22161-81-5

Basic information

• Product Name: (S)-(+)-Ketoprofen
• Synonyms: (+)-hydratropicaci;(S)-(+)-KETOPROFEN;(S)-KETOPROFEN;(S)-(+)-3-BENZOYL-ALPHA-METHYLBENZENE-ACETIC ACID;[S]-2-[3-BENZOYLPHENYL]PROPIONIC ACID;Dexketoprofen;3-(1-Hydrocarboxyethyl)benzophenone;Dexktoprofen
• CAS NO: 22161-81-5
• Molecular Formula: C₁₆H₁₄O₃
• Molecular Weight: 254.28
• EINECS: 1308068-626-2
• Product Categories: Chiral Compound;Intermediates & Fine Chemicals;Pharmaceuticals;Aromatics;Chiral Reagents;Other APIs
• Mol File: 22161-81-5.mol
• Article Data: 52

Chemical Properties

• Melting Point: 75-78 °C(lit.)
• Boiling Point: 431.3 °C at 760 mmHg
• Flash Point: 228.8 °C
• Appearance: white or almost white, crystalline powder.
• Density: 1.198 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.592
• Storage Temp.: -20°C Freezer
• Solubility: insoluble in H2O; ≥10.6 mg/mL in DMSO; ≥20.55 mg/mL in EtOH
• PKA: 4.23±0.10(Predicted)
• CAS DataBase Reference: (S)-(+)-Ketoprofen(CAS DataBase Reference)
• NIST Chemistry Reference: (S)-(+)-Ketoprofen(22161-81-5)
• EPA Substance Registry System: (S)-(+)-Ketoprofen(22161-81-5)

Safety Data

• Hazard Codes: Xn,T
• Statements: 22-36/37/38-50/53-25
• Safety Statements: 26-60-61-45
• RIDADR: UN 2811 6.1/PG 3
• WGK Germany: 3
• RTECS: CY1572790
• Hazardous Substances Data: 22161-81-5(Hazardous Substances Data)

Usage

Chemical Properties

White Solid

Uses

COX inhibitor

Definition

ChEBI: A monocarboxylic acid that is (S)-hydratropic acid substituted at position 3 on the phenyl ring by a benzoyl group. A cyclooxygenase inhibitor, it is used to relieve short-term pain, such as muscular pain, dental pain and dysmenorrhoea.

Biological Activity

(s)-ketoprofen, a dual cox1/2 inhibitor, can be used as a nonsteroidal anti-inflammatory drug to treat arthritis-related inflammatory pains. ketoprofen is photolabile and undergoes degradation when irradiated by sunlight to induce various skin diseases [1].

Clinical Use

#N/A

in vitro

the combination of uvb irradiation with ketoprofen dose-dependently induced the cytotoxicity and suppressed dna synthesis in hacat cells. uvb-irradiated kp inhibited the cell growth and induced g2/m cell cycle arrest by regulating the levels of cdc2, cyclin b1, chk1, tyr15-phosphorylated cdc2 and p21. the dapi staining results has revealed that kp accentuated the apoptotic response to uvb radiation in hacat cells [1].

in vivo

in a placebo-controlled, double-blind study in the rhesus monkeys macaca mulatta with periodontal disease, administeration of kp at 1% level in suitable topical vehicles to the gingiva once daily at a standard dose of 1.8 ml per monkey for 6 months effectively inhibited gcf-ltb4 and gcf-pge2 and positively altered alveolar bone activity [2]. ketoprofen at a dose of 3.63 mg/kg bwt (phenylbutazone equimolar dose) showed significant analgesic effects and reduced hoof pain and lameness to a greater extent [3]. treatment with ketoprofen (40 and 80 mg/kg diet) greatly reduced the incidence of transitional cell carcinoma of the urinary bladder by >70% from that seen in dietary mice [4].

Drug interactions

Potentially hazardous interactions with other drugsACE inhibitors and angiotensin-II antagonists: antagonism of hypotensive effect; increased risk of nephrotoxicity and hyperkalaemiaAnalgesics: avoid concomitant use of 2 or more NSAIDs, including aspirin (increased side effects);avoid with ketorolac (increased risk of side effects and haemorrhage).Antibacterials: possibly increased risk of convulsions with quinolonesAnticoagulants: effects of coumarins and phenindione enhanced; possibly increased risk of bleeding with heparins, dabigatran and edoxaban - avoid long term use with edoxabanAntidepressants: increased risk of bleeding with SSRIs and venlaflaxine.Antidiabetic agents: effects of sulphonylureas enhanced.Antiepileptics: possibly increased phenytoin concentration.Antivirals: increased risk of haematological toxicity with zidovudine; concentration possibly increased by ritonavir.Ciclosporin: may potentiate nephrotoxicity.Cytotoxics: reduced excretion of methotrexate; increased risk of bleeding with erlotinib.Diuretics: increased risk of nephrotoxicity; antagonism of diuretic effect, hyperkalaemia with potassium-sparing diuretics.Lithium: excretion decreased.Pentoxifylline: increased risk of bleedingProbenecid: excretion reduced by probenecid.Tacrolimus: increased risk of nephrotoxicity

Metabolism

Dexketoprofen is the S-enantiomer of ketoprofen.The main elimination route for dexketoprofen is glucuronide conjugation in the liver followed by renal excretion.

references

[1]. liu s, mizu h, yamauchi h. molecular response to phototoxic stress of uvb-irradiated ketoprofen through arresting cell cycle in g2/m phase and inducing apoptosis[j]. biochemical and biophysical research communications, 2007, 364(3): 650-655.[2]. li k l, vogel r, jeffcoat m k, et al. the effect of ketoprofen creams on periodontal disease in rhesus monkeys[j]. journal of periodontal research, 1996, 31(8): 525-532.[3]. owens j g, kamerling s g, stanton s r, et al. effects of ketoprofen and phenylbutazone on chronic hoof pain and lameness in the horse[j]. equine veterinary journal, 1995, 27(4): 296-300.[4]. hawk e t, kelloff g j, mccormick d l. differential activity of aspirin, ketoprofen and sulindac as cancer chemopreventive agents in the mouse urinary bladder[j]. carcinogenesis, 1996, 17(5): 1435-1438.

InChI:InChI=1/C16H14O3/c1-11(16(18)19)13-8-5-9-14(10-13)15(17)12-6-3-2-4-7-12/h2-11H,1H3,(H,18,19)/t11-/m0/s1

Synthetic route

(S)-3-methyl-2-phenylbutylammonium (S)-2-(3-benzoylphenyl)propionate → S-ketoprofen (22161-81-5)

Conditions	Yield
With hydrogenchloride In water at 50℃;	98.3%

ketoprofen (22071-15-4) → S-ketoprofen (22161-81-5)

Conditions	Yield
	96%
Multi-step reaction with 3 steps 1.1: oxalyl chloride / 12 h / 40 °C 2.1: rink amide linker modified polystyrene grafted crowns; piperidine; benzotriazolyloxy-tris(dimethylamino)phosphonium(1+) PF6(1-) / diisopropylethylamine / dimethylformamide / 12 h / 20 °C 2.2: triethylamine / tetrahydrofuran / 12 h / 0 °C 2.3: 104 mg / trifluoroacetic acid / CH2Cl2 / 0.67 h 3.1: LiOH / tetrahydrofuran; H2O / 1 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: oxalyl chloride / 12 h / 40 °C 2.1: triethylamine; (S)-(3-OH-4,4-di-Me-2-oxopyrrolidin-1-yl)CH2COOH on resin / tetrahydrofuran / 0 °C 2.2: LiOH*H2O / tetrahydrofuran; H2O / 4 h / 20 °C View Scheme

(S)-2-(3-Benzoyl-phenyl)-propionic acid (S)-4,4-dimethyl-2-oxo-tetrahydro-furan-3-yl ester → S-ketoprofen (22161-81-5)

Conditions	Yield
With sodium carbonate In methanol; water for 2h; Ambient temperature;	95%

(2S)-[3-(2-hydroxy-1-methyl-ethyl)-phenyl]-phenyl-methanone (1173289-23-0) → S-ketoprofen (22161-81-5)

Conditions	Yield
With Jones reagent In acetone for 12h; Inert atmosphere;	95%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; laccase from Trametes versicolor; oxygen In water at 20℃; for 168h; Enzymatic reaction;	95%
With 2,2,6,6-tetramethyl-piperidine-N-oxyl; sodium hypochlorite; sodium chlorite In water; acetonitrile at 35℃; for 24h; aq. phosphate buffer;	42%

(3S)-4,4-dimethyl-2-oxo-1-phenylpyrrolidin-3-yl (αS)-α-(3-benzoylphenyl)propionate → S-ketoprofen (22161-81-5)

Conditions	Yield
With hydrogenchloride; acetic acid for 2.5h; Heating;	92%

3-(3-benzoyl-phenyl)-2S,3R-dimethyl-oxirane-2-carboxy-5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexane ester → S-ketoprofen (22161-81-5)

Conditions	Yield
Stage #1: 3-(3-benzoyl-phenyl)-2S,3R-dimethyl-oxirane-2-carboxy-5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexane ester With sodium carbonate In dichloromethane; water for 1h; Stage #2: With dihydrogen peroxide; acetic acid at 85℃; for 9h;	85.6%

(S)-ketoprofendiol → S-ketoprofen (22161-81-5)

Conditions	Yield
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; laccase from Trametes versicolor; oxygen In water at 20℃; for 168h; Enzymatic reaction;	82%

C23H20O (1613507-33-7) → S-ketoprofen (22161-81-5)

Conditions	Yield
With sodium periodate; ruthenium(III) trichloride hydrate In tetrachloromethane; water; acetonitrile at 0 - 20℃; for 2h;	69%

ketoprofen 2,2,2-trifluoroethyl ester → S-ketoprofen (22161-81-5)

Conditions	Yield
With sodium hydroxide; Pseudomonas fluorescens MTCCB0015 cell-free extract In phosphate buffer at 37℃; for 20h; pH=7.50;	40%

(+)-α-(3-benzylphenyl)propionic acid (22161-82-6) → S-ketoprofen (22161-81-5) + (3-acetylphenyl)(phenyl)methanone (66067-44-5)

Conditions	Yield
With sodium hydroxide; potassium permanganate In water for 6h; Ambient temperature; Yields of byproduct given;	A n/a B 28.4%

(+)-α-(3-benzylphenyl)propionic acid (22161-82-6) → S-ketoprofen (22161-81-5) + (3-acetylphenyl)(phenyl)methanone (66067-44-5) + R-ketoprofen (56105-81-8)

Conditions	Yield
With sodium hydroxide; potassium permanganate In water for 6h; Ambient temperature; Yield given;	A n/a B 28.4% C n/a

ethyl 2-<3-benzoylphenyl>propionate (60658-04-0) → S-ketoprofen (22161-81-5)

Conditions	Yield
With Tris-HCl buffer at 30℃; for 96h; semipurified lipase of Candida cylindraceae in Tris-HCl buffer;	23.04%
With native lipase from Candida rugosa; water
With Thermotoga maritima esterase Tm1160 In aq. acetate buffer at 70℃; for 23h; pH=5.5; Enzymatic reaction; enantioselective reaction;	n/a

alpha-(m-benzoylphenyl)propionitrile (42872-30-0) → (2R)-2-[3-(phenylcarbonyl)phenyl]propanamide + (S)-2-(3-benzoylphenyl)propanamide (162681-69-8) + (S)-2-(3-benzoylphenyl)propanenitrile (1421692-22-9) + (2R)-[3-(phenylcarbonyl)phenyl]propanenitrile (161527-65-7) + S-ketoprofen (22161-81-5)

Conditions	Yield
With Rhodococcus erythropolis SET1 cells In aq. phosphate buffer at 25℃; pH=7; Microbiological reaction; enantioselective reaction;	A n/a B n/a C n/a D n/a E 20%

ketoprofen methyl ester (57872-48-7, 81601-91-4, 81601-93-6, 47087-07-0) → S-ketoprofen (22161-81-5)

Conditions	Yield
With sodium hydroxide; Pseudomonas fluorescens MTCCB0015 cell-free extract In phosphate buffer at 37℃; for 20h; pH=7.50;	18%

ketoprofen methyl ester (57872-48-7, 81601-91-4, 81601-93-6, 47087-07-0) → S-ketoprofen (22161-81-5) + R-ketoprofen (56105-81-8)

Conditions	Yield
With sodium hydroxide In water at 40℃; for 7.55h; titrisol buffer pH 8, carboxylesterase NP; Yield given. Yields of byproduct given. Title compound not separated from byproducts;
With tris hydrochloride; S. solfataricus esterase In water at 60℃; for 32h; pH=7.0; Enzymatic reaction;

ketoprofen (22071-15-4) → S-ketoprofen (22161-81-5) + R-ketoprofen (56105-81-8)

Conditions	Yield
With phosphate buffer; sodium dodecyl-sulfate; vancomycin at 20℃; Product distribution; electrophoretic enantioseparations, various substrates;
EtOH, TAPS/Tris buffer, pH 7.7;
lipase from Candida rugosa In 2,2,4-trimethylpentane; acetone Product distribution / selectivity; Resolution of racemate;

ethyl 2-<3-benzoylphenyl>propionate (60658-04-0) → S-ketoprofen (22161-81-5) + (R)-(-)-2-(3-benzoylphenyl)propionic acid ethyl ester (136656-96-7)

Conditions	Yield
In water Title compound not separated from byproducts;

2-chloroethyl ester of 2-(3-benzoylphenyl)propionic acid (114315-58-1) → S-ketoprofen (22161-81-5) + (R)-ketoprofen chloroethyl ester (122674-99-1)

Conditions	Yield
With phosphate buffer; C. cylindracea lipase; dextromethorphan at 24℃; for 192h; Product distribution; without amine, enetioselectivity of hydrolysis;

(2R,3S,1''RS)-3-<3'-(hydroxyphenylmethyl)phenyl>butane-1,2-diol → S-ketoprofen (22161-81-5)

Conditions	Yield
With ruthenium trichloride; sodium periodate Yield given;
With ruthenium trichloride; sodium periodate In tetrachloromethane; water; acetonitrile Ambient temperature;

(+)-α-(3-benzylphenyl)propionic acid (22161-82-6) → S-ketoprofen (22161-81-5)

Conditions	Yield
With potassium permanganate
With potassium permanganate; phosphate buffer In water; benzene for 16h; Ambient temperature;

α-(3-benzoylphenyl)acrylic acid (74614-67-8) → S-ketoprofen (22161-81-5) + R-ketoprofen (56105-81-8)

Conditions	Yield
With (-)-Diop; chloro(1,5-hexadiene)rhodium(I) dimer; hydrogen; triethylamine; benzene In ethanol under 53200 Torr; for 20h; Ambient temperature; Yield given. Title compound not separated from byproducts;
With (-)-Diop; chloro(1,5-hexadiene)rhodium(I) dimer; hydrogen; triethylamine In ethanol; benzene under 11172 - 77140 Torr; Product distribution; different solvents, without NEt3, with KOH; other object: optical yield;

2-chloroethyl ester of 2-(3-benzoylphenyl)propionic acid (114315-58-1) → S-ketoprofen (22161-81-5) + R-ketoprofen (56105-81-8)

Conditions	Yield
With water at 40℃; for 40h; Candida rugosa lipase, pH 5; Yield given. Yields of byproduct given. Title compound not separated from byproducts;
With Candida rugosa lipase (Lipase OF); Tween-80 In water at 30℃; for 24h; pH=2.5; Title compound not separated from byproducts;

(S)-ketoprofen β-D-glucuronide → D-glucuronic acid (6556-12-3, 489-91-8, 528-16-5, 552-12-5, 577-46-8, 643-33-4, 2240-07-5, 6294-16-2, 10133-02-5, 18402-78-3, 18968-14-4, 21179-08-8, 23018-83-9, 33599-45-0, 33599-46-1, 46171-67-9, 46171-69-1, 46172-26-3, 70021-34-0, 71031-08-8, 104195-06-4, 106499-29-0, 124817-72-7) + S-ketoprofen (22161-81-5)

Conditions	Yield
With human serum albumin In water at 37℃; pH=7.4; Enzyme kinetics; Hydrolysis; Enzymatic reaction; isotonic 0.067 phosphate buffer;

2-chloroethyl ester of 2-(3-benzoylphenyl)propionic acid (114315-58-1) → S-ketoprofen (22161-81-5)

Conditions	Yield
With lipase OF I In water at 37℃; for 36h; pH=3;

ketoprofen chloride (59512-44-6, 71381-92-5, 109718-56-1) → S-ketoprofen (22161-81-5) + R-ketoprofen (56105-81-8)

Conditions	Yield
Stage #1: ketoprofen chloride With (S)-(3-OH-4,4-di-Me-2-oxopyrrolidin-1-yl)CH2COOH on resin; triethylamine In tetrahydrofuran at 0℃; Stage #2: With lithium hydroxide In tetrahydrofuran; water at 20℃; for 4h; Further stages. Title compound not separated from byproducts.;

(S)-2-(3-Benzoyl-phenyl)-propionic acid (S)-1-carbamoylmethyl-4,4-dimethyl-2-oxo-pyrrolidin-3-yl ester (362470-63-1) → S-ketoprofen (22161-81-5) + R-ketoprofen (56105-81-8) + (S)-(3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)acetamide

Conditions	Yield
With lithium hydroxide In tetrahydrofuran; water at 20℃; for 1h;

ketoprofen chloride (59512-44-6, 71381-92-5, 109718-56-1) → S-ketoprofen (22161-81-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: rink amide linker modified polystyrene grafted crowns; piperidine; benzotriazolyloxy-tris(dimethylamino)phosphonium(1+) PF6(1-) / diisopropylethylamine / dimethylformamide / 12 h / 20 °C 1.2: triethylamine / tetrahydrofuran / 12 h / 0 °C 1.3: 104 mg / trifluoroacetic acid / CH2Cl2 / 0.67 h 2.1: LiOH / tetrahydrofuran; H2O / 1 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: 93 percent / Et3N / CH2Cl2 / 3 h / 0 °C 2: 92 percent / 2 N HCl, AcOH / 2.5 h / Heating View Scheme
Multi-step reaction with 2 steps 1: Et3N / tetrahydrofuran / -10 °C 2: 95 percent / Na2CO3 / methanol; H2O / 2 h / Ambient temperature View Scheme

2-(3-bromophenyl)-2-methyl-[1,3]dioxolane (39172-32-2) → S-ketoprofen (22161-81-5)

Conditions

Yield

Multi-step reaction with 11 steps 1: 1.) Mg, I2 / 1.) anhydrous THF, 4 h, 60 deg C, 2.) THF 2: 97 percent / H2O, 10percent HCl / methanol / 1 h / Ambient temperature 3: 1.) t-BuOK / 1.) anhydrous THF, 30 min, RT, 2.) THF, RT, 24 h 4: 58 percent / LAH / diethyl ether / 6 h / -78 °C 5: 1.) (L)-(+)-diisopropyl tartrate, 4A sieves, Ti(OiPr)4, t-BuOOH / 1.) CH2Cl2, 1 h, 2.) CH2Cl2, -20 deg C, 3.5 h 6: H2, 1M NaOH / 10percent Pd/C / ethanol / Ambient temperature 7: LiBr, NCS / methanol / Ambient temperature 8: TsOH / Ambient temperature 9: 1.) t-BuLi / 1.) Et2O, hexane, -78 deg C, 2.) Et2O, hexane, RT 10: H2O, 5percent HCl / methanol / RT, then -20 deg C 11: RuCl3*H2O, NaIO4 / CCl4; acetonitrile; H2O / Ambient temperature View Scheme

1-[3-(trimethylsilyl)phenyl]ethanone (17983-62-9) → S-ketoprofen (22161-81-5)

Conditions

Yield

Multi-step reaction with 9 steps 1: 1.) t-BuOK / 1.) anhydrous THF, 30 min, RT, 2.) THF, RT, 24 h 2: 58 percent / LAH / diethyl ether / 6 h / -78 °C 3: 1.) (L)-(+)-diisopropyl tartrate, 4A sieves, Ti(OiPr)4, t-BuOOH / 1.) CH2Cl2, 1 h, 2.) CH2Cl2, -20 deg C, 3.5 h 4: H2, 1M NaOH / 10percent Pd/C / ethanol / Ambient temperature 5: LiBr, NCS / methanol / Ambient temperature 6: TsOH / Ambient temperature 7: 1.) t-BuLi / 1.) Et2O, hexane, -78 deg C, 2.) Et2O, hexane, RT 8: H2O, 5percent HCl / methanol / RT, then -20 deg C 9: RuCl3*H2O, NaIO4 / CCl4; acetonitrile; H2O / Ambient temperature View Scheme

benzaldehyde (100-52-7) + sodium cyanate → S-ketoprofen (22161-81-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1.) t-BuLi / 1.) Et2O, hexane, -78 deg C, 2.) Et2O, hexane, RT 2: H2O, 5percent HCl / methanol / RT, then -20 deg C 3: RuCl3*H2O, NaIO4 / CCl4; acetonitrile; H2O / Ambient temperature View Scheme

2-deoxy-2-amino-1,3,4,6-tetra-O-triethylsilyl-β-D-glucopyranosyl + S-ketoprofen (22161-81-5) → 2-deoxy-2-(2-(3-benzoylphenyl) propanoic acid)amino-1,3,4,6-tetra-O-triethylsilyl-β-D-glucopyranosyl

Conditions	Yield
With N,N-dimethylbutylamine; dimethylamino sulfonyl chloride; dmap In acetonitrile at 0 - 20℃; for 12h;	100%

methanol (67-56-1) + S-ketoprofen (22161-81-5) → ketoprofen methyl ester (57872-48-7, 81601-91-4, 81601-93-6, 47087-07-0)

Conditions	Yield
With thionyl chloride at 0℃; Reflux;	100%

S-ketoprofen (22161-81-5) → (2S)-[3-(2-hydroxy-1-methyl-ethyl)-phenyl]-phenyl-methanone (1173289-23-0)

Conditions	Yield
With borane-THF In tetrahydrofuran at 20℃;	99%
With borane-THF In tetrahydrofuran at -20 - 20℃;	55%

methanol (67-56-1) + S-ketoprofen (22161-81-5) → methyl (2S)-2-(3-benzoylphenyl)propanoate

Conditions	Yield
With sulfuric acid Reflux;	98%
Stage #1: methanol; S-ketoprofen for 0.5h; Reflux; Stage #2: With sulfuric acid at 80 - 90℃;	85.3%
With sulfuric acid for 6h; Heating;

S-ketoprofen (22161-81-5) + 2-amino-2-hydroxymethyl-1,3-propanediol (77-86-1) → Enantyum

Conditions	Yield
In ethanol; water at 20℃; for 0.5h;	92%
In ethanol at 20℃; for 0.5h;	92%
In ethanol; butanone; xylene at 0 - 55℃;	85%
In ethanol; butanone; xylene at 0 - 55℃;	84%
In ethanol; water Product distribution / selectivity;

(4-(but-3-en-1-yn-1-yl)phenyl)methanol + S-ketoprofen (22161-81-5) → 4-(but-3-en-1-yn-1-yl)benzyl (S)-2-(3-benzoylphenyl)propanoate

Conditions	Yield
With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃; for 12h; Inert atmosphere; Schlenk technique;	90%

L-Tyr-OMe (1080-06-4) + S-ketoprofen (22161-81-5) → N-(2-(S)-(3-benzoyl)phenyl)propionyl-(S)-tyrosine methyl ester

Conditions	Yield
Stage #1: L-Tyr-OMe; S-ketoprofen With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: With triethylamine In N,N-dimethyl-formamide at 20℃; for 20h;	85%

N-propyl-1H-indol-5-amine (1042539-24-1) + S-ketoprofen (22161-81-5) → 2-(3-benzoylphenyl)-N-(1H-indol-5-yl)-N-propylpropanamide (1239447-67-6)

Conditions	Yield
Stage #1: S-ketoprofen With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: N-propyl-1H-indol-5-amine In N,N-dimethyl-formamide at 20℃; for 2h;	81%

3β-acetoxy-7β-hydroxycholest-5-ene (17974-77-5) + S-ketoprofen (22161-81-5) → (3S,7R,10R,13R,17R)-3-acetoxy-10,13-dimethyl-17-((R)-6-methylheptan-2yl)2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-7-yl (2S)-2-(3-benzoylphenyl)-propanoate

Conditions	Yield
Stage #1: S-ketoprofen With dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.5h; Stage #2: 3β-acetoxy-7β-hydroxycholest-5-ene With dmap at 0℃;	77%

7,8-dihydro-8-oxo-2'-deoxyadenosine (31077-24-4, 62471-63-0) + S-ketoprofen (22161-81-5) → 5'-KP-8-oxodA (1069110-42-4)

Conditions	Yield
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride at 0℃;	76%

1-bromo-2-(triisopropylsilyl)acetylene (111409-79-1) + S-ketoprofen (22161-81-5) → (S)-2-(5-benzoyl-2-((triisopropylsilyl)ethynyl)phenyl)propanoic acid

Conditions	Yield
With N-tert-butoxycarbonyl-L-phenylalanine; silver(I) acetate; sodium acetate; palladium diacetate In 1,2-dichloro-ethane at 60℃; for 16h; Sealed tube; Schlenk technique;	76%

epicholesterol (474-77-1) + S-ketoprofen (22161-81-5) → epi-cholesteryl (S)-2-(3-benzoylphenyl)propionate (913843-19-3)

Conditions	Yield
Stage #1: S-ketoprofen With dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.5h; Stage #2: epicholesterol With dmap In dichloromethane at 0℃; for 8h;	74%

N-propyl-1H-indol-6-amine (1378801-54-7) + S-ketoprofen (22161-81-5) → 2-(3-benzoylphenyl)-N-(1H-indol-6-yl)-N-propylpropanamide (1239447-58-5)

Conditions	Yield
Stage #1: S-ketoprofen With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: N-propyl-1H-indol-6-amine In N,N-dimethyl-formamide at 20℃; for 2h;	73%

S-ketoprofen (22161-81-5) + 5-aminomethylindole (81881-74-5) → N-((1H-indol-5-yl)methyl)-2-(3-benzoylphenyl)propanamide (1239447-45-0)

Conditions	Yield
Stage #1: S-ketoprofen With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 5-aminomethylindole In N,N-dimethyl-formamide at 20℃; for 2h;	73%

(S)-4-(3-aminoazepan-1-yl)coumarin + S-ketoprofen (22161-81-5) → C31H30N2O4

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 0.5h;	73%

N-((1H-indol-5-yl)methyl)propan-1-amine (946774-68-1) + S-ketoprofen (22161-81-5) → N-((1H-indol-5-yl)methyl)-2-(3-benzoylphenyl)-N-propylpropanamide (1239447-69-8)

Conditions	Yield
Stage #1: S-ketoprofen With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: N-((1H-indol-5-yl)methyl)propan-1-amine In N,N-dimethyl-formamide at 20℃; for 2h;	72%

methanesulfonamide (3144-09-0) + S-ketoprofen (22161-81-5) → N-[2-(3-benzoyl-phenyl)-propionyl]-methanesulfonamide

Conditions	Yield
Stage #1: S-ketoprofen With 1,1'-carbonyldiimidazole In dichloromethane at 0 - 5℃; for 2h; Stage #2: methanesulfonamide With 1,2-diazabicyclo[5.4.0]undec-7-ene In dichloromethane for 4h;	70.5%

D-tyrosine methyl ester (3410-66-0) + S-ketoprofen (22161-81-5) → N-(2-(S)-(3-benzoyl)phenyl)propionyl-(R)-tyrosine methyl ester

Conditions	Yield
Stage #1: D-tyrosine methyl ester; S-ketoprofen With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: With triethylamine In N,N-dimethyl-formamide at 20℃; for 20h;	70%

5-amino-1H-indole (5192-03-0) + S-ketoprofen (22161-81-5) → 2-(3-benzoylphenyl)-N-(1H-indol-5-yl)propanamide (1239447-47-2)

Conditions	Yield
Stage #1: S-ketoprofen With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 5-amino-1H-indole In N,N-dimethyl-formamide at 20℃; for 2h;	69%

7α-hydroxycholest-5-en-3β-yl 3-acetate (19317-90-9) + S-ketoprofen (22161-81-5) → (3S,7S,10R,13R,17R)-3-acetoxy-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-7-yl (2S)-2-(3-benzoylphenyl)-propanoate

Conditions	Yield
Stage #1: S-ketoprofen With dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.5h; Stage #2: 7α-hydroxycholest-5-en-3β-yl 3-acetate With dmap at 0℃;	68%

S-ketoprofen (22161-81-5) + N-(tert-butyloxycarbonyl)-L-threonine tert-butyl ester (30588-71-7) → 3-[2(S)-(3-benzoyl-phenyl)-propionyloxy]-2(S)-tert-butoxycarbonylamino-butyric acid tert-butyl ester (852055-86-8)

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 4h;	67%

N1-(1H-indol-6-yl)-N3,N3-dimethylpropane-1,3-diamine (1239447-42-7) + S-ketoprofen (22161-81-5) → 2-(3-benzoylphenyl)-N-(3-(dimethylamino)propyl)-N-(1H-indol-6-yl)propanamide (1239447-64-3)

Conditions	Yield
Stage #1: S-ketoprofen With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: N1-(1H-indol-6-yl)-N3,N3-dimethylpropane-1,3-diamine In N,N-dimethyl-formamide at 20℃; for 2h;	67%

Upstream product

• 59512-44-6 ketoprofen chloride 
• 64-17-5 ethanol 
• 22071-15-4 ketoprofen 
• 71-23-8 propan-1-ol 
• 17983-62-9 1-[3-(trimethylsilyl)phenyl]ethanone 
• 39172-32-2 2-(3-bromophenyl)-2-methyl-[1,3]dioxolane 
• 362470-63-1 (S)-2-(3-Benzoyl-phenyl)-propionic acid (S)-1-carbamoylmethyl-4,4-dimethyl-2-oxo-pyrrolidin-3-yl ester 
• 57872-48-7 ketoprofen methyl ester 
• 114315-58-1 2-chloroethyl ester of 2-(3-benzoylphenyl)propionic acid 
• 140148-26-1 (S)-ketoprofen β-D-glucuronide 
• 74614-67-8 α-(3-benzoylphenyl)acrylic acid 
• 22161-82-6 (+)-α-(3-benzylphenyl)propionic acid 
• 60658-04-0 ethyl 2-<3-benzoylphenyl>propionate 
• 201230-82-2 carbon monoxide 

Downstream Products

• 425369-74-0 (S)-2-(3-Benzoyl-phenyl)-propionic acid (R)-1,2-dimethyl-cyclohexa-2,5-dienylmethyl ester 
• 425369-75-1 (S)-2-(3-Benzoyl-phenyl)-propionic acid (S)-1,2-dimethyl-cyclohexa-2,5-dienylmethyl ester 
• 913843-18-2 β-cholesteryl (S)-2-(3-benzoylphenyl)propionate 
• 878498-39-6 C₂₆H₂₆N₂O₇ 
• 878498-38-5 C₂₆H₂₆N₂O₇ 
• 1173289-53-6 (S)-2-(3-benzoylphenyl)-N-(3,4-dihydroxyphenethyl)propanamide 
• 1173289-39-8 (S)-2-(3-benzoylphenyl)-N-(4-hydroxyphenethyl)propanamide 
• 1173289-67-2 (S)-2-(3-benzoylphenyl)-N-(4-hydroxyphenethyl)-N-(2-methoxyethyl)propanamide 
• 1173289-47-8 (S)-2-(3-benzoylphenyl)-N-(2-hydroxyphenethyl)propanamide 
• 1173289-54-7 (S)-2-(3-benzoylphenyl)-N-(4-hydroxy-3-methoxyphenethyl)propanamide 
• 1173289-56-9 (S)-2-(3-benzoylphenyl)-N-((4-hydroxyphenyl)methyl)propanamide 
• 1173289-68-3 (S)-2-(3-benzoylphenyl)-N,N-bis(4-hydroxyphenethyl)propanamide 
• 1173289-57-0 (S)-2-(3-benzoylphenyl)-N-(4-hydroxyphenyl)propanamide 
• 1173289-51-4 (S)-2-(3-benzoylphenyl)-N-phenethylpropanamide 

Relevant articles and documents

Iterative saturation mutagenesis accelerates laboratory evolution of enzyme stereoselectivity: Rigorous comparison with traditional methods

Efficacy in laboratory evolution of enzymes is currently a pressing issue, making comparative studies of different methods and strategies mandatory. Recent reports indicate that iterative saturation mutagenesis (ISM) provides a means to accelerate directed evolution of stereoselectivity and thermostability, but statistically meaningful comparisons with other methods have not been documented to date. In the present study, the efficacy of ISM has been rigorously tested by applying it to the previously most systematically studied enzyme in directed evolution, the lipase from Pseudomonas aeruginosa as a catalyst in the stereoselective hydrolytic kinetic resolution of a chiral ester. Upon screening only 10 000 transformants, unprecedented enantioselectivity was achieved (E = 594). ISM proves to be considerably more efficient than all previous systematic efforts utilizing error-prone polymerase chain reaction at different mutation rates, saturation mutagenesis at hot spots, and/or DNA shuffling, pronounced positive epistatic effects being the underlying reason.

Reversed-phase high-performance liquid chromatographic separation of some 2-arylpropionic acids using vancomycin as chiral stationary phase

Abstract A rapid, sensitive and reproducible HPLC method has been developed for enantioseparation of six non-steroidal anti-inflammatory drugs, which are acidic compounds: carprofen, fenoprofen, flurbiprofen, ibuprofen, indoprofen and ketoprofen. The effects of the mobile phase composition on retention times and resolutions of the analytes were studied. A column based on vancomycin immobilized by reductive amination to aldehyde functionalised silica was prepared in house and used. The prepared sorbent shows a great stability and selectivity over a range of pH (4-6), and the separation was carried out using the mobile phase composed of a mixture of 40% of methanol in ammonium nitrate buffer (50 mM) at pH 5.0. Another mobile phase consisted of 50% of methanol in phosphate buffer (5A mM) at pH 5.0 was also prepared and tested. The two mobile phases are the optimum conditions obtained. All experiments were conducted at flow rate 0.6 ml/min, using a UV detector wavelength at λ = 254 nm.

Thermostable esterase from a thermoacidophilic archaeon: Purification and characterization for enzymatic resolution of a chiral compound

Homolog to lipolytic enzymes having the consensus sequence Gly-X-Ser-X-Gly, from the Sulfolobus solfataricus P2 genome, were identified by multiple sequence alignments. Among three potential candidate sequences, one (Est3), which displayed higher activity than the other enzymes on the indicate plates, was characterized. The gene (est 3) was expressed in Escherichia coli, and the recombinant protein (Est3) was purified by chromatographic separation. The enzyme is a trimeric protein and has a molecular weight of 32kDa in monomer form in its native structure. The optimal pH and temperature of the esterase were 7.4 and 80°C respectively. The enzyme showed broad substrate specificities toward various p-nitrophenyl esters ranging from C2 to C16. The catalytic activity of the Est3 esterase was strongly inhibited by phenylmethylsulfonyl fluoride (PMSF) and diethyl p-nitrophenyl phosphate. Based on substrate specificity and the action of inhibitors, the Est3 enzyme was estimated to be a carboxylesterase (EC 3.1.1.1). The enzyme with methyl (±)-2-(3- benzoylphenyl)propionate-hydrolyzing activity to (-)-2-(3-benzoylphenyl) propionic acid displayed a moderate degree of enantioselectivity. The product, (-)-2-(3-benzoylphenyl)propionic acid, rather than its methyl ester, was obtained in 80% enantiomeric excess (e.e.p) at 20% conversion at 60°C after a 32-h reaction. This result indicates that S. solfataricus esterase can be used for application in the synthesis of chiral compounds.

Effect of micelles and mixed micelles on efficiency and selectivity of antibiotic-based capillary electrophoretic enantioseparations.

Vancomycin (an oligophenolic, glycopeptide, macrocyclic antibiotic) has been shown to be a superb chiral selector for anionic and neutral compounds. It was found that adding sodium dodecyl sulfate to the run buffer increased efficiency by over 1 order of magnitude, decreased analysis times, and reversed the elution order of the enantiomers. This allows for control of the retention order as well as the resolution of enantiomers in complex mixtures in a single run. A mechanism is proposed which explains all of the observed effects and is verified experimentally. Since vancomycin is present in both the micelle and in free solution, previously proposed micelle-selector models are, at best, limiting cases. A general equation is derived which can be used to describe all possible interactions, including those with the capillary wall, if needed. Also, it is shown that electrophoretic mobilities and not migration times must be used to calculate binding constants of a solute to the micelle, the chiral selector, or both. Furthermore, it is shown that a neutral marker molecule cannot be used to accurately correct mobilities that have been altered due to changes in solution viscosity. While this work utilizes the practical vancomycin-micelle system, the general conclusions and theory apply to most other analogous CE systems as well.

Reshaping the active pocket of esterase Est816 for resolution of economically important racemates

Bacterial esterases are potential biocatalysts for the production of optically pure compounds. However, the substrate promiscuity and chiral selectivity of esterases usually have a negative correlation, which limits their commercial value. Herein, an efficient and versatile esterase (Est816) was identified as a promising catalyst for the hydrolysis of a wide range of economically important substrates with low enantioselectivity. We rationally designed several variants with up to 11-fold increased catalytic efficiency towards ethyl 2-arylpropionates, mostly retaining the initial substrate scope and enantioselectivity. These variants provided a dramatic increase in efficiency for biocatalytic applications. Based on the best variant Est816-M1, several variants with higher or inverted enantioselectivity were designed through careful analysis of the structural information and molecular docking. Two stereoselectively complementary mutants, Est816-M3 and Est816-M4, successfully overcame and even reversed the low enantioselectivity, and several 2-arylpropionic acid derivatives with highEvalues were obtained. Our results offer potential industrial biocatalysts for the preparation of structurally diverse chiral carboxylic acids and further lay the foundation for improving the catalytic efficiency and enantioselectivity of esterases.

Evaluation of the Edman degradation product of vancomycin bonded to core-shell particles as a new HPLC chiral stationary phase

A modified macrocyclic glycopeptide-based chiral stationary phase (CSP), prepared via Edman degradation of vancomycin, was evaluated as a chiral selector for the first time. Its applicability was compared with other macrocyclic glycopeptide-based CSPs: TeicoShell and VancoShell. In addition, another modified macrocyclic glycopeptide-based CSP, NicoShell, was further examined. Initial evaluation was focused on the complementary behavior with these glycopeptides. A screening procedure was used based on previous work for the enantiomeric separation of 50 chiral compounds including amino acids, pesticides, stimulants, and a variety of pharmaceuticals. Fast and efficient chiral separations resulted by using superficially porous (core-shell) particle supports. Overall, the vancomycin Edman degradation product (EDP) resembled TeicoShell with high enantioselectivity for acidic compounds in the polar ionic mode. The simultaneous enantiomeric separation of 5 racemic profens using liquid chromatography-mass spectrometry with EDP was performed in approximately 3?minutes. Other highlights include simultaneous liquid chromatography separations of rac-amphetamine and rac-methamphetamine with VancoShell, rac-pseudoephedrine and rac-ephedrine with NicoShell, and rac-dichlorprop and rac-haloxyfop with TeicoShell.

Enantioselective potential of polysaccharide-based chiral stationary phases in supercritical fluid chromatography

The enantioselective potential of two polysaccharide-based chiral stationary phases for analysis of chiral structurally diverse biologically active compounds was evaluated in supercritical fluid chromatography using a set of 52 analytes. The chiral selectors immobilized on 2.5?μm silica particles were tris-(3,5-dimethylphenylcarmabate) derivatives of cellulose or amylose. The influence of the polysaccharide backbone, different organic modifiers, and different mobile phase additives on retention and enantioseparation was monitored. Conditions for fast baseline enantioseparation were found for the majority of the compounds. The success rate of baseline and partial enantioseparation with cellulose-based chiral stationary phase was 51.9% and 15.4%, respectively. Using amylose-based chiral stationary phase we obtained 76.9% of baseline enantioseparations and 9.6% of partial enantioseparations of the tested compounds. The best results on cellulose-based chiral stationary phase were achieved particularly with propane-2-ol and a mixture of isopropylamine and trifluoroacetic acid as organic modifier and additive to CO2, respectively. Methanol and basic additive isopropylamine were preferred on amylose-based chiral stationary phase. The complementary enantioselectivity of the cellulose- and amylose-based chiral stationary phases allows separation of the majority of the tested structurally different compounds. Separation systems were found to be directly applicable for analyses of biologically active compounds of interest.