JPH0753579A - Production of alpha-aminophosphonic acid derivative - Google Patents

Abstract

PURPOSE:To industrially obtain the subject compound as a raw material for phosphonopeptides having antibacterial, herbicidal or enzyme-inhibitory activity by reaction of an aldehyde with an ammonium salt and a phosphorous diester. CONSTITUTION:(A) An aldehyde of the formula R1CHO [R1 is a (substituted) alkyl, a (substituted)alkenyl, a (substituted)aromatic group, etc.] is reacted with (B) an ammonium salt of the formula NH4X (X<-> is a counter anion) and (C) a phosphorous diester of formula I [R2 is a (substituted)lower alkyl or a (substituted)aryl] pref. in the presence of a water absorbing agent at pref. 0-100 deg.C to obtain the objective alpha-aminophosphonic acid derivative of formula II (e.g. 1-amino-1-phenylmethylphosphonic diethyl hydrochloride).

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a general formula for use as a raw material for the production of phosphonopeptides having antibacterial, herbicidal, and enzyme inhibiting actions.

[0002]

[Chemical 5]

The present invention relates to a method for producing an α-aminophosphonic acid derivative represented by

[0004]

2. Description of the Prior Art Phosphonopeptides in which the C-terminal amino acid of the peptide is replaced with α-aminophosphonic acid are antibacterial
Many are known to have herbicidal and enzyme-inhibiting effects (Yamauchi Kiyoshi, Journal of Organic Synthetic Chemistry, Vol. 46, p. 654 (1988).
Year)). More recently, compounds that inhibit the action of thrombin, which is involved in blood coagulation, have also been reported (C.-LJ Wang et al., Tetrahedron Lett., 33,
7667 (1992).). As a method for producing α-aminophosphonic acid, which is a raw material for producing these phosphonopeptides, conventionally, a method in which a phosphite diester and ammonia are allowed to act on an aldehyde has been known as the simplest method (Kiyo Yamauchi,
Journal of Organic Synthetic Chemistry, Vol. 46, p. 654 (1988)). However, in this manufacturing method, ammonia gas is used and the reaction is carried out under heating conditions, so it is necessary to use an autoclave or a sealed tube. It is considered difficult to industrially produce the α-aminophosphonic acid represented by the above general formula [I] by this production method.

[0005]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide industrially feasible and convenient production of α-aminophosphonic acid, which is a raw material for producing phosphonopeptides which are expected to be used as interesting physiologically active substances. To establish the law.

[0006]

Means for Solving the Problems As a result of intensive investigations by the present inventors, when a phosphite diester and an ammonium salt are allowed to act on an aldehyde, the formation reaction of an α-aminophosphonic acid derivative proceeds under mild conditions. I found a thing. Moreover, in the present production method, since it is not necessary to use an autoclave or the like because an ammonium salt is used in place of ammonia, it has been found that an α-aminophosphonic acid derivative can be produced extremely easily as compared with the conventional method, and the present invention is obtained. It came to completion.

That is, the present invention has the general formula

[0008]

[Chemical 6]

(Wherein R ¹ is a substituted or unsubstituted linear or branched alkyl group, an alkenyl group, or an alkynyl group, or a substituted or unsubstituted aromatic group)
The aldehyde represented by

[0010]

[Chemical 7]

[0011] (wherein, X ^- represents a counter anion) and ammonium salts represented by the following general formula

[0012]

[Chemical 8]

A phosphite diester represented by the formula: wherein R ² represents a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted aryl group.

[0014]

[Chemical 9]

(Wherein R ¹ represents a substituted or unsubstituted linear or branched alkyl group, an alkenyl group, or an alkynyl group, or a substituted or unsubstituted aromatic group, and R ² represents a substituted or unsubstituted An unsubstituted lower alkyl group,
Which represents a substituted or unsubstituted aryl group).

In the above formula, the main chain R ¹ of the aldehyde is
Methyl group which may have a substituent, ethyl group, propyl group, butyl group, pentyl group, hexyl group, octyl group, isopentyl group, neopentyl group, isohexyl group, isopropyl group, s-butyl group, t-butyl Group, t-pentyl group, cyclopropyl group, cyclopentyl group, cyclohexyl group, adamantyl group and other alkyl groups, benzyl group, 2-phenylethyl group and other aralkyl groups, optionally substituted vinyl group, propenyl Groups, butenyl groups, pentenyl groups, alkenyl groups such as hexenyl groups,
Examples thereof include an alkynyl group such as an ethynyl group which may have a substituent and a propynyl group, and an aromatic group such as a phenyl group, a pyridyl group, a thienyl group and an indolyl group which may have a substituent. Further, as the substituent, any group may be used as long as it does not participate in the reaction, for example, a halogen atom, an optionally protected hydroxyl group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, a nitro group, an amidino group, a guanidino group, An alkylthio group,
An arylthio group etc. can be illustrated.

Further, the counter anion X in the ammonium salt in the above formula ^- include hydrogen chloride, hydrogen bromide, hydrogen iodide, Four hydrofluoric acid, perchloric acid, formic acid, acetic acid, propionic acid, chloroacetic acid, dichloroacetic Examples thereof include conjugated bases such as acetic acid, trichloroacetic acid, trifluoroacetic acid, phosphoric acid, phosphorous acid, hypophosphorous acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, fluorosulfonic acid and sulfuric acid. Particularly, as the above ammonium salt, ammonium carboxylate such as ammonium acetate is preferable from the viewpoint of acidity and solubility.

Further, R ^{2 of the} phosphite diester in the above formula is
Examples thereof include alkyl groups such as methyl group, ethyl group, isopropyl group, butyl group, hexyl group and octyl group, aralkyl groups such as benzyl group, and aromatic groups such as phenyl group. More preferably a methyl group,
A lower alkyl group such as an ethyl group is used.

In the reaction, it is preferable that a water-absorbing agent such as molecular sieve 3A or molecular sieve 4A coexists because the reaction proceeds smoothly and in terms of a simple reaction operation.

The reaction is generally carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, but alcohol solvents such as methanol, ethanol, isopropanol and ethylene glycol are preferred. , Ether, tetrahydrofuran, dioxane, ether solvents such as 1,2-dimethoxyethane, halogenated hydrocarbon solvents such as dichloromethane and chloroform, aromatic hydrocarbon solvents such as benzene, toluene and xylene, pyridine and dimethylformamide. Used. More preferably, methanol or ethanol is used. The reaction is usually performed at -50 ° C to 150 ° C, preferably 0 ° C.
To 100 ° C.

The α-aminophosphonic acid diester obtained by the method of the present invention can be isolated and purified by a conventional method. For example, by reacting hydrogen chloride in a mixed solvent of methanol and ether, the α-aminophosphonic acid diester can be obtained. The hydrochloride can be easily obtained as crystals or powder. The α-aminophosphonic acid diester is subjected to acid hydrolysis or alkaline hydrolysis by a known method (Kiyoshi Yamauchi, Journal of Organic Synthetic Chemistry, Vol. 46, p. 654 (1988)) such as heating in an aqueous hydrochloric acid solution. α-aminophosphonic acid,
Alternatively, it can be converted into α-aminophosphonic acid monoester, respectively.

The α-aminophosphonic acid diesters obtained by the above method are racemic, but these are known methods (for example, P. Kafarski et al., Can. J. Chem., 61, 24.
25 (1983).) To obtain both antipodes by optical resolution.

Hereinafter, the present invention will be described in detail with reference to Examples and Reference Examples, but it goes without saying that the present invention is not limited thereto.

[0024]

【Example】

 Example 1

[0025]

[Chemical 10]

Molecular sieves 3A (2 mL) was added to an ethanol solution (200 mL) of ammonium acetate (7.70 g, 0.1 mol).
g) and benzaldehyde (10.61 g, 0.1 mol) were added.
After adding diethyl phosphite (13.81 g, 0.1 mol) at room temperature, the mixture was stirred at 60 ° C. for 44 hours. The reaction solution was returned to room temperature, adjusted to pH 1 with 1N hydrochloric acid, and washed twice with ether. The aqueous layer was adjusted to pH 11 with 1N sodium hydroxide under ice cooling and then extracted 3 times with methylene chloride. After drying the methylene chloride layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain crude diethyl 1-amino-1-phenylmethylphosphonate (14.
36 g, 59 mmol, yield 59%) was obtained as a pale yellow oily substance. This was dissolved in a mixed solvent of ethanol (10 mL) and ether (10 mL) under ice cooling, and hydrogen chloride gas was passed through.
The solvent was distilled off under reduced pressure, and 1-amino-1-phenylmethylphosphonic acid diethyl hydrochloride (14.87 g, 53 mmol, yield 53%)
Was obtained as white crystals.

Mp.159-160 ° C (recrystallized from water) IR (KBr): 3434, 2905, 1607, 1524, 1456, 1393, 124
2, 1163, 1026, 978, . 806, 772, 698, 550cm -1 1 H-NMR (400MHz, CD 3 OD): δ = 1.21 (3H, t, J = 7.1Hz),
1.35 (3H, t, J = 7.1Hz), 3.94 (1H, ddq, J = 7.1, 8.1, 1
1.2Hz), 4.07 (1H, ddq, J = 7.1, 8.1, 11.2Hz), 4.16 (2
H, m), 4.86 (1H, d, J = 17.9Hz), 7.54 (5H, m). Elemental analysis: (C ₁₁ H ₁₉ ClNO ₃ P): Calculated value C = 47.07%, H = 6.82%, N = 4.99%. Analytical value C = 47.28%, H = 7.01%, N = 4.76%.

Reference Example 1

[0029]

[Chemical 11]

Hydrochloride of diethyl 1-amino-1-phenylmethylphosphonate obtained in Example 1 (120.4 mg, 0.43 mmo
l) was dissolved in concentrated hydrochloric acid (10 mL) and heated under reflux for 8 hours. After cooling, the solvent was distilled off under reduced pressure and the hydrochloride of 1-amino-1-phenylmethylphosphonic acid (96.0 mg, 0.43 mmol, yield> 99%)
Was obtained as white crystals.

Mp. 274-277 ° C. (recrystallized from water) IR (KBr): 3438, 3133, 2924, 2616, 2317, 1715, 162
2, 1539, 1503, 1451, 1366, 1348, 1269, 1213, 1082,
1022, 914, . 822, 772, 694, 617cm -1 1 H-NMR (400MHz, CD 3 OD): δ = 4.34 (1H, d, J = 16.4Hz),
7.38 (3H, m), 7.65 (2H, m).

Example 2

[0033]

[Chemical 12]

In the same manner as in Example 1, isobutyraldehyde (3.61 g, 0.05 mol) and ammonium acetate (3.86 g,
0.05mol), diethyl phosphite (6.91g, 0.05mo
l) and a mixture of molecular sieves 3A (1 g) were stirred in ethanol (100 mL) at 60 ° C. for 40 hours to obtain diethyl 1-aminoisobutylphosphonate (5.04 g, 24.1 mmol, 48%) as a pale yellow oily substance. .

¹ H-NMR (400 MHz, CDCl ₃ ): δ = 1.02 (3H,
d, J = 6.8Hz), 1.02 (3H, d, J = 6.8Hz), 1.056 and 1.
058 (total 3H, d, J = 6.8Hz), 1.33 (6H, t, J
= 7.1Hz), 2.12 (1H, m), 2.84 (1H, dd, J = 14.3, 4.2H
z), 4.14 (4H, m) .EI-MS: m / z = 209 (M ⁺ ), 166, 138, 110, 72.

Reference Example 2

[0037]

[Chemical 13]

Diethyl 1-aminoisobutylphosphonate (86.8 mg, 0.42 mmol) obtained in Example 2 was treated with hydrogen chloride in the same manner as in Example 1 to obtain diethyl 1-aminoisobutylphosphonate diethyl hydrochloride ( 68.2mg, 0.28mmo
l, yield 66%) was obtained as white crystals.

Mp.187-188 ° C IR (neat): 3443, 2980, 1589, 1508, 1402, 1260, 104
9, 1026, 986, 810, . 777, 698, 579, 521cm -1 1 H-NMR (400MHz, CD 3 OD): δ = 1.07 (3H, d, J = 6.9Hz),
1.17 (3H, d, J = 7.1Hz), 1.422 (3H, t, J = 7.1Hz), 1.42
4 (3H, t, J = 7.1Hz), 2.32 (1H, m), 3.86 (1H, br), 4.
28 (4H, m). HR-MS (C ₈ H ₂₀ NO ₃ P): Calculated 209.1180. Measured 209.1182.

Reference Example 3

[0041]

[Chemical 14]

Diethyl 1-aminoisobutylphosphonate (94.4 mg, 0.45 mmol) obtained in Example 2 was dissolved in a mixed solvent of ethanol (1 mL) and water (4 mL) to prepare sodium carbonate (57.3 mg, 0.54 mmol). Then, benzyl chloroformate (92.4 mg, 0.54 mmol) was added at 0 ° C., the temperature was gradually raised, and the mixture was stirred at room temperature for 10 hours. Pour the reaction solution into water,
Extracted 3 times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was separated by silica gel column chromatography (ethyl acetate-hexane), and diethyl 1-benzyloxycarbonylaminoisobutylphosphonate (77.4 mg, 0.23 mmol, yield was obtained.
50%) as an oil.

IR (neat): 3245, 2967, 1719, 1535, 138
5, 1290, 1231, 1028, ^{. 966, 747, 563cm -1 1} H-NMR (400MHz, CDCl 3): δ = 0.94 (3H, d, J = 6.9Hz),
0.968 and 0.970 (total 3H, d, J = 6.8Hz, respectively),
1.19 (3H, t, J = 7.1Hz), 1.24 (3H, t, J = 7.1Hz), 2.15
(1H, m), 3.95 (1H, m), 4.04 (4H, m), 4.96 (1H, d,
J = 9.1Hz), 5.04 (1H, d, J = 12.2Hz), 5.11 (1H, d, J = 1
2.2Hz), 7.30 (5H, m) .HR-MS (C ₁₆ H ₂₆ NO ₅ P): Calculated value 343.1547. Found 343.1568.

Example 3

[0045]

[Chemical 15]

In the same manner as in Example 1, isovaleraldehyde (86.1 mg, 1 mmol) and ammonium acetate (77.1 mg,
1 mmol), diethyl phosphite (138.1 mg, 1 mmol),
A mixture of molecular sieves 3A (20 mg) was stirred in ethanol (2 mL) at 60 ° C. for 24 hours to obtain diethyl 1-aminoisovalerphosphonate (71.4 mg, 0.32 mmol, 32%) as a pale yellow oily substance.

IR (neat): 3451, 2959, 2870, 1663, 146
8, 1391, 1368, 1233, 1165, 1098, 1055, 1028, 965,
^{. 785, 563cm -1 1 H-} NMR (400MHz, CDCl 3): δ = 0.90 (3H, d, J = 6.6Hz),
0.97 (3H, d, J = 6.7Hz), 1.34 (6H, t, J = 7.1Hz), 1.47
(2H, m), 1.56 (2H, br), 1.92 (1H, m), 3.04 (1H, dd
d, J = 4.0, 10.7, 10.7Hz), 4.5 (4H, m) .HR-MS (C ₉ H ₂₂ NO ₃ P): Calculated value 223.1336. Measured value 223.1329.

Reference Example 4

[0049]

[Chemical 16]

In the same manner as in Reference Example 3, diethyl 1-aminoisovalerphosphonate obtained in Example 3 (136.8 mg,
0.61 mmol), sodium carbonate (77.9 mg, 0.74 mmol),
1 from benzyl chloroformate (125.5mg, 0.74mmol)
Diethyl benzyloxycarbonylaminoisovalerphosphonate (84 mg, 0.23 mmol, yield 38%) was obtained as an oily substance.

IR (neat): 3239, 3036, 2959, 2870, 172
1, 1543, 1455, 1391, 1370, 1300, 1229, 1165, 1042,
. 970, 741, 698, 565cm -1 1 H-NMR (400MHz, CDCl 3): δ = 0.94 (6H, d, J = 6.6Hz),
1.26 (6H, t, J = 7.1Hz), 1.55 (2H, m), 1.74 (1H, m),
4.07 (1H, m), 4.12 (4H, q, J = 7.1Hz), 4.80 (1H, d,
J = 10.2Hz), 5.07 (1H, d, J = 12.4Hz), 5.16 (1H, d, J =
12.4Hz), 7.35 (5H, m) .HR-MS (C ₁₇ H ₂₈ NO ₅ P): Calculated value 357.1703. Found 357.1691.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Masato Yoshioka 1-2-14 Nunoichi-cho, Higashiosaka-shi, Osaka

Claims (1)

[Claims] 1. The following general formula: (Wherein R ¹ is a substituted or unsubstituted linear or branched alkyl group, an alkenyl group, or an alkynyl group, or a substituted or unsubstituted aromatic group) is added to an aldehyde represented by the following general formula: Chemical 2] (Wherein X ⁻ represents a counter anion), and an ammonium salt represented by the following general formula: (In the formula, R ² is a substituted or unsubstituted lower alkyl group,
(Representing a substituted or unsubstituted aryl group) represented by the formula:
The following general formula: (In the formula, R ¹ represents a substituted or unsubstituted linear or branched alkyl group, an alkenyl group, or an alkynyl group, or a substituted or unsubstituted aromatic group;
² represents a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted aryl group), and a process for producing an α-aminophosphonic acid derivative.