PROCESS FOR THE PREPARATION OF beta , beta -DIALKYL AND beta , beta , beta -TRIALKYL alpha -AMINO ACIDS

Abstract: beta , beta -dialkyl and beta , beta , beta -trialkyl alpha -amino acids are prepared by a novel route involving the reaction and molecular rearrangement of acetoamidoacrylate tricarbonyl iron complexes in the presence of a lithium alkyl. This novel route opens up the possibility of an inexpensive route to highly branched alpha -amino acids some of which have not previously been reported in the literature.

Description: PROCESS FOR THE PREPARATION OF β.β-DIALKYL AND β,β,β-TRIALKYL -AMINO ACIDS FIELD OF INVENTION 5 This invention concerns a novel route for the preparation of β,β- Ik dialkyl and β,β,β-trialkyl α-amino acids, especially the latter. BACKGRODND Highly branched α-amino acids having branching at the β -carbon 10 atom, such as tert.-leucine, viz: (CH-s)2CCH(NH2)COOH, are valuable chemicals with many uses in the chemical, biochemical and medical fields. However they are difficult to prepare by known chemical methods. 15 OBJECTS OF THE INVENTION The object of the invention is to provide an improved route for the chemical synthesis of branched chain α-amino acids with branching at the β-carbon atom. 20 SUMMARY OF THE INVENTION In accordance with the present invention, it has been discovered that such highly branched amino acids are surprisingly obtained in high yield by the reaction of a tertiary or secondary alkyl halide, preferably a bromide or iodide, with an alkyl, preferably lower (C^-Co) 25 alkyl 2-acetamido acrylate tricarbonyl iron complex in the presence of a lithium alkyl. DETAILED DESCRIPTION The reaction of this invention may be represented by the 30 equation: 2-acetamidoacrylate tricarbonyl iron complex H 2 N . ^ C0 2 H (I) CH R* III where R = alkyl, preferably lower (C^-Co) alkyl, most preferably methyl; R' = tertiary or secondary alkyl, preferably (C β 'Cir secondary or tertiary alkyl, e.g. isopropyl, sec. butyl, tert.butyl 1 , 1-dimethyl-n-propyl , 1 , 1-dimethyl-n-butyl etc.; X = halogen, e.g. chlorine, bromine or iodine, preferably bromine or iodine. As will be apparent, the reaction is carried out using readily available starting materials, which are commercially available, as such, or which can themselves easily be prepared by standard organic syntheses. The 2-acetamidoacrylate tricarbonyl iron complex is readily available, for example, by reacting the commercially available 2- acetamidoacrylic acid with methyl iodide (or other alkyl halide or suitable alkylating agent) to produce the corresponding ester, e.g. methyl 2-acetamidoacrylate, which is then reacted with di-iron nonacarbonyl , Fe2(C0)g, to give the air stable, crystalline methyl 2- acetaraidoacrylate iron tricarbonyl complex in high yield. In the initial stage of the two stage reaction procedure of the present invention, the alkyl 2-acetamidoacrylate tricarbonyl iron complex I is reacted with the lithium alkyl to produce an as yet undetermined intermediate, presumably involving an alkyl lithium attack on the metal carbonyl ligand and possibly an acyl group transfer to the 3C carbon atom of the organic ligand. The reaction is performed at low temperature (circa -78°C) using two equivalents of lithium alkyl in a suitable inert solvent, e.g. tetrahydrofuran, with suitable agitation over a period of 30 - 60 minutes. Preferably the reaction is performed under an atmosphere of nitrogen. At the end of the initial reaction, a substantial molar excess (of the order of 10:1 molar ratio relative to the iron carbonyl complex) of alkyl halide is added and the reaction mixture allowed to warm to room temperature. In the third and final stage in the preparation of the protected amino acid (II), the reaction product is subjected to air oxygenation, preferably whilst irradiating the reaction mixture to optimise cleavage of iron-carbon bonds in the product mixture, and assist recovery of the product II. Product II is recovered in approximately equal quantities with an acylated by-product of the formula IV, and from which the product II can be separated by conventional chrotnatography. IV Recovered product II can then be subjected to acid hydrolysis to remove the protecting groups to give the β,β-dialkyl or β,β,β-trialkyl α-amino acid (III) in the form of an acid addition salt. Highest yields (circa 40% based on tricarbonyliron complex) are obtained where the halogenated alkane reactant R'X is a tertiary halide and X is bromine or iodine. As will be seen the invention provides a novel and highly unusual route to β,β-dialkyl and β,β, -trialkyl α-amino acids, i.e. compounds of the formula III, and especially the tertiary compounds Ilia: Ilia where R^ , R 2 and R- j are alkyl groups of 1-3 carbon atoms, several of which compounds have not previously been reported in the literature, e.g. the compounds Ilia where R j . = Pv 2 = CH- j and Ro = C 2 H^ , and where R 1 = R 2 = CH 3 and R3 = n-C 3 H 7 . Also as will be apparent to the person skilled in the art, the novel process of the present invention provides the possibility of a unique route to chiral compounds of formula Ilia (including those where Ri is H) based on the optically active centre C*. The process of the present invention is illustrated by the following Examples. EXAMPLE 1 Preparation of methyl 2-acetamidoacrylate tricarbonyl iron Fe 2 (CO)c-j (15.2g. 41.8 mmol) was reacted with methyl 2- aceta idoacrylate (2.70g. 18.88 mmol) in diethylether (150ml) for 14h at 30°C. The resulting brown mixture was filtered through alumina and the filtrate evaporated to dryness to give methyl 2-acetamidoacrylate tricarbonyliron as a yellow air-stable microcrystalline solid (4.70g. 88%). EXAMPLE 2 Methyl lithium (1.43 ml, 1.4M, 2.00 mmol) was added to a solution of methyl 2-acetamidoacrylate tricarbonyl iron (0.283g. 1 mmol) in dry tetrahydrofuran (25ml) at -78°C under a nitrogen atmosphere and the mixture stirred at -78 C for 40 minutes. Tert. butyliodide (1.2ml 1.85g. 10 mmol) was then added and the mixture stirred at -78 C for a further five minutes. The mixture was then allowed to warm to room temperature and stirred for a further 2h at room temperature. At the end of 2 hours, the solvent was evaporated under reduced pressure to .yield a dark residue which was resuspended in diethylether 5 (25ml). The resulting suspension was irradiated by a 100 bulb under air for 19h, and then filtered through alumina using 300ml of ethyl acetate as an eluant. Evaporation of the filtrate gave a pale yellow oil (99mg) from which were separated by chromatography (Si0 2 ; dichloromethane-ethyl 10 acetate-petroleum ether (40-60°C), 4:7:9 vol.ratio) 0.074g (40% yield) of the compound CHoCONHCHCOOCH I 15 C ( CH 3)3 as a white crystalline solid. The crude product contains the product compound of formula II and a by-product of formula IV in a weight ratio of 75:25. 20 The compound of formula II above was subjected to acid hydrolysis (6N HC1, reflux, 3h) to yield tert. leucine: (CH 3 ) 3 CCH(NH 2 )COOH as the hydrochloride acid addition salt. EXAMPLE 3 25 The general procedure of Example 2 was repeated using each of tert. butyl chloride and tert. butyl bromide in place of the tert. butyl iodide reactant of Example 2. In these experiments also the quantity of the initial tricarbonyl iron reactant was reduced to 0.4 .mmol and the methyl lithium reactant reduced proportionally. 30 In the case of tert. butyl bromide the crude product yield was 48 mg of a mixture containing the compounds of formulae II and IV in a 60:40 ratio. In the case of tert. butyl chloride the yield of crude product reduced to 8 mg and contained other unidentified products besides the •. 35 compounds of formulae II and IV. EXAMPLE 4 The procedure of Example 2 was repeated in two separate runs with 0.4 and 1.0 mmol respectively of the tricarbonyl iron reactant and using 1 ,1-dimethyl-n-propyl iodide as the alkyl halide reactant. Yields of crude product were as follows: Yield of Ratio of CpdII Yield of Crude Product to CpdIV in Cpd.II (mg) crude product recovered 40 80:20 92 75:25 30% Hydrolysis of the protected amino acid of formula II, viz the compound CHoCONHCHCOOCH I CH 3 CCH 3 C 2 H 5 gave the novel compound: 2-amino- ,3-dinethylpentanoic acid in the form of its hydrochloride acid addition salt. EXAMPLE 5 The procedure of Example 2 was repeated in two separate runs with 0.4 and 1.0 mmol respectively of the tricarbonyl iron reactant and using 1 ,1-dimethyl-n-butyl iodide in place of the ter . butyl iodide. Yields of the crude product were as follows. Hydrolysis of the protected amino acid product, viz. the compound: CH gave the novel compound: 2-amino.3 ,3-dimethylhexanoic acid in the form of its hydrochloride acid addition salt. EXAMPLE 6 Following the general procedure of Example 2, but using 0.4 mmol of the tricarbonyliron reactant and a proportionally reduced amount of methyl lithium, the tricarbonyl iron reactant was reacted, in separate runs with isopropyl bromide and isopropyl iodide. Yields of the crude product were as follows: Separation and hydrolysis of the crude product in each case yield the compound 2-amino-3-methylbutyric acid in the form of its hydrochloride acid addition salt. Repetition of the above example using the primary halides ethyl iodide and ethyl bromide produced a complex mixture in low yield .primarily containing compounds of formula IV, confirming the applicability of the present process primarily to sec. and tert. halide reactants, especially the tert. alkyl bromides and iodides (cf. Example 3), in preference to the chlorides. Whilst the invention is broadly applicable to the preparation of β, β-dialkyl and β,β, -trialkyl α-araino acids of formula III where R' is sec. or tert. alkyl, practical and steric consideration suggest a preferred overall limit of 20 carbon atoms, and a preference for sec. and tert. alkyl groups with a lower (C 2 ~C 3 ) alkyl, most preferably, methyl or ethyl, substituent(s) in the 1- position, that is to say compounds where R' is a group, where R' is H or C x - C 3 alkyl, preferably methyl or ethyl; R 2 is G x - C 3 alkyl, preferably methyl or ethyl; and R 3 is C x - C 13 alkyl, preferably C : - C 6 alkyl and preferably straight chain alkyl.

Claims: CLAIMS 1. A process for the preparation of β,β-dialkyl and » > β-trialkyl- α-amino acids of the formula R'CH(NH 2 )C00H, where R' is a tertiary or secondary alkyl group, which comprises reacting an alkyl 2- acetamidoacrylate tricarbonyl iron complex of the formula (CO)- where R is alkyl, with a secondary or tertiary alkyl halide in the presence of a lithium alkyl, recovering from the reaction product a protected amino acid of the formula CH 3 C(0)NHCH(R' )C00R where R and R 1 are above defined, and hydrolysing the product to remove the protecting groups. 2. A process according to claim 1, where R is methyl. 3. A process according to claim 1 or 2, wherein there is used a tert. or secondary alkyl halide of the formula R'X where R 1 is a tertiary or secondary alkyl group of 3-10 carbon atoms and X is Cl, Br or I. 4. A process according to claim 3, where in the halide reactant is a bromide or iodide. 5. A process according to any one of claims 1 to 4, which comprises initially forming a reaction mixture of the alkyl 2-acetamidoacrylate tricarbonyl iron reactant and the lithium alkyl in a solvent under an inert atmosphere, adding the alkyl halide reactant to the reaction mixture thus formed, recovering the protected amino acid from the crude- reaction product, and hydrolysing the protected amino acid to remove the protecting groups. 6. A process according to claim 5, wherein prior to the recovery of the protected amino acid, the crude reaction product is subjected to air oxygenation and simultaneous irradiation to effect decomposition of any iron-carbon bonds remaining in the crude reaction product and to aid recovery of the protected amino acid. 7. β,β-dialkyl and β,β,β-trialkyl α-amino acids when prepared by a process claimed in any one of claims 1 to 6. 8. 2-amino-3 ,3-dimethylhexanoic acid. 9. 2-amino-3 ,3-dimethylpentanoic acid. 10. 2-amino-3-methylbutyric acid.

Inventors: LASTERRA-SANCHEZ MARIA ELENA, THOMAS SUSAN ELIZABETH, LASTERRA-SANCHEZ, MARIA, ELENA, THOMAS, SUSAN, ELIZABETH
Applicants: ASS OCTEL, THE ASSOCIATED OCTEL COMPANY LIMITED
Application year: 1993
Main classification: C07C229
IPC codes: C07C227, C07C229