Hz), 3.79 (dd, 1H, J = 6.9, 8.4 Hz), 3.54-3.62 (m, 1H), 3.38 (s, 3H), 2.32 (dd, 1H, J = 7.7, 12.9 Hz), 2.04 (ddd, 1H, J = 5.1, 9.3, 13.1 Hz);
Minor diastereomer: 1H NMR (300 MHz, CDCl3) δ 7.25-7.28 (m, 4H), 5.16 (d, 1H, J = 4.4 Hz), 4.17 (t, 1H, J = 8.1 Hz), 3.72 (dd, 1H, J = 8.5, 9.7 Hz), 3.42 (s, 3H), 3.32-3.36 (m, 1H), 2.59 (ddd, 1H, J = 5.5, 10.3, 13.7 Hz), 1.91 (ddd, 1H, J = 2.4, 7.7, 10.2 Hz);

13C NMR (75 MHz, CDCl3) δ (ppm) 141.4, 140.0, 132.4, 132.3, 129.1, 128.7, 128.7, 128.5, 105.7, 105.4, 73.7, 73.0, 54.9, 54.7, 43.6, 42.1, 41.4, 41.1.
(20) (a) Oliveira, C. C.; Angnes, R. A.; Correia, C. R. D. J. Org. Chem. 2013, 78, 4373. (b) Oliveira, C. C.; Pfaltz, A.; Correia, C. R. D. Angew. Chem. Int. Ed. 2015, 54, 14036.

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00310

The optimization of a palladium-catalyzed Heck–Matsuda reaction using an optimization algorithm is presented. We modified and implemented the Nelder–Mead method in order to perform constrained optimizations in a multidimensional space. We illustrated the power of our modified algorithm through the optimization of a multivariable reaction involving the arylation of a deactivated olefin with an arenediazonium salt. The great flexibility of our optimization method allows to fine-tune experimental conditions according to three different objective functions: maximum yield, highest throughput, and lowest production cost. The beneficial properties of flow reactors associated with the power of intelligent algorithms for the fine-tuning of experimental parameters allowed the reaction to proceed in astonishingly simple conditions unable to promote the coupling through traditional batch chemistry.

NMR PREDICT

13C NMR PREDICT

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2-chloro-N-(2-phenylethyl)acetamide

2-Chloro-N-(2-phenylethyl)acetamide

• Molecular FormulaC₁₀H₁₂ClNO
• Average mass197.661 

Acetamide, 2-chloro-N-(2-phenylethyl)- 

n-(2-phenylethyl) 2-chloroacetamide

[13156-95-1]

PAPER

HETEROCYCLES

An International Journal for Reviews and Communications in Heterocyclic Chemistry

Web Edition ISSN: 1881-0942

Published online: 11th October, 2016

Paper | Regular issue | Prepress

DOI: 10.3987/COM-16-13538

■ A Concise and Highly Efficient Synthesis of Praziquantel as an Anthelmintic Drug

Zhezhou Yang, Lin Zhang, Huirong Jiao, Rusheng Bao, Weiwei Xu, and Fuli Zhang*

*Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, China

Abstract

A concise and practical synthesis of praziquantel as anthelmintic drug is described. The key steps include a monoalkylation of ethanolamine for the preparation of 2-(2-hydroxyethylamino)-N-phenethylacetamide and a mild oxidation protocol with SO3-Py/DMSO as oxidant to transform alcohol into the corresponding aza-acetal. The telescoped synthesis is composed of five steps without purification of the intermediates, providing an overall yield of 80% with 99.8% purity after crystallization.

Supporting Info. (4.9MB)PDF (363KB)

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A Concise and Highly Efficient Synthesis of Praziquantel as an Anthelmintic Drug

PAPER

HETEROCYCLES

An International Journal for Reviews and Communications in Heterocyclic Chemistry
Web Edition ISSN: 1881-0942

Published online: 11th October, 2016

Paper | Regular issue | Prepress

DOI: 10.3987/COM-16-13538

■ A Concise and Highly Efficient Synthesis of Praziquantel as an Anthelmintic Drug

Zhezhou Yang, Lin Zhang, Huirong Jiao, Rusheng Bao, Weiwei Xu, and Fuli Zhang*

*Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, China

Abstract

A concise and practical synthesis of praziquantel as anthelmintic drug is described. The key steps include a monoalkylation of ethanolamine for the preparation of 2-(2-hydroxyethylamino)-N-phenethylacetamide and a mild oxidation protocol with SO3-Py/DMSO as oxidant to transform alcohol into the corresponding aza-acetal. The telescoped synthesis is composed of five steps without purification of the intermediates, providing an overall yield of 80% with 99.8% purity after crystallization.

Supporting Info. (4.9MB)PDF (363KB)

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2-bromocyclohexane-1,3-dione, Mom will teach you NMR

Mom will teach you NMR,So easy


1H NMR (CDCl3, 300 MHz): δ 6.63(s, 1H), 2.61(t, J = 5.9 Hz, 4H), 2.03 (p, J = 5.9 2 Hz, 2H).

BLACK =1H NMR

RED = 13C NMR

1H NMR PREDICT

13C NMR PREDICT

COCK SAYS MOM CAN TEACH YOU NMR
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1-(biphenyl-4-yl)ethanone

Simultaneous rapid reaction workup and catalyst recovery

Green Chem., 2016, 18,5769-5772
DOI: 10.1039/C6GC02448C, Communication

Zhichao Lu, Zofia Hetman, Gerald B. Hammond, Bo Xu
By combining reaction work-up and catalyst recovery into a simple filtration procedure we have developed a substantially faster technique for organic synthesis.

By combining reaction work-up and catalyst recovery into a simple filtration procedure we have developed a substantially faster technique for organic synthesis. Our protocol eliminates the time-consuming conventional liquid–liquid extraction and is capable of parallelization and automation. Additionally, it requires only minimal amounts of solvent.

Simultaneous rapid reaction workup and catalyst recovery

Zhichao Lu,^a   Zofia Hetman,^a   Gerald B. Hammond*^a and  Bo Xu*^b  

Hide Affiliations

*

Corresponding authors

^a

Department of Chemistry, University of Louisville, Louisville, USA
E-mail: gb.hammond@louisville.edu

^b

College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620, China
E-mail: bo.xu@dhu.edu.cn

Green Chem., 2016,18, 5769-5772

DOI: 10.1039/C6GC02448C

http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C6GC02448C?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

. General procedure for a reaction Step 1. Reaction setup. The reaction is conducted in the usual way with the supported catalyst. Porelite® (typically 1 mL for every 0.1 gram of product) is added to the reaction mixture under stirring, Step 2. Reaction quench and rigid solvent extraction. If needed, the reaction is quenched with a suitable aqueous solution (e.g. NaHCO3 solution). • If the solvent used in the reaction is water-miscible (eg., DMF, methanol, etc.), a minimum amount of water immiscible solvent (e.g. 3 mL ether for every 1 g of product) is added to help organic material become entrenched in Porelite. • If the reaction is conducted in a water immiscible solvent (e.g. toluene, DCM), no extra solvent is needed in most cases. The excess amount of solvent is removed by rotavapor or by nitrogen/air purging (no need to remove the water from the mixture). The reaction mixture is filtered to remove aqueous-soluble components (starting materials, by-products, etc.) and washed with water (or HCl or Na2CO3 solution to remove basic or acidic byproducts. Vacuum is applied to dry the filtrate for 2 minutes to remove any remaining aqueous and volatile solvents. (For automatic flash chromatographic separation, an empty loading cartridge can be used, which can be directly attached to the commercial system. For manual chromatographic separation, a regular Büchner filter can be used). Step 3. Sample loading to chromatographic system. • The loading cartridge can be directly attached to the commercial flash chromatographic system (e.g., CombiFlash Rf series). • For manual chromatographic separation, the polymer powder is loaded directly onto a manual flash silica gel column (dry loading).

Because the polymer pad may contain some trapped air, it is recommended to start with the least polar solvent (e.g., hexane) during chromatographic separation to remove the trapped air.



1-(biphenyl-4-yl)ethanone

1-(biphenyl-4-yl)ethanone

Han, W.; Liu, C.; Jin, Z.-L. Organic Letters 2007, 9, 4005-4007


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1,1-Dimethyl-3-(pyridin-2-yl)urea

Solvent- and halide-free synthesis of pyridine-2-yl substituted ureas through facile C-H functionalization of pyridine N-oxides

Green Chem., 2016, Advance Article
DOI: 10.1039/C6GC02556K, Paper

Valentin A. Rassadin, Dmitry P. Zimin, Gulnara Z. Raskil'dina, Alexander Yu. Ivanov, Vadim P. Boyarskiy, Semen S. Zlotskii, Vadim Yu. Kukushkin
A solvent- and halide-free atom-economical synthesis of practically useful pyridine-2-yl substituted ureas utilizes pyridine N-oxides and dialkylcyanamides.

Solvent- and halide-free synthesis of pyridine-2-yl substituted ureas through facile C–H functionalization of pyridine N-oxides

Valentin A. Rassadin,*^a   Dmitry P. Zimin,^a  Gulnara Z. Raskil'dina,^ab   Alexander Yu. Ivanov,^c  Vadim P. Boyarskiy,^a   Semen S. Zlotskii^b and  Vadim Yu. Kukushkin*^a  

*

Corresponding authors

^a

Institute of Chemistry, Saint Petersburg State University, Universitetskaya Nab. 7/9, 199034 Saint Petersburg, Russia
E-mail: v.rassadin@spbu.ru, v.kukushkin@spbu.ru

^b

Ufa State Petroleum Technological University, Kosmonavtov 1, Ufa, Bashkortostan, Russia

^c

Research Park SPbSU, Center for Magnetic Resonance, Saint Petersburg State University, Universitetskaya Nab. 7/9, 199034 Saint Petersburg, Russia

Green Chem., 2016, Advance Article

DOI: 10.1039/C6GC02556K

A novel solvent- and halide-free atom-economical synthesis of practically useful pyridine-2-yl substituted ureas utilizes easily accessible or commercially available pyridine N-oxides (PyO) and dialkylcyanamides. The observed C–H functionalization of PyO is suitable for the good-to-high yielding synthesis of a wide range of pyridine-2-yl substituted ureas featuring electron donating and electron withdrawing, sensitive, or even fugitive functional groups at any position of the pyridine ring (63–92%; 19 examples). In the cases of 3-substituted PyO, the C–H functionalization occurs regioselectively providing a route for facile generation of ureas bearing a 5-substituted pyridine-2-yl moiety.



1,1-Dimethyl-3-(pyridin-2-yl)urea

1,1-Dimethyl-3-(pyridin-2-yl)urea (4a)3 : From pyridine 1-oxide (1a) (95.0 mg, 1.00 mmol) and dimethylcyanamide (2a) (105 mg, 1.50 mmol), compound 4a (147 mg, 89%) was obtained according to GP1 as a yellow oil, which was then crystalized in the freezer to give pale yellow solid, m.p. = 42.6–43.5 °C, lit.4 m.p. = 44–47 °C (EtOAc/hexane), Rf = 0.25 (EtOAc). 1H NMR (400 MHz, CDCl3): δ = 3.00 (s, 6 H, NCH3), 6.88 (ddd, J = 7.3, 5.0, 0.9 Hz, 1 H), 7.30 (br. s, 1 H), 7.60 (ddd, J = 8.5, 7.3, 1.9 Hz, 1 H), 8.02 (dt, J = 8.5, 0.9 Hz, 1 H), 8.14 (ddd, J = 5.0, 1.9, 0.9 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 36.3 (2 С, CH3), 113.0 (CH), 118.1 (CH), 138.0 (CH), 147.3 (CH), 152.8 (C), 154.8 (C) ppm. NMR data are consistent with previously reported.3 HRMS (ESI), m/z: [M + H]+ calcd. for C8H12N3O+ : 166.0975; found: 166.0977.


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ethyl 13b-nitro-8-tosyl-8,8a,13b,13c-tetrahydro-5H-indolo[2',3':3,4]pyrazolo[5,1- a]isoquinoline-9(6H)-carboxylate

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

Green Chem., 2016, Advance Article
DOI: 10.1039/C6GC02517J, Communication

Xihong Liu, Dongxu Yang, Kezhou Wang, Jinlong Zhang, Rui Wang
A catalyst-free 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines and 3-nitroindoles has been reported under mild conditions.

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 Zhang^a and   Rui Wang*^ab  

http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C6GC02517J?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

*

Corresponding authors

^a

School of Life Sciences, Institute of Biochemistry and Molecular Biology, Lanzhou University, Lanzhou 730000, P. R. China
E-mail: wangrui@lzu.edu.cn

^b

State 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., 2016, Advance Article

DOI: 10.1039/C6GC02517J

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).


ethyl 13b-nitro-8-tosyl-8,8a,13b,13c-tetrahydro-5H-indolo[2',3':3,4]pyrazolo[5,1- a]isoquinoline-9(6H)-carboxylate

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.


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