WO1995027694A1 - PROCEDE D'OBTENTION D'UN DERIVE D'ALCOOL DISUBSTITUE EN α ET $g(b) - Google Patents

PROCEDE D'OBTENTION D'UN DERIVE D'ALCOOL DISUBSTITUE EN α ET $g(b) Download PDF

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Publication number
WO1995027694A1
WO1995027694A1 PCT/JP1995/000656 JP9500656W WO9527694A1 WO 1995027694 A1 WO1995027694 A1 WO 1995027694A1 JP 9500656 W JP9500656 W JP 9500656W WO 9527694 A1 WO9527694 A1 WO 9527694A1
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WO
WIPO (PCT)
Prior art keywords
group
reaction
cyclo
hydrogen
lower alkyl
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PCT/JP1995/000656
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English (en)
Japanese (ja)
Inventor
Masayoshi Murata
Hideo Tsutsumi
Hiroaki Ohtake
Satoshi Yonishi
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Fujisawa Pharmaceutical Co., Ltd.
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Filing date
Publication date
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Publication of WO1995027694A1 publication Critical patent/WO1995027694A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being unsaturated and containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a stereoselective method for producing an ⁇ , page-substituted alcohol derivative having an asymmetric carbon at the a and / 9 positions.
  • the present invention is a synthetic intermediate for producing an amino acid derivative having a renin inhibitory activity by using the method for producing an ⁇ , -disubstituted alcohol derivative.
  • the present invention relates to a method for producing an amino alcohol derivative.
  • a racemate or a diastereomer mixture can be produced from a mixture thereof, such as a macrograph, a fractionated crystal, or the like.
  • a method for producing by optical resolution there is a problem that the yield is low. Therefore, an asymmetric synthesis method for directly producing the desired optically active substance is required.
  • Various studies are underway.
  • the object of the present invention is a method for asymmetrically synthesizing an optical isomer of an ⁇ , / 9-disubstituted alcohol derivative having an asymmetric carbon at a position.
  • asymmetric reduction of 2-methyl acetic acid ethyl ester (Tetrahedron Asymmetry), Vol. 1, Nos. 1 to 4 P. (1990)) and 2—Benzyme methyl acetylacetate Asymmetric reduction of methyl acetate [Jan. Nanoorganic Organic Chemistry]
  • the selectivity of the Sin-Z Zant is low, and in the latter method, the selectivity of the Sin-Z Zant is good.
  • the method of obtaining preferentially the anti body has been known, and the method of obtaining the anti body preferentially has been known so far.
  • R 1 is hydrogen or an organic group
  • R 2 is a substituted or unsubstituted phenol group
  • R 3 is an organic group
  • a and Q each independently represent a lower alkylene group or a single bond.
  • Antibody and “Sin body” are, for example, planar structural formulas
  • Antibody is a formula
  • Preferred “organic groups” include: a hydrocarbon residue; a heterocyclic group A carboxyl group; an acyl group; a carboxyl group or an acyl group substituted with a hydrocarbon residue or a heterocyclic group, respectively; or a hydrocarbon residue in the above-mentioned groups.
  • a hydrogen atom in a heterocyclic group is substituted with another group such as a halogen, a nitro, a hydroxyl, a canebox, an amino, an acyl, or a protected amino.
  • hydrocarbon residues are saturated or unsaturated, linear or branched hydrocarbon residues; saturated or unsaturated, cyclic hydrocarbon residues; saturated.
  • heterocyclic groups are saturated or unsaturated containing at least one oxygen atom, sulfur atom and at least one heteroatom such as Z or nitrogen atom.
  • Monocyclic or polycyclic heterocyclic groups for example,
  • a 7- to 12-membered unsaturated fused heterocyclic group containing 1 to 5 nitrogen atoms such as indolinole, isoindolinole, indolininole, benzene Imidazoline, quinolinore, isoquinolinore, tetrahydroquinole, indazolinole, benzotriazole, imizozo Pyrinole, etc .;
  • a 3- to 8-membered, preferably 5- or 6-membered, unsaturated heteromonocyclic group containing one to two sulfur atoms and one to three nitrogen atoms e.g. Zolinole, isothiazolinole, thiazolinole, thiaziazolinole, etc .;
  • Suitable substituents in "substituted or substituted radicals” include, for example, methyl, ethyl, propyl, isopropyl, and the like. Examples thereof include lower alkyl groups such as butyl and the like, and lower alkyl groups such as benzyl and phenyl.
  • lower alkyl groups include methyl, ethylenol, propyl, isopropyl, butyryl, isobutynol, Such as tertiary butino, etinopropinore, etinobutino, penchinore, isopenchinore, hexinole, methinole hexinole, heptile, etc.
  • Straight-chain or branched-chain alkyl groups are straight-chain or branched-chain alkyl groups.
  • Suitable "lower alkenyl groups" include those having 2 to 2 carbon atoms.
  • Groups having 7 groups for example, linear chains such as bur, aryl, methyl probenole, buteninole, penteninole, hexeninole, methylenolbutenil, etc. Or a branched-chain alkenyl group.
  • Suitable "cyclo lower alkyl groups” include groups having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutinole, cyclopentinole, cyclone Hexinole and cycloheptyl.
  • Suitable "cyclo lower alkenyl groups” include groups having 3 to 7 carbon atoms, such as cyclopentenyl, cyclohexenyl, cycloheptenyl And the like.
  • Preferred aryl moieties in the preferred aryl groups and lower alkoxy groups include phenyl, naphthyl, and lower alkyl-substituted phenyl groups.
  • phenyl eg, tolyl, xylinole, mesityl, kumeninole, di (tertiary-butyl) phenyl
  • phenyl eg, tolyl, xylinole, mesityl, kumeninole, di (tertiary-butyl) phenyl
  • lower alkoxy group Preferable "lower alkoxy group”, “lower alkoxy group” and “lower alkoxy group” in “lower alkoxy group” Is the name of the methoxy, jet, pro box, isopro box, butoxy, iso box Examples thereof include a straight-chain or branched-chain alkyloxy group such as xyl, tertiary butoxy, pentinoreoxy, and hexyloxy.
  • Suitable “protected carboxyl groups” include, but are not limited to, esterified carboxyl groups and thioesterified carboxyl groups. Examples of the ester portion include the lower alkyl groups described above.
  • Suitable "halogens" include fluorine, chlorine, bromine and iodine.
  • Suitable salts of compounds (II) and (IIIa) include, for example, formate, acetate, trifluoroacetate, maleate, tartrate, methansul Organic acid addition salts such as borate, benzenesulfonate and toluenesulfonate, for example, inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate and phosphate And so on.
  • Compound (I) or (I ') can be produced by subjecting compound (II) to an asymmetric reduction reaction in the presence of a transition metal complex catalyst.
  • Suitable transition metal complexes used as a catalyst in this reaction include rhodium-optically active phosphine complex and ruthenium-optically active phosphine complex. And a more preferred example of the complex is
  • This reaction is carried out in the presence of various acids such as, for example, p-tonorenoresphonic acid, methansnorephonic acid, d-camphorsnorephonic acid. I like it.
  • This reaction involves the reaction of methylene chloride, ethylene chloride, benzene, tocrene, geninoleate, terehydrohydran, and dioxane.
  • any solvent that does not adversely affect the reaction such as ethyl acetate, etc., or in a mixed solvent of these solvents and an alcohol such as methanol, for example.
  • Hydrogen pressure 1 It is performed under heating or heating at up to 100 atm.
  • an unsaturated group such as a lower alkenyl group or a cyclo-lower alkenyl group is substituted for R 1 and / or R 3 in the compound ( ⁇ ).
  • the unsaturated bond may be added to hydrogen, but in such a case, the production method may be used. Is included in the range.
  • amino alcohol derivatives (III) include, for example,
  • a) is useful as a synthetic intermediate of an amino acid derivative having renin inhibitory activity, which is useful for treating hypertension such as essential hypertension, renal hypertension, and malignant hypertension, and heart failure.
  • Some things are known (eg, JP-A-61-33153, JP-A-63-253097, JP-A-64-19071, JP-A-4-279570, etc.).
  • an optically active substance is used as a raw material to be used, or the amino alcohol derivative (IIIa) is used.
  • the process for producing the amino alcohol derivatives (III) and (IIIa) of the present invention can be represented by the following reaction formula. Manufacturing method 2
  • R is a benzoyl group
  • R is a cyclohexyl group, a phenyl group or a cyclohexenyl group
  • R 4 is a protected group.
  • the mosquito Norre port key shea based or meant mosquitoes Noreba model Yi Le group, R 1, R i, R 3, A, A 1, Q your good beauty Q 1 is the same as the before their meanings
  • Compound (Ia) can be produced by subjecting compound (IIa) to an asymmetric reduction reaction in the presence of a transition metal complex catalyst.
  • Suitable transition metal complexes used as catalysts in this reaction include the S-coordination complexes exemplified in Production Method 1.
  • This asymmetric reduction reaction can be carried out in the same manner as in the method described in Production Method 1, and the description can be referred to for the reaction conditions and the like. .
  • Compound (II) or a salt thereof can be produced by subjecting compound (Ia) to an amino group-introducing reaction.
  • This reaction for introducing an amino group is a reaction for converting the hydroxyl group at R [of compound (Ia) into an amino group.
  • Curtius transfer reaction, H 0 ⁇ mann transfer reaction and similar reactions, and the reaction conditions are those reactions. You can refer to the customary conditions selected in.
  • an aminoalcohol derivative can be obtained via the oxazolidinone derivative (IV).
  • This oxazo Intermediates such as the lysinone derivative (IV), generated during the introduction reaction of the amino group can be isolated and included in the scope of this step. It is done.
  • Compound (Ib) can be produced by subjecting compound (lib) to an asymmetric reduction reaction in the presence of a transition metal complex catalyst.
  • Suitable transition metal complexes used as catalysts in this reaction include the S-coordination complexes exemplified in Production Method 1.
  • This asymmetric reduction reaction can be carried out in the same manner as in the method described in Production Method 1, and for the reaction conditions and the like, the description can be referred to.
  • the compound (Ilia) or a salt thereof is prepared by subjecting the compound (lb) to an amino group-introducing reaction, followed by a phenyl group or a phenyl group when R is a phenyl group or a hexenyl group.
  • the compound can be produced by subjecting a hexenyl group to a hydrogenation reaction.
  • This amino group introduction reaction can be carried out in the same manner as in the method described in Production Method 2 (Step 2), and the description can be referred to.
  • This hydrogenation reaction can be carried out, for example, by catalytic reduction.
  • Suitable catalysts to be used are, for example, platinum plates, platinum catalysts such as platinum oxide, and Palladium catalysts such as um black, palladium carbon, etc., for example, rhodium black, lipodium catalysts such as lipodium carbon, eg, ruthenium black, ruthenium Commonly used ones, such as ruthenium catalysts such as carbon, may be mentioned.
  • This hydrogenation reaction is usually carried out with water, methanol, ethanol, N, N—dimethylaminophenol, dimethyl alcohol, dioxane, and tetraxane.
  • the reaction is carried out in a conventional solvent that does not adversely affect the reaction of transhydran, acetic acid, etc., at room temperature, under heating, at normal pressure, or under pressurized hydrogen.
  • This hydrogenation reaction is a compound that is a starting material before the amino group introduction reaction, a compound that is a product after the amino group introduction reaction, or a compound or amino group Any of the intermediate compounds isolated during the introduction reaction of the compound may be attached, and all of them are included in the scope of this step.
  • the compound obtained in each of the above-mentioned production methods and each of the steps can be purified by a conventional method such as chromatography, recrystallization and the like.
  • the method of production method 1 of the present invention is superior to the conventional reduction method in the selectivity of the anti-compound compound (I) or (I ′), for example, in the case of amino alcohol. This is an advantageous production method for industrially producing the derivative (III).
  • the amino alcohol derivatives (III) and (IIIa) are produced at a lower yield and higher yield than the conventional method. This is an industrially advantageous production method because it can be used.
  • N-honoleminole 2-cyclohexinolemethyl-1-6-methinolay 3-oxooxoheptanoic acid amide (90 mg) in methanol-butane (1 ml). Then, a 28% sodium methoxide solution in methanol (1 drop) was added, and the mixture was stirred at room temperature for 1 hour. 1 N hydrochloric acid (0.1 ml) was added, and methanol was distilled off under reduced pressure. The obtained crude product was dissolved in ethyl acetate, washed with water, a saturated aqueous solution of sodium hydrogencarbonate, and then with a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure.
  • the obtained oil was heated to 120 ° C. under a reduced pressure of 0.5 mmHg to obtain a crude product (29.21 g).
  • This crude product was distilled under a reduced pressure of 0.3 mmHg to obtain methyl 2- (benzylidene-6-methyl-13-oxoheptanoate (20.28 g).
  • optical isomer ratio was measured by high performance liquid chromatography and NMR.
  • the isomer ratio was determined by high-performance liquid chromatography after N-benzoylation.
  • the isomer ratio was determined by high-performance liquid chromatography using a fluorescence method.
  • Example 2 In the same manner as in (2), (R) — 2 — methoxyl 2 -triphenyl olefin After that, the isomer ratio was examined by high performance liquid chromatography.
  • Example 7 The following compounds were obtained in the same manner as in (4).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Procédé d'obtention d'un dérivé d'alcool disubstitué en α et β selon le système de réaction décrit ci-après, qui se revèle plus favorable que le procédé de réduction classique dans la sélectivité des formes anti, et se révèle ainsi plus avantageux sur le plan industriel. Dans la formule (1), R1 représente l'hydrogène ou un groupe organique; R2 représente un carbamoyle facultativement substitué; R3 représente un groupe organique; et A et Q représentent l'un et l'autre un alkylène inférieur ou une liaison simple.
PCT/JP1995/000656 1994-04-07 1995-04-05 PROCEDE D'OBTENTION D'UN DERIVE D'ALCOOL DISUBSTITUE EN α ET $g(b) WO1995027694A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP6/69159 1994-04-07
JP6915994 1994-04-07
JP7/41753 1995-03-01
JP4175395 1995-03-01

Publications (1)

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WO1995027694A1 true WO1995027694A1 (fr) 1995-10-19

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002020359A (ja) * 2000-07-10 2002-01-23 Nippon Soda Co Ltd アンチ立体配置を有する光学活性β−アミノアルコール類の製造方法
EP2787984A1 (fr) * 2011-12-06 2014-10-15 Ludwig-Maximilians-Universität München Composés à base de bêta-o/s/n acides gras en tant qu'agents antibactériens et anti-protozoaires

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5439059A (en) * 1977-08-26 1979-03-24 Nitto Riken Kogyo Kk Production and use of novel phosphine compound
JPS63310847A (ja) * 1987-06-11 1988-12-19 Takasago Corp 光学活性アルコ−ルの製法
JPH01211551A (ja) * 1988-02-19 1989-08-24 Takasago Internatl Corp 光学活性アルコールおよびその誘導体の製造方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5439059A (en) * 1977-08-26 1979-03-24 Nitto Riken Kogyo Kk Production and use of novel phosphine compound
JPS63310847A (ja) * 1987-06-11 1988-12-19 Takasago Corp 光学活性アルコ−ルの製法
JPH01211551A (ja) * 1988-02-19 1989-08-24 Takasago Internatl Corp 光学活性アルコールおよびその誘導体の製造方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
TETRAHEDRON LETTERS, Vol. 32, No. 43, (1991), HIDEAKI FUJII et al., "A Practical and Stereoselective Reduction of 3-Keto-2-Methyl Esters or 3-Keto-2-Methyl Amides into Erythro-3-Hydroxy-2-Methyl Esters or Erythro-3-Hydroxy-2-Methyl Amides with NaBH4 Catalyzed by MnCalpha2", p. 6147-6150. *
TETRAHEDRON, Vol. 49, No. 48, (1993), MASAHIKO TANIGUCHI et al., "Stereoselective Reduction of 2-Methyl-3-oxo Esters (or Amides) with Sodium Borohydride Catalyzed by Manganese (II) Chloride or Tetrabuthylammonium Borohydride. A Practical Preparation of Enythro and Threo-3-Hydroxy-2-Methyl Esters (or Amides)", p. 11169-11182. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002020359A (ja) * 2000-07-10 2002-01-23 Nippon Soda Co Ltd アンチ立体配置を有する光学活性β−アミノアルコール類の製造方法
JP4658293B2 (ja) * 2000-07-10 2011-03-23 日本曹達株式会社 アンチ立体配置を有する光学活性β−アミノアルコール類の製造方法
EP2787984A1 (fr) * 2011-12-06 2014-10-15 Ludwig-Maximilians-Universität München Composés à base de bêta-o/s/n acides gras en tant qu'agents antibactériens et anti-protozoaires

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