Process for preparation of benzylpiperidine compounds

Abstract: wherein R1 is a hydrogen atom or an amino-protecting group, R2 is a hydrogen atom, a hydrocarbon group optionally having substituents, an alkoxy group optionally having substituents or a heterocyclic group optionally having substituents, and R3 is a lower alkyl group. According to the process as shown in the following scheme having a step for reacting Compound (I) with Compound (II) to produce Compound (III), benzylpiperidine compounds useful as synthesis starting materials of pharmaceutical agents, agricultural chemicals and the like can be produced conveniently by a short step: (end of abstract)

Agent: Takeda Pharmaceuticals North America, Inc Intellectual Property Department - Lincolnshire, IL, US
Inventors: Shokyo Miki, Mitsuhiro Takeda, Koji Nakamoto
USPTO Applicaton #: #20060094877 - Class: 546022000 (USPTO)
Related Patent Categories: Organic Compounds -- Part Of The Class 532-570 Series, Azo Compounds Containing Formaldehyde Reaction Product As The Coupling Component, Carbohydrates Or Derivatives, Hetero Ring Is Six-membered Consisting Of One Nitrogen And Five Carbons, Phosphorus Attached Indirectly To The Six-membered Hetero Ring By Nonionic Bonding

Process for preparation of benzylpiperidine compounds description/claims

The Patent Description & Claims data below is from USPTO Patent Application 20060094877, Process for preparation of benzylpiperidine compounds.

Brief Patent Description - Full Patent Description - Patent Application Claims

[0001] This application is a divisional of U.S. patent application Ser. No. 10/939,293, now U.S. Pat. No. ______ issued ______, which was a divisional of U.S. patent application Ser. No. 10/466,494, now U.S. Pat. No. 6,833,457 issued Dec. 21, 2004, which was the National Phase filing of International Patent Application No. PCT/JP02/00304 filed Jan. 18, 2002.

TECHNICAL FIELD

[0002] The present invention relates to a benzylpiperidine compound useful as a production intermediate for a cyclic amide compound and the like used as a therapeutic agent for acquired immunodeficiency syndrome and a production method thereof.

BACKGROUND ART

[0003] As synthetic methods of benzylpiperidine compounds, (i) a method via reduction of carbonyl group (Wolff-Kishner reduction, etc.) after Friedel-Crafts reaction and (ii) a method via olefin synthesis reaction such as Wittig reaction and Horner-Emmons reaction etc. as shown in the following are known. (i) The method of A. Wick et al. (U.S. Pat. No. 4,690,931, 1987) (ii) The paper of Z-L Zhou et al. (J. Org. Chem., 1999, vol. 64, p. 3763)

[0004] Of the benzylpiperidine compounds, particularly when a compound where a carbamoyl group substitutes on the benzene ring is to be synthesized, a method that goes through an olefin synthesis reactions such as Wittig reaction and the like is advantageous in that the position of substitution can be controlled easily. However, it is not known that benzylpiperidine compounds substituted by a carbamoyl group having an acidic hydrogen disadvantageous to the reaction can be produced through those reactions.

[0005] In addition, Takayanagi et al. (WO98/31661) obtained a benzylpiperidine compound substituted by methoxycarbonyl group, and thereafter converted the methoxycarbonyl group to a substituted carbamoyl group.

[0006] When this example described in WO98/31661 and an azidation reaction are combined, a carbamoyl-substituted benzylpiperidine compound can be synthesized as shown by the following formulas. wherein HOBt is hydroxy-1H-benzotriazole and WSC is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0007] However, the production method is complicated, and the development of an industrially advantageous short-step production method is necessary.

[0008] In view of the above, it is an object of the present invention to provide an industrially advantageous short-step production method of a benzylpiperidine compound wherein a carbamoyl group substitutes on the benzene ring, and to provide a novel synthetic intermediate for this production method.

DISCLOSURE OF THE INVENTION

[0009] In view of the above-mentioned aspects, the present inventors have conducted intensive studies and, as a result, found that the Horner-Emmons reaction between Compound (I) to be described below, which is substituted by a carbamoyl group having an acidic hydrogen disadvantageous to the reaction, and piperidone Compound (II) to be described below unexpectedly proceeds in a good yield, and the handling property during isolation and purification of product can be markedly improved, and succeeded in synthesizing benzylpiperidine Compound (VIII) to be described below from readily available 4-(chloromethyl)benzoyl chloride by short steps via Compound (I), which resulted in the completion of the present invention.

[0010] The present inventors have found a novel production method of Compound (IX) to be described below, which is used for leading the benzylpiperidine Compound (VIII) obtained by the above-mentioned reaction into Compound (X) to be described below, which is useful as a pharmaceutical agent, which resulted in the completion of the present invention.

[0011] Accordingly, the present invention relates to the following (1) to (16). (1) A process for the preparation of a compound represented by the formula: wherein [0012] R.sup.1 is a hydrogen atom or an amino-protecting group and [0013] R.sup.2 is a hydrogen atom, a hydrocarbon group optionally having substituents, an alkoxy group optionally having substituents or a heterocyclic group optionally having substituents, or a salt thereof, which comprises reacting a compound represented by the formula: wherein R.sup.3 is a lower alkyl group and R.sup.2 is as defined above, or a salt thereof, with a compound represented by the formula: wherein R.sup.1 is as defined above, or a salt thereof. (2) A process for the preparation of a compound represented by the formula: wherein [0014] R.sup.2 is a hydrogen atom, a hydrocarbon group optionally having substituents, an alkoxy group optionally having substituents or a heterocyclic group optionally having substituents, and [0015] R.sup.3 is a lower alkyl group, or a salt thereof, which comprises reacting a compound represented by the formula: wherein X.sup.1 is a halogen atom and R.sup.2 is as defined above, or a salt thereof, with a trialkyl phosphite represented by the formula: wherein R.sup.3 is as defined above. (3) A process for the preparation of a compound represented by the formula: wherein [0016] R.sup.1 is a hydrogen atom or an amino-protecting group and [0017] R.sup.2 is a hydrogen atom, a hydrocarbon group optionally having substituents, an alkoxy group optionally having substituents or a heterocyclic group optionally having substituents, or a salt thereof, which comprises reacting a compound represented by the formula: wherein X.sup.1 is a halogen atom and R.sup.2 is as defined above, or a salt thereof, with a trialkyl phosphite represented by the formula: wherein R.sup.3 is a lower alkyl group, and thereafter reacting with a compound represented by the formula: wherein R.sup.1 is as defined above, or a salt thereof. (4) The process of the above-mentioned (3), wherein the compound represented by the formula (IV) or a salt thereof is reacted with the trialkyl phosphite represented by the formula (V) to give a compound represented by the formula: wherein [0018] R.sup.2 is a hydrogen atom, a hydrocarbon group optionally having substituents, an alkoxy group optionally having substituents or a heterocyclic group optionally having substituents, and [0019] R.sup.3 is a lower alkyl group, or a salt thereof. (5) A process for the preparation of a compound represented by the formula: wherein [0020] R.sup.2 is a hydrogen atom, a hydrocarbon group optionally having substituents, an alkoxy group optionally having substituents or a heterocyclic group optionally having substituents, or a salt thereof, which comprises: reacting a compound represented by the formula: wherein X.sup.1 is a halogen atom and X.sup.2 is a leaving group, with a compound represented by the formula: R.sup.2NH.sub.2 (VII) wherein R.sup.2 is as defined above, or a salt thereof, to give a compound represented by the formula: wherein R.sup.2 and X.sup.1 are as defined above, or a salt thereof; reacting the compound represented by the formula (IV) or a salt thereof with a trialkyl phosphite represented by the formula: wherein R.sup.3 is a lower alkyl group; thereafter reacting with a compound represented by the formula: wherein R.sup.1 is a hydrogen atom or an amino-protecting group, or a salt thereof, to give a compound represented by the formula: wherein R.sup.1 and R.sup.2 are as defined above, or a salt thereof; and reducing and thereafter where necessary deprotecting the compound represented by the formula(III) or a salt thereof. (6) The process of the above-mentioned (5) which comprises: reacting a compound represented by the formula: wherein X.sup.1 and X.sup.2 are each a halogen atom, with a compound represented by the formula: wherein R.sup.2 is a hydrogen atom, a hydrocarbon group optionally having substituents, an alkoxy group optionally having substituents or a heterocyclic group optionally having substituents, or a salt thereof, to give a compound represented by the formula: wherein R.sup.2 and X.sup.1 are as defined above, or a salt thereof; reacting the compound represented by the formula (IV) or a salt thereof with a trialkyl phosphite represented by the formula: wherein R.sup.3 is a lower alkyl group, to give a compound represented by the formula: wherein R.sup.2 and R.sup.3 are as defined above, or a salt thereof; reacting the compound represented by the formula (I) or a salt thereof with a compound represented by the formula: wherein R.sup.1 is a hydrogen atom or an amino-protecting group, or a salt thereof, to give a compound represented by the formula: wherein R.sup.1 and R.sup.2 are as defined above, or a salt thereof; and reducing and thereafter where necessary deprotecting the compound represented by formula (III) or a salt thereof (7) A process for the preparation of a compound represented by the formula: wherein [0021] G.sup.1 is a bond, CO or SO.sub.2, [0022] R.sup.2 is a hydrogen atom, a hydrocarbon group optionally having substituents, an alkoxy group optionally having substituents or a heterocyclic group optionally having substituents, [0023] R.sup.4 is a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an alkoxy group optionally having substituents, an aryloxy group optionally having substituents or an amino group optionally having substituents, and [0024] R.sup.5 is a cyclic hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents, which comprises: reacting a compound represented by the formula: wherein X.sup.1 is a halogen atom and X.sup.2 is a leaving group, with a compound represented by the formula: wherein R.sup.2 is as defined above, or a salt thereof, to give a compound represented by the formula: wherein R.sup.2 and X.sup.1 are as defined above, or a salt thereof; reacting the compound represented by the formula (IV) or a salt thereof with a trialkyl phosphite represented by the formula: wherein R.sup.3 is a lower alkyl group; thereafter reacting with a compound represented by the formula: wherein R.sup.1 is a hydrogen atom or an amino-protecting group, or a salt thereof, to give a compound represented by the formula: wherein R.sup.1 and R.sup.2 are as defined above, or a salt thereof; reducing and thereafter where necessary deprotecting the compound represented by the formula (III) or a salt thereof to give a compound represented by the formula: wherein R.sup.2 is as defined above, or a salt thereof; and reacting the compound represented by the formula (VIII') or a salt thereof with a compound represented by the formula: wherein X.sup.3 is a leaving group and G.sup.1, R.sup.4 and R.sup.5 are as defined above, or a salt thereof. (8) The process of any of the above-mentioned (2) to (7), wherein the compound represented by the formula (IV) or a salt thereof is reacted with the compound represented by the formula (V) in the presence of alkali metal iodide. (9) The process of the above-mentioned (8), wherein the alkali metal iodide is potassium iodide. (10) The process of the above-mentioned (1), (3), (4), (5), (6) or (7), wherein the compound represented by the formula (II) or a salt thereof is reacted in the presence of a base. (11) The process of the above-mentioned (10), wherein the base is t-butoxide of an alkali metal. (12) The process of the above-mentioned (11), wherein the base is potassium t-butoxide. (13) A process for the preparation of a compound represented by the formula: wherein [0025] G.sup.1 is a bond, CO or SO.sub.2, [0026] X.sup.3 is a leaving group, [0027] R.sup.4 is a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an alkoxy group optionally having substituents, an aryloxy group optionally having substituents or an amino group optionally having substituents, and [0028] R.sup.5 is a cyclic hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents, or a salt thereof, which comprises reacting a compound represented by the formula: wherein X.sup.3 and R.sup.5 are as defined above, or a salt thereof, with a compound represented by the formula: wherein G.sup.1 and R.sup.4 are as defined above, or a salt thereof. (14) A process for the preparation of a compound represented by the formula: wherein [0029] G.sup.1 is a bond, CO or SO.sub.2, [0030] R.sup.2 is a hydrogen atom, a hydrocarbon group optionally having substituents, an alkoxy group optionally having substituents or a heterocyclic group optionally having substituents, [0031] R.sup.4 is a hydrogen atom, a hydrocarbon group optionally having substituents, a heterocyclic group optionally having substituents, an alkoxy group optionally having substituents, an aryloxy group optionally having substituents or an amino group optionally having substituents, and [0032] R.sup.5 is a cyclic hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents, or a salt thereof, which comprises reacting a compound represented by the formula: wherein X.sup.3 is a leaving group and R.sup.5 is as defined above, or a salt thereof, with a compound represented by the formula: wherein G.sup.1 and R.sup.4 are as defined above, or a salt thereof, to give a compound represented by the formula: wherein G.sup.1, X.sup.3, R.sup.4 and R.sup.5 are as defined above, or a salt thereof, and reacting the compound represented by the formula (IX) or a salt thereof with a compound represented by the formula: wherein R.sup.2 is as defined above, or a salt thereof. (15) The process of the above-mentioned (14), wherein R.sup.2 is a hydrogen atom, R.sup.4 is a methyl group, R.sup.5 is a phenyl group having 1 or 2 substituents selected from the group consisting of a halogen atom and a methyl group, G.sup.1 is a carbonyl, and X.sup.3 is a chlorine atom. (16) A compound represented by the formula:

[0033] As the `halogen atom` denoted by the above-mentioned X.sup.1 and X.sup.2', for example, chlorine atom, bromine atom, iodine atom and the like can be mentioned.

[0034] As the `leaving group` denoted by X.sup.2, for example, a halogen atom (e.g., chlorine atom, bromine atom, iodine atom, etc.), an alkyl or arylsulfonyloxy group (e.g., methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.) and the like can be mentioned.

[0035] As the `amino-protecting group` denoted by R.sup.1, any protecting group can be used as long as it does not inhibit the reaction, and carbamate protecting groups (e.g., benzyloxycarbonyl group, t-butoxycarbonyl group, etc.), amide protecting groups (e.g., formyl group, etc.), aminoacetal protecting groups (e.g., benzyloxymethyl group, etc.), benzyl protecting groups (e.g., benzyl group, etc.) and the like are preferably used. Of these, benzyl group, benzyloxycarbonyl group and t-butoxycarbonyl group are particularly preferable.

[0036] As the `hydrocarbon group` of the `hydrocarbon group optionally having substituents` denoted by R.sup.2, lower alkyl groups (e.g., C.sub.1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl etc. and the like), cycloalkyl groups (e.g., C.sub.3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc. and the like), aryl groups (e.g., C.sub.6-10 aryl group such as phenyl, 1-naphthyl, 2-naphthyl etc. and the like), aralkyl groups (e.g., C.sub.7-10 aralkyl group such as benzyl, phenethyl and the like, preferably phenyl-C.sub.1-4 alkyl group, etc.), and the like can be mentioned.

[0037] As the `alkoxy group` of the `alkoxy group optionally having substituents` denoted by R.sup.2, for example, C.sub.1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy and the like, and the like can be mentioned.

[0038] As the `heterocyclic group` of the `heterocyclic group optionally having substituents` denoted by R.sup.2, aromatic heterocyclic groups and saturated or unsaturated non-aromatic heterocyclic groups, containing, as an atom constituting the ring system (ring atom), at least one of 1 to 3 kinds of hetero atoms, which is selected from oxygen atom, sulfur atom, nitrogen atom and the like, can be mentioned. As the aromatic heterocyclic group, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzisothiazolyl, benzodioxolyl, benzimidazolyl, 2,1,1-benzoxadiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, .alpha.-carbolinyl, .beta.-carbolinyl, .gamma.-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenathridinyl, phenathrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, pyrazolo[3,4-b]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl and the like can be mentioned, and as the saturated or unsaturated non-aromatic heterocyclic groups, for example, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and piperazinyl and the like can be mentioned.

[0039] As the `substituent` of the `hydrocarbon group optionally having substituents`, `alkoxy group optionally having substituents` and `heterocyclic group optionally having substituents`, for example, (1) hydroxyl group, (2) amino group, (3) mono- or di-substituted amino group [e.g., mono- or di-substituted amino group substituted by 1 or 2 substituents selected from C.sub.1-6 alkyl group (methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl), C.sub.1-6 alkanoyl (e.g., acetyl, propionyl, butyryl, etc.), C.sub.7-13 arylcarbonyl (e.g., benzoyl, naphthoyl, etc.) and C.sub.1-6 alkylsulfonyl (methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, etc.)], (4) halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), (5) nitro group, (6) cyano group, (7) C.sub.1-6 alkyl group (methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl, etc.) optionally substituted by halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.) or (8) C.sub.1-6 alkoxy group (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, n-pentyloxy, n-hexyloxy, etc.) optionally substituted by halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), and the like can be mentioned.

[0040] As the R.sup.2, C.sub.1-2 alkyl such as methyl, ethyl and the like and a hydrogen atom are preferable.

[0041] As the lower alkyl group denoted by R.sup.3, for example, those having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl and the like, can be mentioned, with preference given to methyl and ethyl.

[0042] The production methods of the present invention are explained in the following.

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