WO2018011823A1 - Salt of amine-protected (1s,2r,4s)-1,2-amino-n,n-dimethylcyclohexane-4-carboxamide - Google Patents
Salt of amine-protected (1s,2r,4s)-1,2-amino-n,n-dimethylcyclohexane-4-carboxamide Download PDFInfo
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- 0 C*(C(CC1)C2)C1(CS(O)(=O)=O)C2=O Chemical compound C*(C(CC1)C2)C1(CS(O)(=O)=O)C2=O 0.000 description 2
- MCSCBNNXUZEKEC-XHNCKOQMSA-M CC(C)(C)OC(N[C@H](C[C@H](CC1)C([O-])=O)[C@H]1N)=O Chemical compound CC(C)(C)OC(N[C@H](C[C@H](CC1)C([O-])=O)[C@H]1N)=O MCSCBNNXUZEKEC-XHNCKOQMSA-M 0.000 description 2
- JBCOYDRQCPJFHJ-UHFFFAOYSA-N CN(C)C(C1CCCCC1)=O Chemical compound CN(C)C(C1CCCCC1)=O JBCOYDRQCPJFHJ-UHFFFAOYSA-N 0.000 description 2
- RQEUFEKYXDPUSK-ZETCQYMHSA-N C[C@@H](c1ccccc1)N Chemical compound C[C@@H](c1ccccc1)N RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 description 2
- AUNQNSSYIXDICZ-NXEZZACHSA-N CCOC([C@H](CC1)CC(C)(C)C[C@@H]1N)=O Chemical compound CCOC([C@H](CC1)CC(C)(C)C[C@@H]1N)=O AUNQNSSYIXDICZ-NXEZZACHSA-N 0.000 description 1
- MWGHOOBSZNKRCV-VXGBXAGGSA-N CCOC([C@H](CC1)CC(C)(C)C[C@@H]1NC=C)=O Chemical compound CCOC([C@H](CC1)CC(C)(C)C[C@@H]1NC=C)=O MWGHOOBSZNKRCV-VXGBXAGGSA-N 0.000 description 1
- HGVDHZBSSITLCT-JLJPHGGASA-N CN(C)C([C@@H](CC[C@@H]1NC(C(Nc(cc2)ncc2Cl)=O)=O)C[C@H]1NC(c1nc(CCN(C)C2)c2[s]1)=O)=O Chemical compound CN(C)C([C@@H](CC[C@@H]1NC(C(Nc(cc2)ncc2Cl)=O)=O)C[C@H]1NC(c1nc(CCN(C)C2)c2[s]1)=O)=O HGVDHZBSSITLCT-JLJPHGGASA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N Cc(cc1)ccc1S(O)(=O)=O Chemical compound Cc(cc1)ccc1S(O)(=O)=O JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- DRNGLYHKYPNTEA-IZLXSQMJSA-N N[C@H](CC1)CC[C@@H]1C(O)=O Chemical compound N[C@H](CC1)CC[C@@H]1C(O)=O DRNGLYHKYPNTEA-IZLXSQMJSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/19—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- the present invention relates generally to the synthesis of active pharmaceutical agents and more specifically to the preparation of an amine -protected (lS,2R,4S)-l,2-amino-N,N- dimethylcyclohexane-4-carboxamide)camphor sulfonate, which may be an intermediate used in the synthesis of Edoxaban and pharmaceutically acceptable salts, solvates, or salt of solvates thereof. Further, the present invention further provides methods for the synthesis of this intermediate with improved purity.
- Edoxaban exhibits an inhibitory effect on activated blood coagulation factor X (FXa) and as such, is an oral anticoagulant drug used to prevent or treat thrombotic diseases.
- Edoxaban is marketed in the United States as SAVAYSA® and LIXIANA®by Daiichi Sankyo.
- Edoxaban is chemically known as N'-(5-chloropyridin-2-yl)-N-[(lS,2R,4S)-4-(dimethylcarbamoyl)-2-[(5- methyl-6,7-dihydro-4H-[l,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide and is represented by the formula below:
- Edoxaban tosylate monohydrate which is represented below as Formula 1:
- Edoxaban (and salts/solvates thereof) may be prepared by a variety of methods.
- One such method involves use of an intermediate as depicted below, wherein PG is an amine protecting group (herein referred to as amine-protected (lS,2R,4S)-l,2-amino-N,N-dimethylcyclohexane-4- carboxamide)
- U.S. Patent No. 8,686,189 discloses this Boc-protected intermediate as well, along withacid addition salts thereof.
- U.S. Patent No. 8,357,808 discloses a process for the preparation of Edoxabanusingan oxalate salt ofthe Boc-protected intermediate:
- the present invention provides methods for the preparationof a substantiallypure camphor sulfonate salt ofamine- protected( 1 S,2R,4S)- 1 ,2-amino-N,N-dimethylcyclohexane-4-carboxamide (represented by formula (X) below).
- the present invention provides methods for the preparation of camphor sulfonate salt of aBoc-protected [(lR,2S,5S)-l,2-amino-5 [(dimethylamino)carbonyl]cyclohexane]intermediate (( 1 S,2R,4S)- 1 -amino-2-(boc-amino)-N,N dimethylcyclohexane-4-carboxamide), depicted below, with high purity.
- the present invention provides a compound of formula (X), wherein PG is an amine protecting group:
- the amine protecting group is a t-butyloxycarbonyl (Boc) group.
- the present invention provides a process for the preparation of formula (X), which may include the steps of: a) treating formula (Vll)with a base in a solventto obtain formula (VIII)
- PG is an amine protecting group
- the amine protecting group is a t-butyloxycarbonyl (Boc) group.
- the base may be, for example (but not limited to), sodium hydroxide, potassium hydroxide, and lithium hydroxide.
- the solvent may be, for example, a ketone solvent, an ester solvent, acetonitrile, or mixtures thereof.
- suitable ketone solvents include, but are not limited to, acetone, methyl isobutyl ketone, methyl ethyl ketone, and mixtures thereof.
- ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, and mixtures thereof.
- formula (X) may be further converted to Edoxaban, or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a combination thereof.
- the present invention provides a compound of formula (Villa), wherein PG is an amine protecting group
- the amine protecting group is a t-butyloxycarbonyl (Boc) group.
- formula (Villa) may be prepared by a process that includes treating formula (VII) with a base followed by (S)-(alpha)-phenylethylamine in the presence of a solvent
- the base may be, for example (but not limited to), sodium hydroxide, potassium hydroxide, and lithium hydroxide.
- the solvent may be, for example, a ketone solvent, an ester solvent, acetonitrile, or mixtures thereof.
- suitable ketone solvents include, but are not limited to, acetone, methyl isobutyl ketone, methyl ethyl ketone, and mixtures thereof.
- ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, and mixtures thereof.
- Formula (Villa) may be further converted to formula (IX).
- this conversion may be carried out in a solvent.
- suitable solvents include, but are not limited to chlorinated solvents, ketone solvents, ester solvents, toluene, acetonitrile, and mixtures thereof.
- suitable chlorinated solvents include, but are not limited to, methylene dichloride, chloroform, and mixtures thereof.
- suitable ketone solvents include, but are not limited to, acetone, methyl isobutyl ketone, methyl ethyl ketone, and mixtures thereof.
- ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, and mixtures thereof.
- This conversion may be carried out with a suitable base, for example (though not limited to), triethylamine, diisopropylethylamine, diisopropylamine, or N-methylmorpholine.
- formula (IX) may be further converted to formula (X) by a process that includes the following steps: a) reducing the azide of formula (IX);and
- PG amine protecting group
- Edoxaban pharmaceutically acceptable salts, solvates, and solvated salts thereof, prepared by methods disclosed herein may be incorporated into a pharmaceutical dosage form that optionally includes further excipients.
- the present invention provides formula (X):
- PG is an amine -protecting group.
- suitable amine protecting groups as well as suitable conditions for protecting and deprotecting, can be found in prior art, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999; "The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981 ; in “Methoden der organischenChemie", Houben-Weyl, 4th edition, Vol.
- R P is a -C(R PI ) 3 , wherein each R PI is hydrogen or optionally substituted aryl, provided that at least one R PI is not hydrogen;
- Optionally substituted as used herein means the reference group is substituted by one or more groups (e.g., 1 to 5, or 1 to 3, or 1 to 2 groups, or 1 group) that are each independently halo, alkyl, alkoxy, nitro, cyano, tri(Ci_ 3 alkyl)silyl (e.g., trimethylsilyl).
- groups e.g., 1 to 5, or 1 to 3, or 1 to 2 groups, or 1 group
- amine protecting groups include, carbonyls (e.g., methyl carbamate, 9- fluorenylmethyoxycarbonyl (Fmoc), trichloroethoxycarbonyl (Troc), t-butoxycarbonyl (BOC), 2-trimethylsilylethyloxycarbonyl (Teoc), allyloxycarbonyl (Alloc), p-methoxybenzyl carbonyl (Moz), and carboxybenzyl (Cbz)), sulfonyls (e.g., p-toluenesufonyl (Ts), trimethylsilylethanesulfoyl (Ses), t-butylsulfonyl (Bus), 4-methoxyphenylsulfonyl, 4- nitrobenzenesulfonyl (nosyl)), trityl (trt), benzyl (Bn), 3,4-dimethyls
- alkenyl means a straight or branched chain hydrocarbon containing from 2 to 10 carbons, unless otherwise specified, and containing at least one carbon-carbon double bond.
- alkenyl include, but are not limited to, ethenyl, 2- propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l- heptenyl, 3-decenyl, and 3, 7-dimethylocta-2,6-dienyl.
- alkoxy as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
- Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, t-butoxy, pentyloxy, and hexyloxy.
- alkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, unless otherwise specified.
- Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl, isobutyl, t- butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3- dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
- aryl means a monocyclic (i.e., phenyl), bicyclic, or tricyclic ring fused or bridged system containing at least one phenyl ring.
- Non-phenyl rings that are part of a bicyclic or tricyclic ring system may be fully or partially saturated, may contain one or more heteroatoms, each selected from N, S, and O, and may be optionally substituted with one or two oxo and/or thio groups.
- aryl groups include phenyl, napthyl, anthracenyl, and fluorenyl.
- arylalkyl as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
- Representative examples of arylalkylin include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, fluorenylmethyl and 2-naphth-2-ylethyl.
- halo or halogen as used herein, means -CI, -Br, -I, or -F.
- haloalkyl as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
- Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, perfluorononyl, and 2-chloro-3-fluoropentyl.
- heteroaryl means a monocyclic, bicyclic, or tricyclic ring system containing at least one heteroaromatic ring. Any additional rings that are part of a bicyclic or tricyclic ring system may be fully or partially saturated or may be aromatic rings, and each may optionally contain one or more heteroatoms, each selected from N, S, and O.
- monocyclic and bicyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, triazinyl,benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinnolinyl, dihydroquinolinyl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl, and tetrahydr
- heteroarylalkyl as used herein, means a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
- Representative examples of heteroarylalkyl include, but are not limited to, furylmethyl, imidazolylmethyl, pyridinylethyl, pyridinylmethyl, pyrimidinylmethyl, and thienylmethyl.
- t-butyloxycarbonyl(Boc) protecting group is found to be particularly useful as an amine -protecting group.
- formula (X) may be prepared by a process that includes the steps of: a) treating formula (Vll)with a base to obtain formula VIII)
- formula (VIII) may formed by treating formula (VII) with a base.
- suitable bases include sodium hydroxide, potassium hydroxide, and lithium hydroxide.
- This reaction may be carried out in a suitable solvent, for example, an organic solvent.
- suitable organic solvents include, but are not limited to, acetonitrile,ketones, esters, or mixtures thereof.
- suitable ketones include, but are not limited to, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and mixtures thereof.
- suitable esters include, but are not limited to,ethyl acetate, isopropyl acetate, and mixtures thereof.
- formula (VIII) may be converted to formula (IX). This may be carried out using a "direct conversion” or a "two-step conversion.”
- formula (VIII) may be converted directly to formula (IX) bytreating formula (VIII) with a base.
- suitable bases include, but are not limited to,triethylamine, diisopropylethylamine, diisopropylamine, and N-methylmorpholine.
- This reaction may be carried out in a suitable solvent.
- suitable solvents include, but are not limited to, chlorinated solvents, ketone solvents, ester solvents, toluene, acetonitrile, or mixtures thereof.
- suitable chlorinated solvents include, but are not limited to,methylene dichloride, chloroform, and mixtures thereof.
- ketone solvents include, but are not limited to, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and mixtures thereof.
- suitable estersolvents include, but are not limited to, ethyl acetate, isopropyl acetate, and mixtures thereof.
- formula (VIII) may be converted to formula (IX) by first converting formula (VIII) to formula (Villa). This may be carried out by treating formula (VIII) with (S)-(alpha)- phenylethylamine. This may be carried out in a suitable solvent, for example (but not limited to), acetonitrile, a ketone solvent, an ester solvent, or mixtures thereof.
- suitable ketones include but are not limited to, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and mixtures thereof.
- esters include, but are not limited to,ethyl acetate, isopropyl acetate,and mixtures thereof.
- formula (Villa) may be converted to formula (IX). This may be performed using a base.
- suitable bases include, but are not limited to, triethylamine, diisopropylethylamine, diisopropylamine,andN-methylmorpholine. This reaction may be carried out in a solvent.
- Suitable solvents include, but are not limited to, acetonitrile, toluene, chlorinated solvents (e.g., methylene dichloride, chloroform, and mixtures thereof), ketones (e.g., acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and mixtures thereof), esters (e.g., ethyl acetate, isopropyl acetate, and mixtures thereof), and mixtures thereof.
- chlorinated solvents e.g., methylene dichloride, chloroform, and mixtures thereof
- ketones e.g., acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and mixtures thereof
- esters e.g., ethyl acetate, isopropyl acetate, and mixtures thereof
- Formula (IX) may then be reduced.
- Reduction may be carried out by methods well known in the art.
- this reduction may be achieved by hydrogenationaccording to methods and reaction conditions well known to one of skill in the art.
- hydrogenation may be carried out by bubbling hydrogen into the reaction mixture containing palladium on carbon (Pd/C) in an alcoholic solvent such as methanol, ethanol, isopropanol, or mixtures thereof.
- Suitable organic solvents include, but are not limited to,acetonitrile, ketones, esters, and mixtures thereof.
- suitable ketones include, but are not limited to, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and mixtures thereof.
- suitable esters include, but are not limited to, ethyl acetate, isopropyl acetate, and mixtures thereof.
- formula (X) may be converted to Edoxaban, salts, solvates, or solvated salts thereof.
- formula (X) may becondensed with ethyl2-[5- chloropyridin-2-ylamino]-2-oxoacetate to get formula XI.
- formula Xl Upon condensation with 5-methyl- 4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxylic acid hydrochloride, formula Xlmay be converted toEdoxaban free base.
- Edoxaban tosylate monohydrate may then be formed by treatingEdoxaban free base with p-toluenesulfonic acid. This set of reactions is depicted as Scheme I below:
- mesylate is used as a hydroxy protecting group.
- Edoxaban may be converted to a number of other pharmaceutically acceptable salts, which are well-known in the art. Methods for converting compounds into their acid salt forms are also well known in the art, and may be carried out, for example, by reacting a free base moiety on Edoxabanwith a suitable reagent.
- suitable acids include, for example, inorganic acids or organic acids.
- suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid.
- Suitable organic acids include, for example, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid.
- a pharmaceutically acceptable salt may alternatively be prepared by other methods well known in the art, for example, ion exchange.
- Suitable salts include, for example, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, (R,S)-malate, (S)-malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate,
- Edoxaban or salts, solvates, or solvated salts thereof may be prepared using formula VIII by way of Scheme 3 below, where the amine -protecting group, introduced in formula V, is a t-butyloxycarbonyl (Boc) and the hydroxy protecting group, introduced in formula VI, is a mesylate (Ms) group: (SM-)-cycloriexene carboxylic acid
- formula (X) When prepared by methods disclosed herein, formula (X) may be prepared with high purity. In some embodiments, when prepared by the methods disclosed herein, formula (X) may display a purity of more than 99% and enantiomeric excess (ee)of greater than 99.5%. Preparation of the formula (X) intermediate with high purity and yield may, in some embodiments, result in increased purity and yield of subsequent intermediate (e.g., formula (XI)) and increased purity and yield of the final Edoxaban and pharmaceutically acceptable salts, solvates, or solvated salts thereof.
- Mobile phase-B Transfer about 800 mL of Acetonitrile by using a 1000 mL measuring cylinder and 200 mL of Methanol by using a 250 mL (or) 500 mL measuring cylinder into a mobile phase bottle, mix thoroughly to form a uniform mixture of Acetonitrile : Methanol (80:20) v/v and degassed.
- the Edoxabanand pharmaceutical salts, solvates, or solvated salts thereof disclosed herein and prepared by the disclosed methods may be used to formulate an oral dosage form, such as a tablet or a capsule.
- an oral dosage form such as a tablet or a capsule.
- the Edoxaban or pharmaceutical salts thereof of the present invention may be useful to reduce the risk of stroke and systemic embolism in patients withnon-valvular atrial fibrillation, in the treatment of deep vein thrombosis, pulmonary embolism, or any combination thereof.
- the Edoxaban and pharmaceutical salts, solvates, or solvated salts thereof may be formulated into a tablet which may contain inactive ingredients such as mannitol, pregelatinized starch, crospovidone, hydroxypropyl cellulose, magnesium stearate, talc, carnauba wax, or mixtures thereof.
- the tablet may, in some embodiments, be coated with a film that includes additional excipients, artificial colors, and flavors.
- a coating may containhypromellose, titanium dioxide, talc, polyethylene glycol 8000, iron oxide yellow, iron oxide red, and mixtures thereof.
- the tablets may contain Edoxaban, pharmaceutical salts, solvates, or solvated salts thereof at an effective amount of between 15 mg and 60 mg.
- the tablets have 15 mg, 30 mg, or 60 mg of effective Edoxaban.
- an effective amount refers to the amount of active Edoxabanincluded within the dosage form.
- the salt when a salt of Edoxabanis used, the salt may be included in the dosage form at a higher weight to achieve the nominal effective concentration. For example, 20.2 mg of Edoxaban tosylate monohydrate may be included in a dosage form, resulting in a dosage form with an effective amount of 15 mg Edoxaban.
- Formula (II) (lOg) was dissolved in ethanol (50 ml). Potassium carbonate (6.59 g) was added to this solution at 75 °C. The mixture was heated to maintain the temperature at 75 °C for 2 hours and then allowed to cool to room temperature. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. A mixture of ethyl acetate (80 ml) and water (20 ml) was added to the obtained residue and the aqueous and organic layers were separated. The organic layer was then dried over anhydrous sodium sulfate (5g) and the solvent was distilled off under reduced pressure to obtainformula(III) as a pale yellow oil (5.5 g).
- Boc-anhydride was added to a mixture of formula (IV) (5g) in water (40ml) cooled with ice. The reaction mass was stirred at room temperature for 2hours. After completion of the reaction, ethyl acetate was added. The organic layer was separated from the aqueous layer then distilled under reduced pressure to remove the solvent and obtain an oily mass. The obtained oily mass was crystalized with hexanes to obtain formula (V) as a solid (4g).
- Triethylamine (74.83 g,0.738moles) was added to a solution of formula (VIII) (70g, 0.246 moles) in methylene dichloride (350 ml) and the solution was cooled to -5 to -10 °C.
- Pivaloyl chloride (29.66 g, 0.246moles) was then slowly added dropwise and the reaction was maintained at the same temperature for 90minutes.
- Dimethylamine hydrochloride (24.07g, 0.295moles) was then added lot wise and the reaction mixture was maintainedfor 4hours. After completion of the reaction, water (350ml) was added and the layers were separated. The organic layer was subjected to distillation under reduced pressure to remove organic solvent to obtain an oily mass.
- Triethylamine (52.34 g, 0.518 moles) was added to a solution of formula (Villa) (70 g,0.172moles)in methylene dichloride(350ml) and the solution was cooled to -5to-10°C.
- Pivaloyl chloride (24.87g,0.206moles) was slowly added dropwise and the reaction mass was maintained at the same temperature for 90minutes.
- Dimethylamine hydrochloride (16.90g, 0.206moles) was then added lotwise and the reaction mass was maintained at the same temperature for 4hours. After completion of the reaction, water (350ml) was added and the organic and aqueous layers were separated. The organic layer was distilled under reduced pressure to remove the solvent and obtain an oily mass.
- Triethylamine 16.86 ml, 0.049 moles was added to a solution offormula (X) ( 10.0g,0.019moles) in acetonitrile (55ml) at 60 °C.
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Abstract
Disclosed are compounds and methods for the preparation of Edoxaban. In particular, a camphor sulfonate salt of an amine-protected [(1R,2S,5S)-1,2-amino-5-[(dimethylamino)carbonyl] cyclohexane, an intermediate that may be formed in the synthesis of Edoxaban, is disclosed as well as methods of its preparation.
Description
SALT OF AMINE-PROTECTED (lS,2R,4S)-l,2-AMINO-N,N-
DIMETHYLCYCLOHEXANE-4-CARBOXAMIDE
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the priority of earlier Indian provisional patent application no.201641023903, filed on July 13, 2016, which is incorporated herein in its entirety byreference.
FIELD OF THE INVENTION
The present invention relates generally to the synthesis of active pharmaceutical agents and more specifically to the preparation of an amine -protected (lS,2R,4S)-l,2-amino-N,N- dimethylcyclohexane-4-carboxamide)camphor sulfonate, which may be an intermediate used in the synthesis of Edoxaban and pharmaceutically acceptable salts, solvates, or salt of solvates thereof. Further, the present invention further provides methods for the synthesis of this intermediate with improved purity.
BACKGROUND OF THE INVENTION
Edoxabanexhibits an inhibitory effect on activated blood coagulation factor X (FXa) and as such, is an oral anticoagulant drug used to prevent or treat thrombotic diseases. Edoxaban is marketed in the United States as SAVAYSA® and LIXIANA®by Daiichi Sankyo. Edoxabanis chemically known as N'-(5-chloropyridin-2-yl)-N-[(lS,2R,4S)-4-(dimethylcarbamoyl)-2-[(5- methyl-6,7-dihydro-4H-[l,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide and is represented by the formula below:
SAVAYSA® and LIXIANA® contain Edoxaban as monohydrate of the tosylate salt (Edoxaban tosylate monohydrate) which is represented below as Formula 1:
Formula 1
Edoxaban (and salts/solvates thereof) may be prepared by a variety of methods. One such method involves use of an intermediate as depicted below, wherein PG is an amine protecting group (herein referred to as amine-protected (lS,2R,4S)-l,2-amino-N,N-dimethylcyclohexane-4- carboxamide)
For example, U.S. Patent No.7,365,205discloses Edoxaban, pharmaceutical acceptable salts thereof, as well as a process for the preparation of Edoxabanusingthis intermediate, wherein the protecting group (PG) is Boc:
U.S. Patent No. 8,686,189 discloses this Boc-protected intermediate as well, along withacid addition salts thereof.
U.S. Patent No. 8,357,808discloses a process for the preparation of Edoxabanusingan oxalate salt ofthe Boc-protected intermediate:
There is a longstanding need in the field prepare anamine-protected(lS,2R,4S)-l,2-amino-N,N- dimethylcyclohexane-4-carboxamideintermediate with high purity. The present invention provides methods for the preparationof a substantiallypure camphor sulfonate salt ofamine- protected( 1 S,2R,4S)- 1 ,2-amino-N,N-dimethylcyclohexane-4-carboxamide (represented by formula (X) below).
In particular embodiments, the present invention provides methods for the preparation of camphor sulfonate salt of aBoc-protected [(lR,2S,5S)-l,2-amino-5 [(dimethylamino)carbonyl]cyclohexane]intermediate (( 1 S,2R,4S)- 1 -amino-2-(boc-amino)-N,N dimethylcyclohexane-4-carboxamide), depicted below, with high purity.
By using the methods provided herein, high yields ofamine-protected(lS,2R,4S)-l,2-amino-N,N- dimethylcyclohexane-4-carboxamidecamphor sulfonate exhibiting high diastereomeric/ enantiomeric purity may be achieved.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a compound of formula (X), wherein PG is an amine protecting group:
In some embodiments, the amine protecting group is a t-butyloxycarbonyl (Boc) group.
In another aspect, the present invention provides a process for the preparation of formula (X), which may include the steps of: a) treating formula (Vll)with a base in a solventto obtain formula (VIII)
(VIII) (IX) c) reducingthe azide of formula (IX); and
d) treating with (lR)-(-)-10-camphorsulfonic acid to obtain formula (X)
In some embodiments, the amine protecting group is a t-butyloxycarbonyl (Boc) group.
Within the context of this embodiment, the base may be, for example (but not limited to), sodium hydroxide, potassium hydroxide, and lithium hydroxide. The solvent may be, for example, a ketone solvent, an ester solvent, acetonitrile, or mixtures thereof. Examples of suitable ketone solvents include, but are not limited to, acetone, methyl isobutyl ketone, methyl ethyl ketone, and mixtures thereof. Examples of ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, and mixtures thereof.
Within the context of the present invention, formula (X) may be further converted to Edoxaban, or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a combination thereof.
In another aspect, the present invention provides a compound of formula (Villa), wherein PG is an amine protecting group
(Villa)
In some embodiments, the amine protecting group is a t-butyloxycarbonyl (Boc) group.
In yet another embodiment, the present invention provides a process for the preparation of formula (Villa). In one embodiment, formula (Villa) may be prepared by a process that includes treating formula (VII) with a base followed by (S)-(alpha)-phenylethylamine in the presence of a solvent
(VII) (Villa) wherein PG is an amine-protecting group.
Within the context of this embodiment, the base may be, for example (but not limited to), sodium hydroxide, potassium hydroxide, and lithium hydroxide. The solvent may be, for example, a ketone solvent, an ester solvent, acetonitrile, or mixtures thereof. Examples of suitable ketone solvents include, but are not limited to, acetone, methyl isobutyl ketone, methyl ethyl ketone, and mixtures thereof. Examples of ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, and mixtures thereof. Formula (Villa) may be further converted to formula (IX).
(Villa) (IX)
Within the context of this embodiment, this conversion may be carried out in a solvent. Examples of suitable solvents include, but are not limited to chlorinated solvents, ketone solvents, ester solvents, toluene, acetonitrile, and mixtures thereof. Examples of suitable chlorinated solvents include, but are not limited to, methylene dichloride, chloroform, and mixtures thereof. Examples of suitable ketone solvents include, but are not limited to, acetone, methyl isobutyl ketone, methyl ethyl ketone, and mixtures thereof. Examples of ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, and mixtures thereof. This conversion may be carried out with a suitable base, for example (though not limited to), triethylamine, diisopropylethylamine, diisopropylamine, or N-methylmorpholine.
Within the context of this embodiment, formula (IX) may be further converted to formula (X) by a process that includes the following steps: a) reducing the azide of formula (IX);and
b) treating with (lR)-(-)-10-camphorsulfonic acid to obtain formula (X)
In some embodiments, using a t-butyloxycarbonyl group as the amine protecting group (PG) is found particularly useful.
Within the context of the present invention, Edoxaban, pharmaceutically acceptable salts, solvates, and solvated salts thereof, prepared by methods disclosed herein may be incorporated into a pharmaceutical dosage form that optionally includes further excipients.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention provides formula (X):
Within the context of this invention, "PG" is an amine -protecting group. Examples of suitable amine protecting groups, as well as suitable conditions for protecting and deprotecting, can be found in prior art, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999; "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981 ; in "Methoden der organischenChemie", Houben-Weyl, 4th edition, Vol. 15/1, Georg Thieme Verlag, Stuttgart 1974; H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine", Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982; and Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate", Georg Thieme Verlag, Stuttgart 1974.
Amine protecting groups include, for example, -Rp, =RQ, -C(0)R°, -C(O)OR0,-S(O)2R°, and 2- nitrophenylsulfenyl, wherein
R P is a -C(R PI )3, wherein each R PI is hydrogen or optionally substituted aryl, provided that at least one R PI is not hydrogen;
RQ is =C(H)-R°; and
R is hydrogen, C1-10 alkyl, C2-10 alkenyl, C1-10 haloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein each alkyl, aryl, and heteroaryl group is optionally substituted.
"Optionally substituted" as used herein means the reference group is substituted by one or more groups (e.g., 1 to 5, or 1 to 3, or 1 to 2 groups, or 1 group) that are each independently halo, alkyl, alkoxy, nitro, cyano, tri(Ci_3alkyl)silyl (e.g., trimethylsilyl).
Particular examples of amine protecting groups include, carbonyls (e.g., methyl carbamate, 9- fluorenylmethyoxycarbonyl (Fmoc), trichloroethoxycarbonyl (Troc), t-butoxycarbonyl (BOC), 2-trimethylsilylethyloxycarbonyl (Teoc), allyloxycarbonyl (Alloc), p-methoxybenzyl carbonyl (Moz), and carboxybenzyl (Cbz)), sulfonyls (e.g., p-toluenesufonyl (Ts), trimethylsilylethanesulfoyl (Ses), t-butylsulfonyl (Bus), 4-methoxyphenylsulfonyl, 4- nitrobenzenesulfonyl (nosyl)), trityl (trt), benzyl (Bn), 3,4-dimethyoxybenzyl (Dmpm), p- methoxybenzyl (PMB), p-methoxyphenyl (PMP), acetyl (Ac), formyl, trifluoroacetyl (Tfa), benzoyl (Bz), or 2-nitrophenylsulfenyl (Nps).
As used herein,the term "alkenyl" means a straight or branched chain hydrocarbon containing from 2 to 10 carbons, unless otherwise specified, and containing at least one carbon-carbon double bond. Representative examples of alkenyl include, but are not limited to, ethenyl, 2- propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l- heptenyl, 3-decenyl, and 3, 7-dimethylocta-2,6-dienyl.
The term "alkoxy" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, t-butoxy, pentyloxy, and hexyloxy.
The term "alkyl" as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, unless otherwise specified. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl, isobutyl, t- butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3- dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
The term "aryl," as used herein, means a monocyclic (i.e., phenyl), bicyclic, or tricyclic ring fused or bridged system containing at least one phenyl ring. Non-phenyl rings that are part of a bicyclic or tricyclic ring system may be fully or partially saturated, may contain one or more heteroatoms, each selected from N, S, and O, and may be optionally substituted with one or two oxo and/or thio groups. Examples of aryl groups include phenyl, napthyl, anthracenyl, and fluorenyl.
The term "arylalkyl" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkylinclude, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, fluorenylmethyl and 2-naphth-2-ylethyl.
The term "halo" or "halogen" as used herein, means -CI, -Br, -I, or -F.
The term "haloalkyl" as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, perfluorononyl, and 2-chloro-3-fluoropentyl.
The term "heteroaryl," as used herein, means a monocyclic, bicyclic, or tricyclic ring system containing at least one heteroaromatic ring. Any additional rings that are part of a bicyclic or tricyclic ring system may be fully or partially saturated or may be aromatic rings, and each may optionally contain one or more heteroatoms, each selected from N, S, and O. Representative examples of monocyclic and bicyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, triazinyl,benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinnolinyl, dihydroquinolinyl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl, and tetrahydroquinolin-yl.
The term "heteroarylalkyl" as used herein, means a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of
heteroarylalkyl include, but are not limited to, furylmethyl, imidazolylmethyl, pyridinylethyl, pyridinylmethyl, pyrimidinylmethyl, and thienylmethyl.
The term "oxo" as used herein means a =0 group. The term "thio" as used herein means a =S group.
In some embodiments, use of a t-butyloxycarbonyl(Boc) protecting group is found to be particularly useful as an amine -protecting group.
Another aspect of the present invention provides a process for the preparation of formula (X). In one embodiment, formula (X) may be prepared by a process that includes the steps of: a) treating formula (Vll)with a base to obtain formula VIII)
(VII) (VIII) b) converting formula (VIII)to formula (IX)
(VIII) (IX)
c) reducingthe azide of formula (IX);and
(IX) (X)
According tothis embodiment, formula (VIII) may formed by treating formula (VII) with a base. Examples of suitable bases include sodium hydroxide, potassium hydroxide, and lithium hydroxide. This reaction may be carried out in a suitable solvent, for example, an organic solvent.Examples of suitable organic solvents include, but are not limited to, acetonitrile,ketones, esters, or mixtures thereof. Examples of suitable ketones include, but are not limited to, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and mixtures thereof. Examples of suitable esters include, but are not limited to,ethyl acetate, isopropyl acetate, and mixtures thereof.
Next, formula (VIII) may be converted to formula (IX). This may be carried out using a "direct conversion" or a "two-step conversion."
Direct Conversion
(VIII) (IX)
In one embodiment, formula (VIII) may be converted directly to formula (IX) bytreating formula (VIII) with a base. Examples of suitable bases include, but are not limited to,triethylamine, diisopropylethylamine, diisopropylamine, and N-methylmorpholine. This reaction may be carried out in a suitable solvent. Example of suitable solvents include, but are not limited to, chlorinated solvents, ketone solvents, ester solvents, toluene, acetonitrile, or mixtures thereof.
Examples of suitable chlorinated solvents include, but are not limited to,methylene dichloride, chloroform, and mixtures thereof. Examples of suitable ketone solvents include, but are not limited to, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and mixtures thereof. Examples of suitable estersolvents include, but are not limited to, ethyl acetate, isopropyl acetate, and mixtures thereof.
Two-Step Conversion
(VIII) (Villa) (IX)
In one embodiment, formula (VIII) may be converted to formula (IX) by first converting formula (VIII) to formula (Villa). This may be carried out by treating formula (VIII) with (S)-(alpha)- phenylethylamine. This may be carried out in a suitable solvent, for example (but not limited to), acetonitrile, a ketone solvent, an ester solvent, or mixtures thereof. Examples of suitable ketones include but are not limited to, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and mixtures thereof. Examples of suitable esters include, but are not limited to,ethyl acetate, isopropyl acetate,and mixtures thereof. Next, formula (Villa) may be converted to formula (IX). This may be performed using a base. Examples of suitable bases include, but are not limited to, triethylamine, diisopropylethylamine, diisopropylamine,andN-methylmorpholine. This reaction may be carried out in a solvent. Suitable solvents include, but are not limited to, acetonitrile, toluene, chlorinated solvents (e.g., methylene dichloride, chloroform, and mixtures thereof), ketones (e.g., acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and mixtures thereof), esters (e.g., ethyl acetate, isopropyl acetate, and mixtures thereof), and mixtures thereof.
Formula (IX) may then be reduced. Reduction may be carried out by methods well known in the art. For example, this reduction may be achieved by hydrogenationaccording to methods and reaction conditions well known to one of skill in the art. For example, hydrogenation may be
carried out by bubbling hydrogen into the reaction mixture containing palladium on carbon (Pd/C) in an alcoholic solvent such as methanol, ethanol, isopropanol, or mixtures thereof.
Subsequent treatmentwith a (lR)-(-)-10-camphorsulfonic acid in a suitable organic solvent may then generate formula (X).Examples of suitable organic solvents include, but are not limited to,acetonitrile, ketones, esters, and mixtures thereof. Examples of suitable ketones include, but are not limited to, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and mixtures thereof. Examples of suitable esters include, but are not limited to, ethyl acetate, isopropyl acetate, and mixtures thereof.
Within the context of the present invention, formula (X) may be converted to Edoxaban, salts, solvates, or solvated salts thereof. For example, formula (X) may becondensed with ethyl2-[5- chloropyridin-2-ylamino]-2-oxoacetate to get formula XI. Upon condensation with 5-methyl- 4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxylic acid hydrochloride, formula Xlmay be converted toEdoxaban free base. Edoxaban tosylate monohydrate may then be formed by treatingEdoxaban free base with p-toluenesulfonic acid. This set of reactions is depicted as Scheme I below:
Formula-1 Edox
Scheme I
Within the context of the present invention, formula (VII) may be prepared by prior art methods, for example, by a series of reactions depicted in Scheme 2 below:
(VIII) (IX)
Scheme 2 Within the context of this invention, "PG"' in formula VI is a hydroxy protecting group.
Examples of suitable hydroxy protecting groups, as well as suitable conditions for protecting and deprotecting, can be found in prior art, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999; "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981; in "Methoden der organischenChemie", Houben-Weyl, 4th edition, Vol. 15/1, Georg Thieme Verlag, Stuttgart 1974; H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine", Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982; and Jochen Lehmann,
"Chemie der Kohlenhydrate: Monosaccharide und Derivate", Georg Thieme Verlag, Stuttgart 1974. In some embodiments, mesylate is used as a hydroxy protecting group.
In addition to converting Edoxabanfree base to the Edoxaban tosylate monohydrate, Edoxaban may be converted to a number of other pharmaceutically acceptable salts, which are well-known in the art. Methods for converting compounds into their acid salt forms are also well known in the art, and may be carried out, for example, by reacting a free base moiety on Edoxabanwith a suitable reagent.
Examples of suitable acids include, for example, inorganic acids or organic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid. Suitable organic acids include, for example, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid. A pharmaceutically acceptable salt may alternatively be prepared by other methods well known in the art, for example, ion exchange. Additional examples of suitable salts include, for example, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, (R,S)-malate, (S)-malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, phthalate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts.
In particularly useful embodiments of the present invention, Edoxaban or salts, solvates, or solvated salts thereof may be prepared using formula VIII by way of Scheme 3 below, where the amine -protecting group, introduced in formula V, is a t-butyloxycarbonyl (Boc) and the hydroxy protecting group, introduced in formula VI, is a mesylate (Ms) group:
(SM-)-cycloriexene carboxylic acid
(VIII) (IX)
Formula-1 Edoxaban
Scheme 3
In another aspect, the present invention provides formula (Villa), which, as depicted above, may be useful for the preparation of formula IX.
(Villa)
When prepared by methods disclosed herein, formula (X) may be prepared with high purity. In some embodiments, when prepared by the methods disclosed herein, formula (X) may display a purity of more than 99% and enantiomeric excess (ee)of greater than 99.5%. Preparation of the formula (X) intermediate with high purity and yield may, in some embodiments, result in increased purity and yield of subsequent intermediate (e.g., formula (XI)) and increased purity and yield of the final Edoxaban and pharmaceutically acceptable salts, solvates, or solvated salts thereof. For example, the table below provides yield and purity measurements for formula (X), wherein the PG=Boc along with each successive intermediate, as well as the final product prepared by embodiments of methods disclosed herein.
Column X Bridge BEH CI 8, 100x4.6mm, 2.5 μπι
Detector UV at 290 nm
Flow rate 0.8 mL/minute
Injection volume 10 μΐ.
Column oven temp. 30 °C
Acquisition time 30 minutes
Run time : 40 minutes
Diluent : Acetonitrile : Water (1 : 1 v/v)
Buffer Preparation:
Dissolve 1.54 Ammonium Acetate into 1000 mL of water and adjust the pH to 5.00 0.05 with dilute Acetic acid solution. Filter through 0.22 μπι membrane and degas. Mobile phase-A: Buffer
Mobile phase-B: Transfer about 800 mL of Acetonitrile by using a 1000 mL measuring cylinder and 200 mL of Methanol by using a 250 mL (or) 500 mL measuring cylinder into a mobile phase bottle, mix thoroughly to form a uniform mixture of Acetonitrile : Methanol (80:20) v/v and degassed.
The Edoxabanand pharmaceutical salts, solvates, or solvated salts thereof disclosed herein and prepared by the disclosed methods may be used to formulate an oral dosage form, such as a tablet or a capsule.When administered to patients, the Edoxaban or pharmaceutical salts thereof of the present invention may be useful to reduce the risk of stroke and systemic embolism in patients withnon-valvular atrial fibrillation, in the treatment of deep vein thrombosis, pulmonary embolism, or any combination thereof.
The Edoxaban and pharmaceutical salts, solvates, or solvated salts thereof (e.g., Edoxaban tosylate monohydrate) as disclosed and prepared herein may be formulated into a tablet which may contain inactive ingredients such as mannitol, pregelatinized starch, crospovidone, hydroxypropyl cellulose, magnesium stearate, talc, carnauba wax, or mixtures thereof. The tablet may, in some embodiments, be coated with a film that includes additional excipients, artificial colors, and flavors. For example, a coating may containhypromellose, titanium dioxide, talc, polyethylene glycol 8000, iron oxide yellow, iron oxide red, and mixtures thereof. One of skill in the art will be familiar with a variety of excipients and formulations that may be used to prepare desirable dosage forms with desired release characteristics and pharmacokinetic properties without undue experimentation.
In some embodiments, the tablets may contain Edoxaban, pharmaceutical salts, solvates, or solvated salts thereof at an effective amount of between 15 mg and 60 mg. In particularly useful embodiments, the tablets have 15 mg, 30 mg, or 60 mg of effective Edoxaban. Within the context of this invention, an effective amount refers to the amount of active Edoxabanincluded within the dosage form. In some embodiments when a salt of Edoxabanis used, the salt may be included in the dosage form at a higher weight to achieve the nominal effective concentration. For example, 20.2 mg of Edoxaban tosylate monohydrate may be included in a dosage form, resulting in a dosage form with an effective amount of 15 mg Edoxaban.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner. In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention.
All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.
EXAMPLES:
Example 1: Preparation of formula (II):
(S)-(-)-cyclohexene carboxylic acid (Π)
(S)-(-)-3-cyclohexenecarboxylicacid(100g,0.793moles)was added to N-bromosuccinimide (145.3g,0.816moles)and sodium hydroxide(0.5g,0.012moles) in ethyl acetate(200ml) at room temperature and was stirred for 3hours. Then reaction mass was distilled under reduced
pressure, water(500ml)was added, and the reaction mass was heated to 75°C. The obtained mixture was then filteredto obtain a solid which was dried under atmospheric pressure at 50°C to get formula(II) as an off white solid(140g,yield:86%).
Example 2: Preparation of formula (III):
Formula (II) (lOg) was dissolved in ethanol (50 ml). Potassium carbonate (6.59 g) was added to this solution at 75 °C. The mixture was heated to maintain the temperature at 75 °C for 2 hours and then allowed to cool to room temperature. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. A mixture of ethyl acetate (80 ml) and water (20 ml) was added to the obtained residue and the aqueous and organic layers were separated. The organic layer was then dried over anhydrous sodium sulfate (5g) and the solvent was distilled off under reduced pressure to obtainformula(III) as a pale yellow oil (5.5 g).
Example 3 :Preparationof formula (IV):
(HI) (IV)
A mixture formula (III)(5.0g), ethanol (25ml), and ammonia (25ml) was stirred at 45 °C for 24 hours. The reaction mass was distilled under reduced pressure to obtain formula (IV) as an oily mass (6.0g).
Example 4 :Preparationof formula (V):
(IV) (V)
Boc-anhydride was added to a mixture of formula (IV) (5g) in water (40ml) cooled with ice. The reaction mass was stirred at room temperature for 2hours. After completion of the reaction, ethyl acetate was added. The organic layer was separated from the aqueous layer then distilled under reduced pressure to remove the solvent and obtain an oily mass. The obtained oily mass was crystalized with hexanes to obtain formula (V) as a solid (4g).
Example 5 :Preparationof formula (VI):
Triethylamine (5.84 g) and methane sulfonyl chloride (4.28 g) were simultaneously added to a stirred solution of formula (V) (lOg) in acetone (50ml) at 15-20°C. The temperature of the reaction mixture was maintained for 90mins. After completion of the reaction, water (25 ml) was added to the reaction mixture. Then,the mixture was filtered to obtain a precipitate which was dried under reduced pressure to get formula (VI)as an off-white solid (10.5g).
Example 6 :Preparationof formula (VII):
Sodium azide (8.87 g, 0.054 moles) and benzyltriethylammonium chloride was added to a solution of formula (VI) (10g,0.027moles) in N, N-dimethyl formamide (20ml) and stirred at 55- 60 °C for 48 hours. After completion of the reaction, the reaction mixture was cooled the reaction to room temperature and water (40 ml) was added and stirred for 4hours. The mixture was filteredto obtain a precipitate which was washed with water then dried under reduced pressure to obtain formula (Vll)as a solid(6.5g,yield: 76%).
Example 7 :Preparationof formula (VIII):
(VII) (VIII)
A solution of lithium hydroxide (3.226g) dissolved in water (20ml) was added to a stirred solution of formula (VII) (20g) and water (100ml) at room temperature. Then, the reaction mixture was stirred for 18 hours at the same temperature. After completion of reaction, thepH of the solution was adjusted to 4.0-4.5 by using aqueous citric acid solution. A precipitate formed and the mixture was filtered to isolate the solid, which was then dried under reduced pressure to get Formula (VIII) as asolid (16g).
Example 8: a. Direct conversion of formula (VIII) to formula (IX):
(VIII) (IX)
Triethylamine (74.83 g,0.738moles) was added to a solution of formula (VIII) (70g, 0.246 moles) in methylene dichloride (350 ml) and the solution was cooled to -5 to -10 °C. Pivaloyl chloride (29.66 g, 0.246moles) was then slowly added dropwise and the reaction was maintained at the same temperature for 90minutes. Dimethylamine hydrochloride (24.07g, 0.295moles) was then added lot wise and the reaction mixture was maintainedfor 4hours. After completion of the reaction, water (350ml) was added and the layers were separated. The organic layer was subjected to distillation under reduced pressure to remove organic solvent to obtain an oily mass. Isopropyl ether (350ml)was added to the oily mass and the mixture was stirred for 4 hours at room temperature then cooled to 5-10 °C. The mixture was then filtered to isolate a solid which was dried under reduced pressure to get formula (IX)as a solid (60g, yield:78.2%). b. Two-step conversion of formula (VIII) to formula (IX). Conversion of formula (VIII) to formula (Villa):
(VIII) (Villa)
A solution of (S)-(alpha)-phenylethylamine (6.14 g; 0.05 moles)dissolved in acetone (160 ml) was added to a stirred solution of formula (VIII) (16g, 0.056 moles) in acetone (48 ml) at room temperature. The reaction mixture was stirred for 16 hours, filtered, and the obtained solid was dried under reduced pressure to get Formula (Villa) (16 g). Conversion of formula (Villa) to formula (IX):
(Villa) (IX)
Triethylamine (52.34 g, 0.518 moles) was added to a solution of formula (Villa) (70 g,0.172moles)in methylene dichloride(350ml) and the solution was cooled to -5to-10°C. Pivaloyl chloride (24.87g,0.206moles) was slowly added dropwise and the reaction mass was maintained at the same temperature for 90minutes. Dimethylamine hydrochloride (16.90g, 0.206moles) was then added lotwise and the reaction mass was maintained at the same temperature for 4hours. After completion of the reaction, water (350ml) was added and the organic and aqueous layers were separated. The organic layer was distilled under reduced pressure to remove the solvent and obtain an oily mass. Isopropyl ether (350ml)was added to the oily mass and the mixture was stirred for 4 hours at room temperature then cooled to 5-10°C to form a solid. The mixture was filtered to isolate a solid which was dried under reduced pressure to get formula (IX) as a solid (40g, yield:74.4%).
Example 9 :Preparationof formula (X):
10%Pd/C (0.75g,5%loading) was added to a solution of formula (IX)(15g,0.048 moles) in methanol (120 ml) purged with hydrogen gas(3 kg/cm )and stirred for 8 hours at room temperature. After completion of the reaction, the reaction mass was filtered through Hyflo and thefiltratewas concentrated under reduced pressure to get an oily mass. Theoily mass was then dissolved in acetone (150ml) anda solution of (lR)-camphorsulfonic acid (9.5g, 0.040moles)in acetone(45 ml) was added slowly at room temperature. The reaction mass wasthen stirred for 15hours. The reaction mass was filtered and the obtained solid was dried under reduced pressure at 50°C for 4 hours to get formula (X) as white solid (18.0g, yield: 72%; HPLC Purity: 99.7%; ee: 99.9%).
Example 10: Preparationof formula (XI):
Triethylamine ( 16.86 ml, 0.049 moles) was added to a solution offormula (X) ( 10.0g,0.019moles) in acetonitrile (55ml) at 60 °C. Ethyl 2-[5-chloropyridin-2-ylamino]-2- oxoacetate(5.3 g,0.023moles) was then added at same temperature and reaction mass was maintained for 6 hours. After 6hours, the reaction mixture temperature was allowed to decrease to room temperature and then was stirred for 16 hours. The reaction mixture was further cooled to 5- 10 °C and stirred for 90 minutes to obtainformula (XI) as a white precipitate.(7.0g, yield: 77%,HPLC Purity: >99%).
Example 11: Preparationof Edoxaban:
A solution offormula (XI) (7.0g, 0.014moles) inmethylene dichloride(56ml) andmethane sulfonic acid (4.85ml, 0.074 moles) was stirred for 2 hours at room temperature. After completion of the reaction, triethylamine( 15.63ml,0.1 12moles),5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4- c]pyridine-2-carboxylic acid hydrochloride^.86 g,0.0164moles),N-(3-dimethylaminopropyl)-N'- ethylcarbodiimidehydrochloride (3.44g,0.017moles),and 1-hydroxybenzotriazole
(2.43g,0.0158moles) was added while the reaction mixture was cooled with ice. Thereaction mixture was stirred for 18 hours at room temperature after which water (35ml)and methylene dichloride(70ml) was added. The layers were separated the layers and organic layer was concentrated under reduced pressure to get Edoxabanas a solid (7.0g, yield: 85%, HPLC Purity: >99%).
Example 12: Preparation of Edoxaban Tosylate (Formula 1):
Formula 1
P-toluenesulfonic acid (1.73g) was added to a stirred solution of Edoxaban(5.0g), methylene dichloride(5ml),and ethanol(85ml). The mixture was distilled under atmospheric pressure and water(12.5 ml) was addedand the mixturewas heated to 70-75 °C to obtain a clear solution. The reaction mixture was cooled to room temperature and stirred for 16 hours. The solution was filtered to obtain a white precipitate, which was washed with ethanol (5ml) then dried under reduced pressure at room temperature to obtain Formula 1 (5.0g, yield: 75%, HPLC Purity: 99.7%).
Claims
We claim:
1. A compound of formula (X), wherein PG is an amine protecting group
The compound of claim 1 , wherein the amine protecting group is a t- butyloxycarbonyl(Boc) group.
A process for the preparation of formula (X), comprising the steps of: a.) treating formula (Vll)with a base in a solventto obtain formula (VIII)
(VII) (VIII) b.) converting formula (VIII)to formula (IX)
(VIII) (IX)
c). reducingthe azide of formula (IX)andtreating with (lR)-(-)-10- camphorsulfonic acid to obtain formula (X)
(IX) (X) wherein PG is an amine protecting group.
The process according toclaim 3, further comprising converting compound of formula (X) to Edoxaban.
The process according to claim 4, further comprising converting Edoxaban to a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a combination thereof.
A compound of formula (Villa), wherein PG is an amine protecting group
(Villa)
7. The compound of claim 6, wherein the amine protecting group is a t-butyloxycarbonyl (Boc) group.
8. A process comprising converting formula (VII) to formula (Villa) by treating formula VII with a base followed by (S)-(alpha)-phenylethylamine in the presence of a solvent
(VII) (Villa)
wherein PG is an amine-protecting group.
9. The process according to either of claims 3 or 8, wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, and lithium hydroxide.
10. The process of claim 3 or 8, wherein the solvent is selected from the group consisting of ketone solvents, ester solvents, acetonitrile, and mixtures thereof.
11. The process according to claim 9, further comprising the step of converting formula (Villa) to formula (IX)
(Villa) (IX) wherein PG is an amine-protecting group.
12. The process according to claim 11, wherein the solvent in selected from the group consisting of chlorinated solvents, ketone solvents, ester solvents, toluene, acetonitrile, and mixtures thereof.
13. The process according to claim 12, wherein the chlorinated solvent is selected from the group consisting of methylene dichloride, chloroform, and mixtures thereof.
14. The process according to either of claims 10 or 12, wherein the ketone solvent is selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone, and mixtures thereof.
15. The process according to either of claims 10 or 12, wherein the ester solvent is selected from the group consisting ofethyl acetate, isopropyl acetate, and mixtures thereof.
16. The process according to claim 11, further comprising
a. reducing the azide of formula (IX);and b. treating with (lR)-(-)-10-camphorsulfonic acid to obtain formula (X)
(IX) (X)
wherein PG is an amine protecting group.
17. The process according to claim 11, further carried in the presence of a base selected from the group consisting of triethylamine, diisopropylethylamine, diisopropylamine, and N- methylmorpholine.
18. The process according toclaim 16, further comprising converting compound of formula (X) to Edoxaban.
19. The process according to any of claims 3, 8,11, or 16, wherein the amine protecting group is a t-butyloxycarbonyl(Boc) group.
20. A pharmaceutical dosage form comprising the compound prepared by the method of either of claim 4, claim 5, or claim 18.
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JP2019501697A JP6831447B2 (en) | 2016-07-13 | 2017-07-10 | Amine-protected (1S, 2R, 4S) -1,2-amino-N, N-dimethylcyclohexane-4-carboxamide salt |
EP17768248.1A EP3484893A1 (en) | 2016-07-13 | 2017-07-10 | Salt of amine-protected (1s,2r,4s)-1,2-amino-n,n-dimethylcyclohexane-4-carboxamide |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7365205B2 (en) | 2001-06-20 | 2008-04-29 | Daiichi Sankyo Company, Limited | Diamine derivatives |
EP2407457A1 (en) * | 2009-03-10 | 2012-01-18 | Daiichi Sankyo Company, Limited | Process for producing diamine derivative |
EP2589590A1 (en) * | 2010-07-02 | 2013-05-08 | Daiichi Sankyo Company, Limited | Process for preparation of optically active diamine derivative salt |
US8686189B2 (en) | 2005-09-16 | 2014-04-01 | Daiichi Sankyo Company, Limited | Optically active diamine derivative and process for producing the same |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS59497B2 (en) * | 1979-11-01 | 1984-01-07 | フアイザ−・インコ−ポレ−テツド | Antidepressant derivative of trans-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine |
JP2000302779A (en) * | 1999-04-27 | 2000-10-31 | Zeria Pharmaceut Co Ltd | 2-oxoindolin derivative salt and its production |
EP1405852B9 (en) * | 2001-06-20 | 2013-03-27 | Daiichi Sankyo Company, Limited | Diamine derivatives |
JPWO2005066124A1 (en) * | 2003-12-26 | 2007-12-20 | 第一三共株式会社 | Method for producing pyrrolidine derivatives |
JPWO2006088071A1 (en) * | 2005-02-17 | 2008-07-03 | 中外製薬株式会社 | Method for producing compound having anti-HCV action and intermediate thereof |
-
2017
- 2017-07-10 EP EP17768248.1A patent/EP3484893A1/en not_active Withdrawn
- 2017-07-10 WO PCT/IN2017/050286 patent/WO2018011823A1/en unknown
- 2017-07-10 JP JP2019501697A patent/JP6831447B2/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7365205B2 (en) | 2001-06-20 | 2008-04-29 | Daiichi Sankyo Company, Limited | Diamine derivatives |
US8686189B2 (en) | 2005-09-16 | 2014-04-01 | Daiichi Sankyo Company, Limited | Optically active diamine derivative and process for producing the same |
EP2407457A1 (en) * | 2009-03-10 | 2012-01-18 | Daiichi Sankyo Company, Limited | Process for producing diamine derivative |
US8357808B2 (en) | 2009-03-10 | 2013-01-22 | Daiichi Sankyo Company, Limited | Process for producing diamine derivative |
EP2589590A1 (en) * | 2010-07-02 | 2013-05-08 | Daiichi Sankyo Company, Limited | Process for preparation of optically active diamine derivative salt |
Non-Patent Citations (6)
Title |
---|
"The Peptides", vol. 3, 1981, ACADEMIC PRESS |
H.-D. JAKUBKE; H. JESCHEIT: "Aminosauren, Peptide, Proteine", 1982, VERLAG CHEMIE |
HOUBEN-WEYL: "Methoden der organischenChemie", vol. 15/1, 1974, GEORG THIEME VERLAG |
J. F. W. MCOMIE: "Protective Groups in Organic Chemistry", 1973, PLENUM PRESS |
JOCHEN LEHMANN: "Chemie der Kohlenhydrate: Monosaccharide und Derivate", 1974, GEORG THIEME VERLAG |
T. W. GREENE; P. G. M. WUTS: "Protective Groups in Organic Synthesis", 1999, WILEY |
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JP2019522672A (en) | 2019-08-15 |
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