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WO2000053578A1 - Derives de la vitamine d et leur procede de preparation - Google Patents

Derives de la vitamine d et leur procede de preparation Download PDF

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Publication number
WO2000053578A1
WO2000053578A1 PCT/JP2000/001481 JP0001481W WO0053578A1 WO 2000053578 A1 WO2000053578 A1 WO 2000053578A1 JP 0001481 W JP0001481 W JP 0001481W WO 0053578 A1 WO0053578 A1 WO 0053578A1
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group
substituent
polymer residue
derivative
alkynyl
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Japanese (ja)
Inventor
Takashi Takahashi
Makoto Nakazawa
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Kuraray Co Ltd
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Kuraray Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin

Definitions

  • the present invention relates to a method for producing a vitamin D derivative having a novel polymer residue, an indanone derivative having a polymer residue, a vinylamine D derivative having a polymer residue, and a method for producing an indanone derivative having a polymer residue.
  • Method for producing vitamin D derivative having a polymer residue, indanone derivative having a polymer residue, biminamine D derivative having a polymer residue, and indanone derivative having a polymerized residue produced by the present invention The production methods are useful as synthetic intermediates and synthetic methods for vitamin D derivatives, respectively.
  • Biminin D derivatives are a general term for steroid compounds that have an effect on bone in life and an effect of inducing cell differentiation.
  • vitamin D derivatives involve: (1) modification of the functional group on the side chain (carbon chain after steroid skeleton number 20) and increase / decrease of the number of carbon chains, (2) triene and gen moieties (steroid Construction and modification of skeleton numbers 5 to 10 and 19 carbons) 3 Modification of the functional group of the A ring (steroid ring name) and substitution of the upper carbon with a heteroatom, 4 C and D rings (steroid ring name) It is known to modify the functional group of the moiety and to substitute a carbon atom on the ring with a hetero atom. [Refer to Chemical Review, Volume 95, 187M (1989)] .
  • the conventional methods for constructing the triene and gen moieties are as follows: 1) A method that mimics the in vivo reaction of building a gen skeleton on the B-ring and synthesizing it by light and heat reactions [Jusss-li-bi-hi Chemi (Justus Liebiegs Anna 1 en der Chemie), Vol. 533, pp. 118 (1993)], 2) Indanone derivatives and phosphodies corresponding to ring A How to Use the Wittig Reaction with the Nate [Detora's Letters
  • (D), 2), 3) and 4) are convergent synthesis methods among vitamin D derivatives, and various derivatives are synthesized by modifying the C, D ring, side chain and A ring. This is an advantageous synthesis method that can be performed.
  • an object of the present invention is to provide a method for easily synthesizing various vitamin D derivatives by facilitating the separation and purification required for each reaction, and a vitamin D derivative thereof.
  • the present inventors have conducted various studies to solve the above-mentioned problems.As a result, even when a polymer residue is bonded to a synthetic intermediate of a vitamin D derivative, the same effect as in a conventional homogeneous reaction has been observed.
  • the ability to synthesize D derivatives, and the heterogeneity of the reaction.Vitamin D derivatives having polymer residues are not usually dissolved in solvents, so that the post-treatment step after the termination of the reaction is simplified, resulting in a wide variety of types.
  • the present inventors have found that a bismuth D derivative of the present invention can be advantageously produced, and have completed the present invention.
  • Molecules having polymer residues are molecules that do not dissolve the reagent in a solvent and run under homogeneous conditions because the functional groups to be reacted are included in the polymer residues. Is usually different. For this reason, there has been no application of a compound having a polymer residue to the synthesis of a vitamin D derivative, and no application has been made to a complex synthesis method in the formation of a vitamin D derivative. This is the situation.
  • R 26 each represent an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, an alkyloxy group, an alkenyloxy group.
  • a group, an alkynyloxy group, an aryloxy group, an aralkyloxy group (the above groups may have a combined residue or a substituent which may have a substituent), and have a substituent
  • R 12 is it its, alkyl group, alkenyl Group, alkynyl group, aryl group, aralkyl group, alkoxy group, alkenyloxy group, alkynyloxy grave, aryloxy group, aralkyloxy group, (the above groups may have a substituent.
  • vitamin D derivative (I) having a polymer residue A polymer D derivative having a polymer residue [hereinafter abbreviated as vitamin D derivative (I) having a polymer residue].
  • R 27 represents a polymer residue which may have a substituent
  • R 28 , RR 3 o, R 31 , R 32 , R 33 , R 3 ⁇ R 35 , R 3 fi , R 37, R ⁇ R 39 it it, an alkyl group, an alkenyl group, an alkynyl group, ⁇ Li Ichiru group, Ararukiru group, alkyl Ruokishi group, Arukeniruokishi group, an alkynyl old alkoxy group, Ariruokishi group, ⁇ A ralkyloxy group (the above groups may have a substituent), a hydrogen atom, a hydroxyl group which may be protected, or a substituent having any two substituents; R 28 , R 2 ⁇ 5 ; R 30 , R 32 , R 33 ; R 34 , R 3 G ; R 3 b ⁇ R 37 ; R 38 , R 39 together, such connexion may form a good Lee benzylid
  • R 42 represents a polystyrene chain which may have a substituent
  • R 43 and R 44 each represent an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group.
  • the above groups may have a substituent.
  • R 2 ⁇ R 22 , R 2 ⁇ R 24 , R 25 , R 2 S are Alkyl group, alkenyl group, alkynyl tomb, aryl group, aralkyl group, alkyloxy group, alkenyloxy group, alkynyloxy group, aryloxy group, aralkyloxy group (the above groups may have a substituent A good polymer residue or a substituent.),
  • R 28 and R 29 each represent an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, an alkyloxy group, an alkenyloxy group, an alkynyloxy group, an aryloxy group, an aralkyloxy group (the above groups) May represent a substituent.
  • R 27 represents a polymer residue optionally having a substituent.
  • Indanone derivatives having a polymer residue [hereinafter abbreviated as indanone derivatives (IV-1) having a polymer residue].
  • R 42 represents an Borisuchiren chain optionally having a substituent, R 43, R 4 or it it, an alkyl group, an alkenyl group , An alkynyl group, an aryl grave, and an aralkyl group (the following groups may have a substituent.)
  • R 1 R 2 , RR ⁇ R 5 , RR 7 , R 8 , R ", R 1 are each an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, an alkyloxy group, Alkenyloxy group, alkynyloxy group, aryloxy group, aralkyloxy group (the above groups may have a polymer residue which may have a substituent or may have a substituent); Represents a polymer residue which may be a group, a hydrogen atom, a hydroxyl group which may be protected, or represents an S union residue or a substituent which may have a substituent by any two of them.
  • RR 2 ; RR 4 ; R 5 , R u ; R 7 , R, RR 1 each having a substituent.
  • R 45 represents a hydrogen atom
  • X represents a phosphinoxide represented by R 46 R 47 PO
  • R 46 and R 47 each represent an alkyl group, an alkenyl group, an
  • a method for producing a vitamin D derivative (I) having a polymer residue characterized by reacting a cyclohexylideneethyl derivative (hereinafter abbreviated as "cyclohexylideneethyl derivative (V)") in the presence of a base. .
  • R a ", R 31 , R 32 , R:”, R 34 , R 3: ⁇ R: ", R : i 7 , R 38 , R 3 H are each an alkyl group, an alkenyl group An alkynyl group, an aryl group, an aralkyl group, an alkyloxy group, an alkenyloxy group, an alkynyloxy group, an aryloxy group, an aralkyloxy group (the above groups may have a substituent), a hydrogen atom, R 3 I ), R 31 ; R 32 may represent a hydroxyl group which may be protected, or may form an acyl group which may have a substituent by arbitrary two groups; , R '13; R 34, R 5; R 3 ( ⁇ R 37; R'"R 3 S may be formed which may Lee isopropylidene group optionally each have a together a connexion substituent, R " : represents an alkyl, alkenyl, alky
  • cyclohexylideneethyl derivative (hereinafter abbreviated as cyclohexylideneethyl derivative (V-1)] is reacted in the presence of a base to obtain a vitamin D derivative having a polymer residue (1-1). ) Manufacturing method.
  • R f is Alkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, alkyloxy group, alkenyloxy group, alkynyloxy group, aryloxy group, aralkyloxy group (the above groups have the substituent S and may be.), a hydrogen atom, ⁇ carded also good hydroxyl group is protected or may form a good Asetaru body may have a substituent by two ⁇ , R 4 a, R R 4, R 5 , R 51 ; R S 2 , R 53 ; R 55 , R "; R 57 , R 58 ; R r, R f ′ n each have a substituent.
  • indanone derivative (III) May be formed, or an indanone derivative [hereinafter abbreviated as “indanone derivative (III)”) represented by at least one of R 48 to R K1. Reacting with a polymer having a reactive functional group capable of bonding to the indone derivative (IV) having a polymer residue. Construction method.
  • R 2 S and R 29 each represent an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, an alkyloxy group, an alkenyloxy group, an alkynyloxy group, an aryloxy group, an aralkyloxy group (the above The group may have a substituent.)
  • 6-hydroxytetrahydrodanoneone derivative Abbreviated as hydroidanone derivative (I1I-1)] and a polymer having a reactive functional group capable of binding to a hydroxyl group.
  • Method for producing a non-derivative IV- 1).
  • R 42 represents an optionally substituted polystyrene chain
  • R 43 and R 44 represent an alkyl group, an alkenyl group, an alkynyl group, an aryl group, and an aralkyl group, respectively.
  • Z may represent a halogen atom.
  • R 3 , R 3 R 32 , R 33 , R 34 , R: ", R:"',R'", R 38 , R a9 , R A R 49 , R 5 U , R 5 R S 2 , R 53 , R 54 , R 5 f5 , R 5 G , R 57 , s R 59 , R fl Q , and R ′′ 1 are an alkyl group, an alkenyl group, an alkynyl group, an aryl group, and an aralkyl group, respectively.
  • An alkyloxy group, an alkenyloxy group, an alkynyloxy group, an aryloxy group, an aralkyloxy group (the above groups may have a substituent), a hydrogen atom, a hydroxyl group which may be protected or Any two of which may form an optionally substituted acetal, R 3 ", R 31 ; R 32 , 33 ; R 3 ⁇ R 3 S ; R 36 , R ' J 7 ; R 3 ⁇ R 3 fl; R 48, R 49; R 5 0, R 5 1; R 52, R r '3; R 55, R S 6; R 57, R 58; R 5 ⁇ R , it it Together with the arylidene group which may have a substituent.
  • a method for producing a bismuth D derivative hereinafter abbreviated as a bimin D derivative (II)).
  • R 28 , R 2 'R 3 , R 3 ', R '", R a ⁇ R 3 R 3 R 3 fi , R 37 , R 38 , R 39 are each an alkyl group, an alkenyl group Alkynyl group, aryl group, aralkyl group, alkyloxy group, alkenyloxy group, alkynyloxy group, aryloxy group, aralkyloxy group (the above groups may have a substituent), hydrogen atom termination, protection R 8 , R 2 "; R 3 , R 31 ; which may represent a hydroxyl group which may be substituted, or may form an acetal compound which may have a substituent by arbitrary two groups; R 32, R 3 a; R 31, R 5; 3 f ⁇ R 37;!
  • a method for producing a 11-hydroxyviminin D derivative [hereinafter abbreviated as a U-hydroxybiminin D derivative (II-1)].
  • R 3 , R “, R 32 , R 33 , R 34 , R 35 , R 3 R 37 , R 3 ⁇ R : "'are each an alkyl group, an alkenyl group, an alkynyl group, Aryl group, aralkyl group, alkyl group, alkenyloxy group, alkynyloxy group, aryloxy grave, aralkyloxy group (the above groups may have a substituent), hydrogen atom end-, protection R 30 , R 31 ; R 32 , R 33 ; which may represent a hydroxyl group which may be substituted, or may form an acyl group which may have a substituent by arbitrary two groups; R 3 R 35 ; R 3 R , R 37 ; R 38 and R 39 may be taken together to form an optionally substituted ylidene group, and R 40 is It, alkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group,
  • polystyrylsilyloxybiamine D derivative [hereinafter abbreviated as polystyrylsiloxyvitamin D derivative (I-1-2)] and the general formula (VI I)
  • R fi 2 represents an alkyl group, an alkenyl group, an alkynyl group, an aryl group, or an aralkyl group (the following groups may have a substituent.)
  • M is a salt.
  • a metal atom which may be represented by the following general formula (1-1-3): wherein an organic gold bending compound derivative [hereinafter abbreviated as an organometallic compound (VII)]
  • R B The alkyl group represented by R G R ", which may be linear or branched, having 1 to 2 carbon atoms 0, an alkyl group having preferably 1-8, for example, a methyl group, Echiru group, eta -Propyl group, isopropyl group, ⁇ -butyl group, 1-methyl propyl group, trethylethyl group, 2-methylbutyryl group, ⁇ -pentyl group, 1-methylbutyl group, 1,1-dimethylpropyl group, 1, 2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, ⁇ -hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-d
  • the substituent which the alkyl group may have may be any substituent as long as it does not hinder the reaction. Examples thereof include fluorine atom, chlorine atom, bromine atom, iodine atom, Hydroxyl group, alkyloxy group, alkenyloxy group, alkynyloxy group, aryloxy group, aralkyloxy group, alkylsulfonyloxy group, alkenylsulfonyloxy group, alkynylsulfonyloxy group, arylsulfonyloxy group, aralkylsulfonyloxy group Groups, an alkylthio group, an alkenylthio group, an alkynylthio group, an arylthio group, and an aralkylthio group.
  • an acetal form or a thioacetal form may be formed.
  • Alkyl group in 2 beta may have a good polymer residue which may have a substituent certain.
  • the alkenyl group represented by G 2 may be linear or branched, and may have 2 to 20 carbon atoms, preferably 2 to 8 carbon atoms, such as a vinyl group, a probenyl group, Propenyl group, 1-methyl-1-vinyl group, butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-1-propenyl group, 2-methyl-1-propenyl group, 1-methyl-2-probenyl group, 2-methyl-2-probenyl group, 1-methylidene-1-probyl group, 1-pentenyl group, tribenthenyl group, 3_pentenyl group, 4-pentenyl group , 1-methyl-1-butenyl group, Trimethyl-2-butenyl group, trimethyl-3-butenyl group, 1-methylidenebutyl group, 2-methyl-1-butenyl group, 2-methyl-2-butenyl group, 2_methyl-3-butenyl group, 2 -Methylidempty
  • 4-methyl-4-pentenyl group 1-ethyl-1-butenyl group, 1-ethyl-2-butenyl group, 1-ethyl-3-butenyl group, 2-ethyl-1-butenyl group, 2-ethyl-2 -Butenyl group, 2-ethyl-3-butenyl group, 1- (methylethyl) -1-propenyl group, 1- (1-methylethyl) -2-propenyl group, 1-ethyl-2-methyl 1-propenyl group, 1-ethyl-2-methyl-2-bromo group, 1-heptenyl group, 2_heptenyl group, 3-heptenyl group, 4-heptenyl group,
  • 3-ethyl-topentenyl group 3-ethyl-2-pentenyl group, 3-ethyl-3-pentenyl group, 3-ethyl-4-pentenyl group, 1,1-dimethyl-2-pentenyl group, 1J-dimethyl- 3-pentenyl group, 1,1-dimethyl-4-ventenyl group, 2,2-dimethyl-3-ventenyl group, 2,2-dimethyl-4-pentenyl group, 3,3-dimethyl-1-pentenyl group, 3,3-dimethyl-4-pentenyl group, 4,4-dimethyl-1-pentenyl group, 4,4-dimethyl-2-pentenyl group, 1,2-dimethyl-1-pentenyl group, 1,2-dimethyl -2-pentenyl group, 1,2-dimethyl-3-pentenyl group, 1,2-dimethyl-4-pentenyl group, trimethylidene-2-methylpentyl group,
  • 2-methylidene-1-methylpentyl 1,3-dimethyl-1-pentenyl, 1,3-dimethyl-2-pentenyl, 1,3-dimethyl-3-pentenyl, 1,3-dimethyl- 4-pentenyl, trimethylidene-3-methylpentyl, 3-methylidene-1-methylpentyl, 1,4-dimethyl-1-pentenyl, 1,4-dimethyl-2-ventenyl, 1,4- Dimethyl-3-ventenyl group, 1,4-dimethyl-4-pentenyl group, trimethylidene-4-methylpentyl tomb,
  • the substituent which the alkenyl group may have may be any substituent as long as it does not hinder the reaction.
  • examples include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxyl group, Alkoxy grave, alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, alkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, arylsulfonyloxy, aralkylsulfonyl Examples include an xy group, an alkylthio group, an alkenylthio group, an alkynylthio group, an arylthio group, and an aralkylthio group, and these groups may form an acetal form or a thioacetyl form.
  • the alkenyl group in 26 may have a polymer residue which may have a substituent.
  • the alkynyl group represented by 62 may be linear or branched, and has 2 carbon atoms. -20, preferably 2-8 alkynyl groups, such as ethynyl, 1-propynyl, 2-propvinyl, 1-butynyl, 2-butynyl, 3-butynyl, 1 1-pentynyl group, 2-benthynyl group, 3-benthynyl group, 4-benthynyl group, 3-methyl_1-provinyl group, 2-ethynylpropyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynyl group, 4-Hexynyl group, 5-Hexynyl group, 3-Methyl-1-benthynyl group, 4-Methyl-11-pentynyl group, 3,3-Dimethyl-1-pentynyl group, 4-Methyl-2-benthynyl
  • the substituent which the alkynyl group may have may be any substituent as long as it does not hinder the reaction.
  • examples include a fluorine atom, a chlorine atom, a bromine atom, a iodine atom, a hydroxyl group, Alkyloxy, alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, alkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, arylsulfonyloxy, aralkylsulfonyloxy, Examples thereof include an alkylthio group, an alkenylthio group, an alkynylthio group, an arylthio group, and an aralkylthio group. These groups may form an acyl group or a thioacetyl group. RR 2, RR 4, ' ⁇ R 6, R 7, R B ⁇ R! 1, R 10, R 1 R
  • the alkynyl group in 2 fi may have a polymer residue which may have a substituent.
  • the R 5 1 5 2 5 3 5 1 G 5 5 fi S 7 fi 8 5 9 G 0 H 1 R ⁇ Ariru group 2 represents the number of carbon atoms 6-2 0, preferably 6-1 4 Ariru group, Examples include a phenyl group and a naphthyl group.
  • the substituent which the aryl group may have may be any substituent as long as it does not hinder the reaction.
  • the substituent include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxyl group, and the above R An alkyl group represented by 1 or the like, an alkenyl group represented by the above R 1 , an alkynyl group, an alkyloxy group, an alkenyloxy group, an alkynyloxy group, an aryloxy group, an aralkyloxy group, an alkylsulfonyloxy group, Alkenylsulfonyloxy, alkynylsulfonyloxy, arylsulfonyloxy, aralkylsulfonyloxy, alkylthio, alkenylthio, alkynylthio, arylthio, aralkylthio; And these groups may form an acyl group
  • R 2 TI may have a good polymer residue which may have a substituent.
  • RRRRR 5, R R ', R 7, R 8, RR] R 1 R ⁇ 2, R 13, R 14, R' ⁇ R L FI, R I 7, R 18, R 1 S5, R 20, RR 22 , R 2 R 24 , R
  • the aryl moiety is the above aryl group represented by R 1 or the like, and the alkyl moiety has 1 carbon atom.
  • aralkyl groups for example, a benzyl group, a 0-methylbenzyl group, an m-methylbenzyl group, a p-methylbenzyl group, a naphthylmethylene group and the like.
  • the substituent that the aralkyl group may have may be any substituent as long as it does not hinder the reaction. Examples thereof include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxyl group, and an alkyloxy group.
  • R 1 R ⁇ RRR s , R ' ⁇ R 7 , R 8 , R 9 , R 1 U , R 1 ⁇ R 12 , R 13 , R 14 , R 15 R l fi R 17 7 R 18 R 1 H R 2 n ⁇ . 2 1 R 22 R 2 ' Ararukiru group for R 2 "5 R 25 R 2 fi may have a good polymer residue which may have a g substituent.
  • an alkyloxy group represented by R S 8 , R r ' ⁇ R SQ , R'' an alkyloxy group having an alkyl portion having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, for example, the above-described R 1 and the like Examples include an S-merged residue which may have a substituent or an alkyloxy group in which an oxygen atom is bonded
  • the substituent which the alkyloxy group may have may be any substituent as long as it does not hinder the reaction. Examples thereof include a fluorine atom, a chlorine atom, a ⁇ atom, and an iodine atom. , Hydroxyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, aralkyl, alkylsulfonoxy, alkenylsulfonyloxy, alkynylsulfonyloxy, arylsulfonyl Xy, aralkylsulfonyloxy, alkylthio, al Examples thereof include a kenylthio group, an alkynylthio group, an arylthio group, and an aralkylthio group. These groups may form an acyl group or a thioacetal.
  • R 2 R 26 may have a polymer residue which may have a substituent.
  • R 2 a R 29 R 3 C) R 31 R 32 R 33 R 34 R 3 G R 3 e R 3 7, R 38, R 3 H, R 40, R ", R 46, R 47, R 48, R" ⁇ R 'R 5 R 52, R r, ⁇ R 5 ⁇ R 55, R 5 S, R 57, R S 8, R S 9, R e.
  • the alkenyloxy group represented by R S1 may have an alkenyl moiety having 2 to 20, preferably 2 to 8 carbon atoms in the alkenyl portion, for example, may have a substituent represented by R 1 or the like.
  • An alkenyloxy group in which an oxygen atom is bonded to a polymer residue or an alkenyl group which may have a substituent may be mentioned.
  • the substituent which the alkenyloxy group may have may be any substituent as long as the reaction is not hindered.
  • a fluorine atom, a chlorine atom, a bromine atom, an iodine source? Hydroxyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, alkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, arylsulfonyloxy
  • the alkenyloxy group in RR 23 , R 24 , R 2 R 2 fi may have a polymer residue which may have a substituent.
  • R 39 R 4 U R 4 1 R 4 H R 47 R 48 R 49 R 5 n R 5 1 R 52 R B R G ⁇ R 5 S , R 5 K , R 57 , R ⁇ ' 8 , R 59, R li U, as alkynyl Okishi group represented by R fi l is from 2 to 20 carbon atoms in the alkynyl moiety, preferably 2 to 8 of ⁇ Rukiniruokishi group, for example, a substituent represented by such as the above-mentioned R 1 And an alkynyloxy group in which an oxygen atom is bonded to an optionally substituted polymer residue or an alkynyl group which may have a substituent.
  • the substituent which the alkynyloxy group may have may be any substituent as long as it does not hinder the reaction. Examples thereof include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. , Hydroxyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, alkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, arylsulfonyl Xy group, aralkylsulfonyloxy group, alkylthio group, alkenylthio group, alkynylthio group, arylthio group, aralkylthio group, and these groups may form an acetal compound or a thioacetal compound.
  • Arukiniruokishi group in R 21, R 22, R 2 R 2 R 2 ⁇ R 26 may have a polymer residue which may have a substituent.
  • aryloxy group represented by G1 includes aryl having 6 to 20 carbon atoms, preferably 6 to 14 carbon atoms.
  • a carbonyl group for example, an aryl group in which an oxygen atom is bonded to a compound residue which may have a substituent represented by R 1 or the like or an aryl group which may have a substituent.
  • xyl groups for example, an aryl group in which an oxygen atom is bonded to a compound residue which may have a substituent represented by R 1 or the like or an aryl group which may have a substituent.
  • the substituent which the aryloxy group may have may be any substituent as long as the reaction is not hindered.
  • a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, hydroxyl, the alkyl group R 1 or the like is represented
  • the an alkenyl group R 1 or the like is represented
  • alkynyl groups R 1 above or the like is represented
  • Arukiruokishi group Arukeniruoki sheet group, Arukiniruokishi group, Ariruokishi group, Ararukiruokishi group, an alkyl sulfonyl Oxy, alkenylsulfonyloxy, alkynylsulfonyloxy, arylsulfonyloxy, aralkylsulfonyloxy, alkylthio, alkenylthio, alkynylthio, arylthio, Aralkyl thi
  • RR 2, RR 4, R r ⁇ RR 7, R 8, R ⁇ R 1 ' ⁇ R 1 R 12, R 13, R ", R' ⁇ R l R 17, R 18, R l R 20, R 2 ⁇ , Ariruokishi group in R 22, R 23, R 24 , R 2 R 2 B may have a polymer residue but it may also have a substituent.
  • aralkyl groups for example, a polymer residue which may have a substituent represented by R 1 or the like, or an aralkyl group having an oxygen atom bonded thereto which may have a substituent.
  • R 1 or the like a substituent represented by R 1 or the like
  • aralkyl group having an oxygen atom bonded thereto which may have a substituent.
  • a ralkyloxy group a polymer residue which may have a substituent represented by R 1 or the like, or an aralkyl group having an oxygen atom bonded thereto which may have a substituent.
  • the substituent which the aralkyloxy group may have may be any substituent as long as it does not hinder the reaction. Examples thereof include a fluorine atom, a chlorine atom, and a odor. Elemental atom, iodine atom, hydroxyl group, alkyloxy group, alkenyloxy group, alkynoxy group, aryloxy grave, aralkyl group, alkylsulfonyloxy group, alkenylsulfonyloxy group, alkynylsulfonyloxy group, aryl —Rusulfonyloxy group, aralkylsulfonyloxy group, alkylthio group, alkenylthio group, alkynylthio group, arylthio group, and aralkylthio group.
  • Body, thioacetate may be formed.
  • the aralkyl group in R 1 R 20 , R ′′ ⁇ R 22 , R 23 , R 2 R 2 R 2 (; may have a polymer residue which may have a substituent.
  • the alkyl moiety has the same or different carbon number, and has 1 to 20 carbon atoms, preferably A chain acetal having an alkyloxy group of 1 to 10 which may be straight-chain or branched-chain alkyl, such as dimethyl acetate, getyl acetal, di-n-propyl acetate, di Chain acetal such as soprovir acetal and ethyl methyl acetal; Cyclic alkyl groups in which the alkyl moiety of the alkyloxy moiety forming the ring may be linear or branched, and is an alkyl having 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms, for example, , Ethylene acetate, brovirene acetate, trimethylene acetate, 1-methyltrimethylene acetate, 2-methyltrimethylene acetal, 1,1-dimethyltrimethylene acetate, 1 And cyclic acetal such as 1,2-dimethyltrimethylene a
  • the substituent which the acetal compound may have may be any substituent as long as it does not hinder the reaction.
  • substituents include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, Hydroxyl group, alkyloxy group, alkenyloxy group, alkynyloxy group, aryloxy group, aralkyloxy group, alkylsulfonyloxy group, alkenylsulfonyloxy group, alkynylsulfonyloxy group, arylsulfonyloxy group, arral Examples thereof include a killsulfonyloxy group, an alkylthio group, an alkenylthio group, an alkynylthio group, an arylthio group, and an aralkylthio group.
  • the acyl group represented by R 2 ⁇ may have a polymer residue S which may have a substituent.
  • R IG R 17, R 18 ; R z, ⁇ R "; R 22, R 23; R 24, R 25; R 2 ⁇ R 29; R
  • Examples of the arylidene group include those having a double bond and those having a carbon number of 1 to 20 and preferably 1 to 10 forming a ⁇ structure.
  • methylidene, ethylidene, propylidene, 1-methylethylidene, 1-methylpropylidene, 2-methylpropylidene, 1,1-dimethylpropylidene examples thereof include a 1,2-dimethylpropylidene group, a 1,3-dimethylpropylidene group, and a 2,2-dimethylpropylidene group.
  • the substituent which the above-mentioned ylidene group may have may be any substituent as long as it does not hinder the reaction.
  • substituents include a fluorine atom, a chlorine atom, a nitrogen atom, an iodine atom, a hydroxyl group, Alkyloxy, alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, alkylsulfonyloxy, Alkenylsulfonyloxy group, alkynylsulfonyloxy group, arylsulfonyloxy group, aralkylsulfonyloxydi group, alkylthio group, alkenylthio group, alkynylthio group, arylthio group, aralkylthio group These groups may form an acyl group or a thioacetal.
  • R '7, R 1 8; R 2, ⁇ ; R 2 2, R 2 - ⁇ ; R 2 R 25 good Lee isopropylidene group and it it together such connection formed have a substituent It may have a good polymer residue.
  • R 2 1, R ", ⁇ ⁇ respect R 2 ⁇ R 2 R 2 R 27, is a polymer of or a polymer residue which may have a substituent, such as ethylene, propylene, styrene, styrene derivatives (Eg, methyl styrene), methacrylates (eg, methyl methacrylate), acrylates (eg, acrylate), acrylonitrile, vinyl esters (eg, vinyl acetate), vinyl ethers (eg, methyl vinyl ether), butadiene , Isoprene, isobutene, ethylene glycol, propylene glycol, ethylene oxide, propylene oxide and other polymerizable monomers (single ft copolymers, random copolymers consisting of two or more monomers, block copolymers, And other polymers).
  • a substituent such as ethylene, propylene, styrene, styrene derivatives (Eg,
  • polymer ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 1,4-butenediol, 1,2-pentanediol, 1,3-pentanediol, 1,4-pentanediol, 1,5-benzenediol, 1,2-hexanediol, 1,3-hexanediol Polyols such as hexanediol, 1,4-hexanediol, 1,5-hexanediol, 1,6-hexanediol, 1,9-nonanediol, catechol, 1,4-dibenzenemethanol Polyesters with polycarboxylic acids such as malonic acid, succinic acid, glutaric acid, adipic acid, terephthalic acid (alternate), succinic
  • Preferred polymers include various polymers of ethylene, propylene, styrene, and styrene derivatives.
  • any substituent may be used as long as the reaction is not hindered.
  • Good examples include fluorine, chlorine, bromine, iodine, hydroxyl, alkyloxy, alkenyloxy, alkynyloxy grave, aryloxy, aralkyloxy, alkylsulfonyloxy, alkenylsulfonyloxy, and alkynyl.
  • An acetal form and a thioacetyl form may be formed.
  • substituents may include a ring structure having 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms.
  • the ring structure include cyclopropane ⁇ , cyclobutane ring, cyclopentane ⁇ , cyclo Saturated cycloalkane ring such as hexane ring, cycloheptane ring and cyclooctane ring; cycloalkene ring such as cyclobutene ring, cyclopentene ring, cyclohexene ring, cycloheptene ring and cyclooctene ring; aryl such as phenyl grave and naphthyl group And a aralkyl group such as a benzyl group.
  • the hydrogen atoms on these groups may be substituted with the above substituents.
  • substituents include the alkyl group and alkenyl represented by R 1 and the like.
  • Examples of the protecting group include a 1-alkoxyalkyl group such as a methoxymethyl group, a 1-ethoxymethyl group, and a 1-methoxyl group; a 1-year-old oxacycloalkyl group such as a tetrahydrofuranyl group and a tetrahydrobiranyl group; a methyl group; —Alkyl groups such as butyl group; aralkyl groups such as benzyl group; trimethylsilyl group, ethyldimethylsilylyl group, getylmethylsilyl group, triethylsilyl group, isopropyldimethylsilyl group, diisopropylmethylsilyl group, triisopropylmethyl group And tri-substituted silyl groups such as t-butyldimethylsilyl group, t-butyldiphenylsilyl group, and triphenylsilyl group.
  • These protecting groups
  • the molecular weight of the polymer residue is generally in the range of 500 to 500,000 in number average molecular weight, preferably It ranges from 500 to 1000000.
  • the molecular weight of the polystyrene chain which may have a substituent is about 500 to 500,000, preferably 500 to 1,000,000.
  • a polymer residue which may have a substituent refers to a polymer residue remaining on the reaction side as a result of the reaction of one or more reactive functional groups present at the terminal or side chain of the polymer. Group.
  • the functional group may be a functional group capable of forming any bonding mode as long as the vitamin D derivative can be chemically bonded to the polymer.
  • Examples of the bonding mode include a carbon-carbon single bond and a carbon-carbon single bond.
  • Examples include a carbon double bond, a carbon-carbon triple bond, an ether bond, a thioether bond, a silyloxy bond, an ester bond, an amide bond, and the like.A combination of two or more of these bonds may be used as a functional group. Examples thereof include an ether group, a thioether group, a silyloxy group, an oxycarbonyl group, a dioxycarbonyl group, and an amide group.
  • the substituent on the silicon atom constituting the silyloxy bond is an alkyl group, an alkenyl group, an alkynyl group, an aryl group,
  • An alkyl group, an alkenyl group, an alkynyl group, an aryl group, and an aralkyl group represented by the above substituents on the silyl group may be substituted with, for example, an alkyl group, an alkenyl group, or an alkynyl represented by R 1.
  • the bonding in the polymer having a reactive functional group capable of bonding to at least one of R 4 H to Re 1 includes the above-described bonding mode, and the reactive functional group is the same as described above. .
  • Examples of the polymer having a reactive functional group capable of binding to a hydroxyl group include halogens such as fluorine, chlorine, bromine, and iodine; dialkylsilyl chloride, dialkylsilyl bromide, dialkylsilyl iodide, and dialkylsilyl bromide.
  • Halogenosilyl groups such as alkenylsilyl chloride, dialkenylsilyl bromide, dialkenylsilyl iodide, dialkynylsilyl chloride, dialkynylsilyl bromide, dialkynylsilyl iodide; Alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, aralkylsulfonyl, A polymer having a carboxyl group is exemplified.
  • Such halogenosilyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkyl, alkenyl, alkynyl, aryl, and aralkyl tombs are: Examples thereof include an alkyl group, an alkenyl group, an alkynyl group, an aryl group and an aralkyl group represented by R 1 and the like, and these groups may have a substituent.
  • -Vitamin D derivative having a polymer residue represented by general formulas (1), (1-1) and (1-1-1), and a cycloalkyl derivative represented by general formulas (V) and (V-1) Hexylidenethyl derivatives, bimin D derivatives represented by the general formulas (II) and (II-1), and polystyrylsilyllo represented by the general formulas (1-1-2) and (1-1-3)
  • Each of the xvitamin D derivatives has a number of isomers, and in the present invention, they are all ⁇ -isomer.
  • the vitamin D derivatives (1), (I-1) and (I-1) having a polymer residue of the present invention the indanone derivatives (IV) and (IV-1) having a polymer residue And (IV-1), cyclohexylideneethyl derivatives (V) and (Vl), indanone derivative (111), 6-hydroxytetrahydroundanone derivative (III-1), compound (VI), biminin D derivative (11 ), 1-hydroxyvitamin D derivative (11-1), polystyrylsilyloxyvitamin D derivative (1-1-2), and vinylamine D derivative having a polymer residue (1-1-3) )),
  • the present invention includes all of them.
  • any metal atom may be used as long as it is a metal source that imparts nucleophilicity to R fi 2.
  • the metal atom may be lithium or the like.
  • M represents a metal atom constituting a salt
  • halogen such as fluorine, chlorine, bromine, iodine, etc.
  • hydroxide carbonic acid
  • phosphoric acid which form a salt with an alkyloxy group, alkenyloxy group, alkynyloxy group, aryloxy group, aralkyloxy group, etc. Examples are given.
  • the optionally substituted alkyloxy group, alkenyloxy group, alkynyloxy group, aryloxy group, and aralkyloxy group are, for example, the optionally substituted alkyloxy group, alkenyl group represented by R 1 and the like. Oxy, alkynyloxy, aryloxy and aralkyloxy groups.
  • the metal atom which may form the salt represented by M may be a mixture of two or more metal atoms, and examples of such a metal atom include the above-mentioned metal atoms and metal salts.
  • halogen atom in Y and Z examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • alkylsulfonyloxy group examples include, for example, alkyl represented by R 1 described above.
  • a sulfonyloxy group comprising an alkenyl group, an alkynyl group, an aryl group and an aralkyl group.
  • a method for producing a vitamin D derivative (1) having a polymer residue, a vitamin D derivative (1-1) having a polymer residue, and a vitamin D derivative (1-1-1) having a combined residue is described. explain.
  • Method for producing vitamin D derivative (1) having a polymer residue, vitamin D derivative (1-1) having a fi-combined residue, or vitamin D derivative (1-1-1) having a polymer residue May be any method, for example, a method in which an indanone derivative (IV) having a polymer residue and a cyclohexylideneethyl derivative (V) are reacted in the presence of a base, and a method in which an indanone derivative (IV-1) having a polymer residue is reacted with A method of reacting a cyclohexylideneethyl derivative (V-1) in the presence of a base, an indanone derivative having a polymer residue A method of reacting (iv-ii) with a cyclohexylideneethyl derivative (V-1) in the presence of a base can be used.
  • a method of reacting an indanone derivative (IV) having a polymer residue with a cyclohexylideneethyl derivative (V) in the presence of a base; an indanone derivative (IV-1) having a polymer residue and a cyclohexylideneethyl derivative (V- A method for reacting 1) in the presence of a base and a method for reacting an indanone derivative (IV-1-1) having a polymer residue and a cyclohexylideneethyl derivative (V-1) in the presence of a base will be described.
  • any may be a base but if only applied to R 4 5 on Kishiridenechiru derivative cyclohexane (V) and Kishiride Nechiru derivatives cyclohexane (V-1), for example, methyl lithium, Echirurichiumu, n- propyl Alkyl lithiums such as lithium, isopropyllithium, n-butyllithium; aryllithiums such as phenyllithium; lithium amide, sodium amide, potassium amide, lithium diisopropylamide, sodium diisopropylamide, potassium disoproviramide , Lithium dicyclohexyl amide, sodium dicyclohexyl amide, potassium dicyclohexyl amide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bi Metal amides such as (trimethylsilyl) amides; metal hydrides such as lithium hydride, sodium hydride, hydrogen hydr
  • the amount of the base to be used is preferably 0.5 molar equivalent or more, more preferably 0.8 to 10 molar equivalents, with respect to the cyclohexylideneethyl derivative (V) or the cyclohexylideneethyl derivative (V-1).
  • the amount of (v-1) used depends on the indanone derivative (IV) having a polymer residue, the indanone derivative (IV-1) having a coalesced residue, or the indanone derivative having a polymer residue.
  • It is preferably at least 1 molar equivalent, more preferably from 1 to 20 molar equivalents, and particularly preferably from 1 to 10 molar equivalents, based on (IV-1-1).
  • the reaction is usually performed in a solvent that does not adversely influence the reaction.
  • the solvent include ether solvents such as tetrahydrofuran, diethyl ether, and dimethoxetane; and hydrogenated solvents such as toluene, pentane, hexane, heptane, octane, petroleum ether, and mixtures thereof.
  • a solvent or the like is used.
  • the amount of the solvent used is determined based on the indanone derivative having a polymer residue (IV) or the indanone derivative having a polymer residue (IV-1) or the indanone derivative having a polymer residue (IV-1-1). Usually, the range of 1 to 200 times the weight is preferable.
  • the reaction is carried out under an inert gas atmosphere in an indanone derivative (IV) having a polymer residue or an indanone derivative having a polymer residue (IV-1) or an indanone derivative having a polymer residue (IV-1).
  • IV indanone derivative
  • -1-1) is suspended in the above solvent, and a solution obtained by mixing a base with a cyclohexylideneethyl derivative (V) or a cyclohexylideneethyl derivative (V-1) in the above solvent is added to the suspension.
  • the reaction temperature is preferably in the range of 100 ° C to a temperature not exceeding the boiling point of the solvent (for example, in the range of 100 ° C to 200 ° C), and more preferably in the range of 40 ° C to 200 ° C.
  • the reaction time is usually 0.05 hours to 48 hours, preferably 1 hour to 24 hours. Do with.
  • the cyclohexylideneethyl derivative (V) or the cyclohexylideneethyl derivative (V-1) is produced, for example, by the method described in JP-A-6-72928 or a method analogous thereto.
  • the vitamin D derivative (I) having a polymer residue or the bimin D derivative (1-1) having a polymer residue obtained in this manner or the bimin D derivative having a polymer residue (1-1) 1-1-1) is, for example, to add dilute hydrochloric acid, dilute sulfuric acid, aqueous solution of ammonium chloride, saline, water, etc. to the reaction mixture to stop the reaction, and to prepare an organic solvent such as getyl ether, ethyl acetate, methylene chloride, etc.
  • the unreacted cyclohexylideneethyl derivative (V) or cyclohexylideneethyl derivative (V-1) can be recovered in an organic solvent by filtration and washing at the same time.
  • a bimin D derivative having a polymer residue (I) obtained as a filtered product, a bimin D derivative having a polymer residue ([-1), or a bimin D having a polymer residue are obtained.
  • a basic substance and a water-soluble substance can be removed, and the derivative (1-1-1) can be dried.
  • the method for producing the indanone derivative having a polymer residue (IV), the indanone derivative having a ring residue (IV-1) or the indanone derivative having a polymer residue (IV-1-1) is as follows. Any method may be used as long as the polymerization reaction having a bondable reactive functional group is bonded to the indanone derivative (III) or the 6-hydroxytetrahydroindanone derivative (III-1).
  • a method comprising reacting a compound having a reactive functional group capable of binding to at least one of R 48 to R ti 1 with an indanone derivative (III), or a 6-hydroxytetrahydroundanone derivative (II 1-1) Reacting with a polymer having a reactive functional group capable of binding to a hydroxyl group, or reacting a 6-hydroxytetrahydrondanone derivative ( ⁇ -1) with a compound (VI) in the presence of a base.
  • Indanone derivative (III) is described a method of reacting a polymer having a R 4 8 to R at least one allow binding reactive functional groups of the ⁇ of fi 1.
  • the reaction may be carried out by any method as long as it is a method of binding a polymer having a reactive functional group capable of binding to an indanone derivative (III).
  • a method of reacting a 6-hydroxytetrahydroindanone derivative (II 1-1) in which a reactive functional group capable of binding is a hydroxyl group with a polymer having a reactive functional group capable of binding to a hydroxyl group examples include an esterification reaction, a silyl etherification reaction, and an etherification reaction in the presence of a base.
  • the base may be any base, for example, alkyllithiums such as methyllithium, ethyllithium, n-propyllithium, isobromovirlithium, n-butyllithium; aryllithiums such as phenyllithium; lithiumamido Sodium, potassium amide, lithium diisopropyl amide, sodium diisopropylamide, potassium diisopropyl amide, lithium dicyclohexyl amide, sodium dicyclohexyl amide, potassium dicyclohexyl amide, lithium Metal amides such as bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide; lithium hydride, sodium hydride, potassium hydride Lithium methoxide, lithium ethoxide, lithium n-propyloxide, lithium iso-propyloxide, lithium n-butoxide, lithium 2-butoxide, lithium ter
  • the amount of the base to be used is preferably at least 1 molar equivalent, more preferably from 1 to 1 ° molar equivalent, relative to the 6-hydroxytetrahydroundanone derivative (III-1).
  • the amount of compound (VI) to be used is preferably at least 0.001 molar equivalent, more preferably from 0.01 to 10 molar equivalents, based on the 6-hydroxytetrahydroundanone derivative (III-1).
  • the reaction is usually performed in a solvent that does not adversely influence the reaction.
  • the solvent include ether solvents such as tetrahydrofuran, getyl ether, and dimethoxetane; hydrocarbon solvents such as toluene, pentane, hexane, heptane, octane, and oil ether; methylene chloride, dichloroethane, and chlorobenzene.
  • a halogen-containing hydrocarbon-based solvent such as 0 -dichlorobenzene or a mixed solvent thereof is used.
  • the amount of the solvent to be used is generally preferably in the range of 1 to 200 times the weight of the 6-hydroxyltrahydroidanone derivative (III-1).
  • the reaction is usually carried out under an inert gas atmosphere by adding the compound (VI) suspended in the above solvent to a solution of the 6-hydroxytetrahydroundanone derivative ( ⁇ -1) and a base dissolved in the above solvent, or This is performed by adding a solution of the 6-hydroxytetrahydroindanone derivative (III-1) and a base dissolved in the above solvent to the compound (VI) suspended in the solvent.
  • a turbid solution in which the base and the compound (VI) are turbid in the above solvent is added to a solution of the 6-hydroxytetrahydroundanone derivative (III-1) in the above solvent, or the 6-hydroxytetrahydroundanone derivative (III-).
  • the method may be carried out by adding the solution of the above-mentioned solvent in 1) to a suspension of a base and compound (VI) suspended in the above-mentioned solvent.
  • the reaction temperature is preferably in the range of 100 ° C to a temperature not exceeding the boiling point of the solvent (for example, in the range of 100 ° C to 200 ° C), and more preferably in the range of 140 ° C to 200 ° C.
  • the reaction time is generally 0.05 to 48 hours, preferably 1 to 24 hours. Perform in the box.
  • indanone derivative (III) or the 6-hydroxyl-trahidrodandanone derivative (III-1) is described, for example, in Journal of Organic Chemistry, Vol. 51, 1264 (1986). ) Or a method analogous thereto.
  • Compound (VI) can be prepared by, for example, a method of chlorinating a hydrosilane having a polymer residue [Journal of Organic Chemistry] 63, 45 18 (1998 ) See] or an equivalent method.
  • the indanone derivative (IV) having an iS merging residue, the indanone derivative (IV-1) having a merging residue, or the indanone derivative (IV-1-1) having a polymer residue thus obtained is For example, add dilute hydrochloric acid, dilute sulfuric acid, aqueous ammonium chloride, saline, water, etc. to the reaction mixture to terminate the reaction, and wash and filter with an organic solvent such as getyl ether, ethyl acetate, methylene chloride, etc.
  • an organic solvent such as getyl ether, ethyl acetate, methylene chloride, etc.
  • unreacted indanone derivative ( ⁇ ) or 6-hydroxytetrahydroundanone derivative (HI-1) can be recovered in an organic solvent and can be obtained by filtration at the same time.
  • a basic substance and a water-soluble substance can be removed by washing with dilute hydrochloric acid, water, a saline solution, etc., and dried.
  • Biminin D derivative with polymer residue (I) or Biminin-D derivative with polymer residue (1-1) or Biminin D derivative with polymer residue (1-1-1) A method for producing a vinylamine D derivative for removing a polymer residue which may have a substituent will be described.
  • the substituent of the vitamin D derivative (I) having a polymer residue, the vitamin D derivative (1-1) having a polymer residue, or the biminamine D derivative (1-1-1) having a polymer residue is substituted.
  • the method for producing the bismuthin D derivative which removes the polymer residue which may be present may be any method.
  • a method of producing the 1-hydroxylamine D derivative (II-1) by hydrolyzing the derivative (1-1-1) is mentioned.
  • hydroxybimin D derivative (II-1) was obtained from a bimin D derivative (1-1) having a polymer residue or a D-1 derivative (I-1-1) having a polymer residue. ) Is usually carried out by treating under acidic conditions or basic conditions.
  • the acid constituting the acidic condition may be any acid as long as it acts on the polymer residue.
  • hydrogen halides such as hydrogen fluoride, hydrogen chloride, and hydrogen bromide
  • methanesulfonic acid ⁇ - Sulfonic acids
  • sulfuric acid phosphoric acid, and the like.
  • the base constituting the basic condition may be any base as long as it acts on a polymer residue.
  • Examples include lithium methoxide, lithium ethoxide, lithium ⁇ -proviroxide, lithium iso_propyloxide, and lithium.
  • a compound obtained by mixing an amine compound and ammonia at an arbitrary ratio as arsenic acid and a base may be used.
  • ammonium salt can be used.
  • ammonium salt include tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride and the like. .
  • the amount of the acid or salt used is 0.0001 mol based on the amount of the biminamine D derivative having a polymer residue (1) or the vitamin D derivative having a polymer residue (1-1-1). equivalent or more, particularly 0.1 mol equivalent or more, the range from 1 to 5 0 0 molar equivalent is not more preferred D
  • the treatment is usually performed in a solvent that does not adversely influence the reaction.
  • the solvent include ether solvents such as tetrahydrofuran, getyl ether, and dimethoxetane; hydrocarbon solvents such as toluene, pentane, hexane, hebutane, octane, and petroleum ether; methylene chloride, dichloroethane, and the like.
  • Halogen-containing hydrocarbon solvents such as chlorobenzene, 0-dichlorobenzene, etc .; dimethyl sulfoxide, N, N-dimethylformamide, acetonitrile, water, or a mixed solvent thereof is used.
  • the amount of the solvent used is usually 1 to 200 times the weight of the vitamin D derivative (1-1) having a polymer residue or the vitamin D derivative U-1-1) having a polymer residue. It is good.
  • the treatment may be performed without adding the above solvent.
  • the treatment is usually carried out by adding a vinylamine D derivative having a polymer residue (1-1) or a vitamin D derivative having a polymer residue (I-I1) to a turbid solution in which the above solvent is used.
  • Bi This is done by adding a suspension solution of the Yumin D derivative (I-1-1) suspended in the above solvent.
  • the reaction temperature is preferably in the range from 100 ° C. to a temperature not exceeding the boiling point of the solvent (for example, in the range from 100 ° C. to 200 ° C.), and preferably from 140 ° C. to 200 ° C. The range is more preferred.
  • the reaction time is usually from 0.05 to 72 hours, preferably from 1 to 36 hours.
  • the biminamine D derivative (II) or 11-hydroxyviminin D derivative (II-1) thus obtained can be isolated and purified by a method generally used for the isolation and purification of organic compounds. can do.
  • the reaction mixture is poured into saline or water, extracted with an organic solvent such as dimethyl ether, ethyl acetate, or methylene chloride.If necessary, the extract is washed with a saturated aqueous sodium hydrogen carbonate solution to remove acidic substances.
  • Basic substances and water-soluble substances are removed by washing with diluted hydrochloric acid, water, saline, etc., dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, etc., and concentrated, and the resulting crude product is used if necessary. And can be purified by distillation, chromatography, recrystallization, etc.
  • the reaction is usually performed in a solvent that does not adversely influence the reaction.
  • the solvent include ether solvents such as tetrahydrofuran, getyl ether, and dimethoxetane; hydrocarbon solvents such as toluene, pentane, hexane, heptane, octane, and petroleum ether; and mixed solvents thereof.
  • the amount of the solvent to be used is generally preferably in a range of 1 to 200 times the weight of the polystyrylsilyloxybiamine D derivative (1-1-2).
  • the organometallic compound (VII) may be in a solution or solid state, but is dissolved or suspended in the above solvent under an inert gas atmosphere and used as a solution or suspension.
  • the amount of the solvent used is preferably in the range of usually 1 to 200 times the weight of the organometallic compound (VII).
  • the amount of the organometallic compound (VI I) used is polystyrylsilyloxybimin! )
  • the derivative (1-1-2) is preferably at least 1 molar equivalent, more preferably 1 to 50 molar equivalents.
  • the reaction is performed by adding a solution or suspension of the organometallic compound (VII) to a suspension of the above solution of the polystyrylsilyloxybinamine D derivative (1-1-2) under an inert gas atmosphere, The reaction is carried out by adding a suspension of the above solution of the polystyrylsilyloxybiamine D derivative (1-1-2) to a solution of an organic metal compound (V ⁇ ) or a suspension.
  • the reaction temperature is preferably from 100 ° C to a temperature not exceeding the boiling point of the solvent (for example, from 100 ° C to 200 ° C), and more preferably from -78 ° (: to 200 ° C).
  • the reaction time is generally 0.05 to 48 hours, preferably 1 to 24 hours.
  • the organometallic compound (VII) is produced, for example, by the method described in the fourth edition of Experimental Chemistry Course, Vol. 25, 65 (Maruzen, 1991) or a method analogous thereto.
  • the thus obtained vitamin D derivative having a polymer residue (1-1-3) can be reacted, for example, by adding dilute hydrochloric acid, dilute sulfuric acid, aqueous ammonium chloride solution, saline, water, etc. to the reaction mixture. Is stopped, and washed and filtered with an organic solvent such as getyl ether, ethyl acetate, and methylene chloride. Further, by washing the biminamine D derivative (1-1-3) having a polymer residue obtained as a separated product with a dilute hydrochloric acid, water, or a saline solution as necessary, a basic substance, Substances can be removed and dried.
  • -Vitamin D derivatives and bimin D derivatives having a polymer residue obtained by the above production method are useful, for example, as therapeutic agents for osteoporosis [Chemical Review, Vol. 95, p. 1877] (1995)].
  • reaction solution was diluted with water (200IQL), 1N hydrochloric acid was added at 0 ° C, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
  • the concentrate was diluted with ether, and washed sequentially with 0.5 N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline.
  • the organic layer is dried over anhydrous magnesium sulfate, concentrated by filtration _ and filtered to give ethyl (5R, 6S, 7R) -5- (1,1-dimethylethyl) dimethylsilyloxy-1,6-, 7-isopropyl Ridenedoxy-3-oxo-8-nonenate was obtained as a crude product (989 mg).
  • Triethylamine (2.70 mL, 19.3 mmol), triphenylphosphine (500 mg, 1.9 mmol), and palladium acetate (213 mg, 0.949 mmol) were dissolved in dry N, N-dimethylformamide (40 mL).
  • Diphenylphosphine (0.53 mL, 3.05 mmol) was dissolved in dry tetrahydrofuran (8 mL), and n-butyllithium (1.96 mL, 2.98 mmolK 1.53 M hexane solution) was added dropwise at 0 ° C. under argon atmosphere.
  • Vitamin D 2 in a methanol solution in the presence of pyridine with reference to the Journal of Organic Chemistry, Vol. 51, 1264 (11986). Ozone oxidation followed by reduction with sodium borohydride was used for synthesis.
  • reaction solution was cooled to -78 ° C, trimethylsilyl chloride (1.05 mL, 8.27 mmol) was added, and the mixture was stirred at -78 ° C for 1 hour, and then water was added at 0 ° C. Then, the aqueous layer was extracted with hexane.
  • This solution contains [1 R— [1 (S *), 3 a?, 7 a ⁇ ]] — 1-((1, 1-dimethylethyl) dimethylsilyloxy) ethyl) _ 1, 2, 3, 3 a , 7,7a-Hexahydro-1H, 7a-Dimethyl-15,6-oxolan-14H-indene-4-one (2.52 g, 7.44 mmol) in dry Jetyl ether (40 mL) was added, and Stirred for minutes. To this solution, a saturated aqueous ammonium chloride solution (70 mL) and 28-ammonia water (15 mL) were slowly added at 0 ° C.
  • the aqueous layer is re-extracted with getyl ether.
  • the organic layer and the re-extracted solution are combined, washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, concentrated, and the concentrate is purified by silica gel column chromatography ( Ethyl acetate) and has the following physical properties: [1 R— [1 st (S *), 3 a 3, 6 st, 7 a st]] — 6—hydroxyl, 7 a— Dimethyl-14H-indene-14-one-ethanol (72 nig, 100% yield) was obtained.
  • the prepared solution was [1R— [1a (S *), 3a?, 6,7a]] 1-6 — [(2-polystyrylethyl) getylsilyloxy] One, 7a-Dimethyl-4H_indene-14-one-1-ethanol p-toluenesulfonate
  • UV spectrum (ethanol solvent) max: 219nm (£ 19300), 262nm ( ⁇ 14000) ⁇ : 239 ⁇ ( ⁇ 10500)

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Abstract

L'invention concerne des dérivés de la vitamine D ayant des résidus polymères, représentés par la formule générale (I). R?1 à R10 et R13 à R26¿ forment chacun un groupe choisi parmi des alkyle, alcényle, acynyle, aryle, aralkyle, alkyloxy, alcényloxy, alcynyloxy, aryloxy et aralkyloxy (lesquels peuvent avoir chacun un résidu polymère facultativement substitué ou un substituant), un résidu polymère facultativement substitué, H, ou hydroxyle facultativement protégé. Deux éléments quels qu'ils soient de R1 à R10 et de R?13 à R26¿ peuvent former un acétal pouvant avoir un résidu polymère facultativement substitué ou un substituant. R?1 à R10 et R13 à R26¿ peuvent ensemble former des groupes ylidène qui peuvent avoir des résidus polymères facultativement substitués ou substituants. R?11 et R12¿ sont chacun tels que définis ci-dessus pour R1 à R10 à l'exception d'hydroxyle, pour autant qu'au moins un élément de R1 à R26 ait un résidu polymère facultativement substitué ou soit lui-même un tel résidu. Divers dérivés de la vitamine D peuvent être rapidement préparés par une technique de séparation/purification facile.
PCT/JP2000/001481 1999-03-11 2000-03-10 Derives de la vitamine d et leur procede de preparation Ceased WO2000053578A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU29421/00A AU2942100A (en) 1999-03-11 2000-03-10 Vitamin d derivatives and process for the preparation thereof

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JP10992199 1999-03-11
JP11/109921 1999-03-11

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001079165A1 (fr) * 2000-04-18 2001-10-25 Schering Aktiengesellschaft Produit intermediaire de synthese utilise en fabrication de derives d de vitamines
JP2002179727A (ja) * 2000-12-07 2002-06-26 Rikogaku Shinkokai スルホン誘導体及びその製造方法

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0341158A2 (fr) * 1988-05-04 1989-11-08 Medgenix Diagnostics Nouveaux dérivés de la vitamine D : applications thérapeutiques et aux dosages des métabolites de la vitamine D
EP0373687A1 (fr) * 1988-12-12 1990-06-20 Duphar International Research B.V Procédé de conversion photochimique de tachystérols en prévitamines D et de transvitamines D en cis-vitamines D
WO1992004384A1 (fr) * 1990-08-31 1992-03-19 Regents Of The University Of Minnesota Derives de polyethylene-glycol destines a des applications en phase solide
JPH0491074A (ja) * 1990-08-03 1992-03-24 Chugai Pharmaceut Co Ltd 新規なビタミンｄ↓３誘導体
WO1995001987A1 (fr) * 1993-07-09 1995-01-19 Genset Procede de synthese d'acides nucleiques sur support solide et comoposes utiles notamment comme support solide dans ledit procede
US5449668A (en) * 1993-06-04 1995-09-12 Duphar International Research B.V. Vitamin D compounds and method of preparing these compounds
WO1995034813A1 (fr) * 1994-06-14 1995-12-21 Smithkline Beecham Corporation Resines pour synthese a l'etat solide
JPH08176038A (ja) * 1994-12-26 1996-07-09 Kuraray Co Ltd （ｅ）−ヒドロインダン−４−イリデンエタノール誘導体の製造方法
WO1997027226A2 (fr) * 1996-01-23 1997-07-31 Argonaut Technologies, Inc. Supports de polystyrene ultrafonctionnels a greffe de polyethyleneglycol

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0341158A2 (fr) * 1988-05-04 1989-11-08 Medgenix Diagnostics Nouveaux dérivés de la vitamine D : applications thérapeutiques et aux dosages des métabolites de la vitamine D
EP0373687A1 (fr) * 1988-12-12 1990-06-20 Duphar International Research B.V Procédé de conversion photochimique de tachystérols en prévitamines D et de transvitamines D en cis-vitamines D
JPH0491074A (ja) * 1990-08-03 1992-03-24 Chugai Pharmaceut Co Ltd 新規なビタミンｄ↓３誘導体
WO1992004384A1 (fr) * 1990-08-31 1992-03-19 Regents Of The University Of Minnesota Derives de polyethylene-glycol destines a des applications en phase solide
US5449668A (en) * 1993-06-04 1995-09-12 Duphar International Research B.V. Vitamin D compounds and method of preparing these compounds
WO1995001987A1 (fr) * 1993-07-09 1995-01-19 Genset Procede de synthese d'acides nucleiques sur support solide et comoposes utiles notamment comme support solide dans ledit procede
WO1995034813A1 (fr) * 1994-06-14 1995-12-21 Smithkline Beecham Corporation Resines pour synthese a l'etat solide
JPH08176038A (ja) * 1994-12-26 1996-07-09 Kuraray Co Ltd （ｅ）−ヒドロインダン−４−イリデンエタノール誘導体の製造方法
WO1997027226A2 (fr) * 1996-01-23 1997-07-31 Argonaut Technologies, Inc. Supports de polystyrene ultrafonctionnels a greffe de polyethyleneglycol

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001079165A1 (fr) * 2000-04-18 2001-10-25 Schering Aktiengesellschaft Produit intermediaire de synthese utilise en fabrication de derives d de vitamines
JP2002179727A (ja) * 2000-12-07 2002-06-26 Rikogaku Shinkokai スルホン誘導体及びその製造方法

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