R and S Flurbiprofen

(R) and (S)-flurbiprofen (2-(3-fluoro-4-phenyl-phenyl)propanoic acid) enantiomers

Figure 1: Chemical structure of the analyte molecules (R/S)-flurbiprofen (2-(3-fluoro-4-phenyl-phenyl)propanoic acid). The asterisk denotes the stereogenic centre of the enantiomer.

Figure 4: Stacked-plot of the 1H HR/MAS NMR spectra of (R/S)-flurbiprofen together with a) the derivatized amylose-based CSP (AP), b) Eurocel 01 and c) Eurocel 03. Signal assignment was performed with the help of a 2D HR/MAS 1H-1H-COSY NMR spectrum due to the chemical structure presented in Figure 1. S=solvent (methanol, water).

Figure 5: Representative 1D 1H STD HR/MAS NMR spectra of a) (R)-flurbiprofen, b) (S)-flurbiprofen in presence of the amylose-based CSP. All occurring analyte signals in this kind of spectrum show that they received magnetization during selective receptor saturation. The signal intensity of the STD spectrum decreased by more than 95% compared to the OFF-resonance spectrum. S=solvent (methanol).

Improving the Understanding of the Properties and Retention Behavior of Chemically Bonded Stationary Phases Employing Suspended-state HR/MAS NMR Spectroscopy

Klaus Albert*, Volker Friebolin, Silvia Marten, and Helen Yeman Institute of Organic Chemistry, University of Tuebingen, Germany Corresponding Author : Klaus Albert University of Tuebingen, Institute of Organic Chemistry Auf der Morgenstelle 18, D-72076 Tuebingen, Germany Tel: 07071-29-75335 Fax: 07071-29-5875 E-mail: klaus.albert@uni-tuebingen.de Received November 12, 2013; Accepted December 12, 2013; Published December 16, 2013 Citation: Albert K, Friebolin V, Marten S, Yeman H (2013) Improving the Understanding of the Properties and Retention Behavior of Chemically Bonded Stationary Phases Employing Suspended-state HR/MAS NMR Spectroscopy. J Anal Bioanal Tech S12: 001. doi: 10.4172/2155-9872.S12-001 http://www.omicsonline.org/open-access/hr-mas-nmr-spectroscopy-of-chemically-bonded-stationary-phases-2155-9872.S12-001.php?aid=23250 paper 2

2a is flubiprofen

(S)-2a: Using the (S)-selective AMDase variant G74C/M159L/C188G/
V43I/A125P/V156L, (S)-2a (81 mg, 0.331 mmol, 95% yield) was isolated
with an optical purity of 98.1% ee.

1H NMR (400 MHz, Chloroform-d): d=7.58–7.50 (m, 2H), 7.47–7.34
(m, 4H), 7.21–7.13 (m, 2H), 3.80 (q, J=7.2 Hz, 1H), 1.57 ppm (d, J=
7.2 Hz, 3H).


(R)-2a: Using the (R)-selective AMDase variant V43I/A125P/V156L/
M159L, (R)-2a (84 mg, 0.344 mmol, 99% yield) was isolated with an
optical purity of 98.2% ee.
1H NMR (400 MHz, Chloroform-d): d=7.59–7.51 (m, 2H), 7.49–7.34
(m, 4H), 7.23–7.13 (m, 2H), 3.82 (q, J=7.2 Hz, 1H), 1.59 ppm (d, J=
7.2 Hz, 3H).

ChemCatChem 2016, 8, 916 – 921


patent

 http://www.google.com/patents/EP2307335A1?cl=en

Thus, by way of example the schematic process of the invention for flurbiprofen may be represented as follows:

Example 1 - Flurbiprofen
Example 1.1 Resolution procedure
Racemic flurbiprofen (3.0 kg) was charged to a 20 L jacketed glass reactor. Methanol (2.0 L) and toluene (8.0 L) were added. The mixture was heated to dissolve the solid. S-1-Phenylethylamine (0.76 kg) was dissolved in toluene (1.87 L) and the solution was added to the 20 L reactor with stirring at 60⁰C over about 30 minutes. The mixture was cooled gradually to 0 to 5°C to induce crystallisation. The crystals were filtered off, washed with toluene (3 L) and dried in a vacuum oven at 55⁰C to form crude S-flurbiprofen / S-1-phenylethylamine salt (1.4kg). Crude S-flurbiprofen / S-I -phenyl ethylamine salt (1.0 kg) was charged to a 20 L jacketed glass reactor. Toluene (11.4 L) and methanol (2.7 L) were added and the mixture was stirred and heated to 60⁰C to dissolve the solid. The solution was cooled gradually to 0 to 5⁰C to induce crystallisation. The crystals were filtered off, washed with toluene (3 L) and dried in a vacuum oven at 55°C to form pure S-flurbiprofen / S-1-phenylethylamine salt (0.8kg).
Pure S-flurbiprofen / S-1-phenylethylamine salt (2.2kg) was charged to a 20 L jacketed glass reactor. Toluene (7.5 L) was added with stirring. Water (1.9 L) and concentrated hydrochloric acid (0.9 L) were added and the mixture was stirred at 6O⁰C. The lower aqueous layer was separated off and the upper organic layer was retained. The hydrochloric acid wash was repeated, then the toluene solution was washed with water. Additional toluene (1.2 L) was added and then toluene (3.5 L) was distilled off to ensure the solution was free from water. The toluene solution was cooled gradually to -10⁰C to induce crystallisation. The crystals were filtered off, washed with heptane (1.9 L) and dried in a vacuum oven at 4O⁰C to form pure S- flurbiprofen (1.1 kg).
Racemisation procedure Toluene/methanol mother liquors from the filtration of crude S-flurbiprofen / S-I- phenylethylamine salt in the resolution procedure (2 L, containing an estimated 37Og of flurbiprofen) were charged into a 3 L 3 necked round bottomed flask and methanol was distilled out at atmospheric pressure (volume removed approximately 250 ml). The batch was then cooled to around 60°C and washed twice with hydrochloric acid (80 ml concentrated hydrochloric acid in 330 ml of water), and then twice with water (330 ml). Toluene was charged (160 ml) followed by methanol (388 ml) and caustic soda solution (800 ml of 28% w/w solution, 5 molar equivalents). The mixture was heated to reflux for about 6 hours. Solvent was then removed at atmospheric pressure until the vapour temperature reached approximately 85°C. The mixture was cooled to around 60°C and concentrated hydrochloric acid was charged at about 60 to 70°C until the pH of the mixture was 1 or less. The layers were allowed to separate and the bottom aqueous layer removed. The organic layer was washed with water (400 ml) and then azeotroped to dryness using a Dean and Stark trap. A solution of racemic flurbiprofen in toluene remained.
Example 1.2
Variation of solvent quantities
S-Flurbiprofen (2Og) was charged to a 500ml jacketed glass reactor. Toluene (200 ml) was added and the solution was heated to 60⁰C. Sodium hydroxide solution (46 ml of 28% w/w solution, 5.1 molar equivalents) and methanol (70 ml) were added. The mixture was heated to reflux for 4 hours. Solvent was removed by distillation until the distillate temperature reached 100⁰C and the volume removed was replaced with toluene. The reaction mixture was neutralised by addition of hydrochloric acid (60 ml of 36% w/w) at 6O⁰C and the lower aqueous layer was separated off. The organic layer containing the flurbiprofen was analysed and found to have an enantiomeric excess of 5.6%.
The above procedure was repeated at half the scale using different solvent proportions. S-flurbiprofen (1Og) was mixed with toluene (100 ml) and methanol (20 ml). Sodium hydroxide solution (25 ml of 28% w/w solution, 5.6 molar equivalents) was added and the mixture heated to reflux for 3 hours. After distillation of solvent and neutralisation by addition of hydrochloric acid (35 ml of 36% w/w solution), the organic layer was found to contain flurbiprofen with enantiomeric excess of 3.4%.
Example 1.3
Variation of Amount of Sodium Hydroxide
Toluene/methanol mother liquors from the filtration of crude R-flurbiprofen / R-I- phenylethylamine salt in the resolution steps (250 ml, containing an estimated 47g of flurbiprofen) were charged into a 500ml jacketed glass reactor and methanol was distilled out at atmospheric pressure. The mixture was then cooled to around 60°C and washed twice with hydrochloric acid (40 ml concentrated hydrochloric acid in 100 ml of water), and then twice with water (100 ml). Methanol was charged (50 ml) followed by caustic soda solution (see table). The mixture was heated to reflux (see table). Solvent was then removed at atmospheric pressure until the vapour temperature reached approximately 85°C. The mixture was cooled to around 60°C and concentrated hydrochloric acid was charged at about 60 to 70°C until the pH of the mixture was 1 or less. The layers were allowed to separate and the bottom aqueous layer removed. The organic layer was washed with water and then azeotroped to dryness using a Dean and Stark trap. The remaining solution of racemic flurbiprofen in toluene was analysed for enantiomeric purity.

Example 1.4 Large Scale Trial Toluene/methanol mother liquors from the filtration of crude R-Flurbiprofen / R-I- Phenylethylamine salt in the resolution steps (11.5 L, containing an estimated 1.7kg of flurbiprofen enriched in the S-enantiomer) were charged into a 20 L jacketed glass reactor and methanol was distilled out at atmospheric pressure. The mixture was then cooled to around 60⁰C and washed twice with hydrochloric acid (0.6 L concentrated hydrochloric acid in 1.8 L of water), and then twice with water (1.9 L). Additional toluene was charged (1.0 L) followed by methanol (2.5 L) and caustic soda solution (4.5 L of 28% w/w solution, 6.1 molar equivalents). The mixture was heated to reflux for 6 hours. Solvent was then removed at atmospheric pressure until the vapour temperature reached approximately 85°C. The mixture was cooled to around 60°C and concentrated hydrochloric acid (4.5 L of 36% w/w solution) and water (2 L) was charged at about 60 to 70⁰C until the pH of the mixture was 1 or less. Further toluene (3 L) was added and the layers were allowed to separate and the bottom aqueous layer removed. The organic layer was washed with water (3.6 L) and then azeotroped to dryness using a Dean and Stark trap. The remaining solution of racemic flurbiprofen in toluene was analysed giving the results shown below. Typical results obtained from batches carried out using the prior art method for the racemisation as described in US5,599,969 are shown in the Table for comparison.

Example 1.5
Synthesis of R-Flurbiprofen / R-1-Phenylethylamine salt from racemised flurbiprofen
Toluene/methanol mother liquors from the filtration of crude R-flurbiprofen / R-I- phenylethylamine salt in the resolution step (1.25 L, containing an estimated 23Og of flurbiprofen enriched in the S-enantiomer) were charged into a 3 L 3 necked round bottomed glass reactor and methanol (150ml) was distilled out at atmospheric pressure. The mixture was then cooled to around 60°C and washed twice with hydrochloric acid (50ml concentrated hydrochloric acid in 200ml of water), and then twice with water (250ml). Additional toluene was charged (100ml) followed by methanol (180ml), caustic soda solution (250ml of 48% w/w solution, 4.7 molar equivalents) and water (250ml). The mixture was heated to reflux for 6 hours. Solvent was then removed at atmospheric pressure until the vapour temperature reached approximately 85°C. The mixture was cooled to around 60°C and further toluene (380ml) was added. Hydrochloric acid (500ml of 36% w/w solution) was charged at about 60 to 70°C until the pH of the mixture was 1 or less and the layers were allowed to separate and the bottom aqueous layer removed. The organic layer was washed with water (250ml) and then azeotroped to dryness using a Dean and Stark trap. The remaining solution of racemic flurbiprofen in toluene was analysed and found to have an enantiomeric excess of 1.1%. A portion of the resulting solution (16Og) was evaporated to dryness to determine its flurbiprofen content (22g) then redissolved in toluene (5Og) and methanol (Hg). The solution was heated to 60°C and a solution of R-1-phenylethylamine (6.5g) in toluene (14g) was added slowly. The mixture was cooled slowly to 0°C and the crystals were filtered off, washed with toluene (25ml) and dried under vacuum at 60⁰C. Analysis showed an enantiomeric excess of 77%, typical for crude R-flurbiprofen/R-1-phenylethylamine salt. Levels of methyl (2-(2-fluoro-4-biphenylyl)) propionate and l-phenylethyl-(2-2(fluoro-4- biphenylyl))







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