Anesthetic activity of novel water-soluble 2β-morpholinyl steroids and their modulatory effects at GABA(A) receptors

Journal of Medicinal Chemistry

Volumn 40, Issue 11, 1997, Pages 1668-1681

  Anderson, Alison ^a   Boyd, Andrew C ^a   Byford, Alan ^a   Campbell, Alexander C ^a   Gemmell, David K ^a   Hamilton, Niall M ^a   Hill, David R ^a   Hill Venning, Claire ^b   Lambert, Jeremy J ^b   Maidment, Maurice S ^a   May, Valerie ^a   Marshall, Richard J ^a   Peters, John A ^b   Rees, David C ^a   Stevenson, Donald ^a   Sundaram, Hardy ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

^b UNIVERSITY OF DUNDEE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

21 CHLORO 3ALPHA HYDROXY 2BETA (4 MORPHOLINYL) 5ALPHA PREGNAN 20 ONE; 3ALPHA HYDROXY 2ALPHA (2,2 DIMETHYL 4 MORPHOLINYL) 5ALPHA PREGNANE 11,20 DIONE; STEROID; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL TISSUE; ARTICLE; BRAIN ELECTROPHYSIOLOGY; CATTLE; DRUG ACTIVITY; DRUG EFFECT; DRUG POTENCY; DRUG SOLUBILITY; DRUG SYNTHESIS; INTRAVENOUS DRUG ADMINISTRATION; LIGAND BINDING; MOUSE; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ANESTHESIA; ANESTHETICS; ANIMALS; BICYCLO COMPOUNDS, HETEROCYCLIC; BRAIN; CATTLE; CELL MEMBRANE; CHROMAFFIN SYSTEM; ELECTRIC CONDUCTIVITY; ELECTROPHYSIOLOGY; MALE; MICE; MOLECULAR STRUCTURE; MORPHOLINES; PREGNANEDIONES; RADIOLIGAND ASSAY; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, GABA-A; SOLUBILITY; STRUCTURE-ACTIVITY RELATIONSHIP; WATER;

EID: 0030982180     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm960733n     Document Type: Article

References (64)

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37. Substituted morpholines were often not purified or characterized. (a) 2,2-Dimethylmorpholine was prepared by condensation of 1-chloro-2-methyl-2-propanol with ethanolamine and subsequently elaborated by the method of Bettoni et al.: Bettoni, G.; Franchini, C.; Perrone, R.; Tortorella, V. Synthesis and absolute configuration of substituted morpholines. Tetrahedron 1980, 36, 409-415. (b) (R)-2-Methylmorpholine was prepared using the method reported in ref 25a, starting with (R)-methyloxirane, which was synthesized from L-threonine [Rossen, K.; Simpson, P. M.; Wells, K. M. A practical synthesis of both enantiomers of 1-amino-2-propanol and propylene oxide. Synth. Commun. 1993, 23, 1071-1074]. (c) 2-Methylmorpholine and 2-ethylmorpholine: Cottle, D. L.; Jeltsch, A. E.; Stoudt, T. H.; Walters, D. R. The preparation of some C-alkylmorpholines: J. Org. Chem. 1946, 11, 286-291. (d) 2-Propylmorpholine: Vargha, L.; Kasztreiner, E.; Borsy, J.; Farkas, L.; Kuszmann, J.; Dumbovich, B. Synthesis and pharmacological investigation of new alkoxybenzamides-1. 3:4:5-Trimethoxybenzamides. Biochem. Pharmacol. 1962, 11, 639-649. (e) 2-Phenylmethylmorpholine: Brown, G. R.; Forster, G; Foubister, A. J.; Stribling, D. Synthesis and resolution of the novel appetite suppressant 2-benzylmorpholine, a nonstimulant isomer of phenmetrazine. J. Pharm. Pharmacol. 1990, 42, 797-799. (f) (R)-2-(1-Methylethyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylethyl)oxirane, which was synthesized from L-valine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (g) (R)-2-(1-Methylpropyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylpropyl)oxirane, which was synthesized from L-isoleucine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (h) 2,2-Diethylmorpholine was prepared using the method reported in ref 25a, starting with diethyloxirane. (i) 2,2-Dibutylmorpholine was prepared using the method reported in ref 25a, starting with dibutyloxirane. (j) 2,2-Diphenylmorpholine: Moussa, G. E. M.; Basyouni, M. N.; Shaban, M. E. Epoxides: Part I. Synthesis of β,β-diaryl-N-substituted ethanolamines and morpholines. Indian J. Chem., Sect. B 1980, 19B, 798-800. (k) 2,2,6,6-Tetramethylmorpholine: Nowak, E. Synergistic microbicidal compositions comprising triazole and morpholine derivatives. Eur. Pat. Appl. EP 252875, 1988; Chem. Abstr. 1988, 108, 1632646. (l) 2,2-Dimethylthiomorpholine: McManus, J. M.; McFarland, J. W.; Gerber, C. F.; McLamore, W. M.; Laubach, G. D. Sulfamylurea Hypoglycemic Agents. 1. Synthesis and Screening. J. Med. Chem. 1965, 8, 766-776. (m) 2,2,6,6-Tetramethylthiomorpholine was prepared using the method reported in ref 251, starting with 1-amino-2-methyl-2-propanethiol hydrochloride.
38. Substituted morpholines were often not purified or characterized. (a) 2,2-Dimethylmorpholine was prepared by condensation of 1-chloro-2-methyl-2-propanol with ethanolamine and subsequently elaborated by the method of Bettoni et al.: Bettoni, G.; Franchini, C.; Perrone, R.; Tortorella, V. Synthesis and absolute configuration of substituted morpholines. Tetrahedron 1980, 36, 409-415. (b) (R)-2-Methylmorpholine was prepared using the method reported in ref 25a, starting with (R)-methyloxirane, which was synthesized from L-threonine [Rossen, K.; Simpson, P. M.; Wells, K. M. A practical synthesis of both enantiomers of 1-amino-2-propanol and propylene oxide. Synth. Commun. 1993, 23, 1071-1074]. (c) 2-Methylmorpholine and 2-ethylmorpholine: Cottle, D. L.; Jeltsch, A. E.; Stoudt, T. H.; Walters, D. R. The preparation of some C-alkylmorpholines: J. Org. Chem. 1946, 11, 286-291. (d) 2-Propylmorpholine: Vargha, L.; Kasztreiner, E.; Borsy, J.; Farkas, L.; Kuszmann, J.; Dumbovich, B. Synthesis and pharmacological investigation of new alkoxybenzamides-1. 3:4:5-Trimethoxybenzamides. Biochem. Pharmacol. 1962, 11, 639-649. (e) 2-Phenylmethylmorpholine: Brown, G. R.; Forster, G; Foubister, A. J.; Stribling, D. Synthesis and resolution of the novel appetite suppressant 2-benzylmorpholine, a nonstimulant isomer of phenmetrazine. J. Pharm. Pharmacol. 1990, 42, 797-799. (f) (R)-2-(1-Methylethyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylethyl)oxirane, which was synthesized from L-valine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (g) (R)-2-(1-Methylpropyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylpropyl)oxirane, which was synthesized from L-isoleucine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (h) 2,2-Diethylmorpholine was prepared using the method reported in ref 25a, starting with diethyloxirane. (i) 2,2-Dibutylmorpholine was prepared using the method reported in ref 25a, starting with dibutyloxirane. (j) 2,2-Diphenylmorpholine: Moussa, G. E. M.; Basyouni, M. N.; Shaban, M. E. Epoxides: Part I. Synthesis of β,β-diaryl-N-substituted ethanolamines and morpholines. Indian J. Chem., Sect. B 1980, 19B, 798-800. (k) 2,2,6,6-Tetramethylmorpholine: Nowak, E. Synergistic microbicidal compositions comprising triazole and morpholine derivatives. Eur. Pat. Appl. EP 252875, 1988; Chem. Abstr. 1988, 108, 1632646. (l) 2,2-Dimethylthiomorpholine: McManus, J. M.; McFarland, J. W.; Gerber, C. F.; McLamore, W. M.; Laubach, G. D. Sulfamylurea Hypoglycemic Agents. 1. Synthesis and Screening. J. Med. Chem. 1965, 8, 766-776. (m) 2,2,6,6-Tetramethylthiomorpholine was prepared using the method reported in ref 251, starting with 1-amino-2-methyl-2-propanethiol hydrochloride.
39. Substituted morpholines were often not purified or characterized. (a) 2,2-Dimethylmorpholine was prepared by condensation of 1-chloro-2-methyl-2-propanol with ethanolamine and subsequently elaborated by the method of Bettoni et al.: Bettoni, G.; Franchini, C.; Perrone, R.; Tortorella, V. Synthesis and absolute configuration of substituted morpholines. Tetrahedron 1980, 36, 409-415. (b) (R)-2-Methylmorpholine was prepared using the method reported in ref 25a, starting with (R)-methyloxirane, which was synthesized from L-threonine [Rossen, K.; Simpson, P. M.; Wells, K. M. A practical synthesis of both enantiomers of 1-amino-2-propanol and propylene oxide. Synth. Commun. 1993, 23, 1071-1074]. (c) 2-Methylmorpholine and 2-ethylmorpholine: Cottle, D. L.; Jeltsch, A. E.; Stoudt, T. H.; Walters, D. R. The preparation of some C-alkylmorpholines: J. Org. Chem. 1946, 11, 286-291. (d) 2-Propylmorpholine: Vargha, L.; Kasztreiner, E.; Borsy, J.; Farkas, L.; Kuszmann, J.; Dumbovich, B. Synthesis and pharmacological investigation of new alkoxybenzamides-1. 3:4:5-Trimethoxybenzamides. Biochem. Pharmacol. 1962, 11, 639-649. (e) 2-Phenylmethylmorpholine: Brown, G. R.; Forster, G; Foubister, A. J.; Stribling, D. Synthesis and resolution of the novel appetite suppressant 2-benzylmorpholine, a nonstimulant isomer of phenmetrazine. J. Pharm. Pharmacol. 1990, 42, 797-799. (f) (R)-2-(1-Methylethyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylethyl)oxirane, which was synthesized from L-valine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (g) (R)-2-(1-Methylpropyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylpropyl)oxirane, which was synthesized from L-isoleucine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (h) 2,2-Diethylmorpholine was prepared using the method reported in ref 25a, starting with diethyloxirane. (i) 2,2-Dibutylmorpholine was prepared using the method reported in ref 25a, starting with dibutyloxirane. (j) 2,2-Diphenylmorpholine: Moussa, G. E. M.; Basyouni, M. N.; Shaban, M. E. Epoxides: Part I. Synthesis of β,β-diaryl-N-substituted ethanolamines and morpholines. Indian J. Chem., Sect. B 1980, 19B, 798-800. (k) 2,2,6,6-Tetramethylmorpholine: Nowak, E. Synergistic microbicidal compositions comprising triazole and morpholine derivatives. Eur. Pat. Appl. EP 252875, 1988; Chem. Abstr. 1988, 108, 1632646. (l) 2,2-Dimethylthiomorpholine: McManus, J. M.; McFarland, J. W.; Gerber, C. F.; McLamore, W. M.; Laubach, G. D. Sulfamylurea Hypoglycemic Agents. 1. Synthesis and Screening. J. Med. Chem. 1965, 8, 766-776. (m) 2,2,6,6-Tetramethylthiomorpholine was prepared using the method reported in ref 251, starting with 1-amino-2-methyl-2-propanethiol hydrochloride.
40. Substituted morpholines were often not purified or characterized. (a) 2,2-Dimethylmorpholine was prepared by condensation of 1-chloro-2-methyl-2-propanol with ethanolamine and subsequently elaborated by the method of Bettoni et al.: Bettoni, G.; Franchini, C.; Perrone, R.; Tortorella, V. Synthesis and absolute configuration of substituted morpholines. Tetrahedron 1980, 36, 409-415. (b) (R)-2-Methylmorpholine was prepared using the method reported in ref 25a, starting with (R)-methyloxirane, which was synthesized from L-threonine [Rossen, K.; Simpson, P. M.; Wells, K. M. A practical synthesis of both enantiomers of 1-amino-2-propanol and propylene oxide. Synth. Commun. 1993, 23, 1071-1074]. (c) 2-Methylmorpholine and 2-ethylmorpholine: Cottle, D. L.; Jeltsch, A. E.; Stoudt, T. H.; Walters, D. R. The preparation of some C-alkylmorpholines: J. Org. Chem. 1946, 11, 286-291. (d) 2-Propylmorpholine: Vargha, L.; Kasztreiner, E.; Borsy, J.; Farkas, L.; Kuszmann, J.; Dumbovich, B. Synthesis and pharmacological investigation of new alkoxybenzamides-1. 3:4:5-Trimethoxybenzamides. Biochem. Pharmacol. 1962, 11, 639-649. (e) 2-Phenylmethylmorpholine: Brown, G. R.; Forster, G; Foubister, A. J.; Stribling, D. Synthesis and resolution of the novel appetite suppressant 2-benzylmorpholine, a nonstimulant isomer of phenmetrazine. J. Pharm. Pharmacol. 1990, 42, 797-799. (f) (R)-2-(1-Methylethyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylethyl)oxirane, which was synthesized from L-valine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (g) (R)-2-(1-Methylpropyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylpropyl)oxirane, which was synthesized from L-isoleucine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (h) 2,2-Diethylmorpholine was prepared using the method reported in ref 25a, starting with diethyloxirane. (i) 2,2-Dibutylmorpholine was prepared using the method reported in ref 25a, starting with dibutyloxirane. (j) 2,2-Diphenylmorpholine: Moussa, G. E. M.; Basyouni, M. N.; Shaban, M. E. Epoxides: Part I. Synthesis of β,β-diaryl-N-substituted ethanolamines and morpholines. Indian J. Chem., Sect. B 1980, 19B, 798-800. (k) 2,2,6,6-Tetramethylmorpholine: Nowak, E. Synergistic microbicidal compositions comprising triazole and morpholine derivatives. Eur. Pat. Appl. EP 252875, 1988; Chem. Abstr. 1988, 108, 1632646. (l) 2,2-Dimethylthiomorpholine: McManus, J. M.; McFarland, J. W.; Gerber, C. F.; McLamore, W. M.; Laubach, G. D. Sulfamylurea Hypoglycemic Agents. 1. Synthesis and Screening. J. Med. Chem. 1965, 8, 766-776. (m) 2,2,6,6-Tetramethylthiomorpholine was prepared using the method reported in ref 251, starting with 1-amino-2-methyl-2-propanethiol hydrochloride.
41. Substituted morpholines were often not purified or characterized. (a) 2,2-Dimethylmorpholine was prepared by condensation of 1-chloro-2-methyl-2-propanol with ethanolamine and subsequently elaborated by the method of Bettoni et al.: Bettoni, G.; Franchini, C.; Perrone, R.; Tortorella, V. Synthesis and absolute configuration of substituted morpholines. Tetrahedron 1980, 36, 409-415. (b) (R)-2-Methylmorpholine was prepared using the method reported in ref 25a, starting with (R)-methyloxirane, which was synthesized from L-threonine [Rossen, K.; Simpson, P. M.; Wells, K. M. A practical synthesis of both enantiomers of 1-amino-2-propanol and propylene oxide. Synth. Commun. 1993, 23, 1071-1074]. (c) 2-Methylmorpholine and 2-ethylmorpholine: Cottle, D. L.; Jeltsch, A. E.; Stoudt, T. H.; Walters, D. R. The preparation of some C-alkylmorpholines: J. Org. Chem. 1946, 11, 286-291. (d) 2-Propylmorpholine: Vargha, L.; Kasztreiner, E.; Borsy, J.; Farkas, L.; Kuszmann, J.; Dumbovich, B. Synthesis and pharmacological investigation of new alkoxybenzamides-1. 3:4:5-Trimethoxybenzamides. Biochem. Pharmacol. 1962, 11, 639-649. (e) 2-Phenylmethylmorpholine: Brown, G. R.; Forster, G; Foubister, A. J.; Stribling, D. Synthesis and resolution of the novel appetite suppressant 2-benzylmorpholine, a nonstimulant isomer of phenmetrazine. J. Pharm. Pharmacol. 1990, 42, 797-799. (f) (R)-2-(1-Methylethyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylethyl)oxirane, which was synthesized from L-valine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (g) (R)-2-(1-Methylpropyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylpropyl)oxirane, which was synthesized from L-isoleucine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (h) 2,2-Diethylmorpholine was prepared using the method reported in ref 25a, starting with diethyloxirane. (i) 2,2-Dibutylmorpholine was prepared using the method reported in ref 25a, starting with dibutyloxirane. (j) 2,2-Diphenylmorpholine: Moussa, G. E. M.; Basyouni, M. N.; Shaban, M. E. Epoxides: Part I. Synthesis of β,β-diaryl-N-substituted ethanolamines and morpholines. Indian J. Chem., Sect. B 1980, 19B, 798-800. (k) 2,2,6,6-Tetramethylmorpholine: Nowak, E. Synergistic microbicidal compositions comprising triazole and morpholine derivatives. Eur. Pat. Appl. EP 252875, 1988; Chem. Abstr. 1988, 108, 1632646. (l) 2,2-Dimethylthiomorpholine: McManus, J. M.; McFarland, J. W.; Gerber, C. F.; McLamore, W. M.; Laubach, G. D. Sulfamylurea Hypoglycemic Agents. 1. Synthesis and Screening. J. Med. Chem. 1965, 8, 766-776. (m) 2,2,6,6-Tetramethylthiomorpholine was prepared using the method reported in ref 251, starting with 1-amino-2-methyl-2-propanethiol hydrochloride.
42. Substituted morpholines were often not purified or characterized. (a) 2,2-Dimethylmorpholine was prepared by condensation of 1-chloro-2-methyl-2-propanol with ethanolamine and subsequently elaborated by the method of Bettoni et al.: Bettoni, G.; Franchini, C.; Perrone, R.; Tortorella, V. Synthesis and absolute configuration of substituted morpholines. Tetrahedron 1980, 36, 409-415. (b) (R)-2-Methylmorpholine was prepared using the method reported in ref 25a, starting with (R)-methyloxirane, which was synthesized from L-threonine [Rossen, K.; Simpson, P. M.; Wells, K. M. A practical synthesis of both enantiomers of 1-amino-2-propanol and propylene oxide. Synth. Commun. 1993, 23, 1071-1074]. (c) 2-Methylmorpholine and 2-ethylmorpholine: Cottle, D. L.; Jeltsch, A. E.; Stoudt, T. H.; Walters, D. R. The preparation of some C-alkylmorpholines: J. Org. Chem. 1946, 11, 286-291. (d) 2-Propylmorpholine: Vargha, L.; Kasztreiner, E.; Borsy, J.; Farkas, L.; Kuszmann, J.; Dumbovich, B. Synthesis and pharmacological investigation of new alkoxybenzamides-1. 3:4:5-Trimethoxybenzamides. Biochem. Pharmacol. 1962, 11, 639-649. (e) 2-Phenylmethylmorpholine: Brown, G. R.; Forster, G; Foubister, A. J.; Stribling, D. Synthesis and resolution of the novel appetite suppressant 2-benzylmorpholine, a nonstimulant isomer of phenmetrazine. J. Pharm. Pharmacol. 1990, 42, 797-799. (f) (R)-2-(1-Methylethyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylethyl)oxirane, which was synthesized from L-valine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (g) (R)-2-(1-Methylpropyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylpropyl)oxirane, which was synthesized from L-isoleucine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (h) 2,2-Diethylmorpholine was prepared using the method reported in ref 25a, starting with diethyloxirane. (i) 2,2-Dibutylmorpholine was prepared using the method reported in ref 25a, starting with dibutyloxirane. (j) 2,2-Diphenylmorpholine: Moussa, G. E. M.; Basyouni, M. N.; Shaban, M. E. Epoxides: Part I. Synthesis of β,β-diaryl-N-substituted ethanolamines and morpholines. Indian J. Chem., Sect. B 1980, 19B, 798-800. (k) 2,2,6,6-Tetramethylmorpholine: Nowak, E. Synergistic microbicidal compositions comprising triazole and morpholine derivatives. Eur. Pat. Appl. EP 252875, 1988; Chem. Abstr. 1988, 108, 1632646. (l) 2,2-Dimethylthiomorpholine: McManus, J. M.; McFarland, J. W.; Gerber, C. F.; McLamore, W. M.; Laubach, G. D. Sulfamylurea Hypoglycemic Agents. 1. Synthesis and Screening. J. Med. Chem. 1965, 8, 766-776. (m) 2,2,6,6-Tetramethylthiomorpholine was prepared using the method reported in ref 251, starting with 1-amino-2-methyl-2-propanethiol hydrochloride.
43. Substituted morpholines were often not purified or characterized. (a) 2,2-Dimethylmorpholine was prepared by condensation of 1-chloro-2-methyl-2-propanol with ethanolamine and subsequently elaborated by the method of Bettoni et al.: Bettoni, G.; Franchini, C.; Perrone, R.; Tortorella, V. Synthesis and absolute configuration of substituted morpholines. Tetrahedron 1980, 36, 409-415. (b) (R)-2-Methylmorpholine was prepared using the method reported in ref 25a, starting with (R)-methyloxirane, which was synthesized from L-threonine [Rossen, K.; Simpson, P. M.; Wells, K. M. A practical synthesis of both enantiomers of 1-amino-2-propanol and propylene oxide. Synth. Commun. 1993, 23, 1071-1074]. (c) 2-Methylmorpholine and 2-ethylmorpholine: Cottle, D. L.; Jeltsch, A. E.; Stoudt, T. H.; Walters, D. R. The preparation of some C-alkylmorpholines: J. Org. Chem. 1946, 11, 286-291. (d) 2-Propylmorpholine: Vargha, L.; Kasztreiner, E.; Borsy, J.; Farkas, L.; Kuszmann, J.; Dumbovich, B. Synthesis and pharmacological investigation of new alkoxybenzamides-1. 3:4:5-Trimethoxybenzamides. Biochem. Pharmacol. 1962, 11, 639-649. (e) 2-Phenylmethylmorpholine: Brown, G. R.; Forster, G; Foubister, A. J.; Stribling, D. Synthesis and resolution of the novel appetite suppressant 2-benzylmorpholine, a nonstimulant isomer of phenmetrazine. J. Pharm. Pharmacol. 1990, 42, 797-799. (f) (R)-2-(1-Methylethyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylethyl)oxirane, which was synthesized from L-valine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (g) (R)-2-(1-Methylpropyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylpropyl)oxirane, which was synthesized from L-isoleucine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (h) 2,2-Diethylmorpholine was prepared using the method reported in ref 25a, starting with diethyloxirane. (i) 2,2-Dibutylmorpholine was prepared using the method reported in ref 25a, starting with dibutyloxirane. (j) 2,2-Diphenylmorpholine: Moussa, G. E. M.; Basyouni, M. N.; Shaban, M. E. Epoxides: Part I. Synthesis of β,β-diaryl-N-substituted ethanolamines and morpholines. Indian J. Chem., Sect. B 1980, 19B, 798-800. (k) 2,2,6,6-Tetramethylmorpholine: Nowak, E. Synergistic microbicidal compositions comprising triazole and morpholine derivatives. Eur. Pat. Appl. EP 252875, 1988; Chem. Abstr. 1988, 108, 1632646. (l) 2,2-Dimethylthiomorpholine: McManus, J. M.; McFarland, J. W.; Gerber, C. F.; McLamore, W. M.; Laubach, G. D. Sulfamylurea Hypoglycemic Agents. 1. Synthesis and Screening. J. Med. Chem. 1965, 8, 766-776. (m) 2,2,6,6-Tetramethylthiomorpholine was prepared using the method reported in ref 251, starting with 1-amino-2-methyl-2-propanethiol hydrochloride.
44. Substituted morpholines were often not purified or characterized. (a) 2,2-Dimethylmorpholine was prepared by condensation of 1-chloro-2-methyl-2-propanol with ethanolamine and subsequently elaborated by the method of Bettoni et al.: Bettoni, G.; Franchini, C.; Perrone, R.; Tortorella, V. Synthesis and absolute configuration of substituted morpholines. Tetrahedron 1980, 36, 409-415. (b) (R)-2-Methylmorpholine was prepared using the method reported in ref 25a, starting with (R)-methyloxirane, which was synthesized from L-threonine [Rossen, K.; Simpson, P. M.; Wells, K. M. A practical synthesis of both enantiomers of 1-amino-2-propanol and propylene oxide. Synth. Commun. 1993, 23, 1071-1074]. (c) 2-Methylmorpholine and 2-ethylmorpholine: Cottle, D. L.; Jeltsch, A. E.; Stoudt, T. H.; Walters, D. R. The preparation of some C-alkylmorpholines: J. Org. Chem. 1946, 11, 286-291. (d) 2-Propylmorpholine: Vargha, L.; Kasztreiner, E.; Borsy, J.; Farkas, L.; Kuszmann, J.; Dumbovich, B. Synthesis and pharmacological investigation of new alkoxybenzamides-1. 3:4:5-Trimethoxybenzamides. Biochem. Pharmacol. 1962, 11, 639-649. (e) 2-Phenylmethylmorpholine: Brown, G. R.; Forster, G; Foubister, A. J.; Stribling, D. Synthesis and resolution of the novel appetite suppressant 2-benzylmorpholine, a nonstimulant isomer of phenmetrazine. J. Pharm. Pharmacol. 1990, 42, 797-799. (f) (R)-2-(1-Methylethyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylethyl)oxirane, which was synthesized from L-valine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (g) (R)-2-(1-Methylpropyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylpropyl)oxirane, which was synthesized from L-isoleucine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (h) 2,2-Diethylmorpholine was prepared using the method reported in ref 25a, starting with diethyloxirane. (i) 2,2-Dibutylmorpholine was prepared using the method reported in ref 25a, starting with dibutyloxirane. (j) 2,2-Diphenylmorpholine: Moussa, G. E. M.; Basyouni, M. N.; Shaban, M. E. Epoxides: Part I. Synthesis of β,β-diaryl-N-substituted ethanolamines and morpholines. Indian J. Chem., Sect. B 1980, 19B, 798-800. (k) 2,2,6,6-Tetramethylmorpholine: Nowak, E. Synergistic microbicidal compositions comprising triazole and morpholine derivatives. Eur. Pat. Appl. EP 252875, 1988; Chem. Abstr. 1988, 108, 1632646. (l) 2,2-Dimethylthiomorpholine: McManus, J. M.; McFarland, J. W.; Gerber, C. F.; McLamore, W. M.; Laubach, G. D. Sulfamylurea Hypoglycemic Agents. 1. Synthesis and Screening. J. Med. Chem. 1965, 8, 766-776. (m) 2,2,6,6-Tetramethylthiomorpholine was prepared using the method reported in ref 251, starting with 1-amino-2-methyl-2-propanethiol hydrochloride.
45. Substituted morpholines were often not purified or characterized. (a) 2,2-Dimethylmorpholine was prepared by condensation of 1-chloro-2-methyl-2-propanol with ethanolamine and subsequently elaborated by the method of Bettoni et al.: Bettoni, G.; Franchini, C.; Perrone, R.; Tortorella, V. Synthesis and absolute configuration of substituted morpholines. Tetrahedron 1980, 36, 409-415. (b) (R)-2-Methylmorpholine was prepared using the method reported in ref 25a, starting with (R)-methyloxirane, which was synthesized from L-threonine [Rossen, K.; Simpson, P. M.; Wells, K. M. A practical synthesis of both enantiomers of 1-amino-2-propanol and propylene oxide. Synth. Commun. 1993, 23, 1071-1074]. (c) 2-Methylmorpholine and 2-ethylmorpholine: Cottle, D. L.; Jeltsch, A. E.; Stoudt, T. H.; Walters, D. R. The preparation of some C-alkylmorpholines: J. Org. Chem. 1946, 11, 286-291. (d) 2-Propylmorpholine: Vargha, L.; Kasztreiner, E.; Borsy, J.; Farkas, L.; Kuszmann, J.; Dumbovich, B. Synthesis and pharmacological investigation of new alkoxybenzamides-1. 3:4:5-Trimethoxybenzamides. Biochem. Pharmacol. 1962, 11, 639-649. (e) 2-Phenylmethylmorpholine: Brown, G. R.; Forster, G; Foubister, A. J.; Stribling, D. Synthesis and resolution of the novel appetite suppressant 2-benzylmorpholine, a nonstimulant isomer of phenmetrazine. J. Pharm. Pharmacol. 1990, 42, 797-799. (f) (R)-2-(1-Methylethyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylethyl)oxirane, which was synthesized from L-valine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (g) (R)-2-(1-Methylpropyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylpropyl)oxirane, which was synthesized from L-isoleucine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (h) 2,2-Diethylmorpholine was prepared using the method reported in ref 25a, starting with diethyloxirane. (i) 2,2-Dibutylmorpholine was prepared using the method reported in ref 25a, starting with dibutyloxirane. (j) 2,2-Diphenylmorpholine: Moussa, G. E. M.; Basyouni, M. N.; Shaban, M. E. Epoxides: Part I. Synthesis of β,β-diaryl-N-substituted ethanolamines and morpholines. Indian J. Chem., Sect. B 1980, 19B, 798-800. (k) 2,2,6,6-Tetramethylmorpholine: Nowak, E. Synergistic microbicidal compositions comprising triazole and morpholine derivatives. Eur. Pat. Appl. EP 252875, 1988; Chem. Abstr. 1988, 108, 1632646. (l) 2,2-Dimethylthiomorpholine: McManus, J. M.; McFarland, J. W.; Gerber, C. F.; McLamore, W. M.; Laubach, G. D. Sulfamylurea Hypoglycemic Agents. 1. Synthesis and Screening. J. Med. Chem. 1965, 8, 766-776. (m) 2,2,6,6-Tetramethylthiomorpholine was prepared using the method reported in ref 251, starting with 1-amino-2-methyl-2-propanethiol hydrochloride.
46. Substituted morpholines were often not purified or characterized. (a) 2,2-Dimethylmorpholine was prepared by condensation of 1-chloro-2-methyl-2-propanol with ethanolamine and subsequently elaborated by the method of Bettoni et al.: Bettoni, G.; Franchini, C.; Perrone, R.; Tortorella, V. Synthesis and absolute configuration of substituted morpholines. Tetrahedron 1980, 36, 409-415. (b) (R)-2-Methylmorpholine was prepared using the method reported in ref 25a, starting with (R)-methyloxirane, which was synthesized from L-threonine [Rossen, K.; Simpson, P. M.; Wells, K. M. A practical synthesis of both enantiomers of 1-amino-2-propanol and propylene oxide. Synth. Commun. 1993, 23, 1071-1074]. (c) 2-Methylmorpholine and 2-ethylmorpholine: Cottle, D. L.; Jeltsch, A. E.; Stoudt, T. H.; Walters, D. R. The preparation of some C-alkylmorpholines: J. Org. Chem. 1946, 11, 286-291. (d) 2-Propylmorpholine: Vargha, L.; Kasztreiner, E.; Borsy, J.; Farkas, L.; Kuszmann, J.; Dumbovich, B. Synthesis and pharmacological investigation of new alkoxybenzamides-1. 3:4:5-Trimethoxybenzamides. Biochem. Pharmacol. 1962, 11, 639-649. (e) 2-Phenylmethylmorpholine: Brown, G. R.; Forster, G; Foubister, A. J.; Stribling, D. Synthesis and resolution of the novel appetite suppressant 2-benzylmorpholine, a nonstimulant isomer of phenmetrazine. J. Pharm. Pharmacol. 1990, 42, 797-799. (f) (R)-2-(1-Methylethyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylethyl)oxirane, which was synthesized from L-valine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (g) (R)-2-(1-Methylpropyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylpropyl)oxirane, which was synthesized from L-isoleucine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (h) 2,2-Diethylmorpholine was prepared using the method reported in ref 25a, starting with diethyloxirane. (i) 2,2-Dibutylmorpholine was prepared using the method reported in ref 25a, starting with dibutyloxirane. (j) 2,2-Diphenylmorpholine: Moussa, G. E. M.; Basyouni, M. N.; Shaban, M. E. Epoxides: Part I. Synthesis of β,β-diaryl-N-substituted ethanolamines and morpholines. Indian J. Chem., Sect. B 1980, 19B, 798-800. (k) 2,2,6,6-Tetramethylmorpholine: Nowak, E. Synergistic microbicidal compositions comprising triazole and morpholine derivatives. Eur. Pat. Appl. EP 252875, 1988; Chem. Abstr. 1988, 108, 1632646. (l) 2,2-Dimethylthiomorpholine: McManus, J. M.; McFarland, J. W.; Gerber, C. F.; McLamore, W. M.; Laubach, G. D. Sulfamylurea Hypoglycemic Agents. 1. Synthesis and Screening. J. Med. Chem. 1965, 8, 766-776. (m) 2,2,6,6-Tetramethylthiomorpholine was prepared using the method reported in ref 251, starting with 1-amino-2-methyl-2-propanethiol hydrochloride.
47. Substituted morpholines were often not purified or characterized. (a) 2,2-Dimethylmorpholine was prepared by condensation of 1-chloro-2-methyl-2-propanol with ethanolamine and subsequently elaborated by the method of Bettoni et al.: Bettoni, G.; Franchini, C.; Perrone, R.; Tortorella, V. Synthesis and absolute configuration of substituted morpholines. Tetrahedron 1980, 36, 409-415. (b) (R)-2-Methylmorpholine was prepared using the method reported in ref 25a, starting with (R)-methyloxirane, which was synthesized from L-threonine [Rossen, K.; Simpson, P. M.; Wells, K. M. A practical synthesis of both enantiomers of 1-amino-2-propanol and propylene oxide. Synth. Commun. 1993, 23, 1071-1074]. (c) 2-Methylmorpholine and 2-ethylmorpholine: Cottle, D. L.; Jeltsch, A. E.; Stoudt, T. H.; Walters, D. R. The preparation of some C-alkylmorpholines: J. Org. Chem. 1946, 11, 286-291. (d) 2-Propylmorpholine: Vargha, L.; Kasztreiner, E.; Borsy, J.; Farkas, L.; Kuszmann, J.; Dumbovich, B. Synthesis and pharmacological investigation of new alkoxybenzamides-1. 3:4:5-Trimethoxybenzamides. Biochem. Pharmacol. 1962, 11, 639-649. (e) 2-Phenylmethylmorpholine: Brown, G. R.; Forster, G; Foubister, A. J.; Stribling, D. Synthesis and resolution of the novel appetite suppressant 2-benzylmorpholine, a nonstimulant isomer of phenmetrazine. J. Pharm. Pharmacol. 1990, 42, 797-799. (f) (R)-2-(1-Methylethyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylethyl)oxirane, which was synthesized from L-valine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (g) (R)-2-(1-Methylpropyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylpropyl)oxirane, which was synthesized from L-isoleucine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (h) 2,2-Diethylmorpholine was prepared using the method reported in ref 25a, starting with diethyloxirane. (i) 2,2-Dibutylmorpholine was prepared using the method reported in ref 25a, starting with dibutyloxirane. (j) 2,2-Diphenylmorpholine: Moussa, G. E. M.; Basyouni, M. N.; Shaban, M. E. Epoxides: Part I. Synthesis of β,β-diaryl-N-substituted ethanolamines and morpholines. Indian J. Chem., Sect. B 1980, 19B, 798-800. (k) 2,2,6,6-Tetramethylmorpholine: Nowak, E. Synergistic microbicidal compositions comprising triazole and morpholine derivatives. Eur. Pat. Appl. EP 252875, 1988; Chem. Abstr. 1988, 108, 1632646. (l) 2,2-Dimethylthiomorpholine: McManus, J. M.; McFarland, J. W.; Gerber, C. F.; McLamore, W. M.; Laubach, G. D. Sulfamylurea Hypoglycemic Agents. 1. Synthesis and Screening. J. Med. Chem. 1965, 8, 766-776. (m) 2,2,6,6-Tetramethylthiomorpholine was prepared using the method reported in ref 251, starting with 1-amino-2-methyl-2-propanethiol hydrochloride.
48. Substituted morpholines were often not purified or characterized. (a) 2,2-Dimethylmorpholine was prepared by condensation of 1-chloro-2-methyl-2-propanol with ethanolamine and subsequently elaborated by the method of Bettoni et al.: Bettoni, G.; Franchini, C.; Perrone, R.; Tortorella, V. Synthesis and absolute configuration of substituted morpholines. Tetrahedron 1980, 36, 409-415. (b) (R)-2-Methylmorpholine was prepared using the method reported in ref 25a, starting with (R)-methyloxirane, which was synthesized from L-threonine [Rossen, K.; Simpson, P. M.; Wells, K. M. A practical synthesis of both enantiomers of 1-amino-2-propanol and propylene oxide. Synth. Commun. 1993, 23, 1071-1074]. (c) 2-Methylmorpholine and 2-ethylmorpholine: Cottle, D. L.; Jeltsch, A. E.; Stoudt, T. H.; Walters, D. R. The preparation of some C-alkylmorpholines: J. Org. Chem. 1946, 11, 286-291. (d) 2-Propylmorpholine: Vargha, L.; Kasztreiner, E.; Borsy, J.; Farkas, L.; Kuszmann, J.; Dumbovich, B. Synthesis and pharmacological investigation of new alkoxybenzamides-1. 3:4:5-Trimethoxybenzamides. Biochem. Pharmacol. 1962, 11, 639-649. (e) 2-Phenylmethylmorpholine: Brown, G. R.; Forster, G; Foubister, A. J.; Stribling, D. Synthesis and resolution of the novel appetite suppressant 2-benzylmorpholine, a nonstimulant isomer of phenmetrazine. J. Pharm. Pharmacol. 1990, 42, 797-799. (f) (R)-2-(1-Methylethyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylethyl)oxirane, which was synthesized from L-valine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (g) (R)-2-(1-Methylpropyl)morpholine was prepared using the method reported in ref 25a, starting with (R)-(1-methylpropyl)oxirane, which was synthesized from L-isoleucine [Koppenhoefer, B.; Schurig, V. (S)-2-Chloroalkanoic acids of high enantiomeric purity from (S)-amino acids: (S)-2-Chloropropanoic acid and (R)-alkyloxiranes of high enantiomeric purity from (S)-2-chloroalkanoic acids via (S)-2-chloro-1-alkanols: (R)-Methyloxirane. Org. Synth. 1988, 66, 151-159 and 160-172]: no racemization was observed on detosylation. (h) 2,2-Diethylmorpholine was prepared using the method reported in ref 25a, starting with diethyloxirane. (i) 2,2-Dibutylmorpholine was prepared using the method reported in ref 25a, starting with dibutyloxirane. (j) 2,2-Diphenylmorpholine: Moussa, G. E. M.; Basyouni, M. N.; Shaban, M. E. Epoxides: Part I. Synthesis of β,β-diaryl-N-substituted ethanolamines and morpholines. Indian J. Chem., Sect. B 1980, 19B, 798-800. (k) 2,2,6,6-Tetramethylmorpholine: Nowak, E. Synergistic microbicidal compositions comprising triazole and morpholine derivatives. Eur. Pat. Appl. EP 252875, 1988; Chem. Abstr. 1988, 108, 1632646. (l) 2,2-Dimethylthiomorpholine: McManus, J. M.; McFarland, J. W.; Gerber, C. F.; McLamore, W. M.; Laubach, G. D. Sulfamylurea Hypoglycemic Agents. 1. Synthesis and Screening. J. Med. Chem. 1965, 8, 766-776. (m) 2,2,6,6-Tetramethylthiomorpholine was prepared using the method reported in ref 251, starting with 1-amino-2-methyl-2-propanethiol hydrochloride.
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