CN1771248A - Pyrazolidine-1,2-dicarboxyldiphenylamide derivatives as coagulation factor xa inhibitors for the treatment of thromboses. - Google Patents

Pyrazolidine-1,2-dicarboxyldiphenylamide derivatives as coagulation factor xa inhibitors for the treatment of thromboses. Download PDF

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CN1771248A
CN1771248A CNA2004800093744A CN200480009374A CN1771248A CN 1771248 A CN1771248 A CN 1771248A CN A2004800093744 A CNA2004800093744 A CN A2004800093744A CN 200480009374 A CN200480009374 A CN 200480009374A CN 1771248 A CN1771248 A CN 1771248A
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oxo
base
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chlorophenyl
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W·梅德尔斯基
C·察克拉基迪斯
D·多尔施
B·切赞尼
J·格莱茨
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Merck Patent GmbH
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Abstract

The invention relates to a method for the production of compounds of formula (I), wherein R, R<1>, R<2> and R<3> have the meaning cited in claim 1, in addition to compounds of formula (IV) wherein R and R<1> have the meaning cited in claim 1, and are intermediate products for the production of compounds of formula (I).

Description

Preparation 1-N-phenyl-2-N-Phenylpyrrolidine-1,2-dicarboxamide derivatives and as the method for the 1-phenyl amino carbonyl pyrrolidine-2-carboxylic acid derivative of intermediate
The present invention relates to the preparation I compound and the method for available derivative, solvate and steric isomer pharmaceutically thereof, described steric isomer comprises the mixture of its all ratios,
Figure A20048000937400111
Wherein
R is Hal or C ≡ CH,
R 1For H ,=O, Hal, A, OH, OA, A-COO-, A-CONH-, A-CONA-, N 3, NH 2, NO 2, CN, COOH, COOA, CONHA, CONH 2, CON (A) 2, O-allyl group, O-propargyl, O-benzyl ,=N-OH or=N-OA,
R 2Be H, Hal or A,
R 3Be 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2-imino-piperidines-1-base, 2-lminopyrrolidine-1-base, 3-imino-morpholine-4-base, 2-imido imidazolyl alkane-1-base, 2-imino--1H-pyrazine-1-base, 2,6-dioxopiperidine-1-base, 2-oxo piperazine-1-base, 2,6-dioxo piperazine-1-base, 2,5-dioxo tetramethyleneimine-1-base, 2-oxo-1,3-oxazolidine-3-base, 3-oxo-2H-pyridazine-2-base, 2-hexanolactam-1-base (=2-oxo azepan-1-yl), 2-azabicyclic [2.2.2] suffering-3-ketone-2-base, 5,6-dihydro-1H-pyrimidine-2-oxo-1-base, 2-oxo-1,3-oxa-piperidine-3-base or 4H-1,4-oxazine-4-base
Wherein said group also can be single by A or OA-or two replace,
A is not branching, branching or the cyclic alkyl with 1-10 carbon atom, and wherein 1-7 hydrogen atom also can be replaced by fluorine,
Hal is F, Cl, Br or I,
Described method is characterised in that:
A) with formula II compound
Wherein
R 1As above definition,
With the reaction of formula III compound,
Figure A20048000937400122
Wherein
R as above defines,
Obtain formula IV compound
Figure A20048000937400123
Wherein
R and R 1As above definition,
B) subsequently with formula IV compound and the reaction of formula V compound,
R wherein 2And R 3As above definition,
Obtain formula I compound and
C) if desired, a kind of salt by alkali or acid with formula I are converted into it is translated into its pharmaceutically available derivative and/or solvate.
Target of the present invention is to find novel, the improved method of preparation Xa factor inhibitor.
Compare with the currently known methods of prior art, method route of the present invention is shorter and more efficient.
The Xa factor inhibitor can be used for opposing and prevention of thromboembolic disorders, for example restenosis of thrombosis, myocardial infarction, arteriosclerosis, inflammation, palsy, stenocardia, postangioplasty and intermittent claudication.
Xa factor is one of proteolytic enzyme that participates in complicated blood coagulation process.Xa factor promotes that thrombogen is converted into zymoplasm.Zymoplasm is split into fibrin monomer with Fibrinogen, and these monomers are tentatively facilitated thrombosis after crosslinked.The activation of zymoplasm can cause the generation of thrombotic disease.But the inhibition of zymoplasm can suppress to participate in thrombotic fibrinous formation.
For example can be by G.F.Cousins etc. at Circulation 1996,94, the method among the 1705-1712 is measured the restraining effect of zymoplasm.
Therefore, the inhibition of Xa factor can prevent the formation of zymoplasm.
To the inhibition of Xa factor and anti-freezing is solid and the measurement of anti-thrombosis activity can be definite by method in the conventional external or body.For example J.Hauptmann etc. has described a kind of suitable method at Thrombosis andHaemostasis 1990,63 among the 220-223.
The inhibition of Xa factor can be by T.Hara for example etc. at Thromb.Haemostas.1994, and 71, the method among the 314-319 is measured.
Proconvertin a is with after tissue factor combines, and starts the exogenous part of coagulation cascade and impels the activation of the X factor and obtain Xa factor.Therefore, the formation of the inhibition of VIIa factor prevention Xa factor and the formation of ensuing zymoplasm.
To the inhibition of the VIIa factor and anti-freezing is solid and the measurement of anti-thrombosis activity can be definite by method in the conventional external or body.For example H.F.Ronning etc. is at ThrombosisResearch1996, and 84, the ordinary method of measuring the inhibition of the VIIa factor has been described among the 73-81.
Factor IXa produces in the inside of coagulation cascade, participates in the activation of the X factor equally and obtains Xa factor.Therefore, the inhibition of the IXa factor can prevent the formation of Xa factor in a different manner.
To the inhibition of the IXa factor and anti-freezing is solid and the measurement of anti-thrombosis activity can be definite by method in the conventional external or body.For example J.Chang etc. is at Journal of BiologicalChemistry1998, and 273, a kind of suitable method has been described among the 12089-12094.
T.Taniguchi and N.R.Lemoine are in Biomed.Health Res. (2000), 41 (Molecular Pathogenesis of Pancreatic Cancer (molecular pathogenesis of carcinoma of the pancreas)) have pointed out the dependency between the development of the tissue factor TF/VIIa factor and various types of cancers among the 57-59.
The publication of below listing has been described TF-VII and the Xa factor inhibitor antitumor action to all kinds tumour:
K.M.Donnelly etc. are at Thromb.Haemost.1998; 79:1041-1047;
E.G.Fischer etc. are in J.Clin.Invest.104:1213-1221 (1999);
B.M.Mueller etc. are in J.Clin.Invest.101:1372-1378 (1998);
M.E.Bromberg etc. are at Thromb.Haemost.1999; 82:88-92.
WO 03/045912 has described long two-step approach route, and this route is undertaken by the pyrrolidin derivatives (for example BOC-Pro) of N-protected:
Figure A20048000937400141
Helv.Chim.Acta 1998,81, and 1254-1263 has described the reaction (route A]) of primary amine and isocyanic acid 4-chloro phenyl ester.
As route B] shown in, active side-chain radical (for example OH, NH or SH) is reaction there also, obtains two adducts.
Term pharmaceutically available derivative means for example salt and the so-called preceding drug compound of described compound.
In context, A represents alkyl, for not branching (straight chain) or branching, and have 1,2,3,4,5,6,7,8,9 or 10 carbon atom.A preferably represents methyl, also have ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl or the tertiary butyl, also can represent amyl group, 1-, 2-or 3-methyl butyl, 1,1-, 1,2-or 2,2-dimethyl propyl, 1-ethyl propyl, hexyl, 1-, 2-, 3-or 4-methyl amyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3-or 3,3-dimethylbutyl, 1-or 2-ethyl-butyl, 1-ethyl-1-methyl-propyl, 1-ethyl-2-methyl-propyl, 1,1,2-or 1,2,2-trimethylammonium propyl group is gone back preference such as trifluoromethyl.
A very particularly preferably represents to have the alkyl of 1,2,3,4,5 or 6 carbon atom, preferable methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, hexyl or trifluoromethyl.
Hal is preferably F, Cl or Br, also is I.
The present invention preferably relates to the method for the preparation I compound of claim 1, and wherein R is F or Cl.
The method of also preferred claim 1 or 2 preparation I compound, wherein
R 1For H ,=O, OH, OA, A-COO-, N 3, NH 2, O-allyl group or O-propargyl.
The method of preferred especially claim 1 or 2 preparation I compound, wherein R 1Be H or OH.
The method of the preparation I compound of also preferred claim 1-4, wherein
R 3Be 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2-oxo piperazine-1-base or 3-oxo-2H-pyridazine-2-base.
The method of the preparation I compound of also preferred claim 1-5, wherein
A is not branching or the branched-alkyl with 1-6 carbon atom, and wherein 1-3 hydrogen atom also can be replaced by fluorine.
One or multinomial preparation I compound and the method for available derivative, solvate and steric isomer pharmaceutically thereof among the also preferred claim 1-6, wherein said steric isomer comprises the mixture of its all ratios, wherein
R is Hal or C ≡ CH,
R 1Be H, OH or OA,
R 2Be H, Hal or A,
R 3Be 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2-oxo piperazine-1-base or 3-oxo-2H-pyridazine-2-base
A is not branching, branching or the cyclic alkyl with 1-10 carbon atom, and wherein 1-7 hydrogen atom also can be replaced by fluorine,
Hal is F, Cl, Br or I.
One or multinomial preparation I compound and the method for available derivative, solvate and steric isomer pharmaceutically thereof among the also preferred claim 1-7, described steric isomer comprises the mixture of its all ratios, wherein
R is F or Cl,
R 1For H ,=O, OH, OA, A-COO-, N 3, NH 2, O-allyl group or O-propargyl,
R 2Be H, F or A,
R 3Be 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2-oxo piperazine-1-base or 3-oxo-2H-pyridazine-2-base
A is not branching or the branched-alkyl with 1-6 carbon atom, and wherein 1-3 hydrogen atom also can be replaced by fluorine.
One or multinomial preparation I compound and the method for available derivative, solvate and steric isomer pharmaceutically thereof among the preferred especially claim 1-8, described steric isomer comprises the mixture of its all ratios, wherein
R is F or Cl,
R 1Be H or OH,
R 2Be H, F or A,
R 3Be 3-oxo morpholine-4-base,
A is not branching or the branched-alkyl with 1-6 carbon atom, and wherein 1-3 hydrogen atom also can be replaced by fluorine.
Very particularly preferably one or multinomial preparation formula Ia compound and the method for available derivative, solvate and steric isomer pharmaceutically thereof among the claim 1-15, described steric isomer comprises the mixture of its all ratios,
Wherein
R is F or Cl,
R 1Be H or OH,
R 2Be H, F or A,
R 3Be 3-oxo morpholine-4-base,
A is not branching or the branched-alkyl with 1-6 carbon atom, and wherein 1-3 hydrogen atom also can be replaced by fluorine.
Described method is characterised in that:
A) under 60-110 ℃, in the carbonate of basic metal or alkaline-earth metal or bicarbonate aqueous solution with formula II compound
Figure A20048000937400181
Wherein
R 1Be H or OH,
With the reaction of formula III compound,
Figure A20048000937400182
Wherein
R is F or Cl,
Obtain formula IV compound
Figure A20048000937400183
Wherein
R is F or Cl,
R 1Be H or OH,
B) subsequently under 10-70 ℃, in the presence of auxiliary, described auxiliary and formula IV compound formation mixed acid anhydride, with formula IV compound and the reaction of formula V compound,
Wherein
R 2Be H, F or A,
R 3Be 3-oxo morpholine-4-base,
A is not branching or the branched-alkyl with 1-6 carbon atom, and wherein 1-3 hydrogen atom also can be replaced by fluorine,
Obtain formula Ia compound and
C) if desired, a kind of salt by alkali or acid with formula Ia are converted into it is translated into its pharmaceutically available derivative and/or solvate.
Preferred through type II compound and formula III compound the first step a) in prepared in reaction formula I or Ia compound.
Usually in the presence of acid binding agent, in inert solvent, carry out this reaction, described acid binding agent is preferably oxyhydroxide, carbonate, the supercarbonate of basic metal or alkaline-earth metal, or other salt of faintly acid of basic metal or alkaline-earth metal (preferred potassium, sodium, calcium or caesium), for example sodium hydroxide, yellow soda ash, salt of wormwood, cesium carbonate or sodium bicarbonate.
Preferred especially sodium bicarbonate.
Add organic bases, for example triethylamine, xylidine, pyridine or quinoline also are favourable.According to the condition of using, the reaction times can be several minutes-14 days, and preferred 1-10 hour, temperature of reaction was about 0-150 ℃, is generally 20-130 ℃, is preferably 60-110 ℃, very particularly preferably 70-90 ℃.
The example of suitable inert solvent has water, alkane (hexane for example, sherwood oil, benzene, toluene or dimethylbenzene), hydrochloric ether (trieline for example, 1, the 2-ethylene dichloride, tetrachloromethane, chloroform or methylene dichloride), alcohol (methyl alcohol for example, ethanol, Virahol, n-propyl alcohol, the propyl carbinol or the trimethyl carbinol), ether (Anaesthetie Ether for example, Di Iso Propyl Ether, tetrahydrofuran (THF) (THF) Huo diox), glycol ethers (for example ethylene glycol monomethyl ether or single ether, glycol dimethyl ether (diglyme)), ketone (acetone for example, isobutyl methyl ketone (IBMK) or butanone), acid amides (ethanamide for example, N,N-DIMETHYLACETAMIDE or dimethyl formamide (DMF)), nitrile (for example acetonitrile), sulfoxide (for example dimethyl sulfoxide (DMSO) (DMSO)), dithiocarbonic anhydride, carboxylic acid (for example formic acid or acetate), nitro-compound (for example Nitromethane 99Min. or oil of mirbane), the mixture of ester (for example ethyl acetate) or described solvent.Special preferably water.
In second step, formula IV compound and the reaction of formula V compound.
Preferably carry out this reaction in the presence of auxiliary, the hydroxyl of described auxiliary and carboxylic acid forms midbody derivant (for example mixed acid anhydride, active ester, imidazolide) or is converted into the alkyl sulphonyl oxygen base group (preferable methyl alkylsulfonyl oxygen base or trifluoromethyl sulfonyl oxygen base) with 1-6 carbon atom or the aryl sulfonyl oxygen base group with 6-10 carbon atom (preferably phenyl-or p-toluenesulfonyl oxygen base).
At document (for example in standard textbook; as Houben-Weyl; Methoden derorganischen Chemie[Methods of Organic Chemistry (organic chemistry method)]; Georg-Thieme-Verlag has described this type of group of the described carboxylic group of activation in typical acylation reaction in Stuttgart).
Can use various condensing agents to carry out coupled reaction, for example carbodiimide, carbon diimidazole, those uronium class salt (for example TBTU) and acyl chlorides or active ester methods.The best original position of described active ester forms, for example by adding HOBt or N-hydroxyl amber diacyl imines.
Be preferably formed mixed acid anhydride.
This paper especially preferably uses 2-oxyethyl group-1,2-dihydroquinoline-1-ethyl formate (EEDQ).
Usually in inert solvent, carry out this reaction.
According to the condition of using, the reaction times is several minutes-14 days, and preferred 1-20 hour, temperature of reaction was about 0-150 ℃, is generally 0-90 ℃, is preferably 10-70 ℃, preferred 15-30 ℃ especially.
The example of suitable inert solvent has alkane (hexane for example, sherwood oil, benzene, toluene or dimethylbenzene), hydrochloric ether (trieline for example, 1, the 2-ethylene dichloride, tetrachloromethane, chloroform or methylene dichloride), alcohol (methyl alcohol for example, ethanol, Virahol, n-propyl alcohol, the propyl carbinol or the trimethyl carbinol), ether (Anaesthetie Ether for example, Di Iso Propyl Ether, tetrahydrofuran (THF) (THF) Huo diox), glycol ethers (for example ethylene glycol monomethyl ether or single ether, glycol dimethyl ether (diglyme)), ketone (for example acetone or butanone), acid amides (ethanamide for example, N,N-DIMETHYLACETAMIDE or dimethyl formamide (DMF)), nitrile (for example acetonitrile), sulfoxide (for example dimethyl sulfoxide (DMSO) (DMSO)), dithiocarbonic anhydride, carboxylic acid (for example formic acid or acetate), nitro-compound (for example Nitromethane 99Min. or oil of mirbane), the mixture of ester (for example ethyl acetate) or described solvent, preferred especially tetrahydrofuran (THF).
The alkali usable acid of formula I, Ia or formula IV compound is converted into relevant acid salt, for example the alkali and acid reaction in inert solvent (for example ethanol), evaporation subsequently by making equivalent.The acid of suitable this reaction is in particular the acid that those obtain acceptable salt on the physiology.Therefore, can use mineral acid, for example sulfuric acid, nitric acid, haloid acid (for example hydrochloric acid or Hydrogen bromide), phosphoric acid (for example ortho-phosphoric acid) or thionamic acid; Also can use organic acid, be specially aliphatic, alicyclic, araliphatic, aromatics or heterocycle monobasic or polycarboxylic acid, sulfonic acid or sulfuric acid, for example formic acid, acetate, propionic acid, PIVALIC ACID CRUDE (25), diethylacetic acid, propanedioic acid, Succinic Acid, pimelic acid, fumaric acid, toxilic acid, lactic acid, tartrate, oxysuccinic acid, citric acid, glyconic acid, xitix, nicotinic acid, Yi Yansuan, methylsulfonic acid, ethyl sulfonic acid, ethionic acid, 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, tosic acid, naphthalene list sulfonic acid, naphthalene disulfonic acid or lauryl sulfate.The salt (for example picrate) that forms with unacceptable acid on the physiology can be used for separating and/or purifying formula I compound.
On the other hand, formula I, Ia or IV compound available bases (for example sodium hydroxide, potassium hydroxide, yellow soda ash or salt of wormwood) are converted into corresponding metal salt, particularly an alkali metal salt or alkaline earth salt, or are converted into corresponding ammonium salt.
Also can use acceptable organic bases, for example thanomin on the physiology.
The invention still further relates to formula IV compound and pharmaceutically available derivative, solvate and steric isomer, described steric isomer comprises the mixture of its all ratios,
Figure A20048000937400211
Wherein
R be Hal or-C ≡ C-H,
R 1For H ,=O, Hal, A, OH, OA, A-COO-, A-CONH-, A-CONA-, N 3, NH 2, NO 2, CN, COOH, COOA, CONH 2, CONHA, CON (A) 2, O-allyl group, O-propargyl, O-benzyl ,=N-OH or=N-OA,
A is not branching, branching or the cyclic alkyl with 1-10 carbon atom, and wherein 1-7 hydrogen atom also can be replaced by fluorine,
Hal is F, Cl, Br or I.
The invention still further relates to optically active form (steric isomer), enantiomer, racemoid, diastereomer and the hydrate and the solvate of compound of the present invention.
The solvate of term compound means the inert solvent molecule and adds and be incorporated on the described compound, and this form is owing to their power that attracts each other.Solvate is for example monohydrate, dihydrate or alcohol adduct.
Term pharmaceutically available derivative means for example salt and the so-called preceding drug compound of compound of the present invention.
The term prodrug derivant for example means by the formula I compound of alkyl or carboxyl groups, sugar or oligopeptides modification, their in organism rapidly cracking obtain active compound of the present invention.
Int.J.Pharm.115 for example, described in the 61-67 (1995), these prodrug derivants also comprise the biodegradable polymer derivant of The compounds of this invention.
The invention still further relates to the mixture of formula IV compound of the present invention, the mixture of two kinds of diastereomers for example, for example ratio is the mixture of 1: 1,1: 2,1: 3,1: 4,1: 5,1: 10,1: 100 or 1: 1000.
These are the mixture of particularly preferred steric isomer compound.
Particularly formula IV compound can be used for the method for preparation I compound.
Other ethynyl derivatives servings as the Xa factor inhibitor have been described in WO 02/079145.
In WO 99/00121 and WO 00/39118, other aramids have been described.For example
Aromatic Amidine derivatives with anti-thrombosis function is disclosed in EP 0540 051B1.
The ring-type guanidine that is used for the treatment of thrombotic disease has for example been described in WO 97/08165.
For example in WO 96/10022, disclose and had the inhibiting aromatic heterocycle compounds of Xa factor.N-[(amino imino methyl as the replacement of Xa factor inhibitor has been described in WO 96/40679) phenylalkyl] the azaheterocyclyl acid amides.
For all appearance group more than once, their implication is independent of each other.
A represents alkyl, for not branching (straight chain) or branching, and have 1,2,3,4,5,6,7,8,9 or 10 carbon atom.A preferably represents methyl, also have ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl or the tertiary butyl, also can represent amyl group, 1-, 2-or 3-methyl butyl, 1,1-, 1,2-or 2,2-dimethyl propyl, 1-ethyl propyl, hexyl, 1-, 2-, 3-or 4-methyl amyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3-or 3,3-dimethylbutyl, 1-or 2-ethyl-butyl, 1-ethyl-1-methyl-propyl, 1-ethyl-2-methyl-propyl, 1,1,2-or 1,2,2-trimethylammonium propyl group is gone back preference such as trifluoromethyl.
A very particularly preferably represents to have the alkyl of 1,2,3,4,5 or 6 carbon atom, preferable methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, hexyl or trifluoromethyl.
Hal preferably represents F, Cl or Br, and I.
R preferably represents F or Cl.
R 1Preferred expression H ,=O, OH, OA, A-COO-, N 3, NH 2, O-allyl group or O-propargyl, preferred especially H or OH.
Special preferred formula IV compound is selected from:
(2R, 4R)-1-(4-chlorophenyl formamyl)-4-hydroxyl pyrrolidine-2-carboxylic acid,
(2R)-1-(4-chlorophenyl formamyl) tetramethyleneimine-2-carboxylic acid.
Therefore formula IV compound of the present invention different enantiomeric forms can occur because their molecular structure can be chirality.Therefore they can exist with racemic form or with the form of optically active form.
Because the racemic modification of the end product that is obtained by midbody compound or the pharmaceutical active of steric isomer may be different, may need to use the enantiomer of compound of the present invention.In these cases, end product or even intermediate can by chemical process well-known to those skilled in the art or physical method for separation be the enantiomer compound or former state be used to synthesize.
Under the situation of racemic amines, by forming enantiomer by described mixture with the reaction of optically-active resolving agent.The example of suitable resolving agent has opticity acid, for example R and the S form or the various opticity camphorsulfonic acid of the amino acid (for example N-benzoyl proline(Pro) or N-benzenesulfonyl proline(Pro)) of tartrate, diacetyl tartrate, dibenzoyl tartaric acid, amygdalic acid, oxysuccinic acid, lactic acid, suitable N-protected.Be preferably in also that chromatography splits the enantiomerism liquid solution under the help of optically-active resolving agent (for example other derivatives of dinitrobenzoyl phenylglycocoll, cellulosic triacetate or carbohydrate or be fixed on chirality deutero-methacrylate polymers on the silica gel).The eluent of suitable this purpose is the solvent mixture of water or alcohol, hexane/isopropyl alcohol/acetonitrile for example, and for example ratio is 82: 15: 3.
In context, all temperature are all with a ℃ expression.In following examples, " conventional aftertreatment " means and adds entry when needing, regulate pH to 2-10 when needing, composition according to end product, with ethyl acetate or the described mixture of dichloromethane extraction, separate each phase, organic phase is also evaporated through dried over sodium sulfate, and by chromatography and/or recrystallization purifying product on silica gel.Rf value on silica gel; Eluent: ethyl acetate/methanol is 9: 1.
Mass spectrum (MS): EI (Electron Impactionization) M +ESI (electron spray ionisation) (M+H) +FAB (fast atom bombardment) (M+H) +
Embodiment 1
The 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the preparation of 2-diformamide is similar to following flow process and carries out:
Figure A20048000937400251
1.1 13.1g (0.1mol) cis-hydroxyl-D-proline(Pro) is dissolved in 800ml NaHCO 3(in the concentration=0.5mol/l), add 30.7g (0.2mol) isocyanic acid 4-chloro phenyl ester subsequently, this mixture stirred 5 hours down at 80 ℃ solution subsequently.This reaction mixture is cooled to room temperature, and suction filtration is removed sedimentary symmetric urea 1, two (4-chlorophenyl) ureas of 3-and washing, and water is adjusted to pH=1 with about 40ml concentrated hydrochloric acid.Separate this sedimentary product, water with EA after the extraction (post-extracted), the organic moiety that subsequent drying is all.Residue is with MTB ether recrystallization subsequently, obtain 23.3g (81.8%) (2R, 4R)-1-(4-chlorophenyl formamyl)-4-hydroxyl pyrrolidine-2-carboxylic acid 3; Fusing point 132-134 ℃; MS (FAB): m/e=285 (M+H +).
1H?NMR(DMSO-d 6)δ12.00(sbr，1H)，8.39(s，1H)，7.54(d，J＝8.9Hz，2H)，7.26(d，J＝8.9Hz，2H)，4.41-4.24(m，2H)，3.66(dd，J＝5.7?and?5.8Hz，1H)，3.33(dd，J＝4.0?and?4.1Hz，1H)，2.40-2.25(m，1H)，1.96-1.81(m，1H).
Specific rotation: [α] 20 D=+43.7 °; Methyl alcohol, c=0.0198g/2mlC, H, N: theoretical value C50.63, H 4.60, N 9.84 measured value C 51.1H 4.6 N 9.0
1.2 under the room temperature, with 14.24g (0.05mol) 3,9.61g (0.05mol) aminophenyl morpholone mai 4 and 12.37g (0.05mol) 2-oxyethyl group-1,2-dihydroquinoline-1-ethyl formate is dissolved in the 400ml tetrahydrofuran (THF), and stirs 20 hours, forms suspension in this process.Suction filtration is removed this precipitation, extremely does with THF rinsing three times and vapourisation under reduced pressure, obtains 15.9g (69%) 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-diformamide 5; Fusing point 208-210 ℃; MS (FAB): m/e=459 (M+H +).
Be similar to embodiment 1.1 and obtained following material:
(2R)-and 1-(4-chlorophenyl formamyl) tetramethyleneimine-2-formic acid, fusing point 173-175 ℃,
Figure A20048000937400261
MS(FAB)：m/e＝269(M+H +)；
1H?NMR(DMSO-d 6)δ12.37(sbr，1H)，8.37(s，1H)，7.53(d，J＝8.9Hz，2H)，7.26(d，J＝8.9Hz，2H)，4.32(dd，J＝3.5Hz，1H)，3.60-3.41(m，2H)，2.27-2.07(m，1H)，2.00-1.81(m，3H).
Specific rotation: [α] 20 D=+60.9 °; Methyl alcohol, c=0.0189g/2ml
C, H, N: theoretical value C 53.64, H 4.88, N 10.43 measured value C 53.6 H 5.1 N 10.4
Embodiment 2
Be similar to embodiment 1 and prepared following compound:
1) 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R)-and tetramethyleneimine-1, the 2-diformamide,
2) 1-[(4-chlorophenyl)]-2-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R)-and tetramethyleneimine-1, the 2-diformamide,
3) 1-[(4-chlorophenyl)]-2-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
4) 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2S, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
5) 1-[(4-chlorophenyl)]-2-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R)-and tetramethyleneimine-1, the 2-diformamide,
6) 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
7) 1-[(4-chlorophenyl)]-2-{[3-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R)-and tetramethyleneimine-1, the 2-diformamide,
8) 1-[(4-chlorophenyl)]-2-{[3-trifluoromethyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R)-and tetramethyleneimine-1, the 2-diformamide,
9) 1-[(4-chlorophenyl)]-2-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
10) 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-azido-tetramethyleneimine-1, the 2-diformamide,
11) 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-amino-pyrrolidine-1, the 2-diformamide,
12) 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-methoxyl group tetramethyleneimine-1, the 2-diformamide,
13) 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-acetoxyl group tetramethyleneimine-1, the 2-diformamide,
14) 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R)-and 4-oxo-pyrrolidine-1, the 2-diformamide,
15) 1-[(4-chlorophenyl)]-2-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(2S)-and tetramethyleneimine-1, the 2-diformamide,
16) 1-[(4-chlorophenyl)]-2-{[3-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
17) 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2S, 4S)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
18) 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-allyl group oxygen base tetramethyleneimine-1, the 2-diformamide,
19) 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(Propargyl oxygen base) tetramethyleneimine-1, the 2-diformamide.
Embodiment 3
Be similar to the reaction that embodiment 1.1 carries out L-oxyproline and isocyanic acid 4-chloro phenyl ester, also preferred and 1 normal isocyanic acid chloro phenyl ester (chlorophenyl isocyanate) reacts, and preferably carries out in isobutyl methyl ketone (IBMK).
Under-2-0 ℃, 9.4g (71.685mmol) L-oxyproline is dissolved in 71.68mlNaOH solution (in the concentration=1mol/l), the 70ml IBMK solution that adds 11.008g (71.685mmol) isocyanic acid 4-chloro phenyl ester subsequently, this mixture stirred 1 hour down at-1 ℃.Through conventional aftertreatment obtain 18.52g (2S, 4R)-1-(4-chlorophenyl formamyl)-4-hydroxyl pyrrolidine-2-carboxylic acid;
Productive rate: 91%.

Claims (20)

1. preparation I compound and the pharmaceutically method of available derivative, solvate and steric isomer, described steric isomer comprises the mixture of its all ratios,
Figure A2004800093740002C1
Wherein
R is Hal or C ≡ CH,
R 1For H ,=O, Hal, A, OH, OA, A-COO-, A-CONH-, A-CONA-, N 3, NH 2, NO 2, CN, COOH, COOA, CONH 2, CONHA, CON (A) 2, O-allyl group, O-propargyl, O-benzyl ,=N-OH or=N-OA,
R 2Be H, Hal or A,
R 3Be 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2-imino-piperidines-1-base, 2-lminopyrrolidine-1-base, 3-imino-morpholine-4-base, 2-imido imidazolyl alkane-1-base, 2-imino--1H-pyrazine-1-base, 2,6-dioxopiperidine-1-base, 2-oxo piperazine-1-base, 2,6-dioxo piperazine-1-base, 2,5-dioxo tetramethyleneimine-1-base, 2-oxo-1,3-oxazolidine-3-base, 3-oxo-2H-pyridazine-2-base, 2-hexanolactam-1-base (=2-oxo azepan-1-yl), 2-azabicyclic [2.2.2] suffering-3-ketone-2-base, 5,6-dihydro-1H-pyrimidine-2-oxo-1-base, 2-oxo-1,3-oxa-piperidine-3-base or 4H-1,4-oxazine-4-base
Wherein said group also can be single by A or OA-or two replace,
A is not branching, branching or the cyclic alkyl with 1-10 carbon atom, and wherein 1-7 hydrogen atom also can be replaced by fluorine,
Hal is F, Cl, Br or I,
Described method is characterised in that:
A) with formula II compound
Wherein
R 1As above definition,
With the reaction of formula III compound,
Figure A2004800093740003C2
Wherein
R as above defines,
Obtain formula IV compound
Figure A2004800093740003C3
Wherein
R and R 1As above definition,
B) subsequently with formula IV compound and the reaction of formula V compound,
Figure A2004800093740003C4
R wherein 2And R 3As above definition,
Obtain formula I compound and
C) if desired, a kind of salt by alkali or acid with formula I are converted into it is translated into its pharmaceutically available derivative and/or solvate.
2. the preparation I compound of claim 1 and the pharmaceutically method of available derivative, solvate and steric isomer, described steric isomer comprises the mixture of its all ratios, wherein
R is F or Cl.
3. claim 1 or 2 preparation I compound and the pharmaceutically method of available derivative, solvate and steric isomer, described steric isomer comprises the mixture of its all ratios, wherein
R 1For H ,=O, OH, OA, A-COO-, N 3, NH 2, O-allyl group or O-propargyl.
4. claim 1,2 or 3 preparation I compound and the pharmaceutically method of available derivative, solvate and steric isomer, described steric isomer comprises the mixture of its all ratios, wherein
R 1Be H or OH.
5. one or multinomial preparation I compound and the method for available derivative, solvate and steric isomer pharmaceutically thereof among the claim 1-4, described steric isomer comprises the mixture of its all ratios, wherein
R 3Be 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2-oxo piperazine-1-base or 3-oxo-2H-pyridazine-2-base.
6. one or multinomial preparation I compound and the method for available derivative, solvate and steric isomer pharmaceutically thereof among the claim 1-5, described steric isomer comprises the mixture of its all ratios, wherein
A is not branching or the branched-alkyl with 1-6 carbon atom, and wherein 1-3 hydrogen atom also can be replaced by fluorine.
7. one or multinomial preparation I compound and the method for available derivative, solvate and steric isomer pharmaceutically thereof among the claim 1-6, described steric isomer comprises the mixture of its all ratios, wherein
R is Hal or C ≡ CH,
R 1Be H, OH or OA,
R 2Be H, Hal or A,
R 3Be 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2-oxo piperazine-1-base or 3-oxo-2H-pyridazine-2-base
A is not branching, branching or the cyclic alkyl with 1-10 carbon atom, and wherein 1-7 hydrogen atom also can be replaced by fluorine,
Hal is F, Cl, Br or I.
8. one or multinomial preparation I compound and the method for available derivative, solvate and steric isomer pharmaceutically thereof among the claim 1-7, described steric isomer comprises the mixture of its all ratios, wherein
R is F or Cl,
R 1For H ,=O, OH, OA, A-COO-, N 3, NH 2, O-allyl group or O-propargyl,
R 2Be H, F or A,
R 3Be 2-oxo-piperidine-1-base, 2-oxo-pyrrolidine-1-base, 2-oxo-1H-pyridine-1-base, 3-oxo morpholine-4-base, 4-oxo-1H-pyridine-1-base, 2-oxo-1H-pyrazine-1-base, 2-oxo-imidazole alkane-1-base, 2-oxo piperazine-1-base or 3-oxo-2H-pyridazine-2-base
A is not branching or the branched-alkyl with 1-6 carbon atom, and wherein 1-3 hydrogen atom also can be replaced by fluorine.
9. one or multinomial preparation I compound and the method for available derivative, solvate and steric isomer pharmaceutically thereof among the claim 1-8, described steric isomer comprises the mixture of its all ratios, wherein
R is F or Cl,
R 1Be H or OH,
R 2Be H, F or A,
R 3Be 3-oxo morpholine-4-base,
A is not branching or the branched-alkyl with 1-6 carbon atom, and wherein 1-3 hydrogen atom also can be replaced by fluorine.
10. one or multinomial method among the claim 1-9 wherein being reflected at described in the step a) in the presence of basic metal or alkaline earth metal hydroxides, carbonate or the supercarbonate, are carried out in inert solvent or solvent mixture.
11. one or multinomial method among the claim 1-10 are wherein carried out being reflected at described in the step a) in the sodium bicarbonate aqueous solution.
12. one or multinomial method among the claim 1-11 are wherein carried out being reflected at described in the step a) under 60-110 ℃.
13. one or multinomial method among the claim 1-12 wherein are being reflected at 2-oxyethyl group-1 described in the step b), 2-dihydroquinoline-1-ethyl formate (EEDQ) carries out under existing.
14. one or multinomial method among the claim 1-13 are wherein carried out being reflected at described in the step b) under 10-70 ℃.
15. one or multinomial method among the claim 1-14 are wherein carried out being reflected at described in the step b) in the tetrahydrofuran (THF).
16. one or multinomial preparation formula Ia compound and the method for available derivative, solvate and steric isomer pharmaceutically thereof among the claim 1-15, described steric isomer comprises the mixture of its all ratios,
Figure A2004800093740006C1
Wherein
R is F or Cl,
R 1Be H or OH,
R 2Be H, F or A,
R 2Be 3-oxo morpholine-4-base,
A is not branching or the branched-alkyl with 1-6 carbon atom, and wherein 1-3 hydrogen atom also can be replaced by fluorine,
Described method is characterised in that:
A) under 60-110 ℃, in the carbonate of basic metal or alkaline-earth metal or bicarbonate aqueous solution with formula II compound
Wherein
R 1Be H or OH,
With the reaction of formula III compound,
Wherein
R is F or Cl,
Obtain formula IV compound
Wherein
R is F or Cl,
R 1Be H or OH,
B) subsequently under 10-70 ℃, in the presence of auxiliary, described auxiliary and formula IV compound formation mixed acid anhydride, with formula IV compound and the reaction of formula V compound,
Figure A2004800093740008C1
Wherein
R 2Be H, F or A,
R 3Be 3-oxo morpholine-4-base,
A is not branching or the branched-alkyl with 1-6 carbon atom, and wherein 1-3 hydrogen atom also can be replaced by fluorine,
Obtain formula Ia compound and
C) if desired, a kind of salt by alkali or acid with formula Ia are converted into it is translated into its pharmaceutically available derivative and/or solvate.
17. one or multinomial preparation are selected from the following compound and the method for available derivative, solvate and steric isomer pharmaceutically thereof among the claim 1-16, described steric isomer comprises the mixture of its all ratios,
1) 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
2) 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R)-and tetramethyleneimine-1, the 2-diformamide,
3) 1-[(4-chlorophenyl)]-2-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R)-and tetramethyleneimine-1, the 2-diformamide,
4) 1-[(4-chlorophenyl)]-2-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
5) 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2S, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
6) 1-[(4-chlorophenyl)]-2-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R)-and tetramethyleneimine-1, the 2-diformamide,
7) 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
8) 1-[(4-chlorophenyl)]-2-{[3-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R)-and tetramethyleneimine-1, the 2-diformamide,
9) 1-[(4-chlorophenyl)]-2-{[3-trifluoromethyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R)-and tetramethyleneimine-1, the 2-diformamide,
10) 1-[(4-chlorophenyl)]-2-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
11) 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-azido-tetramethyleneimine-1, the 2-diformamide,
12) 1-[(4-chlorophenyl)]-2-{{4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-amino-pyrrolidine-1, the 2-diformamide,
13) 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-methoxyl group tetramethyleneimine-1, the 2-diformamide,
14) 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-acetoxyl group tetramethyleneimine-1, the 2-diformamide,
15) 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R)-and 4-oxo-pyrrolidine-1, the 2-diformamide,
16) 1-[(4-chlorophenyl)]-2-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(2S)-and tetramethyleneimine-1, the 2-diformamide,
17) 1-[(4-chlorophenyl)]-2-{[3-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
18) 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2S, 4S)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
19) 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-allyl group oxygen base tetramethyleneimine-1, the 2-diformamide,
20) 1-[(4-chlorophenyl)]-2-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(Propargyl oxygen base) tetramethyleneimine-1, the 2-diformamide.
18. formula IV compound and pharmaceutically available derivative, solvate and steric isomer, described steric isomer comprises the mixture of its all ratios,
Figure A2004800093740010C1
Wherein
R is Hal or C ≡ CH,
R 1For H ,=O, Hal, A, OH, OA, A-COO-, A-CONH-, A-CONA-, N 3, NH 2, NO 2, CN, COOH, COOA, CONHA, CONH 2, CON (A) 2, O-allyl group, O-propargyl, O-benzyl ,=N-OH or=N-OA,
A is not branching, branching or the cyclic alkyl with 1-10 carbon atom, and wherein 1-7 hydrogen atom also can be replaced by fluorine,
Hal is F, Cl, Br or I.
19. the compound of claim 18 and pharmaceutically available derivative, solvate and steric isomer, described steric isomer comprises the mixture of its all ratios, wherein
R is F or Cl,
R 1For H ,=O, OH, OA, A-COO-, N 3, NH 2, O-allyl group or O-propargyl.
20. the compound of claim 18 or 19 and pharmaceutically available derivative, solvate and steric isomer, described steric isomer comprises the mixture of its all ratios,
Wherein
R is F or Cl,
R 1Be H or OH.
CNA2004800093744A 2003-04-03 2004-03-09 Pyrazolidine-1,2-dicarboxyldiphenylamide derivatives as coagulation factor xa inhibitors for the treatment of thromboses. Pending CN1771248A (en)

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