WO2000010994A1 - Procede de preparation de 2-(aryloxymethyl)-2,5,7,8-tetramethylchroman-6-ols - Google Patents

Procede de preparation de 2-(aryloxymethyl)-2,5,7,8-tetramethylchroman-6-ols Download PDF

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Publication number
WO2000010994A1
WO2000010994A1 PCT/EP1999/005861 EP9905861W WO0010994A1 WO 2000010994 A1 WO2000010994 A1 WO 2000010994A1 EP 9905861 W EP9905861 W EP 9905861W WO 0010994 A1 WO0010994 A1 WO 0010994A1
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WIPO (PCT)
Prior art keywords
alkyl
process according
tetramethylchroman
general formula
mmol
Prior art date
Application number
PCT/EP1999/005861
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English (en)
Inventor
Jacques Gosteli
James Edward Leresche
Alfons Werlen
Original Assignee
Sankyo Company, Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Sankyo Company, Limited filed Critical Sankyo Company, Limited
Priority to AU55141/99A priority Critical patent/AU5514199A/en
Publication of WO2000010994A1 publication Critical patent/WO2000010994A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a process for the preparation of 2- (aryloxymethyl) -2, 5, 7, 8-tetra- r ⁇ ethylchroman-6-ols of the general formula
  • R 1 , R 2 , R 3 , R 4 and R 5 independently of one another are each hydrogen, C ⁇ _ 4 -alkyl, C ⁇ _ 4 -alkoxy, 1-di (Ci- 4 -alkoxy) -C ⁇ - 4 -alkyl, 1, 3-dioxolan-2-yl,
  • C ⁇ _-alkyl is here and below taken to mean methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
  • C ⁇ - 4 -alkoxy is taken to mean the groups composed of C ⁇ - 4 -alkyl and oxygen.
  • 1-Di (Ci- 4 -alkoxy) -Ci- 4 -alkyl means the acetals or ketals of C ⁇ _ 4 -acyl groups obtainable by acetylation with C ⁇ _ 4 -alkanols .
  • 1 , 3-dioxolan-2-yl and 2- (C ⁇ _ 3 -alkyl) -1, 3-dioxolan-2-yl, and 1, 3-dioxan-2- yl and 2- (C ⁇ _ 3 -alkyl) -1, 3-dioxan-2-yl mean the cyclic acetals or ketals of C 1-4 -acyl groups obtainable by acetylation with ethanediol or 1, 3-propanediol, or ketals of C ⁇ _ 4 -aycl groups.
  • C ⁇ - 4 -Acyl groups are, in particular, formyl, acetyl, propionyl, butyryl and isobutyryl .
  • Halogen here means fluorine, chlorine, bromine or iodine, in particular fluorine.
  • Aromatic isocyclic ring systems are taken to mean, for example, phenyl, naphthyl, anthracenyl or phenanthrenyl, and nonaromatic isocyclic ring systems are in particular taken to mean C 3 -8 _ cycloalkyl or bicyclic hydrocarbon radicals such as, for example, norbornyl .
  • Aromatic heterocyclic ring systems are, for example, taken to mean pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, thiophenyl, furyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl or indolyl, and nonaromatic heterocyclic ring systems are, for example, taken to mean pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuryl, thiazo- lidinyl or tetrahydropyranyl .
  • the 2- (aryloxymethyl) -2, 5, 7, 8-tetramethyl- chroman-6-ols which can be prepared according to the invention are pharmaceutical active ingredients or intermediates for the preparation of pharmaceutical active ingredients, for example hypolipidemics (J. Med. Chem, 1989, 32, 421) .
  • compounds of the formula I in particular those in which R 1 , R 2 , R 4 and R 5 are hydrogen and R 3 is amino, can be prepared in two or more stages from the corresponding 6-hydroxy-2, 5, 7, 8-tetramethyl- chroman-2-carboxylic acids or from 2, 5-dihydroxy-3, 4, 6- trimethylacetophenone (EP-A-0 139 421) . It is further known to prepare such compounds from the corresponding 2- (aryloxymethyl) -2,5,7, 8-tetramethylchroman-6-ol-4- ones (EP-A-0 556 830) .
  • the object of the present invention was to provide an alternative process for the preparation of 2- (aryloxymethyl) -2,5,7, 8-tetramethylchroman-6-ols which requires only readily available starting materials and which is suitable for implementation on an industrial scale.
  • R is a protective group which can be cleaved off hydrogenolytically, are reacted with a phenol of the general formula
  • R 1' , R 2 R J R* and R 5' are each as defined above for R 1 , R 2 , R R" and R 5 , or can be converted into one of these groups by hydrogenation or hydrogenolysis, in a first stage to give 2-methyl-l-phenoxy- 4-phenylbutan-2-ols of the general formula
  • R and R 1' to R 5' are as defined above, and the latter can be converted into the target compound in a second and third stage by catalytic hydrogenolysis and optional hydrogenation and subsequent acid-catalysed cyclization.
  • Groups R 1' to R 5' which can be converted by hydrogenation into one of the groups R 1 to R 5 are, for example, nitro (convertible into amino) and 1-hydroxy- Ci- 4 -alkyl or C ⁇ _ 4 -acyl (each convertible into C ⁇ _ 4 -alkyl) . Preference is given to using those phenethyloxiranes (II) in which R is optionally substituted benzyl. Suitable substituents here are, in particular, Ci- 4 -alkyl groups and/or C ⁇ - 4 -alkoxy groups.
  • the reaction of the phenethyloxirane (II) with the phenol (III) is preferably carried out with a strong base in a dipolar aprotic solvent.
  • Suitable strong bases are alkali metal hydrides, Grignard compounds, alkyllithium compounds, alkali metal hydroxides or optionally also alkali metal carbonates. Particular preference is given to sodium hydride.
  • dipolar aprotic solvents are N, N-dimethylacetamide, ⁇ -methylpyrrolidine and, in particular, N, N-dimethyl formamide .
  • the catalysts used for the hydrogenolysis/hydrogenation are preferably heterogeneous noble-metal catalysts.
  • the second and third stage of the process according to the invention are preferably carried out in a single process step. This can be achieved by carrying out the hydrogenolysis/hydrogenation in the presence of a strong acid.
  • suitable strong acids are hydrohalic acids such as hydrochloric acid or hydrobromic acid, sulfonic acids such as p-toluene- sulfonic acid or camphorsulfonic acid or activated carboxylic acids such as trifluoroacetic acid.
  • suitable strong acids are hydrohalic acids such as hydrochloric acid or hydrobromic acid, sulfonic acids such as p-toluene- sulfonic acid or camphorsulfonic acid or activated carboxylic acids such as trifluoroacetic acid.
  • the 2- (4-aminophenoxymethyl) -2,5,7, 8-tetra- methylchroman-6-ol prepared according to the invention is preferably, for the preparation of 5- ⁇ [4- (6-hydroxy- 2,5,7, 8-tetramethylchroman-2-ylmethyloxy) phenyl] - methyl ⁇ thiazolidine-2, 4-dione of the formula
  • R 6 is C ⁇ -6-alkyl, and this is converted into the target compound using thiourea.
  • R 6 is butyl and X is preferably bromine.
  • Trimethylhydroquinone (152.2 g, 1 mol), trimethyl orthoformate (150 ml, 1.37 mol) and methanol (600 ml) were mixed at room temperature and then cooled to 0-3°C. Cone, sulfuric acid (2.5 ml, 2 mmol) was then added and subsequently methyl vinyl ketone (145.3 g, 2.07 mol) was added dropwise over the course of 3 h. The resulting suspension was stirred at room temperature for 44 h. Diethyl ether (450 ml) and saturated aqueous sodium hydrogencarbonate solution (100 ml) were then added, and the two phases were separated. The organic phase was concentrated by evaporation and the solid residue was dried at 50°C/25 mbar. Yield: 246.7 g of crude product (about 100%) .
  • the aqueous phase was extracted with diethyl ether (2 x 200 ml) , and the combined organic phases were washed with water (3 x 200 ml) and dried over sodium sulfate. Following filtration, the solvent was distilled off on a rotary evaporator (30°C/250->25 mbar) . Yield: 57.75 g (about 100%, crude product).
  • 6-Benzyloxy-2-methoxy-2, 5, 7, 8-tetramethyl- chroman 50 g, 153 mmol was dissolved in acetone (300 ml) at room temperature, and hydrochloric acid (0.1 N, 155 ml, 16 mmol) was added thereto. The solvent was then distilled off up to a head temperature of 92 °C. The heating source was removed, and the solution was cooled to 70°C, and acetone (150 ml) was added. The mixture was then further concentrated by evaporation until the head temperature reached 97 °C. After the residue had been cooled to room temperature, diethyl ether (200 ml) was added, and the two phases were separated.
  • Trimethylsulfoxonium iodide (8.74 g, 38.51 mmol) was dissolved in dimethyl sulfoxide (80 ml). Then, 4- (2, 5-dibenzyloxy-3, 4, 6-trimethylphenyl) butan-2-one (10.0 g, 24.84 mmol) was added, and finally a solution of potassium tert-butoxide (4.45 g, 38.51 mmol) in dimethyl sulfoxide (60 ml) was added at room temperature over the course of 10 in. The reaction mixture was stirred at room temperature for 16 h. Water (160 ml) was then added (exothermic reaction) , and the mixture was extracted with dichloromethane (3 x 100 ml) . The combined organic phases were washed with water (2 x 60 ml) . The solvent was distilled off and the solid residue was dried. Yield: 11.27 g (about 100%).
  • Palladium/activated carbon (10% Pd, 43% water content, 0.35 g) was added to a solution of 4- (2, 5- dibenzyloxy-3, 4, 6-trimethylphenyl) -2-methyl-l- (4-meth- oxyphenoxy)butan-2-ol (0.3 g, 0.49 mmol) in methanol (8 ml), and the mixture was stirred at atmospheric pressure under nitrogen at room temperature for 19 h. The catalyst was then filtered off over Celite ® , and the solvent was distilled off on a rotary evaporator. The resulting intermediate (0.19 g) was dissolved in toluene (5 ml), and p-toluenesulfonic acid (21 mg, 0.11 mmol) was added.
  • Palladium/activated carbon (10% Pd, 43% water content, 0.14g) was added to a solution of 4- [2-hydroxy-2-methyl-4- (2, 5-dibenzyloxy-3, 4, 6-trimethylphenyl) butoxyjbenzaldehyde (0.3 g, 0.56 mmol) in ethyl acetate (6 ml), and the mixture was stirred at atmospheric pressure under hydrogen for 20 h at room temperature. During the reaction, more catalyst (0.21 g) and acetic acid (3 ml) were added. The catalyst was then filtered off over Celite ® , and the solvent was distilled off on a rotary evaporator.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention porte des 2-(aryloxyméthyl)-2,5,7,8-tétraméthylchroman-6-ols de formule (I) dans laquelle: R?1, R2, R3, R4 et R5¿ sont chacun indépendamment les uns des autres H, C¿1-4?-alkyle, C1-4-alkoxy, 1-di(C1-4-alkoxy)-C1-4-alkyle, 1,3-dioxolan-2-yle, 1,3-dioxan-2-yle, 2-(C1-3-alkyle)-1,3-dioxolan-2-yle, 2-(C1-3-alkyle)-1,3-dioxan-2-yle, halogène ou amino, ou sont un groupe C1-4-alkyle substitué par un système isocyclique or hétérocyclique aromatique or non aromatique, et qui sont préparés à partir de 2-méthyl-2-phénéthyloxiranes et les phénols substitués correspondants en trois étapes. Les composés du titre sont des substances pharmaceutiques actives ou leurs intermédiaires de préparation.
PCT/EP1999/005861 1998-08-19 1999-08-12 Procede de preparation de 2-(aryloxymethyl)-2,5,7,8-tetramethylchroman-6-ols WO2000010994A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU55141/99A AU5514199A (en) 1998-08-19 1999-08-12 Process for the preparation of 2-(aryloxymethyl)-2,5,7,8-tetramethylchroman-6-ols

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP98115555 1998-08-19
EP98115555.9 1998-08-19

Publications (1)

Publication Number Publication Date
WO2000010994A1 true WO2000010994A1 (fr) 2000-03-02

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WO (1) WO2000010994A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024015425A1 (fr) 2022-07-14 2024-01-18 Fmc Corporation Benzoxazines herbicides

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0129252A2 (fr) * 1983-06-21 1984-12-27 F. Hoffmann-La Roche Ag Procédé pour la préparation de dérivés de hydroquinone optiquement actifs et de d-alpha-tocophérol
EP0139421A1 (fr) * 1983-08-30 1985-05-02 Sankyo Company Limited Dérivés de la thiazolidine, leur préparation et composition les contenant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0129252A2 (fr) * 1983-06-21 1984-12-27 F. Hoffmann-La Roche Ag Procédé pour la préparation de dérivés de hydroquinone optiquement actifs et de d-alpha-tocophérol
EP0139421A1 (fr) * 1983-08-30 1985-05-02 Sankyo Company Limited Dérivés de la thiazolidine, leur préparation et composition les contenant

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024015425A1 (fr) 2022-07-14 2024-01-18 Fmc Corporation Benzoxazines herbicides

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