JPH11322706A - New amino acid derivative and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce a new compound which is an important intermediate for producing medicines such as an antimicrobial agent or an antifungal agent. SOLUTION: This compound is represented by formula I [R is H or an ester- forming group; R<1> is a cycloalkylmethylthio, a (substituted)pyridyl or the like; R<2> and R<3> are each H or methyl ; Boc is tertiary butoxycarbonyl], e.g. methyl 2-(S)-[(t-butoxycarbonyl)amino]-3-[8-(4-methoxyphenylmethoxy)quinolin-5- yl]propionate. The compound is preferably produced by reacting a compound represented by the formula R<4> X [R<4> is a (substituted)pyridine, a (substituted) naphthyl or the like; X is a halogen] with a compound represented by formula II [R<5> is H, phenacyl, N-phthalimidomethyl or the like], as necessary, in the presence of zinc and a palladium complex and then hydrolyzing the resultant compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel amino acid useful as an important intermediate for the production of unnatural amino acids and peptides for antibacterial agents, antifungal agents or other pharmaceuticals, and to a method for producing the same.

[0002]

2. Description of the Related Art Pharmaceutical products using non-natural amino acid derivatives as synthetic intermediates include, for example, antifungal agents (Bio-Organic Medicinal Chemistry Letters, No. 3).
Vol., 1079-1084, 1993), etc., but the present invention relates to novel amino acid derivatives structurally different from these derivatives.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide an intermediate material required for synthesizing a drug using a novel amino acid derivative as an intermediate.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies on a novel amino acid derivative which is an intermediate material for pharmaceutical synthesis, and as a result, have found that the following general formula (1) is useful as an intermediate. The present invention has been completed. That is, the present invention provides a compound represented by the general formula (1): Wherein R is a hydrogen atom or an ester-forming group, and R ¹ is
A cycloalkylmethylthio group, or, respectively, an optionally substituted pyridyl group, naphthyl group, quinolyl group, pyridylthio group, pyridylmethylthio group, pyrimidinylthio group, quinazolinylthio group, naphthylmethylthio group, quinolylmethylthio group, phenyl A methylthio group or a lower alkylthio group, and R ² and R ³ are the same or different and each represent a hydrogen atom or a methyl group]. In the present invention, Boc represents a tertiary butoxycarbonyl group.

[0005] Examples of the "cycloalkylmethylthio group" include C4-C7 cyclic alkylmethylthio groups such as cyclopropylmethylthio, cyclobutylmethylthio, cyclopentylmethylthio, and cyclohexylmethylthio.

"A pyridyl group, a naphthyl group, a quinolyl group, a pyridylthio group, a pyridylmethylthio group, a pyrimidinylthio group, a quinazolinylthio group, which may have a substituent,
"Naphthylmethylthio group, quinolylmethylthio group, phenylmethylthio group, pyridylmethyl group, naphthylmethyl group, quinolylmethyl group, phenylmethyl group, pyrimidinyl group, quinazolinyl group" include one or two hydroxyl groups, methyl groups, tertiary groups. A butoxycarbonyloxy group, a 4-methoxyphenylmethoxy group, a nitro group, an amino group, an acetylamino group, a tert-butoxycarbonylamino group, a tridecanoylamino group, a 4-methoxyphenylmethoxycarbonyl group, a carboxyl group, and the like. Pyridyl group, naphthyl group, quinolyl group, pyridylthio group, pyridylmethylthio group, naphthylmethylthio group, quinolylmethylthio group, phenylmethylthio group,
Examples include a pyridylmethyl group, a naphthylmethyl group, a quinolylmethyl group, a phenylmethyl group, a pyrimidinyl group, and a quinazolinyl group. "It may have a substituent,
As the "lower alkylthio group", straight-chain or branched ones having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, and a butyl group which may have a hydroxyl group, a tertiary butoxycarbonyloxy group, and the like. Can be mentioned.

[0007] The "optionally substituted lower alkyl group" refers to a direct alkyl group such as a methyl group, an ethyl group, a propyl group or a butyl group which may have a hydroxyl group, a tertiary butoxycarbonyloxy group or the like. Examples thereof include a chain or a branched lower alkyl group having 1 to 4 carbon atoms.

The "halogen atom" includes fluorine, chlorine, bromine and iodine atoms.

Examples of the "cycloalkylmethyl group" include C4-C7 cyclic alkylmethyl groups such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

In the case of a pyridyl group, a pyridylthio group, a pyridylmethylthio group, a pyridylmethyl group, a pyrimidinylthio group, a pyrimidinyl group, a quinazolinylthio group, and a quinazolinyl group having a hydroxyl group, their tautomers are also included. .

According to the present invention, the compounds included in the general formula (1) can be synthesized by the methods shown in the following formulas A to D.

A: The compound represented by the formula (1-a) can be prepared by a method described in the literature (Journal of Organic Chemistry, Vol. 57, pp. 3397-3404, 19).
1991 and Vol. 60, pp. 2640-2641, 199
5 years). That is, (3-
a) Active zinc is allowed to act on an organic solvent such as N, N-dimethylformamide, tetrahydrofuran, benzene, N, N-dimethylacetamide or a mixed solvent thereof at room temperature to reflux of the solvent, and then triphenylphosphine is added to a). After adding a phosphine ligand such as tris (O-tolyl) phosphine and a zero-valent or divalent palladium complex, (2-a) is further allowed to act in the same solvent in the same temperature range, thereby obtaining a cup. A ring body (4) is obtained. (4) is a general hydrolysis condition for amino acid esters, that is, hydrolysis with an alkali such as sodium hydroxide or lithium hydroxide, or, in the case of phenacyl ester, a metal-acid such as zinc-acetic acid. (1-a) can be set according to reducing conditions such as acting. Formula A Wherein R ⁴ is a pyridyl group, a naphthyl group, or a quinolyl group which may have a substituent, X is a halogen atom, R ⁵ is a lower alkyl group, a phenacyl group or N
-Represents a phthalimidomethyl group. ]

B: The compound represented by the general formula (1-b) is obtained by converting (3-b) to water or tetrahydrofuran,
An alkyl halide is allowed to act at 0 ° C. to room temperature in an organic solvent such as -dioxane, N, N-dimethylformamide, or a mixed solvent thereof in the presence of an alkali such as sodium hydroxide; After being converted to a sodium salt (for example, an S-trityl derivative is converted to a thiosilver salt with silver nitrate, and then reacted with sodium iodide in an organic solvent such as N, N-dimethylformamide to form a thiosodium salt in the system. Salt can be formed), an organic solvent such as tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, or a mixed solvent thereof at 0 ° C. to 50 ° C., preferably at room temperature. To decompose the ester in the same manner as in the method for obtaining (1-a) to obtain an ester.

When R ⁶ is an aromatic ring, the method described in the literature (Tetrahedron Letters, Vol. 36, No. 4,
(P. 133, 1995), the corresponding (1-b) can also be obtained. That is, (3-
b) and (2-b) (preferably X = I) in an inert solvent such as 1-methyl-2-pyrrolidone, and 1,1′-bis (diphenylphosphino) ferrocene as a ligand Using a zero-valent or divalent palladium complex, a coupled product produced as a result of reacting at 0 ° C. to the solvent reflux temperature can be obtained by decomposing the ester in the same manner as in the method of obtaining (1-a). . Formula B [Wherein R ² and R ³ are the same or different and each represent a hydrogen atom or a methyl group; R ⁵ represents a lower alkyl group, a phenacyl group or an N-phthalimidomethyl group; R ⁶ represents a cycloalkylmethyl group or And pyridyl, pyridylmethyl, naphthylmethyl, quinolylmethyl, phenylmethyl, and lower alkyl, each of which may have a substituent, and X represents a halogen atom. ]

C: The compound represented by the general formula (1-c) can be prepared by a method described in a literature (Tetrahedron Letters, No. 35).
Vol., Pp. 7605-7608 (1994)). That is, (2-c) is converted to tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, methanol, ethanol,
After reacting a base such as sodium hydride or sodium alkoxide in an organic solvent such as butanol or a mixed solvent thereof, it can be obtained by reacting (3-c) at 0 ° C. to a solvent reflux temperature. . Formula C [Wherein R ⁷ represents a pyrimidinyl group or a quinazolinyl group which may have a substituent. ]

D: The compound represented by the general formula (1-e) is obtained by using the compound (1-d) synthesized by the method of the formula B and reducing the nitro group by a general method, ie, catalytic hydrogen reduction. By converting the amino group into a carbamate or an amide using a carbonic acid ester, an acid anhydride or an acid halide, and decomposing the ester in the same manner as in the method for obtaining (1-a). ,Obtainable. Formula D [Wherein R ² , R ³ , and R ⁵ are as described above, and R ⁸ represents hydrogen, an acetyl group, a tridecanoyl group, or a tert-butoxycarbonyl group. ]

[0017]

Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.
The abbreviations used in the examples have the following meanings. ¹ H NMR proton nuclear magnetic resonance spectrum MS electron impact ionization mass spectrometry MS (FAB) fast atom bombardment mass spectrometry CDCl ₃ deuterated chloroform d ₆ -DMSO deuterated dimethyl sulfoxide

Example 1 2- (S)-[(t-butoxycarbonyl) amino]-
Synthesis of methyl 3- [8- (4-methoxyphenylmethoxy) quinolin-5-yl] propionate

In a suspension of zinc powder (409 mg) in tetrahydrofuran (1.25 ml) under an argon stream, 1,2-dibromoethane (28 μl) was added at 60 ° C., stirred for 5 minutes, brought to room temperature, and trimethylsilyl was added. Chloride (38
μl) was added. After stirring for 15 minutes, the temperature was again raised to 60 ° C.
-(R)-[(t-butoxycarbonyl) amino] -3
A mixed solution of methyl-iodopropionate (921 mg) in tetrahydrofuran (3.1 ml) and dimethylacetamide (3.1 ml) was added, and the mixture was stirred for 30 minutes. After addition of bis (tri-o-tolylphosphine palladium) dichloride (123 mg), 5-iodo-8- (4-methoxyphenylmethoxy) quinoline (1.17 g) in tetrahydrofuran (4.1 ml) and dimethylacetamide ( 1 ml), and the mixture was stirred at 60 ° C. for 1 hour, diluted with ethyl acetate, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: hexane: ethyl acetate =
Purification by 1: 1) afforded the title compound. Yield: 524 mg, yield: 37% Yellow amorphous MS (m / z): 466 (M ⁺ )

Example 2 2- (S)-[(t-butoxycarbonyl) amino]-
Synthesis of 3- [8- (4-methoxyphenylmethoxy) quinolin-5-yl] propionic acid

Methyl 2- (S)-[(t-butoxycarbonyl) amino] -3- [8- (4-methoxyphenylmethoxy) quinolin-5-yl] propionate (52
0 mg) in tetrahydrofuran (6 ml) at 0 ° C. was added with 1N sodium hydroxide (2.3 ml).
Methanol (3 ml) was added. After stirring at the same temperature for 30 minutes, ice water (100 ml) was poured, the pH was adjusted to about 5 with a 2N aqueous sodium hydrogen sulfate solution, and ethyl acetate was extracted. The organic layer was washed with saturated saline, dried over sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: methylene chloride: methanol =
10: 1) to give the title compound. Yield 128
mg, 25% yield

¹ H-NMR (d ₆ -DMSO) δ (pp
m): 1.27 (9H, s), 3.14 (1H, dd, J
= 7.3, 14.2 Hz), 3.44-3.60 (1H,
m), 3.76 (3H, s), 3.84-4.00 (1
H, m), 5.15 (2H, brs), 6.96 (2H,
d, J = 8.8 Hz), 7.15 (1H, d, J = 8.8)
Hz), 7.29-7.39 (1H, m), 7.44 (2
H, d, J = 8.8 Hz), 7.50 (1H, dd, J =
4.4, 8.8 Hz), 8.55 (1H, d, J = 8.8)
Hz), 8.80 (1H, d, J = 2.9 Hz)

Example 3 2- (S)-[(t-butoxycarbonyl) amino]-
Synthesis of methyl 3- [3- (4-methoxyphenylmethoxy) -6-methylpyridin-2-yl] propionate

As in Example 1, 2- (R)-[(t-
Butoxycarbonyl) amino] -3-iodopropionate methyl (866 mg) and 2-iodo-3- (4-methoxyphenylmethoxy) -6-methylpyridine (1.0
0 g) to give the title compound. Yield: 575 mg, 47% Yield: yellow oil MS (m / z): 430 (M ⁺ )

Example 4 2- (S)-[(t-butoxycarbonyl) amino]-
Synthesis of 3- [3- (4-methoxyphenylmethoxy) -6-methylpyridin-2-yl] propionic acid

In the same manner as in Example 2, 2- (S)-
[(T-butoxycarbonyl) amino] -3- [3-
The title compound was synthesized using methyl (4-methoxyphenylmethoxy) -6-methylpyridin-2-yl] propionate (0.57 g). 439 mg, 80% yield, pale yellow powder

¹ H-NMR (d ₆ -DMSO) δ (pp
m): 1.33 (9H, s), 2.34 (3H, s),
3.03 (1H, dd, J = 7.8, 14.7 Hz),
3.12 (1H, dd, J = 5.9, 14.7 Hz),
3.75 (3H, s), 4.50 (1H, m), 5.0
3 (2H, s), 6.89 (1H, d, J = 8.3H
z), 6.93 (2H, d, J = 8.8 Hz), 7.25
(1H, d, J = 8.3 Hz), 7.31 (1H, d, J
= 8.3 Hz), 7.46 (2H, d, J = 8.8 Hz)

Example 5 2- (R)-[(t-butoxycarbonyl) amino]-
Synthesis of 3- [4-quinazolinone-2-ylthio] propionic acid

Under an argon stream, sodium hydride (60
% Oil suspension (2.10 g) in N, N-dimethylformamide suspension (10 ml) in 2-mercapto-4 (3H).
A solution of -quinazolinone (9.80 g) in N, N-dimethylformamide (50 ml) was added dropwise over 20 minutes under ice cooling. After stirring at the same temperature for 1 hour, the reaction solution was added to a solution of N- (t-butoxycarbonyl) -L-serine β-lactone (936 mg) in N, N-dimethylformamide (10 ml) under an argon stream. It was added under ice cooling. After stirring at the same temperature for 1 hour, the mixture was neutralized with 1N phosphoric acid and the solvent was distilled off. Methanol was added to the residue, and the insolubles were filtered. The filtrate was concentrated under reduced pressure to 1/3 volume, silica gel was added and concentrated under reduced pressure, and this was put on silica gel column chromatography and eluted with a methylene chloride-methanol mixture to obtain the title compound. 468 mg, 26% yield FAB (+) MS (m / z): 366 [(M +
H) ⁺ ]

Example 6 2- (R)-[(t-butoxycarbonyl) amino]-
Synthesis of 3- [4-pyrimidinone-2-ylthio] propionic acid

Using 2-mercaptouracil (7.05 g), as in Example 5, 2- (R)-[(t-butoxycarbonyl) amino] -3- [4-pyrimidinone-
[2-ylthio] propionic acid was synthesized. FAB (-) MS (m / z): 314 [(M-
H) ^- ]

Example 7 2- (R)-[(t-butoxycarbonyl) amino]-
Synthesis of phenacyl 3- [5- (4-methoxyphenylmethoxycarbonyl) pyridin-2-yl] thiopropionate

In a mixed solvent of N- (t-butoxycarbonyl) -S-triphenylmethyl-L-cysteinephenacyl ester (47.2 g) in tetrahydrofuran (141 ml) -methanol (236 ml), pyridine (663 ml) was added at room temperature. ) And an aqueous solution of silver nitrate (16.5 g) (880)
ml) was added. After stirring at room temperature for 2 hours, the precipitated white crystals were collected by filtration, washed with methanol and diisopropyl ether, dried, and dried with silver N- (t-butoxycarbonyl) -L-cysteinephenacyl ester (33.
3 g) was obtained. Yield 92% 2-chloro-5- (4-methoxyphenylmethoxycarbonyl) was added to a solution of the silver salt (10.0 g) obtained here and sodium iodide (3.36 g) in N, N-dimethylformamide (45 ml). ) N, N of pyridine (5.10 g)
-Dimethylformamide solution (45 ml) was added. 60
After stirring at 12 ° C. for 12 hours, the mixture was poured into ice water and extracted with methylene chloride. The organic layer was filtered through celite, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methylene chloride: hexane = 10: 1) to obtain the title compound. Yield 3.28 g (25% yield from intermediate silver salt)

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.39 (9H, s), 3.76 (1H, dd, J =
7.8, 14.2 Hz), 3.82 (3H, s), 3.9
4 (1H, dd, J = 4.4, 14.2 Hz), 4.72
-4.78 (1H, m), 5.29 (1H, d, J = 1
6.6 Hz), 5.30 (2H, s), 5.54 (1H,
d, J = 16.6 Hz), 6.10 (1H, d, J = 7.
3 Hz), 6.91 (2H, d, J = 8.8 Hz), 7.2
7 (1H, d, J = 7.8 Hz), 7.37 (2H, d,
J = 8.8 Hz), 7.50 (2H, t, J = 7.8H)
z), 7.62 (1H, t, J = 7.8 Hz), 7.90
(2H, d, J = 7.8 Hz), 8.06 (1H, dd,
J = 2.4, 7.8 Hz), 9.03 (1H, d, J =
2.4Hz)

Example 8 2- (R)-[(t-butoxycarbonyl) amino]-
Synthesis of 3- [5- (4-methoxyphenylmethoxycarbonyl) pyridin-2-yl] thiopropionic acid

Phenacyl 2- (R)-[(t-butoxycarbonyl) amino] -3- [5- (4-methoxyphenylmethoxycarbonyl) pyridin-2-yl] thiopropionate (3.28 g) in acetic acid ( To a solution of (59 ml) -water (5.9 ml) was added zinc powder (5.9 g).
Stirred at room temperature for 1 hour. The reaction solution was filtered through celite, and the filtrate was extracted with ether. The organic layer was washed with brine, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methylene chloride: methanol = 20: 1) to give the title compound. . Yield 548mg, 21% colorless oil

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.39 (9H, s), 3.58-3.63 (1H,
m), 3.78-3.82 (1H, m), 4.61 (1
H, brs), 5.295-5.301 (2H, 2s),
6.11 (1H, brs), 6.91 (2H, d, J = 8.
8 Hz), 7.26 (1H, d, J = 8.3 Hz), 7.3
7 (2H, d, J = 8.8 Hz), 8.06 (1H, d
d, J = 2.4, 8.3 Hz), 9.00 (1H, d, J
= 2.4Hz)

Example 9 2- (R)-[(t-butoxycarbonyl) amino]-
Synthesis of N-phthalamidomethyl 3- (5-nitropyridin-2-yl) thiopropionate

To a solution of N- (t-butoxycarbonyl) -S-triphenylmethyl-L-cysteine-N-phthalimidomethyl ester (26.0 g) in tetrahydrofuran (100 ml) was added pyridine (3.63 g) and silver nitrate at room temperature. (7.80 g) aqueous solution (70 ml)
Stir at room temperature for 3 hours. Water (150 ml) was added to the reaction solution, and the supernatant was removed by centrifugation. The precipitate was washed successively with ethanol and a mixed solution of ethanol-isopropyl ether (1: 1), dried in vacuo, and dried to give N- (white crystals). (t-butoxycarbonyl) -L-cysteine-N-phthalimide methyl ester silver salt (13.0 g) was obtained. Yield 64% N, N-dimethylformamide (12%) of the silver salt (13.0 g) obtained here and sodium iodide (4.40 g).
0 ml) solution, 2-chloro-5-nitropyridine (4.65 g) was added, and the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the residue obtained by concentration to dissolve the residue, which was washed with saturated saline, dried over sodium sulfate, and concentrated. The obtained residue was recrystallized from a mixed solution of ethyl-n-hexane to obtain the title compound. 6.30 g (47% yield from intermediate silver salt) pale yellow powder MS (m / z): 502 (M ⁺ )

Example 10 2- (R)-[(t-butoxycarbonyl) amino]-
Synthesis of 3- (5-nitropyridin-2-yl) thiopropionic acid

2- (R)-[(t-butoxycarbonyl) amino] -3- (5-nitropyridin-2-yl)
N-phthalimidomethyl thiopropionate (2.00
Using g), the title compound was synthesized in the same manner as in Example 2. Yield 770 mg, yield 56% Yellow viscous crystals MS (m / z): 343 (M ⁺ )

Example 11 2- (R)-[(t-butoxycarbonyl) amino]-
Synthesis of phenacyl 3- [5- (t-butoxycarbonyloxy) pyridin-2-yl] methylthiopropionate

The title compound was synthesized in the same manner as in Example 7 using 2-chloromethyl-5- (t-butoxycarbonyloxy) pyridine (0.884 g). Yield 1.09 g (65% yield from intermediate silver salt) pale yellow powder

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.47 (9H, s), 1.55 (9H, s), 3.0
5 (1H, dd, J = 6.8, 14.2 Hz), 3.17
(1H, dd, J = 4.4, 14.2 Hz), 3.91
(1H, d, J = 14.2 Hz), 3.95 (1H, d,
J = 14.2 Hz), 4.69-4.74 (1H, m),
5.33 (1H, d, J = 16.1 Hz), 5.47 (1
H, d, J = 16.1 Hz), 5.88 (1H, d, J =
7.3 Hz), 7.39 (1H, d, J = 8.8 Hz),
7.47-7.59 (3H, m), 7.61 (1H,
t, J = 7.3 Hz), 7.90 (2H, d, J = 8.3)
Hz), 8.43 (1H, d, J = 2.4 Hz)

Example 12 2- (R)-[(t-butoxycarbonyl) amino]-
Synthesis of 3- [5- (t-butoxycarbonyloxy) pyridin-2-yl] methylthiopropionic acid

The reaction was carried out using phenacyl 2- (R)-[(t-butoxycarbonyl) amino] -3- [5- (t-butoxycarbonyloxy) pyridin-2-yl] methylthiopropionate (1.02 g). The title compound was synthesized in the same manner as in Example 8. Yield: 715 mg, 89% colorless foam

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.45 (9H, s), 1.56 (9H, s), 2.9
8-3.03 (2H, m), 3.92 (1H, d, J =
14.7 Hz), 4.02 (1H, d, J = 14.7H)
z), 4.50-4.53 (1H, m), 5.78 (1
H, d, J = 7.3 Hz), 7.42 (1H, d, J =
8.3 Hz), 7.61 (1H, dd, J = 2.4,8.
3 Hz), 8.46 (1H, d, J = 2.4 Hz)

Example 13 2- (R)-[(t-butoxycarbonyl) amino]-
3- [4,5-bis (4-methoxyphenylmethoxy)
Synthesis of phenacyl-2-pyridin-2-yl] methylthiopropionate

The title compound was synthesized in the same manner as in Example 7 using 2-chloromethyl-4,5-bis (4-methoxyphenylmethoxy) pyridine (2.11 g). 2.19 g, 59% light red foam

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.46 (9H, s), 2.99 (1H, dd, J =
6.8, 14.2 Hz), 3.10 (1H, dd, J =
4.4, 14.2 Hz), 3.79 (3H, s), 3.8
0 (1H, d, J = 13.2 Hz), 3.81 (3H,
s), 3.85 (1H, d, J = 13.2 Hz), 4.5
6-4.68 (1H, m), 5.06 (2H, s),
5.13 (2H, s), 5.30 (1H, d, J = 1
6.6 Hz), 5.47 (1H, d, J = 16.6 Hz),
6.00 (1H, d, J = 7.3 Hz), 6.86 (2
H, d, J = 8.8 Hz), 6.90 (2H, d, J =
8.8 Hz), 6.98 (1H, s), 7.31 (2H,
d, J = 8.8 Hz), 7.35 (2H, d, J = 8.8)
Hz), 7.47 (2H, t, J = 7.3 Hz), 7.61
(1H, t, J = 7.3 Hz), 7.88 (2H, d, J
= 7.3 Hz), 8.09 (1H, s)

Example 14 2- (R)-[(t-butoxycarbonyl) amino]-
3- [4,5-bis (4-methoxyphenylmethoxy)
Synthesis of [pyridin-2-yl] methylthiopropionic acid

Phenacyl 2- (R)-[(t-butoxycarbonyl) amino] -3- [4,5-bis (4-methoxyphenylmethoxy) pyridin-2-yl] methylthiopropionate (2.19 g) And the title compound was synthesized in the same manner as in Example 8. 1.17 g, 63% colorless foam

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.43 (9H, s), 2.96 (1H, dd, J =
6.4, 13.6 Hz), 3.03 (1H, dd, J =
3.9, 13.6 Hz), 3.79 (3H, s), 3.8
07 (1H, d, J = 13.7 Hz), 3.814 (3
H, s), 3.98 (1H, d, J = 14.7 Hz),
4.33-4.44 (1H, m), 5.04 (2H,
s), 5.14 (2H, s), 6.86 (2H, d, J
= 8.3 Hz), 6.91 (2H, d, J = 8.3 Hz),
6.98 (1H, s), 7.30 (2H, d, J = 8.
3 Hz), 7.33 (2H, d, J = 8.3 Hz), 8.1
1 (1H, s)

Example 15 2- (R)-[(t-butoxycarbonyl) amino]-
Synthesis of 3- [2- (t-butoxycarbonyloxy) phenyl] methylthio-3,3-dimethylpropionic acid

N- (t-butoxycarbonyl) -L-penicillamine (3.00 g) and 2-bromomethyl-t-
To a solution of butoxycarbonyloxybenzene (3.58 g) in N, N-dimethylformamide (30 ml) was added a 1N aqueous sodium hydroxide solution (30 ml) under ice-cooling. After the temperature was adjusted to room temperature, the mixture was stirred for 1 hour, poured into ice water, adjusted to about pH 4 with an aqueous sodium hydrogen sulfate solution, and extracted with ether. The organic layer was washed with water and saturated saline, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methylene chloride: methanol = 20: 1) to give the title compound. Obtained. 4.63 g, 85% yield, colorless amorphous

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.39 (3H, s), 1.45 (12H, s), 1.
56 (9H, s), 3.76 (1H, d, J = 11.7)
Hz), 3.84 (1H, d, J = 11.7 Hz), 4.4
0 (1H, brs), 5.48 (1H, brs), 7.10 −
7.20 (2H, m), 7.22-7.30 (1H,
m), 7.37 (1H, d, J = 7.8 Hz)

Examples 16 to 22 In the same manner as in Example 15, using the corresponding halides, the compounds shown in Tables 1 and 2 were obtained.

[0058]

[Table 1]

[0059]

[Table 2]

Example 24 2- (R)-[(t-butoxycarbonyl) amino]-
Synthesis of phenacyl 3- [5- (t-butoxycarbonyloxy) pyridin-2-yl] thio-3,3-dimethylpropionate

5- (t-butoxycarbonyloxy)-
In a solution of 2-iodopyridine (1.16 g) in N-methylpyrrolidone (7 ml), tris (dibenzylideneacetone) dipalladium (66.2 mg), diphenylphosphinoferrocene (160 mg) and triethylamine (1.
01 ml) at room temperature. After stirring at the same temperature for 20 minutes, a solution of Nt-butoxycarbonyl-L-penicillamine phenacyl ester (1.33 g) in N-methylpyrrolidone (3 ml) was added at room temperature. 1 hour at 60 ° C,
After stirring at 70 ° C. for 2 hours, the reaction solution was poured into water,
Extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 4: 1) to give the title compound. Obtained. FAB (+) MS (m / z): 561 [(M +
H) ⁺ ]

Example 25 2- (R)-[(t-butoxycarbonyl) amino]-
Synthesis of 3- [5- (t-butoxycarbonyloxy) pyridin-2-yl] thio-3,3-dimethylpropionic acid

Phenacyl 2- (R)-[(t-butoxycarbonyl) amino] -3- [5- (t-butoxycarbonyloxy) pyridin-2-yl] thio-3,3-dimethylpropionate (1. Example 8 using 25g)
The title compound was obtained in the same manner as described above. 820 mg yield, 83% colorless amorphous

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.30 (3H, s), 1.37 (3H, s), 1.4
0 (9H, s), 1.57 (9H, s), 4.63 (1
H, d, J = 9.0 Hz), 5.77 (1H, d, J =
9.0 Hz), 7.46 (1H, dd, J = 4.9, 8.
3 Hz), 7.69 (1H, dd, J = 1.5, 8.3H)
z), 8.52 (1H, dd, J = 1.5, 4.9 Hz)

Example 26 2- (R)-[(t-butoxycarbonyl) amino]-
Synthesis of N-phthalimidomethyl 3- (5-aminopyridin-2-yl) thiopropionate

2- (R)-[(t-butoxycarbonyl) amino] -3- (5-nitropyridin-2-yl)
N-phthalimidomethyl thiopropionate (8.20
g) in acetic acid (150 ml), 10% palladium on carbon (2.80 g) was added, and the mixture was added under a stream of hydrogen (3.0 kgf / c
m ² ) and stirred at room temperature for 8 hours. After completion of the reaction, the reaction solution was filtered through celite, and washed with ethyl acetate. After adding a saturated saline solution (200 ml) to the filtrate, an aqueous sodium hydrogen carbonate solution was added to neutralize the filtrate. Separate the ethyl acetate layer,
The extract was washed with an aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: hexane: ethyl acetate = 1: 1).
Purification in 1) gave the title compound. 5.55 g, 72% yield, yellow amorphous

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.39 (9H, s), 3.41 (1H, dd, J =
4.1, 14.4 Hz), 3.52 (1H, dd, J =
6.6, 14.4 Hz), 3.71 (2H, brs), 4.4
6-4.58 (1H, m), 5.71 (1H, d, J =
10.7 Hz), 5.76 (1H, d, J = 9.8 Hz),
6.69 (1H, d, J = 6.8 Hz), 6.86 (1
H, dd, J = 2.9, 8.3 Hz), 7.00 (1H,
d, J = 8.3 Hz), 7.79 (2H, dd, J = 2.
9, 5.4 Hz), 7.92 (2H, dd, J = 2.9,
5.4 Hz), 7.95 (1H, d, J = 2.9 Hz)

Example 27 2- (R)-[(t-butoxycarbonyl) amino]-
Synthesis of N-phthalimidomethyl 3- [5- (t-butoxycarbonyl) aminopyridin-2-yl] thiopropionate

2- (R)-[(t-butoxycarbonyl) amino] -3- (5-aminopyridin-2-yl)
N-phthalimidomethyl thiopropionate (1.90
g) in acetonitrile (50 ml) solution.
-Butyl (910 mg) and N, N-dimethylaminopyridine (100 mg) were added at room temperature. After stirring overnight at room temperature, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent hexane: ethyl acetate = 1: 1).
Purification in 1) gave the title compound. Yield: 770 mg, 33% colorless amorphous FAB (+) MS (m / z): 5
73 [(M + H) ⁺ ]

Example 28 2- (R)-[(t-butoxycarbonyl) amino]-
Synthesis of 3- [5- (t-butoxycarbonyl) aminopyridin-2-yl] thiopropionic acid

2- (R)-[(t-butoxycarbonyl) amino] -3- [5- (t-butoxycarbonyl)
In a solution of N-phthalimidomethyl thiopropionate (2.38 g) in tetrahydrofuran (40 ml) was added a 2N aqueous solution of sodium hydroxide (1.
00 ml) at room temperature. The mixture was stirred at room temperature for 5 hours, allowed to stand overnight, and made weakly acidic (about pH = 4) with 2N hydrochloric acid.
Extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent hexane: ethyl acetate = 2: 1 → 5: 3) to give the title. The compound was obtained. Yield 1.20 g, yield 70% colorless amorphous FAB (+) MS (m / z): 4
13 [(M + H) ⁺ ]

Example 29 2- (R)-[(t-butoxycarbonyl) amino]-
Synthesis of N-phthalimidomethyl 3- (5-acetamidopyridin-2-yl) thiopropionate

2- (R)-[(t-butoxycarbonyl) amino] -3- (5-aminopyridin-2-yl)
N-phthalimidomethyl thiopropionate (5.30
g) was added to a solution of acetic anhydride (50 ml) and stirred at room temperature for 5 hours. The reaction solution was added with water (200 ml) and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. Ethanol was added to the residue, and the mixture was concentrated again under reduced pressure to quantitatively obtain the crude title compound. Crude yield 5.85 g (quantitative) Yellow amorphous

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.38 (9H, s), 2.17 (3H, s), 3.4
0-3.64 (2H, m), 4.50-4.65 (1
H, m), 5.65-5.85 (2H, m), 6.36.
(1H, d, J = 7.3 Hz), 7.07 (1H, d, J
= 8.8 Hz), 7.72-8.00 (5H, m), 8.
08 (1H, s), 8.47 (1H, s)

Example 30 2- (R)-[(t-butoxycarbonyl) amino]-
Synthesis of 3- (5-acetamidopyridin-2-yl) thiopropionic acid

In the same manner as in Example 28, 2- (R)
-[(T-butoxycarbonyl) amino] -3- (5-
Acetamidopyridin-2-yl) thiopropionic acid N
-The title compound was obtained using phthalimidomethyl (3.32 g). 1.31 g, 57% yield, pale yellow amorphous FAB (+) MS (m / z):
356 [(M + H) ⁺ ]

Example 31 2- (R)-[(t-butoxycarbonyl) amino]-
Synthesis of N-phthalimidomethyl 3- (5-tridecanamidopyridin-2-yl) thiopropionate

After heating a solution of tridecanoic acid (1.85 g) in thionyl chloride (30 ml) under reflux for 3 hours, thionyl chloride was distilled off under reduced pressure, a small amount of benzene was added, and the mixture was again distilled under reduced pressure. Tetrahydrofuran (20 ml) was added to the residue, and this was added to 2- (R)-[(t-butoxycarbonyl) amino] -3- (5-aminopyridin-2-yl).
N-phthalimidomethyl thiopropionate (4.00
g) and triethylamine (4.54 g) were added dropwise to a solution of tetrahydrofuran (30 ml) with ice cooling. After stirring at room temperature for 5 hours, saturated saline was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 3: 2) to obtain the title compound. . 4.15 g, 73% yield, pale yellow crystals

¹ H-NMR (CDCl ₃ ) δ (ppm):
0.88 (3H, t, J = 6.8 Hz), 1.15-1.
48 (27H, m), 1.61-1.80 (2H,
m), 2.37 (2H, t, J = 7.6 Hz), 3.52
(1H, dd, J = 4.2, 14.2 Hz), 3.62
(1H, dd, J = 6.6, 14.2 Hz), 4.50-
4.62 (1H, m), 5.67-5.84 (2H,
m), 7.12 (1H, d, J = 8.3 Hz), 7.74
−7.85 (2H, m), 7.85−8.04 (3H,
m), 8.39 (1H, d, J = 2.0 Hz)

Example 32 2- (R)-[(t-butoxycarbonyl) amino]-
Synthesis of 3- (5-tridecanamidopyridin-2-yl) thiopropionic acid

In the same manner as in Example 28, 2- (R)
-[(T-butoxycarbonyl) amino] -3- (5-
The target compound was obtained using N-phthalimidomethyl tridecaneamidopyridin-2-yl) thiopropionate (3.98 g). 2.70 g, 89% yield pale yellow oil FAB (+) MS (m / z): 510
[(M + H) ⁺ ]

Example 33 2- (R)-[(t-butoxycarbonyl) amino]-
3- (5-nitropyridin-2-yl) thio-3,3-
Synthesis of methyl dimethyl propionate

The 2- (R)-[(t-butoxycarbonyl) amino] -3- (5-nitropyridin-2-yl) thio-3,3-dimethylpropionic acid (112 g) obtained in Example 22 was used. N, N-dimethylformamide (500
ml), potassium carbonate (83.4 g) and iodomethane (85.6 g) were added, and the mixture was stirred at room temperature for 8 hours. After standing overnight, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, and insolubles were removed by filtration. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: hexane: ethyl acetate = 3: 1 → 2: 1 → 1:
Purification in 1) gave the title compound. 30.6 g, 26% yield, pale yellow oil

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.43 (9H, s), 1.65 (3H, s), 1.6
7 (3H, s), 3.71 (3H, s), 4.98 (1
H, d, J = 8.3 Hz), 6.60 (1H, d, J =
8.3 Hz), 7.30 (1H, d, J = 8.8 Hz),
8.23 (1H, dd, J = 2.4, 8.8 Hz);
28 (1H, d, J = 2.4 Hz)

Example 34 2- (R)-[(t-butoxycarbonyl) amino]-
3- (5-aminopyridin-2-yl) thio-3,3-
Synthesis of methyl dimethyl propionate

2- (R)-[(t-butoxycarbonyl) amino] -3- (5-nitropyridin-2-yl)
Methyl thio-3,3-dimethylpropionate (30.4
g) was dissolved in ethyl acetate (300 ml) -acetic acid (100 ml), 10% palladium carbon (4.70 g) was added thereto, and the mixture was stirred at room temperature for 6 hours under a hydrogen stream (4 kgf / cm ² ). Thereafter, 10% palladium carbon (1.00 g) and acetic acid (50 ml) were added, and the mixture was further stirred at the same pressure for 8 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, water was added to the residue, neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: hexane: ethyl acetate =
1: 3) to give the title compound. Yield 14.0 g, Yield 50% Black oil

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.46, 1.47, 1.51 (15H, 3s),
74 (3H, s), 4.30 (1H, d, J = 7.8H)
z), 6.89 (1H, dd, J = 2.4, 8.3H
z), 7.27 (1H, d, J = 8.3 Hz), 7.68
(1H, d, J = 7.8 Hz), 8.04 (1H, d, J
= 2.4Hz)

Example 35 2- (R)-[(t-butoxycarbonyl) amino]-
Synthesis of methyl 3- [5- (t-butoxycarbonyloxy) pyridin-2-yl] thio-3,3-dimethylpropionate

2- (R)-[(t-butoxycarbonyl) amino] -3- (5-aminopyridin-2-yl)
Methyl thio-3,3-dimethylpropionate (3.30
Using g) and in the same manner as in Example 27, the title compound was obtained. 1.37 g, 32% yield, yellow viscous crystals

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.41 (3H, s), 1.42 (3H, s), 1.4
5 (9H, s), 1.52 (9H, s), 3.73 (3
H, s), 4.41 (1H, d, J = 8.3 Hz), 6.
56 (1H, s), 7.35 (1H, d, J = 8.3H)
z), 7.74 (1H, d, J = 8.3 Hz), 7.89
(1H, dd, J = 2.4, 8.3 Hz), 8.35 (1
H, d, J = 2.4 Hz)

Example 36 2- (R)-[(t-butoxycarbonyl) amino]-
Synthesis of 3- [5- (t-butoxycarbonyloxy) pyridin-2-yl] thio-3,3-dimethylpropionic acid

Methyl 2- (R)-[(t-butoxycarbonyl) amino] -3- [5- (t-butoxycarbonyloxy) pyridin-2-yl] thio-3,3-dimethylpropionate (1. Using 36 g), the title compound was obtained in the same manner as in Example 2. 235 mg, 18% yield, pale yellow amorphous

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.30 (3H, s), 1.32 (3H, s), 1.3
9 (9H, s), 1.54 (9H, s), 4.47 (1
H, d, J = 8.8 Hz), 5.63 (1H, d, J =
8.8 Hz), 7.17 (1H, s), 7.57 (1H,
d, J = 8.8 Hz), 7.98 (1H, dd, J = 2.
4,8.8 Hz), 8.61 (1H, d, J = 2.4 Hz)

Example 37 2- (R)-[(t-butoxycarbonyl) amino]-
Synthesis of methyl 3- (5-tridecanamidopyridin-2-yl) thio-3,3-dimethylpropionate

2- (R)-[(t-butoxycarbonyl) amino] -3- (5-aminopyridin-2-yl)
Methyl thio-3,3-dimethylpropionate (1.94
Using g) and in the same manner as in Example 31, the title compound was obtained. 2.28 g, 46% yield, light brown oil

¹ H-NMR (CDCl ₃ ) δ (ppm):
0.88 (3H, t, J = 6.9 Hz), 1.19-1.
65 (33H, m), 1.65-1.80 (2H,
m), 2.39 (2H, t, J = 7.3 Hz), 3.73
(3H, s), 4.45 (1H, d, J = 8.8 Hz),
7.35 (1H, d, J = 8.8 Hz), 7.74 (1
H, d, J = 7.8 Hz), 8.04 (1H, d, J =
7.8Hz), 8.48 (1H, s)

Example 38 2- (R)-[(t-butoxycarbonyl) amino]-
Synthesis of 3- (5-tridecanamidopyridin-2-yl) thio-3,3-dimethylpropionic acid

2- (R)-[(t-butoxycarbonyl) amino] -3- (5-tridecanamidopyridine-
The title compound was obtained in the same manner as in Example 2 using methyl 2-yl) thio-3,3, -dimethylpropionate (2.19 g). 1.27 g, 60% yield, light brown oil

¹ H-NMR (CDCl ₃ ) δ (ppm):
0.88 (3H, t, J = 6.8 Hz), 1.19-1.
58 (33H, m), 1.65-1.78 (2H,
m), 2.43 (2H, t, J = 7.3 Hz), 4.49
(1H, d, J = 8.3 Hz), 5.69 (1H, d, J
= 8.3 Hz), 7.58 (1H, d, J = 8.3 Hz),
8.35 (1H, dd, J = 2.4, 8.3 Hz), 8.
56 (1H, s), 8.66 (1H, d, J = 2.4H)
z)

────────────────────────────────────────────────── ─── front page continued (51) Int.Cl. ⁶ identifications FI C07D 213/65 C07D 213/65 213/69 213/69 213/70 213/70 213/73 213/73 213/79 213/79 215/12 215/12 215/26 215/26 239/56 239/56 239/93 239/93 // C07B 61/00 300 C07B 61/00 300 C07M 7:00

Claims (5)

[Claims] 1. General formula (1) [Wherein R represents a hydrogen atom or an ester-forming group;
¹ is a cycloalkylmethylthio group, or a pyridyl group, a naphthyl group, a quinolyl group, a pyridylthio group, a pyridylmethylthio group, a pyrimidinylthio group, a quinazolinylthio group, a naphthylmethylthio group, and a quinolylmethylthio group, each of which may have a substituent. A phenylmethylthio group or a lower alkylthio group, R ² and R ³ are the same or different and each represents a hydrogen atom or a methyl group, and Boc represents a tertiary butoxycarbonyl group]. 2. A compound of the general formula (2-a) R ⁴ X (2-a) wherein R ⁴ is a pyridyl group, naphthyl group or quinolyl group which may have a substituent, and X is A halogen atom] to the compound represented by the general formula (3-a) Wherein R ⁵ represents a hydrogen atom, a phenacyl group, an N-phthalimidomethyl group or a lower alkyl group which may have a substituent, and Boc represents a tertiary butoxycarbonyl group. If necessary, the compound is allowed to act in the presence of a zinc and palladium complex, and then hydrolyzed. [Wherein R ⁴ is as defined above]. 3. General formula (3-b) [In the formula, R ² and R ³ are the same or different and each represent a hydrogen atom or a methyl group, and R ⁵ represents a hydrogen atom, a phenacyl group, an N
A phthalimidomethyl group or a lower alkyl group which may have a substituent, and Boc represents a tertiary butoxycarbonyl group], if necessary, in the presence of a palladium complex or with a sodium salt. After doing
Formula (2-b) R ⁶ X (2-b) [wherein R ⁶ is a cycloalkylmethyl group or a pyridyl group, a pyridylmethyl group, a naphthylmethyl group, a quinolylmethyl group each optionally having a substituent. X is a halogen atom, a phenylmethyl group, a lower alkyl group, and a compound represented by the general formula (1-b ) [Wherein R ² , R ³ , R ⁶ , and Boc are as described above]. 4. The formula (3-c) [Wherein Boc represents a tertiary butoxycarbonyl group], a compound represented by the general formula (2-c) R ⁷ SH (2-c) [wherein R ⁷ may have a substituent A good pyrimidinyl group or a quinazolinyl group] in the presence of a base. [Wherein R ⁷ and Boc are as defined above]. 5. General formula (1-d) [In the formula, R ² and R ³ are the same or different and each represent a hydrogen atom or a methyl group, and R ⁵ represents a hydrogen atom, a phenacyl group, an N
A phthalimidomethyl group or a lower alkyl group which may have a substituent, and Boc represents a tertiary-butoxycarbonyl group]. Performing a reduction such as catalytic hydrogenation to hydrolyze the ester or carbonate ester,
General formula (1-e) characterized in that the ester is deprotected after the reaction with an acid anhydride, an acid halide or the like. [Wherein R ² , R ³ , and Boc are as described above, and R ⁸ represents hydrogen, an acetyl group, a tridecanoyl group, or a tertiary butoxycarbonyl group].