WO2008066083A1 - Procédé de production d'un dérivé de n-(n'-glycyle substitué)-2-cyanopyrrolidine - Google Patents

Procédé de production d'un dérivé de n-(n'-glycyle substitué)-2-cyanopyrrolidine Download PDF

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WO2008066083A1
WO2008066083A1 PCT/JP2007/072973 JP2007072973W WO2008066083A1 WO 2008066083 A1 WO2008066083 A1 WO 2008066083A1 JP 2007072973 W JP2007072973 W JP 2007072973W WO 2008066083 A1 WO2008066083 A1 WO 2008066083A1
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group
salt
general formula
compound represented
compound
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PCT/JP2007/072973
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Japanese (ja)
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Toru Kuroda
Masanori Hatsuda
Shota Toshikawa
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Mitsubishi Tanabe Pharma Corporation
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Priority to JP2008547016A priority Critical patent/JP5165584B2/ja
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    • 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel method for producing a ⁇ - ( ⁇ '-substituted dalicyl) 2 -cyanopyrrolidine derivative useful as a medicament for the treatment of diabetes.
  • ⁇ - ( ⁇ '-substituted glycyl) -2-cyanopyrrolidine derivatives are useful as dipeptidyl peptidase IV (DPPIV) inhibitors, and are active ingredients of pharmaceuticals (diabetes therapeutics, etc.) It is known that it can be used as a production intermediate.
  • DPPIV dipeptidyl peptidase IV
  • Raw materials such as loacetyl-2-cyanopyrrolidine compounds are used as amine compounds (primary amines).
  • Patent Document 1 W01998 / 19998 (Novartis)
  • Patent Document 2 WO2000 / 34241 (Novartis)
  • Patent Document 3 WO2001 / 96295 (Novartis)
  • Patent Document 4 WO2002 / 30890 (Tanabe Seiyaku)
  • Patent Document 5 WO2002 / 30891 (Tanabe Seiyaku)
  • Patent Document 6 WO2002 / 51836 (Kyowa Hakko Kogyo)
  • Patent Document 7 WO2004 / 92127 (Novartis)
  • Non-Patent Document l Villhauer et al., J. Med. Chem., 2002, 45, 2362-2365
  • the present invention reduces the production of by-products and improves the quality of N— ( ⁇ ′-substituted dalicyl) 2 It is intended to provide a method for efficiently producing a conductor.
  • A -CH one or — S—;
  • Substituted may! /, Adamantyl group or Substituted or less! /, A lower alkyl group,
  • Z represents a reactive residue, and other symbols have the same meaning as described above, and a compound represented by the general formula [III]
  • R x represents an amino group protecting group selected from a benzyl group, a substituted benzyl group, an aryl group, a silyl group, and a nitrobenzenesulfonamide group, and other symbols have the same meanings as described above.
  • the step of converting the compound represented by the general formula [V] or a salt thereof into the compound represented by the general formula [I] or a salt thereof is performed, for example, by any of the following methods (1) or (2): be able to.
  • R y represents an amino-protecting group that can be removed by acid treatment, and other symbols have the same meaning as described above.
  • the amino-protecting group R y is removed, and if desired, it is further subjected to a salt-forming reaction to convert it to a compound represented by the general formula [I] or a salt thereof.
  • the present invention also relates to a method for producing a salt of an N- ( ⁇ '-substituted dalicyl) -2-cyanopyrrolidine derivative represented by the general formula [I], which comprises the general formula [VII]
  • the amino group protecting group R y is removed from the compound represented by the following by acid treatment:
  • the present invention includes a compound represented by the general formula [VII].
  • the compound represented by the general formula [VII] has a power that has not been known in the art so that it can be industrially produced without going through the compound [I] or a salt thereof.
  • This compound is a novel compound that can be produced industrially for the first time by the method of the present invention.
  • the present invention is also a first amino group protecting group other than a ⁇ benzyl group or a substituted benzyl group.
  • the first amino group protecting group is removed by reacting the protected amine compound in the presence of a radium catalyst to obtain a primary or secondary amine compound. Then, the primary or secondary amine compound is reacted with benzaldehyde or substituted benzaldehyde under a nitrogen atmosphere,
  • the present invention relates to a substitution method for protecting an amino group, which comprises obtaining a protected amine compound.
  • ⁇ — ( ⁇ ′-substituted glycyl) -2-cyanopyrrolidine derivative can be produced efficiently, and a high-quality target product can be obtained.
  • the amino-protecting group represented by R x is a compound of compound [II] and compound [III] or a salt thereof. >'If it is a protecting group that does not interfere with the reaction, the amino group protecting group may be, for example, a-group, a substituted benzylenole group (4-methoxybenzenole group, etc.), an aryl group, a silyl group (trimethyl) , Tri-lower alkylsilyl groups such as triethylsilyl; t-group; etc.) and nitrobenzenesulfonamide groups can be suitably used.
  • the amino group protecting group may be, for example, a-group, a substituted benzylenole group (4-methoxybenzenole group, etc.), an aryl group, a silyl group (trimethyl) , Tri-lower alkylsilyl groups such as triethylsilyl; t-group; etc.) and nitrobenzen
  • benzyl group and 4-methoxybenzyl group are preferable.
  • the amino protecting group represented by R y may be an amino protecting group that can be removed by acid treatment (preferably by acid treatment under mild conditions).
  • Examples of such an amino-protecting group include a t-butoxycarbonyl group and a benzyloxycarbonyl group, and among these, a t-butoxycarbonyl group is preferable.
  • the reactive residue represented by Z includes a halogen atom (Cl, Br, I etc.), a lower alkylsulfonyloxy group (methanesulfonyloxy etc.), a halo lower alkylsulfonyloxy group.
  • a conventional reactive residue such as a nyloxy group, a aryloxy group, and the like can be suitably used.
  • a logogen atom (Cl, Br, I, etc.), a methanesulfonyloxy group, a nyloxy group, etc. are preferred.
  • halogen atoms (Cl, Br, I, etc.) are preferred.
  • reaction of compound [II] with compound [III] or a salt thereof can be carried out in the presence or absence of a deoxidizer, in a suitable solvent or without solvent.
  • Examples of the deoxidizer include inorganic bases (for example, alkali metal hydrides such as sodium hydride, Alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal alkoxides such as sodium methoxide, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, etc.) or organic bases (eg, triethylamine, diisopropylethylamine) N-methylmorpholine, pyridine, dimethylaniline, dimethylaminopyridine, etc.) can be suitably used.
  • inorganic bases for example, alkali metal hydrides such as sodium hydride, Alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal alkoxides such as sodium methoxide, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, etc.
  • organic bases eg, triethylamine, diisopropylethylamine N-methylmorpholine, pyridine
  • This reaction suitably proceeds at 0 to 120 ° C, particularly at room temperature to 80 ° C.
  • any solvent that does not adversely influence the reaction may be used.
  • acetonitrile is particularly preferred, with acetonitrile, acetonitrile, toluene and ethyl acetate being preferred.
  • Removal of the amino protecting group (R x ) from compound [IV] or a salt thereof can be carried out by a conventional method.
  • removal of a benzyl group, a substituted benzyl group and an aryl group can be carried out in a suitable solvent or without a solvent in the presence or absence of a noradium carbon catalyst, a noradium catalyst, or the like.
  • the removal of such a protecting group preferably proceeds at 0 to 100 ° C, particularly at room temperature to 80 ° C.
  • Any solvent may be used as long as it does not adversely influence the reaction.
  • ethanol isopropyl alcohol, propyl alcohol, water, or a mixed solvent thereof can be appropriately used.
  • the removal of the silyl group can be carried out by acid treatment or fluorine treatment.
  • the removal of the nitrobenzenesulfonamide group can be carried out by treatment with a thiol derivative.
  • the dehydration reaction of compound [V] or a salt thereof is carried out in a suitable solvent or insoluble in the presence of a dehydrating agent. It can be carried out with a medium.
  • a dehydrating agent other than acetic anhydride because the amino group in the molecule is trifluoroacetamidolated.
  • dehydrating agents phosphorus oxychloride (POC1), phosphorus pentachloride (PCI), T3P (trade name; C1
  • POC1 phosphorus oxychloride
  • This reaction suitably proceeds at 20 to 100 ° C, particularly 0 to 50 ° C.
  • the solvent may be any solvent that does not adversely affect the reaction.
  • black mouth form or a mixed solvent thereof can be appropriately used.
  • acetonitrile is particularly preferred, with acetonitrile and methylene chloride being preferred.
  • the reaction for adding an amino group-protecting group () to compound [V] or a salt thereof can be carried out by a conventional method.
  • a solvent acetonitrile, ethanol, ethyl acetate, methylethylketone, methylene chloride, etc.
  • the reaction proceeds suitably at 0 to; 120 ° C, particularly from room temperature to 70 ° C.
  • the dehydration reaction of the compound [VI] is carried out in the presence of a dehydrating agent in a suitable solvent or in the absence of a solvent S.
  • Dehydrating agents include phosphorus oxychloride (POC1), phosphorus pentachloride (PCI), T3P (trade name; Clari).
  • p-toluenesulfuryl chloride trifluoroacetic anhydride, and the like can be suitably used.
  • phosphorus oxychloride (POC1) p-toluenesulfuryl chloride, Fluoroacetic anhydride is preferred.
  • P-Toluenesulfuryl chloride is particularly preferred.
  • bases such as pyridine and triethylamine may be added to promote the reaction! /.
  • this reaction is preferably carried out under low temperature conditions (120 ° C to room temperature).
  • low temperature conditions 120 ° C to room temperature.
  • p-toluenesulfuryl chloride heating (room temperature To 60 ° C).
  • the solvent may be any solvent that does not adversely influence the reaction.
  • Ethyl, toluene, methylene chloride, dichloroethane, chloroform, or a mixed solvent thereof can be appropriately used.
  • acetonitrile is particularly preferred, with acetonitrile and methylene chloride being preferred.
  • Removal of the amino-protecting group () from the compound [VII] can be carried out by a conventional method.
  • it can be carried out by an acid treatment (treatment with trifluoroacetic acid, hydrochloric acid, sulfuric acid, other inorganic acids or organic acids) in an appropriate solvent or without a solvent.
  • the reaction can be suitably carried out at 0 to 100 ° C, particularly at room temperature to 60 ° C.
  • the solvent may be any solvent that does not adversely influence the reaction, for example, a hydrophilic solvent such as 2-butanone, acetone, methanol, ethanol, water, ethyl acetate, isopropyl acetate, diethyl ether, or the like.
  • a mixed solvent can be used as appropriate.
  • ethanol and ethanol are particularly preferred, with ethanol being preferred.
  • the salt of the compound [I], [III], [IV] or [V] is not particularly limited, and for example, a salt with an inorganic acid such as hydrochloride or sulfate, or methanesulfonate, An organic acid salt such as p-toluenesulfonate can be used.
  • the salt when the compound [I] is used as an active ingredient of a pharmaceutical product is preferably a pharmacologically acceptable salt.
  • a pharmacologically acceptable salt for example, as a pharmacologically acceptable salt,
  • Inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate or hydrobromide, acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, p — Organic acid salts such as toluene sulfonate or maleate. Also Cal When it has a substituent such as a boxyl group, a salt with a base (for example, an alkali metal salt such as sodium salt or potassium salt or an alkaline earth metal salt such as calcium salt) can be used.
  • a salt with a base for example, an alkali metal salt such as sodium salt or potassium salt or an alkaline earth metal salt such as calcium salt
  • These salts can be produced by a conventional salt formation reaction.
  • the salt formation reaction may be performed simultaneously with the removal (deprotection) of the amino group protecting group.
  • the amino group protecting group (R y ) is removed from the compound represented by the general formula [VII].
  • the acid treatment may be performed using an acid (inorganic acid or organic acid) corresponding to the target product to be obtained.
  • the compound [I], compound [VII] or their starting compounds of the present invention is isolated as a free salt or a salt thereof and purified. Isolation and purification can be performed by applying ordinary chemical operations such as extraction, concentration, crystallization, filtration, recrystallization, and various types of chromatography.
  • the starting compound in the above method can be produced by a known method and / or a method described in Reference Examples below, or a combination thereof.
  • the group represented by R in compounds [I], [III], [IV], [V], [VI] and [VII] is particularly a cyclic group.
  • R in compounds [I], [III], [IV], [V], [VI] and [VII] is particularly a cyclic group.
  • R is more specifically represented by, for example, the following R A , R B and Group.
  • R A a group represented by the following formula:
  • X A represents N (R A3 ) O or one CO 2.
  • R A3 represents a hydrogen atom or a lower alkyl group.
  • R AU and R A12 are each a hydrogen atom, a lower alkyl group
  • RAU and RA12 are preferably a hydrogen atom or a lower alkyl (such as methyl) group, particularly preferably a hydrogen atom.
  • R A21 represents the following (1) or (2).
  • a monocyclic hydrocarbon group having 37 carbon atoms (i) selected from a nitrogen atom, an oxygen atom and a sulfur atom;! to a monocyclic heterocyclic group containing 2 heteroatoms; or (iii A nitrogen atom, an oxygen atom and a sulfur atom; a bicyclic heterocyclic group formed by condensing 2 to 5 7-membered rings containing 4 to 4 hetero atoms;
  • R A22 is substituted! /, May! /, A cyclic group, and the cyclic group moiety is
  • a monocyclic hydrocarbon group having 37 carbon atoms (i) selected from a nitrogen atom, an oxygen atom and a sulfur atom;! to a monocyclic heterocyclic group containing 2 heteroatoms; or (iii A nitrogen atom, an oxygen atom, and a sulfur atom;! —A bicyclic heterocyclic group containing 4 hetero atoms and 5 condensed with two 7-membered rings;
  • R B represents a group represented by the following formula.
  • R Bi R represents a hydrogen atom, 1 represents a hydroxy group, a lower alkoxy group or a lower alkanoyloxy group; or R B1 and R B2 each independently represent a lower alkyl group .
  • R G represents a mono-substituted amino lower alkyl group.
  • R A21 is an optionally substituted cyclic group, specifically, for example,
  • the cyclic group which may have the same or different 1-3 substituents selected from the following substituent groups is mentioned.
  • substituent groups selected from the following substituent groups.
  • Halogen atom cyano group; nitro group; oxo group; force rubamoyl group; lower (C 1) alkyl group
  • phenyl group optionally substituted with a norogen atom, cyano group, nitro group or oxo group; substituted with norogen atom, cyano group, nitro group or oxo group May be a lower phenyl (C) alkyl group;
  • a monocyclic 5- to 6-membered heterocyclic group optionally substituted by a halogen atom, a cyano group, a nitro group or an oxo group;
  • a monocyclic 5- to 6-membered heterocyclic group O— which may be substituted with a halogen atom, a cyano group, a nitro group or an oxo group;
  • a monocyclic 5- to 6-membered heterocyclic group CO— which may be substituted with a halogen atom, a cyano group, a nitro group or an oxo group.
  • R A21 is an optionally substituted amino group, specifically, for example, examples thereof include an amino group which may have the same or different 1 or 2 substituents selected from the following substituent group.
  • 1-6 3-8 1-6 a lower (C 1) alkyl group, a pyrimidinyl group, a thiazolyl group, and a thiadiazolyl group.
  • R A22 for example,
  • the cyclic group which may have the same or different 1-3 substituents selected from the following substituent groups is mentioned.
  • substituent groups selected from the following substituent groups.
  • Examples include groups selected from piperidyl, piperazil, morpholinyl, indolinyl, isoindolinyl, thiazolopyridyl, and cyclic groups in which some or all of them are saturated.
  • An oxo group a lower (C 1) alkanoyl group; a lower (C 2) cycloalkanoyl group;
  • R B specifically, for example, include the following groups.
  • R is a group represented by R D
  • R D Specific examples of the compound [I] wherein R is a group represented by R D include, for example, (2S) — 1— [(3 hydroxy-1- 1-adamantyl) amino] acetyl-2-cyanopyridine.
  • Compound R is the group represented by R e as [I], specifically, for example, include the following compounds.
  • R X1 represents a benzyl group or a substituted benzyl group, and other symbols represent the same meaning as described above,
  • substitution method for protecting the amino group is:
  • the first amino group protecting group is removed by reacting an amine compound protected with a first amino group protecting group other than an ⁇ benzyl group or a substituted benzyl group in the presence of a palladium catalyst to obtain a primary or After obtaining the secondary amine compound,
  • a reduction reaction is carried out in the presence of the same palladium catalyst as in the above-mentioned ⁇ to obtain a second amino group protecting group selected from a benzyl group and a substituted benzyl group.
  • a method for substitution of amino group protection characterized in that a protected amine compound is obtained.
  • the removal reaction of the ⁇ -amino-protecting group can be carried out by applying conventional reaction conditions using a palladium catalyst.
  • reaction conditions and reaction time of (ii) are not particularly limited as in the conventional method.
  • the reaction can be performed at room temperature for 1 to 5 hours.
  • the reduction reaction (iii) is preferably performed under conditions of room temperature and normal pressure.
  • the reaction time is preferably !! to 5 hours, more preferably! To 2 hours.
  • the hydrogen replacement in (iii) can be performed by performing decompression, degassing and hydrogen introduction 1 to 3 times.
  • Examples of the palladium catalyst used in the above (i) and (iii) include a palladium carbon catalyst and a palladium hydroxide carbon catalyst, and among these, a palladium carbon catalyst is preferable.
  • the first amino group protecting group of (i) above may be an amino group protecting group other than a benzyl group and other than a substituted benzyl group and removable with a palladium catalyst.
  • Examples of the first amino group protecting group include, for example,
  • Examples thereof include a benzyloxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a 2-phenoleethoxycarbonyl group, a 0-piperidinyloxycarbonyl group, and a p-nitrobenzyloxycarbonyl group. Of these, a benzyloxycarbonyl group is particularly preferable.
  • the second amino group protecting group in (iii) above is a force selected from a benzyl group and a substituted benzyl group (4-methoxybenzyl etc.) Of these, a benzyl group is particularly preferred.
  • Examples of the amine compound protected with the first amino group-protecting group (i) above include, for example, the general formula [VIII]
  • RD represents a lower alkyl group, a lower alkoxy lower alkyl group, a hydroxy lower alkyl group, an aryl substituted lower alkyl group, an optionally substituted lower cycloalkyl group, or an optionally substituted aryl group.
  • R Z represents an amino group other than a benzyl group and other than a substituted benzyl group, which can be removed by a palladium catalyst.
  • Aryl groups include phenyl, naphthyl and the like.
  • the group represented by R D is, for example, an optionally substituted lower cycloalkyl group (in the 4-position and 1-position,! /, Substituted! /, May! / , Cyclohexenole, etc.), substituted! /, Mayo! /, Adamantyl group and substituted! /, Mayo! /, Lower alkyl groups, etc., more specifically R a, R B, and it includes a group represented by R e, without limitation.
  • the primary or secondary amine compound (ii) may be primary or secondary! /, But is particularly preferably a primary amine compound.
  • suitable primary amine compounds include those represented by the general formula [IX]
  • R X1 represents a benzyl group or a substituted benzyl group, and other symbols have the same meaning as described above,
  • amino group-protecting substitution method of the present invention it is possible to maintain the same reaction system (one-pot), and it is extremely efficient and industrial that it is not necessary to isolate a product in the middle and to cause a side reaction.
  • substitution of an amino-protecting group substitution from a benzyloxycarbonyl group or the like to a benzyl group or a substituted benzyl group
  • Reference Examples 3 (2) to (3), Reference Examples 4 (2) to (3), and Reference Example 5 below describe in detail the amino group protecting substitution method of the present invention as an example thereof. However, these do not limit the invention of this application! /.
  • the alkyl group, lower alkoxy group, and lower alkylamino group include straight-chain or branched-chain groups having carbon atoms of! -6, and particularly those having 1 to 4 carbon atoms.
  • examples of the lower alkanoyl group and the lower alkanoylamino group include linear or branched groups having 2 to 7 carbon atoms, particularly 2 to 5 carbon atoms.
  • Examples of the lower cycloalkyl group and the lower cycloalkenyl group include those having 3 to 8 carbon atoms, especially 3 to 6 carbon atoms.
  • Examples of the lower alkylene group include straight-chain or branched-chain ones having carbon numbers of! To 6 and particularly 1 to 4 carbon atoms.
  • Examples of the lower alkenyl group and lower alkenokenylene group include those having 2 to 7 carbon atoms, especially 2 to 5 carbon atoms.
  • examples of the halogen atom include fluorine, chlorine, bromine and iodine.
  • MS′APCI (m / z) represents a mass analysis value (atmospheric pressure chemical ionization mass spectrum).
  • phj is a phenyl group
  • Boc represents a tert-butoxycarbonyl group.
  • Example 1 [0072] Hereinafter, the present invention will be described in more detail by way of examples. However, these examples limit the present invention. [0073] Example 1
  • aqueous layer is washed with ethyl acetate (1.6 U.
  • the aqueous layer is made alkaline by adding 40% potassium carbonate aqueous solution (0.689 U), and ethyl acetate (1.6 U and isopropyl alcohol (0. Extract with 16 U.
  • the aqueous layer is extracted with ethyl acetate (0.32 U.
  • the organic layers are combined, dried over magnesium sulfate (159 g), filtered, and concentrated to give (2S) — 2— Forced ruber moyl 1- [N benzylenotrans-4 (morpholinocarbonino) cyclohexylamino] acetyl pyrrolidine is obtained.
  • (2S) 2-cyanone 1- [trans 4- (4-acetylbiperazine 1-ylcarbonyl] Nore) cyclohexylamino] acetyl pyrrolidine hydrochloride is obtained.
  • the reaction mixture is ice-cooled, the precipitated crystals are filtered off, and the crystals are washed with isopropyl acetate. After separation, wash the organic layer with 26% saturated saline, add 26% saturated saline and a small amount of 40% aqueous potassium carbonate to pH 9 After washing, adjusting to 10 and separating the liquid twice, add anhydrous magnesium sulfate and silica gel to the organic layer, stir, and filter off insoluble matter.
  • trans-4- (4-acetylbiperazine-1-ylcarbonyl) cyclohexylamine is obtained as a reaction product.
  • Benzaldehyde (1.45 g) is added to the reaction solution (2) containing 10% palladium carbon catalyst (50% Wet product) under a nitrogen atmosphere and stirred at room temperature for 1 hour. Degassed under reduced pressure and introduced with hydrogen three times to replace the hydrogen. Stir at room temperature and normal pressure for 1 hour and 20 minutes. The catalyst is removed by filtration and concentrated. The residue is crystallized from a heptane / tert butyl methyl ether (3: 1) mixture and then separated by filtration to give trans-4-benzylamino-1-N, N-dimethylcyclohexanecarboxamide. Melting point: 69 ° C
  • the target compound that is, (2S) -2-cyanol 1 [trans 4 (morpholinocarbonyl) cyclohexylamino] acetylpyrrolidine could not be obtained.
  • N-Benzinoretrans 4 4 Acetenorebiperazine 1 Inorecanole poninole
  • potassium carbonate anhydrous fine powder (962 mg) and sodium iodide (44 mg) were added, and the mixture was reacted at 60 ° C for 3.5 hours.
  • the mixture was cooled to room temperature, and insoluble materials were removed by filtration.
  • the filtrate was concentrated, partitioned between ethyl acetate (20 mL) and water (15 mU and 10% aqueous quenate (10 mL), and separated.
  • the present invention is an industrially advantageous method for producing an N- ( ⁇ '-substituted dalysyl) -2-cyanopyrrolidine derivative.

Abstract

L'invention concerne un procédé permettant de produire un dérivé de N-(N'-glycyle substitué)-2-cyanopyrrolidine de haute qualité ayant un degré d'efficacité élevé. La présente invention concerne spécifiquement un procédé permettant de produire un dérivé de N-(N'-glycyle substitué)-2-cyanopyrrolidine, représenté par la formule générale [I] [où A représente -CH2- ou -S- ; et R représente un groupe cycloalkyle inférieur qui peut être substitué, un groupe adamantyle qui peut être substitué, ou analogue] ou un sel de celui-ci, qui comprend les étapes consistant à faire réagir un composé représenté par la formule générale [II] [où Z représente un résidu réactif] avec un composé représenté par la formule générale [III] [où Rx représente un groupe benzyle ou analogue], ou un sel de celui-ci, pour produire un composé représenté par la formule générale [IV] ou un sel de celui-ci, enlever un groupe de protection amino Rx du composé résultant pour produire un composé représenté par la formule générale [V] ou un sel de celui-ci, et convertir le composé résultant en un composé représenté par la formule générale [I] ou son sel à travers une étape impliquant une réaction de déshydratation.
PCT/JP2007/072973 2006-11-29 2007-11-28 Procédé de production d'un dérivé de n-(n'-glycyle substitué)-2-cyanopyrrolidine WO2008066083A1 (fr)

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CN103787944A (zh) * 2012-11-01 2014-05-14 天津药物研究院 1-(2-氯乙酰基)-2-(s)-腈基吡咯烷的制备方法

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CN103787944A (zh) * 2012-11-01 2014-05-14 天津药物研究院 1-(2-氯乙酰基)-2-(s)-腈基吡咯烷的制备方法

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