The invention refers to a process for the reductive amination of a-keto carboxylic acids catalyzed by transition metal containing compounds.

Amines such as adamantyl glycine are key intermediates of therapeutic compounds, e. g. (3-hydroxyadamantan-l-yl)-glycine for dipeptityl peptidase IV inhibitors including Saxagliptin.

Saxagliptin (15',35',5 ₁ S -2-[(25)-2-amino-2-(3-hydroxy-l-adamantyl)acetyl]-2-azabicyc lo [3.1.0]hexane-3-carbonitrile or its hydrochloride salt is an orally active reversible dipeptidyl peptidase-4 (DD4) inhibitor, which is a therapeutic agent for treatment of type-2 diabetes mellitus, obesity or related diseases, and is disclosed for example in US 6,395,767 B2, example 60.

Saxagliptin can be produced by coupling (S)-N-Boc-3-hydroxyadamant-l-yl glycine and methanoprolineamide as shown in the following scheme:

BOC-S-HADGLY ABH-Amid.salt BOC-SAXA-Amid BOC-SAXA

SAXA SAXA-HH Therefore 3-hydroxyadamant-l-yl glycine or a derivative thereof is a key intermediate for the synthesis of Saxagliptin.

For the production of amino acids several routes have been described in literature. According to EP 1 559 710 A2 adamantyl carboxylic acid is esterified. The ester is reduced to the alcohol with L1AIH ₄ and then subjected to an oxidation to give an aldehyde. The aldehyde is then transformed under asymmetric Strecker conditions with KCN to give a nitrile which is then hydrolysed under hydrogen to yield the amino substituted compound. This process is disadvantageous as it needs several steps and expensive chemicals.

According to WO 2004052850 A2 a reductive amination of an a-oxo acetic acid substituted with an adamantyl rest is performed using an enzymatic enzyme, or transamination with a cell line. Alternatively, the aminolysis of an a-bromo-carboxylic acid followed by resolution is described.

According to WO2005106011 A2 amines are obtained by several steps including an enzymatic amination or transamination with a cell line.

According to WO 2006128952 Al 3-hydroxyadamantaneglyoxylic acid is obtained by contacting a 1-acyl derivative of an adamantane with an oxidant under oxidizing conditions. There is no mentioning of the production of the corresponding amine substituted compound, however.

A general review on reductive amination, including enzyme-catalyzed examples is given by Tripathi, R. P.; Verma, S. S.; Pandey, J.; Tiware, V. K. Curr. Org. Chem. 2008, 12, 1093. The reductive amination of a-keto carboxylic acids is only mentioned together with the use of amino acid dehydrogenases. Tararov, V. I.; Borner, A. Synlett 2005, 203, gives a general review on enantioselective reductive amination using hydrogen (H ₂ ). For a general review on the synthesis of chiral amines, including transition metal catalysed reductive amination see Nugent, T. C; El-Shazly, M. Adv. Synth. Catal. 2010, 352, 753. itamura, M.; Lee, D.; Hayashi, S.; Tanaka, S.; Yoshimura, M. J. Org. Chem. 2002, 67, 8685 describes a catalytic Leuckart-Wallach-type reductive amination of ketones applicable to a-keto acids. As catalysts group 8, 9 and 10 metal complexes having e. g. cyclopentadyenyl ligands were used. But there is no mentioning concerning the amination of a-keto carboxylic acids substituted with a cycloalkyl group and substituted derivatives thereof Tararov, V. I.; Kadyrov. R.; Riermeier, T. H.; Borner, A. Chem. Commun. 2000, 1867 refer to the reductive amination of aldehydes and ketones with primary amines catalyzed by homogenous rhodium complexes using 50 bar molecular hydrogen. According to WO 03/014061 Al and corresponding US 2004/0484900 amines are produced by reaction of aldehydes or ketones with ammonia or primary or secondary amines in the presence of a hydrogen-donor and the presence of homogeneous metal catalysts of the iron- and cobalt-sub-group. As hydrogen-donors e. g. isopropanol, ammonium formate, triethylammonium formate and formic acid-triethylamine mixtures may be used.

The methods known in the art for the reductive amination of keto carboxylic acids suffer from several disadvantages, e. g. expensive catalysts, use of high pressures of molecular hydrogen, separate addition of ammonia.

It is an object of this invention to provide an improved process for the preparation of oc- amino acids substituted by e. g. cycloalkyl or similar groups.

Unless otherwise indicated the term cycloalkyl as employed herein alone or as part of another group includes saturated cyclic hydrocarbon groups containing 1 to 3 rings, which includes monocyclic, bicyclic and tricyclic alkyls which includes bridge polycyclic alkyls containing in total 3 to 20 carbon atoms which includes cyclopropyl, cyclobutyl, cylcopentyl, cyclohexyl, adamantyl, norbornyl and 2,2,2-bicyclooctanyl. Unless otherwise indicated substituents on the cycloalkyl group as employed herein can be halogens, alkyl, alkoxy, hydroxyl, aryl, aryloxy, arylalkyl, cycloalkyl, alkylhydroxy, alkylamido, alkylamino, oxo, acyl, amino, nitro, cyano, thiol, alkylthio, carboxycarbonyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkanoyl, formyl, sulfonyl and sulfinyl.

The term nitrogen source refers to ammonia and its derivatives - i.e. primary and secondary amines - and salts thereof.

The term hydrogenating reagent refers to all compounds and compound mixtures that are able to generate hydrogen under reaction conditions, e.g. molecular hydrogen, formate salts, phosphinic acid and its salts, alkylhydrosilanes and -siloxanes, 1 ,4-dihydropyridines and derivatives thereof (Hantz'sch esters) and related unsaturated heterocycles. The present invention refers to a process for the preparation of a compound IV of the formula

A— CH— COOH NH ₂ by transformation, preferably reductive amination, of a compound I of the formula

or a derivative thereof wherein

A denotes a cycloalkyl substituent or substituted derivatives thereof, preferably adamantyl or substituted adamantyl, and the process comprises reacting of at least one compound of formula I with a hydrogenating reagent and a nitrogen source in the presence of a transition metal catalyst III.

In a preferred embodiment, the hydrogenating reagent is hydrogen and the nitrogen source is ammonia. Hydrogen and ammonia are preferably generated in situ from a compound II. The process according to the present invention is preferably performed in the absence of molecular hydrogen as cover gas and enzymes. In one preferred embodiment substituent A in compound I is adamantyl which is substituted or unsubstituted.

Compounds II generating ammonia and hydrogen is preferably a mixture of an ammonium salt and formate salt, more preferably ammonium formate.

The catalyst III is a mono- or polynuclear transition metal complex which may contain one or more mono- or polydentate, neutral or anionic ligands. Preferably, this transition metal catalyst contains palladium, rhodium or iridium.

In one preferred embodiment the process according to the present invention is catalyzed homogeneously by a catalyst III, preferably with a rhodium (Rh) or an Iridium (Ir) containing catalyst. In another preferred embodiment the catalysis is performed heterogeneously by a catalyst III, preferably with a palladium catalyst, particularly a palladium catalyst coated on a carrier like charcoal or insoluble inorganic materials. A preferred carrier is charcoal.

In the following the following nomenclature is used if not stated otherwise: ADMK: Adamantylmethylketone

ADGA: Adamantylglyoxylic acid

HADGA: 3-Hydroxyadamantylglyoxylic acid

ADGLY: Adamantylglycinic acid

HADGLY: 3-Hydroxyadamantylglycinic acid ADGA is well known in the art; with the described methodology it can be conveniently and selectively prepared by oxidizing ADMK with oxidants such as KMn0 ₄ in a suitable solvent such as water. This makes it a suitable starting material for the following steps. In one preferred embodiment of the invention HADGLY is produced in the following sequence of steps:

1. Reductive amination of ADGA using catalyst III, a nitrogen source and a hydrogenation reagent under formation of ADGLY

2. Oxidation of ADGLY with an oxidant to give HADGLY.

Preferred catalyst III for step 1 is a mono- or polynuclear transition metal complex which may contain one or more mono- or polydentate, neutral or anionic ligands. Preferably, this transition metal catalyst contains palladium, rhodium or iridium.

In one preferred embodiment the process according to the present invention is catalyzed homogeneously by a catalyst III, preferably with a rhodium (Rh) or an Iridium (Ir) containing catalyst. In another preferred embodiment the catalysis is performed heterogeneously by a catalyst III, preferably with a palladium catalyst, particularly a palladium catalyst coated on a carrier like charcoal or insoluble inorganic materials.

Preferred nitrogen source is ammonia or any of its derivatives - i.e. primary and secondary amines - or salts thereof. Preferred hydrogenation reagent is molecular hydrogen or formate salts.

Preferred oxidants for step 2 are: sodium nitrite, nitric acid, oxygen, dioxirane, potassium permanganate, preferably HN0 ₃ . The oxidation reaction is preferably performed in an acidic solvent such as TFA (trifluoracetic acid), methane sulfonic acid, triflic acid (trifluormethanesulfonic acid) or H ₂ S0 ₄ , preferably H ₂ S0 ₄ . The oxidation is preferably performed at a temperature of -20°C to -40°C, preferably 0 °C to 25 °C.

This total sequence is laid out in the following reaction scheme:

ADMK ADGA ADGLY HADGLY In another preferred embodiment HADGLY is directly obtained from HADGA by reductive amination using catalyst III, a nitrogen source and a hydrogenation reagent.

Preferred catalyst III is a mono- or polynuclear transition metal complex which may contain one or more mono- or polydentate, neutral or anionic ligands. Preferably, this transition metal catalyst contains palladium, rhodium or iridium.

In one preferred embodiment the process according to the present invention is catalyzed homogeneously by a catalyst III, preferably with a rhodium (Rh) or an Iridium (Ir) containing catalyst. In another preferred embodiment the catalysis is performed heterogeneously by a catalyst III, preferably with a palladium catalyst, particularly a palladium catalyst coated on a carrier like charcoal or insoluble inorganic materials.

Preferred nitrogen source is ammonia or any of its derivatives - i.e. primary and secondary amines - or salts thereof.

Preferred hydrogenation reagent is molecular hydrogen or formate salts.

This sequence is laid out in the following reaction scheme:

HADGA may be obtained by oxidation of ADGA as described with reference to the oxidation of ADGLY to HADGLY.

Examples

In the examples below, the following abbreviations have the following meanings. Any abbreviations not defined have their generally accepted meaning.

ADMK: Adamantylmethylketone

ADGA: Adamant- 1-yl glyoxylic acid

ADGLY: Adamant- 1-yl glycine

Boc: fert-butoxycarbonyl Pentamethylcyclopentadienyl

Eq.: molar equivalent

HADGA: 3-Hydroxyadamant-l-yl glyoxylic acid

HADGLY: 3-Hydroxyadamant-l-yl glycine

Example 1

Step 0, Preparation of educt

Pyridine (3 Eq., 40.8 mL, 0.51 mol) and KOH (1.2 Eq., 13.2 g, 0.20 mol) were added at room temperature to a suspension of ADMK (1 Eq., 30 g, 0.17 mol) in 500 mL H ₂ 0 and the mixture was warmed to 60 °C. KMn0 ₄ (2 Eq., 53.7 g, 0.34 mol) was added in three portions under ice cooling, so that the temperature of the reaction did not exceed 60 °C, and the mixture was stirred for 3 h at this temperature. The mixture was filtered off while hot, and the remaining solid was washed with 300 mL hot H ₂ 0. After cooling, the aqueous phase was extracted with EtOAc (2 x 150 mL). The aqueous phase was then acidified (pH < 1) and extracted again with EtOAc (3 x 250 mL). The combined organic phases were washed with brine, dried over Na ₂ S0 ₄ and the solvent removed in vacuo. Yield: 33 g (93 %). NMR: (δ, 1H, 300 MHz, DMSO-d ₆ ): 1.99 - 1.97 (m, 3H, Ad), 1.81 - 1.80 (m, 6H, Ad), 1.67 - 1.66 (m, 6H, Ad).

Step 1 , Reductive amination

1.1 Rh-catalyzed reductive amination: Degassed MeOH (19.2 mL) was added under nitrogen atmosphere to a mixture of ADGA (1 Eq., 2.0 g, 9.6 mmol), ammonium formate (5 Eq., 3.0 g, 48 mmol) and [Cp*RhCl ₂ ] ₂ (0.25 mol%, 14.8 mg, 0.024 mmol) and the mixture was stirred at 55 °C for 18 h, whereupon the reaction mixture turned from orange to grey. The precipitated white solid was filtered off, washed with chilled MeOH and dried. Yield: 1.78 g (88 %). 1.2 Pd-catalyzed reductive amination:

MeOH (15 mL) was added under nitrogen atmosphere to a mixture of ADGA (lEq., 1.0 g, 4.8 mmol), ammonium formate (5 Eq., 1.5 g, 24 mmol) and Pd/C (5 mol%, 5 % wt, 560 mg, 0,24 mmol) and the mixture was stirred in a closed system at 50 °C for 18 h. After cooling, the mixture was filtered over Celite and the filter cake was washed with 1.5 M HCI in MeOH. After evaporation of the solvent, the remaining solid was taken in acetone and the pH of the mixture set to 5. The resulting white solid was filtered off and dried to give ADGLY. Yield: 584 mg (58 %).

NMR: (as hydrochloride salt, δ, 1H, 300 MHz, DMSO-d ₆ ): 8.35 (s, 3H, NH ₃ ), 3.35 (d, J = 5.1 Hz, 1 H, CH), 1.96 (s, 3H, Ad), 1.66 - 1.53 (m, 12H, Ad).

Step 2, Oxidation:

ADGLY (450 mg, 2.15 mmol) was added portion wise to a cooled mixture of HN0 ₃ (65 %, 1.6 Eq., 0.24 mL, 3.44 mmol) and H ₂ S0 ₄ (95 %, 37.3 Eq., 4.5 mL, 80.20 mmol) at 0 °C. The reaction was stirred at room temperature for 4.5 h, after which the thick yellow solution was hydrolyzed with ice. The pH of the solution was set to 5, and 50 mL MeOH were added. The mixture was allowed to stand in the fridge overnight, after which the precipitated inorganic salts were filtered off. The filtrate was concentrated in vacuo and water was removed by azeo tropic distillation with CH ₂ C1 ₂ (2 x 20 mL). Upon addition of acetone (20 mL), a white solid precipitated which was filtered off and dried to yield HADGLY (320 mg, 66 %) as a white solid.

NMR: (as hydrochloride salt, δ, ¾ 300 MHz, DMSO-d ₆ ): 8.35 (s, 2H, NH ₂ ), 5.50 (bs, 2H, COOH, OH), 3.42 (d, J= 5.2 Hz, 1 H, CH), 2.12 (s, 2Η, Ad), 1.58 - 1.38 (m, 12Η, Ad).

Example 2 50.0 g HADGA (223 mmol, leq) were dissolved in 800 mL degassed methanol under nitrogen atmosphere in a 3 neck round bottom flask equipped with a reflux condenser, a mechanic stirrer and a thermometer. To the solution 70.3 g ammonium formate (1115 mmol, 5 eq) and 350 mg rhodium catalyst [RhCp*Cl ₂ ] ₂ (0.567 mmol, 0.25 mol%) was added under protecting atmosphere. The formed orange solution was stirred at 50 °C for 24 h. During the reaction time the color changed from orange to green/black and a suspension occurs. After 24 h the mixture was cooled to room temperature and the precipitate was filtered off and washed with small amounts of methanol. The white solid (57.0 g) was dried under vacuum (40 °C/ < 40 mbar) gaining 43.2 g (169 mmol, 86 %) HADGLY as a white solid. The solid was not solvable in any solvent that can be used for NMR spectroscopy. For this a small amount of HADGLY is dissolved in 1M HCI in methanol and the solvent is evaporated afterwards. The hydrochloride salt is solvable in DMSO. In NMR spectroscopy no side product has been identified.

1H-NMR HCI-salt (d6-DMSO, 300 mHz) (ppm) = 1.38 - 1.66 (m, 12 H), 2.12 (m, 2 H), 3.43 (m, 1H), 4.67 (b, 3H), 8.32 (b, 2H).

¹³ C-NMR HCI-salt (d6-DMSO), 75 MHz) (ppm) = 29.3, 34.8, 36.7, 37.1, 37.5, 38.7, 41.2, 45.9, 61.0, 66.7, 169.3.

Melting point: 302 °C

MS (ESI; PI): 225 [M + H] ⁺ , 214 [M+H-C] ⁺ , 158 [M-H ₅ N0 ₃ ] ⁺