GB1590938A - Chromane derivatives - Google Patents

Chromane derivatives Download PDF

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GB1590938A
GB1590938A GB1953678A GB1953678A GB1590938A GB 1590938 A GB1590938 A GB 1590938A GB 1953678 A GB1953678 A GB 1953678A GB 1953678 A GB1953678 A GB 1953678A GB 1590938 A GB1590938 A GB 1590938A
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F Hoffmann La Roche AG
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Priority claimed from LU77344A external-priority patent/LU77344A1/xx
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    • 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
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
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    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/06—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by conversion of non-aromatic six-membered rings or of such rings formed in situ into aromatic six-membered rings, e.g. by dehydrogenation
    • C07C37/07—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by conversion of non-aromatic six-membered rings or of such rings formed in situ into aromatic six-membered rings, e.g. by dehydrogenation with simultaneous reduction of C=O group in that ring
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    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with no unsaturation outside the aromatic ring
    • C07C39/11—Alkylated hydroxy benzenes containing also acyclically bound hydroxy groups, e.g. saligenol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C46/00—Preparation of quinones
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    • 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
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    • 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
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
    • C07D317/20—Free hydroxyl or mercaptan
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/26—Radicals substituted by doubly bound oxygen or sulfur atoms or by two such atoms singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/30—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
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

(54) CHROMANE DERIVATIVES (71) We, F. HOFFMANN-LA ROCHE & CO., AKTIENGESELLSCHAFT, a Swiss Company of 124-184 Grenzacherstrasse, Basle, Switzerland, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention relates to chromane derivatives.
The present invention is concerned in one aspect with novel compounds of the general formulae
wherein R1 and R2 each represent a lower alkyl group.
The compounds of formulae I and II are valuable intermediates in the synthesis of vitamin E.
As used in this specification, the term "lower alkyl" means both straight-chain and branched-chain saturated hydrocarbon groups containing from 1 to 7 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl etc). The term "halogen" includes bromine, chlorine, fluorine and iodine. The term "alkali metal" includes sodium, potassium, lithium etc.
In the structural formulae given in this specification, a tapered line ( ) indicates a substituent which is pointed out of the plane of the paper towards the reader and a broken line (----) indicates a substituent which is pointed into the plane of the paper away from the reader.
The term "lower alkoxy" used in this Specification means an alkoxy group containing from 1 to 7 carbon atoms (e.g. methoxy, ethoxy, propoxy, isopropoxy etc). The term "lower alkanoyl" means alkanoyl groups containing from 2 to 6 carbon atoms (e.g. acetyl and propionyl). The term "aryl" means mononuclear aromatic hydrocarbon groups (e.g. phenyl, tolyl etc), which can be unsubstituted or which can carry in one or more positions a lower alkylenedioxy, halogen, nitro, lower alkyl or lower alkoxy substituent, and polynuclear aryl groups (e.g. naphthyl, anthryl, phenanthryl, azulyl etc), which can be unsubstituted or which can carry one or more of the aforementioned substituents. The preferred aryl groups are the substituted and unsubstituted mononuclear aryl groups, particularly the phenyl group. The term "aryl-(lower alkyl)" means aryl-alkyl groups in which the aryl and lower alkyl moieties are as defined earlier, particularly the benzyl group. The term "aroic acid" means acids in which the aryl moiety is as defined earlier. The preferred aroic acid is benzoic acid.
The term "ester protecting group removable by hydrolysis" used in this Specification means any conventional organic acid protecting group which can be removed by hydrolysis. Any conventional ester which can be hydrolysed to yield the acid can serve as the protecting group. Examples of esters useful for this purpose are the lower alkyl esters, particularly the methyl ester, the aryl esters, particularly the phenyl ester, and the aryl-(lower alkyl) esters, particularly the benzyl ester. The alcohols used to form the hydrolysable ester protecting groupare lower alkanols, aryl-(lower alkanols) and reactive derivatives thereof.
The term "ether protecting group removable by hydrogenolysis or acidcatalysed cleavage" means any ether which, upon acid-catalysed cleavage or hydrogenolysis, yields the hydroxy group. A suitable ether protecting group is, for example, the tetrahydropyranyl ether or 4 - methyl - 5,6 - dihydro - 2H - pyranyl ether. Other ether protecting groups are aryl-methyl ethers such as the benzyl, benzhydryl or trityl ethers, alpha(lower alkoxy)-(lower alkyl) ethers such as the methoxymethyl ether, allylic ethers or trialkylsilyl ethers such as the trimethylsilyl ether or dimethyltertbutylsilyl ether. Other ethers which are preferred are tertbutyl ethers.
The preferred ethers which are removed by acid-catalysed cleavage are tertbutyl and tetrahydropyranyl. Acid-catalysed cleavage is carried out by treatment with a strong organic or inorganic acid. Among the preferred inorganic acids are the mineral acids such as sulphuric acid, hydrohalic acid etc. Among the preferred organic acids are lower alkanoic acids such as acetic acid, trifluoroacetic acid etc and arylsulphonic acids such as paratoluenesulphonic acid etc. The acidcatalysed cleavage can be carried out in an aqueous medium or in an organic solvent medium. When an organic acid is used, the organic acid can be the solvent medium. In the the case of tertbutyl, an organic acid is generally used with the acid forming the solvent medium. In the case of tetrahydropyranyl ethers, the cleavage is generally carried out in an aqueous medium. In carrying out this acid-catalysed cleavage, temperature and pressure are not critical and it can be carried out at room temperature and atmospheric pressure.
The preferred ethers which are removable by hydrogenolysis are the arylmethyl ethers such as the benzyl ether or substituted-benzyl ethers. The hydrogenolysis can be carried out by hydrogenation in the presence of a suitable hydrogenation catalyst. Any conventional method of hydrogenation can be used.
Any conventional hydrogenation catalyst (e.g. palladium or platinum) can be used.
The compounds of formulae I and II hereinbefore can be prepared starting from the compound of formula
as shown in the following Formula Scheme in which R' and R2 have the significance given earlier:
Having regard to the foregoing Formula Scheme, the compound of formula IV is converted into the compound of formula V by selective reduction using a borane complex such as a borane-methyl sulphide complex in the manner described by Lane et al., J. Org. Chem 39, 3052 (1974).
The compound of formula V is converted into a compound of formula VI by treatment with a compound of the general formula
wherein R5, R1 and R2 each represent a lower alkyl group.
The conversion of the compound of formula V into a compound of formula VI using a compound of formula XVI is carried out in the presence of a strong acid.
Any conventional strong acid can be used. Included among the conventional strong acids are organic acids such as paratoluenesulphonic acid and inorganic acids such as sulphuric acid and the hydrohalic acids (e.g. hydrochloric acid). In carrying out the treatment an inert solvent can be used. Among the preferred solvents are the organic solvents such as tetrahydrofuran, dioxan etc. The temperature and pressure are not critical and the treatment can be carried out at room temperature and atmospheric pressure. The treatment can, however, also be carried out an elevated temperature. Generally, the treatment is carried out a temperature of from 20"C to 1000C.
A compound of formula VI is converted into a compound of formula VII by saponification. Any conventional saponification method can be used. Among the preferred methods is the treatment of a compound of formula VI with a strong aqueous base and subsequent neutralisation of the mixture. Any conventional alkali metal base (e.g. sodium hydroxide or potassium hydroxide) can be used.
After treatment with the strong base, the mixture is neutralised by treatment with an aqueous inorganic acid (e.g. sulphuric acid or hydrochloric acid). Temperature and pressure are not critical and the saponification can be carried out at room temperature and atmospheric pressure. The saponification can, however, also be carried out at an elevated temperature and pressure.
The conversion of a compound of formula VII into a compound of formula VIII is carried out by treating a compound of formula VII with N,N'carbonyldiimidazole and then reacting the product obtained with 2,5 - dihydroxy 2,5 - dimethyl - 1,4 - dithiane. The treatment can be carried out in an inert organic solvent medium. Any conventional inert organic solvent medium can be used.
Among the preferred solvents are the ether solvents (e.g. tetrahydrofuran, dioxan, diethyl ether etc). The preferred solvent is tetrahydrofuran. Temperature and pressure are not critical and the treatment can be carried out at room temperature and atmospheric pressure. It can, however, also be carried out at an elevated or reduced temperature. Generally, the treatment is carried out at a temperature of from 0 C to 1000C, with a temperature of from 20"C to 400C being preferred. In carrying out the treatment, the N,N' - carbonyldiimidazole is added first. The 2,5 - dihydroxy - 2,5 - dimethyl - 1,4 - dithiane can be added shortly after or as soon as the addition of the N,N' - carbonyldiimidazole has been completed. An intermediate is formed after the addition of the N,N' - carbonyldiimidazole. This intermediate has the general formula
wherein R' and R2 have the significance given earlier.
A compound of formula VIIA is converted immediately upon reaction with 2,5 - dihydroxy - 2,5 - dimethyl - 1,4 - dithiane into a compound of formula VIII.
This reaction is carried out under the same conditions used to form a compound of formula VIIA. For instance, the reaction is carried out in an inert organic solvent medium. Any conventional inert organic solvent can be used. Among the preferred solvents are the ether solvents (e.g. tetrahydrofuran). As in the reaction with the N,N' - carbonyldiimidazole, the temperature and pressure are not critical and the reaction can be carried out at room temperature and atmospheric pressure. If desired, it can be carried out at a higher or lower temperature.
A compound of formula VIII is converted into a compound of formula IX by treatment with a bis(tertiary amino) (alkyl or aryl)phosphine. Any conventional bis(tertiary amino)-(alkyl or aryl)phosphine can be used. Preferred among such substituted-phosphines is bis(3 - dimethylamino - 1 - propyl) - phenylphosphine.
The amino group in the phosphine is a tertiary amino group which is trisubstituted with lower alkyl groups. The phosphorus atom in the phosphine is also monosubstituted by either a lower alkyl group or an aryl group. Generally, the treatment is carried out in the presence of a lithium salt. Any conventional lithium salt (e.g. a lithium halide) can be used. Among the preferred lithium salts are lithium bromide, lithium chloride etc. In carrying out the treatment, an inert organic solvent medium is used, this solvent being any conventional inert organic solvent (e.g. acetonitrile, dimethylformamide, tetrahydrofuran, dimethyl sulphoxide etc). The treatment is generally carried out at a temperature of from 50"C to 1200C, with a temperature of from about 80"C to 1000C being preferred.
A compound of formula IX is converted into a compound of formula X by reaction with a compound of the general formula
wherein Rlo represents a lower alkyl group.
The reaction is carried out in the presence of a strong base. Any conventional strong base can be used. Among the preferred strong bases are the alkali metal lower alkoxides (e.g. sodium methoxide, potassium ethoxide,etc). Generally, the reaction is carried out in an inert organic solvent. Among the preferred solvents are the lower alkanols (e.g. methanol, ethanol, isopropanol etc). The temperature and pressure are not critical and the reaction can be carried out at room temperature and atmospheric pressure. It may also be carried out at higher or lower temperature. Generally, the reaction can be carried out at any temperature from 10"C to 1250C, with a temperature of from about 15 C to 350C being preferred.
A compound of formula X is converted into a compound of formula XI by treatment with an aluminium hydride reducing agent at a temperature of from 120"C to 1800C. Any conventional aluminium hydride reducing agent which does not decompose at a temperature above 1200C, preferably from 1200C to 1800C, can be used. Among the preferred aluminium hydride reducing agents are sodium dihydro - bis(2 - methoxy - ethoxy)aluminate and di(lower alkyl)aluminium hydrides such as diisobutylaluminium hydride. In carrying out this treatment, any inert organic solvent can be used. Among the preferred inert organic solvents are the inert organic solvents boiling above 120"C at atmospheric pressure (e.g.
diglyme, xylene etc). If desired, inert organic solvents which have lower boiling points can be used. However, when these low boiling inert organic solvents are used, the treatment is carried out under pressure to prevent the solvent from boiling.
A compound of formula XI is converted into a compound of formula XII by oxidation with a nitrososulphonate salt of the general formula O-N(SO3)2Xm (XXI) wherein X represents an ammonium, alkali metal or alkaline earth metal ion and m stands for 1 or 2 with the proviso that m stands for 2 when X represents an ammonium ion or an alkali metal ion and m stands for I when X represents an alkaline earth metal ion.
Included among the preferred nitrosulphonate salts is Fremy's salt. In carrying out the oxidation any of the conditions which are conventionally adopted when oxidising with Fremy's salt or with other nitrososulphonate salts can be used.
Generally, the oxidation is carried out in an aqueous medium. The temperature and pressure are not critical and the oxidation can be carried out at room temperature and atmospheric pressure. The oxidation may, however, be carried out at a temperature of from OOC to 300 C.
A compound of formula XII is converted into a compound of formula I by hydrogenation in the same manner as described hereinafter in connection with the conversion of the compound of formula XIV into a compound of formula II.
A compound of formula XI is converted into the compound of formula XIII by acid hydrolysis. Any conventional acid hydrolysis method can be used.
The compound of formula XIII is converted into the compound of formula XIV by oxidation with a nitrosodisulphonate. This oxidation is carried out in the same manner as described earlier in connection with the oxidation of a compound of formula XI to give a compound of formula XII.
The compound of formula XIV is converted into the compound of formula II by hydrogenation. Any conventional hydrogenation method can be used. The hydrogenation can be carried out using conventional hydrogenation catalysts (e.g.
palladium or platinum).
As mentioned earlier, the compounds of formula I and II are valuable intermediates in the synthesis of optically active vitamin E.
In this synthesis, the compounds of formulae I and II are firstly converted into the compound of the formula
The compounds of formula I can be converted into the compound of formula XVIII by treatment with a strong acid in the presence of water. In carrying out this treatment, any conventional strong acid can be used. Included among the preferred strong acids are the inorganic acids (e.g. sulphuric acid, hydrohalic acids such as hydrobromic acid and hydrochloric acid, perchloric acid etc). On the other hand, the treatment can be carried out using a strong organic acid such as a sulphonic acid. Included among the strong organic acids are methanesulphonic acid and para-toluenesulphonic acid. The treatment is carried out at a temperature of from 60"C to 1000 C. Generally, the treatment is carried out in an aqueous medium. On the other hand an inert organic solvent may be used in combination with water as the medium. The preferred inert organic solvents are the polar solvents. Any conventional polar solvent can be used. Included among the conventional inert organic polar solvents are tetrahydrofuran, acetonitrile, ethanol etc.
The compound of formula II can be converted into the compound of formula XVIII in the same manner as described earlier for the conversion of the compound of formula I into the compound of formula XVIII. In carrying out this conversion (i.e. treatment with a strong acid), the temperature and pressure are not critical and the treatment can be carried out at room temperature and atmospheric pressure. It can, however, also be carried out at an elevated or reduced pressure and temperature. Furthermore, whereas the acid treatment of a compound of formula I is carried out in the presence of water, the acid treatment of the compound of formula II to give the compound of formula XVIII can be carried out in an anhydrous medium as well as in the presence of water. As the anhydrous medium, any inert organic solvent can be used. Among the preferred inert organic solvents are the solvents mentioned earlier in connection with the conversion of a compound of formula I into the compound of formula XVIII.
The compound of formula XVIII can be converted- into a compound of the general formula
wherein R together with the oxygen atom to which it is attached forms an ester protecting group removable by hydrolysis or an ether protecting group removable by hydrogenolysis or acid-catalysed cleavage, and the latter can be converted into a compound of the general formula
wherein R has the significance given earlier.
The compound of formula XVIII is converted into a compound of formula XIX by selective etherification to provide an ether protecting group (i.e. a phenolic ether protecting group removable by hydrogenolysis).
A compound of formula XIX is converted into a compound of formula XX by oxidation. Any conventional method of converting an alcohol into an aldehyde can be used to bring about this oxidation. Included among the preferred oxidising agents are silver carbonate, a chromium trioxide/pyridine complex (Collins reagent), chromium trioxide dispersed in a carrier such as graphite (Lalancette reagent) and chromium trioxide in pyridine (Sarett reagent). In carrying out this oxidation, any of the conditions conventionally used in oxidations with these reagents can be used.
A compound of formula XX can be converted into optically active alphatocopherol and derivatives thereof according to known methods.
While only the formation of the 2(S) isomer of formula XX is illustrated, the compound of formula XX can be produced in any desired isomeric form depending upon the isomeric form of the compound of formula IV used as a starting material.
If the 2(R) isomer of formula IV is used, then the 2(R) isomer of formula XX will be produced. If a racemate of formula IV is used, then a racemate of formula XX is formed. The various steps of the process described earlier maintain the same stereoconfiguration as in the compound of formula IV throughout the conversion into the compound of formula XX.
The following Examples illustrate the present invention. The "usual work-up" referred to in the Examples involved three extractions with the specified solvent.
Organic solutions were then washed with saturated brine, dried over anhydrous magnesium sulphate, filtered and concentrated on a rotary evaporator under water aspirator pressure. Residues were dried to constant weight under a high vacuum at 400-500C or water aspirator pressure in the case of volatile materials.
Example 1 (S)-(+)-5-(Hydroxymethyl)-5-methyldihydro-2(3H)-furanone To a solution of 14.8 g (102.7 mmol) of (S) - (-) - 2-methyl - 5 oxotetrahydro - 2 - furoic acid [melting point 840-870C; []D5=-16.56 ] in 70 ml of dry tetrahydrofuran were added dropwise 10.1 ml (8.1 g; 106.7 mmol) of boranemethyl sulphide complex while stirring over a period of 0.5 hour. Occasional icebath cooling was used to maintain the internal temperature below 30"C. After stirring at room temperature for 1.5 hour, the mixture was cautiously decomposed by the dropwise addition of 6.2 ml of water. The mixture was then concentrated under water aspirator pressure and the residue was taken up in ethyl acetate and filtered. The solids were washed thoroughly with ethyl acetate and filtered. The solids were washed thoroughly with ethyl acetate and the filtrate and washings were combined and concentrated in vacuo to give 13.6 g of (S) - (+) - 5 (hydroxymethyl)- 5 - methyldihydro - 2(3H)- furanone in the form of a colourless oil which was used without further purification.
A sample of (S) - (+) - (hydroxymethyl)- 5 - methyldihydro - 2(3H) furanone was chromatographed on 40 parts of silica gel. Elution with benzene/ethyl acetate (1:1 voVvol) and ethyl acetate yielded the pure lactone which was recrystallised from ether/ligroin to give (S) - (+) - 5 - (hydroxymethyl) - 5 methyldihydro - 2(3H) - furanone in the form of a colourless solid of melting point 44.5 46.5 C; [a]D5=+17.76 (c=l in chloroform).
Example 2 (S) - (+) - 2,2,4 - Trimethyl - 1,3 - dioxolane - 4 - -propanoic acid A solution of 13.6 g (104.6 mmol) of (S) - (+) - 5 - (hydroxymethyl) - 5 methyldihydro - 2(3H) - furanone and 283 mg (1.64 mmol) of paratoluenesulphonic acid monohydrate in 161 ml of 2,2 - dimethoxypropane was stirred at room temperature for 3.75 days. 0.26 ml of pyridine was then added and the mixture was concentrated under water aspirator pressure. The residual ester, (S)- (+)- methyl 2,2,4 - trimethyl - 1,3 - dioxolane - 4 - propanoate, was dissolved in 180 ml of methanol containing 29.27 g (444 mmol) of 85% by weight aqueous potassium hydroxide. The resulting solution was stirred at room temperature for 4 hours and then concentrated in vacuo. The syrupy residue was diluted with ice/water and the solution was extracted with ether, the ether extract being discarded. The aqueous- lkaline solution was layered with ether and carefully acidified to pH 2.6 (pH meter) with 3-N hydrochloric acid. Work-up with ether in the usual manner gave 16.1 g (83.3% overall based on the furoic acid in Example 1) of (S) - (+) - 2,2,4 - trimethyl - 1,3 - dioxolane - 4 - propanoic acid in the form of an oil. This was used without further purification.
Crude (S) - (+) - 2,2,4 - dimethyl - 1,3 - dioxolane - 4 - propanoic acid was evaporatively distilled to give pure (S) - (+) - 2,2,4 - trimethyl - 1,3 dioxolane - 4 - propanoic acid in the form of a colourless oil of boiling point 80"- 900C (bath temperature)/0.15 mmHg; [a]25=+l.580 (c=2.02 in chloroform).
Example 3 (S) - (+) - Methyl 2,2,4 - trimethyl - 1,3 - dioxolane - 4 - propanoate A solution of 6.3 g (48.5 mmol) of (S) - (+) - 5 - (hydroxymethyl) - 5 methyldihydro - 2(3H) - furanone and 133 mg of para-toluenesulphonic acid monohydrate in 75 ml of 2,2-dimethyloxypropane was stirred and refluxed for 3.5 hour, then cooled in an ice-bath, diluted with ether and washed with saturated aqueous sodium bicarbonate solution. The organic solution was processed in the usual manner to give 8.2 g of a yellow oil. This oil was chromatographed on 400 g of silica gel. Elution with benzene/ethyl acetate (9:1 vol/vol and 4:1 vol/vol) gave the ester, (S) - (+) - methyl 2,2,4 - trimethyl - 1,3 - dioxolane - 4 - propanoate, which was evaporatively distilled to yield 4.6 g (47%) of a colourless liquid of boiling point 900-1000C (bath temperature)/12 mmHg; []D5=+1.74 (c=2 in benzene). An analytical sample of (S) - (+) - methyl 2,2,4 - trimethyl - 1,3 - dioxolane - 4 propanoate was obtained by re-chromatography and redistillation of a sample; [a]6=+2,97" (c=2 in benzene).
Example 4 (S) - (+) - 4 - (3,5 - dioxo - 1 - hexyl) - 2,2,4 - trimethyl - 1,3 - dioxolane To a stirred solution of 10 g (53.2 mmol) of (S) - (+) - 2,2,4 - trimethyl - 1,3 dioxolane - 4 - propanoic acid in 100 ml of anhydrous tetrahydrofuran were cautiously added 9.04 g (55.8 mmol) of N,N' - carbonyldiimidazole (gas evolution).
The solution was stirred for 1 hour at room temperature and then treated with 4.78 g (26.6 mmol) of 2,5 - dihydroxy - 2,5 - dimethyl - 1,4 - dithiane. Stirring was continued for 4 hours at room temperature, the mixture was diluted with water and worked-up with ether in the usual manner. The orange.oily residue (14.3 g) was chromatographed on 400 g of silica gel. Elution with benzene/ethyl acetate (9:1 vol/vol and 4:1 vol/vol) yielded 11.1 g (80.20/,) of the thiol ester, (S) - 3 - (2,2,4 trimethyl - 1,3 - dioxolan - 4 - yl) - propanoic acid 2 - oxopropyl - S - ester, in the form of a yellow oil.
To a solution of 10.6 g (40 mmol) of the foregoing thiol ester in 32 ml of dry acetonitrile were added 3.85 g (44.4 mmol) of anhydrous lithium bromide. After solution had occurred, 33 g (123 mmol) of bis(3 - dimethyl - amino - I propyl)phenylphosphine were added. Separation of a solid soon began as the mixture was stirred and heated at 850--900C. After heating for 4.5 hours, the mixture was cooled and poured into ice/water. The aqueous phase was layered with ether and acidified to pH 3.3 (pH meter) by the dropwise addition of 3-N aqueous hydrochloric acid. Work-up with ether in the usual manner gave 8.7 g of crude product in the form of a yellow oil. This oil was chromatographed on 350 g of silica gel. Elution with hexane/ether (4:1 and 2:1 vol/vol) gave (S) - (+) - 4 - (3,5 dioxo - 1 - hexyl) - 2,2,4 - trimethyl - 1,3 - dioxolane which was evaporatively distilled. There were obtained 6.57 g (72%) of pure (S) - (+) - 4 - (3,5 -'dioxo - I hexyl) - 2,2,4 - trimethyl - 1,3 - dioxolane in the form of a pale yellow oil of boiling point 95Ol050C (bath temperature)/0.005 mmHg; [a]025=+8.540 (c=2 in chloroform).
Basification of the acidic-aqueous solution followed by ether extraction allowed recovery of the excess phosphine reagent.
Example 5 (S) - (+) - Dimethyl 2 - hydroxy - 6 - methyl - 4 - (2,2,4 - trimethyl - 1,3 dioxolan - 4 - ethyl) - 1,3 - benzenedicarboxylate A solution of 6.0 g (26;3 mmol) of (S) - (+) - 4 - (3,5 - dioxo - 1 - hexyl) 2,2,4 - trimethyl - 1,3 - dioxolane (prepared as described in Example 4) and 5.83 g (33.4 mmol) of dimethyl 1 ,3-acetonedicarboxylate in 33.6 ml of 0.85-M methanolic sodium methylate was stirred at room temperature for 21 hours. The resulting yellow solution was poured into ice/water, layered with ether and the pH was adjusted to 3 by the addition of 3-N aqueous hydrochloric acid. Work-up with ether in the usual manner gave 10.9 g of a yellow oil. This oil was chromatographed on 350 g of silica gel. Elution with benzene/ethyl acetate (9:1 and 4:1 vol/vol) gave 8.82 g (91.7%) of (S) - (+) - dimethyl 2 - hydroxy - 6 - methyl - 4 - (2,2,4 - trimethyl 1,3 - dioxolane - 4 - ethyl) - 1,3 - benzene - dicarboxylate in the form of a yellow oil; [a]5=+5.44" (c=2 in chloroform); gas-chromatographic analysis indicated a purity of 92.4%. An analytical sample was obtained by careful re-chromatography and evaporative distillation to give pure (S) - (+) - dimethyl 2 - hydroxy - 6 methyl - 4- (2,2,4 - trimethyl - 1,3 - dioxolan - 4- ethyl) - 1,3 benzenedicarboxylate in the form of a viscous pale yellow oil of boiling point 1250-l300C (bath temperature)/0.003 mmHg; [cr125=+6.071 (c=2 in chloroform).
Example 6 A solution of 1.02 g (2.79 mmol) of (S) - (+) - dimethyl 2 - hydroxy - 6 methyl - 4- (2,2,4 - trimethyl - 1,3 - dioxolan - 4- ethyl) - 1,3 benzenedicarboxylate in 5 ml of xylene was added dropwise over a period of 5 minutes to a stirred solution of 6 ml (21.7 mmol) of 70% sodium dihydrobis (2 methoxy - ethoxy)aluminate (in benzene) in 5 ml of xylene. The resulting solution was stirred and refluxed for 3.75 hours and then cooled to 100C, at which point a solution of 1.16 ml of concentrated sulphuric acid in 5 ml of water was cautiously added dropwise. The resulting slurry was diluted with 23 ml of methanol and stirred and refluxed for 10 minutes. After cooling, the slurry was filtered and the granular solid was washed with methanol and then with ether. The filtrate and washings were combined and concentrated in vacuo. The residue was taken up in ether and the solution was washed with brine and processed in the usual manner to give 769 mg of a yellow oil. This oil was chromatographed on 30 g of silica gel. Elution with hexane/ether (4:1, 2:1 and 1:1 vol/vol) gave 640 mg (82.5%) of (S) - (+) - 2,3,6 trimethyl - 5 - (2,2,4 - trimethyl - 1,3 - dioxolan - 4 - ethyl)phenol in the form of a colourless oil which crystallised.
Example 7 (S) - (+) - 2,3,6 - Trimethyl - 5 - (2,2,2 - trimethyl - 1,3 - dioxolan - 4 - ethyl) p - benzoquinone A solution of 2.02 g (7.66 mmol) of (S) - (+) - 2,3,6 - trimethyl - 5 - (2,2,4 trimethyl - 1,3 - dioxolane viscous orange oil which was used without further purification. A sample was chromatographed on 50 parts of silica gel. Elution with hexane/ether (4:1 vol/vol) yielded an analytical sample of (S)- (+)- 2,3,6 - trimethyl- 5- (2,2,4 - trimethyl - 1,3 - dioxolan - 4 - ethyl) - p - benzoquinone in the form of a viscous orange oil; [(r]5=+6.39" (c=2 in chloroform).
Example 8 (S) - (+) - 5 - (3,4 - Dihydroxy - 3 - methyl - 1 - butyl) - 2,3,6 - trimethylphenol A solution of 1.4 g (5.04 mmol) of (S) - (+) - 2,3,6 - trimethyl - 5 - (2,2,4 trimethyl - 1,3 - dioxolan - 4 - ethyl)phenol in 28 ml of methanol and 5.5 ml of 1 N aqueous hydrochloric acid was stirred at room temperature for 20 hours, then poured into saturated brine and worked-up with ether in the usual manner.
Trituration of the solid residue with ether gave 0.8 g (66.7%) of pure (S) - (+) - 5 (3,4 - dihydroxy - 3 - methyl - I - butyl) - 2,3,6 - trimethylphenol in the form of a colourless solid of melting point 1450--146"C; [a]25-+2.200 (c=2 in ethanol).
The ether filtrate from the foregoing trituration was concentrated and the residue was recrystallised from ethyl acetate to give an additional 139 mg (11.7%) of (S) - (+) - 5 - (3,4 - dihydroxy - 3 - methyl - I - butyl) - 2,3,6 - trimethylphenol.
Example 9 (S) - (+) - 5 - (3,4 - Dihydroxy - 3 - methyl - I - butyl) - 2,3,6 - trimethyl - p benzoquinone 0.5 g (2.1 mmol) of (S) - (+) - 5 - (3,4 - dihydroxy - 3 - methyl - 1 - butyl) 2,3,6 - trimethylphenol was treated with Fremy's salt as described in Example 7.
There were obtained 480 mg (90.7 /") of (S) - (+) - 5 - (3,4 - dihydroxy - 3 methyl - 1 - butyl) - 2,3,6 - trimethyl - p - benzoquinone in the form of a yellow solid of melting point 109 112.5 C. Recrystallisation from chloroform/hexane gave 370 mg of a yellow solid of melting point 111.5 -113 C; [α ]D25=+6.28 (c=2 in chloroform).
Example 10 A solution of 0.405 g (1.6 mmol) of (S) - (+) - 5 - (3,4 - dihydroxy - 3 methyl - 1 - butyl) - 2,3,6 - trimethyl - p - benzoquinone in 20 ml of ethyl acetate was stirred in an atmosphere of hydrogen in the presence of 0.04 g of 5% by weight palladium on 95% by weight charcoal until hydrogen uptake ceased (ca, 1 hour; 38 ml of hydrogen absorbed). The catalyst was filtered off and the filtrate was concentrated to give 0.41 g of (S) - 5 - (3,4 - dihydroxy - 3 - methyl - 1 - butyl) 2,3,6 - trimethylhydroquinone in the form of a tan solid of melting point 124"-- 131.5 C.
Example 11 0.531 g (1.82 mmol) of (S) - (+) - 2,3,6 - trimethyl - 5 - (2,2,4 - trimethyl 1,3 - dioxolan - 4 - ethyl) - p-benzoquinone was hydrogenated as described in Example 10. 50 ml of hydrogen were absorbed. There was obtained 0.54 g of (S) (+)- 2,3,6 - trimethyl - 5 - (2,2,4 - trimethyl - 1,3 - dioxolan - 4ethyl)hydroquinone in the form of a tan solid.
Example 12 A mixture of-0.32 g (1.26 mmol) of (S) - (+) - 5 - (3,4 - dihydroxy - 3 - methyl 1 - butyl) - 2,3,6 - trimethylhydroquinone, 25 mg of paratoluenesulphonic acid monohydrate and 25 ml of benzene was stirred and refluxed for 1.25 hour. The resulting solution was cooled, washed with sodium bicarbonate solution and processed in the usual manner to give 0.393 g of a semi-solid residue which was chromatographed on 25 g of silica gel. Elution with toluene/ethyl acetate (9: 1, 4:1 and 2:1 vol/vol) yielded 0.237 g (79.7%) of (S) - (+) - 6 - hydroxy - 2,5,7,8 tetramethylchroman - 2 - methanol in the form of a cream coloured solid of melting point 122"--1240C; [a]=+l.090 (c=2.195 in ethanol).
Example 13 A solution of 0.455 g (1.54 mmol) of (S) - (+) - 2,3,6 - trimethyl - 5 - (2,2,4 trimethyl - 1,3 - dioxolan - 4 - ethyl)hydroquinone and 2 ml of 1 - N aqueous sulphuric acid in 10 ml of methanol was stirred and refluxed for 1.5 hours. After cooling, the mixture was treated with saturated brine and worked-up with ether in the usual manner to give 0.362 g of a brown glass. This glass was triturated with ether to give a solid which was removed by filtration. The ether solution was chromatographed on 25 g of silica gel. Elution with toluene/ethyl acetate (4:1 and 2:1) yielded 0.125 g (34.4%) of (S) - (+) - 6 - hydroxy - 2,5,7,8 - tetramethyl chroman - 2 - methanol in the form of a colourless solid of melting point 124.5 127.5 C; [a]5=+1.040 (c=2.115 in ethanol).
Example 14 (S) - (-) - 6 - Benzyloxy - 2,5,7,8 - tetramethylchroman - 2 - methanol A mixture of 0.55 g (2.33 mmol) of (S)- (+)- 6 - hydroxy - 2,5,7,8 tetramethylchroman - 2 - methanol, 790 mg (5.72 mmol) of anhydrous potassium carbonate, 0.68 ml (748 mg; 5.93 mmol) of benzyl chloride (distilled from and stored over potassium carbonate) and 4.5 ml of dimethylformamide was stirred for 22 hours at room temperature, poured into water and worked-up with ether in the usual manner. There was obtained 0.89 g of a yellow oily product which was chromatographed on 35 g of silica gel. Elution with benzene/ethyl acetate (19:1 and 9:1) gave 724 mg (97.1%) of (S) - (-) - 6 - benzyloxy - 2,5,7,8 tetramethylchroman - 2 - methanol in the form of a colourless solid of melting point 66"--69.5"C; [a]c25=2.35o (c=1.2 in chloroform).
Example 15 (S) - (+) - 6 - Benzyloxy - 2,5,7,8 - tetramethylchroman - 2 - carboxaldehyde To a stirred mixture of 36 ml of dry methylene chloride, 2.8 ml of dry pyridine and 1.46 g (14.6 mmol) of chromium trioxide was added a solution of 645 mg (1.9g mmol) of (S) - (-) - 6 - benzyloxy - 2,5,7,8 - tetramethylchroman - 2 - methanol in 5 ml of methylene chloride. The dark mixture was stirred for 40 minutes at room temperature, the organic solution was decanted and the dark residue was washed with ether and methylene chloride. The combined organic solutions were diluted with ether, washed with 1 - N sodium hydroxide, water and 1 - N hydrochloric acid and work-up was then completed in the usual manner. The yellow oily product (590 mg) was chromatographed on 50 g of silica gel. Elution with hexane/ether (19:1 vol/vol) gave 492 mg (76.7%) of pure (S) - (+) - 6- benzyloxy - 2,5,7,8 tetramethyl- chroman - 2- carboxaldehyde in the form of an oil which crystallised to yield a colourless solid of melting point 560--580C; tal25=+ 1 1.89c (c=5.2 in chloroform).
Example 16 (2R,4'R,8'R) - a - Tocopheryl acetate A solution of 570 mg (1.03 mmol) of (3R,7R) hexahydrofarnesyltriphenylphosphonium bromide in 5.6 ml of anhydrous dimethoxyethane was stirred at room temperature while 0.43 ml (1.03 mmol) of 2.4 - M n - butyllithium in hexane was added. The resulting red solution was stirred for 2 hours at room temperature, a solution of 153 mg (0.472 mmol) of (S) - (+) 6 - benzyloxy - 2,5,7,8 - tetramethylchroman - 2 - carboxaldehyde in 1.5 ml of anhydrous dimethoxyethane was added and stirring was continued for 3 hours at 650-700C. After cooling, the mixture was poured on to cold dilute sulphuric acid and work-up with ether was carried out in the usual manner. The product (520 mg) was a mixture of oil and solid which was triturated with hexane. The hexane solution was decanted and concentrated in vacuo to give 287 mg of oily material which was chromatographed on 15 g of silica gel. Elution with hexane/ether (19:1 vol/vol) yielded 168 mg (68.7%) of 1',2' - dehydrotocopherol benzyl ether in the form of a colourless oil. This oil (165 mg; 0.318 mmol) in 15 ml of ethyl acetate was stirred with 68 mg of 5% palladium-on-carbon in an atmosphere of hydrogen until gas uptake ceased. The catalyst was filtered off and the filtrate was concentrated in vacuo to give 120 mg (88.2 /,,) of (2R,4'R,8'R) - a - tocopherol in the form of a colourless oil which was homogeneous on thin-layer chromatographic analysis. The infrared and nuclear magnetic resonance spectra of this oil were identical with those of natural d - a - tocopherol.
A solution of 112 mg (0.26 mmol) of the foregoing oil in 0.75 ml of dry pyridine and 0.59 ml of acetic anhydride was stirred at room temperature for 17 hours and concentrated under a high vacuum. The residue was taken up in hexane and the solution was washed with water and brine and processed in the usual manner. The oily product was chromatographed on 7 g of silica gel. Elution with hexane/ether (9:1 vol/vol) gave 105 mg of (2R, 4'R, 8'R) - a - tocopheryl acetate. Evaporative dlstillation yielded 90 mg (73.7 /") of colourless oil of boiling point 2050C (bath temperature)/0.02 mmHg.

Claims (2)

What we claim is:
1). A compound of the general formula
wherein R1 and R2 each represent a lower alkyl group.
2) A process for the preparation of the compound of the formula
which process comprises treating a compound of the general formula
wherein Rl and R2 each represent a lower alkyl group, with a strong acid, the treatment of a compound of formula I being carried out in the presence of water and the treatment of a compound of formula II being carried out either in an anhydrous medium or in an aqueous medium.
GB1953678A 1977-05-16 1978-05-15 Chromane derivatives Expired GB1590938A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003031429A1 (en) * 2001-10-05 2003-04-17 Wyeth A process for the stereoselective synthesis of 2-hydroxymethyl-chromans
WO2003031428A1 (en) * 2001-10-05 2003-04-17 Wyeth Stereospecific process for the synthesis of 2-yl chroman derivatives

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ZA739471B (en) * 1972-12-22 1974-08-28 Hoffmann La Roche Chromane derivatives

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003031429A1 (en) * 2001-10-05 2003-04-17 Wyeth A process for the stereoselective synthesis of 2-hydroxymethyl-chromans
WO2003031428A1 (en) * 2001-10-05 2003-04-17 Wyeth Stereospecific process for the synthesis of 2-yl chroman derivatives
US6700001B2 (en) 2001-10-05 2004-03-02 Wyeth Process for stereoselective synthesis of 2-hydroxymethyl chromans
US6716998B2 (en) 2001-10-05 2004-04-06 Wyeth Process for synthesis of 2-yl chroman derivatives

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