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Aminoacids

Patent:
Assignee:
Utility:

Aminoindanes
K. Curry, US Patent 6,699,909 (March 2, 2004)
Prescient NeuroPharma Inc.
Treatment of Chronic Neurodegenerative Diseases

Reaction
HO
CO2H
iii>

Note 2

CO2H

HO2C

HO,C^NHa

i- Thionyl chloride, aluminum chloride, nitrobenzene
ii- Potassium cyanide, ammonium carbonate, water
iii- Sodium hydroxide, hydrochloric acid, propylene oxide
Experimental
1. 3-Carboxy-l-indanone
Phenylsuccinic acid (4.0 g) and 4 ml thionyl chloride were refluxed 30 minutes, 8 ml
nitrobenzene and aluminum chloride (4 g) added, and stirred 2 hours at 85 °C. The mixture
was poured into 125 ml water, nitrobenzene removed by steam distillation, and the product
isolated after re-crystallization in water in 80% yield. ^H-NMR data supphed.
2. cis/trans-3-Carboxy-l-indane-5,5'-hydantoin
The product from Step 1 (l.Ommol) was dissolved in 20ml water in a sealed tube containing KCN (l.Ommol) and (NH4)2C03 (2.0mmol) then heated to 90-100°C 16 hours.

Derivatives Derivative Yield (%) CO2H 90 HO. cis/trans-l-Ammoindane-l. extracted with ethyl alcohol.3-dicarboxylic acid The product from Step 2 was refluxed in 45 ml 2 M NaOH 16 hours. cooled.C NH2 C02H 77 H02C NHo ay CO2H 14 /^NH2 HO2C ^ Notes 1. acidified with 6 M HCl. Other examples of the Bucherer reaction used in preparing aminoacid hydantoins are provided (1). The stereoisomers were isolated and re-crystallized in ethyl alcohol/water. 3.l y MeO. filtered. Aminoindolanes of the current invention having extended carbon chain lengthts at the 2 position were also prepared by the author as illustrated in Eq. and extracted with ethyl alcohol. concentrated. MeO.118 ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY The dark solution was cooled. 1: MeQ Eq. . 2. ^H-NMR data for each isomer supplied. and used in Step 3 without further purification. The mixture was purified by chromatography on Spectrum 1X4 anion exchange resin with dilute HO Ac. acidified with 6 M HC.

(I). triphenylethermethyl chloromethyl ether iii. R. Chem.Sodium hydroxide. 2002). G. US Patent 5. US Patent 6.Sodium azide.0 PO2H A/.Potassium cyanide.784. Med. H.H. H. dicyclohexylcarbodiimide ii. Lee etaU US Patent 6.952 (February 4. palladium on carbon.939.202 (August 31. of the current invention were prepared and are described.1-Trimethylsilylimidazole.384. . 1999). In subsequent investigations (2.AMINOACIDS 119 i. Stilz etaU US Patent 6.514.3) cubane derivatives. water V. 1569 (1998) . Zoller etal. tetramethylsilane.U. pyridine iv.H H2N (I) References 1. Pellicciari etaU Bioorg. Pajouhesh etal.061 (May 7. J. ammonium carbonate. 2004) 3. benzylchloroformate.556 (August 17. hydrogen 3. 8.Lett.Methyl alcohol. 2003) 2.

filtered. methyl alcohol Experimental 1.0-bis-(trimethylsilyl)acetamide (0.70 mol) was added N. and the residue pH adjusted to 8 using 50 ml NH4OH.626 (June 10. CH2CI2. and concentrated. the mixture stirred.ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY 120 Patent: Aminopropylphosphinic Acids T. 80:20:1. the mixture stirred 3 hours. concentrated.Ammonium hypophosphite. 1:3. Elebring etal. 600 ml EtOAc saturated with HCl gas was added. and product eluted with NH40H/methyl alcohol. 6:3:1. The residue was dissolved in 400 ml CH2CI2 and 250 ml methyl alcohol. ^H-NMR data supplied.14 mol) dissolved in 300 ml CH2CI2 was added. The mixture was passed through a Dowex. and dissolved in 400 ml methyl alcohol.0H NHo . filtered. concentrated. The reaction was quenched with 150 ml methyl alcohol and 60 ml water. then cooled to 0°C. Derivatives .t-Butyl(2S)-2-fluoro-3-iodopropylcarbamate. and the product isolated in 17% yield as a white solid. 1:1. and stirred an additional 45 minutes. ammonium hydroxide. CH2CI2 ii. The mixture was further purified by chromatography using CH2Cl2/methyl alcohol/NH40H. At ambient temperature. The mixture was stirred 45 minutes. Thereafter. 50WX8-200 mesh H+ form column using methyl alcohol/water. 150 ml CH2CI2 added. the solids filtered.RTM. and the filtrate concentrated. t-butyl(2S)-2-fluoro-3-iodopropylcarbamate (0. The residue was triturated with 400 ml CH2Cl2/methyl alcohol/NH40H. (2S)-(3-Amino-2-fluoropropyl)phosphinic acid To ammonium hypophosphite (0. 2003) Assignee: AstraZeneca AB Utility: Treatment of Upper Gastrointestinal Tract Disorders Reaction OSiMeg PH N I SiMe3 ^ ? c - MegSiO MeaSiO Not Isolated i.71 mol) at such a rate that the temperature remained between 35-40°C.576. US Patent 6. hydrogen chloride.

AMINOACIDS 121 Ri Hydrogen Hydrogen Fluorine Hydroxyl R.251 (March 26. D.567.S.461. C. Marescavy etal US Patent 5. (I) 3. 1996) and US Patent 5.922 (April 18.840 (October 22. (I). 1995) 2. Hall etal US Patent 5. is described (2).507.G. The preparation of 3-methyl-3-hydroxy-3-(2-methylcyclohexyl)-2-(4-chlorobenzylaniine)-propyl phosphinic acid. Hydroxyl Oxypropyl Hydrogen Fluorine Yield (%) 59 73 34 56 Notes 1. Soriano etal. 1985) . 2.040 (October 24. US 4. 1995) 3. R. 2-Oxiniinoalkylphosphonic acid esters have also been prepared (3). References 1.407. Aminopropylphosphinic acids have also been prepared by reacting alkylphosphonite derivatives with propylene oxide followed by amination (1).

Nitromethane. Bryans etaU US Patent 6.Triethylphosphonoacetate. sodium hydride. . tetrabutylammonium fluoride. dioxane Experimental 1. THF ii.4-Dimethyl-cyclopentylidene-acetic acid. MS and ^H-NMR data supplied.4]-l-aza-nonan-2-one The product from Step 2 (4. The organic phase was dried. The product was isolated by filtration through celite in 95% yield.4-Dimethyl-l-nitromethyl-cyclopentyl)-acetic acid. MS. 2. the residue purified by flash chromatography using silica gel with EtOAc/heptane.122 ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY Patent: Cyclic Aminoacids and Derivatives Thereof Useful as Pharmaceutical Agents J. IR. 60% dispersion in oil (18. added to nitromethane (35. THF iii. and ^H-NMR data supphed.Hydrochloric acid.S. 2003) Assignee: Warner-Lambert Company Utility: Treatment of Neuropathological Diseases Reaction o COsEt NHo / CO2H COsEt HCl Note 1 i. (+/—)-trans-7.Raney nickel. ethyl ester NaH. trans-3. and stirred at 70°C 6 hours. IR.635. then partitioned between 200 ml diethylether and 150 ml water. It was stirred 15 minutes at 0°C and trans-3. and the product isolated in 94% yield. ethyl ester The product from Step 1 (16. trans-(3. 1:9. stirred 2 hours. methyl alcohol.25 mmol) was suspended in 50 ml THF and triethylphosphonoacetate (19.8-Dimethyl-spiro[4. and the product isolated as in Step 1 in 29% yield. The mixture was warmed to ambient temperature.2 mmol) was dissolved in 10 ml THF. concentrated. 3.30 mmol) added. The extract was treated with 30 ml HCl.673 (October 21.4 dimethylcyclopentyl ketone (17. The mixture was cooled to ambient temperature and extracted with 50 ml EtO Ac.2 mmol) and 22 ml 1 M BU4NF in THF. and ^H-NMR data supplied.7 mmol) was dissolved in 50 ml methyl alcohol and hydrogenated using Raney nickel under 40 psi hydrogen at 30 °C for 5 hours. 50 ml brine.54 mmol) in 10 ml THF added. hydrogen iv. MS.

40 mmol) was dissolved in 5 ml dioxane. Cyclohexyl-)S-amino acids have been prepared by the hydrogenation of 1-cyanocyclohexaneacetic acid and are described (3). MS. washed 3 times with 30 ml CH2CI2. .4-dimethyl-cyclopentyl)-acetic acid hydrochloride The product from Step 3 (4. it was diluted with 20 ml water. The preparation of spiro-lactone intermediates of the current invention is described (1) 2.4-dimethyl1 O/T cyclopentyl)-acetic acid • HCl HCl H2N CO2H (3R.4R)-(l-aminomethyl-3. (1 -Aminomethyl-cyclobutyl)-acetic acid • HCl 144 (cis/trans)"( 1 . (+/-)-trans-(l-Ammomethyl-3. and ^H-NMR data supplied.Aminomethyl-benzylacetic acid-HCl 234 CO2H CO2H * (la. Alternative methods for preparing cyclopentane-j8-amino acids are discussed (2). The residue was triturated with EtOAc and the product isolated in 69% yield. 3/3. and concentrated. 4/^)-(l-aminomethyl-3. and the mixture refluxed 4 hours.AMINOACIDS 123 4. 3. Derivatives Aminoacid Name MS HCl HoN \ CO2H y HCl H2N HCl H2N I.4-dimethylcyclopentyl)-acetic acid-HCl Notes 1. 15 ml 6M HCl added. Thereafter.

Chem. J. Mittendorf ^f fl/. J.631.362.883 (November 8. J. Org. 1994) . Doyle etal. US Patent 5. 3035 (1995) 2.. US Patent 5.124 ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY References 1. 60.291 (May 20. 1997) 3. R. Jennings etal.A.

1 mol) and triethylamine (0. acetic acid. as well as these Secondary Amidoalkyl Carbonic Acid Derivatives I. THF iii. 2. 2-(2-Aceto-3-methyl-butylamido)-2-methyl-propyl-l-carbonic acid. methyl ester The product from Step 1 (lOmmol) was dissolved in 100 ml THF to which was added lOmmol apiece of HO Ac and isobutyraldehyde. Thereafter the reaction was stirred 2 hours at 0 °C then quenched by pouring into 10% NaHCOg ice water solution. and triphosgene (0.147.AMINOACIDS Patent: Assignee: Utility: 125 Isocyanoalkyl. US Patent 6. the product purified by chromatography using alumina. trifluoroethyl alcohol Experimental 1. Their Conversion into Secondary Amidoalkyl Carbonic Acid Derivatives by Isocyanide Multicomponent Reactions. and isolated in 80% yield.Isobutyraldehyde.033 mol) introduced in portions. and the product isolated using the procedure described in Step 1. The mixture was extracted 3 times with CH2CI2. triphosgene. (2-Isocyano-2-methyl)-propyl-l-carbonic acid methyl ester (2-Formamido-2-methyl)-propyl-l-carbonic acid methyl (0. Ugi etal. .240 (November 14. Carbonic Acid Derivatives.CH2CI2. The mixture was kept at 25 °C and monitored until the reaction was completed. triethylamine ii. j8-alanine. the residue dissolved in CH2CI2. 2000) Ugichem GmbH Amino Acid Precursors Reaction O \ / Y OMe OCN Note 1 TO O Note 2 r/» X^O^^OMe OMe ^ ^ V ^ N ^ ^ O i. cooled to -20°C. Thereafter the solvent was removed.3 mol) were dissolved in CH2CI2.Isobutyaldehyde.

When treated with sodium hydroxide dissolved in THF the product of Step 1 was converted into 2-propyl-a-hydroxy-acetic acid as is illustrated in Eq. Y^. methyl isocyanide 2. and the mixture mixture stirred and monitored until the reaction was complete. potassium t-butoxide .126 ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY 3. Thereafter. Thereafter. Notes 1. acetone.THF. 3: i. when the Step 2 phenyl ester was hydrolysized with potassium t-butoxide. An alternative method for preparing isocyano carboxylic esters using methyl isocyanate. and chloroformic acid benzyl ester was also described by the author and illustrated in Eq. the corresponding oxazolidinone was obtained as illustrated in Eq.. 2: \ / B. 1: O 0"^CI Eq.^^~-r- ^ ^ -j^-oH i. 2-(2-N-azidinyl-2-one)-3-methyl-propyl-l-carbonic acid. 1 i ^ ^^^^/v^NCO II i.Acetone. sodium hydroxide In addition. it was filtered through celite and the product isolated according to the procedure in Step 1. the product from Step 1 (lOmmol) was added. methyl ester Ten millimoles apiece of isobutyraldehyde.THF. j8-alanine and trifluoroethyl alcohol along with molecular sieves were reacted for 24 hours at 25 °C.

(I). aldehyde. I. I. methyl ester. was also prepared by the author as illustrated in Eq. US Patent 6. I. Chem. 89. 4: Eq. 3. 765 (1994) 2. Additional isocyanoalkylcarbonic acid derivatives of the current investigation were prepared by the author in a subsequent investigation and are discussed (3). S.509. 2003) .AMINOACIDS 127 3. References 1. 5. Marcaccini. 11657 (1996). Angew.Isobutyraldehyde 4. Other Ugi peptide preparations using an amino acid. 723 (1987). Ugi etal. Yamada. the product. and isocyanate (1) or isocyanide (2) are described. Ugi. T. 2-(N-benzyl-N-acyl-3-methyl-butylaniido)-2-methyl-propyl1-carbonic acid. methyl alcohol ii..463 (January 21. Lett.4 OCN^^V" ^ Q ^ JL^ VV^H^V" (I) i.. Ugi. Chem. By reacting the product of Step 1 with benzyl amine and then introducing co-reagents. 52. etal. 267 (1999). Synthesis.Acetic acid. Tetradedron. 35.

hydrogen. mp = 103-105°C. The mixture was concentrated. 2-Ethoxycarbonyl-8-N-Boc-aminomethylene-l-azaspirononane The product from Step 1 (34. CH2CI2. purified by column chromatography with hexanes/EtOAc.020 (January 16. N-t-butylcarboxy anhydride iii.2-diazatricyclodecane A solution of ethyl 2.10-di-ene-6-keto-undecanoic acid (3.32 mmol) and stirred ovemight at ambient temperature. stirred for 1 hour. platinum(IV)oxide. diethyl ether ii.41 mmol) and the mixture hydrogenated at 80 psi overnight.E. Inc. IR. 2001) Pharmacopeia. l-N-Boc-3-Ethoxycarbonyl-l. and the residual dissolved in 100 ml 1M HCl in methyl alcohol.21 mmol) was dissolved in 25% TFA in CH2CI2.175. To this was added Pt02 (4. ^H-NMR. to remove . Template for Synthetic Receptor and Enzyme Intermediates Reaction Phase I: Azaspirononane Synthesis COgEt COsEt 111 OEt 5 N-Boc NH-Boc Notes 1. The resulting oil was dissolved in 250 ml CH2CI2 containing 9.2 Note 3 ^^^ NH-Boc i. Dolle etal. allylchloroformate Experimental Azaspirononane Intermediate 1.30 mmol) and t-butylcarbazate in 10 ml diethyl ether was stirred at ambient temperature overnight and the resulting white precipitate isolated by filtration in 97% yield. concentrated.Trifluoroacetic acid. and elemental analysis data supphed.Disopropylethylamine. 1:1. US Patent 6. 2.5 ml TEA and Boc anhydride (51.t-Butylcarbazate.ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY 128 Patent: Assignee: Utility: Spirodiamino Acid Scaffold for Combinatorial Synthesis R.

Tentagel-graft-(bis-2. and extracted 3 times with 50 ml CH2CI2. MS data supplied.4-bromomethyl-3-nitro benzoic acid. . and washed as in Step 5 and the product isolated.Piperidine. diisopropylcarbodiimide vi. diisopropylcarbodiimide 5. vii. hydroxybenzotriazole. and the product isolated in 87% yield.6-Fmoc-lysine)amide Tentagel (1.2nmiol) added.6 ml DIEA and allylchloroformate (78. The product was purified by chromatography with hexanes/EtOAc. 6. the residual treated with 0. and stirred overnight. 2 Tentagel-NH2 + HO.32mmol/g. and isolated in 77% yield. DMF. 0. drained. y O ^^2 ":^X: Tentagel- Tentagel-HN \ NO2 Br Br V.N-dimethyl formamide. 0.2 g.129 AMINOACIDS excess Boc reagent followed by CH2Cl2/methyl alcohol/NH40H.384 mmol) was suspended in a solution of bis-Fmoc lysine (1. hydroxybenzotriazole.12 mmol) and diisopropylcarbodiimide (2. MS data supplied.12 mmol) and hydroxybenzotriazole (1. N. ^NH-Fmoc Tentagel-HN^>. Tentagel-graft-lysine amide The resin from Step 5 (1. washed with DMF. 4:1.2 g) was dissolved in piperidine/DMF.1.22 mmol). l-Allylcarbamoyl-2-hydroxycarbonyl-8-N-Boc-aminomethylene-l-azaspirononane The product from Step 2 (39. 1:1. shaken for 90 minutes. Phase II : Preparation of Tentegel Polymer Anchor NH-Fmoc Eq.Bis-Fmoc-lysine. drained.5 M citric acid.^.18 mmol) was dissolved in 200 ml CH2CI2.^ ^ T NH-Fmoc Tentagd-HN . methyl alcohol and CH2CI2 and the product isolated. The solvent was removed. treated with 20. The suspension was shaken overnight.l0:1:0.

3 mmol) and 1 ml diisopropylcarbodiimide dissolved in 6 ml DMF.6-di-benzylbromo-3-nitro-benzamide)lysine The product from Step 6 was suspended in 4 ml DMF.2 mmol).10-di-ene-6-keto-undecanoic acid was previously prepared by the author and is described (1). Tentagel-graft-N-[(2-methoxybenzyl)-N-(l-allylcarbamoyl-8-NBoc-aminomethylene-l-azaspirononane)]-2-amide The product from Step 8 was suspended in 5 ml DMF and treated with the product from Step 3 (2. The suspension was shaken overnight. drained.3 Polymer ••• 1 \ ^ L \ Polymeriv HN^_^DCH3 f/ ^ \ viii. 1 .2-Methoxybenzylamine. washed as in Step 5.130 ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY 7. was also provided by the author and is described below: . 9.N-dimethyl-formamide 8. 1 -hydroxybenzotriazole. Notes 1. Tentagel-graft-(2. The suspension was shaken overnight. Phase III: Azaspirononane Attachment to Scaffold Polymer Eq. Tentagel-graft-N-(2-methoxybenzyl)amine A suspension of the resin from Step 7 (Ig) in 10 ml THF was mixed with 2-methoxybenzylamine (3 mmol) and shaken overnight. (I).3 mmol) and 1ml diisopropylcarbodiimide dissolved in 6 ml DMF. treated with 4-bromomethyl-3-nitro benzoic acid (2. and the product isolated.Allylcarbamoyl-2-hydroxycarbonyl-8-N-Bocaminomethylene-1 -azaspirononane. Diazatricyclodecane was prepared by the author by the reaction of hydrazone and ethyl 2. 3.2 mmol).10-undecadienoic and is described. The product of Step 1 using vinyl 2. THF xi-1 . hydroxybenzotriazole (2. diisopropylcarbodiimide. washed as in Step 7. and the product isolated. N.Allylcarbamoyl-2-methoxycarbonyl-8-N-Boc-aminomethylene-1 -azaspirononane. hydroxybenzotriazole (2. and the product isolated. It was drained and washed as in Step 5 filtered. drained. 2. dried.

228 (July 24.255.551 (April 17.. US Patent 6. etal. III. K. 1327 (1987) R. and the mixture extracted with 50 ml EtOAc. The product was purified using column chromatography with hexanes/EtOAc. 2001) . Chem. 2001) R.AMINOACIDS 131 The product from Step 3 (30.E.40 mmol) was dissolved in 50 ml 1M NaOH in methyl alcohol. and ester amide (4) libraries were prepared. etal. Chem. ^H-NMR and MS data suppHed. 3. stirred 5 hours. the pH acidified with citric acid. In subsequent investigations by the author.S. US Patent 6. III. amide alcohol (3). US Patent 6. re-crystallized in the eluting solvent. combinatorial hydroxy-amino acid amide (2).265. 4. Dolle. Dolle.E. 4. III.120 (July 3. Armstrong. 2. and concentrated. and isolated in 80% yield. washed with CH2CI2.E. etal. Dolle. Soc. J. The residue was treated with 100 ml aqueous NaHCOg.218. 2001) R. Reference 1. Comm.