DE19519983A1 - New di:alkyl 1-acylamino-2-aryl-ethyl-phosphonate ester(s) - Google Patents

Abstract

Dialkyl 1-acylamino-2-arylethylphosphonates of formula (I) are new: R<1> = phenyl (opt. substd. by F, NO2, CF3, alkyl or alkoxy), biphenylyl, thienyl, furyl, pyridyl, naphthyl or anthracenyl; R<2> = formyl, acetyl, benzoyl (Bz), benzyloxycarbonyl (Cbz), t-butoxycarbonyl (Boc) or o-nitrobenzoyl; R<3> = 1-3C alkyl.

Description

The invention relates to new aryl-substituted aminoacylated Phosphonic acid derivatives in optically active form or as a race mat and a process for the preparation of these compounds by asymmetric catalytic hydrogenation suitable pre stages with chiral or achiral complex catalysts. The The invention also deals with the novel, suitable ones Preliminary stages. Their use is also shown.

Aryl-substituted aminoacylated phosphonic acid derivatives are little known so far.

Optically active α-aminophosphonic acids or their are known Derivatives that are manufactured by different processes that can. In addition to classic racemate separations, porridge takes stoichiometric methods, which are all op Serve more active auxiliaries. These procedures are based doing so on C-C, C-P, C-H or C-N tying reactions simultaneous introduction of the (des) chiral centers (Zen trums). The state of the art is in a review article by B. Dharwan and D. Redmore in Phosphorus, Sulfur and Silicon 32 (1987), 119 until 1986, and in a white teren by V.P. Kukhar, V.A. Soloshonov and V.A. Solodenko in Phosphorus, Sulfur and Silicon 92 (1994), 239-264 has been put.

It is also known that in addition to auxiliaries Synthesize two other methods for asymmetric hydrology tion of α, β-unsaturated-α-N-formylphosphonic acid dimer ethyl esters or ZNHC (= CH₂) PO (OR) ₂ compounds with rhodium complex catalysts have been described (U. Schöllkopf, I. Hoppe and A. Thiele, Lieb. Ann. Chem. 1985, 555-559, and US-A-5 321 153). In the first process, the synthesis is to unusual α-aminophosphonic acids especially for AlaP wrote. Only the (+) - DIOP-Rh- Complex suitable, which in poor activity AlaP in  76% ee resulted, whereby only the methyl- not the ethylphos phonat as substrate reacted at all and the classic ones Rhodium complex catalysts such as DIPAMP-Rh, NORPHOS-Rh completely failed. On the other hand, according to US patent application 5 321 153 for the hydrogenation of ZNHCH (= CH₂) PO (OMe) ₂ to aryl, Alkyl and cycloalkyl compounds DIPAMP used, all things under weak pressure. There are high chemical levels booty achieved by optical yields of 90% ee. On The disadvantage, however, is that for five-ring chelating agents According to the existing low activity, for example the N- [1- (dimethoxyphosphoryl)] - 4-phenylethenyl formamide with a substrate / catalyst ratio of 144: 1 at a pressure of 40 psi only in 16 hours hydrated.

The formation of a CH-N bond through enantioselective Reduction of an analog Schiff base as a preliminary stage Aluminum amalgam only led to moderate chemical and opti yields (67% ee) (X.Y. Jiao, W.X. Chen and B.F. Hu, Synth. Commun. 22: 1179 (1992).

The object of the invention is to provide new aryl-substituted amino To provide acylated phosphonic acid derivatives, where too their manufacture while avoiding the above Share to develop a synthesis process, which ever target product with chiral or achiral rhodium com plex catalysts through asymmetric catalytic hydrogenation optionally from suitable unsaturated precursors aryl-substituted aminoacylated phosphonic acid derivatives at high speed and with optically active ven form also with high stereoselectivity and a high Substrate / catalyst ratio allowed.

This task is solved according to the requirements.

The new aryl-substituted aminoacylated phosphonic acid derivatives have the general formula I,

in the
R¹ = phenyl, fluorophenyl such as 2-, 3- or 4-fluorophenyl, nitrophenyl such as 4-nitrophenyl, trifluoromethylphenyl, alkylphenyl such as 4-methylphenyl, alkoxyphenyl such as 4-methoxyphenyl or dimethoxyphenyl, biphenyl, thienyl such as 2- or 3-thienyl, furyl such as 2- or 3-furyl, pyridyl such as 3- or 4-pyridyl, naphthyl such as 1- or 2-naphthyl and anthracenyl,
R² = formyl, acetyl, benzoyl, benzyloxycarbonyl (CbZ), tert-butoxycarbonyl (BOC) and o-nitrobenzoyl as well
R³ = methyl, ethyl, propyl and isopropyl.

The invention further relates to a method for the manufacture position of the compounds of formula I by Invention according to an α-N-acyl-protected-β-substituted alkenophos Phonic acid derivative of the general formula II,

in the
R¹, R² and R³ have the meanings given in the general formula I,
in the presence of a chiral or achiral rhodium complex catalyst of the general formula IV,

in the
X = α-naphthoxyalkyl such as α-naphthoxymethyl and
Y = hydrogen or
XY = a cyclopentane fused in the 1,3-position and
Z = an n-alkyl, iso-alkyl or cycloalkyl group,
is asymmetrically hydrogenated in a solvent or a suspension at temperatures between -20 ° C and + 50 ° C and a hydrogen pressure between 0.05 and 2.0 MPa.

The present invention also encompasses the process of Treatment of the compounds of formula II includes. So these compounds are made from β-substituted-N-acylated ten aminophosphonic acid derivatives of the general formula III,

in the
R¹ = has the meaning given in the general formula I and
R² = represents a benzoyl radical,
via chlorine addition under conversion with P (OR³) ₃, wherein R³ has the meaning given in the general formula I, obtained.

According to the invention for the production of the new connection gene of formula I in optically active form the prochiral Precursors under these mild conditions at high speeds and high stereoselectivity due to the chiral Asymmetrically hydrogenated catalyst, preferably with regard to the speed by the presence of a seven ring linked metal chelates and in terms of stereoselecti vity due to the presence of different phosphorordona Toratoms, which allow preferred conformations.

The hydrogenation can be carried out in alcoholic solution, preferably in methanolic solution, but also in suspensions.

The introduced crystalline ones Rhodium complex catalysts allow the execution of the Pro  Processes at temperatures between -20 ° C and + 50 ° C. Before however, hydrogenation is carried out at room temperature.

The hydrogenations are carried out in a pressure range the between 0.05 and 2.0 MPa hydrogen pressure, preferably two however at normal pressure.

According to the invention, the catalyst does not have to be crystalline lie. It can also be generated in situ from the ligand and a ge suitable cocatalyst such as [Rh (COD) ₂] BF₄ who manufactured the. The cationic form of the complex catalyst will be prefers.

The target product is produced as a racemate in same way using the rhodium catalyst in achiral shape.

The unnatural aminophosphonic acid derivatives obtained, for example the esters and analogues that can be produced from them Acids, due to their potential herbicide, are antibacterial Excellent antibiotic and antiviral activity net. The effect extends to both the phosphonic acid rederivate directly as well as particularly on those with them prepared di- and oligopeptides.

The invention is illustrated by the following examples refines without restricting it.

example 1 α-N-Benzoylamino-β-phenyl-ethylenephosphonic acid dimethyl ester

16.9 g (0.05 mol) of N-benzoylamino-α, β-dichlorocinnamic acid suspended in 25 ml of benzene and 7 ml (0.06 mol) of P (OMe) ₃ added with stirring at room temperature. After decay the reaction is left overnight. The low Impact is filtered off and the filtrate is concentrated in vacuo. The residue crystallizes when ether is added. The order crystallization from ethanol / water gives 6.6 g (39.6%) melting point 151-153 ° C.

Calculated:
C 61.63%; H 5.48%; N 4.23%; P 9.35%;
found:
C 61.65%; H 5.65%; N 4.32%; P 10.81%.
31 P NMR: δ 17.6 ppm (CDCl₃).

Example 2 (S) -α-N-Benzoylamino-β-phenyl-ethylphosphonic acid dimethyl ester

α-N-Benzoylamino-β-phenyl-ethylenephosphonic acid dimethyl esters according to Example 1 (1 mmol) are dissolved in 15 ml of methanol Presence of 0.01 mmol of the complex catalyst (S) -PROPRAPHOS-Rh (1, Formula IV: X = α-naphthoxymethyl, Y = H, Z = isopropyl) at 25 ° C and 0.1 MPa H₂ pressure hy third. In a half-life of 7 min. becomes the reaction approach hydrogenated. Then the solvent in vacuo deducted, the residue dissolved in a few benzene, over a 0.5 cm layer of silica gel filtered, taking the rhodium is removed complex and the filtrate again is narrowed. The yield is 95-99%. The enantiomer excess is 90% and is determined by HPLC on a chira cel OD column (from Baker Chemicals, Groß-Gerau) on the liquid Chromatograph 1090, Hewlett-Packard, determined. Mp 115-118 ° C, HPLG: <99%, C₁₇H₂₀NO₄P (333.3).

Calculated:
C 61.25%; H 6.05%; N 4.20%; P 9.29%;
found:
C 61.28%; H 6.12%; N 4.23%; P 9.91%.

[α] = 101.9 (c = 1.01 methanol). The configuration is the (S) shape.
31 P NMR: δ 27.1 ppm (CDCl₃).

Example 3

Analogously to Example 2, the catalyst (S) -2 (formula IV: X = α-naphthyloxy, Y = H, Z = cyclopentyl) in one half waiting time of 6 min. hydrogenated, the yield 97% and the enantiomeric excess is 91%. The configuration is the (S) -form.  

Example 4

Analogously to Example 2, the catalyst is hydrogenated (R) -1 and worked up. The analog (R) product is created. o. [α] = -80.0 (c = 1.01 MeOH).

Example 5 (S) -α-N-Benzoylamino-β-phenyl-ethylphosphonic acid diethyl ester

α-N-Benzoylamino-β-phenylethylenephosphonic acid diethyl ester is hydrogenated and worked up according to Example 2, where with the yield 96% and the enantiomeric excess 92% is. 0₁₉H₂₄NO₄P (361.4).

Calculated:
C 63.15%; H 6.69%; N 3.88%; P 8.57%;
found:
C 63.40%; H 6.59%; N 4.01%; P 8.51.

[α] = +86.0 (c = 1 MeOH), 31 P NMR: δ 24.6 ppm (CDCl₃), Mp 76-81 ° C.

Example 6 α-N-Benzoylamino-β-4-fluorophenyl ethylene phosphonic acid dimethyl ester

Analogously to Example 1, the dimethyl ester is prepared using 4-fluorobenzaldehyde via oxazolone synthesis according to Erlenmeyer and chlorination to give N-benzoylamino-α, β-dichloro-4-fluorocinnamic acid after conversion with trimethyl phosphite.
Mp 157-159 ° C. C₁₇H₁₇NO₄FP (349.3).

Calculated:
C 58.45%; H 4.91%; N 4.01%; P 8.87%;
found:
C 58.41%; H 4.91%; N 4.21%; P 9.02%.
31 P NMR: δ 17.6 ppm (CDCl₃).

Example 7 (S) -α-N-benzoylamino-β-4-fluorophenylethylphosphonic acid dimethyl ester

Analogously to Example 2, the ester prepared according to Example 6 is hydrogenated and worked up in the presence of catalyst (S) -1. The yield is 96% and the enantiomeric excess 89%. Recrystallized from ethanol / water.
Mp 149-151 ° C, HPLC: 99% ee. C₁₇H₁₉NO₄FP (351.3).

Calculated:
C 58.12%; H 5.45%; N 3.99%; P 8.82%;
found:
C 58.29%; H 5.38%; N 4.04%; P 8.71.

[α] = +98.2 (c = 1.01 MeOH), 31 P NMR: δ 26.9 ppm (CDCl₃).

Example 8 α-N-Benzoylamino-β-2-fluorophenyl ethylene phosphonic acid di methyl ester

The ester is prepared analogously to Example 6. Mp 120-123 ° C, C₁₇H₁₇NO₄FP (349.3).

Calculated:
C 58.45%; H 4.91%; N 4.01%; P 8.87%;
found:
C 58.47%; H 4.86%; N 4.10%; P 9.02%.

31 P NMR: δ 16.8 ppm (CDCl₃).

Example 9 (S) -α-N-benzoylamino-2-fluorophenylethylphosphonic acid dimethyl ester

Analogously to Example 2, the one prepared according to Example 8 is used Ester hydrogenated in the presence of the catalyst (S) -1 and worked, the yield 97% and the enantiomers excess is 92%. An oil is obtained. C₁₇H₁₉NO₄FP (351.3).

Calculated:
C 58.12%; H 5.45%; N 3.99%; P 8.82%;
found:
C 58.58%; H 5.66%; N 3.94%; P 9.64%.

[α] = +97.7 (c = 1.01 MeOH), 31 P NMR: δ 26.6 ppm (CDCl₃).  

Example 10 (S) -α-N-Benzoylamino-β-phenyl-ethylphosphonic acid dimethyl ester

Analogously to Example 2, however, with the use of 10 mmol Substrate and with the catalyst (S) -1 at half value time of 46 min. hydrated. The yield is 96% and that Enantiomeric excess 88%. Analytics see Example 2.

Example 11 (S) -α-N-benzoylamino-β-phenyl-ethylphosphonic acid diethyl ester

Analogous to Example 5, however, with the use of 10 mmol Substrate and with the catalyst (S) -1 at half value time of 70 min. hydrated. The yield is 95% and the enantiomeric excess 89%. Analytics see Example 5.

Example 12 (S) (R) -α-N-benzoylamino-β-phenyl-ethylphosphonic acid di methyl ester

Analogously to Example 2, α-N-benzoylamino-β-phenylethylene is used dimethyl phosphonic acid with the catalyst (S) (R) -1 hydrated. The racemate is obtained. Analytics see Example 2.

Claims (8)

1. aryl-substituted aminoacylated phosphonic acid derivatives of the general formula I, in which mean:
R¹ = phenyl, fluorophenyl such as 2-, 3- or 4-fluorophenyl, nitrophenyl such as 4-nitrophenyl, trifluoromethylphenyl, alkylphenyl such as 4-methylphenyl, alkoxyphenyl such as 4-methoxyphenyl or dimethoxyphenyl, biphenyl, thienyl such as 2- or 3-thienyl, furyl such as 2- or 3-furyl, pyridyl such as 3- or 4-pyridyl, naphthyl such as 1- or 2-naphthyl, anthracenyl,
R² = formyl, acetyl, benzoyl, benzyloxycarbonyl (CbZ), tert-butoxycarbonyl (BOC), o-nitrobenzoyl,
R³ = methyl, ethyl, propyl, isopropyl. 2. A process for the preparation of the compounds of the formula I according to claim 1, characterized in that an α-N-acyl-protected-β-substituted alkenophosphonic acid derivative of the general formula II, in the
R¹, R² and R³ have the meanings given in the general formula I,
in the presence of a chiral or achiral rhodium complex catalyst of the general formula IV, in the
X = α-naphthoxyalkyl such as α-naphthoxymethyl,
Y = hydrogen or
XY = a cyclopentane fused in the 1,3-position and
Z = an n-alkyl, iso-alkyl or cycloalkyl group,
is asymmetrically hydrogenated in a solvent or a suspension at temperatures between -20 ° C and + 50 ° C and a hydrogen pressure between 0.05 and 2.0 MPa. 3. The method according to claim 2, characterized in that hydrogenation in alcoholic solution, preferably in metha nolischer solution, or suspension. 4. The method according to claim 2, characterized in that is hydrogenated at normal pressure. 5. The method according to claim 2, characterized in that the catalyst in crystalline form or in situ from the Ligands and a suitable cocatalyst such as [Rh (COD) ₂] BF₄ is used. 6. The method according to claim 2, characterized in that the racemate by using the rhodium catalyst in achiral form is obtained.   7. The method according to claim 2, characterized in that the α-N-acyl-protected-β-substituted Alkenphosphonsäu rederivat of formula II from a β-substituted-N-acylated aminophosphonic acid derivative of the general formula III, in the
R¹ = has the meaning given in the general formula I and
R² = represents a benzoyl radical,
via chlorine addition under conversion with B (OR³) ₃, wherein R³ has the meaning given in the general formula I, is obtained. 8. Use of the manufactured according to claims 2 to 6 connections and the di- and Oligopeptides as a herbicide, bactericide, antibiotic or as an antiviral.