PL149757B1 - Method of obtaining novel esters of n-/triarylmethyl/-1-aminoalkyl phosphonic acids in particular n-/triarylmethyl/ aminomethylphosphonic esters - Google Patents

Description

PATENT DESCRIPTION

149 757

Additional patent to patent no. Applied for: ⁸⁷ ° 5 12 (p. 265687)

Precedence —C z n c l n 1 a

Patent Office hla!

Int. Cl. ⁴ C07F 9/4 <l

OFFICE

PATENT

PRL

Application announced: 88 11 24 Patent description was published: 90 07 31

Creators of the invention: Mirosław Soroka, Jan Zygmunt

Entitled by the patent: Wrocław University of Technology, Wrocław (Poland)

METHOD OF MAKING NEW LISTS OF N- / TRIARYIL-METHYL0 / -1-AMINO-ALKYLPHOSPHONIC ACIDS, ESPECIALLY ESTERS OF N- / TRIARYLOMETHYL / -AMINOMETHYLPHOSPHONIC

The present invention relates to a process for the preparation of N- (triarylmethyl) 1-aminoalkylphosphonic acid esters represented by the general formula 1, wherein Ar is phenyl,

R is an alkyl or hydrogen radical and R * is an alkyl or phenyl radical. The invention relates in particular to a process for the preparation of new N- (triary lornethyl / aminomethylphosphonic acid esters) represented by the general formula 1, in which Ar and R * have the above meanings, and R is hydrogen.

Esters of N- / triarylmethyl / -1-aminoalkylphosphonic acids are widely used for the synthesis of various, functional derivatives of 1-aminoalkylphosphonic acids, especially esters of 1-aminoalkylphosphonic acids, which are substrates for the synthesis of various technically useful derivatives, especially phosphonopeptides characterized by strong activity biological. Moreover, these compounds are substrates for the synthesis of the known 1-aminoalkylphosphonic acids, in particular amino methylphosphonic acid.

So far, there is no known process for the preparation of N- (triarylmethyl) 1-aminoalkylphosphonic acid esters.

The process according to the invention consists in reacting one mole part of an N-alkylidene triarylmethylamine of the general formula II, in which Ar and R have the previously given meanings, with at least one mole part of an acid phosphite of the general formula III, in which R * has the meanings given previously, the reaction being carried out at a temperature of 270-400 K, preferably at a temperature of about 370 K, preferably in an organic solvent, which may be, in particular, an excess of acid phosphite, until the reactants have reacted, and the product is then isolated by any known method , preferably by distilling off the solvent under reduced pressure and crystallizing the residue.

149 757

In a variant of the process according to the invention, instead of pure N-alkylidene triarylmethylaraine, the crude condensation product of one mole part of triarylmethylamine is reacted with at least one mole part of an alkanol of general formula IV, the reactions being carried out analogously to the previous procedure.

A variant of the process according to the invention also consists in that an N-alkylidenetriarylamine of the general formula II is prepared in the presence of an acid phosphite of the general formula III and the reaction is continued under the same conditions as before.

The main technical and operational advantage resulting from the use of the method according to the invention is the preparation of new esters of N- / triarylmethyl / -1-aminoalkylphosphonic acids, especially N- / triarylornethyl / aminomethylphosphonic acid esters, with yields above 70% in a crystalline form, which are sufficiently pure and they are directly applicable as intermediates for the synthesis of many different 1-aminoalkanoic acid derivatives. Also, thanks to their crystalline form, they can be easily brought to a state of high purity by means of additional crystallization.

The subject matter of the invention is presented in the examples.

Example I. A mixture of N-methylidene-triphenylmethylamine (2.71 g,

0.010 mol) and dimethyl phosphite (5 * 50 g, 0.050 mol) are heated in a bath with a temperature of about 370 K, which causes the dissolution of the reactants, followed by the separation of the crystalline product, combined with an increase in the temperature of the reaction mixture due to a slightly exothermic effect of this reaction. Heating is continued for about 0.5 hours, then the mixture is cooled to room temperature, then mixed with methanol (20 ml) and allowed to crystallize at a temperature below 260 K for several hours. The crystalline solid is filtered, washed with cold methanol (3 x 10 ml) and then air dried at approximately 310 K for several hours. Obtained as a result of dimethyl N- / triphenethyl / aminomethylphosphonate (3.60 g, 95% yield) as a white, crystalline product with a melting point of 483-484 K (chloroform / methanol), the identity of which is confirmed by spectroscopic data: IR (KBr): 3330w (NH); 3080w, 3065w, 3O2Ow, (ArH); 2950w, 2860w, 2810w (CH); 1595w (ArH); 1480m, I445m (CH); 1230s (P-0); 1O45s, 1015vs (P-O-C); 885s, 845s, 770s, 610s. 1WR (chloroform-d, ppm): 2.07t, br (1H, NH, J? 7Hz); 2.61 dxd (2H, J? 7 Hz, J? 13.5 Hz); 3.84d (6H, J-11Hz); 7.2-7.6β (15H).

Example II. A mixture of N-ethylidene triphenylmethylamine (2.85 g,

0.010 mol) and dimethyl phosphite (5.50 g, 0.050 mol) were heated in a bath of about 370 K, which causes the dissolution of the substrates. Then, heating is continued for an hour, then the excess phosphite is distilled off under reduced pressure from a bath at a temperature of about 370 K, and the obtained solid residue is mixed with methanol (10 ml) and allowed to crystallize at a temperature below 260 K for several hours. The crystalline solid is filtered, washed with cold methanol (3 x 5 ml) and then air dried at about 310 K for several hours. The result is dimethyl N- (triphenylmethyl) -1-aminoethylphosphonate (2.96 g, 75% yield) as a white, crystalline product with a melting point with decomposition of 464-468 K (methanol), the identity of which is confirmed by spectroscopic data:

IR (KBr): 3265s (NH); 3085w, 306Ow, 3020w (ArH); 2955w, 2915w, 2 & 45w (CH); 1595w (ArH), 1485m, 1440m (CH); 1230vs (P> 0); 1O55s, 1020s (P-O-C); 825s, 790s, 735m, 700s. NMR (chloroform-d, ppm): 0.47dxd (3H, J = 7Hz, J = 18Hz); 2.9d (1H, NH, J = 7Hz);

3.2m (1H); 3.78d and 3.82d (6H, J = 11Hz); 7.1-7.4m (9H, aroma); 7.5-7.8m (6H, aroma).

Example III. The procedure is as in Example 2 with the difference that instead of dimethyl phosphite (5.50 g, 0.050 mol), a mixture of dimethyl phosphite (2.20 g, 0.020 mol) and toluene (10 ml) is used and the reaction mixture is heated under with reflux for 2 hours.

149 757

Obtained as a result of dimethyl N- (triphenylmethyl) -1-aminoethylphosphonate (2.80 g, 72% yield) as a white, crystalline product with a melting point of 464-468 K (methanol), the identity of which is confirmed by spectroscopic data: IR (KBr): 3265s (NH); 3O85w, 3O6Ow, 3020w (ArH); 2955w, 2915w,

2845w (CH); 1595w (ArH); 1485m, 1440m (CH); 1230vs (P-0); 1O55s, 1020s (P-O-C);

825s, 790s, 735®, 700s. IWR (chloroform-d, cf, ppm): 0.47dxd (3H, J? 7Hz, J? 18Hz);

2.9d (1H, NH, J-7Hz); 3.2m (1H); 3.78d and 3.82d (6H, J-11Hz); 7.1-7.4m (9H, aroma); 7.5-7.8m (6H, aroma).

Example IV. A mixture of N- (2-methylpropylidene) triphenylmethylamine (3.13 g, 0.010 mol) and dimethyl phosphite (5.50 g, 0.050 mol) is heated in a 370 K bath, which causes the dissolution of the starting materials. Then the heating is continued for 2 hours, then the excess phosphite is distilled off under reduced pressure from a bath of about 370 K, and the oily residue obtained is treated with boiling hexane (20 ml) and allowed to crystallize at a temperature below 260 K for several hours. The crystalline precipitate is filtered, washed with cold hexane (3 x 5 ml) and then air dried at about 310 K for several hours.

There is obtained dimethyl N- (triphenylmethyl) -1-amino-2-methylpropylphosphonate (2.75 g, 65% yield) as a white, crystalline product with a melting point of 405-407 K (hexane), the identity of which is confirmed by spectroscopic data : IR (KBr): 3325m (NH); 3O6Ow, 3030w (ArH); 2980w, 2950m, 2875w,

2850w (CH); 1590w (ArH); 1470m, 1435m (CH); 1225s (P-0); 1050s, 1020vs (P-O-C);

810s, 765s, 740s, 690s. NMR (chloroform-d, 6, ppm): 0.95d and 1.02d (6H, J = 2.5 Hz, J -1.5 Hz); 1.5m (1H); 2.8d, broad (1H, NH); 3.00dxdxd (1H, J = 2Hz, J-21.5Hz);

3.76d and 3.78d (6H, J-10.5Hz); 7.4-7.6m (9H); 7.7-7.9m (6H);

Example 5 The procedure is as in Example 4, except that N-propylidene-triphenylmethylamine (2.99 g, 0.010 mol) is used instead of N- (2-methylpropylidene) - N-propylidene triphenylmethylamine. Dimethyl 1-aminopropylphosphonate (2.86 g, 70% yield) as a white, crystalline product with a melting point with a decomposition of 416-417.5K (methanol), the identity of which is confirmed by spectroscopic data: IR (KBr): 3255s (NH); 3O55w, 3020w, (ArH); 2990w, 2950w, 2875w, 2840w (CH); 1590w (ArH); 1480m, 1440m (CH);

1225vs (P-0); 1050s, 1015vs (P-O-C); 825m, 765s, 735m, 695s. NMR (chloroform-d, 6, ppm): 0.63t (3H, J = 6Hz); 1.0m (2H); 2.3s, widen. (1H, NH); 3.O5dxt (1H, J = 6Hz, J? 19Hz); 3.85d (6H, J = 10.5Hz); 7.2-7.4m (9H, aroma); 7.6-7.8m (6H, aroma).

Example VI. The procedure is as in Example 4, except that N- (3-methylbutylidene / triphenethylamine (3.27 g, 0.010 mol) is used instead of N- (2-methylpropylidene). phenylethyl / 1-amino-3-methylbutylphosphonate dimethyl (3.27 g, 75% yield) as a white, crystalline product with a melting point of 364-368 K (hexane), the identity of which is confirmed by spectroscopic data: IR (KBr) : 3260m (NH); 3O55w, 3020w (ArH); 2990w, 2950w, 2860w, 2840w (CH); 1590w (ArH); 1480m,

1440m (CH); 1225vs (P-0); 1045s, 1015s (P-O-C); 825m, 78cm, 770m, 700s. NMR (chloroform-d, ci, ppm): 0.55d and 0.60d (6R, J = 6.5); 0.9-1.7m (1H + 2H); 2.35s, extend.

(1H, NH); 2.92dxt (1H, J-5Hz, J = 16Hz); 3.33d (6H, J = 10.5HZ-); 7.2-6.4m (9H, aroma); 7.5-7.7m (6 lb, aromatic).

Example VII. The procedure is as in example 2 with the difference that instead of N-ethylidene-triphene lornethylamine, a reaction mixture obtained by heating under reflux for 2 hours of triphenylmethylamine (2.59 g, 0.010 mol) and ethanal (0.66 g, 0.015 mol) is used. in benzene (10 ml), separation

149,757 water and evaporation of the solvent in vacuo afforded dimethyl N- (triphenylmethyl) -1-aminoethyphosphonate (2.84 g, 72% yield) as a white crystalline product, m.p. decomposition of 464-468 K (methanol), the identity of which is confirmed by spectroscopic data:

IR (KBr): 3265s (NH); 3085 *, 3060 *, 3020 * (ArH); 2955 *, 2915w, 2845w (CH); 1595 * (ArH); 1485m, 1440m (CH); 1230vs (P-0); 1O55s, 1020s (P-O-e); 825s, 790s, 735m, 700s. NMR (chloroform-d, E, ppm): 0.47dxd (3H, J = 7Hz, J = 18Hz); 2.9d (1H, NH, J = 7Hz);

3-2m (1H); 3.78d and 3.82d (6H, J-11Hz); 7.1-7.4m (9H, aroma); 7.5-7.8m (6H, aroma).

Example VIII. A mixture of triphenylmethylamine (2.59 g, 0.01 mol), ethanol (0.66 g, 0.015 mol), toluene (10 ml) and dimethyl phosphite (1.1 g,

0.01 mol) is heated to reflux for 2 hours, removing the azeotropically evolving water in a Dean-Stark apparatus, then volatile components are evaporated under reduced pressure from a bath of about 370 K, and the resulting solid residue is treated with methanol (10 ml) and left to crystallize at a temperature below 260 K for several hours. The crystalline precipitate is filtered off, washed with cold methanol (3 x 5 ml) and then air dried at approximately 310 K for several hours. Obtained as a result of dimethyl N- (triphenylmethyl) -1-aminoethylphosphonate (2.96 g, 75% yield) in the form of a white, crystalline product with a melting point of 464-468 K (methanol), the identity of which is confirmed by spectroscopic data: IR ( KBr): 3265s (NH); 3085w, 3060m, 3020w (ArH); 2955 * »2915 *» 2845w (CH); 1595 * (ArH); I485m, 1440m (CH); 1230vs (P = 0); 1O55s, 1020s (P-O-C); 825s, 790s,

735m, 700s. NMR (chloroform-d), d *, ppm): 0.47dxd (3H, J = 7Hz, J = 18Hz); 2.9d (1H,

NH, J-7Hz); 3.2m (1H); 3.78d and 3.82d (6H, J? 11Hz); 7.1-7.4m (9H, aroma); 7.5-7.8m (6H, aroma).

Example IX. The procedure is as in * Example 1, with the difference that instead of dimethyl phosphite, diethyl phosphite (4.14 g, 0.030 mol) is used, an analogous procedure gives the N- / lornethyl / aminomethyl-phosphonate diethyl Io-phosphonate ( 1.85 g, 90% yield) as a crystalline product with a melting point of 388-390 K (chloroform / methanol), the identity of which is confirmed by spectroscopic data: IR (KBr): 3280s (NH); 3080w, 306Ow, 3020 * (ArH); 29B5m, 2905 *, 2870w, 2825 * (CH); 1595 * (ArH); 1485m, 1440m (CH); 1235s (P <0); 1045s, 1015vs (P-O-C); 965s, 820s, 745s, 695s. NMR (chloroform-d, &lt; 5, ppm): 1.42t (6H, J? 7.3Hz); 2.3s, broad (1H, NH); 2.55d (2H, J-14Hz); 4.25dxq (4H, J? 7.3Hz, J-7Hz); 7.2-7.7m (15H).

EXAMPLE 10 The procedure is as in * Example 1, except that diphenylphosphite (2.58 g, 0.011 mol) is used instead of dimethyl phosphite (2.58 g, 0.011 mol), an analogous procedure gives N- / triphenylmethyl / aminomethylphosphonate diphenyl (4.95 g. 98% yield) as a crystalline product with a melting point of 403-409 K (benzene / hexane), the identity of which is confirmed by spectroscopic data: IR (KBr): 3290 *, (NH); 3060w, 3025 * (ArH); 2940 *, 2865 *, 2815 * (CH); 1585m (ArH); 1480s, 1440® (CH); 1260s (P <O); 1180s,

1160s (P-O-C); 950s, 760s, 700s, 685s. MIR (chloroform-d, α2 ppm): 2.3t, broad (1H, NH); 2.95dxd (2H, J = 5Hz, J &lt;14Hz); 7.3-7.6o (25H); on addition of deuterium oxide, signal 2.3 disappears, while signal 2.95 gives a doublet.

149 757

Claims (3)

Patent claims 1. Method for the preparation of new esters of N- (triarylmethyl / -1-aminoalkylphosphonic acids, especially N- (triarylornethyl / aminomethyl phosphonic acid esters) represented by the general formula 1, in which Ar is phenyl, R is an alkyl radical or hydrogen, preferably R is a hydrogen atom, and R * is an alkyl or phenyl radical, characterized in that one mole moiety of the N-alkylidene triarylornethylamine of the general formula II, in which Ar and R are as defined above, is reacted with at least one part molar ratio of acid phosphite of the general formula III, in which R * is as defined above, and the reaction is carried out at a temperature of 270-400 K, preferably at a temperature of about 370 K, preferably in an organic solvent, which may be in particular an excess of acid phosphite, until to react the reactants, and then isolating the product by any known means, preferably by distilling off the solvent under reduced pressure, and crystallization remains s. 2. A method for the preparation of new N- (triarylmethyl / -1-aminoalkylphosphonic acid esters, especially N- (triarylmethyl) aminomethylphosphonic acid esters represented by the general formula 1, in which Ar is phenyl, R is an alkyl radical or hydrogen, preferably R is a hydrogen atom, and R * represents an alkyl or phenyl radical, characterized in that one mole part of the triarylornethylamine is reacted with at least one mole part of the aldehyde of formula IV, in which R is as defined above, the reaction being carried out in an organic solvent at a temperature of 270-370 K, preferably at the boiling point of the organic solvent, and then, after the water has been separated off in any known manner, the solvent is evaporated off under reduced pressure and the remaining crude condensation product is reacted with an acid phosphite of the general formula 3, wherein R * is as defined above, the reaction being carried out at a temperature of 270-400 K, preferably at a temperature of about 370 K, preferably in an organic solvent, which may be in particular an excess of acid phosphite, until the reactants have reacted, and then the product is isolated by any known method, preferably by distilling off the solvent under reduced pressure and crystallizing the residue. Method for the preparation of new esters of N- (triarylmethyl / -1-aminoalkylphosphonic acids, especially esters of N- (triarylmethyl / aminomethylphosphonic acids) represented by the general formula 1, in which Ar is phenyl, R is an alkyl radical or hydrogen , preferably R is a hydrogen atom, and R * is an alkyl or phenyl radical, characterized in that one mole part of the triarylmethylamine is reacted with at least one mole part of an alkanal of the general formula IV in which R is as defined above, in the presence of an acidic acid. a phosphite of the general formula 3 &lt; * &gt; in which R * is as defined above, and the reaction is carried out at a temperature of 270-400 K, preferably at a temperature of about 370 K, preferably in an organic solvent, which may in particular be an excess of acid phosphite, until the reactants have reacted, and then the product is isolated by any known method, preferably by distilling off the solvent under reduced pressure and crystallizing the residue. 149 757 R Ar ₃ C-NH-CH-P (O) (OR ') ₂ MODEL 1. R-CH = N-CAr ₃ PATTERN 2. hp (o) (or ') ₂ MODEL 3. R-CHO MODEL 4. Printing House of the Polish Patent Office. Circulation 100 copies Price 1500 PLN