EP2611770A1 - Process for the reductive amination of -keto carboxylic acids - Google Patents

Process for the reductive amination of -keto carboxylic acids

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Publication number
EP2611770A1
EP2611770A1 EP11749456.7A EP11749456A EP2611770A1 EP 2611770 A1 EP2611770 A1 EP 2611770A1 EP 11749456 A EP11749456 A EP 11749456A EP 2611770 A1 EP2611770 A1 EP 2611770A1
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EP
European Patent Office
Prior art keywords
process according
compound
hadgly
reductive amination
adgly
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP11749456.7A
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German (de)
French (fr)
Inventor
Thorsten Wilhelm
Kerstin Knepper
Wolfgang Felzmann
David Benito-Garragori
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Sandoz AG
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Sandoz AG
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Priority to EP11749456.7A priority Critical patent/EP2611770A1/en
Publication of EP2611770A1 publication Critical patent/EP2611770A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
    • C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • 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-azabicyclo [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.
  • DD4 dipeptidyl peptidase-4
  • Saxagliptin can be produced by coupling (S)-N-Boc-3-hydroxyadamant-l-yl glycine and methanoprolineamide as shown in the following scheme:
  • SAXA SAXA-HH Therefore 3-hydroxyadamant-l-yl glycine or a derivative thereof is a key intermediate for the synthesis of Saxagliptin.
  • 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.
  • an enzymatic enzyme or transamination with a cell line.
  • the aminolysis of an a-bromo-carboxylic acid followed by resolution is described.
  • WO2005106011 A2 amines are obtained by several steps including an enzymatic amination or transamination with a cell line.
  • keto carboxylic acids suffer from several disadvantages, e. g. expensive catalysts, use of high pressures of molecular hydrogen, separate addition of ammonia.
  • 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.
  • 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.
  • nitrogen source refers to ammonia and its derivatives - i.e. primary and secondary amines - and salts thereof.
  • 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 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.
  • 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.
  • 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.
  • this transition metal catalyst contains palladium, rhodium or iridium.
  • 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.
  • a catalyst III preferably with a rhodium (Rh) or an Iridium (Ir) containing catalyst.
  • 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.
  • 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.
  • HADGLY is produced in the following sequence of steps:
  • 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.
  • this transition metal catalyst contains palladium, rhodium or iridium.
  • 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.
  • a catalyst III preferably with a rhodium (Rh) or an Iridium (Ir) containing catalyst.
  • 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.
  • 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.
  • this transition metal catalyst contains palladium, rhodium or iridium.
  • 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.
  • a catalyst III preferably with a rhodium (Rh) or an Iridium (Ir) containing catalyst.
  • 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.
  • HADGA may be obtained by oxidation of ADGA as described with reference to the oxidation of ADGLY to HADGLY.
  • ADGA Adamant- 1-yl glyoxylic acid
  • ADGLY Adamant- 1-yl glycine
  • HADGLY 3-Hydroxyadamant-l-yl glycine
  • 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 %).
  • 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.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

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

Description

Process for the reductive amination of a-keto carboxylic acids
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',51S -2-[(25)-2-amino-2-(3-hydroxy-l-adamantyl)acetyl]-2-azabicyclo [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 L1AIH4 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 (H2). 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 NH2 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 KMn04 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 HN03. The oxidation reaction is preferably performed in an acidic solvent such as TFA (trifluoracetic acid), methane sulfonic acid, triflic acid (trifluormethanesulfonic acid) or H2S04, preferably H2S04. 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 H20 and the mixture was warmed to 60 °C. KMn04 (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 H20. 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 Na2S04 and the solvent removed in vacuo. Yield: 33 g (93 %). NMR: (δ, 1H, 300 MHz, DMSO-d6): 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*RhCl2]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-d6): 8.35 (s, 3H, NH3), 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 HN03 (65 %, 1.6 Eq., 0.24 mL, 3.44 mmol) and H2S04 (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 CH2C12 (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-d6): 8.35 (s, 2H, NH2), 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*Cl2]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).
13C-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-H5N03]+

Claims

Claims
1. A process for the preparation of a compound IV of the formula
A— CH— COOH
NH2 by transformation 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 at least one compound of formula I with a hydrogenating reagent and a nitrogen source in the presence of a transition metal catalyst III.
2. Process according to claim 1 wherein compound I is an adamantylglyoxylic acid.
3. Process according to claim 1 wherein the hydrogenating reagent is hydrogen and the nitrogen source is ammonia.
4. Process according to at least one of the preceding claims, wherein ammonia and hydrogen are generated in situ from at least one compound II.
5. Process according to claim 4 wherein compound II contains an ammonium ion and a formate ion, preferably ammonium formate.
6. Process according to at least one of the preceding claims wherein catalyst III is a homogeneous or heterogeneous transition metal catalyst, preferably containing Rh, Ir or Pd.
7. Process according to at least one of the preceding claims wherein the catalysis is performed homogeneously by a Rh or Ir containing catalyst.
8. Process according to at least one of the preceding claims wherein the catalysis is performed homogeneously by a compound of the formula
[Cp*MCl2]2 M = Rh, Ir as catalyst III.
9. Process according to at least one of the preceding claims wherein the catalysis is performed heterogeneously by a Pd containing catalyst III.
10. Process according to at least one of the preceding claims wherein HADGLY is produced in the following sequence of steps:
1. Reductive amination of ADGA under formation of ADGLY
2. Oxidation of ADGLY with an oxidant to give HADGLY.
11. Process according to at least one of the preceding claims wherein HADGLY is produced in the following sequence of steps:
1. Oxidation of ADMK to ADGA
2. Reductive amination of ADGA under formation of ADGLY
3. Oxidation of ADGLY with an oxidant to give HADGLY.
12. Process according to at least one of the preceding claims wherein HADGLY is directly obtained from HADGA by reductive amination.
13. Process for the production of a pharmaceutical active ingredient wherein an amine prepared in a process according to at least one of the preceding claims is used.
14. Process according to claim 13 wherein the active pharmaceutical ingredient is Saxagliptin.
EP11749456.7A 2010-09-03 2011-09-02 Process for the reductive amination of -keto carboxylic acids Withdrawn EP2611770A1 (en)

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PCT/EP2011/065216 WO2012028721A1 (en) 2010-09-03 2011-09-02 PROCESS FOR THE REDUCTIVE AMINATION OF α-KETO CARBOXYLIC ACIDS

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