EDOXABAN INTERMEDIATE, 2-amino-5-methyl-4,5,6,7-tetrahydro thiazolone [5,4-c] pyridine

ENDOXABAN





2-amino-5-methyl-4,5,6,7-tetrahydro thiazolone [5,4-c] pyridine 

(Reference Example 1)　2-amino-5-methyl-4,5,6,7-tetrahydro thiazolone [5,4-c] pyridine (1-n) (The method described in WO 2005/047296 Pamphlet )

[0091]

[Of 35] 　in 2-PrOH (1.44L) solution was heated to 50 ℃ 1- methyl-4-piperidone (180.0g), 2-PrOH (360mL) solution of cyanamide (67.0g), and sulfur powder (51.0 g) it was added. Pyrrolidine (13.3mL) was added to the reaction mixture, after stirring for 2 hours at 50 ℃, followed by stirring overnight and allowed to cool to room temperature. 　The reaction mixture was cooled to 10 ℃ less in an ice water bath and stirred for 1 hour at the same temperature. Is filtered and the precipitated crystals were washed with 2-PrOH (540mL), the title compound was dried under reduced pressure at 40 ℃ (209.9g, 78%) was obtained.

[0092]

¹ H-NMR (CDCl ₃ ) ppm: 4.86 (Br, 2H), 3.47-3.46 (t, 2H, J = 1.9 Hz), 2.78-2.71 (M, 2H), 2.71-2.65 (M, 2H), 2.47 . (s, 3H)
MS (FAB) M / z: 170 (M + H) ⁺
elemental analysis: C ₇ H ₁₁ N ₃ as S,
　theoretical value: C, 49.68; H, 6.55; N, 24.83; S, 18.95
　measured value: C, 49.70; H, 6.39; N, 24.91; S, 19.00.




 

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(E)-2-(1,6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)ethylamine hydrochloride

Reference Example 7 (E)-2-(1,6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)ethylamine hydrochloride

To a mixed suspension of (E)-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)acetonitrile (10.0 g, 50.7 mmol) in toluene (37.5 mL) and methanol (12.5 mL) were added activated cobalt (7.22 g) and 14.4% aqueous solution of potassium hydroxide (1.4 g), and stirred for 6.5 hrs at to 50° C. under hydrogen atmosphere (0.2 MPa). The reaction solution was filtered, and to the filtrate were added toluene (170 ml) and methanol (35 ml) to separate the layers. 0.5N Hydrochloric acid (101 mL) was added to the organic layer, and stirred for 30 minutes at 25 to 30° C. Then, the layers were separated, and active charcoal (1 g) was added to the aqueous layer, followed by stirring. The active charcoal was removed by filtration to give an aqueous solution of title compound (246 g, Net 12.0 g, yield 99.6%).

http://www.google.com/patents/US20130079397

(E)-2-(6,7-dihydro-1H-indeno[5,4-b]furan-8(2H)-ylidene)acetonitrile

CAS NO.: 196597-79-2

Purity: 98.00%

Formula: C13H11NO

Molecular Weight: 197.24

Product description： Intermediate of Ramelteon CAS#196597-26-9

REFERENCE EXAMPLE 6 
(E)-(1,6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)acetonitrile

To a solution of toluene (184 g), 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (8.5 g, 48.9 mmol) and diethyl cyanomethylphosphonate (10.4 g, 58.7 mmol) was added dropwise 28% sodium methoxide solution in methanol (11.3 g) over 1 hr under ice-cooling, and reacted for 4 hrs. To the reaction solution was added dropwise water (85 μg), and warmed, then the layers were separated. The organic layer was washed with water, and filtered to remove dusts under pressurization. The organic layer was concentrated under reduced pressure, and to the residue was added methanol and concentrated under reduced pressure to substitute the solvent. After stirring for 1 hr under heating with reflux, the solution was cooled and matured for 1 hr. The crystallization solution was filtered, and the crystals were dried under reduced pressure to give title compound (amount 8.1 g, yield 84.4%).

(1,6,7,8-tetrahydro-2H-indeno [5,4-b]furan-8-yl)acetonitrile

(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)acetonitrile of formula (10):

enantioselective reduction on the intermediate of formula (10) to obtain (1,6,7,8-tetrahydro-2H-indeno [5,4-b]furan-8-yl)acetonitrile of formula (XI)

http://www.google.com/patents/US8242291
EXAMPLE 8

This example refers to reaction i of the process of the invention.

The product of formula (X) obtained as described in example 7 is dissolved in 22 kg of THF at room temperature. 2.8 kg of tetrabutylammonium fluoride trihydrate are added to the solution ensuring that the temperature does not exceed 30° C. (slight exothermia). It is kept under agitation for at least one hour at T=25±5° C. monitoring the progress of the reaction (TLC).

In a separate reactor a solution of 9 kg of NaCl in 45 l of water is prepared. At the end of the reaction the solution of NaCl is poured onto the reaction solution regulating the temperature so that it does not exceed 30° C. It is agitated for a few minutes and then re-extracted twice with 18 kg of isopropyl acetate. The collected organic phases are washed twice with 30 kg of water. The organic phase is concentrated to dryness distilling the solvent at a reduced pressure and T=45±5° C. 2.40 kg of oily residue are obtained which is purified by chromatography on 40 kg of silica gel (heptane:ethyl acetate 85:15). After elimination of the solvent at reduced pressure and T=45±5° C., 934 g of intermediate (XI) is obtained which is refluxed in 2.8 l of methanol in the presence of decolouring carbon. The suspension is hot filtered. Part of the solvent is distilled at reduced pressure until a residual volume of approximately 2.4 l is obtained. It is cooled to 0<T<5° C. for approximately 2 hours before filtering the solid. The product is dried at T=45° C. and at reduced pressure for approximately 12 hours. 577 g of intermediate (XI) are obtained of quality suitable for continuation of the synthesis. A sample of the product thus obtained, after further chromatographic purification for analytical purposes, undergoes ¹H-NMR and mass analysis obtaining the following result:

Electronic impact mass: [M⁺]=199; [M⁺]−CH₂CN=159

¹H-NMR (500 MHz, CDCl₃): δ (ppm)

1.98-2.08 ppm, m, 1H, 2.40-2.50 ppm, m, 1H, 2.52-2.59 ppm, dd, J=8 Hz, J=15 Hz, 1H, 2.66-2.75 ppm, dd, J=6 Hz, J=15 Hz, 1H, 2.81-2.88 ppm, m, 1H, 2.96-3.04 ppm, m, 1H; 3.13-3.22 ppm, m, 1H, 3.28-3.36 ppm, 1H, m; 3.48-3.56 ppm, m, 1H, 4.52-4.69 ppm, m, 2H, 6.69 ppm, d, J=8 Hz, 1H, 7.02 ppm, d, J=8 Hz, 1H.

(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[1,2]thiazolo[3,4-(/]pyrimidin-3- yl)acetic acid

(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[1,2]thiazolo[3,4-(i]pyrimidin-3-yl)acetic acid

Step 1 : Methyl 6-amino-l,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5- carbodithioate: 
¹H NMR (300 MHz, CF₃COOD) δ 2.73 (s, 3H), 3.51 (s, 3H), 3.62 (s, 3H).

Step 2: 5,7-Dimethyl-3-(methylsulfanyl)[1,2]thiazolo[3,4-ύT|pyrimidine-4,6(5H,7H)- dione: 

¹H NMR (300 MHz, DMSO-^₆) δ 2.67 (s, 3H), 3.18 (s, 3H), 3.40 (s, 3H). 

Step 3: 5,7-Dimethyl-3-(methylsulfonyl)[1,2]thiazolo[3,4-(/]pyrimidine-4,6(5H,7H)- dione:  

 ¹H NMR (300 MHz, DMSO-(Z₆) δ 3.26 (s, 3H), 3.49 (s, 3H), 3.71 (s, 3H).

Step 4: Diethyl (5,7-dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[1,2]thiazolo[3,4-d]pyrimidin- 3-yl)propanedioate:  ¹H NMR (300 MHz, DMSO-(Z₆) δ 1.32 (t, J = 7.2 Hz, 6H), 3.40 (s, 3H), 3.64 (s, 3H), 4.24-4.37 (m, 4H), 6.05 (s, 1H).

Step 5: Ethyl (5,7-dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[1,2]thiazolo[3,4-d]pyrimidin-3- yl)acetate:; ¹H NMR (300 MHz, DMSCM₆) δ 1.34 (t, J = 6.9 Hz, 3H), 3.40 (s, 3H), 3.63 (s, 3H), 4.30 (q, J= 6.9 Hz, 2H), 4.50 (s, 2H)

Step 6: (5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[1,2]thiazolo[3,4-(/]pyrimidin-3- yl)acetic acid: The title compound was prepared according to same procedure as described for Intermediate 1, Step 5 by using above Step 5 intermediate (9.0 g, 31.8 mmol), 6 N H₂SO₄ (80 ml) and dioxane (80 ml) to give 5.8 g of the product as yellow solid; 

 ¹H NMR (300 MHz, DMSO-^₆)
δ 3.22 (s, 3H),
3.46 (s, 3H),
4.51 (s, 2H),
13.45 (br s, 1H).  -0H

Interpretation

 

http://www.google.com/patents/EP2411397A1?cl=en 

(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[1,2]thiazolo[5,4-(i]pyrimidin-3-yl)acetic acid

 

¹H NMR (300 MHz, DMSO-<4) δ 3.22 (s, 3H), 3.46 (s, 3H), 3.96 (s, 2H), 12.57 (br s, 1H).

2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[1,2]thiazolo[3,4-ύT|pyrimidin-3-yl)-N-{4- [3 -fluoro-4-(trifluoromethyl)phenyl] - 1 ,3 -thiazol-2-yl } acetamide

 ¹H ΝMR (300 MHz, DMSO-^₆) δ 3.23 (s, 3H), 3.48 (s, 3H), 4.83 (s, 2H), 7.86-8.07 (m, 4H), 12.96 (br s, 1H); APCI-MS (m/z) 500.06 (M+H)⁺.

2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[1,2]thiazolo[3,4-ύT|pyrimidin-3-yl)-N-{4- [3 -(trifluoromethy l)pheny 1] -1,3 -thiazol-2 -y 1 } acetamide

 ¹H NMR (300 MHz, DMSO-^₆) δ 3.23 (s, 3H), 3.48 (s, 3H), 4.82 (s, 2H), 7.67- 7.72 (m, 2H), 7.96 (s, 1H), 8.20-8.26 (m, 2H), 12.93 (br s, 1H); APCI-MS (m/z) 482.07 (M+H)⁺.

Ethyl (5,7-dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[1,2]thiazolo[5,4-ύT|pyrimidin-3- yl)acetate

 ¹H NMR (300 MHz, CDCl₃) 
δ 1.28 (t, J= 7.2 Hz, 3H), -CH2CH3
3.39 (s, 3H), 
3.56 (s, 3H), 
4.12 (s, 2H), -CH2CH3
4.21 (q, J= 6.9 Hz, 2H).

1H NMR of the 2-Amino-4-phenyl-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline

¹H NMR of the 2-Amino-4-phenyl-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline 5a





http://article.sapub.org/10.5923.j.chemistry.20140401.04.html

American Journal of Chemistry

p-ISSN: 2165-8749    e-ISSN: 2165-8781

2014;  4(1): 29-34

doi:10.5923/j.chemistry.20140401.04

Harvinder Singh Sohal¹, Rajshree Khare¹, Arun Goyal¹, Andrew Woolley², Kishanpal Singh³, Rajeev Sharma⁴

¹Department of Chemistry, Maharishi Markandeshwar University, Mullana-133 207, Haryana, India

²Department of Chemistry, University of Toronto, 80 St. George St. Toronto, ON, M5S 3H6, Canada

³Department of Chemistry, Punjabi University, Patiala-147 001, Punjab, India

⁴Department of Chemistry, Multani Mal Modi College, Patiala-147 001, Punjab, India

Correspondence to: Harvinder Singh Sohal, Department of Chemistry, Maharishi Markandeshwar University, Mullana-133 207, Haryana, India.

Email:

Multi-component Approach for the Synthesis of Fused Dihydropyridines via Unsymmetrical Hantzch Condensation Using Glycerol as Green Solvent

2-Amino-4-phenyl-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline (5a): 

mp. 277–278 °C; IR (KBr): ΰ = 3436, 3324, 3214, 2197, 1719, 1498 cm⁻¹. 

¹H NMR (400 MHz, CDCl₃): δ(ppm) = 1.02 (s, 3H, CH₃), 1.09 (s, 3H, CH₃), 2.01–2.37 (m, 4H, 2×CH₂), 4.38 (s, 1H, CH), 5.36 (s, 2H, NH₂), 7.07–7.29 (m, 5H, ArH), 8.94 (s, 1H, NH). 


¹³C NMR (100 MHz, CDCl₃): δ(ppm) = 27.4, 29.5, 32.8, 36.9, 39.4, 50.8, 59.7, 113.5, 119.7, 126.2, 127.8, 128.4, 143.9, 155.3, 166.3, 197.7.

MS (EI) m/z 294.3 (M+). 

Anal. Calcd for C₁₈H₁₉N₃O: C, 73.72; H, 6.48; N, 14.33. Found: C, 73.61; H, 6.58; N, 14.31.


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LITTLE SISTER WILL TEACH YOU NMR.....6,7-methylenedioxy-4-phenylcoumarin

LITTLE SISTER WILL TEACH YOU NMR

6,7-methylenedioxy-4-phenylcoumarin
8-Phenyl-6H-[1,3]dioxolo[4,5-g]chromen-6-one

6H-1,3-Dioxolo[4,5-g][1]benzopyran-6-one, 8-phenyl-

Molecular Formula: C₁₆H₁₀O₄

Molecular Weight: 266.2482

Coumarins are naturally occurring molecules that are found in plants that have numerous uses in the medical field because of its biological activity.  The wide varieties of its uses include antibiotics, anticoagulants, and sometimes even used in the perfume industry.   

SYNTHESIS

Synthesis of 6,7-methylenedioxy-4-phenylcoumarin from sesamol and ethyl phenylpropiolate using a Pd(OAc)2 catalyst to illustrate coumarin synthesis. This procedure is simple and easy and can be applied to the synthesis of other coumarins that have electron-rich phenol groups. The reaction is conducted by stirring a solution of Pd(OAc)2, sesamol and ethyl phenylpropiolate in trifluoroacetic acid at room temperature (15-20 degrees C) under atmospheric conditions.

STEP 1

phenyl acetylene is the starting material

Ethyl Phenylpropiolate: 

Phenylacetylene (500 mg, 4.896 mmol, 1 equivalent) was added to a round bottom flask and flushed with nitrogen.  A septum and balloon of nitrogen was then attached and 3-4mL of THF was added by syringe.  The flask was cool to -78^oC in a dry ice and acetone bath.  Next, n-butyllithium (2.36 mL, 1.2 equivalent) was added to the solution and allowed to warm to 0^oC for 1 hour.  The solution was cooled to -78^oC again for 15 minutes, and then ethyl chloroformate (0.702 mL, 7.344 mmol, 1.5 equivalent) was added dropwise by syringe and allowed to warm again to 0^oC.  The reaction mixture was then quenched by adding 10mL of saturated aqueous NaHCO₃ and allowed to stir for 15 minutes. The resulting substance Ethyl Phenylpropiolate was a yellowish-orange liquid.  

¹H NMR (200 MHz, CDCl₃) δ 7.60-7.26 (m, 5H),

4.38 (m, 2H),      -O CH2 CH3

1.44 (m, 3H);   -O CH2 CH3

IR (neat, NaCl)

3551.4, 3399.9, 3958.2, 2934.4, 2872.2, 2236.4, 2211.6, 1744.0, 1709.5 cm^-1

The conversion of phenylacetylene to ethyl phenylpropiolate was made apparent by the comparison of IR spectras.  The phenylacetylene reference IR spectra found on the Spectral Database of Organic Compounds shows a strong peak at about 3300 that the IR of the intermediate lacks.  Also the intermediate’s IR contains strong peaks at 3000 and 2230 which are both absent from the starting material’s IR spectrum.  Both of these changes indicate a successful conversion of phenylacetylene to the intermediate ethyl phenylpropiolate. 

STEP 2

This specific reaction will result in a ring closure and addition of the ethyl phenylpropiolate aided by the palladium acetate catalyst.  The palladium catalyst allows for the addition of an ester to a phenol resulting in a ring closure and product coumarin derivative.

6,7-methylenedioxy-4-phenylcoumarin:  

Sesamol (0.075g, 0.5167mmol, 0.9 equivalent) and ethyl phenylpropiolate (102mg, 0.57405 mmol,1 equivalent) and Palladium acetate (Pd(OAc)₂)(0.00394g, 3mol%) were added to a 1 dram vial and cooled to 0^oC in an ice water bath.  Trifluoroacetic acid (0.5mL) was added to the vial, then the vial was capped and the reaction allowed to proceed overnight. The resulting solid was a brown, sticky, crystalline (0.387 mmol, 67 %yield). 

 ¹H NMR (300 MHz, CDCl₃)

δ 7.55-7.38 (m, 5H),

6.90 (s, 1H),

6.83 (s, 1H),

6.24 (s, 1H),

6.05 (s, 2H);  CH2 SANDWICHED BETWEEN 2 OXYGEN ATOMS

IR (DCM, NaCl)

3553.8, 3401.9, 2958.2, 2872.2, 2236.3, 2211.4, 1744.4, 1717.4 cm^-1

References

Kotani, M., Yamamoto, K., Oyamada, J., Fujiwara, Y., Kitamura, T.,Synthesis, 2004, 9, 1466-1470.

Oyamada, J., Jia, C., Fujiwara, Y., Kitamura, T., 2002, Chemistry Letters,2002, 3, 380-381.

Kitamura, T., Yamamoto, K., Kotani, M., Oyamada, J., Jia, C., Fujiwara, Y.,Bulletin of the Chemical Society of Japan, 2003, 76, 1889-1895 http://www.ncbi.nlm.nih.gov/pubmed/17446885 http://wenku.baidu.com/view/ce68818683d049649b665879.html Mech   The insertion of the ethyl phenylpropiolate to the sesamol-palladium intermediate is initially achieved in a cis confirmation.  There is then an internal rearrangement of the palladium and CO₂Et ligands to the trans confirmation which then allows for an electrophilic aromatic substitution to close the ring.

 ETHYL PHENYL PROPIOLATE





Ethyl phenylacetylenecarboxylate~Phenylpropiolic acid ethyl ester

  1H NMR 13 C NMR


    MASS
      IR


    RAMAN



  UNDERSTAND SPECTRA WITH METHYLENE DIOXY GROUP USING  A DIFFERENT EXAMPLE


4-Bromo-1,2-(methylenedioxy)benzene 1H NMR


  13 C NMR   IR   MASS     RAMAN  


  PRESENTING TO YOU COUMARIN TO UNDERSTAND SPECTRA COUMARIN






  1H NMR   13 C NMR IR   MASS   RAMAN  



  NOW PHENYL ACETYLENE






  1H NMR         13 C NMR   MASS   IR AND