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Tegafur

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Jun 012017

Tegafur

CAS 17902-23-7

2,4(1H,3H)-Pyrimidinedione, 5-fluoro-1-(tetrahydro-2-furanyl)-

Molecular Weight,200.17, MF C₈ H₉ F N₂ O₃
172-173 °C

Miyashita, Osamu; Chemical & Pharmaceutical Bulletin 1981, 29(11), PG 3181-90

Uracil, 5-fluoro-1-(tetrahydro-2-furyl)-

Utefos

Venoterpine

WY1559000

YR0450000

5-fluoro-1-tetrahydrofuran-2-ylpyrimidine-2,4(1H,3H)-dione

Carzonal

N1-(2′-Furanidyl)-5-fluorouracil

Synonyms:Ftorafur
ATC:L01BC03

EINECS:241-846-2
LD₅₀:800 mg/kg (M, i.v.); 775 mg/kg (M, p.o.);
685 mg/kg (R, i.v.); 930 mg/kg (R, p.o.);
34 mg/kg (dog, p.o.)

Derivatives, monosodium salt

Formula:C₈H₈FN₂NaO₃
MW:222.15 g/mol
CAS-RN:28721-46-2

Tegafur (INN, BAN, USAN) is a chemotherapeutic prodrug of 5-flourouracil (5-FU) used in the treatment of cancers. It is a component of the combination drug tegafur/uracil. When metabolised, it becomes 5-FU.^[1]

Medical uses

As a prodrug to 5-FU it is used in the treatment of the following cancers:^[2]

Stomach (when combined with gimeracil and oteracil)
Breast (with uracil)
Gallbladder
Lung (specifically adenocarcinoma, typically with uracil)
Colorectal (usually when combined with gimeracil and oteracil)
Head and neck
Liver (with uracil)^[3]
Pancreatic

It is often given in combination with drugs that alter its bioavailability and toxicity such as gimeracil, oteracil or uracil.^[2] These agents achieve this by inhibiting the enzyme dihydropyrimidine dehydrogenase (uracil/gimeracil) or orotate phosphoribosyltransferase (oteracil).^[2]

Image result for tegafur

Adverse effects

The major side effects of tegafur are similar to fluorouracil and include myelosuppression, central neurotoxicity and gastrointestinal toxicity (especially diarrhoea).^[2] Gastrointestinal toxicity is the dose-limiting side effect of tegafur.^[2] Central neurotoxicity is more common with tegafur than with fluorouracil.^[2]

Image result for tegafur

Pharmacogenetics

The dihydropyrimidine dehydrogenase (DPD) enzyme is responsible for the detoxifying metabolism of fluoropyrimidines, a class of drugs that includes 5-fluorouracil, capecitabine, and tegafur.^[4] Genetic variations within the DPD gene (DPYD) can lead to reduced or absent DPD activity, and individuals who are heterozygous or homozygous for these variations may have partial or complete DPD deficiency; an estimated 0.2% of individuals have complete DPD deficiency.^[4]^[5] Those with partial or complete DPD deficiency have a significantly increased risk of severe or even fatal drug toxicities when treated with fluoropyrimidines; examples of toxicities include myelosuppression, neurotoxicity and hand-foot syndrome.^[4]^[5]

Mechanism of action

It is a prodrug to 5-FU, which is a thymidylate synthase inhibitor.^[2]

Pharmacokinetics

It is metabolised to 5-FU by CYP2A6.^[6]^[7]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.^{[§ 1]}

The interactive pathway map can be edited at WikiPathways: “FluoropyrimidineActivity_WP1601”.

Image result for tegafur

Image result for tegafur SYNTHESIS

MASS SPECTRUM

1H NMR

13C NMR

RAMAN

Synthesis

Image result for tegafur SYNTHESIS

Substances Referenced in Synthesis Path

CAS-RN	Formula	Chemical Name	CAS Index Name
58138-78-6	C₁₀H₁₉FN₂O₂Si₂	1,3-bis(trimethylsilyl)fluorouracil	2,4(1H,3H)-Pyrimidinedione, 5-fluoro-1,3-bis(trimethylsilyl)-
13369-70-5	C₄H₇ClO	2-chlorotetrahydrofuran	Furan, 2-chlorotetrahydro-
1191-99-7	C₄H₆O	2,3-dihydrofuran	Furan, 2,3-dihydro-
51-21-8	C₄H₃FN₂O₂	5-fluorouracil	2,4(1H,3H)-Pyrimidinedione, 5-fluoro-

Image result for tegafur

ChemSpider 2D Image | Tegafur | C8H9FN2O3

SYN1

CN 106397416

SYN 2

Advanced Synthesis & Catalysis, 356(16), 3325-3330; 2014

PATENTS

CN 106397416

CN 104513230

CN 103159746

PATENT

CN 102285972

tegafur is a derivative of 5-fluorouracil, and in 1967, Hiller of the former Soviet Union synthesized tegafur (SA Hiller, RA Zhuk, M. Yu. Lidak, et al. Substituted Uracil [ P, British Patent, 1168391 (1969)). In 1974, it was listed in Japan. China was successfully developed by Shandong Jinan Pharmaceutical Factory in 1979. Its present origin is Shanghai and Shandong provinces and cities. The anti-cancer effect of tegafur is similar to that of 5-fluorouracil and is activated in vivo by 5-fluorouracil through liver activation. Unlike 5-fluorouracil, tegafur is fat-soluble, has good oral absorption, maintains high concentrations in the blood for a long time and easily passes through the blood-brain barrier. Clinical and animal experiments show that tegafur on gastrointestinal cancer, breast cancer is better, the role of rectal cancer than 5-fluorouracil good, less toxic than 5-fluorouracil. Teflon has a chemotherapy index of 2-fold for 5-fluorouracil and only 1 / 4-1 / 7 of toxicity. So the addition of fluoride is widely used in cancer patients with chemotherapy.

[0003] The first synthesis of tegafur is Hiller ([SA Hiller, RA Zhuk, Μ. Yu. Lidak, et al. Substituted Uracil [P], British Patent, 1168391 (1969)]. 5-fluorouracil or 2,4-bis (trimethylsilyl) -5-fluorouracil (Me3Si-Fu, 1) and 2-chlorotetrahydrofuran (Thf-Cl), and it is reported that this synthesis must be carried out at low temperature (- 20 to -40 ° C), because Thf-Cl is unstable, and excess Thf-Cl results in a decomposition reaction, thereby reducing the yield of Thf-Fu.

[0004] Earl and Townsend also prepared 1_ (tetrahydro-2-furyl) uracil using Thf-Cl and 2,4-bis (trimethylsilyl) uracil, and then using trifluoromethyl fluorite to product Fluorination. Mitsugi Yasurnoto reacts with the Friedel-Crafts catalyst in the presence of 2,4-bis (trimethylsilyl) -5-fluorouracil (Me3Si-U, 1) 2-acetoxytetrahydrofuran (Thf-OAc, 2) (Kazu Kigasawa et al., 2-tert-Butoxy), & lt; RTI ID = 0.0 & gt;, & lt; / RTI & gt; (K. Kigasawa, M. Hiiragi, K. ffakisaka, et al. J. Heterocyclic Chem. 1977, 14: 473-475) was reacted with 5-Fu at 155-160 ° C. Reported in the literature for the fluoride production route there are the following questions: 1, high energy consumption. In the traditional synthesis method, in order to obtain the product, the second step of the reaction needs to continue heating at 160 ° C for 5-6 hours, high energy consumption; 2, difficult to produce, low yield: 5-fluorouracil as a solid powder The reaction needs to be carried out at a high temperature (160 ° C), which requires the use of a high boiling solvent N, N-dimethylformamide (DMF). But it is difficult to completely remove the fluoride from the addition of fluoride, because DMF can form hydrogen bonds with the fluoride molecules, difficult to separate from each other; 3, in order to unreacted 5-fluorouracil and tegafur separation and recycling , The use of carcinogenic solvent chloroform as a extractant in the conventional method to separate 5-fluorouracil and tegafur. However, the main role of chloroform on the central nervous system, with anesthesia, the heart, liver, kidney damage; the environment is also harmful to the water can cause pollution. Therefore, the use of volatile solvent chloroform, even if the necessary measures to reduce its volatilization, will still cause harm to human health and the environment; 4, low yield. Since both NI and N-3 in the 5-fluorouracil molecule react with 2-tert-butoxytetrahydrofuran, the addition of tegafur is also the addition of 1,3-bis (tetrahydro-2-furyl) -5 – Fluorouracil. Therefore, the improvement of the traditional production process of tegafur is a significant and imminent task.

Example 1 (for example, the best reaction conditions):

Weigh 3.5 g (50 mmol) of 2,3-dihydrofuran, 1.9 g (50 mmol) of ethanol was added to a one-necked flask. To this was added 15 ml of tetrahydrofuran (THF). And then weighed 10. 0 mg CuCl2, microwave irradiation 250W at 25 ° C reaction 0. 6h. Cool to room temperature, add 1.95 g (15 mmol) of 5-fluorouracil (5-Fu), and microwave irradiation at 400 ° C for 100 ° C. After distilling off the low boiling solvent, the oil was obtained. Rinsed with ether to give a white solid which was recrystallized from anhydrous ethanol to give 1.34349 g of product. Melting point: 160-165 ° C. The yield was 75%.

[0011] Example 2

Weigh 3,5 g (50 mmol) of 2,3-dihydrofuran and 3.8 g (100 mmol) of ethanol were added to a single-necked flask. To this was added 15 ml of tetrahydrofuran (THF). And then weighed 5mg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cool to room temperature, add 1.95 g (15 mmol) of 5-fluorouracil (5-Fu), microwave irradiation 400W, reaction temperature 60 ° C under the reaction pool. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from absolute ethanol to give the product 0. 46 g. Melting point: 160-165 ° C. The yield was 15%.

[0012] Example 3

Weigh 3.5 g (50 mmol) of 2,3-dihydrofuran, 1.9 g (50 mmol) of ethanol was added to a one-necked flask. To this was added 15 ml of tetrahydrofuran (THF). And then weighed 20mg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cooled to room temperature, add 1.95 g (15 to 01) 5-fluorouracil (5 call 11), microwave irradiation 2001, reaction temperature 1301: reaction lh. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from anhydrous ethanol to give the product 1.81 g. Melting point: 160-165 ° C. The yield was 61%.

[0013] Example 4

Weigh 3.5 g (50 mmol) of 2,3-dihydrofuran and 19 g (500 mmol) of ethanol were added to a single-necked flask. To this was added 20 ml of tetrahydrofuran (THF). And then weighed IOmg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cooled to room temperature, add 1.95 g (15 to 01) 5-fluorouracil (5 call 11), microwave irradiation 2001, reaction temperature 1101: reaction lh. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from absolute ethanol to give product U6g. Melting point: 160-165 ° C. The yield was 43%.

[0014] Example 5

Weigh 3,5 g (50 mmol) of 2,3-dihydrofuran and 9.5 g (250 mmol) of ethanol were added to a single-necked flask. To this was added 30 ml of tetrahydrofuran (THF). And then weighed IOmg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cooled to room temperature, add 1.95 g (15 to 01) 5-fluorouracil (5 call 11), microwave irradiation 6001, reaction temperature 1001: reaction lh. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from absolute ethanol to give 1.15 g of product. Melting point: 160-165 ° C. The yield was 38%.

[0015] Example 6

Weigh 3.5 g (50 mmol) of 2,3-dihydrofuran, 1.9 g (50 mmol) of ethanol was added to a one-necked flask. To this was added 25 ml of tetrahydrofuran (THF). And then weighed 15mg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cooled to room temperature, add 1.95 g (15 to 01) 5-fluorouracil (5 call 11), microwave irradiation 5001, reaction temperature 1101: reaction lh. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from anhydrous ethanol to give product 2.10 g. Melting point: 160-165 ° C. The yield was 70%.

Paper

A novel protocol for preparation of tegafur (a prodrug of 5-fluorouracil) is reported. The process involves the 1,8-diazabicycloundec-7-ene-mediated alkylation of 5-fluorouracil with 2-acetoxytetrahydrofuran at 90 °C, followed by treatment of the prepurified mixture of the alkylation products with aqueous ethanol at 70 °C. The yield of the two-step process is 72%.

Synthesis of Tegafur by the Alkylation of 5-Fluorouracil under the Lewis Acid and Metal Salt-Free Conditions

Aleksandra Zasada, Ewa Mironiuk-Puchalska, and Mariola Koszytkowska-Stawińska ^*

Faculty of Chemistry, Warsaw University of Technology, ul. Noakowskiego 3, 00-664 Warszawa, Poland

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00103

*E-mail: [email protected].

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.7b00103

Click to access op7b00103_si_001.pdf

Tegafur, a prodrug of 5-fluorouracil (5-FUra), was discovered in 1967. The compound features high lipophilicity and water solubility compared to 5-FUra. Tegafur is used as a racemate since no significant difference in antitumor activity of enantiomers was observed.

The prodrug is gradually converted to 5-FUra by metabolism in the liver. Hence, a rapid breakdown of the released 5-FUra in the gastrointestinal tract is avoided.(6) In injectable form, tegafur provoked serious side effects, such as nausea, vomiting, or central nervous system disturbances.

The first generation of oral formulation of tegafur , UFT) is a combination of tegafur and uracil in a fixed molar ratio of 1:4, respectively. The uracil slows the metabolism of 5-FUra and reduces production of 2-fluoro-α-alanine as the toxic metabolite. UFT was approved in 50 countries worldwide excluding the USA.

S-1 is the next generation of oral formulation of tegafur.(7) It is a combination of tegafur, gimeracil, and oteracil in a fixed molar ratio of 1:0.4:1, respectively.

Gimeracil inhibits the enzyme responsible for the degradation of 5-FUra. Oteracil prevents the activation of 5-FUra in the gastrointestinal tract, thus minimizing the gastrointestinal toxicity of 5-FUra. S-1 is well-tolerated, but its safety can be influenced by schedule and dose, similar to any other cytotoxic agent. Since common side effects of S-1 can be managed with antidiarrheal and antiemetic medications, the drug can be administered in outpatient settings. S-1 was approved in Japan, China, Taiwan, Korea, and Singapore for the treatment of patients with gastric cancer.

In 2010, the Committee for Medicinal Products for Human Use (CHMP), a division of the European Medicines Agency (EMA), recommended the use of S-1 for the treatment of adults with advanced gastric cancer when given in a combination with cisplatin. Currently, S-1 has not been approved by the FDA in the United States.

There is a great interest in further examination of S-1 as an anticancer chemotherapeutic. Currently, 23 clinical trials with S-1 has been registered in National Institutes of Health (NIH). Combinations of S-1 and other anticancer agents have been employed in a majority of these trials.

5-Fluoro-1-(tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (Tegafur)

δ_H 1.89–2.10 (m, 3H), 2.38–2.45 (m, 1H), 3.97–4.01 (q-like m, 1H), 4.20–4.24 (dq-like m), 5.97–5.98 (m, 1H), 7.41 (d, ³J_HF 6.1), 9.21 (bs, 1H, NH).

δ_C 23.82, 32.90, 70.26, 87.58, 123.63 (d, ²J_CF 33.89), 140.33 (d, ¹J_CF 237.20) 148.66, 156.9 (d, ²J_CF 26.81).

HRMS m/z calcd for C₈H₁₀N₂O₃F [M – H]⁺ 201.0670, found 201.0669.

Elemental analysis. Found C%, 46.42; H%, 4.45; N%, 13.35. Calcd for 3(C₈H₉N₂O₃F)·H₂O: C%, 46.61; H%, 4.73; N%, 13.59.

PATENT CITATIONS

Cited Patent	Filing date	Publication date	Applicant	Title
CN85108855A *	Nov 6, 1985	Sep 24, 1986	Central Chemical Research Institute	Preparation of 1- (2-tetrahydrofuryl) -5-fluorouracil
GB1168391A *				Title not available
JPS5452085A *				Title not available
JPS5455581A *				Title not available
JPS5459288A *				Title not available
JPS52118479A *				Title not available
JPS54103880A *				Title not available
US4256885 *	Dec 10, 1976	Mar 17, 1981	Mitsui Toatsu Kagaku Kabushiki Kaisha	Process for the preparation of 1- (2-tetrahydrofuryl) -5-fluorouracil
US5075446 *	Oct 12, 1990	Dec 24, 1991	Korea Advanced Institute Of Science & Technology	Synthesis of tetrahydro-2-furylated pyrimidine derivatives

NON-PATENT CITATIONS

Reference
1	*	KAZUO KIGASAWA, et al .: ” Studies on the Synthesis of Chemotherapeutics. Synthetic of 1- (2-Tetrahydrofuryl) -5-fluorouracil [Ftorafur] (Studies on the Syntheses of Heterocyclic Compound. Part 703) “, “J. HETEROCCLIC CHEM ., Vol. 14, 31 May 1977 (1977-05-31), pages 473 – 475

References

El Sayed, YM; Sadée, W (1983). “Metabolic activation of R,S-1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur) to 5-fluorouracil by soluble enzymes”. Cancer Research. 43 (9): 4039–44. PMID 6409396.
2
Sweetman, S, ed. (14 November 2011). “Martindale: The Complete Drug Reference”. Pharmaceutical Press. Retrieved 12 February 2014.
3
Ishikawa, T (14 May 2008). “Chemotherapy with enteric-coated tegafur/uracil for advanced hepatocellular carcinoma.” (PDF). World Journal of Gastroenterology : WJG. 14 (18): 2797–2801. doi:10.3748/wjg.14.2797. PMC 2710718 . PMID 18473401.
4
Caudle, KE; Thorn, CF; Klein, TE; Swen, JJ; McLeod, HL; Diasio, RB; Schwab, M (December 2013). “Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing.”. Clinical pharmacology and therapeutics. 94 (6): 640–5. doi:10.1038/clpt.2013.172. PMC 3831181 . PMID 23988873.
5
Amstutz, U; Froehlich, TK; Largiadèr, CR (September 2011). “Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity.”. Pharmacogenomics. 12 (9): 1321–36. doi:10.2217/pgs.11.72. PMID 21919607.
6
Nakayama, T; Noguchi, S (January 2010). “Therapeutic usefulness of postoperative adjuvant chemotherapy with Tegafur-Uracil (UFT) in patients with breast cancer: focus on the results of clinical studies in Japan.” (PDF). The Oncologist. 15 (1): 26–36. doi:10.1634/theoncologist.2009-0255. PMC 3227888 . PMID 20080863.
7

Matt P, van Zwieten-Boot B, Calvo Rojas G, Ter Hofstede H, Garcia-Carbonero R, Camarero J, Abadie E, Pignatti F (October 2011). “The European Medicines Agency review of Tegafur/Gimeracil/Oteracil (Teysuno™) for the treatment of advanced gastric cancer when given in combination with cisplatin: summary of the Scientific Assessment of the Committee for medicinal products for human use (CHMP).” (PDF). The Oncologist. 16 (10): 1451–1457. doi:10.1634/theoncologist.2011-0224. PMC 3228070 . PMID 21963999.

(1) Hirose, Takashi; Oncology Reports 2010, V24(2), P529-536
(2) Fujita, Ken-ichi; Cancer Science 2008, V99(5), P1049-1054
(3) Tahara, Makoto; Cancer Science 2011, V102(2), P419-424
(4) Chu, Quincy Siu-Chung; Clinical Cancer Research 2004, V10(15), P4913-4921
(5) Tominaga, Kazunari; Oncology 2004, V66(5), P358-364
(6) Peters, Godefridus J.; Clinical Cancer Research 2004, V10(12, Pt. 1), P4072-4076
(7) Kim, Woo Young; Cancer Science 2007, V98(10), P1604-1608
Hillers, Solomon; Puti Sinteza i Izyskaniya Protivoopukholevykh Preparatov 1970, VNo. 3, P109-12
Grishko, V. A.; Trudy Kazakhskogo Nauchno-Issledovatel’skogo Instituta Onkologii i Radiologii 1977, V12, P110-14
Ootsu, Koichiro; Takeda Kenkyushoho 1978, V37(3-4), P267-77
“Drugs – Synonyms and Properties” data were obtained from Ashgate Publishing Co. (US)
Yabuuchi, Youichi; Oyo Yakuri 1971, V5(4), P569-84
Germane, S.; Eksperimental’naya i Klinicheskaya Farmakoterapiya 1970, (1), P85-92
JP 56046814 A 1981

AIST: Integrated Spectral Database System of Organic Compounds. (Data were obtained from the National Institute of Advanced Industrial Science and Technology (Japan))
ACD-A: Sigma-Aldrich (Spectral data were obtained from Advanced Chemistry Development, Inc.)
Nomura, Hiroaki; Chemical & Pharmaceutical Bulletin 1979, V27(4), P899-906
Sakurai, Kuniyoshi; Chemical & Pharmaceutical Bulletin 1978, V26(11), P3565-6
Miyashita, Osamu; Chemical & Pharmaceutical Bulletin 1981, V29(11), P3181-90
Lukevics, E.; Zhurnal Obshchei Khimii 1981, V51(4), P827-34
Needham, F.; Powder Diffraction 2006, V21(3), P245-247

Tegafur
Clinical data


AHFS/Drugs.com	International Drug Names
Pregnancy category	AU: D
Routes of administration	Oral
ATC code	L01BC03 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only)
Pharmacokinetic data
Biological half-life	3.9-11 hours
Identifiers
IUPAC name [show]
Synonyms	5-fluoro-1-(oxolan-2-yl)pyrimidine-2,4-dione
CAS Number	17902-23-7
PubChem CID	288216
ChemSpider	254191
UNII	1548R74NSZ
KEGG	D01244
ChEMBL	CHEMBL20883
ECHA InfoCard	100.038.027
Chemical and physical data
Formula	C₈H₉FN₂O₃
Molar mass	200.16 g/mol
3D model (Jmol)	Interactive image
SMILES [hide] FC=1C(=O)NC(=O)N(C=1)[C@@H]2OCCC2

///////////TEGAFUR

FC1=CN(C2CCCO2)C(=O)NC1=O

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Novel diarylheptanoids as inhibitors of TNF-α production

Sameer Dhuru^a, Dilip Bhedi^a, Dnyaneshwar Gophane^a, Kiran Hirbhagat^a, Vijaya Nadar^a, Dattatray More^a, Sapna Parikh^a, Roda Dalal^a, Lyle C. Fonseca^a, Firuza Kharas^a, Prashant Y. Vadnal^a, Ram A. Vishwakarma^a, H. Sivaramakrishnan^a*

^aDepartment of Medicinal Chemistry, Piramal Life Sciences Limited, 1 Nirlon Complex, Off Western Express Highway, Goregaon (E), Mumbai 400 063, India

^bDepartment of Pharmacology, Piramal Life Sciences Limited, 1 Nirlon Complex, Off Western Express Highway, Goregaon (E), Mumbai 400 063, India

Bioorg. Med. Chem. Lett. 21 (2011) 3784–3787

[Link: http://pubs.rsc.org/en/content/articlelanding/2013/cc/c2cc36389e#!divAbstract]

Graphical abstract

Synthesis and anti-inflammatory activity of novel diarylheptanoids [5-hydroxy-1-phenyl-7-(pyridin-3-yl)-heptan-3-ones and 1-phenyl-7-(pyridin-3-yl)hept-4-en-3-ones] as inhibitors of tumor necrosis factor-α (TNF-α production is described in the present article. The key reactions involve the formation of a β-hydroxyketone by the reaction of substituted 4-phenyl butan-2-ones with pyridine-3-carboxaldehyde in presence of LDA and the subsequent dehydration of the same to obtain the α,β-unsaturated ketones. Compounds 4i, 5b, 5d, and 5g significantly inhibit lipopolysaccharide (LPS)-induced TNF-α production from human peripheral blood mononuclear cells in a dose-dependent manner. Of note, the in vitro TNF-α inhibition potential of 5b and 5d is comparable to that of curcumin (a naturally occurring diarylheptanoid). Most importantly, oral administration of 4i, 5b, 5d, and 5g (each at 100 mg/kg) but not curcumin (at 100 mg/kg) significantly inhibits LPS-induced TNF-α production in BALB/c mice. Collectively, our findings suggest that these compounds may have potential therapeutic implications for TNF-α-mediated auto-immune/inflammatory disorders.

Scheme 1. Synthetic scheme

Table 1.

Table 2.

Highlights

Designed and synthesized a novel series of diarylheptanoids.
Compounds 4i, 5b, 5d, and 5g significantly inhibit in vitro TNF-α production from human cells.
Oral administration of these compounds significantly inhibits TNF-α production in mice.
These compounds may have potential therapeutic implications for TNF- α -mediated auto-immune/inflammatory diseases.

ABOUT GUEST BLOGGER

Dr. Dnyaneshwar B. Gophane, Ph. D.

Post doc fellow at Purdue university and university of Iceland

Email, [email protected]

Dr. Dnyaneshwar B. Gophane completed his B.Sc. (Chemistry) at Anand college of science, Pathardi (Ahmednagar, Maharashtra, India) in 2000 and M.Sc. (Organic Chemistry) at Department of Chemistry, University of Pune (India) in 2003. From 2003 to 2008, he worked in research and development departments of pharmaceutical companies like Dr. Reddy’s Laboratories and Nicholas Piramal India Limited, where he involved in synthesizing novel organic compounds for in vitro and in vivo screening and optimizing process for drug molecule syntheses. In 2008, Dnyaneshwar joined Prof. Sigurdsson’s laboratory for his Ph.D. study at the University of Iceland. His Ph.D. thesis mainly describes syntheses of nitroxide spin-labeled and fluorescent nucleosides and their incorporation into DNA and RNA using phosphoramidite chemistry. These modified nucleosides are useful probes for studying the structure and dynamics of nucleic acids by EPR and fluorescence spectroscopies. In 2014, after finishing his Ph.D., he worked as post doc fellow in same laboratory and mainly worked on spin labelling of RNA. At the university of Purdue in his second post doc, he was totally dedicated to syntheses of small molecules for anti-cancer activity and modification of cyclic dinucleotides for antibacterial activity. During his research experience, he has authored 8 international publications in peer reviewed journals like Chemical Communications, Chemistry- A European Journal, Journal of organic chemistry and Organic and Biomolecular Chemistry.

Dnyaneshwar B. Gophane, Guest blogger, Hydrogen-bonding controlled rigidity of an isoindoline-derived nitroxide spin label for nucleic acids Dnyaneshwar B. Gophane Hydrogen-bonding controlled rigidity of an isoindoline-derived nitroxide spin label for nucleic acids

breakthrough designation Comments Off

May 032017

Hydrogen-bonding controlled rigidity of an isoindoline-derived nitroxide spin label for nucleic acids

Dnyaneshwar B. Gophane and Snorri Th. Sigurdsson*

^a Department of Chemistry, Science Institute, University of Iceland, Dunhaga 3, 107 Reykjavik, Iceland

Chem. Commun., 2013, 49, 999—1001

[Link: http://pubs.rsc.org/en/content/articlelanding/2013/cc/c2cc36389e#!divAbstract]

Graphical abstract

Two new nitroxide-modified nucleosides, ^OxU and ^ImU, were synthesized and incorporated into DNA. ^ImU has lower mobility in duplex DNA due to an intramolecular hydrogen bond.

Abstract

Nucleosides spin-labelled with isoindoline-derived benzimidazole (^ImU) and benzoxazole (^OxU) moieties were synthesized and incorporated into DNA oligonucleotides. Both labels display limited mobility in duplex DNA but ^ImU was less mobile, which was attributed to an intramolecular hydrogen bond between the N-H of the imidazole and O4 of the uracil nucleobase.

Scheme 1. Literature methods for synthesis of diamino isoindoline 6.

Scheme 2. Improved synthesis of diamino isoindoline 6.

Scheme 3. Synthesis of benzimidazole derivative phosphoramidites 10.

str3

Scheme 4. Synthesis of benzoxazole derivative phosphoramidites 14.

Highligts

Synthesized novel nitroxide-labelled benzimidazole (^ImU) and benzoxazole (^OxU) derivatives of 2′-deoxyuridine as spin probes for nucleic acids.
Both ^ImU and ^OxU had limited mobility in duplex DNA, in particular ^ImU, indicating that rotation around the single bond linking the spin label to the uracil is restricted.
^ImU is the first example of using intramolecular hydrogen-bonding to restrict spin label mobility.
^ImU should not only be a good label for accurate distance measurements in oligonucleotides, but also yield information about the relative orientation of the labels.

ABOUT GUEST BLOGGER

Dr. Dnyaneshwar B. Gophane, Ph. D.

Post doc fellow at Purdue university and university of Iceland

Email, [email protected]

Dr. Dnyaneshwar Gophane

Phone: +917083553405 and +917558215379

These modified nucleosides are useful probes for studying the structure and dynamics of nucleic acids by EPR and fluorescence spectroscopies. In 2014, after finishing his Ph.D., he worked as post doc fellow in same laboratory and mainly worked on spin labelling of RNA. At the university of Purdue in his second post doc, he was totally dedicated to syntheses of small molecules for anti-cancer activity and modification of cyclic dinucleotides for antibacterial activity. During his research experience, he has authored 8 international publications in peer reviewed journals like Chemical Communications, Chemistry- A European Journal, Journal of organic chemistry and Organic and Biomolecular Chemistry.

Dr. D. Srinivasa Reddy has been appointed as an editor of Bioorganic & Medicinal Chemistry Letters, Elsevier Publications.

INDIA Comments Off

May 012017

Dr. D. Srinivasa Reddy has been appointed as an editor of Bioorganic & Medicinl Chemistry Letters, Elsevier Publications. Congratulation Sir !

Click here for details. https://www.journals.elsevier.com/bioorganic-and-medicinal-chemistry-letters

GUEST BLOGGER, Dr Pravin Patil, A New Combination of Cyclohexylhydrazine and IBX for Oxidative Generation of Cyclohexyl Free Radical and Related Synthesis of Parvaquone

Uncategorized Comments Off

Apr 292017

Image for unlabelled figure

As a GUEST BLOGGER, myself Dr Pravin Patil, presenting my paper as below

A New Combination of Cyclohexylhydrazine and IBX for Oxidative Generation of Cyclohexyl Free Radical and Related Synthesis of Parvaquone

Pravin C Patil*^a and Krishnacharya G Akamanchi

Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai-400 019.

^aPresent address: Department of Chemistry, University of Louisville, Louisville, KY, USA.

*Corresponding Author: [email protected]

Tetrahedron Letters 2017, 58 (19), 1883-1886 (Recently published)

[Link: http://www.sciencedirect.com/science/article/pii/S004040391730429X]

Graphical Abstract:

Abstract: The present paper demonstrate a single-step and straightforward synthesis of parvaquone through intermediacy of cyclohexyl radical generated from novel combination of cyclohexylhydrazine and o-iodoxybenzoic acid and subsequently trapped by 2-hydroxy-1,4-naphthoquinone. Formation of cyclohexyl free radical using this new combination was reaffirmed by cyclohexylation of readily available 2-amino-1, 4-naphthoquinone.

Scheme: Literature methods for synthesis of parvaquone

Scheme: IBX mediated oxidative arylation towards synthesis of 1 (Parvaquone)

Scheme : Cyclohexyl radical mediated postulated mechanism for formation of Parvaquone, 1

Synthesis of 2-cyclohexyl-3-hydroxy-1,4-naphthoquinone (parvaquone) (1): To a solution of 3 (1.0 g, 5.74 mmol) in acetonitrile (20 mL) was added IBX (3.80 g, 13.6 mmol) in one lot and stirred for 5 min at room temperature. To this was added dropwise a solution of 8 (0.78 g, 6.8 mmol) dissolved in 10 mL of acetonitrile over the course of 20 min. During the addition of 8 exotherm (up to 35 °C) was observed with evolution of nitrogen gas in the form of bubbles. Reaction progress was monitored by TLC (using mobile phase, hexane: ethyl acetate/5:95). After satisfactory TLC, water (20 mL) was added to the reaction mixture and acetonitrile was evaporated using rotary evaporator. To the residue obtained was added dichloromethane (30 mL). Oganic layer was separated and washed with saturated sodium bicarbonate solution followed by saturated solution of sodium sulphite. Separated organic layer was dried over anhydrous sodium sulphate and evaporated to obtain crude 1 which was further purified by column chromatography (mobile phase – hexane: ethyl acetate/5:95) to afford 1 as yellow solid, (0.88 g, 60% yield); mp 136-138 °C (lit.¹⁸135-136°C); FT-IR (KBr): 3585, 3513, 3071, 2926, 2853, 1666, 1604, 1590 cm^-1;

¹H NMR (300 MHz; CDCl₃): δ 8.10-8.06 (d, J = 12 Hz, 2H), 7.74-7.67 (d, J = 22 Hz, 2H, 7.45 (s, 1H, OH), 3.11-3.03 (t, J = 16 Hz, 1H), 1.99-1.34 (m, 10H); ¹³C NMR (75 MHz; CDCl₃): δ 184.5, 181.9, 152.8, 135.1, 134.9, 132.7, 129.2, 127.9, 126.9, 125.9, 35.1, 29.2, 26.7, 25.9.

Highlights

New method of generating cyclohexyl radical by using IBX and cyclohexylhydrazine.
Parvaquone synthesized in 60% yield using metal, hazardous peroxide free conditions.
Described method has advantages of single step and mild reaction conditions.
The mechanism for cyclohexyl radical mediated synthesis of parvaquone is postulated.

please note………

Image result for A new combination of cyclohexylhydrazine and IBX for oxidative generation of cyclohexyl free radical and related synthesis of parvaquone

ABOUT GUEST BLOGGER

Dr. Pravin C. Patil

Postdoctoral Research Associate at University of Louisville

see…….http://oneorganichemistoneday.blogspot.in/2017/04/dr-pravin-patil.html

Dr. Pravin C Patil completed his B.Sc. (Chemistry) at ASC College Chopda (Jalgaon, Maharashtra, India) in 2001 and M.Sc. (Organic Chemistry) at SSVPS’S Science College Dhule in North Maharashtra University (Jalgaon, Maharashtra, India) in year 2003. After M.Sc. degree he was accepted for summer internship training program at Bhabha Atomic Research Center (BARC, Mumbai) in the laboratory of Prof. Subrata Chattopadhyay in Bio-organic Division. In 2003, Dr. Pravin joined to API Pharmaceutical bulk drug company, RPG Life Science (Navi Mumbai, Maharashtra, India) and worked there for two years. In 2005, he enrolled into Ph.D. (Chemistry) program at Institute of Chemical Technology (ICT), Matunga, Mumbai, aharashtra, under the supervision of Prof. K. G. Akamanchi in the department of Pharmaceutical Sciences and Technology.

After finishing Ph.D. in 2010, he joined to Pune (Maharashtra, India) based pharmaceutical industry, Lupin Research Park (LRP) in the department of process development. After spending two years at Lupin as a Research Scientist, he got an opportunity in June 2012 to pursue Postdoctoral studies at Hope College, Holland, MI, USA under the supervision of Prof. Moses Lee. During year 2012-13 he worked on total synthesis of achiral anticancer molecules Duocarmycin and its analogs. In 2014, he joined to Prof. Frederick Luzzio at the Department for Chemistry, University of Louisville, Louisville, KY, USA to pursue postdoctoral studies on NIH sponsored project “ Structure based design and synthesis of Peptidomimetics targeting P. gingivalis.

During his research experience, he has authored 23 international publications in peer reviewed journals and inventor for 4 patents.

//////////////Parvaquone, guest blogger, pravin patil

Dr. Vinayak Pagar( GUEST BLOGGER) Development of a Povarov Reaction/Carbene Generation Sequence for Alkenyldiazocarbonyl Compounds

cancer, new drugs, spectroscopy, SYNTHESIS Comments Off

Apr 282017

Discussing my paper……..

Metal-catalyzed cycloadditions of alkenyldiazo reagents are useful tools to access carbo- and heterocycles.[1] These diazo compounds are chemically sensitive toward both Brønsted orLewis acids. Their reported cycloadditions rely heavily on the formation of metal carbenes to initiate regio- and stereoselective [3+n] cycloadditions (n=2–4) with suitable dipolarophiles.[2–4] A noncarbene route was postulated for a few copper-catalyzed cycloadditions of these diazo species, but they resulted in complete diazo decomposition.[3a, 4a, 5] oyle and co-workers reported[4a] a [3+2] cycloaddition of the alkenylrhodium carbene A with imines to give dihydropyrroles (Scheme 1a). We proposed a cycloaddition the tetrahydroquinoline derivatives 3 and 3’, as well as the tetrahydro-1H-benzo[b]azepine species 4. Access to these frameworks are valuable

Access to these frameworks are valuable for the preparation of several bioactive molecules including 2-phenyl-2,3-
dihydroquinolone,[8a] L-689,560,[8b] torcetrapib,[8c] martinellic acid,[8d] OPC-31260,[8e] OPC-51803,[8f] and tetraperalone A (Figure 1).[8g] Their specific biological functions have been well documented.[8]

Spectral data for ethyl 2-diazo-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-4-yl) acetate (2a)

Yellow Semi-Solid;

IR (KBr, cm-1 ): 3542 (m), 2117 (s), 3015 (s), 1737 (s), 1564 (s), 1334 (m), 1137 (s), 817 (s);

1H NMR (600 MHz, CDCl3): δ 7.41 (d, J = 7.3 Hz, 2 H), 7.36 ~ 7.33 (m, 2 H), 7.30 (t, J = 7.3 Hz, 2 H), 7.07 (d, J = 7.6 Hz, 1 H), 7.04 (t, J = 7.6 Hz, 1H), 6.71 (t, J = 7.2 Hz, 1H), 6.55 (d, J = 7.9 Hz, 1H) 4.56 (dd, J = 11.0, 2.3 Hz, 1H ), 4.25 (q, J = 7.1 Hz, 2H ), 4.21 (dd, J = 11.0, 5.3 Hz, 1H ), 4.01 (s, 1H) 2.36 ~ 2.33 (m, 1H), 2.00 (dd, J = 11.8, 2.3 Hz, 1H ), 1.28 (t, J = 7.1 Hz, 3H);

13C NMR (150 MHz, CDCl3): δ 167.2, 145.3, 142.9, 128.6, 128.0, 127.8, 126.5, 126.4, 118.8, 117.9, 114.4, 60.9, 59.5, 56.2, 36.8, 32.6, 14.4.

HRMS calcd for C19H19N3O2: 321.1477; found: 321.1483.

Communication

Development of a Povarov Reaction/Carbene Generation Sequence for Alkenyldiazocarbonyl Compounds^†

Authors, Appaso Mahadev Jadhav, Vinayak Vishnu Pagar, and Rai-Shung Liu*, DOI: 10.1002/anie.201205692

^†We thank the National Science Council, Taiwan, for financial support of this work., [*] A. M. Jadhav, V. V. Pagar, Prof. Dr. R.-S. Liu

Department of Chemistry, National Tsing Hua University
Hsinchu (30013) (Taiwan)
E-mail: [email protected]

Abstract

Rings aplenty: A HOTf-catalyzed (Tf=trifluoromethanesulfonyl) Povarov reaction of alkenyldiazo species has been developed and delivers diazo-containing cycloadducts stereoselectively (see scheme). The resulting cycloadducts provide access to six- and seven-membered azacycles through the generation of metal carbenes as well as the functionalization of diazo group.

[1] Selected reviews: a) M. P. Doyle,M. A. McKervy, T. Ye, Modern Catalytic Methods for Organic Synthesis with Diazo Compounds, Wiley, New York, 1998; b) A. Padwa, M. D. Weingarten, Chem. Rev. 1996, 96, 223; c) H. M. L. Davies, J. R. Denton, Chem. Soc. Rev. 2009, 38, 3061; d) M. P. Doyle, R. Duffy, M. Ratnikov, L. Zhou, Chem. Rev. 2010, 110, 704; e) H. M. L. Davies, D. Morton, Chem. Soc. Rev. 2011, 40, 1857; f) Z. Zhang, J. Wang, Tetrahedron
2008, 64, 6577.
[2] Selected examples for carbocyclic cycloadducts, see: a) L. Deng, A. J. Giessert, O. O. Gerlitz, X. Dai, S. T. Diver, H. M. L. Davies, J. Am. Chem. Soc. 2005, 127, 1342; b) H. M. L. Davies, Adv. Cycloaddit. 1999, 5, 119; c) H. M. L. Davies, B. Xing, N. Kong, D. G. Stafford, J. Am. Chem. Soc. 2001, 123, 7461; d) H. M. L. Davies, T. J. Clark, H. D. Smith, J. Org. Chem. 1991, 56, 3819; e) Y. Liu, K. Bakshi, P. Zavalij, M. P. Doyle, Org. Lett. 2010, 12, 4304; f) J. P. Olson, H. M. L. Davies, Org. Lett. 2008, 10, 573.
[3] For oxacyclic cycloadducts, see: a) X. Xu, W.-H. Hu, P. Y. Zavalij, M. P. Doyle, Angew. Chem. 2011, 123, 11348; Angew. Chem. Int. Ed. 2011, 50, 11152; b) M. P. Doyle, W. Hu, D. J. Timmons, Org. Lett. 2001, 3, 3741.

[4] For azacyclic cycloadducts, see selected reviews: a) M. P. Doyle, M. Yan, W. Hu, L. Gronenberg, J. Am. Chem. Soc. 2003, 125, 4692; b) J. Barluenga, G. Lonzi, L. Riesgo, L. A. Lpez, M. Tomas, J. Am. Chem. Soc. 2010, 132, 13200; c) M. Yan, N. Jacobsen, W. Hu, L. S. Gronenberg, M. P. Doyle, J. T. Colyer, D. Bykowski, Angew. Chem. 2004, 116, 6881; Angew. Chem. Int. Ed. 2004, 43, 6713; d) X.Wang, X. Xu, P. Zavalij, M. P. Doyle, J. Am.
Chem. Soc. 2011, 133, 16402; e) Y. Lian, H. M. L. Davies, J. Am. Chem. Soc. 2010, 132, 440; f) X. Xu, M. O. Ratnikov, P. Y. Zavalij, M. P. Doyle, Org. Lett. 2011, 13, 6122; g) V. V. Pagar, A. M. Jadhav, R.-S. Liu, J. Am. Chem. Soc. 2011, 133, 20728; h) R. P. Reddy, H. M. L. Davies, J. Am. Chem. Soc. 2007, 129, 10312.

[5] Y. Qian, X. Xu, X.Wang, P. Zavalij,W. Hu, M. P. Doyle, Angew. Chem. 2012, 124, 6002; Angew. Chem. Int. Ed. 2012, 51, 5900.
[6] Povarov reactions refer to the formal [4+2] cycloadditions of Naryl imines with enol ethers or enamines. See reviews: a) L. S. Povarov, Russ. Chem. Rev. 1967, 36, 656; b) V. V. Kouznetsov, Tetrahedron 2009, 65, 2721; c) D. Bello, R. Ramn, R. Lavilla, Curr. Org. Chem. 2010, 14, 332; d) M. A. McCarrick, Y. D. Wu, K. N. Houk, J. Org. Chem. 1993, 58, 3330; e) A. Whiting, C. M. Windsor, Tetrahedron 1998, 54, 6035.

[7] For Povarov reactions catalyzed by Brønsted acids, see selected examples: a) H. Xu, S. J. Zuend, M. G. Woll, Y. Tao, E. N. Jacobson, Science 2010, 327, 986; b) T. Akiyama, H. Morita, K. Fuchibe, J. Am. Chem. Soc. 2006, 128, 13070; c) H. Liu, G. Dagousset, G. Masson, P. Retailleau, J. Zhu, J. Am. Chem. Soc. 2009, 131, 4598; d) G. Dagousset, J. Zhu, G. Masson, J. Am. Chem. Soc. 2011, 133, 14804; e) H. Ishitani, S. Kobayashi, Tetrahedron Lett. 1996, 37, 7357; f) G. Bergonzini, L. Gramigna, A. Mazzanti, M. Fochi, L. Bernardi, A. Ricci, Chem. Commun.
2010, 46, 327; g) L. He, M. Bekkaye, P. Retailleau, G. Masson, Org. Lett. 2012, 14, 3158.

[8] a) Y. Xia, Z.-Y. Yang, P. Xia, K. F. Bastow, Y. Tachibana, S.-C. Kuo, E. Hamel, T. Hackl, K.-H. Lee, J. Med. Chem. 1998, 41, 1155; b) R.W. Carling, P. D. Leeson, A. M. Moseley, J. D. Smith, K. Saywell, M. D. Trickelbank, J. A. Kemp, G. R. Marshall, A. C. Foster, S. Grimwood, Bioorg. Med. Chem. Lett. 1993, 3, 65;
c) D. B. Damon, R. W. Dugger, R.W. Scott, U.S. Patent 6,689,897, 2004; d) D. A. Powell, R. A. Batey, Org. Lett. 2002, 4, 2913; e) A. Matsuhisa, K. Kikuchi, K. Sakamoto, T. Yatsu, A. Tanaka, Chem. Pharm. Bull. 1999, 47, 329; f) M. Y. Christopher, E. A. Christine, D. M. Ashworth, J. Barnett, A. J. Baxter, J. D. Broadbridge, R. J. Franklin, S. L. Hampton, P. Hudson, J. A. Horton, P. D. Jenkins, A. M. Penson, G. R.W. Pitt, P. Rivire,
P. A. Robson, D. P. Rooker, G. Semple, A. Sheppard, R. M.Haigh, M. B. Roe, J. Med. Chem. 2008, 51, 8124; g) C. Li, X. Li, R. Hong, Org. Lett. 2009, 11, 4036.

About author( Me)

Dr. Vinayak Pagar

Postdoctoral Research Fellow at The Ohio State University

Vinayak Vishnu Pagar was born in Nasik, Maharashtra (India) in 1983. He obtained his BSc and MSc degrees in chemistry from the University of Pune (India) in 2004 and 2006, respectively. From 2006–2010, he worked as Research Associate in pharmaceutical companies like Jubilant Chemsys Ltd. and Ranbaxy Laboratories Ltd. (India). In 2010, he joined the group of Professor Rai-Shung Liu to pursue his PhD degree in National Tsing Hua University (Taiwan) and completed it in 2014. Subsequently, he worked as a postdoctoral fellow in the same group for one year. Currently, he is working as a Research Scientist at The Ohio State University, Columbus, Ohio USA. His research focused on the development of new organic reactions by using transition-metal catalysis such Gold, Silver, Rhodium, Zinc, Cobalt, Nickel and Copper metals which enables mild, diastereoselective, enantioselective and efficient transformations of variety of readily available substrates to wide range of synthetically useful nitrogen and oxygen containing heterocyclic products which are medicinally important. He published his research in a very high impact factor international Journals includes J. Am. Chem. Soc., Angew. Chem. Int. Ed., J. Org. Chem., Chem- A. Eur. Journal, Org. Biomol. Chem., and Synform (Literature Coverage).

Dr. Vinayak Pagar

Postdoctoral Researcher

Department of Chemistry and Biochemistry

The Ohio State University

100 West 18th Avenue

Columbus, Ohio 43210 USA

[email protected]

/////////Vinayak Pagar, Postdoctoral Research Fellow, The Ohio State University, blog, Povarov Reaction, Carbene Generation Sequence, Alkenyldiazocarbonyl Compounds

Towards nitrile-substituted cyclopropanes – a slow-release protocol for safe and scalable applications of diazo acetonitrile

spectroscopy, SYNTHESIS Comments Off

Apr 222017

Towards nitrile-substituted cyclopropanes – a slow-release protocol for safe and scalable applications of diazo acetonitrile

Green Chem., 2017, Advance Article

DOI: 10.1039/C7GC00602K, Communication

Katharina J. Hock, Robin Spitzner, Rene M. Koenigs
Applications of diazo acetonitrile in cyclopropa(e)nation reactions are realized in a slow-release protocol with bench-stable reagents. Cyclopropyl nitriles are obtained in one step in good diastereoselectivity on a gram-scale providing an efficient entry into this class of fragrances and drug-like molecules.

trans-2-phenylcyclopropane-1-carbonitrile

colorless solid (46 mg, 81%);

m.p. = 29°C;

1 H-NMR (600 MHz, CDCl3): δ = 7.34 – 7.30 (m, 2H), 7.28 – 7.24 (m, 1H), 7.12 – 7.08 (m, 2H), 2.63 (ddd, J = 9.2, 6.7, 4.7 Hz, 1H), 1.62 (dt, J = 9.2, 5.4 Hz, 1H), 1.55 (ddd, J = 8.7, 5.5, 4.8 Hz, 1H), 1.45 (ddd, J = 8.8, 6.7, 5.3 Hz, 1H);

13C-NMR (151 MHz, CDCl3): δ = 137.55, 128.76, 127.41, 126.31, 121.05, 24.90, 15.24, 6.63;

HRMS (ESI): m/z calc. for [C10H9NNa]: 166.06272, found 166.06276;

IR (KBr): νmax/cm-1 = 3044, 2235, 2098, 1761, 1600, 1461, 1220, 1051, 920, 705.

The analytical data is in correspondence with the literature [2]

[2] M. Gao, N. N. Patwardhan, P. R. Carlier, J. Am. Chem. Soc., 2013, 135 (38), 14390–14400

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C7GC00602K?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

Towards nitrile-substituted cyclopropanes – a slow-release protocol for safe and scalable applications of diazo acetonitrile

Katharina J. Hock,^a Robin Spitzner^a and Rene M. Koenigs*^a

Author affiliations

*Corresponding authors

^aRWTH Aachen University, Institute of Organic Chemistry, Landoltweg 1, D-52074 Aachen, Germany
E-mail: [email protected]

Abstract

Diazo acetonitrile has long been neglected despite its high value in organic synthesis due to a high risk of explosions. Herein, we report our efforts towards the transient and safe generation of this diazo compound, its applications in iron catalyzed cyclopropanation and cyclopropenation reactions and the gram-scale synthesis of cyclopropyl nitriles.

//////////

Dimethylcarbamoyl Chloride, a known carcinogen

PROCESS Comments Off

Mar 142017

Identifiers

CAS Number	79-44-7
ECHA InfoCard	100.001.099
PubChem	6598
Properties
Chemical formula	C₃H₆ClNO

Dimethylcarbamoyl Chloride

Mechanisms for the Formation of Dimethylcarbamoyl Chloride

Thionyl chloride is the most common reagent in process chemistry for the conversion of a carboxylic acid to an acid chloride. One of the primary factors is cost, since the reagent is inexpensive and represents one of the most cost-efficient ways of preparing acid chlorides. However, one disadvantage of thionyl chloride is the potential formation of dimethylcarbamoyl chloride, a known carcinogen in animal models, when used in combination with DMF as catalyst.

Dimethylcarbamoyl chloride is a reagent for transferring a dimethylcarbonyl group to alcoholic or phenolic hydroxyl groups forming dimethyl carbamates, usually having pharmacological or pesticidal activities. Because of its high toxicity and its carcinogenic properties shown in animal experiments and presumably also in humans,^[1] dimethylcarbamoyl chloride can only be used under stringent safety precautions.

Production and occurrence

The production of dimethylcarbamoyl chloride from phosgene and dimethylamine (DMA) was reported as early as 1879 (reported as “Dimethylharnstoffchlorid” – dimethylurea chloride).^[2]

Dimethylcarbamoyl chloride can be produced in high yields (90%) at 275 °C by reacting phosgene with gaseous dimethylamine in a flow reactor.^[3] To suppress the formation of ureas excessive phosgene is used (in a 3:1 ratio).

The reaction can also be carried out at the laboratory scale with diphosgene or triphosgene and a aqueous dimethylamine solution in the two-phase system benzene+xylene/water in a stirred reactor with sodium hydroxide as an acid scavenger. However, considerably lower yields (56%) are achieved due to the hydrolysis sensitivity of dimethylcarbamoyl chloride .^[4]

Dimethylcarbamoyl chloride is also formed (together with methyl chloride) when reacting phosgene with trimethylamine.^[5]

A more recent process is based on dimethylamine chloride, which is converted practically quantitatively to dimethylcarbamoyl chloride on a palladium catalyst under pressure with carbon monoxide at room temperature.^[6]

Dicarbamoyl chloride can also be formed in small amounts (0-20 ppm) from dimethylformamide (DMF) in the Vilsmeier-Haack reaction^[7] or when DMF is used as a catalyst in the reaction of carboxylic acids with thionyl chloride to the corresponding carboxylic acid chlorides.^[8]

The tendency towards dicarbamoyl chloride formation depends on the chlorination reagent (thionyl chloride> oxalyl chloride> phosphorus oxychloride) and is higher in the presence of a base. However, dicarbamoyl chloride hydrolyses very quickly to dimethylamine, hydrochloric acid and carbon dioxide (with a half-life of about 6 minutes at 0 °C) so that less than 3 ppm of dicarbamoyl chloride are found in the Vilsmeier product after aqueous work-up.^[9]

Properties[edit]

Dimethylcarbamoyl chloride is a clear, colorless, corrosive and flammable liquid with a pungent odor and a tear-penetrating effect, which decomposes rapidly in water.^[10]Because of its unpleasant, toxic, mutagenic and carcinogenic properties^[11]^[12] it has to be used under extreme precautions.

Dimethylcarbamoyl chloride behaves like an acid chloride whose chlorine atom can be exchanged for other nucleophiles. Therefore, it reacts with alcohols, phenols and oximes to the corresponding N, N-dimethylcarbamates, with thiols to thiolourethanes, with amines and hydroxylamine to substituted ureas, and with imidazoles and triazoles to carbamoylazoles.^[13]

Dimethylcarbamoyl chloride is less reactive and less selective to substrates with multiple nucleophilic centers than conventional acid chlorides.

Unsaturated conjugated aldehydes such as (2E)-butenal react with dimethylcarbamoyl chloride forming dienyl carbamates, which can be used as dienes in Diels-Alder reactions.^[14]

Alkali metal carboxylates react with dimethylcarbamoyl chloride forming the corresponding dimethylamides. Dimethylcarbamoyl chloride reacts with anhydrous sodium carbonate^[15] or with excess dimethylamine to tetramethylurea.^[16]

The reaction of dimethylcarbamoyl chloride with DMF forms tetramethylformamidinium^[17] chloride which is a major intermediate in the preparation of tris(dimethylamino)methane, a reagent for the introduction of enamine functions in conjunction with activated methylene groups^[18] and the preparation of amidines.^[19]

Dimethylcarbamoyl chloride is a starting material for the insecticide class of the dimethyl carbamates^[20] which act as inhibitors of acetylcholinesterase, including dimetilane,^[21]and the related compounds isolane, pirimicarb and triazamate.

The quaternary ammonium compounds neostigmine^[22] finds pharmaceutical applications as acetylcholinesterase inhibitors. It is obtained from 3-dimethylaminophenol and dimethylcarbamoyl chloride and subsequent quaternization with methyl bromide or dimethyl sulfate^[23]

and pyridostigmine, which is obtainable from 3-hydroxypyridine and dimethylcarbamoyl chloride and subsequent reaction with methyl bromide.^[24]

Dimethylcarbamoyl chloride is also used in the synthesis of the benzodiazepine camazepam.^[25]

Image result for Dimethylcarbamoyl Chloride

13c NMR

MASS

RAMAN

References

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