Field of the invention

The present invention is directed to a new process for a regio- and stereoselective synthesis of α-halo-β-amino esters and α-halo-β-amino amides.

Background of the invention

Certain GABAe-receptor agonists as well as methods of making said compounds are disclosed in WO 98/ 11885 Al and in WO 01/ 42252 Al.

GABA _B receptor agonists are being described as being of use in the treatment of central nervous system (CNS) disorders, such as muscle relaxation in spinal spasticity, cardiovascular disorders, asthma, gut motility disorders such as irritable bowel syndrome (IBS) and as prokinetic and anti-tussive agents. GABA _B receptor agonists have also been disclosed as useful in the treatment of emesis (WO 96/11680, A2) and, as mentioned above, in the inhibition of transient lower oesophageal sphincter relaxations, TLOSR (WO 98/11885, Al).

EP 0356128, Al, describes the use of the specific compound (3-aminopropyl) methyl phosphinic acid, as a potent GABA _B receptor agonist, in therapy. EP 0181833, Al, discloses substituted 3-aminopropyl phosphinic acids (or more correctly 3-aminopropyl phosphonous acids having very strong affinities towards GABA _B receptor sites. EP 0399949, Al, discloses derivatives of (3-aminopropyl)methyl phosphinic acid that are described as potent GABA _B receptor agonists. These compounds are stated to be useful as muscle relaxants. EP 0463969, Al, and FR 2722192, A, are both applications related to 4- aminobutanoic acid derivatives having different heterocyclic substituents at the β-carbon of the butyl chain.

Synthesis of α-halo-β-amino esters has been disclosed by Gani et al. (J. Chem. Soc. Chem. Commun., 16, 1983, 898-900, Gani; Hitchcock, Young). The synthesis described herein is a single step reaction performed by reaction between (N-dibenzyl)-(2-amino-3-hydroxy)- propionic acid and (diethylamino)sulphur trifluoride (a compound as hereinafter is called DAST). However, DAST is a thermally unstable compound and has risks when handed in bulk quantities.

Still a further fluorination procedure is described by Picq et al. (Carbohydr. Res. 166, 1987, 309-313. Picq, Anker). This fluorination reaction however included a different type of molecule.

Description of the invention

The present invention provides a new process for large-scale halogenation i.e. for large- scale preparation of α-halo-β-amino esters or α-halo-β-amino amides. The reaction is a regioselective synthesis as well as a stereoselective synthesis of the α-halo-β-amino ester and α-halo-β-amino amide. The compound obtained by the process can be further processed to corresponding α-halo-β-amino acids.

One object of the present invention is to provide a process enabling the different reaction steps to be performed in a consecutive order, thus avoiding the time-consuming step of isolation, separation and filtration of the product after each reaction steps. This provides a more environmentally friendly process provided, as less amounts of, for example, solvents are needed for the process.

A further object of the present invention is to provide a process suitable for full-scale preparation with reactants that are easier and safety to handle, in comparison with DAST as this reactant is a thermally unstable compound.

The present invention, is a step- wise reaction for synthesising a compound of formula I:

wherein A is O or N;

R is a Ci- Cβ alkyl, optionally substituted by an aryl or a heteroaryl;

2 3

R and R are each and independently a C\- Cio alkyl, optionally substituted or interrupted by an aryl or a heteroaryl; and X is selected from F, Cl, Br, or I.

The reaction is a halogenation procedure comprising the consecutive sequence of following reactions: a) di-N-alkylation of α-amino-β-hydroxy-ester, or of α-halo-β-hydroxy-amide; b) formation of a leaving group on the alcohol function; and c) halogenation.

In one embodiment the reaction sequence comprises the following steps: a) reacting compound of formula II

wherein

A represents O or N;

R is as defined above;

2 3 with R -Z or with R -Z, or a mixture thereof wherein

2 3

R and R are each and independently C\- C\Q alkyl, optionally substituted by aryl, heteroaryl,

Z is selected from Cl, Br, I; the reaction is hereinafter referred to "di-N-alkylation reaction", a reaction to provide a compound of formula III

Step b: transforming the alcohol to a leaving group Y, to give a compound of formula IV

wherein

A represents O or N; R represents a Cj- Cg alkyl, optionally substituted with aryl, heteroaryl;

2 3

R and R each independently represents Cj- Cio alkyl, optionally substituted by aryl, heteroaryl; and

Y represents the leaving group.

Step c: reacting compound of formula IV with a halogen source to give the compound of formula I. This compound is an intermediate in the process for synthesis of, for example alkyl phospinic acids.

The starting material to be used for the synthesis of compounds of formula I according to the process provided by the present invention are commercial available, for example from Sigma-Aldrich.

The term "Ci-C^o alkyl" as used throughout this specification includes linear, branched or cyclic C J-C jo alkyl. Examples of C]-C \Q alkyl include, but are not limited to methyl, ethyl, propyl, n-propyl, isopropyl, cyclopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, cyclopentyl, hexyl and cyclohexyl.

The term "cyclic C3-C6 alkyl" as used throughout this specification means a cyclic alkyl having from 3 to 6 carbon atoms in the ring. Examples of cyclic C ₃ -C ₆ alkyl are cyclic propyl, cyclic butyl, cyclic pentyl, and cyclic hexyl.

The term "cyclic C3-C6 heteroalkyl" as used throughout this specification means a cyclic alkyl which one or more of the from 3 to 6 in the ring are elements other than carbon, such as N, S and O.

The term "aryl" as used throughout this specification means an aromatic ring having from 6 to 10 carbon atoms, such as phenyl and naphtyl.

The term "heteroaryl" as used throughout this specification means an aromatic ring in which one or more of the from 5-10 atoms in the ring are elements other than carbon, such as N, S and O.

As used herein, the term "leaving group", denoted Y in the compound of formula IV, can be formed by reaction of III with a reagent suitable for the suitable for the present reaction which can be selected from a group consisting of mesylate (-0802CHs) ₅ tosylate - OSO ₂ (C ₆ H ₄ ) CH ₃₎ Inflate (-OSO ₂ CF ₃ ), nosylate (-OSO ₂ (C ₆ H ₄ ) CH ₃ ). These reagents are commercial available in their respectively chloride or/and anhydride form. The invention is not restricted to the leaving groups mentioned above.

As used herein the term "halogene source" denotes any compound abel to donate a halide, such compounds can be selected from the group comprising potassium halide, tetraalkyl ammoniumhalide or pyridine hydrohalide. The halide used is selected from fluoride, chloride, bromide, and iodide. Non-limiting examples of halogene source are triethyl amine trihydrofluoride, potassium fluoride, tetrabutyl arnmoniumfluoride, pyridine hydrofluoride, triethyl amine hydrochloride, trimethyl amine hydrochloride, potassium chloride, tetrabutyl ammoniumchloride, and pyridine hydrochloride. However, the group of halogenating agents is not restricted to these mentioned.

Suitable solvent for the reaction sequence is selected from the group comprising toluene, methyl ύ-o-butylketone, ethylacetate, acetonitrile, or an equivalent solvent, or mixture thereof.

The reaction is performed as stepwise reaction wherein the different step follows in a consecutive order, thus, without isolation of the intermediates.

One object of the present invention is to provide a process for the production of α-halo-β- amino esters with high enantioselective excess. The process of the invention can be stereoselective and more than 98 % enantiomeric excess (%ee) can be achieved. Also when production on larger scale, i.e. of volumes equal or larger than 50 1, high enantiomeric excess is achieved. The stereoselectivity of the reaction can be obtained by specific selection of reactants, for example by coupling a sterically hindered group such as benzyl- group to enantiomerically pure (>99 %ee) methyl-(2-amino-3-hydroxy)-propionic acid.

A further object of the invention is to provide a process for the production of a compound of formula I wherein X represents fluorine or chlorine and Rj represents methyl.

The procedure is regioselective, it is possible to provide the desired isomer in a ratio of 15- 20: 1.

The process according to the present invention provides a good yield, i.e. 80 % or higher and reduced production time when performed on larger scale.

The compound of formula I may be further processed, even without isolation, for example, by reduction of the ester functionality forming the corresponding alcohol. This reaction is suitable performed by sodium borohydride using polyethylene glycol 400 (PEG) as solvent (Santaniello, Ferraboschi, Fiecchi, Grisenti, Manzocchi, J.Org. Chem. 1987, 52, pp. 671- 4). Surprisingly it was found that the reaction proceeded to completion by using toluene (or tetrahydrofuran) as solvent with as little as 10 % (v/v) PEG present. This also enabled an easy extractive work-up procedure with water. By adding PEG slowly to the mixture of sodium borohydride and (methyl(2i?)-3-(dibenzylamino)-2-fluoropropanate), dissolved in toluene, severe foaming during the reaction could be avoided. Hence, an effective and practical protocol for the reduction of an ester-functionality was developed, suitable also for large-scale production.

The examples below will further illustrate the reaction sequence of the invention. These examples are not intended to limit the scope if the invention as defined hereinabove or as claimed below.

EXAMPLES: Example 1:

Step l: Di-N-alkylation 943 g NaHCθ3 (11.2 mol, 4.5 eq.) and 841 g benzylbromide (4.86 mol, 2 eq.) were dispensed in 2.8 L acetonitrile/water 5:2 mixture and heated to 50 ⁰ C. 400 g of L-Serine- methylester x HCl (2.54 mol, 1.02 eq) was added slowly. The reaction mixture was heated over night (13 hours) and then cooled to 18 ⁰ C. HPLC showed 96 % conversion to methyl N ₅ N dibenzylserinate. The inorganic salts were filtered off and washed with 500 mL toluene. IL toluene and 500 mL water were added to the filtrate, the layers were separated after 15 minutes stirring (two clear phases).

1.5 L water was charged to the organic layer, stirred and separated. 320 g NaCl had to be charged to get separation of the layers. The organic layer was dried by distillation (T(jacket)=30°C, 0.08 bar). Approximately IL was distilled off and 1.5L toluene was added.

Water content: <0.1 % (w/v) Acetonitrile (GC): 0.1 % (w/w)

Step 2: Transforming of alcohol to a leaving group - mesylation

The reaction mixture was cooled to 6° C. 280 g triethyl amine (2.74 mol, 1.1 eq) was charged followed by slow addition (Ih 15 min) of 318 g mesyl chloride (2.74 mol, 1.1 eq) diluted in 200 mL toluene. The addition was exothermic, temperature was raised to 15 ⁰ C. +99 % conversion was achieved after 35 minutes (HPLC). 2L water was charged at 10 ⁰ C followed by 150 g Na ₂ CC>3 (s) and 300 mL toluene.

The water layer was removed and the organic layer was washed with 1.5 L water and 50 g Na ₂ CC^ (s). The water layer was removed and the organic layer dried by distillation

((T(jacket)=25 ⁰ C, 0.06 bar). Approximately 20OmL (from 4L to 3.8 L) solvent was distilled off and 500 mL toluene was charged. Water content: <0.1 % (w/v)

Step 3 Halogenation - fluorination

41Og triethylamin trihydrofluoride (2.49 mol, 1.0 eq.) was charged to the reaction mixture, which then was heated to 89 °C. After 2.5 h 99 % conversion (HPLC) was achieved and the reaction-mixture was cooled to 20 °C and stirred over night. 1 L water was charged and pH was adjusted with NH4OH, concentrated (390 mL) to pH 10. The layers were separated and the organic layer washed twice with 1.5 L water.

A 50 mL sample was removed from the 4 L reaction mixture and concentrated to a brownish oil, 8.84 g(98.0 % ee (HPLC); purity (GC) 86 % methyl (2i?)-3-(dibenzylamino)- 2-fluoropropanate, (5 % fluor regioisomer and 4.4 % toluene).

Yield 83 %.

Example 2

1.Og N,N-dibenzylserinate (3.3 mmol, 1.0 eq) was dissolved in 8 mL methyl isobutyl ketone. To the clear solution 0.291 mL mesyl chloride (3.7 mmol, 1.1 eq) was charged followed by 0.515 mL triethyl amine (3.7 mmol, 1.1 eq) yielding a thick slurry, which was diluted with 3 mL methyl isobutyl ketone. The reaction mixture was heated to 110°C and stirred for one hour. After cooling to ambient temperature the reaction mixture was washed two times with 7 mL Water. The water layers were discarded and the organic layer filtrated through sodium sulphate followed by concentration under vacuum yielding methyl (2R)-3- (dibenzylamino)-2-chloropropanate as an oil. Purity 92.7 area% (GC).