GB2105716A - Process for the preparation of N-hydroxy amino acid derivatives - Google Patents

Abstract

A process for the preparation of in acid of the general formula: <IMAGE> or a salt or an ester thereof, wherein each of R<1> and R<2> independently represents a hydrogen atom or an optionally substituted alkyl, cycloalkyl or aryl group, comprises reacting an ester of an acid of the general formula: <IMAGE> in which R<2> represents a hydrogen atom or an optionally substituted alkyl, cycloalkyl or aryl group and L represents a suitable leaving group, with hydroxylamine, to yield an ester of the acid of the general formula <IMAGE> optionally converting the resulting ester into the corresponding free acid or a salt thereof; and acylating the resulting compound with a suitable acylating agent; and if desired converting a resulting ester of the acid I into any required salt or ester of the free acid, by methods analogous to known methods.

Description

SPECIFICATION Process for the preparation of N-hydroxy amino acid derivatives This invention relates to a process for the preparation of N-hydroxy amino acid derivatives.

J. Biol, Chem. 1963, 283 No. 12, pg. 3999, discloses that certain N-acyl N-hydroxy amino acid derivatives have been tested in vitro for activity as inhibitors of certain enzymatic processes. Our Co- pending Application No. 8201 677 discloses that certain compounds of this chemical type show valuable fungicidal activity.

Compounds of this type can be synthesized via the corresponding nitrone as described in USP 3154578. However, the Applicants have now discovered, an improved synthetic route.

Accordingly, the invention provides a process for the preparation of an acid of the general formula

or a salt or an ester thereof, wherein each of R1 and R2 independently represents a hydrogen atom or an optionally substituted alkyl, cycloalkyl or aryl group, which comprises reacting an ester of an acid of the general formula:

in which R2 represents a hydrogen atom or an optionally substituted alkyl, cycloalkyl or aryl group and L represents a suitable leaving group, with hydroxylamine, to yield an ester of the acid of the general formula

optionally converting the resulting ester into the corresponding free acid or a salt thereof; and acylating the resulting compound with a suitable acylating agent; and if desired converting a resulting ester of the acid I into any required salt or ester or the free acid, methods analogous to known methods.

An alkyl group R1 or R2 preferably has up to 6, especially up to 4, carbon atoms. An aryl group is preferably a phenyl group. A cycloalkyl group preferably has from 3 to 6 carbon atoms.

Optional substituents include for example halogen atoms and alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, cyano, nitro, amino, carboxy, alkoxycarbonyl, phenyl and phenoxy groups, any alkyl moiety present preferably having up to 4 carbon'atoms.

Preferably R1 represents a hydrogen atom or an unsubstituted alkyl or aryl group. Especially preferred are those compounds in which R' represents a methyl or phenyl group or, especially, a hydrogen atom.

Preferably R2 represents a hydrogen atom, an unsubstituted alkyl group, a phenyl group or a benzyl group. Especially preferred are compounds in which R2 represents a methyl group.

A salt of the acid I may contain the monovalent anion in which the carboxyl group is ionised or the divalent anion in which the N-hydroxy group is also ionised. Polyvalent metal ions generally form salts with, or chelates derived from, the diva lent anion, while monovalent metal ions can form mono- or divalent salts. Weak bases in general form only monovalent salts.

Typical metal salts include salts of lithium, sodium, potassium, magnesium, calcium, zinc, copper, lead, manganese or iron.

Typical non-metal salts include ammonium and substituted ammonium salts, for example those in which the cation has the formula ONR4R5RBR7 in which each of R4, R5, R6 and R7 independently represents a hydrogen atom or an optionally substituted alkyl, cycloalkyl or aryl group having up to 12 carbon atoms. Optional substituents include for example halogen atoms and alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, cyano, nitro, amino, carboxy, alkoxycarbonyl, phenyl and phenoxy groups, any alkyl moiety present preferably having up to 4 carbon atoms.

Further suitable substituted ammonium salts include those in which the nitrogen atom forms part of a saturated or unsaturated ring, which may also contain one or more additional hetero-atoms, especially nitrogen, oxygen and/or sulphur atoms. Typical salts of this type are pyridinium, pyrrolidinium, piperidinium and morpholinium salts.

Further suitable salts include those with polymeric substances containing basic groups, such as ion exchange resins. Such salts can be especially useful in applications where insoluble materials are required.

Suitable esters of the acid I include optionaly substituted alkyl, cycloalkyl and aryi esters, where the preferred optional substituents are as described above. Preferred esters are unsubstituted alkyl esters preferably having up to 4 carbon atoms in the alkyl moiety.

Any leaving group L which will be displaced by the hydroxylamine can be used. Suitable moieties includes halogen, especially chlorine or bromine, atoms, and organic sulphonic acid groups of the formula QSO2O- where Q is a hydrocarbon group, for example an alkyl, aryl or alkaryl group; typical groups of this type are mesylate and tosylate groups. The reaction with hydroxylamine is preferably carried out in the presence of an acid acceptor, for example an amine, e.g. a trialkylamine.

The molar ratio of the reactants is not crucial. It may be convenient to use approximately stoichiometric quantities, and preferably at least one mole of hydroxylamine is used per mole of starting ester. An excess of hydroxylamine may be used as an acid acceptor. The reaction may for example be carried out at a temperature in the range of from 0 to 1 000 C, especially 1 5 to 700 C.

If desired, the hydroxylamine may be prepared in situ, for example by reaction of a hydroxylamine salt, such as hydroxylamine hydrochloride, with a base, for example an alkali metal hydroxide or alkoxide or an amine.

If desired, the ester Ill may be converted by known methods into the corresponding free acid or salt, which is then acylated. Preferably however it is the ester which is acylated.

Any suitable acylating agent may be used for reaction with the compound Ill, for example an anhydride, ester or acid halide derived from the acid RtCOOH. Mixed anhydrides are often useful. When R' represents a hydrogen atom, preferred acylating agents are the mixed anhydride of formic acid and acetic acid, which may be added as such, or formed in situ from a mixture of formic acid with acetic anhydride. Preferably at least one mole, for example from 1 to 5 moles, of acylating agent is used per mole of compound Ill.The reaction may for example be carried out at a temperature in the range of from 0 to 1000C, especially 1 5 to 700 C. In some cases, when using an ester Ill but requiring a salt or acid as the final product, it is possible to convert the ester group in the ester Ill into the free acid or a salt thereof in the same reaction vessel as the acylation, if the acylation step is carried out under conditions to which the acid group is not stable, for example under strongly acidic conditions.

An especially preferred method of preparing a free acid I or a salt thereof, involves the use of an ester in which the ester group is readily removed in the last step of the process. Such esters include for example the benzyl or, especially, the tertiary butyl ester, which groups are readily removed by hydrolysis or solvolysis either after the acylation step or simultaneously with the acylation step.

The starting ester of the acid II may be prepared in any suitable manner, for example by transesterification of any other ester of the acid II, or by esterification of the free acid or its acid halide. A preferred method of preparing the tertiary butyl ester comprises reaction of the free acid II with 2methyl propane under acidic conditions. Suitable acid catalysts for use in this embodiment include, for example, mineral acids such as sulphuric acid, organic acids such as p-toluene sulphonic acid, and acidic ion exchange resins.

If it is desired to prepare a single optical isomer of the required compound where R2 is other than a hydrogen atom, this may be done by using as starting material the appropriate chiral ester, and by conducting the various reaction steps under carefully controlled reaction conditions to avoid racemisation. The use of organic sulphonic acid leaving groups L is especially useful when working with chiral materials.

The following Examples illustrate the invention.

EXAMPLE I (Prior art method - Synthesis via Nitrone Z-benzaldodime (1.0 mole) and alpha-bromopropionic acid (1.1 mole) were added to sodium ethoxide solution, prepared from sodium metal (2 mole) in ethanol (41). The solution was heated for three hours at 6'5-700C with stirring, cooled, and the crystals of the sodium salt of N-benzylidene alanine N-oxide filtered off. The product was dissolved in water and acidified with 2N HCI. The crystals obtained were washed with either and dried to yield the free acid. mpt. 1 68-1 700C.

This acid nitrone (40 g) was treated with formic acid (400 ml) and acetic anhydride (80 ml) and stirred at room temperature for 1 hr., then stirred a further 3/4 hr., at 40-450C and solvents evaporated. The resultant oil was dissolved in water, washed with benzene and the aqueous layer neutralized by the addition of concentrated ethanolic sodium hydroxide solution. Ethanol was added slowly, and the resulting sodium salt of N-formyl-N-hydroxy alanine was filtered off. mpt 193--1950C.

Analysis: Calc. C 31% H 3.9% N 9.0% Found 30.5 4.2 8.8 The free acid was conveniently obtained by passing the sodium salt down a Dowex-50 ion exchange column and eluting with water, and had a melting point of 77-790C.

Analysis: Calc. C 36.1 % H 5.25% N 10.5% Found 36.3 5.3 10.4 EXAMPLE II Synthesis via butylation In a Parr hydrogenation flask was placed alpha-bromopropionic acid (0.33 mole), isobutylene (2 mole) and concentrated sulphuric acid (1.7 mls). The reaction mixture was shaken for 48 hrs., then poured into a vigorously stirred solution of 20% sodium hydroxide, extracted with ether and dried to yield the crude tert. butyl ester of alpha-bromo-propionic acid.

Hydroxylamine was generated in methanol by the addition of 0.1 mole of sodium methoxide or hydroxide to 0.1 mole of hydroxylamine hydrochloride, followed by filtering off the sodium chloride, and was added to the above ester (0.1 mole) and triethylamine (0.1 mole) in methanol, and the reaction mixture refluxed for 24 hrs. After cooling, ether was added and the insoluble triethylamine hydrobromide filtered off. Evaporation of the solvents yielded a semi-solid product which was treated with petroleum ether (40-60) and filtered. The product was recrystallized from petrol (80--100) to yield N-hydroxy alanine tert. butyl ester, mpt. 69-700C.

This product (5 g) was stirred at room temperature for 1 hr., with formic acid (50 ml) and acetic anhydride (10 ml) then a further 1 hr., at 40--450 C. The solvents were removed at low temperature, the residue dissolved in water and washed with benzene. The aqueous layer was treated with an equivalent of concentrated aqueous sodium hydroxide solution and ethanol slowly added to yield the sodium salt of N-formyl-N-hydroxy alanine, mpt. 1 86-1 870C.

EXAMPLE Ill Following the procedure described under Example II, further N-formyl-N-hydroxy amino acid derivatives were prepared whose melting points and analyses are given in Table 1, in which compounds are identified by reference to the structure:-

TABLE 1

COMPOUND mpt (OC) ANALYSIS % R2 T R3 C H N C2H6 H 135-137 Calc. 40.8 6.12 9.5 Found 40.9 6.3 9.3 Phenyl H 112-114 Calc. 55.4 4.6 7.2 Found 54.6 4.8 7.2 C6H5CH2 Na 153-155 Calc. 52.0 4.3 6.05 Found 52.0 4.4 6.1 QH5 Na 214-217 Calc. 35.5 4.7 8.3 Found 35.4 4.7 8.0 (CH3)2CHCH2 Na 240-243 Calc. 42.6 6.1 7.1 Found 42.4 6.1 7.0 CH3 C2H6 undistill- Calc. 44.7 6.85 8.7 able oil Found 44.2 6.7 8.4 (CH3)2CH Na 239-241 Calc. 39.3 5.5 7.65 Found 39.3 5.3 7.8 Further compounds preparable by the process according to the invention are given in our copending Application No. 8201677.

EXAMPLE IV Preparation of polyvalent metal salts To a solution of N-hydroxy-N-formyl alanine (1 mole) in water was added, with stirring, lead acetate (1 mole) in water. The precipitate obtained was dried under high vacuum for several days to yield the lead salt, mpt 1 800C (dec).

Analysis: Calc. C 14.2% H 1.46% 4.15% Found 13.8 1.7 3.8 Following a similar procedure the following salts of the same acid with other polyvalent ions were obtained Calcium. mpt. above 3000C.

Analysis: Calc. C 25.4% H 3.7% N 7.4% Found C 23.6 H 4.1 N 6.8 Copper. mpt. 203-2050C (dec) Analysis: Calc. C 22.6% H 3.3% N 6.6% Found C 21.5 H 3.1 N 5.5 EXAMPLE V Direct synthesis of isomers from optically active starting materials.

The S optical isomer of 2-mesyloxypropionic acid (0.35 mol) was dissolved in pyridine (25 ml) and t-butanol (500 ml), and phosphoryl chloride (65 g) was added, with stirring, at -50C. After a further 30 minutes stirring at -50C, and a further 2 hours at 200C, the mixture was poured into ice-water, and methylene chloride was added. The organic layer was washed successively with dilute hydrochloric acid, sodium bicarbonate, and water, and then evaporated to give a solid which was recrystalised from light petroleum ether to give 0.269 mol of (S) t-butyl 2-mesyloxypropionate (a yield of 77%).

0.05 mol of this ester was then dissolved in N-methylpyrrolidone (25 ml) and hydroxylammonium chloride (0.051 mol) and triethylamine (0.1 mol) were added. The mixture was stirred overnight at 500 C, after which time it was poured into water, diethyl ether was added, the organic layer was evaporated down and the resulting product was purified by chromatography over silica using diethyl ether and methylene chloride as eluants. (R) t-butyl 2-hydroxyaminopropionate, having an optical rotation in chloroform solution of +22.60, was obtained in 67% yield. This material could then be reacted with formic acid and acetic anhydride as described in (B) above, to give the required product.

Claims (11)

1. A process for the preparation of an acid of the general formula

or a salt or an ester thereof, wherein each of R' and R2 independently represents a hydrogen atom or an optionally substituted alkyl, cycloalkyl or aryl group, which comprises reacting of an ester of an acid of the general formula:

in which R2 represents a hydrogen atom or an optionally substituted alkyl, cycloalkyl or aryl group and L represents a suitable leaving group, with hydroxylamine, to yield an ester of the acid of the general formula

optionally converting the resulting ester into the corresponding free acid or a salt thereof; and acylating the resulting compound with a suitable acylating agent; and if desired converting a resulting ester of the acid I into any required salt or ester of the free acid, by methods analogous to known methods.

2. A process as claimed in claim 1, in which R1 represents a hydrogen atom or an unsubstituted alkyl or aryl group.

3. A process as claimed in claim 2, in which R' represents a hydrogen atom.

4. A process as claimed in any one of claims 1 to 3, in which R2 represents a hydrogen atom or an unsubstituted alkyl, phenyl or benzyl group.

5. A process as claimed in claim 4, in which R2 represents a methyl group.

6. A process as claimed in any one of claims 1 to 5, in which L represents a chlorine or bromine atom or a group of the formula QSO2O- where 0 is a hydrocarbon group.

7. A process as claimed in any of claims 1 to 6, in which the acylating agent is an an hydride, ester or acid halide derived from the acid R'COOH.

8. A process as claimed in claim 7, in which R' represents a hydrogen atom and the acylating agent is the mixed an hydroxide of formic acid and acetic acid.

9. A process as claimed in any one of claims 1 to 8, in which a tertiary butyl ester is used as starting material.

10. A process as claimed in claim 1, carried out substantially as described in either Example II or Example V herein.

11. A compound of the formula I or a salt or an ester thereof as defined in claim 1, whenever prepared by a process as claimed in any one of claims 1 to 11.

optionally converting the resulting ester into the corresponding free acid or a salt thereof; and acylating the resulting compound with a suitable acylating agent; and if desired converting a resulting ester of the acid I into any required salt or ester of the free acid, by methods analogous to known methods.