Simple and effective method for two-step synthesis of 2-(1,3-dithian-2-ylidene)-acetonitrile

Simple and effective method for two-step synthesis of 2-(1,3-dithian-2-ylidene)-acetonitrile (75% overall yield) and molecular modeling calculation of the mechanism by B3LYP and the 6-311++G(2df,2p) basis set.

http://dx.doi.org/10.5935/0100-4042.20140308

Publicado online: dezembro 12, 2014

Método alternativo para a síntese e mecanismo de 2-(1,3-ditiano-2-ilideno)-acetonitrila

Marcelle S. Ferreira; José D. Figueroa-Villar*

Quim. Nova, Vol. 38, No. 2, 233-236, 2015

Artigo http://dx.doi.org/10.5935/0100-4042.20140308

*e-mail: jdfv2009@gmail.com

MÉTODO ALTERNATIVO PARA A SÍNTESE E MECANISMO DE 2-(1,3-DITIANO-2-ILIDENO)-ACETONITRILA

Marcelle S. Ferreira e José D. Figueroa-Villar* Departamento de Química, Instituto Militar de Engenharia, Praça General Tiburcio 80, 22290-270

Rio de Janeiro – RJ, Brasil

Recebido em 18/08/2014; aceito em 15/10/2014; publicado na web em 12/12/2014

ALTERNATIVE METHOD FOR SYNTHESIS AND MECHANISM OF 2-(1,3-DITHIAN-2-YLIDENE)-ACETONITRILE. We report an alternative method for the synthesis of 2-(1,3-dithian-2-ylidene)-acetonitrile using 3-(4-chlorophenyl)-3-oxopropanenitrile and carbon disulfide as starting materials. The methanolysis of the intermediate 3-(4-chlorophenyl)-2-(1,3-dithian-2-ylidene)-3- oxopropanenitrile occurs via three possible intermediates, leading to the formation of the product at a 75% overall yield. Molecular modeling simulation of the reaction pathway using B3LYP 6-311G++(2df,2p) justified the proposed reaction mechanism. Keywords: 2-(1,3-dithian-2-ylidene)-acetonitrile; reaction mechanism; methanolysis; molecular modeling.

3-(4-clorofenil)-2-(1,3-ditiano-2-ilideno)-3-oxopropanonitrila (3): Cristal amarelo. Rendimento: 95%, 2,80 g, pf 158-160 °C, lit.21 159-160 °C;

IV (KBr, cm-1): 2198 (CN), 1612 (C=O), 1585, 1560 (aromático), 678 cm -1 (C-S);

1H RMN (300 MHz, CDCl3) δ 2,38 (m, J 6,9, 2H, CH2); 3,01 (t, J 6,6, 2H, SCH2); 3,17 (t, J 7,2 , 2H, SCH2); 7,43 (d, J 8,5, 2H); 7,83 (d, J 8,5, 2H);

13C RMN (75 MHz, CDCl3) δ 23,9 (CH2), 30,4 (SCH2), 104,2 (CCO), 117,5 (CN), 128,9, 130,5, 135,6, 139,2 (aromático), 185,2 (C=CS), 185,4 (CO).

21.......Rudorf, W. D.; Augustin, M.; Phosphorus Sulfur Relat. Elem. 1981, 9, 329.

...........................................

Síntese da 2-(1,3-ditiano-2-ilideno)-acetonitrila (1) Em um balão de fundo redondo de 100 mL foram adicionados 0,400 g (1,4 mmol) de 3-(4-clorofenil)-2-(1,3-ditiano-2-ilideno)-3- -oxopropanonitrila (2) dissolvidos em 15 mL de THF seco, 0,140 g (20 mmol) de sódio e 15 mL de metanol seco sob atmosfera de nitrogênio. A mistura reacional foi mantida sob agitação à 25 °C por 48 h. Em seguida, a mistura reacional foi dissolvida em 30 mL de água destilada e extraída com acetato de etila (3 x 20 mL). A fase orgânica foi seca em sulfato de sódio anidro, filtrada e concentrada a vácuo para se obter o produto bruto, que foi purificado por cromatografia em coluna (silica gel e hexano:acetato de etila 7:3).

2-(1,3-ditiano-2-ilideno)-acetonitrila (1): Cristal branco. Rendimento: 75%, 165 mg, pf. 60-63 °C, lit1 60-62 °C;

1 H RMN (300 MHz, CDCl3) δ 2,23 (m, J 6,8, 2H, CH2); 3,01 (t, J 7,5, 2H, SCH2); 3,06 (t, J 6,9, 2H, SCH2), 5,39 (s, 1H, CH);

13C RMN (75 MHz, CDCl3) δ 22,9 (CH2), 28,7 (SCH2), 28,8 (SCH2), 90,4 (CHCN), 116,3 (CN), 163,8 (C=CS).

1.........Yin, Y.; Zangh, Q.; Liu, Q.; Liu, Y.; Sun, S.; Synth. Commun. 2007, 37, 703.

 

CAS 113998-04-2

• C6 H7 N S2
• Acetonitrile, 2-​(1,​3-​dithian-​2-​ylidene)​-
• 157.26

Melting Point

60-62 °C

1.  Creemer, Lawrence C.; Synthetic Communications 1988, V18(10), P1103-10 
2. Yin, Yanbing; Synthetic Communications 2007, V37(5), P703-711 

1H  NMR  predict

2-(1,3-dithian-2-ylidene)-acetonitrile

ACTUAL 1H NMR VALUES

1 H RMN (300 MHz, CDCl3)

δ 2,23 (m, J 6,8, 2H, CH2);

3,01 (t, J 7,5, 2H, SCH2);

3,06 (t, J 6,9, 2H, SCH2),

5,39 (s, 1H, CH);

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13C NMR PREDICT

ACTUAL 13C NMR VALUE

13C RMN (75 MHz, CDCl3)

δ 22,9 (CH2),

28,7 (SCH2),

28,8 (SCH2),

90,4 (CHCN),

116,3 (CN),

163,8 (C=CS)

COSY NMR PREDICT

SYNTHESIS

  

2-(1,3-ditiano-2-ilideno)-acetonitrila (1): Cristal branco. Rendimento: 75%, 165 mg, pf. 60-63 °C, lit1 60-62 °C;

1 H RMN (300 MHz, CDCl3) δ 2,23 (m, J 6,8, 2H, CH2); 3,01 (t, J 7,5, 2H, SCH2); 3,06 (t, J 6,9, 2H, SCH2), 5,39 (s, 1H, CH);

13C RMN (75 MHz, CDCl3) δ 22,9 (CH2), 28,7 (SCH2), 28,8 (SCH2), 90,4 (CHCN), 116,3 (CN), 163,8 (C=CS). 

WILL BE UPDATED WATCH OUT.....................

Departamento de Química, Instituto Militar de Engenharia, Praça General Tiburcio

Instituto Militar de Engenharia, Rio de Janeiro. BELOW

Entrada do antigo Instituto de Química da UFRGS, um prédio histórico

Equipe - Os módulos foram fabricados na Unisanta sob a supervisão do professor Luiz Renato Lia, coordenador do Curso de Engenharia Química, ...

Instituto de Florestas da Universidade Federal Rural do Rio de Janeiro

Praça General Tibúrcio

Praça General Tibúrcio com o Morro da Urca ao fundo

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.

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.

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.

S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

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.

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.

COCK WILL TEACH YOU NMR

COCK SAYS MOM CAN TEACH YOU NMR

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

http://newdrugapprovals.org/

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Enzymatic resolution of antidepressant drug precursors in an undergraduate laboratory

EducaçãoQuim. Nova 2015, 38(2), 285-287

Enzymatic resolution of antidepressant drug precursors in an undergraduate laboratory

Luís M. R. SolanoI; Nuno M. T. LourençoII,*

This paper describes a multi-step chemo-enzymatic synthesis of antidepressant drug precursors.

http://dx.doi.org/10.5935/0100-4042.20140306

Publicado online: novembro 13, 2014

Quim. Nova, Vol. 38, No. 2, 285-287, 2015

Educação http://dx.doi.org/10.5935/0100-4042.20140306

*e-mail: nmtl@tecnico.ulisboa.pt

ENZYMATIC RESOLUTION OF ANTIDEPRESSANT DRUG PRECURSORS IN AN UNDERGRADUATE LABORATORY

Luís M. R. Solanoa and Nuno M. T. Lourençob,* a Faculdade de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal b Departamento de Bioengenharia, Instituto de Biotecnologia e Bioengenharia, Instituto Superior Técnico, Av. Rovisco Pais, 1, 1049-001 Lisboa, Portugal

Recebido em 07/07/2014; aceito em 17/09/2014; publicado na web em 13/11/2014

The use of biocatalysts in synthetic chemistry is a conventional methodology for preparing enantiomerically enriched compounds. Despite this fact, the number of experiments in chemical teaching laboratories that demonstrate the potential of enzymes in synthetic organic chemistry is limited. We describe a laboratory experiment in which students synthesized a chiral secondary alcohol that can be used in the preparation of antidepressant drugs. This experiment was conducted by individual students as part of a Drug Synthesis course held at the Pharmacy Faculty, Lisbon University. This laboratory experiment requires six laboratory periods, each lasting four hours. During the first four laboratory periods, students synthesized and characterized a racemic ester using nuclear magnetic resonance spectroscopy and gas chromatography. During the last two laboratory periods, they performed enzymatic hydrolysis resolution of the racemic ester using Candida antarctica lipase B to yield enantiomerically enriched secondary alcohol. Students successfully prepared the racemic ester with a 70%-81% overall yield in three steps. The enzymatic hydrolysis afforded (R)- secondary alcohol with good enantioselectivity (90%–95%) and reasonable yields (10%–19%). In these experiments, students were exposed to theoretical and practical concepts of aromatic acylation, ketone reduction, esterification, and enzymatic hydrolysis. Keywords: sec-alcohols; esters; lípase; enantiomers; resolution.

READ AT

http://quimicanova.sbq.org.br/imagebank/pdf/v38n2a20.pdf

 

................

S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

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.

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.

COCK WILL TEACH YOU NMR

COCK SAYS MOM CAN TEACH YOU NMR

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

http://newdrugapprovals.org/

Join me on Linkedin

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Flupirtine, D 9998

2-amino-6-(4-fluoro-benzylamino)- pyridin-3-yl)-carbamic acid ethyl ester, is unique as a non-opioid, non-NSAID, non-steroidal analgesic with a favorable tolerability. It first became available in Europe in 1984, and was sold mainly under the names Katadolon, Trancolong, Awegal, Efiret, Trancopal Dolo, and Metanor

PHASE 2

MS

• Neuronal potassium channels (7)
• Membrane resting potential (6)
• NMDA receptor channels (indirectly)(14)

• Originally developed by Asta Medica (1) (4)
• Being developed and commercialized to treat fibromyalgia by Synthetic Biologics (1)

Flupirtine

75507-68-5 maleate
56995-20-1 (free base)

LAUNCHED

1986 NEUROPATHIC PAIN

Flupirtine maleate is the INN for 2-amino-3-ethylcarbamato-6- (4-fluoro-benzylamino) maleate, CAS: 75507-68-5, molar mass 420.40 g / mol, molecular formula C1 5 H17FN4O2 • C4H4O4, and corresponds to the structure of formula I.

Flupirtine maleate is used, for example, under the trade name Katadolon® as an analgesic.

PATENT
http://www.google.com/patents/CN103086963A?cl=en
FIG. 1 is flupirtine maleate 1H NMR.
[0021] FIG. 2 is flupirtine maleate A crystal X-ray diffraction pattern

Example 3
2-Amino-3-nitro-6-chloropyridine 246g, and 254g of triethylamine were added to 800ml of ethanol-necked flask and stirred under heating to reflux, fluorine was slowly added dropwise benzylamine 80g, reaction of 6 hours, the reaction was completed After the dropwise addition of purified water 500ml, cooled slowly with stirring to room temperature, filtered, dried to give 2-amino-3-nitro-6-p-fluoro-benzylamino-pyridine.
[0033] The ferric chloride hexahydrate was dissolved in purified water 41g 200ml, adding activated charcoal 20g, heated to 50 ° C, a saturated solution of sodium hydroxide was added 45g (24g of sodium hydroxide dissolved in 21ml water), 60 ° C with stirring I hours, cooled to room temperature, filtered, and dried to give ferric hydroxide / activated carbon catalyst.
[0034] A mixture of 2-amino-3-nitro-6-p-fluorobenzyl-aminopyridine 104.Sg, ferric hydroxide / activated carbon catalyst was added to 20g 2L reaction flask was added 95% ethanol 1200ml, heated with stirring to 90 ° C. Insulation 60% hydrazine hydrate was added dropwise 250g. Drops Bi insulation response to 3h. Completion of the reaction, the reaction solution is filtered hot with concentrated hydrochloric acid to 240ml and 95% ethanol IOOOml reaction flask. (TlO ° C crystallization I h, filtered, dried to give 2,3-amino-6-fluoro-benzyl-aminopyridine on
Hydrochloride.
[0035] A mixture of 2,3-diamino-6-p-fluoro-benzylamino-pyridine hydrochloride 132g, 800ml of isopropanol was added to a 2L reaction flask, the temperature control to 28 至 30 ° C, was slowly added dropwise acetic acid ester 39g. Stirred for 0.5 hours, was slowly added dropwise triethylamine 70g, after stirring for 0.5 hours, complement ethyl chloroformate 5g, stirred for 15 minutes, additional triethylamine remaining 10g. Continue stirring for I hour. The reaction solution was concentrated under reduced pressure to about 800ml of distillate was distilled out. The remaining reaction solution was poured into an aqueous solution of maleic acid with a good (39g of maleic acid was dissolved in purified water IlOOml), stirred for 30 minutes at room temperature, (T5 ° C was stirred for 5 ~ 8 hours, filtered, dried to give the maleic acid flupirtine crude.
[0036] The crude flupirtine maleate product 100g, 2000ml of ethanol into the reaction flask and heated to 70~80 ° C, was added 5g of activated carbon and dissolved, and incubated I hour, filtered hot, O~5 ° C CRYSTALLIZATION 3 hours, filtered and dried to give crude I. The crude product I 90g, 450ml of ethanol into the reaction flask and heated 20h, and then slowly cooled to room temperature, O~5 ° C for 2 hours, filtered, and dried to give crystal form A of flupirtine maleate product.













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paper

J Pharm Biomed Anal. 2014 Mar;90:27-34. doi: 10.1016/j.jpba.2013.11.015. Epub 2013 Nov 27.

Flupirtine maleate is a centrally acting, non-opioid, nonsteroidal antiinflammatory analgesic. During the manufacturing of flupirtine maleate, two unknown impurities present in the laboratory batches in the range of 0.05-1.0% along with the known impurities in HPLC analysis. These unknown impurities were obtained from the enriched mother liquor by column chromatography. Based on the complete spectral analysis (MS, (1)H, (13)C, 2D NMR and IR) and knowledge of the synthetic scheme of flupirtine maleate, these two new impurities were designated as diethyl 5-((4-fluorobenzyl)amino)-2-oxo-1H-imidazo[4,5-b]pyridine-1,3(2H)-dicarboxylate (impurity-I) and diethyl(6-((4-fluorobenzyl)amino)pyridine-2,3-diyl)dicarbamate (impurity-II). Impurity isolation, identification, structure elucidation and the formation of impurities were also discussed. Preparation and structure elucidation of impurity-III were also first reported in this paper.

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journal of pharmaceutical and biomedical analysis, 90, 2014, 27-34

 

  1H NMR INTERPRETATIONS/PREDICTIONS

13C  NMR INTERPRETATIONS/PREDICTIONS

…….

PAPER

Helvetica Chimica Acta, , vol. 77, # 8 p. 2175 – 2190

AND GIVES PRODUCT

ALSO AN INTHelvetica Chimica Acta, , vol. 77, # 8 p. 2175 – 2190

…………..

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.

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.

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.

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.