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122 L-Proline, 1-[2-(3,4,5-Trimethoxyphenyl)-2-Oxoethyl] 3-Phenylpropylamide Hydrochloride
EXAMPLE 122 L-Proline, 1-[2-(3,4,5-Trimethoxyphenyl)-2-Oxoethyl] 3-Phenylpropylamide Hydrochloride Following the procedure described in Example 120, the coupling of N-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl]-L-proline hydrochloride (300 mg, 0.83 mmol) and 3-phenylpropylamine (0.36 mL, 2.5 mmol) provided, after treatment with HCl in Et2 O, 120 mg of the hydrochloride salt of L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] 3-phenylpropylamide as a powder. LSIMS [M-HCl]=441 (mass calculated for C25 H32 N2 O5 +HCl=477.00).
L-Proline, 1-[2-(3,4,5-Trimethoxyphenyl)-2-Oxoethyl] 4-Methoxybenzamide Hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride In diethyl ether; ethyl acetate
132 L-Proline, 1-[2-(3,4,5-Trimethoxyphenyl)-2-Oxoethyl] 4-Methoxybenzamide Hydrochloride
EXAMPLE 132 L-Proline, 1-[2-(3,4,5-Trimethoxyphenyl)-2-Oxoethyl] 4-Methoxybenzamide Hydrochloride Following the procedure described in Example 120, the coupling of N-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl]-L-proline hydrochloride (250 mg, 0.69 mmol) and 4-methoxybenzylamine (0.27 mL, 2.1 mmol) provided, after treatment with HCl in Et2 O, 90 mg of the hydrochloride salt of L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] 4-methoxybenzamide as a powder. Rf=0.38 (free base in EtOAc) LSIMS [M-HCl]=443 (mass calculated for C24 H30 N2 O6 +HCl=478.98).
L-Proline, 1-[2-(3,4,5-Trimethoxyphenyl)-2-Oxoethyl] 2-Methoxybenzamide Hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride In diethyl ether
134 L-Proline, 1-[2-(3,4,5-Trimethoxyphenyl)-2-Oxoethyl] 2-Methoxybenzamide Hydrochloride
EXAMPLE 134 L-Proline, 1-[2-(3,4,5-Trimethoxyphenyl)-2-Oxoethyl] 2-Methoxybenzamide Hydrochloride Following the procedure described in Example 120, the coupling of N-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl]-L-proline hydrochloride (250 mg, 0.69 mmol) and 2-methoxybenzylamine (0.27 mL, 2.1 mmol) provided, after treatment with HCl in Et2 O, 120 mg of the hydrochloride salt of L-Proline, 1-[2-(3,4,5-Trimethoxyphenyl)-2-Oxoethyl] 2-Methoxybenzamide as a powder. Rf =0.38 (free base in EtOAc) LSIMS [M-HCl]=443 (mass calculated for C24 H30 N2 O6 +HCl=478.98).
123 L-Proline, 1-[2-(3,4,5-Trimethoxyphenyl)-2-Oxoethyl] 4-Phenylbutylamide Hydrochloride
EXAMPLE 123 L-Proline, 1-[2-(3,4,5-Trimethoxyphenyl)-2-Oxoethyl] 4-Phenylbutylamide Hydrochloride Following the procedure described in Example 120, the coupling of N-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl]-L-proline hydrochloride (300 mg, 0.83 mmol) and 4-phenylbutylamine (0.39 mL, 2.5 mmol) provided, after treatment with HCl in Et2 O, 170 mg of the hydrochloride salt of L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] 4-phenylbutylamide as a powder. LSIMS [M-HCl]=455 (mass calculated for C26 H34 N2 O5 +HCl=491.03).
L-Proline, 1-[2-(3,4,5-Trimethoxyphenyl)-2-Oxoethyl] 1-methyl-3-phenylpropylamide Hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride In diethyl ether
138 L-Proline, 1-[2-(3,4,5-Trimethoxyphenyl)-2-Oxoethyl] 1-methyl-3-phenylpropylamide Hydrochloride
EXAMPLE 138 L-Proline, 1-[2-(3,4,5-Trimethoxyphenyl)-2-Oxoethyl] 1-methyl-3-phenylpropylamide Hydrochloride Following the procedure described in Example 120, the coupling of N-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl]-L-proline hydrochloride (250 mg, 0.69 mmol) and 1-methyl-3-phenylpropylamine (0.34 mL, 2.1 mmol) provided, after treatment with HCl in Et2 O, 40 mg of the hydrochloride salt of L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] 1-methyl-3-phenylpropylamide as a foam. LSIMS [M-HCl]=455 (mass calculated for C26 H34 N2 O5 +HCl=491.03).
143 L-Proline, 1-[2-(3,4,5-Trimethoxyphenyl)-2-Oxoethyl] tert-Butylamide Hydrochloride
EXAMPLE 143 L-Proline, 1-[2-(3,4,5-Trimethoxyphenyl)-2-Oxoethyl] tert-Butylamide Hydrochloride Following the procedure described in Example 120, the coupling of N-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] -L-proline hydrochloride (250 mg, 0.69 mmol) and t-butylamine (0.22 mL, 2.1 mmol) provided, after treatment with HCl in Et2 O, 146 mg of the hydrochloride salt of L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] tert-butylamide as a powder. Rf=0.42 (for free base: EtOAc) LSIMS [M-HCl]=379 (mass calculated for C20 H30 N2 O5 +HCl=414.93).
L-Proline, 1-[2-(3,4,5-Trimethoxyphenyl)-2-Oxoethyl] 1,2-Diphenylethylamide Hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride In diethyl ether; ethyl acetate
144 L-Proline, 1-[2-(3,4,5-Trimethoxyphenyl)-2-Oxoethyl] 1,2-Diphenylethylamide Hydrochloride
EXAMPLE 144 L-Proline, 1-[2-(3,4,5-Trimethoxyphenyl)-2-Oxoethyl] 1,2-Diphenylethylamide Hydrochloride Following the procedure described in Example 120, the coupling of N-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl]-L-proline hydrochloride (250 mg, 0.69 mmol) and 1,2-diphenylethylamine (0.40 mL, 2.1 mmol) provided, after treatment with HCl in Et2 O, 95 mg of the hydrochloride salt of L-proline, 1-[2-(3,4,5-trimethoxyphenyl)-2-oxoethyl] 1,2-diphenylethylamide as a powder. Rf=0.56 (free base in EtOAc) LSIMS [M-HCl]=503 (mass calculated for C30 H34 N2 O5 +HCl=539.07).
Stage #1: 2-azido-3-(benzyloxy)benzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h;
Stage #2: L-proline hydrochloride With triethylamine In tetrahydrofuran; water at 0 - 20℃; for 2h; Further stages.;
Stage #1: 2-azidobenzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h;
Stage #2: L-proline hydrochloride With triethylamine In tetrahydrofuran; water at 0 - 20℃; for 2h; Further stages.;
Stage #1: 2-carboxy-4-chlorophenyl azide With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h;
Stage #2: L-proline hydrochloride With triethylamine In tetrahydrofuran; water at 0 - 20℃; for 2h; Further stages.;
Stage #1: 2-azido-3,5-dibromobenzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h;
Stage #2: L-proline hydrochloride With triethylamine In tetrahydrofuran; water at 0 - 20℃; for 2h; Further stages.;
Stage #1: 2-azido-4,5-dimethoxybenzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h;
Stage #2: L-proline hydrochloride With triethylamine In tetrahydrofuran; water at 0 - 20℃; for 2h; Further stages.;
Stage #1: 2′-azido-4′-(benzyloxy)-5′-methoxybenzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h;
Stage #2: L-proline hydrochloride With triethylamine In tetrahydrofuran; water at 0 - 20℃; for 2h; Further stages.;
Stage #1: C19H18N6O8 With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h;
Stage #2: L-proline hydrochloride With triethylamine In tetrahydrofuran; water at 0 - 20℃; for 2h; Further stages.;
Stage #1: C20H20N6O8 With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h;
Stage #2: L-proline hydrochloride With triethylamine In tetrahydrofuran; water at 0 - 20℃; for 2h; Further stages.;
Stage #1: C21H22N6O8 With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h;
Stage #2: L-proline hydrochloride With triethylamine In tetrahydrofuran; water at 0 - 20℃; for 2h; Further stages.;
General procedure: Compounds 1-3 (each 1 mg) were hydrolyzed in HCl (6 N; 1 mL) for 20 h at 110 °C. The solution was then evaporated to dryness and redissolved in H2O (250 muL). A 1percent (w/v) solution (100 muL) of l-FDAA in acetone was added to an aliquot (50 muL) of the acid hydrolyzate solution. After addition of NaHCO3 solution (1 N; 20 muL) the mixture was incubated at 45 °C for 1 h. The reaction was then quenched by addition of HCl (2 N, 10 muL). Analyses of the FDAA-derivatized hydrolyzates of compounds 1-3 and standard FDAA-derivatized amino acids were carried out by HPLC (Waters 600E; solvents: A. water+0.2percent TFA, B. MeCN; linear gradient: 0-5 min, 15percent B; 5-50 min, 15-45percent B; 50-55 min, 45percent B; temperature, 30 °C; flow rate, 1 mL/min; UV detection at lambdamax 340 nm). Retention times (min) of the amino acids derivatives were as follows: l/d-Ala, tR 29.6/34.4 min; l/d-Pro, tR 30.6/32.3 min; l/d-Phe, tR 40.8/51.2 min. The derivatized hydrolyzates of 1-3 showed peaks designated as l-Ala, l-Pro, and l-Phe. All amino acids of these cyclopeptides were established as l-configuration.
General procedure: Compounds 1-3 (each 1 mg) were hydrolyzed in HCl (6 N; 1 mL) for 20 h at 110 °C. The solution was then evaporated to dryness and redissolved in H2O (250 muL). A 1percent (w/v) solution (100 muL) of l-FDAA in acetone was added to an aliquot (50 muL) of the acid hydrolyzate solution. After addition of NaHCO3 solution (1 N; 20 muL) the mixture was incubated at 45 °C for 1 h. The reaction was then quenched by addition of HCl (2 N, 10 muL). Analyses of the FDAA-derivatized hydrolyzates of compounds 1-3 and standard FDAA-derivatized amino acids were carried out by HPLC (Waters 600E; solvents: A. water+0.2percent TFA, B. MeCN; linear gradient: 0-5 min, 15percent B; 5-50 min, 15-45percent B; 50-55 min, 45percent B; temperature, 30 °C; flow rate, 1 mL/min; UV detection at lambdamax 340 nm). Retention times (min) of the amino acids derivatives were as follows: l/d-Ala, tR 29.6/34.4 min; l/d-Pro, tR 30.6/32.3 min; l/d-Phe, tR 40.8/51.2 min. The derivatized hydrolyzates of 1-3 showed peaks designated as l-Ala, l-Pro, and l-Phe. All amino acids of these cyclopeptides were established as l-configuration.
General procedure: Compounds 1-3 (each 1 mg) were hydrolyzed in HCl (6 N; 1 mL) for 20 h at 110 °C. The solution was then evaporated to dryness and redissolved in H2O (250 muL). A 1percent (w/v) solution (100 muL) of l-FDAA in acetone was added to an aliquot (50 muL) of the acid hydrolyzate solution. After addition of NaHCO3 solution (1 N; 20 muL) the mixture was incubated at 45 °C for 1 h. The reaction was then quenched by addition of HCl (2 N, 10 muL). Analyses of the FDAA-derivatized hydrolyzates of compounds 1-3 and standard FDAA-derivatized amino acids were carried out by HPLC (Waters 600E; solvents: A. water+0.2percent TFA, B. MeCN; linear gradient: 0-5 min, 15percent B; 5-50 min, 15-45percent B; 50-55 min, 45percent B; temperature, 30 °C; flow rate, 1 mL/min; UV detection at lambdamax 340 nm). Retention times (min) of the amino acids derivatives were as follows: l/d-Ala, tR 29.6/34.4 min; l/d-Pro, tR 30.6/32.3 min; l/d-Phe, tR 40.8/51.2 min. The derivatized hydrolyzates of 1-3 showed peaks designated as l-Ala, l-Pro, and l-Phe. All amino acids of these cyclopeptides were established as l-configuration.
6
To a round-bottom flask equipped with magnetic stirrer containing (S)-pregabalin (412 mg, 2.59 mmol) and L-proline·HCl (392 mg, 2.59 mmol, 1.0 eq), was added ACN (8 mL). The resultant suspension was stirred at room temperature overnight. The solid was filtered with a sintered funnel (porosity 3), washed with ACN (3 mL) and dried under vacuum at room temperature to give co-crystal of (S)-pregabalin - L-proline - HCl (1:1:1) as a white powder (743 mg, 93% yield).
Stage #1: Boc-Goly-Val-Ala-OMe With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -20℃;
Stage #2: L-proline hydrochloride With 4-methyl-morpholine In tetrahydrofuran at 20℃; for 14h;
(S)-methyl-1-((3'S,4'S)-4'-(tert-butoxycarbonylamino)-3'-hydroxy-5'-phenylpentanoyl) pyrrolidine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 24h;
1 General procedure for compounds 2a-c
General procedure: To a 0 °C cooled mixture of compound 1 (0.2 g; 0.647 mmol) andthe appropriate hydrochloride (L-Phe-OMe.HCl, L-Val-OMe.HCl orL-Pro-OMe.HCl) (1.15 mmol) in dry CH2Cl2 (10 mL) were addedEDC.HCl (0.186 g; 0.970 mmol), HOBt (0.13 g; 0.970 mmol) and N-methylmorpholine(0.21 mL; 1.94 mmol). The mixture was stirredat room temperature for 24 h and the volatiles were removed underreduced pressure. The resulting residue was dissolved in CH2Cl2(50 mL) and successively washed with 5% H3PO4 (50 mL), 20%Na2CO3 (50 mL), water (40 mL) and brine (50 mL) and dried withNa2SO4 after which it was filtered and evaporated under reducedpressure. The products were purified by flash chromatography onsilica gel using EtOAc/hexane as eluents.
With thionyl chloride; triethylamine at 20℃; for 10h;
3.2.1. Synthesis of Amino Acid Methyl Esters (as Hydrochlorides) 1, 2, 3 and 4
General procedure: (a) The corresponding amino acid (alpha-L-alanine, beta-alanine, 0.1 mol) was dissolvedin 100 mL methanol and 0.2 mol of freshly distilled trimethylchlorosilane was addedwith stirring at room temperature. After the completion of the reaction (about 12 h),the solvent was evaporated under reduced pressure to give the esters 1 ((S)-1-methoxy-1-oxopropan-2-aminium chloride (S-alanine methyl ester hydrochloride)) and 2 (3-methoxy-3-oxopropan-1-aminium chloride (beta-alanine methyl ester hydrochloride)).(b) 0.1 mol of amino acid (L-proline, L-tyrosine) was mixed with freshly distilled SOCl2(0.3 mol) and Et3N (0.1 mol) in 100 mL methanol at room temperature. After thecompletion of the reaction (about 10 h), the mixture was neutralized with Et3N, thevolatiles were removed under reduced pressure to give the amino acid methyl esters3 ((S)-methyl pyrrolidine-2-carboxylate hydrochloride (L-proline methyl ester hydrochloride))and 4 ((S)-methyl 2-amino-3-(4-hydroxyphenyl)propanoate hydrochloride(L-tyrosine methyl ester hydrochloride)).Yields: 75-99% for both methods.
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