DD230865B1 - PROCESS FOR THE PREPARATION OF HYDRAZINOCARBONSAEUREDERIVATES BY N-AMINATION OF AMINOCARBONSAEUREDERIVATES - Google Patents

Description

For this 2 pages formulas

Field of application of the invention

The invention relates to a process for the preparation of hydrazino carboxylic acid derivatives by N-amination of aminocarboxylic acid derivatives.

Hydrazinocarboxylic acids and their derivatives are useful as intermediates, eg. B. for the synthesis of peptide analogues, or as biologically active compounds of interest (W. Knobloch et al., J. prakt. Chem., 36 [1967], 29).

For example, L-2-hydrazino-2- (3,4-dihydroxybenzyl) -propionic acid is an effective L-DOPA decarboxylase inhibitor that does not pass through the blood-brain barrier.

Characteristic of the known state of the art

It has already been proposed in DD-PS 240818, optically active hydrazinocarboxylic acids of the general formula I, in

R ¹ to R ⁴ = H, alkyl (C ₁ to C ₈ , branched or unbranched, optionally substituted), aryl or aralkyl (such as eg.

Phenyl, benzyl, also substituted, ζ. By hydroxy, alkoxy, acyloxy, alkyl, alkoxyalkylideneoxy and

Alkylidenedioxy groups, preferably in the 4- or 3,4-position), η = 0 (α-hydrazinocarboxylic acid derivatives), 1 to 6,

R ⁵ = COOR ⁶ , CN, CONH ₂ ,

R ^e = H, alkyl (C ₁ to C ₁₈ , branched or unbranched, optionally substituted), aryl or aralkyl

(optionally substituted),

mean, by N-amination of amino acid derivatives of the formula II, in which R ⁷ to R ¹⁰ and R ¹¹ for R ¹ to R ⁴ or

R ⁵ have the meaning given (R " Φ COOH), with an oxaziridine of the general formula III in which R ¹² and R ¹³ = H, alkyl (C ¹ to C ₁₈ , branched or unbranched, optionally substituted or members of a common ring) to represent.

As starting materials of this process hitherto aminocarboxylic acid compounds of the general formula II have been used with derivatized in any structural case carboxyl function R ¹¹ (eg., Carboxylic acid esters, amides or nitriles).

The application of the insoluble or sparingly soluble in the aminating free aminocarboxylic acids, however, did not lead to hydrazino carboxylic acids, but with accelerated thermal decomposition of the oxaziridine to form nitrogen-free compounds and chemically undefined, strongly colored decomposition products.

If the substituent R ⁷ also contained phenolic hydroxyl groups, they had to be in etherified or esterified form to avoid side reactions in order to obtain products of high quality which are suitable, for example, for pharmaceutical applications, at all costly and uneconomical purification steps (chromatographic separation processes) ,

If it was also desired to eliminate these protective groups in the isolation of the object compounds I, the use of partly drastic reaction conditions (for example concentrated hydrobromic acid, higher temperatures) associated with yield losses was necessary.

In this way, it was possible for the first time, from the esterified La-methyl-DOPA precursor of the formula IV the already mentioned effective decarboxylase inhibitor L-2-hydrazino-2- (3,4-dihydroxybenzyl) propionic acid with the help of a few technological steps in good Yield and quality.

Furthermore, it is known that o-dihydroxybenzene derivatives can be easily reacted with boric acid or boric acid compounds because of the sterically induced stability of the resulting cyclic orthoboric acid esters (five- and six-membered structures) (Houben-Weyl, Meth. D. Org. Ch., Vol VI / 2 [1963], 205).

The esterification can also be carried out in aqueous solution with boric acid salts (Houben-Weyl, Meth. D. Org. Ch., Vol. VI / 2 [1963], 209.221 to 225).

Thus, from aqueous solution with catechol and boric acid in the presence of sodium ions even the corresponding 2,2-dihydroxy-benzo-1,3,2, -dioxa-borolates of the formula V (Monobrenzcatechinborate) isolated (H. Schäfer, Z. Anorg. Ch.

250 [1942], 127).

Compounds of this type are suitable for the temporary protection of orthoständiger phenolic hydroxy groups and were therefore used to increase the selectivity of N-acetylation of phenylalanine derivatives (DE-OS 21 53823 of 28/10/1971).

In contrast, for the preparation of hydrazinocarboxylic acid derivatives, in particular by N-amination of aminocarboxylic acid derivatives, no starting products have been used with esterified by boric acid phenolic hydroxy groups and boric acid and their compounds are not added as adjuvants in such reactions.

Object of the invention

The object of the invention is to prepare hydrazino carboxylic acids or their esters by a novel process for the N-amination of readily available, N-unprotected 3,4-dihydroxybenzyl-substituted amino acids or amino acid esters in a rational procedure, with any asymmetric center present being retained.

Explanation of the essence of the invention

The invention has for its object to develop a generally applicable, technically simple and safe process for the preparation of hydrazino carboxylic acids, which does not have the disadvantages of the previously known method by appropriate choice of the reaction conditions.

There has now been a process for the preparation of hydrazinocarboxylic acid derivatives of the general formula VI in which

R ¹ = 3,4-dihydroxybenzyl,

R ² to R ⁴ = H, alkyl (C ₁ to C ₁₈ , branched or unbranched, optionally substituted),

η = O (α-hydrazinocarboxylic acid derivatives), 1 to 6,

R ⁵ = COOR ⁶ ,

R ⁶ = H, alkyl (C ₁ to C ₁₈ , branched or unbranched, optionally substituted),

mean, found by an amino acid derivative of the general formula VII, in which R ⁷ to R ¹⁰ and R ^{11 have} the meaning given for R ¹ to R ⁴ or R ⁵ , but need not be identical to these, and R ^{11 is} a carboxyl radical in which the hydrogen is replaced by an alkali or alkaline earth metal atom, with an oxaziridine of the general formula VIII, in which R ¹² and R ¹³ = H, alkyl having C ₁ to C ₁₈ , the branched or in the presence of a solvent at a temperature of -20 to + 200 ° C and subsequent addition of aqueous mineral acid, wherein by removing the water and excess mineral acid and / or by adjusting a certain pH range, optionally in a further solvent, the target products Vl in substance, usually in crystalline form, are isolated, and which is characterized in that the reaction in a mixture of water and a water-immiscible solvent in the presence of orthoboric acid, or a boric acid compound such. For example, sodium tetraborate or a Orthoborsäurealkylester, optionally

with the addition of a phase transfer catalyst. ;? '

Thus, according to the process of the invention, the reaction of the amino acid derivative of general formula VII with oxaziridine VIII in a two-phase solvent (eg toluene and water) in the presence of a boric acid compound suitable for temporary complexation of the phenolic hydroxy groups and optionally, especially if R ^{11 is} a carboxylate anion is carried out with the addition of a phase transfer catalyst (such as, for example, quaternary ammonium salts).

The water-soluble complex boric acid esters of compounds VII or VI which are only intermediately formed in this procedure are no longer stable in weakly acidic medium (pH 1 to 4) and, if they have not already been isolated during the formation of the primary reaction product from aminocarboxylic acid derivative and oxaziridine (phase transition). disintegrate, cleaved hydrolytically in the inventive extractive isolation of the target compounds Vl from the reaction mixture with dilute aqueous mineral acids at room temperature.

The elimination in the production of o-dihydroxybenzylsubstituierten compounds according to the previous method necessary cleavage of some very resistant protecting groups in a yield reduction up to 20% leading process step (eg., Ether splitting with boiling 48% hydrobromic acid) could thus be circumvented.

From the aqueous phase of the reaction mixture, the boric acid used as an excipient and a small amount of unreacted starting material can be recovered almost quantitatively by suitable measures and used again in the process.

The target products prepared by the process according to the invention are, surprisingly, free from interfering by-products, colored admixtures and unreacted starting compounds, without requiring special purification steps in their isolation.

It is possible to dispense with the usual protective measures against side reactions, such as exclusion of oxygen, addition of antioxidants, exclusion of heavy metal ions, etc., which are customary with conventional o-dihydroxybenzyl-containing compounds.

This made it possible, even the technically available, optically active amino acid L-2-methyl-DOPA or their lower alkyl esters or their alkali metal or alkaline earth metal salts to the already mentioned decarboxylase inhibitor L-2-hydrazino-2- (3,4-dihydroxybenzyDpropionsäure to implement in good yield and quality with the help of few technological steps.

The following examples serve to illustrate the invention.

embodiments example 1

L-2-hydrazino-2- (3,4-dihydroxybenzyl) propionic acid

10 g (44 mM) of L-2-amino-2- (3,4-dihydroxybenzyl) -propionic acid methyl ester are added under slight heating to a suspension of 18 g of sodium tetraborate · decahydrate (borax) in 55 ml of dist. Water and stirred until Auflösuncj the amino acid ester.

This mixture is stirred intensively with einertoluenischen solution of 3,3-pentamethylene-oxaziridine 8OmM 1 hour at 7O ⁰ C and 2 hours at 85 ⁰ C and made phase separation after cooling.

The organic phase is extracted with 100 ml of 6N HCl and the combined extracts are heated to 95 ⁰ C for 2 hours.

The residue obtained by evaporation under reduced pressure is taken up in 95% ethanol and from this solution the target product is precipitated with diethylamine by adjusting the pH from 6 to 6.5 in the form of the crystalline monohydrate.

Yield: 5.2 g (48%) or 78.2% calc. On reacted starting material.

Mp 192 to 194 ° C (Zers.)

Recrystallization of the crude product from water containing a small amount of sodium bisulfite gives a purer fraction of mp 203-205 ° C (dec.).

Example 2

L-2-hydrazino-2- (3,4-dihydroxybenzyl) propionic acid

10 g (42 mM) of L-2-amino-2- (3,4-dihydroxybenzyl) propionic acid · 1.5H ₂ O are added to a suspension of 17 g of sodium tetraborate · decahydrate in 50 ml of dist. Add water and stir for 30 minutes while stirring with nitrogen.

Heated to 40 ° C until a clear solution is formed.

After addition of 10 ml of 4N Natriumhydroxidlosung and 0.2 g of triethylbenzylammonium chloride (TEBA), the mixture with a toluenischen solution of 84mM 3,3-Pentamethylenoxaziridin for 1 hour at 70 ⁰ C and 3 hours at 85 ⁰ C intensively stirred.

After cooling, the phase separation is carried out and the organic phase extracted with 30 ml of 6N hydrochloric acid. The hydrochloric acid extract is added to the alkaline aqueous phase of the reaction mixture and concentrated together under reduced pressure and evaporated to dryness after filtering off the precipitated boric acid.

The residue is digested in the cold with 80 ml of absolute ethanol and from this alcoholic solution after addition of 0.5 ml of dist. Water the target product with diethylamine by adjusting the pH to 3.5 in the form of the crystalline monohydrate deposited.

Yield: 6.1 g (59%), mp 192-194 ⁰ C (dec.).

Example 3

L-2-hydrazino-2- (3,4-dihydroxybenzyl! -Propionic acid

10 g (44 mM) of L-2-amino-2- (3,4-dihydroxybenzyl) -propionic acid methyl ester are added to a solution of 2.9 g of orthoboric acid in 90 ml of distilled water and stirred with gentle warming until the amino acid derivative is dissolved.

Is then added a solution of toluenische 55mm 3,3-pentamethylene-oxaziridine is added and stirred the mixture of 4 hours intense at 80 to 85 ⁰ C.

After cooling, the phase separation is carried out and the organic phase extracted with 100 ml of 6N HCl.

The combined hydrochloric acid extracts are heated for 2 hours at 95 ⁰ C and evaporated under reduced pressure to dryness. The residue thus obtained is taken up in 95% ethanol, and from this solution the crude product is precipitated with diethylamine by adjusting the pH to 6.4 in the form of the crystalline monohydrate.

Yield: 6.7 g (62%), mp 192-194 ⁰ C. (Dec.).

Example 4

L-2-hydrazino-2- (3,4-dihydroxybenzyl) propionate

10 g (44 mM) of L-2-amino-2- (3,4-dihydroxybenzyl) -propionic acid methyl ester are added to a solution of 2.9 g of orthoboric acid in 90 ml of water and stirred with gentle heating until the amino acid derivative dissolves. Finally, a toluene solution of 5OmM 3,3-pentamethyleneoxaziridine is added and the mixture is stirred vigorously at 85 ° C. for 4 hours.

After cooling to 65 to 70 ⁰ C is carried out before the phase separation and extracted the organic phase with 25 ml of 2 N hydrochloric acid.

From the hydrochloric acid extract, the target product is precipitated by adding 6 N sodium hydroxide solution to pH 8.0 and saturating the solution with sodium chloride in crystalline form

Yield: 7.0 g (66.2%), mp 156-158 ° C / a / l ^s = + 5.6 ° (c = 2, methanol)

R ²

С - (CR ³ R ⁴ ), I ³

NH -

-В? (D

-С - (CR ⁹ R ¹⁰ ) _n - R ¹¹ (И)

12

NH

13

(III)

MeO-L - MeO -

соомѳ

(IV)

о он

O ^ ^ OHNa

(V)

R ²

R ¹ - С - (CR ³ R ⁴ ) I NH -

-В? (VI)

В? - σ - (CR ⁹ E ¹⁰ ) _д - R ¹¹

12

, 13 (VII) (VIII)

Claims (8)

claims: 1. Process гиг Preparation of hydrazinocarboxylic acid derivatives of the general formula VI in which R ¹ = 3,4-dihydroxybenzyl, R ² to R ⁴ = H, alkyl with C ₁ to C ₁₈ , branched or unbranched, optionally substituted, η = O-hydrazinocarboxylic acid derivatives, 1 to 6, R ⁵ = COOR ⁶ , R ⁶ = H, alkyl with C ₁ to C ₃ branched or unbranched, optionally substituted, mean, by N-amination of aminocarboxylic acid derivatives of the general formula VII, in which R ⁷ to R ¹⁰ or R ^{11 have} the meaning given for R ¹ to R ⁴ or R ⁵ , but need not be identical with these, and R ^{11 is} a carboxyl radical in which the hydrogen is replaced by an alkali or alkaline earth metal atom, with an oxaziridine of the general formula VIII, in which R ¹² and R ¹³ = H, alkyl having C ₁ to C ₁₈ , the branched or are unbranched, optionally substituted or are members of a common ring, mean, in the presence of a solvent at a temperature of -20 to + 20O ⁰ C and then adding aqueous mineral acid, wherein by removing the water and excess mineral acid and / or by adjusting a certain pH range, optionally in a further solvent, the target products V) are isolated in substance, characterized in that the reaction in a mixture of water r and a water-immiscible solvent in the presence of orthoboric acid or a boric acid compound, such as. For example, sodium tetraborate or a Orthoborsäurealkylester, optionally with the addition of a phase transfer catalyst is performed. 2. The method according to claim 1, characterized in that a quaternary ammonium salt is used as the phase transfer catalyst. 3. Process according to claims 1 and 2, characterized in that as oxaziridine 3,3-Pentamethylenoxaziridin VIII in the meaning R ¹² and R ¹³ = - (CH ₂ Is- is used. 4. Process according to claims 1 to 3, characterized in that 0.8 to 2.0 mol, preferably 1.1 to 1.4 mol 3,3-pentamethyleneoxaziridine per mole of amino acid derivative VII are used. 5. Process according to claims 1 to 4, characterized in that toluene or a mixture of water and toluene is used as the solvent for the heating of VII and VIII. 6. Process according to claims 1 to 5, characterized in that VII and VIII are heated for up to 12 hours, preferably 1 to 4 hours, under reflux or partial distilling off of the solvent. 7. Process according to claims 1 to 6, characterized in that the compounds Vl are obtained in salt-like, dissolved form by an extraction process, wherein as the extraction medium preferably aqueous hydrohalic acids are used. 8. .Process according to claims 1,2 and 7, characterized in that the aqueous mineral acid extracts before the isolation of the compounds Vl at a pressure to 20at, preferably at atmospheric pressure, optionally under a protective gas, a temperature up to 16O ⁰ C. , preferably in the range of 80 to 120 ⁰ C, are exposed.