WO2004099136A1 - ピロリジン誘導体の製造方法 - Google Patents
ピロリジン誘導体の製造方法 Download PDFInfo
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- WO2004099136A1 WO2004099136A1 PCT/JP2004/006471 JP2004006471W WO2004099136A1 WO 2004099136 A1 WO2004099136 A1 WO 2004099136A1 JP 2004006471 W JP2004006471 W JP 2004006471W WO 2004099136 A1 WO2004099136 A1 WO 2004099136A1
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- 0 CC1=CCC=C(C(NC2=CC(Cl)=C=C(CC(O)=O)C=C2Cl)=*)c2c1cccc2 Chemical compound CC1=CCC=C(C(NC2=CC(Cl)=C=C(CC(O)=O)C=C2Cl)=*)c2c1cccc2 0.000 description 4
- ZYVBYRKLECISLP-IUCAKERBSA-N CC(C)(C)OC(N(C1)[C@H](CO)C[C@@H]1OC)=O Chemical compound CC(C)(C)OC(N(C1)[C@H](CO)C[C@@H]1OC)=O ZYVBYRKLECISLP-IUCAKERBSA-N 0.000 description 1
- JUWWYVCNZFCWNH-WDSKDSINSA-N CO[C@@H]1CN[C@H](CO)C1 Chemical compound CO[C@@H]1CN[C@H](CO)C1 JUWWYVCNZFCWNH-WDSKDSINSA-N 0.000 description 1
- UPEGZTKVOGNGIP-QESAQDPVSA-N C[n]1c(cccc2)c2c(C(Nc(cc(c(CC(N(C2)[C@H](CO[C@H](CC3)CC[C@@H]3C(O)=O)C[C@@H]2OC)=O)c2)Cl)c2Cl)=O)c1 Chemical compound C[n]1c(cccc2)c2c(C(Nc(cc(c(CC(N(C2)[C@H](CO[C@H](CC3)CC[C@@H]3C(O)=O)C[C@@H]2OC)=O)c2)Cl)c2Cl)=O)c1 UPEGZTKVOGNGIP-QESAQDPVSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
Definitions
- the present invention relates to a method for producing a compound useful as an intermediate for producing a compound having excellent VLA-4 inhibitory activity and safety, and a novel useful intermediate. Itoda
- the compound represented by the following general formula (1) exhibits an anti-inflammatory effect based on an excellent VLA-4 inhibitory effect and is expected as a highly safe pharmaceutical compound (WO 2002/2002). No. 053534 bread fret).
- a methyl ether structure is formed by a Mitsunobu reaction with a primary hydroxyl group of hydroxypurine, and a benzoic acid unit is introduced after converting a carboxylic acid moiety into a hydroxymethyl group. Subsequent reduction of the benzene ring at the benzoic acid site The 1,4-cyclohexanecarboxylic acid ester obtained in a large number of cis-forms obtained by the reaction was synthesized by carrying out an isomerization reaction via an enolate (International Publication No. No. 3 5 3 4 bread fret).
- the Mitsunobu reaction requires the use of azo reagents, which have the danger of explosion, and requires a purification process to remove large amounts of unnecessary substances derived from the reagents used. There are difficulties during synthesis.
- the reduction reaction of the benzene ring generates many cis-forms, so an isomerization step was necessary to obtain the trans-form.
- the ester hydrolysis treatment proceeds under the isomerization reaction conditions and carboxylic acid is by-produced. Had occurred.
- a cis-form compound which is predominantly formed in the reduction reaction of compound (V) requires an isomerization step to a trans-form compound, but the conventional method (International Publication No. (See No. pamphlet) required a long time. But It was found that the isomerization reaction was completed in a very short time by using an aprotic polar solvent such as N, N-dimethylformamide as a solvent. This not only shortened the reaction time, but also clarified that carboxylic acid by-products due to ester hydrolysis can be suppressed and re-esterification can be omitted.
- an aprotic polar solvent such as N, N-dimethylformamide
- the present invention has been completed by finding a method for more efficiently producing an intermediate compound (VI-trans) which is important as an intermediate for producing the compound (1).
- the present invention provides a compound of the formula (I)
- R 11 represents a protecting group for an amino group
- R 2 represents a protecting group for a hydrogen atom or a hydroxyl group. However, when both are protecting groups, they are not the same protecting group.
- R 11 and R 2 have the same meanings as above, and R 3 is an arylsulfonyl group which may have a substituent or an alkylsulfonyl group which may have a substituent Means.
- R 4 represents an alkyl group which may have a substituent or an aralkyl group which may have a substituent
- M represents an alkali metal atom.
- the present invention relates to each of the following:
- R 3 is a paratoluenesulfonyl group or a methanesulfonyl group
- R 4 is a methyl group or an ethyl group
- R 1 represents a hydrogen atom or an amino protecting group
- R 4 has the same meaning as above. You.
- the present invention also relates to a method for producing the compound represented by the formula:
- the present invention relates to each of the following:
- R 1 is a tertiary butoxycarbonyl group
- R 4 is a methyl group or an ethyl group
- aprotic polar solvent is N, N-dimethylformamide, N-methyl-2-pyrrolidone, or dimethylsulfoxide;
- R 4 represents an alkyl group which may have a substituent or an aralkyl group which may have a substituent.
- R 4 represents an alkyl group which may have a substituent or a substituent It also means a aralkyl group.
- One preferred example of the process of the present invention comprises the following steps starting from hydroxyproline.
- the method shown here is a method carried out without protecting the hydroxyl group of hydroxyproline. That is, according to the method of the present invention, the hydroxyl group of hydroxyproline can be converted without protection. However, it goes without saying that a similar conversion step can be carried out by protecting this hydroxyl group.
- the protecting group to be employed may be selected from those commonly used in this field. More preferably, a protecting group different from the protecting group on the nitrogen atom of the ring is employed.
- This step is a step of converting the carbonyl group of compound (2a) into a hydroxymethyl group.
- R 11 is a protecting group for a nitrogen atom (an amino group) (for example, “Protecting group” is described in “Protecti ve Gr oup sin Or anic Synthesis, eds. By TW Greene and PG Wu. ts, John William & Sons, Inc., New York, 1991)).
- the protecting group include carbonate-based, acyl-based, aralkyl-based and aralkyl-based protecting groups, and may be a substituted or unsubstituted benzyloxycarbonyl group or a tert-butoxycarbonyl group.
- the compound (2b) can be obtained by applying a well-known reduction method (for example, WO2002 / 053534 pamphlet) which is generally used as a method for converting a hydroxyl group into a hydroxymethyl group.
- a reducing agent may be reacted, but dipolane can be suitably used as the reducing agent. Dipolane may be generated during the reaction, but using a commercially available poran-dimethyl sulfide complex (Fieser and Fiesers Reagents for Organic Synthesis, 15, 44., etc.) and other polan complexes. Is also good.
- the solvent used for the dipolane reduction is not particularly limited as long as it does not inhibit the reaction.
- hydrocarbon solvents such as toluene and ether solvents such as getyl ether and tetrahydrofuran can be mentioned, and ether solvents such as tetrahydrofuran are preferred.
- the reaction temperature may be between 178 ° C and the boiling point of the solvent, preferably between 0 ° C and the boiling point of the solvent.
- the reaction time may be between 5 minutes and 24 hours, but usually completes in about 30 minutes to 5 hours.
- the compound (2a) produced after the reaction can be isolated and produced by treating the reaction solution by a commonly used method and further by a usual method.
- This step is a step of converting a hydroxymethyl group into a substituted sulfonyloxy group, and is a step of converting a hydroxyl group into a leaving group for a substitution reaction.
- the leaving group is not limited to a substituted sulfonyloxy group, and is not particularly limited as long as it functions as a leaving group such as a halogen atom.Other substituents may be used, but a substituted sulfonyloxy group is used. It is convenient and most preferred.
- R 11 has the same meaning as described above.
- R 3 is a substituted sulfonyl group, which means a substituted or unsubstituted arylsulfonyl group or a substituted or unsubstituted alkylsulfonyl group.
- the substituted sulfonyl group a p-toluenesulfonyl group and a methanesulfonyl group are preferable.
- the starting compound (2b) has one secondary and one primary hydroxyl group, but by adjusting the amount of reagent used and the reaction temperature, the primary hydroxyl group present in the hydroxymethyl group can be reduced.
- Selective conversion to a substituted sulfonyloxy group Can be.
- the reaction may be carried out by reacting a substituted sulfonyl halide, preferably chloride in the presence of a salt group. Specifically, the reaction can be carried out by the following method.
- the substituted sulfonyl halide used is selected from those corresponding to the sulfonyl employed. Examples thereof include p-toluenesulfonyl chloride and methanesulfonyl chloride. It is preferable to use these in an amount of 1 to 2.5 moles, preferably 1 to 1.5 moles, per 1 mole of the compound (2b).
- Examples of the base to be used include alkylamines such as triethylamine, N, N-dimethylaniline, pyridin, and 4-dimethylaminopyridine; aromatic bases; and organic bases such as nitrogen-containing heterocyclic compounds; or Alkali metal, alkaline earth metal carbonate, hydrogen carbonate and the like, and inorganic bases such as anhydrous potassium carbonate, anhydrous sodium carbonate and sodium hydrogen carbonate may be used.
- organic bases such as triethylamine and 4-dimethylaminopyridine. These may be used in an amount of 1 to 10 equivalents, preferably 1 to 2.5 equivalents, relative to the compound (2b), and may be used in an equimolar amount to the substituted sulfonyl halide used. No.
- the reaction solvent is not particularly limited as long as it does not inhibit the reaction, but a hydrocarbon solvent such as toluene, an ether solvent such as getyl ether and tetrahydrofuran, and a chlorine solvent such as methylene chloride and 1,2-dichloroethane.
- a hydrocarbon solvent such as toluene
- an ether solvent such as getyl ether and tetrahydrofuran
- a chlorine solvent such as methylene chloride and 1,2-dichloroethane.
- Preferred solvents include chlorinated solvents such as methylene chloride and 1,2-dichloroethane.
- the reaction temperature may be in the range of 178 ° C to the boiling point of the solvent, but preferably in the range of 0 ° C to room temperature.
- the reaction time may be between 5 minutes and 24 hours, but is usually completed in about 30 minutes to 6 hours.
- Compound (3) is usually an unstable compound, but is not isolated and purified. Both can be used in the next step with sufficient purity after confirmation of their production with equipment.
- This step is a step of introducing a benzoic acid unit into compound (3).
- the benzoic acid unit 4-hydroxybenzoic acid ester may be used.
- methyl esters and ethyl esters are commercially available.
- This benzoic acid compound may be converted to a sodium, potassium, or lithium phenolate derivative, or further to a calcium phenolate derivative, and a coupling reaction with the compound (3) may be carried out.
- This reaction is a general reaction of phenol anion, and is known as a reaction for forming an aryl ether bond. Therefore, in the compound of the formula (III), the metal atom (cation) represented by M may be a metal atom selected from an alkali metal atom or an alkaline earth metal atom. Of these, an alkali metal atom is preferable, and lithium, sodium, or potassium is preferable, and sodium or potassium is more preferable.
- the solvent used for the reaction is not particularly limited as long as it does not inhibit the reaction, but a hydrocarbon solvent such as toluene, an ether solvent such as getyl ether or tetrahydrofuran, or N, N-dimethylformamide, N- Non-protonic polar solvents such as methyl-2-piperidone and dimethyl sulfoxide can be mentioned. Of these, tetrahydrofuran, N, N-dimethylformamide and the like are preferred, and those which are anhydrous within a commonly used range are preferred.
- 4-hydroxybenzoic acid esters are added to anhydrous potassium carbonate and anhydrous sodium carbonate such as alkali metal and alkaline earth metal carbonates and bicarbonates.
- the reaction may be carried out by adding an inorganic base such as aluminum, sodium bicarbonate and the like, and the compound (3).
- a method may be used in which 4-hydroxybenzoic acid ester is treated with a metal hydride to prepare a phenolate in advance, and then the compound (3) is added.
- the reaction temperature ranges from 0 ° C to the boiling point of the solvent, preferably from 20 ° C to 120 ° C.
- the reaction time may be between 30 minutes and 24 hours, but usually completes in about 30 minutes to 4 hours.
- This reaction is preferably carried out under anhydrous conditions in order to avoid hydrolysis of the ester group and decomposition of the sulfonyloxy compound (3).
- This step is a step of converting the coordination of a hydroxyl group present as a substituent on the ring to hikara / 3 (or changing the coordination of the carbon atom to which the hydroxyl group is bonded from the R coordination to the S coordination). Convert to.)
- This step is hydroxyl group of the compound (4) into ester or formyl body reactions using accompanied by steric inversion of the hydroxyl group Mitsunobu (5) [step then R 2 2 is a substituent (protecting group)
- step e This is the step of selectively desorbing [step e].
- a compound (6) in which the coordination of the hydroxyl group is inverted from a to / 3 can be obtained.
- Such a series of conversion reactions can be easily carried out by a known method (International Publication No. WO 2001/002 006 Pamphlet and International Publication WO 02/053534). Bread fried).
- R 11 and R 4 are as defined above.
- R 2 2 denotes an unsubstituted or substituted ⁇ b I group, Arukaroiru group or formyl group, preferably 4-Nitorobe Examples include benzoyl group, benzoyl group, acetyl group, and formyl group. Of these, 4-nitrobenzoyl, acetyl, and formyl groups are particularly preferred.
- Examples of the carboxylic acid used in [Step d] include 4-nitrobenzoic acid, benzoic acid, acetic acid, and formic acid, and among them, 412-nitrobenzoic acid and formic acid are preferable.
- Examples of the phosphine reagent used for the reaction include triphenylphosphine and the like.
- the reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include hydrocarbon solvents such as toluene and ether solvents such as dimethyl ether and tetrahydrofuran. Of these, tetrahydrofuran Is preferred.
- the azo reagent to be used include commercially available azodicarboxylates, for example, diisopropyl azodicarbonate and getyl azodicarbonate.
- the reaction temperature may range from 0 ° C. to the boiling point of the solvent.
- the compound (5) can be purified by column chromatography using silica gel or the like, but may be separated and purified after the subsequent [Step e] without purifying at this stage.
- Step e is a deesterification or deformylation step, which may be performed by a known method which is easily distinguished from the carboxylate group present in the molecule and selectively carried out.
- ester cleavage may be performed using an alcoholic solvent such as ethanol or methanol, an ethereal solvent such as tetrahydrofuran, or the like, preferably using tetrahydrofuran or ethanol. If necessary, water may be added to the solvent in an amount equivalent to a stoichiometric equivalent to 10-fold molar amount.
- an alcoholic solvent such as ethanol or methanol
- an ethereal solvent such as tetrahydrofuran, or the like
- water may be added to the solvent in an amount equivalent to a stoichiometric equivalent to 10-fold molar amount.
- the reaction can be carried out at a temperature in the range of 0 to the boiling point of the solvent. It is preferable to carry out in a range.
- the reaction time may be between 5 minutes and 24 hours, but is usually completed in about 30 minutes to 4 hours.
- This step is a step of introducing a methyl group into a hydroxyl group on the ring to convert it into a methoxy group.
- This step may be performed using a general method for methylating a hydroxyl group, that is, treatment with a methylating reagent in the presence of a base.
- Methylation reagents include methyl halides, with methyl iodide being most preferred.
- the base to be used is preferably a metal hydride, and sodium hydride or lithium hydride can be suitably used.
- the reaction solvent is not particularly limited as long as it does not inhibit the reaction.
- hydrocarbon solvents such as toluene, ether solvents such as getyl ether and tetrahydrofuran, or N, N-dimethylformamide, N-methyl- — Aprotic polar solvents such as pyrrolidone and dimethyl sulfoxide; and tetrahydrofuran, N, N-dimethylformamide and the like are preferable.
- the solvent is preferably anhydrous as long as it is generally available.
- the reaction can be carried out at a temperature ranging from 178 ° C to the boiling point of the solvent, preferably from 120 ° C to room temperature.
- reaction time may be between 30 minutes and 24 hours, but usually completes in about 1-5 hours.
- this step is preferably performed under anhydrous conditions and further under a nitrogen stream to prevent cleavage of the ester and decomposition of R 1 which is a protecting group for the pyrrolidine ring nitrogen atom.
- This step is a step of removing the protecting group on the nitrogen atom.
- This elimination of the protective group is particularly preferred when the protective group present in compound (7) is a protective group containing an aromatic ring. This is because if the aromatic ring contained in the protecting group is reduced by the reduction reaction of the aromatic ring in the benzoic acid portion carried out in the subsequent step, the subsequent reaction becomes complicated.
- This step is performed by a known method for removing a protecting group on a nitrogen atom, depending on the protecting group selected (for example, Protective Group Organic Compound, eds. By TW Gr e. ene and PG Products, John Wiley & Sons, Inc., New York, 1991).
- R 11 and R 4 are as defined above.
- R 11 is a benzyloxycarbonyl group
- deprotection may be carried out under neutral conditions by catalytic hydrogenation, but the catalyst used may be palladium such as palladium monocarbon or palladium (II) hydroxide.
- a catalyst or a platinum catalyst such as platinum dioxide can be used.
- the solvent to be used is not particularly limited as long as it does not inhibit the reaction.
- examples of the solvent include alcohol solvents such as ethanol and methanol, and ether solvents such as tetrahydrofuran. Ethanol is good Good.
- the hydrogen pressure can be in the range of normal pressure to 1 OMpa, preferably in the range of normal pressure to IMpa.
- This step is a step of reducing the benzene ring part in the unit introduced as a benzoic acid unit and converting it into a cyclohexane ring.
- R 4 has the same meaning as described above.
- a method known as a mild condition may be applied.
- a method such as WM Pear 1 man (Organic Synthesis, Collective vevolume 5, p 670-672, John Wiley & Sons, Inc.) is exemplified. be able to. It is stated that this reduction reaction has high cis selectivity, and that 1,4-cis isomers can be obtained predominantly.
- the catalyst poison-free nitrogen atom which hinders the progress of the reaction in the catalytic reduction step, is converted into a salt by adding an acid in advance, and then the reaction is carried out.
- a tertiary butoxycarbonyl group is advantageous for protecting the nitrogen atom and improving the operability of the next step (isomerization and separation and purification of isomers).
- the protecting group to be introduced is not limited to a tertiary butoxycarbonyl group, and other protective groups that perform the same function as the tertiary butoxycarbonyl group are introduced. Needless to say, it may be a group.
- a benzyloxycarbonyl group which may have a substituent may be employed.
- the catalyst used in the step of hydrogenating the ring may be a commercially available palladium carbon catalyst, a platinum oxide catalyst, a strontium carbonate catalyst, a rhodium-alumina catalyst, or the like. Rhodium-alumina catalyst is most preferred.
- the amount of catalyst used can range from 1% to 50%, preferably from 3% to 20%, based on the weight of the substrate to be reduced.
- the solvent is not particularly limited as long as it does not inhibit the reaction.
- Alcohol solvents such as ethanol and methanol, and ether solvents such as tetrahydrofuran and dioxane can be used, and preferably an alcohol solvent. Yes, methanol or ethanol.
- Acetic acid or trifluoroacetic acid is preferably added as a co-solvent to this solvent in a volume ratio of 5% to 20%.
- the hydrogen pressure for the reaction can be carried out in the range of normal pressure to 10 MPa, but is preferably in the range of normal pressure to 1.5 MPa.
- the reaction temperature may range from 0 ° C to 100, preferably from 20 ° C to 60 ° C.
- the reaction time may be between 1 hour and 72 hours, but is usually completed in about 2 hours to 48 hours.
- the subsequent step of introducing a tertiary butoxycarbonyl group or another protecting group may be carried out by a known method for protecting a nitrogen atom (an amino group) (see above, Protecti V e Group sin Organic Synthesis). eds. by TW Greene and PG Wuts, John Wiley and Sons, Inc., New York, 1991).
- This step is a step of converting the predominantly generated cis isomer into the trans isomer in the benzene ring reduction step.
- R 4 has the same meaning as described above.
- This step comprises the step of increasing the ratio of the trans-isomer of the desired relative configuration by isomerizing the compound (10) via enolate, and separating and purifying these two isomers.
- the carboxylic acid compound by-produced during the isomerization can be easily converted to the desired ester compound (11) by performing the esterification again.
- a methyl ester compound (10) in which R 4 is a methyl group In methanol, sodium methoxide was used as a base, and heating was carried out under reflux with stirring for 15 hours to several days.
- reaction temperature was reduced to 50 ° C. or lower and the amount of the solvent varied depending on the substrate when the reaction was performed in place of the aprotic polar solvent N, N-dimethylformamide or the like. It was found that the isomerization reaction reached a steady state in a very short reaction time of 5 minutes to 1 hour, albeit with a small difference.
- the carboxylic acid by-product of the hydrolyzed product can be suppressed to a small amount, and the re-esterification step can be omitted, which is advantageous. It becomes.
- the reaction may be carried out by dissolving the starting material in an aprotic polar solvent such as N, N-dimethylformamide, N-methyl-2-pyrrolidone, or dimethylsulfoxide.
- an aprotic polar solvent such as N, N-dimethylformamide, N-methyl-2-pyrrolidone, or dimethylsulfoxide.
- 1 to 3 moles of the compound (10) is coexisted with the corresponding alcohol. Is preferred.
- Examples of the base used include sodium hydride.
- Reaction temperatures may range from 0 to 50 ° C, preferably 0. ⁇ , et al. 25 ° C. While maintaining the temperature, the above base is added, and while the progress of the reaction is being monitored, the mixture is further stirred at room temperature to 50 ° C for 5 minutes to 1 hour, and then diluted with diluted hydrochloric acid and neutralized. The reaction can be terminated.
- An aprotic polar solvent such as N, N-dimethylformamide and N-methyl-2-pyrrolidone, preferably N, N-dimethylformamide, is used as a reaction solvent, and anhydrous potassium carbonate and anhydrous sodium carbonate are used as bases. Then, the corresponding R 4 -bromide or R 4 -chloride may be reacted as an alkylating agent. If the ester is a methyl ester, carry out the esterification using a commercially available trimethylsilyldiazomethane in a mixture of getyl ether, benzene and methanol (4: 1, v / v). It is also possible.
- the method for separating and purifying the trans compound (11) can be carried out by ordinary column chromatography using silica gel, and higher separation efficiency can be achieved by using a commercially available medium pressure preparative column separation device. can get. Separation can also be performed by using other methods, for example, HPLC.
- This step is a step of deprotecting a protecting group on a nitrogen atom.
- R 4 has the same meaning as described above.
- This step is performed by a known method for removing a tertiary butoxycarbonyl group, which is a protecting group on the nitrogen atom (Protecti V e Group Synthetic Synthesis, eds. By TW Greene and PG Wu ts , John Wiley & Sons, Inc., New York, 1991), and the same applies to other protecting groups.
- compound (12) can be deprotected using a commercially available 4N hydrochloric acid-dioxane or trifluoroacetic acid.
- a chlorine-based solvent such as salted methylene may be used as an auxiliary solvent.
- the reaction can be performed at a temperature ranging from 0 ° C to the boiling point of the solvent.
- the reaction time may be between 5 minutes and 24 hours, but usually completes in about 30 minutes to 5 hours.
- the reaction solvent is distilled off, and the compound (12) is isolated as a salt with the acid used, for example, a hydrochloride or trifluoroacetate.
- the acid used for example, a hydrochloride or trifluoroacetate.
- These salts can be used as they are in the next reaction, but they can also be neutralized using saturated aqueous sodium hydrogen carbonate and isolated as the free amine compound (12).
- the compound (12) thus produced is a compound which can be produced by the method described in this publication, similarly to a known method, for example, the method described in WO 2002/053534 pamphlet. It can be used in the condensation reaction with (20) to convert to compound (13).
- Compound (13) can also be produced by the method shown below (
- R 5 represents a linear or branched alkyl group, a substituted or unsubstituted arylalkyl group, preferably a methyl group, an ethyl group, a tertiary butyl group, a benzyl group, -Methoxybenzyl group, of which a methyl group or an ethyl group is preferable.
- This step is a general reaction for hydrolyzing an ester to a free carboxylic acid, and is a general method for converting an alkoxyl group into a carboxylic acid (Protective Group Organic Organism). Synt hesis, eds. By TW Greene and PG Wuts, John Wiley & Sons, Inc., New 'York, 1991).
- R 4 has the same meaning as described above. This step is for condensing the compound (12) and the compound (20) and can be easily carried out by a known reaction.
- the solvent to be used is not particularly limited as long as it does not inhibit the reaction.
- Halogenated hydrocarbon solvents such as methylene chloride, hydrocarbon solvents such as toluene, ether solvents such as tetrahydrofuran, or N , N-dimethylformamide, N-methyl
- Aprotic polar solvents such as 2-pyrrolidone; Of these, methylene chloride or N, N-dimethylformamide is preferred.
- 1-ethyl-3- (3-dimethylaminopropyl) propyldiimide hydrochloride, N, N-dicyclohexylcarbodiimide, N, N-carbonyldiimidazole, or the like The reaction may be carried out using a condensing agent which is a product.
- a condensing agent which is a product.
- the reaction is preferably carried out using (3-dimethylaminopropyl) carbopimide hydrochloride and N, N-dicyclohexyl carbopimide.
- the reaction temperature may be in the range of 120 ° C to the boiling point of the solvent, and preferably in the range of 0 ° C to room temperature.
- this reaction is carried out based on the catalytic amount of an organic amine base such as triethylamine or N, N-dimethylaminopyridine, or an organic amine base, and an active esterification reagent such as 1-hydroxybenzotriazole. It may be carried out in the presence of a quantity.
- an organic amine base such as triethylamine or N, N-dimethylaminopyridine, or an organic amine base
- an active esterification reagent such as 1-hydroxybenzotriazole
- R 4 has the same meaning as described above.
- the compound (13) is obtained by converting the compound (19) or the compound into a reactive derivative such as an acid halide (eg, acid chloride), and then subjecting the compound (21) to a known condensation reaction. And condensed.
- a reactive derivative such as an acid halide (eg, acid chloride)
- Solvents used for converting commercially available 1-methyl-3-indolecarboxylic acid (19) to, for example, acid chloride include methylene chloride, chlorinated solvents such as 1,2-dichlorobenzene, toluene, benzene and the like.
- chlorinated solvents such as 1,2-dichlorobenzene, toluene, benzene and the like.
- the solvent include hydrocarbon solvents and ether solvents such as tetrahydrofuran, and preferred are chlorine solvents such as methylene chloride and 1,2-dichlorobenzene.
- the reaction temperature may range from 0 to the boiling point of the solvent.
- chlorinating reagent usually used when converting a carboxylic acid to an acid chloride, such as salted oxalyl and thionyl chloride, may be used.
- the solvent used in the step of condensing the acid chloride of compound (19) with compound (21) is a chlorinated solvent such as methylene chloride and 1,2-dichloroethane, and a carbonic acid such as toluene and benzene.
- a chlorinated solvent such as methylene chloride and 1,2-dichloroethane
- a carbonic acid such as toluene and benzene.
- examples thereof include a hydrogen solvent and an ether solvent such as tetrahydrofuran, and preferably a chlorine solvent such as dimethylene salt.
- the reaction temperature may range from 0 to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
- Examples of the base used include stoichiometric organic bases such as triethylamine.
- This step is used when synthesizing a derivative in which the 1-methyl-3-indolecarboxylic acid moiety is isotope-labeled, or when synthesizing an active metabolite, or 1-methyl-3-indolcarboxylic acid. It is effective when synthesizing a compound having a modified indolecarboxylic acid moiety.
- Compound (21) is a novel compound, and useful compounds such as compounds (1) and compounds having VLA-4 inhibitory activity, for example, compounds (1a) to (1f) shown below. It is useful as a synthetic intermediate for active substances.
- ester of compound (13) is subjected to a known method such as hydrolysis, catalytic hydrogenation, etc. (ProtetechtiVeGroupsinOrganic)
- Triethylamine (133. lml, 0.956mo1) and 4-dimethylaminopyridine (5.84g, 47.8mmo1) were added to the mixture, and then cooled to -10 ° C and p-toluenesulfonylk was added. Mouth lid (100.24 g, 0.526 mol 1) was added slowly. After completion of the addition, the reaction solution was stirred at the same temperature for 1 hour and further at 5 ° C for 18 hours. Under cooling, 1NHC 1 (500 ml) was added to the reaction solution, and the mixture was extracted with a black hole form.
- 1NHC 1 500 ml
- reaction solution was diluted with ethyl acetate (2000 ml), washed successively twice with cooling water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
- the obtained residue was purified by column chromatography using silica gel (4 kg), and the title compound (76.3) was obtained from n-hexane-ethyl acetate (2: 1 to 2: 3, v / v) stream.
- 65 g, 40.1%, (4R) -hydroxy- (2S) -hydroxymethylpyrrolidine-one yield from benzyl rubonic acid in 2 steps) was obtained as a pale orange oil.
- the obtained residue was purified by column chromatography using silica gel (1.5 kg), and the title compound (70.68) was purified from n-hexane monoethyl acetate (2: 1, v / v) stream. g, 96.9%) as a pale orange oil.
- the extract was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
- the obtained residue was dissolved in DMF (300 ml), and anhydrous potassium carbonate (34.21 g, 0.248 mol) and iodide chill (6.60 ml, 82.5 mmol) were added with stirring at room temperature. The mixture was stirred for 13 hours.
- the reaction solution was diluted with ethyl acetate (1000 ml), washed with cooling water, and dried over anhydrous sodium sulfate.
- the precipitated insoluble material was separated by filtration under reduced pressure, and washed with chloroform-methanol (200 ml, 10: 1, v / v). The filtrate was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography using silica gel (1.2 kg), and the title compound (45.35 g, 99%) was obtained from a stream of formyl ethyl monoacetate (4: 1, v / v). .8%) as a pale yellow amorphous.
- reaction solution was poured into ice water (100 ml) and extracted with ethyl acetate.
- the extract was washed with saturated saline (twice), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
- the obtained residue was purified by column chromatography using silica gel.
- Transform form ethyl acetate (9: 1 to 4: 1, V / v) was used to obtain trans-1-([2S , 4 S) — 1— (4-amino-1,2,5-dichlorophenyl) acetyl-1-methoxypyrrolidine—2-yl] methoxycyclohexane—one-potency ethyl ester of rubonic acid (2 1) (2.48 g, 94%) as a colorless solid.
- Trans-1 4 ((2 S, 4 S) — 1— ⁇ 2,5-dichloro-4— [(1-methylindole—3-yl) carpoxamide] phenyl ⁇ acetyl—4-methoxy Pyrrolidine-1-yl) Methoxycyclohexane-11-Ethyl ester of rubonate (13)
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2005506035A JPWO2004099136A1 (ja) | 2003-05-09 | 2004-05-07 | ピロリジン誘導体の製造方法 |
US10/556,043 US7345179B2 (en) | 2003-05-09 | 2004-05-07 | Process for producing pyrrolidine derivative |
EP04731729A EP1623975A4 (en) | 2003-05-09 | 2004-05-07 | PROCESS FOR PREPARING A PYRROLIDINE DERIVATIVE |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2003131978 | 2003-05-09 | ||
JP2003-131978 | 2003-05-09 | ||
JP2003-144430 | 2003-05-22 | ||
JP2003144430 | 2003-05-22 | ||
JP2003209579 | 2003-08-29 | ||
JP2003-209579 | 2003-08-29 |
Publications (1)
Publication Number | Publication Date |
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WO2004099136A1 true WO2004099136A1 (ja) | 2004-11-18 |
Family
ID=33436999
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2004/006471 WO2004099136A1 (ja) | 2003-05-09 | 2004-05-07 | ピロリジン誘導体の製造方法 |
Country Status (4)
Country | Link |
---|---|
US (1) | US7345179B2 (ja) |
EP (1) | EP1623975A4 (ja) |
JP (1) | JPWO2004099136A1 (ja) |
WO (1) | WO2004099136A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1698611A1 (en) * | 2003-12-26 | 2006-09-06 | Daiichi Pharmaceutical Co., Ltd. | Process for producing phenylacetic acid derivative |
WO2007069635A1 (ja) * | 2005-12-13 | 2007-06-21 | Daiichi Sankyo Company, Limited | Vla-4阻害薬 |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7691894B2 (en) * | 2003-07-24 | 2010-04-06 | Daiichi Pharmaceutical Co., Ltd. | Cyclohexanecarboxylic acid compound |
JPWO2005066124A1 (ja) * | 2003-12-26 | 2007-12-20 | 第一三共株式会社 | ピロリジン誘導体の製造法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS61251635A (ja) * | 1985-04-30 | 1986-11-08 | Fuji Photo Film Co Ltd | エ−テルの製造方法 |
JPH06306025A (ja) * | 1992-11-30 | 1994-11-01 | Sankyo Co Ltd | ジアリールアルカン誘導体 |
WO2002053534A1 (fr) * | 2000-12-28 | 2002-07-11 | Daiichi Pharmaceutical Co., Ltd. | Inhibiteurs de vla-4 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MXPA01013406A (es) | 1999-06-30 | 2003-09-04 | Daiichi Seiyaku Co | Compuestos inhibidores de vla-4. |
-
2004
- 2004-05-07 WO PCT/JP2004/006471 patent/WO2004099136A1/ja active Search and Examination
- 2004-05-07 EP EP04731729A patent/EP1623975A4/en not_active Withdrawn
- 2004-05-07 JP JP2005506035A patent/JPWO2004099136A1/ja not_active Withdrawn
- 2004-05-07 US US10/556,043 patent/US7345179B2/en not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS61251635A (ja) * | 1985-04-30 | 1986-11-08 | Fuji Photo Film Co Ltd | エ−テルの製造方法 |
JPH06306025A (ja) * | 1992-11-30 | 1994-11-01 | Sankyo Co Ltd | ジアリールアルカン誘導体 |
WO2002053534A1 (fr) * | 2000-12-28 | 2002-07-11 | Daiichi Pharmaceutical Co., Ltd. | Inhibiteurs de vla-4 |
Non-Patent Citations (1)
Title |
---|
See also references of EP1623975A4 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1698611A1 (en) * | 2003-12-26 | 2006-09-06 | Daiichi Pharmaceutical Co., Ltd. | Process for producing phenylacetic acid derivative |
EP1698611A4 (en) * | 2003-12-26 | 2007-10-31 | Daiichi Seiyaku Co | PROCESS FOR PRODUCING A PHENYLACETIC ACID DERIVATIVE |
WO2007069635A1 (ja) * | 2005-12-13 | 2007-06-21 | Daiichi Sankyo Company, Limited | Vla-4阻害薬 |
US8129366B2 (en) | 2005-12-13 | 2012-03-06 | Daiichi Sankyo Company, Limited | VLA-4 inhibitory drug |
Also Published As
Publication number | Publication date |
---|---|
EP1623975A4 (en) | 2008-07-02 |
US20070105935A1 (en) | 2007-05-10 |
US7345179B2 (en) | 2008-03-18 |
EP1623975A1 (en) | 2006-02-08 |
JPWO2004099136A1 (ja) | 2006-07-13 |
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