KR100264113B1 - Process For Preparing Chiral Ethyl (5-Amino-1,2-Dihydro-2-Methyl-3-Phenylpyrido[3,4-b]Pyrazin-7-Yl)Carbamate - Google Patents

Abstract

The present invention provides a novel chemical preparation method of chiral ethyl (5-amino-1,2-dihydro-2-methyl-3-phenylpyrido [3,4-b] pyrazin-7-yl) carbamate and It relates to novel intermediates used for chemical synthesis.

Description

Process for preparing chiral ethyl (5-amino-1,2-dihydro-2-methyl-3-phenylpyrido [3,4-VII] pyrazin-7-yl) carbamate {Process For Preparing Chiral Ethyl (5 -Amino-1,2-Dihydro-2-Methyl-3-Phenylpyrido [3,4-ｂ] Pyrazin-7-Yl) Carbamate}

The invention relates to a novel chemical preparation of chiral ethyl (5-amino-1,2-dihydro-2-methyl-3-phenylpyrido [3,4-b] pyrazin-7-yl) carbamate and to It relates to novel intermediates used for synthesis.

The novel process of the present invention consists of a method that is significantly improved over the process for preparing the compounds described in US Pat. No. 4,866,059, issued September 12,1989. The method of the present invention is (S) of ethyl (5-amino-1,2-dihydro-2-methyl-3-phenylpyrido [3,4-b] pyrazin-7-yl) carbamate known as an anticancer agent. It is a synthesis method of-(-)-and (R)-(+)-isomers. The process of the present invention provides a better process because it does not need to use the oxidation step with chromium trioxide described in US Pat. No. 4,866,059.

The novel method of the present invention is shown in the following scheme.

In the above scheme, * is used to indicate that the arrangement of carbon atoms is (S)-(-)-or (R)-(+)-. The compound represented by the formula (5a) is a novel compound and is part of the present invention. These compounds are represented in more detail by the following formulas (1b) and (2b).

In the above schemes and in formulas 1b and 2b, R and R ₁ are lower alkyl having 1 to 4 carbon atoms, ie methyl, ethyl, n-propyl or n-butyl. It is preferable that each of R and R ₁ is methyl. PG in the compounds of formulas (1a) and (2a) of the scheme represents a protecting group and may be carbenzyloxy (phenylmethoxycarbonyl), benzhydryloxycarbonyl or tert-butoxycarbonyl. Preferred protecting group is carbobenzyloxy. The chiral protective alanine of formula (1a) is treated with tertiary alkyl amine and lower alkyl chloroformate in a suitable solvent such as tetrahydrofuran, dioxane or diethyl ether, followed by di (lower) in chloroform or dichloromethane. Treated with alkylhydroxylamine. This hydroxylamine has the formula RNHOR _{1 in} which each of R and R ₁ is a lower alkyl group having 1 to 4 carbon atoms. This lower alkyl chloroformate may have a straight or branched chain alkyl group having 1 to 5 carbon atoms, preferably a methyl group. The reaction is carried out at a temperature of -25 ° C to + 25 ° C, preferably at a temperature of -10 ° C. Examples of lower alkyl tertiary amines include triethylamine or N-methylpiperidine, with the latter being preferred. The resulting amide (2a) is a lower alcohol, for example methanol or ethanol, or an ether, for example in the presence of palladium on charcoal when the protecting group (PG) is carbenzyloxy or benzhydryloxycarbonyl Deprotection by debenzylation with a catalyst using hydrogen gas in a solvent such as dioxane, tetrahydrofuran or diethyl ether. When the protecting group (PG) of the compound of the formula (2a) is tert-butoxycarbonyl, the protecting group is removed using, for example, trifluoroacetic acid, to obtain compound (3a) as a trifluoroacetic acid salt. Without isolation, the compound of formula (3a) is added to ethyl 2-amino-3-nitro-4-chloro in the presence of tert-alkylamine such as triethylamine or N-methylpiperidine in a lower alcohol solvent such as methanol or ethanol. React with pyridine-6-carbamate. When compound (3a) is in the form of an acetate or trifluoroacetic acid salt, excess tert-alkylamine is used. Carbamates represented by compound (5a) are temperatures of 0 ° C. to 65 ° C. according to the method described in Nahm and Weinrab, Tetrahedron Letters 22 (39: 3881-3818, page 1981). In an ether solvent such as tetrahydrofuran, diethyl ether or dioxane, preferably at a temperature of 0 ° C., a phenyl Grignard reagent such as phenylmagnesium bromide, phenylmagnesium iodide, or phenyllithium is treated. The ketone represented by the formula (6a) is reduced cyclization in acetic acid in the presence of Raney nickel to give the desired product (7a) as an acetate or reduced cyclization in ethanol to give the free base (7a).

The most preferred embodiment of the present invention is shown in Scheme 2 below.

In Scheme 2, Cbz is carbenzyloxy, Ph is phenyl, THF is tetrahydrofuran, and all reactants have the common meaning recognized in the art.

In the above scheme, when the R (+)-enantiomer of N-carbenzyloxyalanine is substituted for S (-) enantiomer, an R (+) product corresponding to (7) is obtained.

Compounds represented by formulas (7a) and (7) are described in US Pat. No. 4,866,059, issued September 12,1989. These compounds are useful as anticancer agents and can be administered in the manner described in patent 4,866,059. The proportions of use of the compounds described in US Pat. No. 4,866,059 and methods of formulating the compounds are described in particular in columns 1, 7 to 2, 33, 3 and 67, 4, 4, 25, 25, and prior art It describes as a literature.

Salts of compounds of formulas (7a) and (7) can generally be prepared as described in US Pat. No. 4,866,059. Particularly preferred salts are salts formed with isethionic acid, the details of which are described in the specific examples below.

As mentioned above, the compounds represented by the formulas (1b) and (2b) are novel compounds and are important intermediates in the preparation of the compounds of the formulas (7a) and (7). Most preferred compounds of formulas (1b) and (2b) are those in which R and R ₁ are each methyl, ie ethyl (S)-[6-amino-4-[[2- (methoxymethylamino) -1-methyl -2-oxoethyl] amino] -5-nitro-2-pyridinyl] carbamate or ethyl (R)-[6-amino-4-[[2- (methoxymethylamino) -1-methyl-2 -Oxoethyl] amino] -5-nitro-2-pyridinyl] carbamate compound.

The present invention is explained in more detail by the following examples.

<Example 1>

Of ethyl (+)-(R)-(5-amino-1,2-dihydro-2-methyl-3-phenylpyrido [3,4-b] pyrazin-7-yl) carbamate isethionate Produce

<Step 1>

Preparation of Phenylmethyl (R)-[2-methoxymethylamino-1-methyl-2-oxoethyl] carbamate

A stirred suspension of 102.4 g of N, O-dimethylhydroxylamine hydrochloride (1.05 M) in 600 ml of dichloromethane is cooled to −10 ° C. under N ₂ atmosphere and 109.1 g (1.10 M) of N-methylpiperidine are added. To prepare a clear solution. 223.2 g (1M) of N-[(phenylmethoxy) carbonyl] -D-alanine was dissolved in 600 ml THF in a separate flask. To the clear solution, 2 L of dichloromethane and 109.1 g (1.1 M) of N-methylpiperidine were added under a N ₂ blanket. The solution was cooled to 0 ° C. with vigorous stirring and 99.2 g (81.1 ml, 1.05 M) of methyl chloroformate were added all at once. The mixture was stirred at 0 ° C. to −10 ° C. for 10 minutes and a pre-prepared low temperature N, O-dimethylhydroxylamine solution was transferred to the mixture via cannula. The mixture was stirred at 0 ° C. for 1 hour and further stirred for 12 hours without external cooling. The mixture was cooled back to 0 ° C., extracted twice with 1 L of cold HCl (0.5 N), 1 L of saturated NaHCO ₃ solution, 1 L of saturated NaCl solution and dried over MgSO ₄ . The solution was evaporated under high vacuum (0.2 mm) to give a white solid to give 228.3 g (86%) of the title compound. Melting point 82 ° C. to 84 ° C .; IR (KBr): 3288, 1720, 1656, 1616, 1540 cm ^-1 . ¹ H-NMR (d ₆ -DMSO): 7.60 (d, 1H, J = 7.6 Hz); 7.36-7.30 (m, 5 H); 5.01 (s, 2 H); 4.51-4.42 (m, 1 H); 3.73 (s, 3 H); 3.10 (s, 3 H); 1.17 (d, 3H, J = 7.1 Hz).

Mass spectrometry (FAB): M + 1 = 267, 223, 206, 178, 159, 139, 119, 91.

Elemental Analysis for C ₁₃ H ₁₈ N ₂ O ₄ :

Theoretical: C, 58.64; H, 6.76; N, 10.51

Found: C, 58.70; H, 6. 99; N, 10.35.

<Step 2>

(R) Preparation of 2-Amino-N-methoxy-N-methyl-propanamide

A solution of 120 g (0.45 M) of the compound obtained in step 1 in 1.2 L of anhydrous EtOH was hydrogenated on 5 g of 20% Pd / C at 50 psi (3.40 atm). The catalyst was removed and the solution was evaporated to give 102 g (100%) of a colorless viscous oil. This oil was kept under high vacuum and used without further purification.

<Step 3>

Preparation of ethyl (R)-[6-amino-4-[[2- (methoxymethylamino) -1-methyl-2-oxoethyl] amino] -5-nitro-2-pyridinyl] carbamate

To a stirred solution of 102 g (0.45 M) of the compound obtained in step 2 in 1.8 L of anhydrous ethanol 60.6 g (83.2 ml, 0.6 M) triethylamine and ethyl 2-amino-3-nitro-4-chloropyridine-6-carr 126 g (0.48 M) of bamate were added. This mixture was heated at reflux under N ₂ for 24 h and the residue obtained by evaporation was dissolved in 2 L of EtOAc. This EtOAc solution was extracted with H ₂ O 2 L. The aqueous layer was extracted again with 1 L of EtOAc. The combined EtOAc layers were extracted twice with 500 mL of H ₂ O, with 1 L of saturated NaCl and dried over MgSO ₄ . 152 g of the residue obtained by evaporation of the mixture was chromatographed on SiO _{2 using} petroleum ether: EtOAc (70:30 to 50:50) as eluent to afford 135 g (84%) of the title compound. Melting point 95 ° C.-97 ° C .;

[α] ²³ _D -71.6 ° (C = 1.139 in CHCl ₃ ); IR (KBr): 3467, 3344, 1740, 1670, 1653, 1646, 1604 cm ^-1 . ¹ H-NMR (CDCl ₃ ): 9.56 (d, 1H, J = 6.8 Hz); 7.77 (s, 1 H); 6.71 (s, 1 H); 4.68-4.59 (m, 1 H); 4.21 (q, 2 H); 3.86 (s, 3 H); 3.27 (s, 3 H); 1.54 (d, 3H, J = 6.7 Hz); 1.29 (t, 3H, J = 7.1 Hz).

Mass spectrometry (CI): M + 1 = 357, 341, 327, 311, 296, 280, 268.

Elemental Analysis for C ₁₃ H ₂₀ N ₆ O ₆ :

Theoretical: C, 43.82; H, 5. 66; N, 23.58

Found: C, 43.58; H, 5. 76; N, 23.07.

<Step 4>

Preparation of ethyl (R)-[6-amino-4-[(1-methyl-2-oxo-2-phenylethyl) amino] -5-nitro-2-pyridinyl] carbamate

A 1.9 M solution of PhMgBr in 3 L of diethyl ether was freshly prepared from 46.2 g (1.9 M) of magnesium crumb, 298.3 g (200 ml, 1.9 M) of bromobenzene and 2.14 g of I ₂ . The dark solution was kept under N ₂ . In a separate flask a solution of 130 g (0.365 M) of the compound obtained in step 3 in anhydrous THF 3 L was cooled with stirring to 0 ° C. under N ₂ . Freshly prepared solution of PhMgBr was added slowly through the cannula at 0 ° C. with vigorous stirring. The dark suspension was stirred at rt for 16 h. The mixture was poured into 2 L saturated NH ₄ Cl solution and quenched, and the organic layer was separated. The aqueous layer was extracted with 2 L EtOAc. The combined EtOAc layers were washed four times with 1 L of H ₂ O, 1 L of saturated NaCl solution and dried over MgSO ₄ . After evaporating the solvent, 180 g of the residue was chromatographed on SiO _{2 using} petroleum ether: EtOAc (7: 3 to 1: 1) as eluent to afford 62.5 g (46%) of the title compound. Melting point 95 ° C.-97 ° C .; Softened at 90 ° C.

HPLC: 89% [α] ²³ _D = -32 ° (1.01% in CHCl ₃ ); IR (KBr): 3477, 3344, 1740, 1717, 1695, 1690, 1685, 1599, 1576, 1563, 1559, 1418, 1300, 1278, 1255, 1211, 1096, 972, 702 cm ^-1 .

¹ H-NMR (CDCl ₃ ): δ 10.04 (d, 1H, J = 6.1 Hz); 8.04 (d, 2H, J = 7.2 Hz); 7.68-7. 51 (m, 3 H); 6.86 (S, 1 H); 5.31-5.19 (m, 1 H); 4.23 (q, 2 H); 1.61 (d, 3 H, J = 7 Hz); 1.32 (t, 3H, J = 7.1 Hz).

MS (CI) M + l = 374, 358, 326, 324, 310, 278, 268.

<Step 5>

Of ethyl (+)-(R)-(5-amino-1,2-dihydro-2-methyl-3-phenylpyrido [3,4-b] pyrazin-7-yl) carbamate isethionate Produce

A solution of 52 g (6a) (0.139 M) in 1 L of anhydrous EtOH was hydrogenated over 50 g of RaNi at 50 psi (3.40 atm) for 36 hours. The catalyst was removed and the solvent evaporated to give 48.9 g of a brown foam. The foam was chromatographed on SiO _{2 using} petroleum ether: EtOAc (1: 1) as eluent to yield ethyl (+)-(R)-(5-amino-1,2-dihydro-2- as yellow solid. 25.7 g (56%) of methyl-3-phenylpyrido [3,4-b] pyrazin-7-yl) carbamate were obtained. Melting point 148 ° C-151 ° C (softened at 120 ° C).

HPLC: 92% [α] ²³ _D = + 547 ° (C = 1.154% in CHCl ₃ ); IR (KBr): 3392, 2976, 1733, 1728, 1719, 1702, 1611, 1579 cm ^-1 . ¹ H-NMR (CDCl ₃ ): δ 8.21 (bm, 1H); 7.94-7.9 (m, 2 H); 7.46-7.40 (m, 3 H): 6.72 (s, 1 H); 5.24 (bs, 2 H); 4.82-4.79 (m, 1 H); 4.53 (bs, 1 H); 4.22 (q, 2 H); 1.33-1.25 (m, 6 H).

Mass spectrometry (CI): M + 1 = 326, 325, 310, 280, 264, 251, 238.

Elemental Analysis for C ₁₇ H ₁₉ N ₅ O ₂ :

Theoretical: C, 62.76; H, 5.89; N, 21.52.

Found: C, 63.07; H, 5.95; N, 19.59.

To a solution of 18.95 g of carbamate solution (58.2 mM) obtained above in 200 ml of methanol was added 0.168 N (329 ml, 55.3 mM) of methanol solution of isethionic acid under stirring. After 1 hour, the solvent was evaporated and the remaining dark foam was dissolved in 440 ml of acetonitrile with slight warming under argon atmosphere. The solution was filtered and left at room temperature to give 15.7 g (56%) of fine tan crystals. HPLC: 96%. 13.5 g (29.9 mM) of 7a isethionate were further purified by redissolution in 700 ml of acetonitrile at reflux in the presence of 0.7 g of ascorbic acid. The solution was filtered to high temperature and slowly cooled to give 9.7 g of fine tan crystalline product. Melting point 164-167 ° C.

HPLC: 98.5%, chiral HPLC: 100%, [a] ²³ _D = + 394 ° (C = 0.972, MeOH); IR (KBr): 3434, 3420, 3295, 3285, 3273, 3192, 3186, 3173, 3162, 3158, 3148, 2980, 1727, 1662, 1635, 1607, 1591, 1572, 1533, 1467, 1448, 1250, 1222 , 1215, 1182, 1148, 1124, 1068, 1035, 696 cm ^-1 . ¹ H-NMR (d ₆ -DMSO): δ 11.62 (bs, 1H); 11.05 (bs, 1 H); 8.49 (bs, 1 H); 8.16-8.14 (m, 2 H); 7.71 (bs, 2 H); 7.49-7.47 (m, 3 H); 5.92 (s, 1 H); 5.15-5.08 (m, 1 H); 4.24 (q, 2H, J = 7 Hz); 3.63 (t, 2H, J = 6.7 Hz); 2.62 (t, 2H, J = 6.7 Hz); 1.29 (t, 3H, J = 7.1 Hz); 1.15 (d, 3 H, 6.5 Hz).

Mass spectrometry (FAB). M ⁺ +1 = 325 (451-127 = ); 310, 277, 264, 251, 238, 223, 202, 194, 167, 155, 133, 104, 91, 84, 77, 66, 65, 51, 45.

Elemental analysis for C ₁₇ H ₁₉ N ₅ O ₂ · C ₂ H ₆ SO ₄ :

Theoretical: C, 50.54; H, 5.58; N, 15.51; S, 7.10.

Found: C, 50.52; H, 5. 46; N, 15.58; S, 6.97.

<Example 2>

Of ethyl (-)-(S)-(5-amino-1,2-dihydro-2-methyl-3-phenylpyrido [3,4-b] pyrazin-7-yl) carbamate isethionate Produce

<Step 1>

Preparation of Phenylmethyl (S)-[2-methoxymethylamino-1-methyl-2-oxoethyl] carbamate

A stirred suspension (10 mM) of 10.73 g of N, O-dimethylhydroxylamine hydrochloride in 100 ml of dichloromethane is cooled to 0 ° C. under N ₂ atmosphere and 12 g (14.7 mL, 121 mM) of N-methylpiperidine Was added to prepare a clear solution. In a separate flask 24.5 g (110 mM) of N-[(phenylmethoxy) carbonyl] -L-alanine was dissolved in 100 ml of THF. To the clear solution, 200 ml of dichloromethane and 12 g (14.7 ml, 121 mM) of N-methylpiperidine were added under an N ₂ blanket. The solution was cooled to −10 ° C. to −15 ° C. with vigorous stirring, and 10.4 g (8.5 ml, 110 mM) of methyl chloroformate were added all at once. The mixture was stirred at −10 ° C. to −15 ° C. for 10 minutes and the pre-prepared N, O-dimethylhydroxylamine solution at 0 ° C. was transferred to this mixture via cannula. The mixture was stirred at 0 ° C. for 1 hour and further stirred for 16 hours without cooling. The reaction mixture was diluted with 200 ml of dichloromethane, cooled to 0 ° C., twice with 200 ml of HCl (0.1 N), twice with 100 ml of saturated NaHCO ₃ solution, extracted with 200 ml of saturated NaCl solution, and extracted with MgSO ₄ . Dried. The solid obtained by evaporation of the solution under high vacuum (0.02 mm) gave 26.4 g (90%) of the title compound as a white solid. Melting point 86 ° C. to 88 ° C .;

[α] ²³ _D = -1.3 ° (C = 1.038% in CHCl ₃ ); IR (KBr): 3284, 1723, 1719, 1662, 1655 cm ^-1 . ¹ H-NMR (CDCl ₃ ): δ 7.35 (s, 5H); 5.55 (d, 1 H, J = 8 Hz); 5.13 (d, 1 H, J = 12.2 Hz); 5.06 (d, 1H, J = 12.8 Hz); 4.79-4.56 (m, 1 H); 3.77 (s, 3 H); 3.21 (s, 3 H); 1.34 (d, 3H, J = 6.7 Hz).

Mass spectrometry (EI) M + 1: 267, 223, 207, 206, 178, 151, 134, 107, 92, 91.

Elemental Analysis for C ₁₃ H ₁₈ N ₂ O ₄ :

Theoretical: C, 58.64; H, 6.81; N, 10.52.

Found: C, 58.58; H, 6.83; N, 10.42.

<Step 2>

Preparation of (S) -2-amino-N-methoxy-N-methyl propanamide

A solution of 5.4 g (20.3 mM) of the compound obtained in step 1 in 75 ml of CH ₃ OH was hydrogenated over 0.5 g of 20% Pd / C at 50 psi (3.40 atm) for 1.5 hours. The catalyst was removed and the solution was evaporated to give 4.6 g (100%) of a colorless viscous oil. This oil was kept under high vacuum and used without further purification.

<Step 3>

Preparation of ethyl (S)-[6-amino-4-[[2- (methoxymethylamino) -1-methyl-2-oxoethyl] amino] -5-nitro-2-pyridinyl] carbamate

To a stirred solution of 4.6 g (20 mM) of the compound obtained in step 2 in 100 ml of absolute ethanol 2.5 g (3.45 ml, 25 mM) and ethyl 2-amino-3-nitro-4-chloropyridine-6-carth 5.5 g (21 mM) of bamate were added. The mixture was heated at reflux under N ₂ for 19 h and the residue obtained by evaporation was dissolved in 100 ml of EtOAc. This EtOAc solution was washed twice with 50 ml of H ₂ O and dried over MgSO ₄ . 8.5 g of the residue obtained by evaporation of the mixture was chromatographed on SiO _{2 using} petroleum ether: EtOAc (3: 2 to 2: 3) as eluent to afford 6 g (70%) of the title compound. Melting point 85 ° C.-92 ° C .;

[α] ²³ _D = + 69.3 ° (1.1% C in CHCl ₃ ); IR (KBr): 3333, 1741, 1669, 1597, 1591 cm ^-1 . ¹ H-NMR (CDCl ₃ ): δ 9.58 (d, 1H, J = 5.9 Hz); 7.65 (bs, 1 H); 6.71 (s, 1 H); 4.68-4.56 (m, 1 H); 4.22 (q, 2 H); 3.86 (s, 3 H); 3.27 (s, 3 H); 1.54 (d, 3H, J = 6.7 Hz); 1.30 (t, 3H, J = 7.3 Hz).

Mass spectrometry (CI), M +1: 357, 356, 341, 323, 311, 280, 269, 268, 252, 223, 222.

Elemental Analysis for C ₁₃ H ₂₀ N ₆ O ₆ :

Theoretical: C, 43.82; H, 5. 66; N, 23.58.

Found: C, 43.62; H, 5.49; N, 23.02.

<Step 4>

Preparation of ethyl (S)-[6-amino-4-[(1-methyl-2-oxo-2-phenylethyl) amino] -5-nitro-2-pyridinyl] carbamate

A 0.74 M solution of phenyl magnesium bromide in ether was freshly prepared from 26.7 g (1.1 M) magnesium crumb and 157 g (105.3 ml, 1 M) bromobenzene in 1 L of diethyl ether. The mixture was filtered under N ₂ to remove unreacted magnesium. An amount of solution was titrated against sec-butanol using phenanthroline as an indicator to determine molarity (0.74 M) (see J Organometallic Chem, 1967; 9: 165). In a separate flask a solution of 3.8 g of the compound obtained in step 3 in 200 ml of dry THF (10.7 mM) was stirred at room temperature under N ₂ . A solution of PhMgBr (0.74 M) was added in 6 portions (6 × 14.3 ml) at 15 minute intervals with vigorous stirring. The dark suspension was stirred for 14 hours at room temperature. The mixture was poured into 250 ml saturated NH ₄ Cl solution and the organic layer was separated. The aqueous layer was extracted twice with 200 ml of EtOAc. The combined organic layers were washed twice with 200 ml of H ₂ O, 100 ml of saturated NaCl and dried over MgSO ₄ . After evaporation of the solvent, 4.54 g of the residue was chromatographed on SiO _{2 using} petroleum ether: EtOAc (1: 1) as eluent to afford 1.94 g (49%) of the title compound. Melting point 102 ° C.-106 ° C .;

[a] ²³ _D = + 35 ° (C = 1.025% in CHCl ₃ ); IR (KBr): 3421, 1740, 1736, 1718, 1695, 1685, 1677, 1653, 1599 cm ^-1 . ¹ H-NMR (CDCl ₃ ): δ 9.94 (s, 1H); 9.78 (d, 1 H, J = 6.2 Hz); 8.08 (d, 2H, J = 7.2 Hz); 7.76-7.59 (m, 3 H); 6.76 (s, 1 H); 5.48-5.43 (m, 1 H); 4.12 (q, 2 H); 1.47 (d, 3H, J = 6.8 Hz); 1.22 (t, 3 H, J = 7.2 Hz).

Mass spectrometry (FAB): M + 1 = 374.1, 358, 329, 302, 268, 252, 223.

Elemental Analysis for C ₁₇ H ₁₉ N ₅ O ₅ :

Theoretical: C, 54.64; H, 5.09; N, 8.75.

Found: C, 54.78; H, 5.11; N, 18.71.

<Step 5>

Of ethyl (-)-(S)-(5-amino-1,2-dihydro-2-methyl-3-phenylpyrido [3,4-b] pyrazin-7-yl) carbamate isethionate Produce

A solution of 1.67 g (4.5 mM) of the compound obtained in step 4 in 100 ml of anhydrous EtOH was hydrogenated on 50 g of RaNi under 50 psi (3.40 atm) for 1.5 hours. The catalyst was removed and the solvent evaporated to ethyl (-)-(S)-(5-amino-1,2-dihydro-2-methyl-3-phenylpyrido [3,4-b] pyrazine as a yellow foam. -7-yl) carbamate 1.36 g (93%) were obtained.

HPLC 94%, chiral HPLC 95.6%, and R-enantiomer 3.8%. IR (KBr): 3407, 3397, 3391, 3374, 2975, 1733, 1724, 1719, 1701, 1611, 1578, 1558, 1539, 1533, 1497, 1446, 1410, 1220 cm ^-1 . ¹ H-NMR (CDCl ₃ ): δ 8.05 (bs, 1H); 7.94-7.91 (m, 2 H); 7.46-7. 41 (m, 3 H); 6.72 (s, 1 H); 5.19 (bs, 2 H); 4.85-4.77 (m, 1 H); 4.50 (s, 1 H); 4.22 (q, 2 H); 2.57 (bs, 1 H); 1.33-1.25 (m, 6 H).

Mass spectrometry (CI): M + 1 = 326.

To a solution of 0.47 g of the free base obtained above (1.4 mM) in 20 ml of methanol was added 0.153 N (9.0 ml, 1.37 mM) of a methanol solution of isethionic acid under argon atmosphere. The obtained clear solution was filtered. The solvent was evaporated and the remaining foam dissolved in 25 ml of acetonitrile at reflux temperature. The solution was filtered to high temperature, slowly cooled to give fine tan crystals which were dried and weighed 0.46 g (74%).

HPLC: 97%, chiral HPLC 97.2%, melting point 164 ° C.-166 ° C .; [a] _D ²³ = -394 ° (0.886% in CH ₃ OH).

The product was further purified by chromatography on SiO _{2 using} hexanes: EtOAc (6: 4) as the eluent to afford the free base with a chemical purity of 99.5% and reforming the isethionate.

IR (KBr): 3444, 3435, 3429, 3422, 3306, 3295, 3284, 3270, 3263, 3256, 3243, 3227, 3199, 3187, 3164, 3149, 1727, 1658, 1635, 1607, 1591, 1534, 1448 , 1251, 1218, 1212, 1182, 1149, 1123, 1068, 1035, 696 cm ^-1 . ¹ H-NMR (DMSO): δ 11.60 (bs, 1 H); 11.00 (s, 1 H); 8.51 (d, 1 H, J = 2 Hz); 8.17-8.14 (m, 2 H); 7.72 (bs, 2 H); 7.49-7.47 (m, 3 H); 5.97 (s, 1 H); 5.14-5.10 (m, 1 H); 4.24 (q, 2 H); 4.14 (bs, 1 H); 2.67 (t, 2H, J = 6.8 Hz); 2.68 (t, 2H, J = 6.8 Hz); 1.29 (t, 3H, J = 7.1 Hz); 1.20 (d, 3H, J = 6.5 Hz).

Mass spectrometry (FAB): M + 1 = 325 (451-127), 310, 296, 279, 278, 264, 252, 238, 221, 210, 194, 167.

_{C 17 H 19 N 5 O 2} · C 2 H 6 O 4 S element for analysis:

Theoretical: C, 50.54; H, 5.58; N, 15.51; S, 7.10.

Found: C, 50.71; H, 5.67; N, 15.50; S, 6.84.

The process of the present invention provides a better process because it does not need to use the oxidation step with chromium trioxide described in US Pat. No. 4,866,059.

Claims (4)

N-protected S-(-)-L-alanine or N-protected R-(+)-L-alanine was treated with tertiary aliphatic amine and lower alkylchloroformate in a suitable solvent, followed by -25 ° C to 25 ° C Treatment with di- (lower) alkyl hydroxylamine hydrochloride in a suitable solvent under a nitrogen atmosphere at a temperature of to afford an amide of formula (1) or (2), deprotecting the amide, and the presence of tertiary alkylamine in a lower alcohol solvent Under reaction with ethyl 2-amino-3-nitro-4-chloropyridine-6-carbamate to obtain carbamate of formula 3 or 4, which was treated with phenyl Grignard reagent in a suitable solvent Ethyl (S)-[6-amino-4-[(1-methyl-2-oxo-2-phenylethyl) amino] -5-nitro-2-pyridinyl] carbamate or ethyl (R)-[6 -Amino-4-[(1-methyl-2-oxo-2-phenylethyl) amino] -5-nitro-2-pyridinyl] carbamate And, by means of reducing cyclization with Raney nickel and reacting the product obtained with a pharmaceutically acceptable acid, if a pharmaceutically acceptable salt is required. 1,2-dihydro-2-methyl-3-phenylpyrido [3,4-b] pyrazin-7-yl) carbamate and ethyl (+)-(R)-(5-amino-1,2 -Dihydro-2-methyl-3-phenylpyrido [3,4-b] pyrazin-7-yl) carbamate and a pharmaceutically acceptable salt thereof. A compound according to claim 1, wherein (S)-[6-amino-4-[(1-methyl-2-oxo-2-phenylethyl) amino] -5-nitro-2-pyridinyl] carbamate or ethyl ( R)-[6-amino-4-[(1-methyl-2-oxo-2-phenylethyl) amino] -5-nitro-2-pyridinyl] carbamate is reduced ring in acetic acid in the presence of Raney nickel To obtain the desired product as an acetate. A compound according to claim 1, wherein (S)-[6-amino-4-[(1-methyl-2-oxo-2-phenylethyl) amino] -5-nitro-2-pyridinyl] carbamate or ethyl ( R)-[6-amino-4-[(1-methyl-2-oxo-2-phenylethyl) amino] -5-nitro-2-pyridinyl] carbamate is reduced ring in ethanol in the presence of Raney nickel To obtain the desired product as the free base. The equimolar amount of ethyl (-)-(S)-(5-amino-1,2-dihydro-2-methyl-3-phenylpyrido [3,4-b] pyrazine-7- 1) Carbamate and methanol solution of isethionic acid were reacted to give ethyl (-)-(S)-(5-amino-1,2-dihydro-2-methyl-3-phenylpyrido [3,4 -b] a method of obtaining isethionate of pyrazin-7-yl) carbamate.