PL148859B1 - Method of obtaining aminophosphonic esters - Google Patents

Description

The present invention relates to a process for the preparation of aminophosphonic acid esters of general formula 1f in which R is hydrogen, lower alkyl or cycloalks, R2 is hydrogen, lower alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, aminoalkyl, or R and R together with carbon atom. they are placed on a cycloalkyl ring, R5 is alkoxy, lower alkyl or aryl, R is lower alkyl, and n = 0,1,2,3.

These esters are isolated in the free state, or optionally in the form of their salts, preferably oxalates.

Aminophosphonic acid esters in free and salt form are used as substrates in the synthesis of antibacterial and herbicidal phosphonopeptides, which is known from the Polish patent specification No. 112 289 and from B. Lejczak, P. Katarski, H. Sztajer, P. Mastalerz, J.Med. Chem., 29, 2212/1986 /, P. Kafarski, B. Lejczak, M. Mastalerz, J. Szewczyk, C. Kfesielewski, Can. J. Chem., 60, 3081 (1982), B.Lejczak, P.Kafarski, R.Gancarz, E.Jaskulska, P.Mastalerz, J.S.Wieczorek, M.Król Pestic Sci., 16, 227 (1985).

All the methods known to date for the preparation of aminophosphonic acid esters are based on multistage syntheses, one of which is the formation of a phosphor-carbon bond, and none of these methods are general enough to maintain all types of these connections. The main disadvantage of these methods in the production of aminophosphonic acid esters is the need to select appropriate substrates and production methods depending on the chemical structure of the desired product and the multistage of the reaction, which in turn causes a significant reduction in the overall efficiency of the process, as well as the need to use many different methods of purifying the final product. and intermediate products. A further disadvantage is often the need to prepare a suitable reaction substrate. 148 8592 148 859 Known from the publication: J.Kowalik, L.Kupczyk-Subotkowska, P.Mastalerz, Synthesis 57/1981 / the method of obtaining 1-aminoalkanephosphonic acid esters consists in reacting the acid chloride with trialkyl phosphite in the first stage , isolates the reaction product of the dialkyl 1-oxane alkanophosphonate by distillation under reduced pressure, transforms it in the second step in an oxime treatment with hydroxylamine in alcohol, and the obtained dialkyl 1-hydroxyiminoalkanephosphonate is reduced with zinc in anhydrous formic acid and the ester obtained is separated as the oxalate.

Known from the writings of: W. Kochmann, Z.Chem. 16, 184/1976 /, T.Ya.Medved, M.I.Kabachnik, Izv. Akad. Nauk SSSR, ser. khim., 314/1954 / and 1357/1957 / the method of preparing 1-aminoalkanephosphonic acid esters consists in heating a mixture of dialkyl phosphite, aldehyde or ketone and gaseous ammonia in an autoclave, and then separates the dialkyl 1-hydroxyphosphonate and the desired ester by distillation under reduced pressure. The yields of both known methods of obtaining 1-aminoalkanephosphonic acid dialkyl esters do not exceed 5096.

The known method of preparing 2-aminoethanephosphonic acid dialkyl esters described in the publication: P. Kafarski, P. Mastalerz, Annals of Chemistry 51, 433 (1977) consists in obtaining in the first stage dialkyl cyano-methane phosphonates by reacting chloroacetonitrile with trialkyl phosphite, and then reducing this product with hydrogen in an autoclave in the presence of excess ammonia gas. Vacuum distillation of the reaction mixture yields the desired ester. The overall yield of this method of production is about 4 ($.

The invention relates to a process for the preparation of aminophosphonic acid esters of general formula I wherein R is hydrogen, lower alkyl or cycloalkyl, R is hydrogen, lower alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, aminoalkyl or R and R together with a carbon atom. on which they are located is a cycloalkyl ring, R4 is alkoxy, lower alkyl or aryl, R is lower alkyl, and n * 0,1,2,3.

The essence of the invention consists in boiling the aminophosphonic acids with an excess of preferably 5-20 times in excess of the trialkyl orthoformate until the substrates react, and then the N-formyl-aminophosphonic acid dialkyl ester is separated from the post-reaction mixture, and then in any desired The known process is converted into a halide of an aminophosphonic acid dialkyl ester, which is also converted into the free ester of aminophosphonic acid in any known manner.

The essential technical advantage of the process according to the invention is the use of readily available aminophosphonic acids as starting materials for the preparation of their dialkyl esters. An additional significant advantage of this method is the simple production technology and the high reaction yield, usually exceeding 5 ($, which is not achievable with the methods known to date. The ester prepared according to the invention can be converted into a salt thereof, preferably oxalate, in any known manner.

The invention is illustrated in the working examples and in the reaction scheme.

Example 1 2.2 g (0.22 mole) of aminomethanophosphonic acid is refluxed with 70 ml of ethyl orthoformate for 6 hours, removing the ethanol formed. After filtering off the unreacted aminomethanophosphonic acid and evaporating the volatile components of the reaction mixture under reduced pressure, diethyl-N-formylaminomethanophosphonate is obtained, which is dissolved in a saturated solution of hydrogen chloride in methanol and left for 12 hours. After the excess hydrogen chloride and methanol have been distilled off under reduced pressure, 2.35 g of diethyl aminomethane phosphonate hydrochloride are obtained in the theoretical yield of 5% as an oil. The structure of this salt is confirmed by the 1 H NMR spectrum (in D 2 O) 6 in ppm: 1.65 (triplet, J 7.5 Hz, 6H, 2xCH 3), 3.80 (doublet, J = 14 Hz, 2H, CH2), 4. 34 (qq, J 7.5 Hz, 4H, 2xOCH2) .148 859 3 Example II. The procedure is analogous to that in Example 1, except that the separated diethyl aminomethanophosphonate hydrochloride is converted into diethyl aminomethanophosphonate by dissolving it in 50 ml of chloroform, adding excess potassium carbonate and stirring for 2 hours. After filtering off the solids and removing the chloroform by distillation, a yield of 51% of theory is obtained, 1.75 g of diethyl aminomethane phosphonate. The structure of this ester is confirmed by the H NMR spectrum (in D 2 O) (f in ppm: 1.63 (triplet, J 7.5 Hz, 6H, 2xCH 3), 3.79 (doublet, J 14 Hz, 2H, CH 2 P (f 4.36) / quartet-quartet, J 7.5 Hz, 4H, 2xOCH3 /.

Example III. The procedure is analogous to that of Example II, except that diethyl aminomethylphosphonate is dissolved in dry ether and an equimolar amount, i.e. 0.95 g of anhydrous oxalic acid in ether, is added. The precipitated oxalate, mp 394-396 K, is collected by filtration. The overall yield of this process is 50% of the theoretical amount.

Example IV. The procedure is analogous to that of Example III, with the difference that 2.5 g (0.02 mol) of 1-aminoethane phosphonic acid is used instead of aminomethanophosphonic acid. This gives 2.75 g of diethyl 1-aminoethanephosphonate oxalate, m.p. 392-394 K, with a yield of 51% of theory.

EXAMPLE 5 The procedure is analogous to that of Example IV, except that instead of ethyl orthoformate, 120 ml of methyl orthoformate are used and heating is continued for 10 hours. This gives 2.5 g of dimethyl 1-aminoethanephosphonate oxalate, m.p. 396-398 K, and a yield of 50% of theory.

Example VI. The procedure is analogous to Example III, with the difference that 2.5 g (0.02 mol) of aminomethane / P-ethyl / phosphinic acid are used instead of aminomethanophosphonic acid. There are obtained 3 * 5 g of aminomethane (p-ethyl) oxalate ethyl phosphinate with a yield of 72% of theory and a melting point of 377-379 K.

Example VII. The procedure is analogous to that of Example 3, except that 3.7 g (0.22 moles) of 1-aminoethane (P-phenyl) phosphinic acid are used instead of aminomethanophosphonic acid. The yield is 86% of theory, 5.2 g of ethyl 1-aminoethane oxalate / P-phenyl / ethyl phosphinate, mp 409-411 K.

Example VIII. The procedure is analogous to that in example III, with the difference that 3.35 g (0.02 moles) of 1-amino-1,2-dimethylpropane-phosphonic acid are used instead of aminomethanophosphonic acid. This is obtained with a yield of 72% of theoretical yield 4. 5 of diethyl 1-amino-1,2-dimethylprpanophosphonate oxalate, m.p. 397-398 K.

Example IX. The procedure is analogous to that in Example III, except that 3.3 g (0.22 moles) of 1-amino-cyclopentane-phosphonic acid are used instead of aminomethanophosphonic acid. The yield of 63% of theory is obtained 3.9 g of diethyl 1-aminocyclopentanephosphonate oxalate with a melting point of 355-356 K.

Example X The procedure is analogous to that of Example III, except that 3.8 g (0.22 moles) of amino-dicyclopropylmethanophosphonic acid are used instead of aminomethanophosphonic acid. With a yield of 52% of theory, 3.5 g of diethyl aminodicyclopropylmethynophosphonate oxalate are obtained in the form of thick oil.

The structure of this salt is confirmed by the 1H NMR spectrum (in D 2 O) in ppm: 1.67 and 1.71 (triplet, J 7.5 Hz, 3H, CH 2), 1.3-2.7 (multiplet, 10H4xCH2, 2xCH) /, 4.35-4.8 (multiplet, 10H4xCH22xCH), 4.35-4.8 (multiplet, 4H, 2xOCH2).

Example XI. The procedure is analogous to that of Example III, except that 4.0 g (0.02 mole) of 2-amino-1-phenylethanophosphonic acid are used instead of aminomethanophosphonic acid. The yield is 93% of theory 7.5 g of diethyl 2-amino-1-phenylethanophosphonium oxalate, m.p. 404-405 K.4 148 359 Example XII. The procedure is analogous to that in Example III, with the difference that 3.0 g (0.22 mol) of 4-amino-butane-phosphonic acid are used instead of aminomethanophosphonic acid. The yield of 5% of theoretical yield is 3.2 g of diethyl 4-aminobutanephosphonate oxalate, mp 405-406 K.

PATENT APPLICATION A method for the preparation of aminophosphonic acid esters of the general formula 1, wherein 1 2 R is hydrogen, lower alkyl or cycloalkyl, R is hydrogen, lower 1 2 alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, aminoelkyl, or R and R together with the carbon atoms on which they are located constitute a cycloalkyl ring, R 5 is alkoxy, lower alkyl or aryl, R is lower alkyl, n = 0,1,2,3, characterized by that the aminophosphonic acids are boiled with an excess, preferably 5-20 times, of the trialkyl orthoformate until the reactants have reacted, and then the dialkyl ester of N-formylaminophosphonic acid is separated from the reaction mixture, which then is converted into the halide of the dialkyl ester of the acid in a known manner aminophosphonic acid, which is also converted into the free ester of the aminophosphonic acid by any known method.

R <O PATTERN. 1 R * OH * 'fe -QRH hx / ch3om R * OR * & NOR.

R5 * OH Utb R3 5t »Printing office of the Polish Patent Office. Mintage 100 copies

Price 1500 PLN