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[ CAS No. 74103-06-3 ] {[proInfo.proName]}

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Chemical Structure| 74103-06-3
Chemical Structure| 74103-06-3
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Product Details of [ 74103-06-3 ]

CAS No. :74103-06-3 MDL No. :MFCD00864281
Formula : C15H13NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :OZWKMVRBQXNZKK-UHFFFAOYSA-N
M.W : 255.27 Pubchem ID :3826
Synonyms :
RS37619

Calculated chemistry of [ 74103-06-3 ]

Physicochemical Properties

Num. heavy atoms : 19
Num. arom. heavy atoms : 11
Fraction Csp3 : 0.2
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 69.81
TPSA : 59.3 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.93 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.99
Log Po/w (XLOGP3) : 2.72
Log Po/w (WLOGP) : 2.29
Log Po/w (MLOGP) : 1.24
Log Po/w (SILICOS-IT) : 2.01
Consensus Log Po/w : 2.05

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -3.37
Solubility : 0.11 mg/ml ; 0.00043 mol/l
Class : Soluble
Log S (Ali) : -3.62
Solubility : 0.0614 mg/ml ; 0.00024 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.23
Solubility : 0.152 mg/ml ; 0.000594 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.79

Safety of [ 74103-06-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 74103-06-3 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 74103-06-3 ]

[ 74103-06-3 ] Synthesis Path-Downstream   1~85

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YieldReaction ConditionsOperation in experiment
47.5% With sodium hydroxide; In tetrahydrofuran; for 9h;Reflux; Green chemistry; One equivalent of compound 6 and a second organic solvent are sequentially added to the reactor.The second organic solvent is tetrahydrofuran, the weight ratio of the second organic solvent to the compound 6 is 8:1, stirring, adding 5 equivalents of the alkali solution,The alkali solution is sodium hydroxide having a mass concentration of 30%, and the addition is completed, and the mixture is heated and refluxed for 9 hours.After the reaction is completed, the tetrahydrofuran is concentrated under reduced pressure until no liquid flows out, and the temperature is cooled to below 45 C.Extract three times with methyl tert-butyl ether, add 10 g of methyl tert-butyl ether each time, and stir for 10 minutes.The mixture was allowed to stand for separation, the organic phase was separated, and the aqueous phase was adjusted to pH 2.5 with concentrated hydrochloric acid, then ethyl acetate was added and stirred for 10 minutes.The mixture was allowed to stand for stratification, the aqueous phase was separated, and the organic phase was washed three times with water, and 10 g of water was used each time to remove the aqueous phase. The organic phase was concentrated under reduced pressure until no liquid was discharged, and the temperature in the autoclave was controlled at 50 C, and concentrated to an oil.Petroleum ether was added dropwise to precipitate, stirred at 50 C, cooled to 12 C, filtered, and the filter cake was rinsed with petroleum ether.And drying under reduced pressure at 50 C, the solid is ketorolac,
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  • [ 108061-03-6 ]
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  • ketorolac acid <(N,N-dimethylamino)carbonyl>methyl ester [ No CAS ]
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  • [ 74103-06-3 ]
  • [ 77-86-1 ]
  • (2,3-dihydro-1H-pyrrolizin-5-yl)(phenyl)methanone [ No CAS ]
  • 5-Benzoyl-2,3-dihydro-pyrrolizin-1-one [ No CAS ]
  • (1-hydroxy-2,3-dihydro-1H-pyrrolizin-5-yl)(phenyl)methanone [ No CAS ]
  • 5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid (2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-amide [ No CAS ]
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  • [ 5856-63-3 ]
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  • (R)-5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid ((R)-1-hydroxymethyl-propyl)-amide [ No CAS ]
  • (S)-5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid ((R)-1-hydroxymethyl-propyl)-amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
A method according to claim 8wherein the non-steroidal anti-inflammatory agent is selected from the group consisting of: flurbiprofen; diclofenac; ketorolac; and,
7.77 g (86%) b) Preparation of (-) ketorolac 106 ml of 2N sulfuric acid was added to a stirred suspension of 19.8 g (0.036 mol) of the above cinchonidinium salt in 2121 ml of water. The mixture was extracted with ethyl acetate (400 ml) and the extract was washed with water, dried over anhydrous CaCl2 and evaporated in vacuo. The crude acid was crystallized from a mixture of 140 ml of ethyl acetate and 80 ml of hexane to give 7.77 g (86%) of pure (-)-ketorolac, m.p. 172-174 C.; [alpha]D =-175 (cl, MeOH).
EXAMPLE 6 Preparation of 5-Benzoyl-2,3-Dihydro-1H-Pyrrolizine-1-Carboxylic Acid A mixture of diethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,1dicarboxylester (21 mg, 0.06 mmole) dissolved in 1 ml of diethylether and 20% sodium hydroxide solution(0.35 ml) was stirred and refluxed for 24 hours. The aqueous layer was washed with ether(1 ml), and acidified with concentrated hydrochloric acid. Then, the aqueous layer was washed with ethyl acetate, and the extracted material was heated for 4 hours at 70 C. Finally, the ethyl acetate solution was concentrated under reduced pressure to yield a final productproduct 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid (4 mg, 93%) as a pure solid.
A. A mixture of two esters (0.273 g) was heated at reflux temperature in water (1 ml) methanol (3 ml) solution with six equivalents of potassium hydroxide for 0.5 hour. The solvent was removed in vacuo, water (50 ml) was added and the solution was made acidic with 10% hydrochloric acid. The product was extracted with ethyl acetate, the extract was washed with water, dried over sodium sulfate, and evaporated in vacuo. The solid residue (0.232 g, 85%) had m.p. 158 and was identical to an authentic specimen of 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid prepared by another route.
A. A mixture of two esters (0.273 g) was heated at reflux temperature in water (1 ml) methanol (3 ml) solution with six equivalents of potassium hydroxide for 0.5 hour. The solvent was removed in vacuo, water (50 ml) was added and the solution was made acidic with 10% hydrochloric acid. The product was extracted with ethyl acetate, the extract was washed with water, dried over sodium sulfate, and evaporated in vacuo. The solid residue (0.232 g, 85%) had m.p. 158 and was identical to an authentic specimen of 5-benzoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid prepared by another route.
Most preferred and exemplary compounds useful in the method of the present invention include, but are not limited to, 5-benzoyl-1,2-dihydro-3H-pyrrolo(1,2-a)-pyrrole-1-carboxylic acid, 5-(para-methylthio)benzoyl-1,2-dihydro-3H-pyrrolo(1,2-a)-pyrrole-1-carboxylic acid, 5-(para-methoxy)-benzoyl-1,2-dihydro-3H-pyrrolo(1,2-a)-pyrrole-1-carboxylic acid

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  • 5-benzoyl-2,3-dihydro-1<i>H</i>-pyrrolizine-1-carboxylic acid octyl ester [ No CAS ]
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  • [ 64-17-5 ]
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  • 5-benzoyl-2,3-dihydro-1<i>H</i>-pyrrolizine-1-carboxylic acid ethyl ester [ No CAS ]
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  • 5-benzoyl-2,3-dihydro-1<i>H</i>-pyrrolizine-1-carboxylic acid isobutyl ester [ No CAS ]
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  • 5-benzoyl-2,3-dihydro-1<i>H</i>-pyrrolizine-1-carboxylic acid decyl ester [ No CAS ]
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  • 5-benzoyl-2,3-dihydro-1<i>H</i>-pyrrolizine-1-carboxylic acid tetradecyl ester [ No CAS ]
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  • [ 67-63-0 ]
  • 5-benzoyl-2,3-dihydro-1<i>H</i>-pyrrolizine-1-carboxylic acid isopropyl ester [ No CAS ]
  • 5-benzoyl-2,3-dihydro-1<i>H</i>-pyrrolizine-1-carboxylic acid isopropyl ester [ No CAS ]
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  • (+)-(R)-5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid butyl ester [ No CAS ]
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  • (+)-(R)-5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid butyl ester [ No CAS ]
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  • (-)-(S)-5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid butyl ester [ No CAS ]
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  • 5-benzoyl-2,3-dihydro-1<i>H</i>-pyrrolizine-1-carboxylic acid hexyl ester [ No CAS ]
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  • [ 916165-56-5 ]
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  • C15H12NO2NHC6H4OH [ No CAS ]
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  • C15H12NO2NHC6H4OCOCH3 [ No CAS ]
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  • [ 1885-14-9 ]
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  • compound 19 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 24h; To a solution of ketorolac (D9) (74 mg; 0.29 mmole) in dry [CH2CL2] (5 ml) under argon, 0.380 mL (2.73 mmole) of triethylamine, 80 mg (0.59 mmole) of 1- hydroxybenzotriazole, 230 mg (0.29 mmole) [OF ML2] and 235 mg (1.23 mmole) of 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride were added. The reaction mixture was stirred for 24 hours at room temperature in a flow of argon, then evaporated to a smaller volume under reduced pressure and purified on a silica gel column (eluant: [CHCL3] : MeOH: [NH40H] = 6: 1: 0.1). 110 mg of compound 19 was obtained. MS [(NEZ)] : 1029.5 [MH] +. IR (KBr) [CM-1] : 3448,2972, 2936,2876, 1719, 1655,1624, 1572,1561, 1544,1492, 1465,1430, 1400,1379, 1342,1272, 1167, 1109,1052, 1013,1000, 958,894, 835,797, 758,724, 699,670.
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  • [ 71-23-8 ]
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  • [ 538-75-0 ]
  • ketorolac n-propyl ester [ No CAS ]
  • [ 35168-15-1 ]
YieldReaction ConditionsOperation in experiment
With dmap; In tetrahydrofuran; at 0℃; for 12h; <strong>[74103-06-3]Ketorolac</strong> tromethamine was purchased from Sigma (Saint Louis, Mo., USA). <strong>[74103-06-3]Ketorolac</strong> was obtained from its tromethamine salt using a precipitation method. Following adding 1 N HCl drop by drop into a ketorolac tromethamine solution, ketorolac was precipitated. The collected precipitate was purified by extraction with ethyl acetate, followed evaporation to dryness. The purity of ketorolac was checked by melting point measurement and HPLC analysis. The obtained product was measured to have a melting point of 155 C., virtually the same as reported in literature. The obtained product has a purity of >99% as determined by HPLC analysis. To a 250-mL ice-bathed round-bottomed flask were added 45 mL of tetrahydrofuran (THF; Mallinckrodt Baker, New Jersy, USA) and 0.0135 mole of ketorolac. Subsequently, 0.0148 mole of propyl alcohol (Mallinckrodt Backer, New Jersey, USA) and 0.00135 mole of 4-dimethylaminopyridine (DMAP; Sigma, Missouri, USA) were gradually added into the flask with stirring. Finally, 0.0148 mole of N,N'-dicyclohexylcarbodiimide (DCC; Merck, Darmstadt, Germany) was added into the flask under argon gas. Following stirring for 12 hrs, a waste product (N,N-dicyclohexylurea) was precipitated from the reaction mixture. After filtering off the precipitate, the remaining solution was concentrated by vacuum evaporation and then mixed with 100 ml of ethyl acetate. The resultant mixture was washed with 50 ml of 5% HCl and 5 ml of brine (saturated saline solution). The organic (ethyl acetate) layer was collected and concentrated by vacuum evaporation. The thus-obtained concentrate was subjected to column chromatography with 10% ethyl acetate in hexane, and purified ketorolac propyl ester was obtained. The production of the title compound was affirmed by Tables 2-6, which summarized the physical characteristics, mass spectrum data, infra-red (IR) spectrum data, ultraviolet (UV) spectrum data and 1H-NMR spectrum data of ketorolac propyl ester, respectively. Detected Properties of the Title Compound: Representative 1H-NMR (400 MHz, CDCl3): 7.82 (d,2H,Ar-H,J=7.9 Hz), 7.53 (m,1H,Ar-H), 7.45 (t,2H,Ar-H,J=7.7 Hz,7.4 Hz), 6.82 (d,1H,J=4.0 Hz), 6.11 (d,1H,J=4.1 Hz), 4.59-4.41 (m,2H), 4.16-4.05 (m,3H), 2.96-2.77 (m,2H), 1.74 (m,2H), 0.96 (t,3H,J=7.5 Hz,7.2 Hz). Representative mass fragments (amu): 297, 210,105, 77 [detection was carried out using GC-MS spectroscopy (Spectrum RXI, Perkin Elmer, UK)]. Representative IR absorption (cm-1): 2967.3, 1735.8, 1624.0, 1574.7, 1465.1, 1431.6, 1269.0 [detection was carried out using FT-IR spectroscopy (Spectrum RXI, Perkin Elmer, UK)].
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  • ketorolac tromethamine [ No CAS ]
  • [ 74103-06-3 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; In water; Ketorolac tromethamine was purchased from Sigma (Saint Louis, Mo., USA). Ketorolac was obtained from its tromethamine salt using a precipitation method. Following adding 1 N HCl drop by drop into a ketorolac tromethamine solution, ketorolac was precipitated. The collected precipitate was purified by extraction with ethyl acetate, followed evaporation to dryness. The purity of ketorolac was checked by melting point measurement and HPLC analysis. The obtained product was measured to have a melting point of 155 C., virtually the same as reported in literature. The obtained product has a purity of >99% as determined by HPLC analysis. To a 250-mL ice-bathed round-bottomed flask were added 45 mL of tetrahydrofuran (THF; Mallinckrodt Baker, New Jersy, USA) and 0.0135 mole of ketorolac. Subsequently, 0.0148 mole of propyl alcohol (Mallinckrodt Backer, New Jersey, USA) and 0.00135 mole of 4-dimethylaminopyridine (DMAP; Sigma, Missouri, USA) were gradually added into the flask with stirring. Finally, 0.0148 mole of N,N'-dicyclohexylcarbodiimide (DCC; Merck, Darmstadt, Germany) was added into the flask under argon gas. Following stirring for 12 hrs, a waste product (N,N-dicyclohexylurea) was precipitated from the reaction mixture. After filtering off the precipitate, the remaining solution was concentrated by vacuum evaporation and then mixed with 100 ml of ethyl acetate. The resultant mixture was washed with 50 ml of 5% HCl and 5 ml of brine (saturated saline solution). The organic (ethyl acetate) layer was collected and concentrated by vacuum evaporation. The thus-obtained concentrate was subjected to column chromatography with 10% ethyl acetate in hexane, and purified ketorolac propyl ester was obtained. The production of the title compound was affirmed by Tables 2-6, which summarized the physical characteristics, mass spectrum data, infra-red (IR) spectrum data, ultraviolet (UV) spectrum data and 1H-NMR spectrum data of ketorolac propyl ester, respectively. Detected Properties of the Title Compound: Representative 1H-NMR (400 MHz, CDCl3): 7.82 (d,2H,Ar-H,J=7.9 Hz), 7.53 (m,1H,Ar-H), 7.45 (t,2H,Ar-H,J=7.7 Hz,7.4 Hz), 6.82 (d,1H,J=4.0 Hz), 6.11 (d,1H,J=4.1 Hz), 4.59-4.41 (m,2H), 4.16-4.05 (m,3H), 2.96-2.77 (m,2H), 1.74 (m,2H), 0.96 (t,3H,J=7.5 Hz,7.2 Hz). Representative mass fragments (amu): 297, 210,105, 77 [detection was carried out using GC-MS spectroscopy (Spectrum RXI, Perkin Elmer, UK)]. Representative IR absorption (cm-1): 2967.3, 1735.8, 1624.0, 1574.7, 1465.1, 1431.6, 1269.0 [detection was carried out using FT-IR spectroscopy (Spectrum RXI, Perkin Elmer, UK)].
With hydrogenchloride; In water;Product distribution / selectivity; EXAMPLE 1 PREPARATION OF A 4-ARM PEG (20K) - KETOROLAC DELIVERY SYSTEM One gram (1.0 g) of ketorolac tris salt was converted to ketorolac by dissolution in 15 niL DI H2O, followed by addition of 30 mL IN HCl. The resulting solution was stirred until a white solid precipitated. The product was collected by filtration, dried under vacuum, and used in the following synthetic transformations.; EXAMPLE 2 PREPARATION OF A 4-ARM PEG (40K) - KETOROLAC DELIVERY SYSTEM[0194] Ketorolac was prepared from the corresponding tris salt as described in Example 1.
With potassium hydrogensulfate; In ethyl acetate; at 20℃; for 0.166667h; KTL-T (2.66 mmol, 1.0 g) was weighed into an Erlenmeyer flask, and an appropriate amount of ethyl acetate and potassium bisulfate solution (1 mol / L) was added, and magnetic stirring was performed at room temperature for 10 minutes.The ethyl acetate layer was collected and the solvent was removed by rotary evaporation to obtain KTL as a white solid
YieldReaction ConditionsOperation in experiment
Example 8 5-benzoyl-2,3-dihydro-1H-Pyrrolizine-1-Carboxylic Acid Morpholinocarbonyloxyethyl Ester Using the same procedure as that given in example 4, the prodrug of Ketorolac was produced. M.P=69-72 C. IR cm-1: carbonyls at 1745, 1705, 1625. 1H NMR,(CDC13), delta2.8 (m,2H, pyrrolidine); 3.3-3.7 (m,8H, morpholine); 4.1 (m, 1H, pyrrolidine); 4.3-4.7 (m,6H, O(CH2)20 & -CH2 pyrrolidine); 6.1 (d, 1H, pyrrol H, J=4 Hz); 6.8 (d, 1H, pyrolle H, J=4 Hz); 7.4-7.6 (m,3H, aromatic); 7.8 (d,2H, aromatic, J=7 Hz).
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  • [ 140947-23-5 ]
  • 5-Benzoyl-z,3-dihydro-1H- pyrrolizine-1-carboxylic acid [ No CAS ]
  • [ 74103-06-3 ]
YieldReaction ConditionsOperation in experiment
400 mg (93%) With sodium hydroxide; In diethyl ether; A Compound of Formula II, 5-Benzoyl-z,3-dihydro-1H- pyrrolizine-1-carboxylic acid A mixture of diethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate (600 mg, I.69 mmol) in diethyl ether and 20% aqueous sodium hydroxide (10 mL) was refluxed with vigorous stirring for 24 hours. The aqueous layer was washed with ether (20 mL), and acidified with concentrated hydrochloric acid. The aqueous layer was washed with ethyl acetate (3*20 mL). The ethyl acetate extracts were combined and warmed at 70 C. for 4 hours. The ethyl acetate solution was concentrated under reduced pressure to yield 400 mg (93%) of 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid as a pure solid.
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  • [ 140947-23-5 ]
  • 5-(4-Benzoyl)-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid [ No CAS ]
  • [ 74103-06-3 ]
YieldReaction ConditionsOperation in experiment
400 mg (93%) With sodium hydroxide; In diethyl ether; 8A. A Compound of Formula II, 5-(4-Benzoyl)-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid A mixture of diethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate (600 mg, 1.69 mmol) in diethyl ether and 20% aqueous sodium hydroxide (10 mL) was refluxed with vigorous stirring for 24 hours. The aqueous layer was washed with ether (20 mL), and acidified with concentrated hydrochloric acid. The aqueous layer was washed with ethyl acetate (3*20 mL). The ethyl acetate extracts were combined and warmed at 70 C. for 4 hours. The ethyl acetate solution was concentrated under reduced pressure to yield 400 mg (93%) of 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid (ketorolac).
  • 58
  • acetone hexane [ No CAS ]
  • sodium thiomethylate (sodium methyl mercaptan) [ No CAS ]
  • [ 74103-06-3 ]
  • [ 144-55-8 ]
  • [ 2524-64-3 ]
  • methyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-thiocarboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N2; triethylamine; In tetrahydrofuran; ethyl acetate; EXAMPLE 1 Preparation of methyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-thiocarboxylate In a heat-dried, stirred, N2 blanketed 25 ml flask with side-arm and septum 130 mg of 5-benzoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid is dissolved in 8 ml of dry THF. Fifty-nine (59) mul of triethylamine, followed by 81 mul of diphenylchlorophosphate are added, and the turbid mixture is heated in a 55 oil bath. After 2 hours the reaction mixture is cooled in ice, and then filtered into a fresh, dry N2 blanketed 50 ml flask with side-arm and septum, washing the filter cake with additional THF. 1.35 ml of a 0.92 N solution of sodium thiomethylate (sodium methyl mercaptan) is added to the solution of the above intermediate in the flask, and the mixture is heated at 55 for 11/2 hours, after which the reaction is complete. The resulting product is added to ethyl acetate and dilute aqueous sodium bicarbonate is added. The extract is washed three times with H2 O, dried over Na2 SO4, and evaporated to dryness. Two crystallizations of the residue from acetone-hexane affords pure colorless needles of methyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-thiocarboxylate, m.p. 69.
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  • [ 98-85-1 ]
  • [ 74103-06-3 ]
  • (d)-5-benzoyl-1,2-dihydro-3H-pyrrolo-[1,2-α]pyrrole-1-carboxylic acid-(l)-α-phenethyl ester [ No CAS ]
  • (l)-5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid-(l)-α-phenethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; trifluoroacetic anhydride; In water; benzene; EXAMPLE 12 B To a solution of 300 mg. of 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 25 ml. of dry benzene, 0.58 g. of trifluoroacetic anhydride is added. The mixture is stirred at room temperature for 10 minutes and the resulting solution is cooled to 0-5 C and 1.4 g. of dry triethylamine is added, followed immediately by the addition of 0.5 g. of (l)-alpha-phenyl ethyl alcohol. The thus-obtained reaction solution is stirred at room temperature for 15 minutes and poured into 20 ml. of water containing 1 ml. of triethylamine, followed by extraction with ethyl acetate. The ethyl acetate extract is dried over sodium sulfate, followed by removal of the solvent and excess (l)-alpha-phenyl ethyl alcohol under vacuum to yield 0.42 g. of a mixture of (l)-5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid-(l)-alpha-phenethyl ester and (d)-5-benzoyl-1,2-dihydro-3H-pyrrolo-[1,2-alpha]pyrrole-1-carboxylic acid-(l)-alpha-phenethyl ester which is separated by high pressure liquid chromatography (using 4% EtOAc/hexane on a 11 mm. * 50 cm., 10mum. Lichrosord Sl-60 column) to give 180 mg. of a more polar ester (alphaDMeOH -145.7) and 178 mg. of a less polar ester (alphaDMeOH +128.6).
  • 60
  • [ 74103-06-3 ]
  • [ 80965-09-9 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; EXAMPLE 19 A solution of 200 mg. of 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 5 ml. of dichloromethane is treated with an excess of ethereal diazomethane, and the reaction mixture is maintained at room temperature for 30 minutes. The solvents and excess reagent are eliminated under reduced pressure and the residue crystallized from ethyl acetate-methanol, to yield methyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate.
YieldReaction ConditionsOperation in experiment
83.4% Preparation of ketorolac and ketorolac tromethamine A mixture of 34.4 g (100 mmol) 5-benzoyl-N-methyl-N-phenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide, 25 g sodium hydroxide in 25 mL water, and 80 mL methanol was refluxed for 5 hours. The mixture was cooled to room temperature, stirred under nitrogen for sixteen hours, and then diluted with 80 mL of water. The mixture was extracted with toluene (2*50 mL), and the aqueous and organic phases were separated. The aqueous phase was acidified with 6 N hydrochloric acid (110 mL). The resulting precipitate was extracted several times with dichloromethane (1*150 mL), (1*75 mL), (1*50 mL). The combined extract was treated with FILTROL (activated clay decolorizing agent) (4.5 g) for 30 minutes, filtered, and concentrated by atmospheric distillation. Hexane (190 mL) was added and the entire mixture allowed to cool to room temperature and then further cooled to 0 C. to -5 C. The product, 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid (ketorolac) was collected by filtration, washed with 100 mL of hexane/dichloromethane (7:3 v/v), and dried at 60 C. to 70 C. under vacuum, to yield ketorolac (21.3 g, 83.4% yield), mp 152 C. to 162 C.
  • 62
  • 4-arm-PEG-20K [ No CAS ]
  • [ 74103-06-3 ]
  • 4-arm-PEG-20K-ketorolac [ No CAS ]
YieldReaction ConditionsOperation in experiment
95% With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; One gram (1.0 g) of ketorolac tris salt was converted to ketorolac by dissolution in 15 niL DI H2O, followed by addition of 30 mL IN HCl. The resulting solution was stirred until a white solid precipitated. The product was collected by filtration, dried under vacuum, and used in the following synthetic transformations.[0193] 4-arm-PEG-20K (2.O g, MW=20 kDa), ketorolac (151 mg), HOBT (11 mg),DMAP (73 mg) and DCC (413 mg) were dissolved in anhydrous CH2CL2 (80 mL) to form a yellow solution which was then stirred at RT overnight. The resulting reaction mixture was filtered to remove any undissolved solids, and the solvent removed by rotary evaporation. IPA (~200 mL) was then added to the remaining residue to precipate the product. The product was collected by filtration, and rinsed with ethyl ether. The recovered solid was dried under vacuum overnight. Yield of product (designated JY424, or 4-arm PEG-20K- KETO) was 95%. Based upon 1H NMR analysis, the drug loading amount was approximately 5% by weight.
  • 63
  • 4-arm-PEG-40K [ No CAS ]
  • [ 74103-06-3 ]
  • 4-arm-PEG-40K-ketorolac [ No CAS ]
YieldReaction ConditionsOperation in experiment
94% With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; <strong>[74103-06-3]Ketorolac</strong> was prepared from the corresponding tris salt as described in Example 1. 4-arm-PEG-40K (2.0 g, MW=40 kDa), ketorolac (76 mg), HOBT (6 mg),DMAP (37 mg) and DCC (207 mg) were dissolved in anhydrous CH2CL2 (80 mL) to form a yellow solution which was then stirred at RT overnight. The resulting reaction mixture was filtered to remove any undissolved solids, and the solvent removed by rotary evaporation. IPA (-200 mL) was then added to the remaining residue to precipate the product. The product was collected by filtration, and rinsed with ethyl ether. The recovered solid was dried under vacuum overnight. Yield of product (designated JY425 or 4-arm PEG-40K- KETO) was 94%. Based upon 1H NMR analysis, the drug loading amount was approximately 2.3% by weight.
  • 64
  • 4-arm-PEG-40K-ketorolac [ No CAS ]
  • 4-arm-PEG-40K [ No CAS ]
  • [ 74103-06-3 ]
YieldReaction ConditionsOperation in experiment
With water; at 37℃; for 0 - 150h;pH 7.4;PBS buffer;Kinetics; A release study was conducted to examine the release profiles of parent drug, ketorolac, from illustrative multi-arm polymer delivery systems to which the drug was covalently but releasably attached. A. Sample Preparation:[0196] 4-arm PEG-20K KETO: 40.0 mg of 4-arm-20K-Ketorolac (JY424) was dissolved in 10 mL PBS, pH 7.4. After total dissolution, the solution was stored at 370C. Analysis was based upon HPLC results. On the first day, two HPLC injections were carried out, thereafter, one injection was made daily to provide the release profile reported herein. -4-arm PEG-40K KETO: The sample was prepared in an identical fashion to 4-arm-20K-KETO.B. Analytical Method[0197] An HPLC method was employed to determine release profiles using a two- solvent gradient system. Solvent A was 0.1% TFA in H2O; Solvent B was acetonitrile. A UV detector was employed at a wavelength of 280 nm. Release of unmodified parent drug from the delivery system was confirmed by NMR.C. Results[0198] As stated above, the kinetics of the reaction, i.e.ths release rate of drug as a function of time, was measured for both 4-arm-PEG-20K-ketorolac and 4-arm PEG-40K- EPO <DP n="65"/>ketorolac in PBS buffer, at pH 7.4 at 370C. Based upon the kinetic data, half-lives were determined for each of the illustrative conjugates. The half-life of the 4-arm-PEG~20K- ketorolac conjugate was 55 hours. The half-life of the 4-arm-PEG-40K-ketorolac conjugate was 43 hours. [0199] Based upon the above, it can be seen that the half-lives of both of these conjugate-based delivery systems is approximately 2 days. The half-life of non-conjugated ketorolac is about 2 hours. Thus, the illustrative conjugate delivery sytems described in these examples are effective to increase the half-life of ketorolac more than 5-fold; in the case of the 20 kD multi-armed PEG conjugate, the half-life of the drug is increased over 27 times, while in the case of the 40 kD multi-armed PEG conjugate, the half life of the drug is increased over 20 times.[0200] A plot demonstrating the pharmacokinetics of these delivery systems is provided in FIG. 1.
  • 65
  • 4-arm-PEG-20K-ketorolac [ No CAS ]
  • 4-arm-PEG-20K [ No CAS ]
  • [ 74103-06-3 ]
YieldReaction ConditionsOperation in experiment
With water; at 37℃; for 0 - 150h;pH 7.4;PBS buffer;Kinetics; A release study was conducted to examine the release profiles of parent drug, ketorolac, from illustrative multi-arm polymer delivery systems to which the drug was covalently but releasably attached. A. Sample Preparation:[0196] 4-arm PEG-20K KETO: 40.0 mg of 4-arm-20K-Ketorolac (JY424) was dissolved in 10 mL PBS, pH 7.4. After total dissolution, the solution was stored at 370C. Analysis was based upon HPLC results. On the first day, two HPLC injections were carried out, thereafter, one injection was made daily to provide the release profile reported herein. -4-arm PEG-40K KETO: The sample was prepared in an identical fashion to 4-arm-20K-KETO.B. Analytical Method[0197] An HPLC method was employed to determine release profiles using a two- solvent gradient system. Solvent A was 0.1% TFA in H2O; Solvent B was acetonitrile. A UV detector was employed at a wavelength of 280 nm. Release of unmodified parent drug from the delivery system was confirmed by NMR.C. Results[0198] As stated above, the kinetics of the reaction, i.e.ths release rate of drug as a function of time, was measured for both 4-arm-PEG-20K-ketorolac and 4-arm PEG-40K- EPO <DP n="65"/>ketorolac in PBS buffer, at pH 7.4 at 370C. Based upon the kinetic data, half-lives were determined for each of the illustrative conjugates. The half-life of the 4-arm-PEG~20K- ketorolac conjugate was 55 hours. The half-life of the 4-arm-PEG-40K-ketorolac conjugate was 43 hours. [0199] Based upon the above, it can be seen that the half-lives of both of these conjugate-based delivery systems is approximately 2 days. The half-life of non-conjugated ketorolac is about 2 hours. Thus, the illustrative conjugate delivery sytems described in these examples are effective to increase the half-life of ketorolac more than 5-fold; in the case of the 20 kD multi-armed PEG conjugate, the half-life of the drug is increased over 27 times, while in the case of the 40 kD multi-armed PEG conjugate, the half life of the drug is increased over 20 times.[0200] A plot demonstrating the pharmacokinetics of these delivery systems is provided in FIG. 1.
  • 66
  • [ 18274-81-2 ]
  • [ 74103-06-3 ]
  • 5-(p-hydroxyphenyl)-3H-1,2-dithiol-3-thione ketorolac ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 4-pyrrolidin-1-ylpyridine; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 0.5h; The ketorolac ester was prepared employing dicyclohexylcarbodiimide (DCC) as coupling agent in presence of 4-pyrrolidinylpyridine. The solvent used was methylene chloride purified on basic Al2O3 to remove traces of ethanol. In a 50 ml flask, 1.17 mmol of ketorolac and 2.15 ml of methylene chloride were charged as well as 0.014 mol of 4-pyrrolidinylpyridine, 1.17 mmol of 5-(p-hydroxyphenyl)-3H-1,2-dithiol-3-thione and 1.47 mmol of DCC (25% excess) in 1.5 ml of methylene chloride. The mixture was stirred for 30 minutes at room temperature. At the end of the reaction, after filtration the solution was extracted with 10% acetic acid, then with 0.1N NaOH and finally with brine. After removal of the solvent, the product was chromatographed on silica gel with dichoromethane and crystallized by ether: melting point 146-147C. Anal. calcd. C24H17NO3S3 C% 62.18; H% 3.69; N% 3.02; S% 20.75; found C% 61.85; H% 3.60; N% 2.83; S% 21.10.
  • 67
  • [ 110-52-1 ]
  • [ 74103-06-3 ]
  • C34H32N2O6 [ No CAS ]
  • 68
  • [ 4244-84-2 ]
  • [ 74103-06-3 ]
  • [ 863126-60-7 ]
  • 69
  • [ 1115-59-9 ]
  • [ 74103-06-3 ]
  • [ 1093407-68-1 ]
  • 70
  • [ 1118-89-4 ]
  • [ 74103-06-3 ]
  • [ 1093407-76-1 ]
  • 71
  • [ 3182-93-2 ]
  • [ 74103-06-3 ]
  • [ 1093407-70-5 ]
  • 72
  • [ 2899-28-7 ]
  • [ 74103-06-3 ]
  • [ 1093407-69-2 ]
  • 73
  • [ 17609-47-1 ]
  • [ 74103-06-3 ]
  • [ 1093407-71-6 ]
  • 74
  • [ 2743-40-0 ]
  • [ 74103-06-3 ]
  • [ 1093407-72-7 ]
  • 75
  • [ 74103-06-3 ]
  • ketorolac anhydride [ No CAS ]
  • 76
  • [ 74103-06-3 ]
  • [ 16115-68-7 ]
  • [ 1093407-74-9 ]
  • 77
  • [ 74103-06-3 ]
  • (2S,3S)-ethyl 2-amino-3-methylpentanoate hydrochloride [ No CAS ]
  • [ 1093407-73-8 ]
  • 78
  • [ 74103-06-3 ]
  • [ 66635-93-6 ]
  • [ 66635-92-5 ]
YieldReaction ConditionsOperation in experiment
With chiral stationary phase including isopropyl-functionalized CF6; In ethanol; n-heptane; trifluoroacetic acid; at 20℃;Purification / work up; In addition to the foregoing, numerous other chromatographic separations using a column bonded with a CSP including a derivatized cyclofructan residue were carried out. Tables 5-9 list some additional examples of chromatographic separations using a column bonded with a CSP of the present invention. AU examples of chromatographic separations using columns bonded with CSPs of the present invention were carried out using the following experimental conditions and procedures.|0132| The high performance liquid chromatography (HPLC) column packing system was composed of an air driven fluid pump (HASKEL, DSTV- 122), an air compressor, a pressure regulator, a low pressure gauge, two high-pressure gauges (10,000 and 6,000 psi), a slurry chamber, check valves, and tubings. The CSPs were slurry packed into a 25 cm x 0.46 cm (inner diameter, I. D.) stainless steel column.|0133| The HPLC system was an Agilent 1 100 system (Agilent Technologies, Palo Alto,CA), which consisted of a diode array detector, an autosampler, a binary pump, a temperature- controlled column chamber, and Chemstation software. All chiral analytes were dissolved in ethanol, methanol, or other appropriate mobile phases, as indicated. For the LC analysis, the injection volume and flow rate were 5 muL and 1 mL/min, respectively. Separations were carried out at room temperature (~20 0C) if not specified otherwise. The wavelengths of UV detection were 195, 200, 210, and 254 nm. The mobile phase was degassed by ultrasonication under vacuum for 5 min. Each sample was analyzed in duplicate. Three operation modes (the normal phase mode, polar organic mode, and reversed phase mode) were tested, unless indicated otherwise. In the normal phase mode, heptane with ethanol or isopropanol was used as the mobile phase. In some cases, trifluoroacetic acid (TFA) was used as an additive, as indicated. The mobile phase of the polar organic mode was composed of acetonitrile/methanol and small amounts of acetic acid and triethylamine. Water/acetonitrile or acetonitrile/acetate buffer (20 mM, pH = 4.1 ) was used as the mobile phase in the reversed-phase mode.|0134| Two different supercritical fluid chromatographic instruments were used. One was a Berger SFC unit with an FCM 1200 flow control module, a TCM 2100 thermal column module, a dual pump control module, and a column selection valve. The flow rate was 4 mL/min. The cosolvent was composed of methanol/ethanol/isopropanol = 1 : 1 : 1 and 0.2% diethylamine (DEA). The gradient mobile phase composition was 5% cosolvent hold during 0- 0.6 min, 5-60% during 0.6-4.3 min, 60% hold during 4.3-6.3 min, 60%-5% during 6.3-6.9 min, and 5% hold during 6.9-8.0 min. The other SFC system was a Jasco (MD, USA) system comprised of an autosampler unit (AS-2059-SF Plus), a dual pump module (PU-2086 Plus), a column thermostat module (CO-2060 Plus), a UV/Vis detector (UV-2075 Plus), and a back pressure regulator module (SCH-Vch-BP). Unless otherwise specified, the mobile phase was composed of CCVmethanol (0.1 % TFA or 0.1% diethylamine). The flow rate was 3 mL/min.|0135| For the calculations of chromatographic data, the "dead time" to was determined by the peak of the refractive index change due to the sample solvent or determined by injecting l ,3,5-tri-/e/-/-butylbenzene in the normal phase mode.
  • 80
  • [ 74103-06-3 ]
  • [ 116539-58-3 ]
  • [ 1309349-73-2 ]
YieldReaction ConditionsOperation in experiment
Example 3: <strong>[74103-06-3]Ketorolac</strong>/(S)-duloxetine amorphous salt.; A solution of ketorolac (14.3 mg, 0.056 mmol, 1 eq) in 0.56 mL of methanol was added to a solution of (S)-duloxetine (16.7 mg, 0.056 mmol, 1 eq) in 0.36 mL of methanol. The mixture was evaporated to dryness, and the residue obtained was suspended in diisopropyl ether (2.3 mL) for 12 h at 50C. The resulting oil was separated from the solution and dried under vacuum for 4 h at 40C to give a brown solid corresponding to the salt ketorolac/(S)- duloxetine.Additionally, the salt has also been obtained starting with a ratio of ketorolac/(S)-duloxetine of 2:1 and 1 :2.Characterization of ketorolac/(S)-duloxetine amorphous salt 1H N R (400 MHz, c/4-methanol) delta: 2.38-2.47 (m, 1 H), 2.56-2.65 (m, 1 H), 2.70 (s, 3H), 2.68-2.77 (m, 1 H), 2.80-2.89 (m, 1 H), 3.12-3.21 (m, 1 H), 3.24-3.30 (m. 1H), 3.91 (dd, J = 8 Hz, J = 5 Hz, 1 H), 4.29-4.36 (m, 1 H), 4.49-4.56 (m, 1 H), 5.95 (dd, J = 8 Hz, J = 5 Hz, 1 H), 6.10 (d, J = 4 Hz, 1 H), 6.78 (dd, J = 4 Hz, J = 2 Hz, 1 H), 6.94-6.98 (m, 2H), 7.16 (d, J = 4 Hz, 1 H), 7.27 (t, J = 8 Hz, 1 H), 7.33 (dd, J = 7 Hz, J = 1 Hz, 1 H), 7.40-7.56 (m, 7H), 7.73 (d, J = 7 Hz, 1 H), 7.76-7.81 (m, 1 H), 8.27-8.31 (m, 1 H).XRPD (see figure 4)
In methanol;Product distribution / selectivity; Example 3: <strong>[74103-06-3]Ketorolac</strong>/(S)-duloxetine amorphous salt. A solution of ketorolac (14.3 mg, 0.056 mmol, 1 eq) in 0.56 mL of methanol was added to a solution of (S)-duloxetine (16.7 mg, 0.056 mmol, 1 eq) in 0.36 mL of methanol. The mixture was evaporated to dryness, and the residue obtained was suspended in diisopropyl ether (2.3 mL) for 12 h at 50C. The resulting oil was separated from the solution and dried under vacuum for 4 h at 40C to give a brown solid corresponding to the salt ketorolac/(S)-duloxetine. Additionally, the salt has also been obtained starting with a ratio of ketorolac/(S)-duloxetine of 2:1 and 1:2.Characterization of ketorolac/(S)-duloxetine amorphous salt 1H NMR (400 MHz, d4-methanol) delta: 2.38-2.47 (m, 1H), 2.56-2.65 (m, 1H), 2.70 (s, 3H), 2.68-2.77 (m, 1H), 2.80-2.89 (m, 1H), 3.12-3.21 (m, 1H), 3.24-3.30 (m, 1H), 3.91 (dd, J = 8 Hz, J = 5 Hz, 1H), 4.29-4.36 (m, 1H), 4.49-4.56 (m, 1H), 5.95 (dd, J = 8 Hz, J = 5 Hz, 1H), 6.10 (d, J = 4 Hz, 1H), 6.78 (dd, J = 4 Hz, J = 2 Hz, 1H), 6.94-6.98 (m, 2H), 7.16 (d, J = 4 Hz, 1H), 7.27 (t, J = 8 Hz, 1H), 7.33 (dd, J = 7 Hz, J = 1 Hz, 1H), 7.40-7.56 (m, 7H), 7.73 (d, J = 7 Hz, 1H), 7.76-7.81 (m, 1H), 8.27-8.31 (m, 1H). XRPD (see figure 4)
  • 81
  • [ 74103-06-3 ]
  • 5-benzoyl-1-(2-hydroxy-ethyl)-1H-pyrrole-2-carboxylic acid [ No CAS ]
  • 82
  • [ 74103-06-3 ]
  • [ 54910-89-3 ]
  • [ 1331729-86-2 ]
YieldReaction ConditionsOperation in experiment
56% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 18h; Scheme 1: Preparation of [l-[Methyl{(R)-3-phenyl-3-[4- (trifluoromethyl)phenoxy]propyl}-amino]methyl}-2,3-dihydro-lH-pyrrolizin-5- yl](phenyl)methanone (2b)IBX. DMSO.2bPreparation of 5-Benzoyl- V-methyl- V-{(R)-3-phenyl-3-[4- (trifluoromethyl)phenoxy] propyl} -2,3-dihydro-lH-pyrrolizine-l-carboxamide (103). To a suspension of 101 (700 mg, 2.28 mmol) and 102 (878 mg, 2.33 mmol) in anhydrous dichloromethane (15 mL) was added EDC'HCl (700 mg, 3.65 mmol), 1- hydroxybenzotriazole (490 mg, 3.62 mmol) and triethylamine (2.50 mL, 17.9 mmol) sequentially. The reaction mixture was stirred at room temperature for 18 h.Subsequently it was diluted with dichloromethane (5 mL), brine (20 mL) and extracted with dichloromethane (3 x 15 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 2: 1 Hexanes/EtOAc) to yield 103 (750 mg, 56%) as a hydroscopic white solid: 1H NMR (300 MHz, CDC13) ) delta 7.81-7.79 (m, 2H), 7.47-7.26 (m, 1 1H), 6.90-6.78 (m, 3H), 5.95-5.90 (m, 1H), 5.20-5.17 (m, 1H), 4.60-4.45 (m, 2H), 4.27-4.23 (m, 1H), 3.79-3.42 (m, 2H), 3.25 (d, J = 8.4 Hz, 2H), 3.01 (d, J = 7.2 Hz, 2H), 2.39-2.19 (m, 2H).
  • 84
  • [ 74103-06-3 ]
  • C15H15N3O2 [ No CAS ]
  • 85
  • [ 74103-06-3 ]
  • [ 1262801-33-1 ]
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