GB2119376A - Process for the preparation of N-Hydroxy amino acid derivatives - Google Patents

Abstract

A process for the preparation of an 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, which comprises reacting an ester of an acid of the general formula: <IMAGE> in which R<2> is as defined above and L represents a 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 processforthe preparation of N-hydroxy amino acid derivatives.

J. Biol. Chem. 1963,283 No. 12, pg. 3999, discloses that sertain 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.8201677 discloses that certain compounds ofthis chemical type show valuable fungicid- al activity.

Compounds of this type can be synthesised via the corresponding nitroneas described in USP3154578.

However, the Applicants have nowdiscoveredan improved synthetic route.

Accordingly, the invention provides a process for the preparation ofan acid ofthe 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, cycloalkl or aryl group, which comprises reacting an ester of an acid ofthe general formula:

in which R2 represents a hydrogen atom oran 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

optionallyconvertingthe 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 orthe free acid, by methods analogous to known methods.

An alkyl group R1 or R2 preferably has upto 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 phenoxygroups, any alkyl moiety present preferably having up to 4 carbon atoms.

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

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

Asaltoftheacidl maycontainthemonovalent anion in which the carboxyl group is ionisedor the divalent anion in which the N-hydroxy group is also ionised. Polyvalent metal ionsgenerallyform salts with, or chelates derivedfrom, the divalent anion, while monovalent metal ions can form mono- or divalent salts. Weak bases in generalform only monovalent salts.

Typical metal salts include salts of lithium, sodium, potassium, magnesium, calsium,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 +NR4R5R6R7 in which each of R4, R5, R6 and R7 independently represents a hydrogen atom oran optionallysubsti- tuted 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 phenoxygroups, any alkyl moiety present preferably having up to 4 carbon atoms.

Further suitable substituted ammonium salts includethose 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 ofthis 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 ofthe acid I include optionally substituted alkyl, cycoalkyl and aryl 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 Lwhich will be displaced bythe hydroxylamine can be used. Suitable moieties include halogen, especially chlorine or bromine, atoms, and organic sulphonic acid groups oftheformula QSO2Oj-where Qis a hydrocarbon group, for example an alkyl, aryl or alkaryl group; typical groups of this type are the 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 hydroxylamine is used per mole of starting ester. An excess of hydroxylamine may be used as an acid acceptor. The reaction mayforexample be carried outata temperature in the range of from 0 to 1 OO"C, especially 15 to 700C.

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 R1COOH. Mixed anhydrides are often useful. When R represents a hydrogen atom, prefered acylating agents are the mixed anhydride offormic acid and aceticacid,which may be added as such, or formed in situfrom 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 offrom 0 to 1 OO"C, especially 15 to 700C. 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 saltthereofin the same reaction vessel as the acylation, if the acylation step is carried out under conditions to which the ester group is not stable, for example under strongly acidic conditions.

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

The starting ester ofthe acid ll may be prepared in any suitable manner, for example bytransesterification of any other ester of the acid II, or by esterification ofthefree acid or its acid halide. A preferred method of preparing the tertiary butyl ester comprises reaction of the free acid II with 2-methyl 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 isomerof the required compound where R2 is otherthan a hydrogen atom, this may be done by using as starting material the appropriate chiral ester, and by conduct ing the various reaction steps under carefully control- led reaction conditions to avoid racemisation. The use of organic sulphonic acid leaving groups L is especially useful when working with chiral materia Is.

Thefollowing Examples illustratethe invention.

Example (Prior art method) - Synthesis via Nitrone Z-benzaldoxime (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 heatedforthree hours at 65-700C with stirring, cooled, andthe crystals of the sodium salt of N-benzylidene alanine N-oxide filtered off. The product was dissolved in water and acidified with 2N HCl.The crystalsobtained werewashedwith ether and driedto yield the free acid. mpt 168-170 C.

This acid nitrone (40g) was treated with formic acid (400m1) and acetic anhydride (80ml) and stirred at room temperaturefor 1 hr.,then stirred a further314 hr., at 40-45"C and solvents evaporated. The resultant oil was dissolved in water, washed with benzene and the aqueous layer neutralised by the addition of concentrated ethanolic sodium hydroxide solution Ethanol was added slowly, and the resulting sodium salt of N-formyl-Nlhydroxy alanine was filtered off.

mFt 19S195 C.

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 EXowex-5 ion exchange column and eluting with water, arid had a melting pointof77-79 C.

Analysis: Calc. C 36.1.% II 5.25% N 10.5 S Found 36.3 5.3 10.4 Example II Synthesis via butylation In a Parr hydorgenation flask ways placed alphabromopropionic acid (0.33 mole), isobutylene(2 mole) and concentrated sulphuric acidf1 .7mis). The reaction mixture was shaken for 48 hrs.,then poured into a vigorously stirred solution of 20% sodium hydroxide, extracted with ether and driedtoyield the crude tert. butyl ester of alpha-bromo-propionic acid.

Hydroxylamine was generated in methanol by the addition of 0.1 mole of sodium methoxideorhydrox- ide to 0.1 mole of hydroxylamine hydrochloride, followed byfiltering off the sodium chloride, and was added to the above ester (0.1 mole) and triethylamine(O.1 mole) in methanol, and the reaction mixture refluxedfor 24 hrs. After cooling, ether was added and the insoluble triethylamine hydrobromide filtered off. Evaporation ofthesolvents yielded a semi-solid product which was treated with petroleum ether(40-60) and filtered. The product was recrystalized from petrol(80-I 00) toyield N-hydroxy alanine tert. butyl ester, mpt. 69-70 C.

This product (5g) was stirred at room temperature for 1 hr., with formicacid(50ml) and acetic anhydride (1 Oml) then a further 1 hr., at40-45oC.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-formyt-N-hydroxy alanine, mpt. 186-1 870C.

Example 111 Following the procedure described under Example ll,further N-fo rmyl-N-hyd roxy amino acid derivatives were prepared whose melting,points and analyses are given in Table 1, in whicb'1the compounds are identified by reference to the structure::-

rare 1 COMPOUND mpt ( C) ANALYSIS % R2 R3 C H N C2H5 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 6 5 2 Na 153-155 Calc. 52.0 4.3 6.05 Found 52.0 4.4 6.1 C2H5 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 C N 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 ourcopending Application No. 8201677.

Example IV Preparation ofpolyvalent 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 1800C (dec).

Analysis: Calc. C 14.2% H 1.46% N 4.15% Found 13.8 1.7 3.8 Following a similar procedurethe following salts of the same acid with other polyvalent ions were obtained: Calcium. mpt. above 300 C.

Analysis: Calc. C 25.4% H 3.7% N 7.4% Found C 23.6 H 4.1 N 6.8 Copper. mpt. 203-205 C(decì Analysis: Calc. C 22.6% H 3.3% N 6.6% Found C 21.5 H 3.1 N 5.5 Example Directsynthesis ofisomers from optionally active starting materials.

The S optical isomer of 2-mesyloxypropionic acid (0.35mol)was dissolved in pyridine (25ml) and t-butanol (500ml), and phosphoryl chloride (65g) was added, with stirring, at -5 C. After a further 30 minutes stirring at -5"C, and a further 2 hours at 20 C, the mixture was poured into ice-water, and methylene chloride was added. The organic layerwas washed successively with dilute hydrochloric acid, sodium bicarbonate, and water, and then evaporated to give a solid which was recrystalised from light petroleum etherto give 0.269 mol of(S)t-butyl 2-mesyloxypropionate (a yield of 77%).

0.05 mol of this esterwasthendissolved in N-methylpyrrolidone (25ml) and hydroxylammonium chloride (0.051 moll and triethylamine (0.1 mol) were added. The mixture was stirred overnight at 50 C, after which time it was poured into water, diethyl either as added, the organic layer ways 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 +22.6 , 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 processforthe preparation of an acid of the general formula

our a salt or an esterthereof, wherein each of Rd1 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 R2representsa hydrogen atom oran optionally substituted alkyl, cycoalkyl or aryl group and L represents a suitable leaving group, with hydroxylamine,to yield an ester of the acid ofthe general formula

optionally converting the resulting ester into the corresponding free acid ora saltthereof; 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 ofthe free acid, by methods analogous to known methods.

2. A process as claimed in claim 1, in which R' represents a hydrogen atom oranunsubstituted alkyl oraryl group.

3. A process as claimed in claim 2, in which 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, phenyf 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 oftheformula QSO2O-whereQ is a hydrocarbon group.

7. A process as claimed in any of claims 1 to 6, in which the acylating agent is an anhydride, ester or acid halide derived from the acid R1COOH.

8. Aprocess as claimed in claim 7, in which R1 represents a hydrogen atom and the acylating agent is the mixed anhydride 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. Acompound oftheformula I ora saltoran ester thereof as defined in claim 1,whenever prepared by a process as claimed in any one of claims 1 to 11.