EP2611770A1 - Procédé d'amination réductrice d'acides -céto-carboxyliques - Google Patents

Procédé d'amination réductrice d'acides -céto-carboxyliques

Info

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
Authority
EP
European Patent Office
Prior art keywords
process according
compound
hadgly
reductive amination
adgly
Prior art date
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.)
Withdrawn
Application number
EP11749456.7A
Other languages
German (de)
English (en)
Inventor
Thorsten Wilhelm
Kerstin Knepper
Wolfgang Felzmann
David Benito-Garragori
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sandoz AG
Original Assignee
Sandoz AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sandoz AG filed Critical Sandoz AG
Priority to EP11749456.7A priority Critical patent/EP2611770A1/fr
Publication of EP2611770A1 publication Critical patent/EP2611770A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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.

Landscapes

  • 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

Cette invention concerne un procédé d'amination réductrice d'acides α-céto-carboxyliques catalysé par des composés contenant un métal de transition.
EP11749456.7A 2010-09-03 2011-09-02 Procédé d'amination réductrice d'acides -céto-carboxyliques Withdrawn EP2611770A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP11749456.7A EP2611770A1 (fr) 2010-09-03 2011-09-02 Procédé d'amination réductrice d'acides -céto-carboxyliques

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP10175258 2010-09-03
PCT/EP2011/065216 WO2012028721A1 (fr) 2010-09-03 2011-09-02 Procédé d'amination réductrice d'acides α-céto-carboxyliques
EP11749456.7A EP2611770A1 (fr) 2010-09-03 2011-09-02 Procédé d'amination réductrice d'acides -céto-carboxyliques

Publications (1)

Publication Number Publication Date
EP2611770A1 true EP2611770A1 (fr) 2013-07-10

Family

ID=44532885

Family Applications (1)

Application Number Title Priority Date Filing Date
EP11749456.7A Withdrawn EP2611770A1 (fr) 2010-09-03 2011-09-02 Procédé d'amination réductrice d'acides -céto-carboxyliques

Country Status (2)

Country Link
EP (1) EP2611770A1 (fr)
WO (1) WO2012028721A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110041267A (zh) * 2019-05-29 2019-07-23 宁夏蓝丰精细化工有限公司 多菌灵清洁生产系统

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI20120842A1 (it) * 2012-05-16 2013-11-17 Chemelectiva S R L Intermedi utili per la preparazione di saxagliptina e processo per la loro preparazione
CN104370769B (zh) * 2013-08-14 2017-05-31 重庆博腾制药科技股份有限公司 一种制备羟基金刚烷甘氨酸衍生物的方法
JP6440132B2 (ja) 2014-12-15 2018-12-19 オルガノフール スウェーデン エービー 不均一系金属触媒反応によるアルデヒドまたはケトンからのアミドおよびアミンの合成
CN104892443B (zh) * 2015-04-07 2016-08-24 嘉兴学院 (s)-3-羟基金刚烷甘氨酸的制备方法

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6395767B2 (en) 2000-03-10 2002-05-28 Bristol-Myers Squibb Company Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
DE10138140A1 (de) 2001-08-09 2003-02-20 Degussa Verfahren zur Herstellung von Aminen durch reduktive Aminierung von Carbonylverbindungen unter Transfer-Hydrierungsbedingungen
JP4015510B2 (ja) 2002-09-09 2007-11-28 日本エー・エス・エム株式会社 半導体集積回路の多層配線用層間絶縁膜及びその製造方法
US7420079B2 (en) 2002-12-09 2008-09-02 Bristol-Myers Squibb Company Methods and compounds for producing dipeptidyl peptidase IV inhibitors and intermediates thereof
US7741082B2 (en) 2004-04-14 2010-06-22 Bristol-Myers Squibb Company Process for preparing dipeptidyl peptidase IV inhibitors and intermediates therefor
FI120765B (fi) 2005-05-31 2010-02-26 Kemfine Group Ltd Menetelmä adamantaanijohdannaisten valmistamiseksi

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2012028721A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110041267A (zh) * 2019-05-29 2019-07-23 宁夏蓝丰精细化工有限公司 多菌灵清洁生产系统

Also Published As

Publication number Publication date
WO2012028721A1 (fr) 2012-03-08

Similar Documents

Publication Publication Date Title
US10533028B2 (en) Ruthenium complexes and their uses as catalysts in processes for formation and/or hydrogenation of esters, amides and related reactions
US8835691B2 (en) Process for homogeneously catalyzed, highly selective direct amination of primary alcohols with ammonia to primary amines with a high volume ratio of liquid phase to gas phase and/or high pressures
EP1903027A1 (fr) Procédé de préparation de l' acide amino-4 butyrique ou de ses derivés et leur utilisation pour la préparation des inhibiteurs NEP
García-Álvarez et al. Thiazolyl-phosphine hydrochloride salts: effective auxiliary ligands for ruthenium-catalyzed nitrile hydration reactions and related amide bond forming processes in water
EP2611770A1 (fr) Procédé d'amination réductrice d'acides -céto-carboxyliques
US20090247744A1 (en) Hydroformylation process for pharmaceutical intermediate
Jiang et al. Asymmetric transfer hydrogenation catalysed by hydrophobic dendritic DACH–rhodium complex in water
EP3414215B1 (fr) Complexes à base de manganèse et leurs utilisations servant à une catalyse homogène
EP3390421B1 (fr) Complexes métalliques
EP1930315A1 (fr) Procede de fabrication d'un compose alkyle mono-substitue utilisant de l'aldimine ou un derive d'aldimine
Zheng et al. Ruthenium-catalyzed synthesis of N-substituted lactams by acceptorless dehydrogenative coupling of diols with primary amines
Ma et al. A New Phosphine‐Amine‐Oxazoline Ligand for Ru‐Catalyzed Asymmetric Hydrogenation of N‐Phosphinylimines
CA2671830C (fr) Procede catalytique pour hydrogenation asymetrique
US6225499B1 (en) Process for preparing aminoarylacetylenes
MX2010014510A (es) Sintesis de aminas quirales.
Tran et al. N-Carboxyanhydrides directly from amino acids and carbon dioxide and their tandem reactions to therapeutic alkaloids
CN111072642B (zh) 一种5-琥珀酰亚胺色酮类化合物的制备方法
Zhang et al. Direct Asymmetric Aldol Reaction Co‐catalyzed by Amphiphilic Prolinamide Phenol and Lewis Acidic Metal on Water
Tat'yana An asymmetric metal-templated route to amino acids with an isoquinolone core via a Rh (iii)-catalyzed coupling of aryl hydroxamates with chiral propargylglycine Ni (ii) complexes
Tydlitát et al. Phenylalanine‐Derived Imidazolines Bearing Heteroaromatic Pendants: Synthesis, Characterization, and Application in the Asymmetric Henry Reaction
Singh et al. Role of ancillary ligands in selectivity towards acceptorless dehydrogenation versus dehydrogenative coupling of alcohols and amines catalyzed by cationic ruthenium (ii)–CNC pincer complexes
Gerasimchuk et al. Novel L-threonine-based ionic liquid supported organocatalyst for asymmetric syn-aldol reactions: Activity and recyclability design
Chen et al. Chiral Amidophosphane–Rhodium (I)-Catalyzed Asymmetric Conjugate Arylation of Acyclic Enones with Arylboronic Acids
Hert Transition Metal Catalysts for the Hydrogenation of Carbon Dioxide to Value Added Materials
Aburatani et al. Hf (Otf) 4-catalyzed 1, 4-addition reactions of indole to enone in the presence of meso and chiral pyridine-diamine ligands

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20130228

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20140731

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTG Intention to grant announced

Effective date: 20160408

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: SANDOZ AG

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20160819