JPH09241284A - New oxyazaphosphorine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new oxyazaphosphorine derivative having herbicidal activity by reacting 1,2-0-isopropylidene-α-D-xylofuranosecyclic-3(O), 5-(substituted-N)-phosphorochloridate with an amino acid ester. SOLUTION: This new oxyazaphosphorine derivative is represented by formula I [R<1> to R<3> are each H, a (substituted) 1-6C alkyl, a (substituted)aralkyl or (substituted)phenyl], e.g. 1,2-O isopropylidene-α-D-xylofuranose-cyclic-3-(O), 5(benzyl-N)-phosphoroamidate-P-glycine methylester] and is useful as a compound having herbicidal activity. The compound is obtained by reacting 1,2-O- isopropylidene-α-D-furanose-cyclic-3(O), 5(substituted-N)-phosphorochloridate represented by formula II with an amino acid ester represented by formula III [e.g. glycine methyl ester] in the presence of a base.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a phosphorus compound having an oxyazaphosphorine skeleton in which amino acid esters are bound to a phosphorus atom constituting an oxyazaphosphorine ring by a nitrogen atom of an amino group, and a method for producing the same.

[0002]

2. Description of the Related Art As a compound having an O-P-N bond in the ring, for example, a cycloalkyl group represented by the formula [IV], which is one of the most commonly used anti-cancer agents of alkylation type at present. Phosphamide is known.

[0003]

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[0004]

DISCLOSURE OF THE INVENTION The present invention focuses on the oxyazaphosphorine skeleton having an O—P—N bond possessed by this cyclophosphamide, and has a functional group replacing the bischloroethyl group of cyclophosphamide. Invented to introduce. In addition, it is important that the compound has a sterically single structure from the viewpoint of searching for physiologically active compounds. Therefore, the present invention provides an oxy compound having herbicidal activity by using L-phenylalanine and D-xylose as starting materials, in which only one isomer of phosphorus is obtained at the stage of cyclophosphamide ring formation among optically active compounds. Provided are an azaphosphorine compound and a method for producing the same.

[0005]

Hereinafter, the present invention will be described in detail. The present invention has the formula [I]

[0006]

[Chemical 6]

(In the formula, R ¹ , R ² and R ³ are each independently a C _1-6 alkyl group which may have a substituent, an aralkyl group which may have a substituent, or And an oxyazaphosphorine compound represented by the formula (II), which represents a phenyl group which may have a substituent.

[0008]

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(In the formula, R ¹ has the same meaning as described above.)
A compound represented by the formula [III] in the presence of a base.

[0010]

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## STR1 ## wherein R ² and R ³ have the same meanings as described above, and an amino acid ester represented by the formula is reacted.

[0012]

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A method for producing an oxyazaphosphorine compound represented by:

In the formula [I], the substituents R ¹ , R ² and R ³ are each independently a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t.
-A straight or branched C _1-6 alkyl group such as butyl, pentyl and hexyl groups, a halogen atom such as fluorine, chlorine and bromine at an arbitrary position of a benzene ring, an alkyl group such as methyl, an alkoxy group such as methoxy. Substituted with a benzyl group which may be substituted with a nitro group, a halogen atom such as fluorine, chlorine or bromine, an alkyl group such as methyl, an alkoxy group such as methoxy, or a nitro group at any benzene ring position Aralkyl group such as phenethyl group, halogen atom such as fluorine, chlorine and bromine at any position of benzene ring, alkyl group such as methyl, alkoxy group such as methoxy, benzyl which may be substituted with nitro group etc. Group, a halogen atom such as fluorine, chlorine or bromine at any benzene ring position, an alkyl group such as methyl,
Examples thereof include an alkoxy group such as methoxy and a phenyl group which may be substituted with a nitro group.

Examples of the substituent of the C _1-4 alkyl group which may have a substituent include a hydroxyl group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, an amino group and an amide group. . More specific C _1-4 alkyl groups which may have a substituent include methyl, isopropyl, isobutyl, carboxymethyl, aminocarbonylmethyl, 4-amino-n-butyl, mercaptothio, 2-mercaptoethyl, A benzyl, hydroxymethyl, 1-hydroxyethyl group etc. can be mentioned.

More specifically, examples of the substituent of the C _1-4 alkyl group which may have a substituent include a hydroxyl group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, an amino group and an amide group. can do. More specific C _1-4 alkyl groups which may have a substituent include methyl, isopropyl, isobutyl, carboxymethyl, aminocarbonylmethyl, 2-aminocarbonylethyl, 4-amino-n-butyl and mercaptothio. Two
-Mercaptoethyl, phenyl, benzyl, hydroxymethyl, 1-hydroxyethyl groups and the like can be mentioned.

Examples of the amino acid ester derivative represented by the formula [III] include glycine, L-alanine, L-leucine, L-isoleucine, L-serine, L-threonine,
L-cysteine, L-methionine, L-proline, L-
Aspartic acid, L-glutamic acid, L-histidine,
Examples thereof include esters such as L-lysine, L-ortinine, L-arginine, L-phenylalanine, L-tyrosine, and L-tryptophan.

Examples of the ester of amino acid ester include linear or branched alkyl ester such as methyl, ethyl, propyl and isopropyl, and aralkyl ester such as benzyl.

[0019]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the present invention can be produced as follows.

(1) Synthesis of amino acid ester

The starting amino acid ester was obtained by reacting an α-amino acid with an alcohol in the presence of an acid catalyst such as thionyl chloride or p-toluenesulfonic acid. The amino acid ester is used in the form of a salt such as hydrochloride or p-toluenesulfonate. A synthesis example is shown below. An optically active amino acid ester can be obtained by using an optically active amino acid as a starting material.

(2) Production of compound [II] D-xylose can be used as a starting material and produced according to the following reaction formula.

[0023]

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(3) Production of Compound [I] The compound [I] can be obtained by reacting the amino acid ester obtained as described above with the compound [II]. The reaction formula is shown below.

[0025]

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That is, 0.5 mol to 5. mol per 1 mol of the amino acid ester [III] in an inert solvent such as THF, dimethoxyethane, dimethylformamide, dimethylsulfoxide, benzene, toluene and chloroform.
It is carried out by reacting 0.5 to 3.0 molar equivalent of compound [II] in the presence of 0 molar equivalent of a base. Examples of the base used include organic bases such as triethylamine, diethylisopropylamine, pyridine and piperidine, alkali metal carbonates such as potassium carbonate and sodium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and sodium methylate. , Sodium ethylate, alkali metal alkoxides such as potassium t-butoxide, and the like. When the amino acid ester is a salt (hydrochloride, p-toluenesulfonate, etc.), 1 mol equivalent of a base is further added. is necessary. The reaction proceeds smoothly in the range of -10 ° C to 200 ° C. The structure of the reaction product was determined by NMR, IR, MASS spectrum and the like.

[0027]

Next, the present invention will be described in more detail with reference to examples.

(1) Synthesis of L-phenylalanine methyl ester hydrochloride

30 ml of methanol was cooled to -10 ° C, and 11.0 ml of thionyl chloride was added dropwise with stirring. After stirring for 15 minutes, L-phenylalanine 7.0
0 g (42.5 mmol) was added, and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off from the reaction product under reduced pressure to obtain 9.04 g of the desired product. Yield quantitative m. p. 155-160 ° C. ¹ H-NMR (D ₂ O, δ ppm): 3.39 (d,
2H, J = 6.5 Hz), 3.94 (s, 3H), 4.
50 (t, 1H, J = 6.5 Hz), 7.2-7.8
(M, 5H)

(2) 1,2-O- from D-xylose
Isopropylidene-a-D-xylofuranose Synthesis of cyclic-3 (O), 5 (benzyl-N) -phosphoryl chloride

(2-1) Synthesis of 1,2,3,5-di-O-isopropylidene-a-D-xylofuranose [VI] D-xylose [V] 30.0 g (0.20 mol)
Dried acetone 500.0 ml, anhydrous copper sulfate 60.0
g (3.8 mmol), sulfuric acid 8.0 ml (0.15 mo
1) was added and the mixture was stirred at room temperature for 1 week. After neutralizing with calcium hydroxide and filtering, the filtrate is concentrated under reduced pressure to obtain the desired product 2
9.28 g (0.14 mol) was obtained. (Yield 67.8
%) ¹ H-NMR (CDCl ₃ ): δ (ppm); 1.26 (s, 3H, CCH ₃ ) 1.32 (s, 3H, CCH ₃ ) 1.44 (s, 3H, CCH ₃ ) 1 _{.49 (s, 3H, CCH 3} ) 3.8-4.4 (m, 4H, H-3,4,5,5 ') 4.52 (d, 1H, H-2, J HH = 3. 76 Hz) 5.99 (d, 1H, H-1, J _HH = 3.76 Hz)

(2-2) Synthesis of 1,2-O-isopropylidene-a-D-xylofuranose [VII] 1,2,3,5-di-O-isopropylidene-a-D-
To a solution of xylofuranose in 29.3 g (0.13 mol) of methanol (100.0 ml) was added 150% of 1% diluted sulfuric acid.
0 ml was added, and the mixture was stirred at room temperature for 8 hours while confirming the reaction by TLC. The mixture was neutralized with barium carbonate and then filtered, and the filtrate was evaporated under reduced pressure. Chloroform (60.0 ml) in the residue
Was added and dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain 23.1 g (0.12 mol) of the desired product. (Yield 91.55%) ¹ H-NMR (CDCl ₃ ): δ (ppm); 1.26 (s, 3H, CCH ₃ ) 1.49 (s, 3H, CCH ₃ ) 3.8-4. 4 (m, 6H, H- 3,4,5,5 ', OH × 2) 4.47 (d, 1H, H-2, J HH = 3.6Hz) 5.97 (d, 1H, H- 1, J _HH = 3.6Hz)

(2-3) 1,2-O-isopropylidene-5-O-tosyl-a-D-xylofuranose [VII
I] Synthesis of 1,2-O-isopropylidene-a-D-xylofuranose in 15.9 g (84.5 mmol) of a dry pyridine solution (40.0 ml), 16.8 g of tosyl chloride (8
7.9 mmol) in dry pyridine (30.0 ml)
Was added dropwise at 0 ° C, and the mixture was stirred as it was for 6 hours, then 2 in a refrigerator.
Left for days. After pyridine was distilled off under reduced pressure at 40 ° C or lower, chloroform (80.0 ml) was added to the residue and water (3
After washing with 0 ml × 3) and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 28.22 g (82.0 mm) of the desired product.
ol). (Yield 97.0%) ¹ H-NMR (CDCl ₃ ): δ (ppm); 1.25 (s, 3H, CCH ₃ ) 1.45 (s, 3H, CCH ₃ ) 2.41 (s, _{3H, Ph CH 3) 4.0-4.4 (} m, 4H, H-3,4,5,5 ') 4.62 (d, 1H, H-2, J HH = 3.67Hz) 4. 80 (bs, 1H, OH) 5.88 (d, 1H, H-1, J HH = 3.67Hz) 7.53 (ABq, 4H, Ph)

(2-4) 5- (N-benzylamino)-
5-deoxy-1,2-0-isopropylidene-a-D
-Synthesis of xylofuranose [IX] 1,2-O-isopropylidene-5-O-tosyl-a-
6.70 g (19.5 mmo) of D-xylofuranose
l) To an ethanol solution (50.0 ml), 10.0 ml
An ethanol solution (30.0 ml) of benzylamine (91.54 mmol) was added, and the mixture was refluxed for 6 hours. The solvent was distilled off under reduced pressure, and the residue was ethyl acetate: n-hexane = 2: 1.
The solution of was added slowly to precipitate insoluble matter, which was then filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (developing solution; ethyl acetate: n-hexane = 2: 1) to obtain 3.23 g (11.6 mmol) of the desired product. (Yield 59.4%) ¹ H-NMR (CDCl ₃ ): δ (ppm); 1.29 (s, 3H, CCH ₃ ) 1.45 (s, 3H, CCH ₃ ) 2.8-3. 5 (m, 2H, H- 5,5 ') 3.75 (s, 2H, CH 2 Ph) 4.0-4.8 (m, 4H, H-3,4, OH, NH) 4.47 (d, 1H, H-2 , J HH = 3.76Hz) 5.92 (d, 1H, H-1, J HH = 3.76Hz) 7.2-7.5 (m, 5H, Ph)

(2-5) 1,2-O-isopropylidene-a-D-xylofuranose cyclic-3
Synthesis of (O), 5 (benzyl-N) -phosphoryl chloride [II] 5- (N-benzylamino) -5-deoxy-1,2-
Using 3.27 g (11.71 mmol) of O-isopropylidene-a-D-xylofuranose, a method similar to the above was carried out to obtain 2.38 g (6.65 mmo) of the desired product.
1) was obtained. (Yield 56.8%) ¹ H-NMR (CDCl ₃ ): δ (ppm); 1.33 (s, 3H, CCH ₃ ) 1.46 (s, 3H, CCH ₃ ) 3.1-3. 6 (m, 2H, H-5, 5 ') 3.8-4.1 (m, 1H, N CH Ph) 4.1-4.3 (m, 1H, H-4) 4.3-4 .6 (m, 1H, N CH 'Ph) 4.70 (d, 1H, H-2, J HH = 3.8Hz) 4.83 (br, 1H, H-3) 6.01 (d, 1H , H-1, J _HH = 3.8 Hz) 7.1-7.5 (m, 5H, Ph) ¹³ C-NMR (CDCl ₃ ): δ (ppm); 26.13 (CH ₃ ) 26.49. (CH ₃ ) 46.66 (C-5) 51.24 (N CH ₂ Ph, J _PC = 2.0 Hz) 72.11 (C-2) 83.56 (C-4) 84.04 (C- 3) 104.75 (C _{CH 3)) 112.59 (C-} 1) 128.02 (p-Ph) 128.47 (o-Ph) 128.67 (m-Ph) 134.63 (x-Ph) 31 P-NMR (CDCl ₃ ) δ (ppm); 11.651 IR (cm-1): 1215 (P = O), 1020 (P-O-C)

(3) Reaction of compound [II] with amino acid ester

(Example 1) 1,2-O-isopropylidene-a-D-xylofuranose cyclic-3
(O), 5 (benzyl-N) -phosphoramidate P
-Synthesis of glycine methyl ester [Ia] 1,2-O-isopropylidene-a-D-xylofuranose cyclic-3 (O), 5 (benzyl-N)-
0.41g (1.48mmo) of phosphoryl chloride
The same reaction was carried out using l) to obtain 0.34 g of the desired product (0.84 mmol). (Development liquid; ethyl acetate:
Methanol = 10: 1 (yield 79.1%) ¹ H-NMR (CDCl ₃ ): δ (ppm); 1.33 (s, 3H, CCH ₃ ) 1.47 (s, 3H, CCH ₃ ). 3.2-3.5 (m, 2H, H- 5,5 ') 3.65 (s, 3H, OCH 3) 3.7-4.4 (m, 6H, NH 2 Ph, H-4, _{NH, NC H 2) 4.64 (} d, 1H, H-2, J HH = 3.8Hz) 4.84 (br, 1H, H-3) 6.02 (d, 1H, H-1, J _HH = 3.8 Hz) 7.2-7.6 (m, 5H, Ph) ³¹ P-NMR (CDCl ₃ ) δ (ppm); 9.321 IR (cm-1): 3200 (NH), 1770 ( NHC (O)), 1234 (P = O), 1020 (P-O-C)

(Example 2) 1,2-O-isopropylidene-a-D-xylofuranose cyclic-3
(O), 5 (benzyl-N) -phosphoramidate P
Synthesis of-(L-alanine methyl ester) [Ib] 1,2-O-isopropylidene-a-D-xylofuranose cyclic-3 (O), 5 (benzyl-N)-
0.40g (1.42mmo of phosphoryl chloride
The same reaction is carried out using 1) to give 0.47 g of the desired product.
(1.11 mmol) was obtained. (Developer: ethyl acetate:
Methanol = 10: 1) (yield 78.5%) TLC: Rf = 0.66 ¹ H-NMR (CDCl ₃ ): δ (ppm); 1.25 (CH ₃ (amino acid)) 1.25 ( _{CH 3) 1.39 (CH 3)} 3.23 (H-5) 3.28 (H-5 ') 3.34 (NH) 3.66 (OCH 3) 3.93 (NCH (amino acid)) 4.00 (NCHPh) 4.12 (H-4) 4.28 (NCH'Ph) 4.47 (H-2) 4.75 (H-3) 5.93 (H-1) 7.1- 7.5 (m, 5H, Ph) ¹³ C-NMR (CDCl ₃ ) δ (ppm); 20.75 (CH ₃ , J _PC = 6.7 Hz) 26.16 (CH ₃ ) 26.55 (CH ₃ ) 46.23 (C-5, J PC = 2.0Hz) 50.42 (NCH) 50.92 (N CH 2 Ph, J P _{C = 2.7Hz) 52.18 (OCH 3} ) 73.31 (C-2, J PC = 4.7Hz) 80.43 (C-4, J PC = 6.7Hz) 84.25 (C-3 , J _PC = 10.0 Hz) 104.93 (C (CH ₃ )) 112.30 (C-1) 127.45 (p-Ph) 127.81 (o-Ph) 128.64 (m-Ph). 136.51 (x-Ph) 173.56 (C = 0) ³¹ P-NMR (CDCl ₃ ) δ (ppm); 9.224 IR (cm −1): 3200 (NH), 1740 (NHC (O)). ), 1240 (P = O), 1040 (P-O-C)

(Example 3) 1,2-O-isopropylidene-a-D-xylofuranose cyclic-3
(O), 5 (benzyl-N) -phosphoramidate P
-(L-phenylalanine methyl ester) [Ic]
Synthesis of 1,2-O-isopropylidene-aD-xylofuranose cyclic-3 (O), 5 (benzyl-N)-
0.34g (1.22mmo) of phosphoryl chloride
The same reaction is carried out using 1) to obtain 0.35 g of the desired product.
(0.69 mmol) was obtained. (Development liquid; ethyl acetate:
Methanol = 10.1) (yield 71.0%) TLC: Rf = 0.65 ¹ H-NMR (CDCl ₃ ): δ (ppm); 1.22 (s, 3H, CCH ₃ ) 1.35 ( _{s, 3H, CCH 3) 2.7-2.9} (m, 2H, Ph CH 2 (amino aci d) 3.0-3.3 (m, 2H, H-5,5 ') 3.59 ( _{s, 3H, OCH 3) 3.7-4.2} (m, 4H, NH 2 Ph, H-4, NH) 4.31 (d, 1H, H-2, J HH = 3.8Hz) 4. 66 (br, 1H, H- 3) 5.83 (d, 1H, H-1, J HH = 3.8Hz) 7.1-7.5 (m, 5H, Ph) 31 P-NMR (CDCl 3 ) Δ (ppm); 8.836 IR (cm-1): 3450 (NH), 1761 (NHC (O)), 1240 (P = O), 1030 (P-O-C).

(Example 4) 1,2-O-isopropylidene-a-D-xylofuranose cyclic-3
(O), 5 (benzyl-N) -phosphoramidite P
Synthesis of-(L-leucine methyl ester) [Id] 1,2-O-isopropylidene-a-D-xylofuranose cyclic-3 (O), 5 (benzyl-N)-
Phosphorchloridate 0.47g (1.31mmo
The same reaction is performed using l), and 0.33 g of the desired product
(0.79 mmol) was obtained. (Development liquid; ethyl acetate:
Methanol = 10: 1) (60.2% ^{yield) TLC: Rf = 0.62 1 H} -NMR (CDCl 3): δ (ppm); 1.33 (s, 3H, CCH 3) 1.46 ( _{s, 3H, CCH 3) 3.1-3.6} (m, 2H, H-5,5 ') 3.8-4.1 (m, 1H, N CH Ph) 4.1-4.3 ( m, 1H, H-4) 4.3-4.6 (m, 1H, N CH 'Ph) 4.70 (d, 1H, H-2, J HH = 3.8Hz) 4.83 (br, 1H, H-3) 6.01 ( d, 1H, H-1, J HH = 3.8Hz) 7.1-7.5 (m, 5H, Ph) 13 C-NMR (CDCl 3) δ (ppm ); 22.19 (CH ₃ × 2) 22.79 (CH ₂ ) 24.55 (CH) 26.04 (CH ₃ ) 26.46 (CH ₃ ) 46.07 (C-5, J _PC = 2) 0.0 Hz) 0.59 (NCH) 51.85 (N CH 2 Ph, J PC = 2.7Hz) 53.40 (OCH 3) 73.20 (C-2, J PC = 4.7Hz) 80.40 (C- 4, J _PC = 6.7 Hz) 84.11 (C-3, J _PC = 10.0 Hz) 104.90 ( C (CH ₃ )) 112.21 (C-1) 127.33 (p-Ph) 127.78 (o-Ph) 128.53 (m-Ph) 136.43 (x-Ph) 174.14 (C = O) ³¹ P-NMR (CDCl ₃ ) δ (ppm); 10.0984 IR ( cm-1): 3400 (NH), 1740 (NHC (O)), 1220 (P = O), 1020 (P-O-C).

The yield of the target compound and ³¹
P-NMR is shown in Table 1.

[0042]

[Table 1] * The chemical shift of Compound 18 is δ = 11.651

[0043]

The oxyazaphosphorine derivative of the present invention has herbicidal activity. Further, according to the production method of the present invention, it is possible to react with various neutral, acidic, alkaline amino acids whose N-terminal is not protected, and various peptide esters.

 ─────────────────────────────────────────────────── --- Continuation of the front page (72) Inventor Kuniaki Seo 482-6 Shimochikari, Nagaizumi-cho, Sunto-gun, Shizuoka Prefecture

Claims (2)

[Claims] 1. The formula [I]: (In the formula, R ¹ , R ² and R ³ are each independently a hydrogen atom, an optionally substituted C _1-6 alkyl group,
It represents an aralkyl group which may have a substituent or a phenyl group which may have a substituent. ) An oxyazaphosphorine compound represented by: 2. A formula [II]: (Wherein R ¹ has the same meaning as described above), in the presence of a base, a compound of the formula [III] (Wherein, R ² and R ³ have the same meanings as described above), and the amino acid ester represented by the formula is reacted. (In the formula, R ¹ , R ² and R ³ have the same meanings as described above.) A method for producing an oxyazaphosphorine compound.