CA1246610A - Process of producing catechol derivatives - Google Patents

Abstract

Abstract of the Disclosure A process of producing a catechol derivative represented by the formula

Description

PROCESS OF ~RODUCING CATECHOL DERIVATIVES

FIELD OF THE INVENTION
This invention relates to process o' producing novel catechol derivatives useful -Eor medicaments and intermediates thereoE.

BACKGROUND OF THE INVENTION
It is generally considered that in allergic astnma and other atopic diseases of man or anaphylactic shock in animals, several chemical mediators are released from lung and other tissues cause troul:les in living bodies, such as the constriction of smooth muscles, e.g., ~ronchi, pulmonary artery, etc., and the enhance-ment of vascular permeability ln the sl~in. As such chemical me~iators, there ar~ histamine and SRS-A (slow reacting substance of anaphylaxis). ~listamine plays an important role in guinea pig anaphylactic shock but not in allergic asthma in man (Eiser, "Pharmac. Ther.", 17, 239-250(1982)), whereas a number of lines evidence suggest that SRS-A is the most important chemical mediator of allergic asthma in man (Brocklehurst, "J.
Physiol." 151, 416-435(l960), Austen and Orange, "Am.
Rev. Resp. Dis.", 12, 423-436(1975); adams and Lichtensteinr "J. Immunol.", 122, 555-562(1979).
The development of the medicaments for the pro-phylaxis, eliminatlon, and reduction of immediate hypersensitlvity reactions was per~ormed amimin~ at inhibiting the production and release of such chemical :: :
mediators o~ antagoni~iny the action oE these chemical ~; : i .

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mediators. As an inhibitor of histamine release, disodium cromoglycate (DSCG) is well known and as an inhibitor of ac~ions induced by histamine, various anti-histamics are commercially available. On the other hand, SRS-A is known as a slow reactive and long acting chemical mediator while histamine is a rapid acting and short acting chemical mediator, and it has recently been recognized that SRS-A :is a mixture of Leukotriens C4, D4 and E4 the structures of which have been clarified by Dr. Samuelsson . SRS A, i. e., ~eukotriens are lipoxigenase products of polyunsaturated fatty acids (in particular, arachidonic acid) and it has been reported that SRS-A has various activities such a5 enhancement of mucus pxoduction, reduction o~
mucociliary transport, coronary artery constrictor action, reduction of cardiac contractility, etc., in addition to the actions in the above-described allerglc reactions. Only a few materials have been known as the medlcaments for inhiblting the production and release of SRS-A or the medicaments antagonizing these actions of SRS-A and they have not yet been clinically used.
As the result of various invenstigations on find:ing medicaments capable of inhibiting the production and release o~ SRS-A or medicaments capable of an~a-gonizing the actions of SRS-A, the inventors have ~: :
discovered that the compounds of this invention as . ~

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described hereinabove are useful as medicaments capable of very strongly inhibiting the formation and release of SRS-A and/or medicaments capable of antagonizing the actions of SRS-A and the present invention has been attained based on the discovery~

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; The invention is a catechol derivative represented by the general ~ormula (1) 0~
r 2--~OR 1 w~lerein R' represents a hydrogen atom.
R2 represents a hydrogen atom or a halogen ato~; X
represents a straight chain or branched alkylene group having 1 to 15 carbon atoms or a vinylene group, Y represents a carbonyl oR3 : group or a group shown by the formula-C- (wherein R3 and R4 which may be the same or different, each represents a hydrogen atom or a lower alkyl group); and Z represents a hydrogen atom, a straight chain or branched alkyl group having 1 to 15 carbon atoms : or cycloalkyl the sum of the carbon atoms or said X and Z being at least 7.
~, - .
~, :
~ : ~ Now, the "lower alkyl group" shown by R3 and R4 in the `i :
~ above-identified general formula is a straight chain or branched r alkyl group having 1 to ~ carbon atoms, ~, '';~

such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a pentyl group, etc.
The "halogen atom" shown by R2 in the foregoing general formula includes a chlorine atom, a bromine atom, an iodine atom and a fluorine atom.
The "straight chain alkylene group" shown by X
includes a methylene group, an ethylene group, a propylene group, a pentanylene group (or pentamethylene group, -(CH2)5-), a hexanylene group (hexamethylene group, -(CH2)6-), a heptanylene group (heptamethylene group, -(CE~2)7-), a nonanylene group (nonamethylene group, -(CH2)g-)~ an undecanylene gorup (undecamethylene group, -(CH2)11-), a tridecanylene ~roup (tridecametylene group, -(CH2)13-), a tetradecanylene group (tetradeca- - ---methylene group, -(CH2)14-), a pentadecanylene group (pentadecamethylene group, -(CH2)15-), etc. Also, the "branched alkylene group" shown by X includes the above-described straight chain alkyl groups having a lower alkyl group of l to 5 carbon atoms at the optional posltion thereof. Specific examples of the branched alkylene group are a propylene ~roup (-CHCH2-~, an : CH3 ethylethylene group (-CH2fH-),etc.

~ CH2CH3 : ~ OR3 Exa~lples of the group shown by -C- represented by : R4:
Y ln the foregoing general formula are a hydroxymethylene -:~
.

, 5 ~
group, a methoxymethylene group, a methylhydroxymethylene group (-C-), a methylmethoxymethylene group (-C-) 9 an ethylhydroxy-~H3 OH ~H3 ~ethylene group (-G-), etc.
IH2C~3 The "straight chain alkyl group" shown by Z in the foregoing general formula includes a propyl group, a pentyl group, a hexyl group, an octyl group, a nonyl group, a decyl group, a undecyl group, etc. Also9 the "branched alkyl group" shown by Z includes alkyl groups having a lower alkyl group of 1 to 5 carbon atoms at an optional position thereof and specific examples are an isopropyl group, an isobutyl group, a 1-methylhexyl group, a 1-ethylpentyl group, a 1,5-dimethylhexyl group, a 2,3,5-trimethyl-heptyl group, a 4-propylnonyl group, a l-hexylpeptyl group, etc.
Also, the "cycloalkyl group" shown by Z includes a cyclopentyl group, a cyclohexyl group, etc.
When X represents a branched alkylene group9 Y represents the group shown by -C-, and/or Z represents a branched alkyl group, which has a different alkyl groups on a branched carbon atom, the ; compound of this invention shown by the above described general formula has at least one asymmetric carbon atom. Thus, the desired compounds of this invention include each separated ~ steroisomer based on the asymmeteric carbon atom and a mixture of ; : these steroisomers.
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Since the compounds of this invention shown by general forl~ula (I) inhibit very potently the formation and release of SRS-~, the compounds are useful for the prophylaxis and treatment for various allergic diseases (e. g., bronchial asthma, allergic rhinitis~ and urticaria) and ischemic heart diseas~s and inflamations caused by SRS~A.

Pharmacological experiment A) Passi~e peritoneal anaphylaxis(PPA) n rats The method was based on that of Orange et al1).
Briefly, male Wistar rats weighing 275 to 325 g (Shizuoka Fxp. Animal Agric, Coop. ~ssoc.) were sensi-tized by intraperitoneally (i.p.) injecting 5 ml of diluted (40-fold) mouse anti~DN~ reaginic serum (PCA
titer: 1280). After 4 hr, 5 ml of Tyrode solution containing 250 ~g heparin and 2 mg DNP-3SA was injected i.p. Test drugs (100 ~g/kg) were dissolved in 0.6 ml of saline and injected i.p. 30 sec before antigen administration. Five min,later, the rats were decapi-tated and the peritoneal fluid was collected by opening the peritoneal cavity into polycarbonate tubes in ice.
The supernatant was separated for bioassay from the cellular residue by centrifugation at 2000 rpm for ;

min at 4~C.
Histamine and SRS-A were assayed using isolated guinea-pig ile~ in the presence of 10 7M FPL-55712 and .
10 61~ mepyramine, respectively, in addition ~o S x 10 7 M atropine.

~,, ' ' One unit of CRS-A refers to the concentration required to produce a contraction Ot the guinea-pig ileum equal in amplitude to that produced by 5 ng histamine base in that assay.
1) Orange et al (1970) J. Immunol. 105, 10~7-1095 .: , :

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~ ol As shown in Table 1, the compounds of this invention more effectively inhibited the antigen-induced SRS-A release -than histamine release, whereas DSCG inhibited the histamine release 7 n a relatively selective manner.
These results suggest tha~ there is a difference of the actions between the compounds of this invention and DSCG.
B) Assay of 5-lipoxy~enase and cyclooxyvenase The method was based on that of Koshihara et all).
In the case of assay of 5-lipoxygenase activity, enzyme fraction from mastocytoma P-815 cells (107 cells/ml) was incubated with 0.2 ~Ci [1-14C]-arachidonic acid (56.9 Ci/mol~, 0 ~ mM CaC12, 2 x 10 5~l lndoemthacin and various concentrations of test drugs at 37C for 5 min.
In the case of assay of cyclooxygenase activity, CaC12 ~and indomethacin were omitted from the above lncubatio~n mixture and incubation was performed at 37C for~7 min.
Both reactions were teTminated by adjusting -the p~i of~
the~mixture to~3.0 ~ith HCl. After extraction of the ` products with 8;volume ethyl acetate, each e~tract l~as concentrated and applied to TLC plate. For the separation of HET~s and prostaglandins) thin-layer chromatogr~aphr~;~vas~carrled out uslng solvent system:~
pe~troleum~ether/dlethyl ether/acetic acid (50:50:l~ and ethyl~acetate/2~,2,~4-trimethylpentane/acetic acld/water (ll 5 2.lQ, upper~phase),;respectively. ~Radloactive spo~ts~were dete~cted by auroradiography and scraped off : :: ~ : :

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and counted using liquid scintillation spectrometer.
The activities o-f 5-lipoxygenase and cycloo~ygenase were expressed as the sum of radioactivities due to 5-HETE and 5,12-diHETE and due to PGD2, PGE2 and PGF2U
respectively. The IC 50 values were calculated by Probit method.
1) Koshihara et al. ~1982) FEBS Letters 143, 13-16.

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The conlpounds of this invention dose-dependently inhibited the formation of 5-lipoxygenase products in doses between 0.01 to 10 ~M; their IC 50 values were shown in Table 2. On the contrary, at 10 ~M they showed weak inhibition or enhancement of the formation of cyclooxygenase products.
These results indicate that the compounds of this invention specifically inhibit 5-lipo~ygenase.
The compounds of this in~ention shown by general formula (I) can be stably administered orally or paren-; terally by themselves or as medicament compositions [e.g., tablets, capsuels (including soft capsules, microcapsules, etc.,), po~ders, granules, pills, ointments, syrups,injections, inhala~ors, plasters, etc.,~ mi~ed with known pharmaceutically allowable carriers, excepients, etc. The doses thereof depend upon the subject to be administered, the manner of administration, the condition of disease, etc.~ but are ordinary 0.1 to 500 mg per day per adult and is proper to admlnister orally or parenterally in two or three times per day.
Thé compounds of this invention shown by generalformula (I) can be prepared by the methods shown in thé following reaction formulae:

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0~ ~
?~

~?hen ~' in (_I) lS -v:nen .~' ln (I, ) _5 2n alkylene 5~oU? o_ 1 - ( C~i2 )m ~ CH=C~;-to 1; carbon z ,olr.s OR ' , OH / Oi~
,~ OR 1 ~OR~ ~ ~

~" - C~ - Z X ' ~ 2 ) ~ ct~ ~v,~ ( O, v ) _ Z

( __ 3 ) 0~ 1 ~
OP~-X-Y-Z (I ) where~in Rl, R2! X, Y, and Z have the same significance as defined above; R' represents a protective group for the hydroxy group capable of being easily removed; Rl' represents a protective group for the hydroxy group capable of being easily removed xl represents a straight chain or branched alkylene group having 1 to 15 carbon atoms, an ~lkenylene group represented by the ~: formula -(CH2)m',CH=CH-(wherein m represents O or an integer O

~ of 1 ~o 13j, a group represented by the formula -C-~CH2)m"- :
i ; ~ (wherein m" represents an integer of 1 to 14)~ or a ~roup : represented by the : ~ :
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l 6~ 6~
OH
general formula -CH-(CH2)m" - (wherein m" has the same significance as above); said (CH2)m' - and - (CH2)m" -may have branch; Y' represents a carbonyl group or oR3 l a group shown by -C- (R3'and R4, which may be the same or different, each represents a hydrogen atom or a lower alkyl group;

said R3' may mean a protective group for a hydroxy group; the sum of said X' and Z being at least 7.
In the above-described methods, a 1-(3-hydroxy(or 3-lower alkoxy)-4-hydroxyphenyl)alkane of general formula (1) is produced by reducing or hydrolyzing the corresponding 1-(3,4-disubstituted phenyl)alkane or 1-~3,4-disubstituted phenyl)alkene. The reduction includes ~a) the removal of the protective group for tl the hydroxy group, (b) the reduction of a carbonyl group (-C-) OH
shown by Y' into a hydroxymethylene group (-CH-), and (c) the saturation of an unsaturated bond (alkenylene group alkylene group).
The reduction may be performed in an optical order.
Also, by properly selecting the condition, the reduction may be a partial reduction.
The removal of the protection group for hydroxy group of the foregoing reduction (a) differs according to the kind of the protective group. In the production method of the compounds of this invention, a benzyl group, a p-methoxybenzyl group, a ben~yloxycarbonyl group, a methoxymethyl group, an acetyl group, a benzoyl group, etc~, are employed as a protective group and the removal of the protective group is usually performed by a catalytic reduction using palladium-carbon as a catalyst, the reduction by metallic sodium in liquid ammonia, an acid hydrolysis or an alkali hydrolysis.
The conversion of a carbonyl group into a corresponding hydroxymethylene group of reduction ~b) is performed by a chemical reducing using aluminum lithium hydride (LiAlH4), sodium boron hydride (NaBH4), etc., or a catalytic reduction using palladium-carbon, etc.
Also, the reduction of an alkenylene group ~-(CH2)m~CH=CH-) into an alkylene group (-tCH2)mlCH2CH2-) of the reudction (c) is performed by a catalytic redUction using palladium-carbon, Raneynickel catalyst, platinum black, etc.
For the production methods of the compounds o~
this invention shown by general formula (I), there are further a halogenation of a benzene ring, a lower alokxylation of a hydroxy group, etc. These reactions are performed by ordinary manners.
Then, the following examples are intended to llustrate the compounds of this invention shown by ~formula (I) and the production methods of the compounds ~but not to limit in any way.
In addtion, since the raw materials used in the following examples include novel compounds, the production methods of these compounds are explained by , , ~66 :~

the following reference examples Reference Example 1 (a) OCH2 ~ d OCH_ O CH2 ~ (cH~O)2pcH2ccH(cH2)~
CHO O CH2 ~

CH=CHCCH(CH2)3c~3 ~H3 While stirring a mixture of 400 mg of oily sodium hydride ~60~) and 50 m1 of 1l2-dimethoxyethane, a mixture of 2.36 g of dimethyl (3-methyl-2-oxo)heptyl phosphonate and 5 ml of dimeth-oxyethane was added dropwise to the mixture at 20Dto 25~C. Then, af~er stirring the resultant mixture for 2 hours at room temperature~ the reaction mixture was cooled to 5 to 7 C and a mixture of 2.3 g of 3,4-dibenzyloxybenzaldehyde and 5 ml of dimethoxyethane was added dropwise to the reaction mixture.
After stirring the reaction mixture for 2 hours at room temperature, 300 ml of water was added to the reaction mixture and the product was extracted with 50 ml of toluene-n-hexane ~1:1).
The extract was washed with water, dried over anhydrous magnesîum sulfate; and concentrated under reduced pressure to provide a sticky residue. The residue was applied to silica gel (70-ml) column chromatography and eluted ~ith a mixture of n-hexane and ether (4:1) to provide 1.2 g of 1-(3~4-diben~yloxyphenyl)-4-methyl-1-octen-3-one.

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ting point 62 - 64C.
Reference Example 1 (b) (Raw material in Example 1) ~0 CH2 ~

CH=cHcc,H(cll2)3c~l3 CH=CHCHCH~CHz)3CH3 CH~ I I
~ OHCH3 To a mixture obtained by adding 0.1 ~ of lithium aluminum hydride to 20 ml of ether was added 0.55 CJ of 1-(3,4-dibenzyloxyphenyl~-1-octen-3-one under ice-cooling and the mixture was stirred for one hour at room temperature. TQ the reaction mixture was yradually addecl 10 ml of an aqueous 10% hydro-chloric acid solution and the ether layer was collected, washed with water, and concentrated under reduced pressure to provide a solid product.
By washing the product with a mixture of ether and n-hexane ~1 : 3), 0.4 g of 1-~3,4-dibenzyloxyphenyl)-4-methyl-1-octen -3-ol ~s Obtained.
~101tin~ POint 77- 78C.
Then, by following the same procedures as in Reference Example 1 (a) and ~b), the following compounds o~f~Reference Exampl~e 2 (a) and (b) were obtained and by fo1lowing~the same procedure as in ReEerence Example 1 (a~), the followlng compound~s of Reference Examples 3 to 7 were obtained.

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Refe~ence E~ample 2 (a) (Ra~l material in Example 3) @ ~ C~-130)2Pc~l2c(c~l2)5 ~ ~ CH2- ~

CHO CH-cHc(cH2)5cH3 1-(3,4-Dibenzyloxyphenyl)-l-nonen-3-one. Melting point 78 - 80C.
Elemental analysis for C~gH3203:
C H
Calculated: 81.27% 7.53%
Found: 81.21% 7.65%
Reference Example 2 (b) (Raw material in Example 2) ~IJslng the compouncl obtained in th~ above step ~a)) CH2~g) f;~ OCH2~

CH=CHCH(CH2~5CH3 OH
1-~3,4-Dibenzyloxyphenyl)-l-nonen-3-ol. Melting point 90 - 92C.
Reference Example 3 (Raw material in Example 4 OCH~ ~ O O OCH
CH2 ~ (CH30)z CH2C(CH2)11CH3~ ~

CH=CHC(CH2)11CH3 3,4-Dibenzyloxyphenyl~ pentadecen -3-one.
Meltlng pOillt 81 - 82 C.

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~lementa~ analysis for C35H~ ,03 C H
Calculated: 81.99% 8.65%
Found: 81.78% 8.81%

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. , Reference Example 4 ~Raw material in Example 5) /~OCH ~ 11 11 1 ~.o CH2~

2 (CH o)2pcH2ccH(cH2)3cH3 ~ J
ili 2 3 CHO CH=CHCC~(CH2)3CH3 1-(3~4-Dibenzyloxyphenyl)-4-ethyl-1-octen-3-one.
Oily product.
Nuclear magnetic resonance spectra (in CDC13, TMS internal standard, ppm.) 0.86(6H), 1.1-1.9(8H), 2.65(1H), 5.15(4H), 6.4-7.6(15H).
Re~erence Example S (Raw material i.n Example 6) CH2-~ 0 CH24~
CH2 ~ (cH3o)2pcH2c(cH2)2cH3 ~ 2 ~

CHO CH=CHC(CH2)2CH3 ].-(3,4-Dibenzyloxyphenyl)-l-hexen-3-one.
Melting point 82 - 84C
Elemental analysis for C26H263 C H
Calculated: 80.80% 6.78%
~ Found: ~80.80~ 6.81%
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Reference E~ample 6 (Raw mate~ial in Example 7 OCH2~ 0 0 OCH
~-OCH2 (CH30)2pcH2c(cH~)4cH3 ~ OCH

CHO CH=cHc(cH2)4cH3 1-(3,4-Dibenzyloxyphenyl)-l-octen-3-on~.
Melting point 71 - 73C
Elemental analysis for C28H30O3:
C H
Calculated: 81.13~ . 7.29%
Found: 80.91~ 7.47%
Reference Example 7 (Raw material in Exampl.e 8) OCH2~ 0 CH2~3) ~,OCH2~ ~f)CH
(C~130)2PcH~c(cH2)6cH3 ~ y o~
CHO CN=CHC(CH2)6CH3 1-(3,4-Dibenzyloxyphenyl)-l-decen-3-one.
Melting point 73 - 75C
Elemental analysis ~or C30H34O3:~
C H
Calculated: 81.41~ 7.74%
Found: 81.26~ 7.97%
In addition, the properties and production methods o~ dimethyl 2-oxoalkylphosphonates used in the above re~ference examples are shown below.

.

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Method A:

Il n-BuLi ~CH30)2P~H3 + CH3cH2cH2cooc2Hs O O
1~ 11 (CH30)2PcH2ccH2cH2cH3 In 65 ml of anhydrous tetrahydrofuran was dissolved 12.75 g of dimethyl methylphosphonate and the solution was cooled below -70C. Then, while stirring the solution under nitrogen stream, 67 ml of a hexane solution (lO viW%) of n-butyl lithium (n-BuLi) cooled below -70C was added dropwise to the solution over a 30 minute period and the mixture was stirred for lS minutes a-t the same temperature. Then, a solution o 5.8 g o~ ethyl n-butyrate in 15 Inl of anhydrous tetrallydro-furan cooled below -70C was added dropwise to the mixture over a lS minute period and the resultant mixture was stirred for l.5 hours below -7~0C and then : for 2 hours at room temperature.
~; ~ The reaction mixture thus obtained was ice-cooled, mixed with lO ml of glacial acetic acid, and the solvent ~as distilled off from the mixture under reduced pressure. To the residue was added 50 ml of water and~the product was extracted thrice each time with 50 ml of ethyl ether. The extracts were combined with each other and washed twice each time with 20 ml o~ a satura~ted agueous sod-um chlor1de so1ut1on. After drying the extract by anhydrous magnesium sul.ate, the so1vent was distill~ed off under~reduced pressure and the residue was vacuum-distiIled to provide :

~ , 9.7 g of dimethyl ~-o~o pentylphosphonate.
Boiling point 95-97C/0.9 mm Hg.
By following the procedure as in Method A, the phosphonate compounds having the following -formulae were prepared.
Boil:ing point Q o ~CH30)2PCH2c(cH2)4cH3 113 115C/0. 8 mm Hg O O
(CH30)2PcH2c(c~2)6cH3 129-132C/O.9 mm Hg O ~IIH2CH3 (CH30)2PC~2 ( 2)3 3 126-128C/0.85 mm Hg (CH30)2Pc~l2cc~(cH2)3c 3 104-108C/0.25 mm Hg O O
(CH30)2PcH2c(cH2)5c 3 120-123C/O. a mm Hg ~ lethod B:
O (~
~I li (cH30)2pcH2c(cH2)llcH3 A mixture of 2.5 g of dimethyl methylphosphonate and 15 ml Oe anhydrous tetrahydroEuran was cooled below -70C and 13.5 rnl of a hexane solution (10 v/w%) of n-butyl lithium cooled below -70C was added dropwise to the rnixture with stirring under nitrogen stream over a 30 minute period followed by stlrring for 15 minutes ~at the same temperature. Then, a mixture of 2.4 g of ethyl tridecanoate and 5 ml of anhydrous tetrahydro-furan was added dropwise~o the mixture over a 10 minute period and the resultant mixture was stirred eOr 1 hour at a ~temperature below -70C and then for 2 hours at `

room temperature.
The reaction mixture thus obtained was ice-cooled, mixed with 2 ml of glacial acetic acid, the mixture was concentrated under reduced pressure~ and then extracted thrice each time with 10 ml of ethyl ether. The extracts were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide an oily product. The oily produce ~las applied to silica gel (40 ml~ column chromatography and eluted with ethyl ether to provide 2.5 g of dimethyl 2-oxo-tetradecanoylphosphonate.
Boilin~ polnt 37-38C.
Reference Example 8 (Raw material in Example 13) OC~12 ~ OCH
~)CH2~ > ~_ OCH

CH2CHO CH2lH(CH2)7cH3 OH
After gradùally adding 0.5 g of 3,4-dibenzyloxy-phenyl_acetaldehyde to 10 mg of an ether solution of n-octylmagnesium bromide obtained from 0.12 g of magnesium and 0.97 g of n-octyl bromide, the mixture was stirred for 30 minutes at room temperature. To the reaction mixture thus obtained was added 10 ml of an acid aqueous 5~ hydrochloric/ solu~tion and aEter stirring the mixture/ the ether layer was collected.
The~ether solution was washed with water, dried Q~er anhydrous magneslum sulfate, and concentrated under : ::

reduced pressure to provide 0.5 g of 1-(3,4-dibenzyl-oxyphenyl)-2-clecanol.
Melting point 55-57C (n-hexane~.
Elemental analysis for C30H38O3:
C H
Calculated: 80.54% 8.78%
Found: 80.68% 8.58~
By following the procedure as in Reference Example 8, the following compounds (Reference Examples 9 to 11) were prepared. The names of these cornpounds are shown below together with the melting points and/or nuclear magnetic resonance spectra (in CDC13, TMS
internal standard, ppm).
Reference Example 9 (Raw material i.n Example 16) 1-(3,4-Dibengyloxyphenyl)-2-nonanol.

0.7-1.6(15H), 2.57(2H), 3.63(1H), 5.08(4H~, ~ 6.5-7.5(13H).
: Reference Example 10 (Raw material i.n Example 17) -1-(3,4-Dibenzyloxyphenyl)-2-undecanol.

Melting point 55-57 C.

0.7-1.6(19H), 2.57(2H), 3.59(1H), 5.07(4H), : :6.5-7.5(13H).

Elemental analysis for C31H40O3: :

C H

; Calculated: 80.83% 8.75 Found: 80.83% : 8.89 .

.

Reference Example 11 (Raw material in Example 18) 2-(3,4-Dibenzyloxyphenyl)-l-cyclohexyl-l--ethanol.
Melting point 73-75C.
Elemental analysis for C28H32O3:
C H
Calculatedi 80.73% 7.74%
Found: 80.65% 7.80%
Reference Example 12 (Raw material in Example 143 OCH2 ~ C~2 ~,0 CH2~ ~OCH2~

CH2CH~CH2)8cH3 C112C(C~2!8CH3 To a mixture of 15 ml of methylene chloride and 1.2 ml of pyridine was gradually added 2 g of chromic anhydride under cooling to 0C to -5C and after stirr-ing the mixture for 10 minutes at 0 to -3C, a solution of 0.9 g of 3,4-dibenzyloxyphenyl-2-undecanol in 3 ml of methylene chloride was added to the mixture.
After further stirring the mixture for 20 minutes at 0 to 10C, the supernatent methylene chloride solution was concentrated under reduced pressure. The residue was appllèd to silica gel~column chromatography ; and eluted with toluene to provide 0.8 g of 1-(3,4-dibenzyloxyphenyl)-2-undecanone.
Melting point 68C.

.

~ ' ..

E~emen~al analysis for C31H3~O3:

C H

Calculated: 81.18% 8.35Ps Found: 81.13% 8.28~

Reference Example 13 (Ra~i material in Example 15) OCH2 ~ OCH2 ~
f~ OCH2~ ~ OCE!2-~
(CH30)2P-c~2c(c~2)5 3 ~
--,~ 1 o CH CHO ~l 2 CH2CH=CHC(C~2)5CH3 To a solution obtained by adding 200 mg of oily sodium hydride (60~) to a mixture of 25 ml of 1,2-dimethoxyethane and 10 ml of dimethyl sulfoxide was added d~opwise a mi~ture of 1.2 g of diemthyl 2-oxo-octylphosphonate and 3 ml of dimethoxyethane at 20 to 25C. Thereaf-ter, the mixture was stirred for 2 hours at room temperature and after adding thereto small pieces of dry ice, the mixture was further stirred for 5 minutes. To the reaction mixture was added 200 ml of water and the product was extracted with toluene. The extract was washed with water, dried o~er anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was applied to silica gel column chromatographyand eluted with a mixture of toluene and ethyl acetate (10 : 1) to provide 0.5 g of 1-(3,4-dibenzyloxyphenyl~-2-decen-4-one as an olly product.
~ Nuclear magnetic resonance spectra (in CDC13, T.~S

: ~:

,. ~, ~66~

internal standard, ppm) 0.7-1.8(11H~, 2.42(2H), 3~24(2H), 5.09(4H)9 6.0-7.7(15H) Reference Example 14 ~Raw material in Example 19) By following the procedure as in Reference Example 13, 1-(3,4-dibenzyloxyphenyl)-3-decen-5-one was obtained from 1-(3,4-dibenzyloxyphenyl)propionaldehyde and dimethyl 2 oxohexyl-phosphonate.
Melting point 38 - 39~C.
Elemental ànalysis for C30H343:
C H
Calculated: 81.41~ 7O74 Found: 81.48X 7.76~
Reference Example 15 (Raw material in Example 20) (a) OCEI2 ~ OCH~
OCH2~ Br ~pC~2~

~JJ 3 ( 2 ) 4 COOH ? ~ :
CEO C~= CH ( C~2 ) 3 COO~
pH
O%pd_~ ~ 0 ~1 . .
(CH2) ;cooa A mix~ure of 2 g of oily sodium hydride (60~) and 90 ml of dimethyl sulfoxide was stirred for l hour at 55 - 60~C and then allowed to cool to room temperature. To the mixture was added dropwise a mixture of ll g of (4-carboxybutyl)triphenylphosphonium bromide and 2S ml of dimethy-l sulfoxide at room temperature.
Thereafter, the mixture was stirred for 30 minutes at room temperature '- .
~, . . .

. . . .

6~

and then to the reaction mixture was added drop~ise a mixture of 8 g of 3,4-dibenzyloxybenzaldehyde and 30 ml of dimethyl sulfoxide.
After further stirring the mixture for one hour at room temperature, 5 g of dry ice was added to the reaction mixture and after further adding thereto 250 ml of water and 50 ml of àn aqueous 10~ hydrochloric acid solution, the product was extracted with 300 ml of ether. The extract was washed with water, dried over anhydrous magnèsium sulfate, and concentrated under reduced pressure to provide a sticky product. The product was applied to silica gel (150 ml) column chromatography and eluted with a mixture of n-hexane and ether (1 1) to provide 8.5 9 of 6-(3,4-dibenzyloxyphenyl)-5-hexenoic acid. The product was dissolved in 30 ml of ethanol and catalytically reduced using 1 g of 10~
palladium-carbon as a catalyst until the absorption of hydrogen stopped. Then, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to provide 3.8 g of 6-(3,4-dihydroxyphenyl)hexanoic acid. 'Melting point 109 C.

',~

, (b) ~0~1~ CH2~ ~ , (~H2)5COOH (CH2)scOocH2 ~
OCH2 g~ OCH2 -~
~OCH2 ~ ~ ~DCH

(CH2)60H (CH2)6Br A mixture of 3.8 g of 6-(3,4-dihydroxyphenyl)-hexanoic acid, 3.6 g o~ benzyl chloride, 9.4 g of potassium carbonate, 0.1 g of potassium iodide, 0.1 g of tetra-n-butylammonium bromi.de, and 50 ml of N~M-dimethylfor~amide was stirred overnight at room temperature. After the reaction was over, 200 ml of water was added to the reaction mixture and the product was extracted thrice each time uith 100 ml of ether. The extracts were combined with each other, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide a sti.cky product. The product was applied to silica gel (150 ml~ column chromatography and eluted with a mixture of toluene and ethyl acetate (19 1) to : : ~
provide 3.4 g of benzyl 6-(3,4-dibenzylo~yphenyl)-hexanate.
:: : ` : : :
~ I~he product thus obtained was dissolved in 20 ml of .
ether~and the~solution was added dropwise to a~mixture of 0.5 g of lithium aluminum hydrlde and S0 ml of etner : : :
~ under ice-coolin~. Thereafter, the mixture was stirred 6~

for one hour at room temperature and 30 ml of an aqueous 10~
hydrochloric acid solution was added to the reaction mixture under ice-cooling. The organic layer thus formed was collected, washed with water, dried over anhydrous magnesium sulfate, and concentrated und~r reduced pressure to provide a sticky product.
The product was applied to silica gel (100 ml) column chromatography and eluted with a mixture of toluene and ethyl acetate (4:1) to provide 1.95 g of 6-(3,4-dibenzyloxyphenyl)~
hexanol.
The product was dissolved in 10 ml of methylene chloride and the solution was added dropwise at room temperaturè to a methylene chloride solution (containing 0.45 g of pyridine) of triphenylphosphinedibromide prepared from 1.57 g of triphenyl-phosphine and 0.88 g of bromine. Thereafter, the mixture was stirred overnight at room temperature and the reaction mixture thus obtained was washed with diluted hydrochloric acid, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure~ The residue was applied to silica gel (50 ml) column chromatography and eluted with a mixture of n-hexane~and toluene (2:1) to provide 1.08 g of 6-(3,4-dibenzyloxyphenyl)hexyl bromide as an oil.
Nuclear magnetic resonance spectra (in CDC13, TMS internal standard, ppm) 1.0-2.0(8H), 2,50(2H~, 3.38(2H)~ 5,13(2H)~ 5.16(2H), 6.6 -6.92(3H), 7.10 7,60 (lOH).
:, , .
,.
. . , ( C ) OCH~ OC~
OCH2 ~ ~C~2 (CH2)6 Br (C~2)7CCH.3 A mixture of 0.5 g of 6-(3,4-dibenzyloxyphenyl)hexyl bromide, 0~12 g of actyl~cetone, 0.15 g of potassium carbonate, 0.02 g of sodium iodide, and 5 ml of ethanol was refluxed for 20 hours. To the reaction mixture was added 1~ ml of water and the product was extracted with 20 ml of ether. The extract was washed with wa~er, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide a sticky product. The product was applied to silica gel (45 ml) column chromatography and eluted with ~ mixture of toluene and ethyl acetate (30:1) to provide 33 mg of 9-(3,4-dibenzyloxyphenyl)-2-nonanone as an oil.
Nuclear magnetic resonance spectra (in CDCl3, TMS internal s~an dard, ppm):
1.0~2~0(1~H)~ 2.10(3H), 2.20-2.70(4H), 3.0B(2H), 3.10(2H), 6.50 - 7.0(3H)9 7.20 - 7.60(10H~.

'`~

:
.

.

Reference Example 16 ~;, DCN2~ CH31 f~3 2~3 CH=cHcHcH(cH2)3cH3 CH=C~TH--- IH(C~2)3 3 OUCH3OCH3 C~3 To a mixture of 130 mg of oily sodium hydride (60%) and 15 ml of N,N-dimethylformamide were added dropwise, in succession, a solution of 1.27 g of 1-(3,4-dibenzyloxyphenyl)-4-methyl-l-octen-3-ol obtained in Reference Example 1 in 5 ml of N9N-dime~hylformamide and 500 mg of methyl iodide with stirring under ice-cooling. After stirring the mixture overnight at room temperature, 150 ml of water was added to the reaction mixture and the product was extracted with 30 ml of ethyl acetate. The extract was wash,ed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide a sticky product. The product was applied to silica gel (40~9) column chromatography and eluted with a mixture of n-hexane and ether (4:1) to provide 97D mg of 1-(3,4-dibenzy~oxyphenyl)-3-methoxy-4-methyl-1-octene. Melting point 36 - 38 C.

:
, ,:

~; ' ', ' :

, , ~. ' .

Reference Example 17 (Raw material in Example 23) (a) ClCH2 ~
HO(CH2)100H ' - ~ HO(cH2)loocH2 ~) In 20 ml of xylene was dissolved 35 g of decanediol by heating and after adding thereto 1.65 g of metallic sodium at 130 C, the mixture was heated for one hour at 125 to 130 C. To the reaction mixture was added dropwise 9.5 g of benzyl chloride at 120--130 C and the mixture was further heated for one hour at 130 C. The reaction mixture was cooled to 110 C and after adding thereto 50 ml of toluene, the mixture was filtered while the mixture was in a ho, state. The filtrate was ice-coolecl to pr~-ipitate crystals, which were collectsd by filtration to recover 24 g of decanediol used as the ra-~ m~terial. On the other hand, the filtrate was concentrated under reduced press~re to ~rovide an oily product. The product WIS
applied to silica gel column chromatography and eluted with a mixture of ~oluene and ethyl acetate (8 : 2) to provide 13 g of oily 10-benzyloxy-1-decanol.
Nuclear magentic resonance spectra (in CDC13, TMS, ppm):
1.1-2.0(16H,(CH2) a ), 3.43(2H, t, - CH ? o~

3.59/~-~2H, t, -CH2-OH), 4.47(2H, s, -OCH2- ~ ), 28(5H, H of benzene ring) ~ . , :

' ' (b) ~O(~H2)loocH2 ~ 2~ Cl(CH2)1oOCH2~ ~

A mlxture of 7 g of 10-benzyloxy-1-decanol, 8 ml of thionyl chloride, and 0.2 ml of dimethylformamide was heated to 50 to 60 C for one hour. After the reaction was over, the reaction mi~ture was concentrated under reduced pressure, the residue was dissolved in 50 ml of n-hexane, and after washing the solution with water, the solution over was dried / ~anhydrous magnesium sulfate. Then, the solvent was distilled off and the residue was applied to silica yel column chromatography and eluted with toluene to provide 6.7 g of oily 10-benzylo,cy-1-chlorodecane. Boiling point 135 - 140C (0.6 - 0.9 mm Hg).
Nuclear ~agnetic resonance spectra ~in CDC13, TMS 7 ppm):
1-1-2.0(16H, (CH2)8), 3~43(2H, t, -CH2-0-), 3.49(2H~ t, -CH2Cl), 4.47(2H, s, -OCH2-~, 7.28(5H, H of benzene riny).

( c ) OCH2 ~ 2 2 Ci(CH2)100~H2 ~ ~ OC 2 C~10 C~ ~C~ o ~ ~9 ~~ OH

:~ : :: :
:

:
' To a mixture of 1 ml o-f anhydrous ether and 0.6 g of metallic magnesium were added 0.1 ml of ethyl iodide and a piece of iodine crystal followed by heating to initiate the reac-tion and then a mixture of 6.7 g oflO-benzyloxy-l-chlorodecane and 10 ml of anhydrous ether was added dropwise to the aforesaid mixture.
After the reaction was over, the reaction mixture was refluxed for 2 hours. After cooling, the reaction mixture was added dropwise to a solution of 6 g of 3,4-dibenzyloxybenzaldehyde dissolved in 30 ml of tetrahydrofuran at 0 to 5C. Thereafter, the mixture was stirred for 30 minutes at room temperature and after adding 300 ml of an aqueou~ 1~
hydrochloric acid solution to the reaction mixture, the product was extracted with 100 ml of toluene. me over /
extract was washed with water, dried / anhydrous magnesium sulfate, and then the solvent was distilled off under~reduced pressure. The residue was dissovled in 30 ml of ethanol, the solution was allowed to stand overnight under cooling to 0 to 5C, and the crystals thus precipitated were collected by filtration.
By drying the crystals, S g of ll-benzylo~y-1-(3,4-dibenzyloxyphenyl)-l-undecanol was obtained. Melting polnt 50 - 52C.
Elemental analysis for C3~H46O4 C

Calculated: 80.~3~ 8.18~5 Found: 80.5S% 7.94 " ~ , ., .

.

6~ L0 Reference Example 18 (Raw material in Example 24) (a) To a mixture of 2.16 9 of benzyl alcohol and 30 ml of dimethylformamide was added 1.2 9 of oily sodium hydride (60X).
After stirring the mixture for 30 minutes at 20to 25 Cl 10 9 of 1,12-dibromo-dodecane was added to the mixture in one portion foilowed by stirring for 2 hours at 25~to 30D(. After the reaction was oYer, 30C ml of water was added to the reaction mixture and the~product was extracted with n-hexane. The extract was washed with water, dried over anhydrous magnexium sulfate, and then, the solvent was distilled off. The oily residue was applied to silica gel column chromatography and eluted with a mixtLlre Qf n-hexane and ether (9:1) to provide 3.8 9 of 12-benzyloxy-1-bro~lododecane as an oily product.
Nuclear magnetic resonance spectra tin CDC13, TMS, ppm~:
1.1 - 2.0(20H,-(CH2)10-), 3.38(2H, t, -CH2-Br), 3.44(2H, t, -CH2-0-), 4.47(2H, s, -OCH2 ~ ), 7.28(5H 9 H of benzene ring) (b) By following the procedure as in Reference Example 17-(c) using the compound in the above step (a~, the following compound was obtained.

~66~
1-Benzyloxy-13-(3,4-dibenzyloxyphenyl)-1-tridecanol. Melting point 51 - 53C.
Elemental analysis for C40H504 C H
Calculated~ 80.77~ 8.47 Found: 81.01~ 8.74%
Reference Example l9A (Raw material in Example 25A) (a) 3y foll~owing the procedure as in Reference Example 18 (a) using 1,8-dibromooctane, 8-benzyloxy-1-bromooctane was obtained as an oily product.
Nuclear magnetic resonance spectra (in CDCl3, TMS, ppm) 1.1-2.1(12H, -(CH2)6-), 3.38(2H, t, -CH2Br), 3.44(2H, t, -CH20-), 4.47~2H, s, -OCH2- ~ ), 7.28 (5H, H of benzene ring).
(b) By following the procedure as in Reference Example 17~c) using the compound obtained in the above step (a), 9-benzyloxy-1-(3,4-dibenzyloxyphenyl)-1-nonanol was obtained. Melting point 46 - 48 C. ~ ~
Elemental analysis for C36H424:
C H
Calculated: 80.26~ 7.86~
Found: 80.08g 7.90%

~: :

:: :
:

: `: ~ : ' : : .
`, :~
"

: :

i6~

Reference Example 19B (Raw material in Example 25B) (a) By following the procedure as in Reference Example 17(a) and (b) using nonanediol, 9-benzyloxy-1-chlorononane was obtained. Boiling point 128 - 130C
(0.6 - 0.7 mmHg).
(b) By following the procedure as in Reference Example 17(c) using 9-benzyloxy-1-chlorononane, 10-benzyloxy-1-(3,4-dibenzyloxyphenyl)-1-decanol was obtained. Melting point 45 - 47C.
Elemental analysis for C37~4O4:
C H
Calculated: 80.40% 8.02~
Found: 80.30% 8.02%

Reference Example 20 (Raw material in Example 26) By following the procedure as in Reference Example 17(c) using 4-benzyloxy-3-methoxybenzaldehyde and~10~
benzyloxy-1-chlorodecane, 11-bezyloxy-1-(4-benzyloxy-3-methoxyphenyl)-1-undecanol was obtained.
; Melting point 43 - 45C.
Elemental analysis for C32H42O4:
C H
Calculated: 78.33% 8.63 ~ Found: 78.24~ 8.62 `': ~ :

~`' ,: : '~';'''., ~ ' :

~2 Reference Example 21 (Raw material in Example 27) OCOCH O O

_OCH3 NaH, (CH3)2Pc~2ctc 2)5 3 CE~O

~3flCOCH3 O
CH=C~C~c~2~scH3 To a mixture of 400 mg of oily sodium hydride (60X) and 50 m1 of 1,2-dimethoxyethane was added dropwise a mixture of 3.06 9 of dimethyl 2-oxooc~ylphosphonate and 10 ml of dimethoxyethane with stirring under ice-cooling. After adding thereto 5 ml of dimethylsulfoxide and stirring the mixture for one hour at room temperature, a mixture of 2.22 g of 3,4-diacetoxybenzaldehyde and 10 ml o~ dimethoxyethane was added dropwise to the mixture. After stirring the resultant mixture for 4 hours at room temperature, 400 ml of water was added to the reaction mixture and the product was extracted twice each time with 50 ml o~ ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was applied to silica gel (120 g) column chromatography and eluted with a mixture of toluene and ethyl acetate (20:1) to provide 2.67 9 of 1-(3,4-diacetoxyphenyl)-1 nonen-3-one.

. .. . . .

-.:

6~
a3 Melting point 71 - 72C

By following the procedure as in Reference Example 21, the compounds of following Reference Examples 22 to 24 were prepared.

Reference E~.ample 22 (Raw material in Example 28) OCOCH3 (CH30)2PcH2ccH(c~2)3cH3 ~ ~ 3 - ' ~ OCH3 CHO CH=CH~CH(CH2)3CEl3 1-(3,4-Diacetoxyphenyl)-4-~.ethyl-1-octen-3-one.
Oily product.
Nuclear magnetic resonance spectra ~In CDC13, ~IS
internal standard, ppm):
0.89(3H), 1.05-1.9(9H), 2.30(6H), 2,^75(1H), 6.6-7.7(5EI).
Reference Example 23 (Raw material in Example 29) OCOCH3 ef 3 1OCOCH3 OCOCH3 (CE130)2PCH2CCH(CH2)4CH3 ~ OCOCH3 CHO Cu=c~ccHtcHz)4cH3 1-(3,4-Diacetoxyphenyl)-4-methyl-1-nonen-3-one.
Oily product.
Nuclear magnetic resonance spectra (in CDC13, TMS

internal standard, ppm):
9.88(3H), 1.05-l.9(llH), 2.30(6H), 2.77~1H), 6.66-7.7(5H).

.
..~., 44 ~t;i6 ~4) Reference Example 24 (Raw material in Example 303 ~ ~ DCHOCH
[~CC~3 (CH3)2PCH2C (CH2)6 3 CHO CH= CH~ ( CH2 ) 6 CH3 1-(3,4-Diacetoxyphenyl)-l-decen-3-one.
Melting point 66 - 67' C.
Elemental analysis for C20H265:
C H
Calculated: 69.34% 7~56 Found: 69.33~ 7.72~
Reference Example 25 (Raw material in Example 31) ~'()CR2~ ~ ~ ( )\"/C~

CHO
OC~2~ ' ``v _ ~c~

C~=C (C~2 ) 6~C~3 .
To a mixture of 12.7 g of 3~4-dibenzyloxybenzaldehyde and 150 ml of tetrah~drofuran was added dropwise an ether solution of Grignard reagent prepared from 10.4 g of 2-methyl-2-(6-bro~ohexyl) :.
-1,3-dioxolane and 1.1 g of magnesium at a temperature below 5 C.
:~ After stirring the mixture for 2 hours at room temperature, water was added to the mixture and acidifying the mixture by the .. .
addition of ~ ' .
. ' . . ' .

` ~

lZ~6;~

dlluted hyclrochloric acid, the reaction mlxture thus obtained was extracted with toluene. The extract was washed with water, dried by anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue were added 300 ml of acetone and 0.1 g of p-toluenesulfonic acid, the mixture was stirred over-night at room temperature and concentrated under reduced pressure. The residue was extracted with toluene and the extrac~ was washed with an aqueous 5 solution, sodium hydrogencarbonate/ /washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide an oily product. The product was applied to silica gel (500 ml) column chromatography ancl eluted with a mixture of toluene and ethyl acetate (19 : 1) to provide 4~4 g of 1-(3,4-dibenzyloxyphenyl)~l,8-nonanecllone. Melting point 64 -66C.
Reference Example 26 (Raw material in Example 32) :, ~

pCH2 ~ 3 OCH2 ~
~oFH2~3 --, $ocH2~) ~;~ : : O=c(cH2)6c~H3 fH~CH2?6faC~3 OH OH

A mixture of 0.8 g of 1-(3,~1-dibenzyloxyphenyl) : ~
1,8-nonanedione andlO ml of tetrahydrofuran was aclded to a solution of O.l g of lithium aluminum hydride in 50 ml of ether under ice-cooling followed by stirring ~.
......

for 2 hours at room temperature. Then, 50 ml of toluene ~.~as added to the reaction mixture and the mixture was acidified by the addit.ion of diluted hydrochloric acid The toluene layer was collected, washed with an aqueous 5~

sodium hydrogencarbona-te solution, washed with water, over dried ~ ~anhydrous magnesium car~onate, and concentrated under reduced pressure to provide 0.8 g of 1-(3,4-dibenzyloxyphenyl)-1,8-nonanedlol as an oil.
Nuclear magentic resonance spectra (in CDC13, ~MS, ppm):
1.05-1.80(15H), 3.8-4.0(1H), 4.56(1H), 5.13(2H), 5.20(2H), 6.80-7.60(13H).
Reference Example 27 (Raw material in E~a~ple 33) (a) OCH2~ 0 CH2~3 2 ~ _ ~ ~ O

CHO ~(cH2)7ccH~

~ y following the procedure as in Rererence Example 25 using a Grignard reagent prepared from 3 g of 3,4-dibenzyloxybenzaldehyde, 2.5 g of 2-methyl-(7-bromo-heptyl)-1,3-dioxolane,and 0.3 g o~ magnesium, 0.8 g of :
1-(3,4-dibenzyloxyphenyl)-1~9-decanedione wasobtained.

Melting point 72 - 74C.

~: :
;~

.

~6~

~oc~

C ( C~ CCX
,~ 2 ~ 11 3 F~ ' C~2 ~ 7 I HCH3 OH Ol~

By following the procedure as in Reference Example 26 using 1 g of 1-(394-dibenzyloxyphenyl)-l,9-decanedione a~ the raw material, 1.0 9 of 1-(3/4-dibenzyloxyphenyl)-1,9-decanediol was obtained. Melting point 66C.

Reference Example 28 (Raw material in Example 34) OC~ ~7~
'~7-~3 C~O : CO ( C7 ) 6 Cc-7 c~3 By following the procedure as in Reference Example 25 using 8 g of 3,4 dibenzyloxybenzaldehyde, and a Grignard reagent prepared from B g of 2-ethyl-2-(6-bromo-hexyl)-1,3-dioxsolane, and 850 mg of magnesium, 2 9 of 1-(3,4-dibenzyloxyphenyl)-1,8-decanedione was obtained.
~ Melting poin~ 67 - 68 C.
: Reference Example 29 (Raw material in Example 35) (a) :
~ OC~

,~, C~AO ?~2 . _ 6 3 .
. . ,.

~6~

A mixture of 640 mg of oily sodium hydride (60%) and 10 ml of dimethyl sulfoxide was stirred for 45 minutes at 75 to 80 C.
After cooling the mixture, a mixture of 50 ml of dimethyl sulfoxide and 8.2 g of 8-ethylenedioxynonyl triphenylphosphonium bromide prepared from 2-methyl-2-(7-bromoheptyl)-1,3-dioxolan and triphenylphosphin was added to the mixture. After 10 minutes, a mixture of 2.5 g of 3.4-dibenzyloxybenzaldehyde and 10 ml of dimethyl sulfoxide was added to the mixture at room temperature and the resultant mixture was stirred overnight. To the reaction mixture was added 500 ml of water and the product was extracted with ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide an oily product. The product was applied to silica gel (200 ml) column chromatography and eluted with a mixture of n-hexane and ether (1:1) to provide 1.4 g of 1-(3,4-dibenzyloxyphenyl)-9-ethylenedioxy-1-decene.
Nuclear magnetic resonance spectra (in CDCl3, TMS, ppm):
1.05~1.8(11H), 1.9 - 2.4(2H), 3.85(4H), 5,05(4H), 6.0 -7.5(15H).
(b) OC~ OCP.
I ~,OC',~ ~fC'.~, C~=CH(C~7)6CC~3 C~=C~(Cn ) CC~~

-1~

~ , . ~ ,.

6i~63 A mix-ture of 1.4 g of 1-(3,4-dibenzyloxyphenyl)-9-ethylenedioxy-l-decene, 50 ml of acetone, and 50 my of p-toluenesulfonic acid was stirred overnight at room temperature. After adding thereto 50 mg of sodium carbonate, the reaction mixture was concentrated under reduced perssure, and after adding thereto 50 ml of water, the product ~as extracted with toluene. The extract was washed with water, dried over anhydrous magneslum sulfate, and concentrated under reduced pressure to provide 1.1 g of 1-(3,4-dibenzyloxyphenyl)-l-decen-9-one as an oil.
Nuclear magnetic resonance spectra (in CDC13, TMS, ppm):
1.05-1.8(8H), 2.1(3H), 2.1-2.6(4H), 5.16(aH), 6.0-7.6(15H).
Reference Example 30 (Raw material in Example 36) OCH2~

+ (CH30)2P CH2C (CH2)5CH3 CHO ~ 2-~ 1~
CH=CHC(CH2)5CH3 By following the procedure as in Reference Example 1 (a) using 1.2 g of 4-benzyloxy-3-methoxybenzaldehyde and I.53 g of dimethyl 2-oxooctylphosphonate, I.27 g of 1-(4-benzyloxy-3-methoxyphenyl)-1-nonen-3-one was obtained. Melting point 78 81 C.

:

.. . . .. . .

~o Reference Example 31 (Raw material in Example 37) OH ~OCH2~ OCH ~3 CH2CH2~(cH2)5cH3 CH2CH~(cH2)5 3 CH2CH2c(cH2)5cH3 ~ a) To a solution of 1.2 g of 1-(3,4-dihydroxyphenyl)-3-nonanone in 10 ml of dimethylformamide wa~ added 200 mg of oily sodium hydride (60~) and after stirring the mlxture for 15 minutes at room temperature, 0~9 q of benzyl bromide was added to the mixture followed by stirring for 15 minutes at room temperature. After further adding thereto 200 mg of oily sodium hydride (60~) and stirring the mixture for 15 minutes at room temperature,0.9 g of benzyl bromide was added to the mixture followed by stirring for 1.5 hours at room temperature. After adding 50 ml of water to the reaction mixture, the product was extracted with toluene. The extract was over washed with water, dried / / anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was applied to silica gel column chromatography and eluted with toluene to provide 1.8 g of 1-~3r4-dibenzyloxyphenyl)-3-nonanone as a sticky product.
Nuclear magnetic resonance spectra ~in CDC13, T~IS, ppm) :
:

.

0 87(3H, -CH3), 1.05-1.8(8H, (CH2)4 -CH2-), 2.55-2.85l4H, -CH2CCH2-), 5.07(4H, -OCH2 x 2), 6.5-7.5(13H) (b) A solution of 1.75 g of 1-(3,4-di~enzyloxy-phenyl)-3-nonanone in 10 ml of tetrahydro-furan was cooled to 0 to 5C and then anether solution of a Grignard reagent prepared from 0.24 g of metallic magnesium and 1.7 g of methyl iodide was added dropwise to the mixture. Thereafter, the resultant mixture was stirred for 15 minutes and after adding thereto 50 ml of an aqueous 5% hydrochloric acid solution, the product was extracted with toluene.
over The ex-tract was washed with water, dried ~ /anhydrous magnesium sulfate, and the solvent was distilled off 1.6 g of under reduced pressure to provide/1-(3,4-diben~yloxy-phenyl)-3-methyl-3-nonanol.
Nuclear magnetic resonance spectra (in CDC13, TMS, ppm): CH
l_3 0.88(3H, -CH3), 1.1-1.9(15H, -CH2-C(OH)-(CH2)5-, [1.18(3H, -CH3)]), 2.4-2.8(2H, -CH2-), 5.08(4H, -OCH2-x 2), 6.5-7.6(13H).
Reference Example 32 (Raw material in ~xample 38) ; oC~2~9 oCH2~;3 ~ a2~ ~ ~oCH24 '~ ~ ; CH2CH2CH CH~CH2CH ~

. :

52 ~
A solution of 0O4 9 of 3-(3,4-dibenzyloxyphenyl) propionaldehyde in 5 ml of anhydrous tetrahydrofuran was cooled to 0to 5C and then 5 ml of an ether solution oF cyclohexyl magnesium bromide prepared from 0.12 g of metallic magnesium and 0.82 9 of cyclohexyl bromide was added dropwise to the sclvent.
Thereafter~ the reaction mixture was stirred for 15 minutes and after adding thereto 50 ml of an aqueous 5~ hydrochloric acid solution, the product was extracted with 30 ml of toluene. The extract was washed with water9 dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to provide an oily product. The product was applied to silica gel column chromatography and eluted with toluene to provide 0.2 9 of 3-(3,4-dibenzyloxyphenyl)-1-cyclo hexyl-l-propanol. Melting point 107 - 108C.
Elemental analysis for C29H303 C H
Calculated: 80.89% 7.96~
Found: 80.88% 8.15%
Example 1 ,0C32~ ~

CP~ C2 2C':i C:~(C~ P.3 P'CalaC-~(C'2)3C~3 aC-3 In 20 ml of ethanol was dissolved 0.4 9 of 1 (3,4-~"~

~2~66~L~

clibenzyloxyphenyl)--4-methyl-1-octen-3-ol and the compound th~ls dissolved was catalytically reduced using 0.1 g of 10% palladium-carbon as a catalyst until the absorption of hydrogen stopped. After the reaction was over, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to provide 0.23 g of 1-(3/4-dihdyroxyphenyl)-4-methyl-3-octanol.
Nuclear magnetic resonance spectra lin CDC13, TMS
internal standard, ppm):
0.7-1.3(15H), 2.57(2H), 3.45(1H), 6.4-6.8(3H) Example 2 OCH2 ~ OH
oCH2~

CH=cHcH(cH2)5cH3 H2cH~ ICH(CH2)5CH3 OH OH

By following the same procedure as in Example 1 using 0.85 g of 1-(3,4-dibenzyloxyphenyl)-1-nonen-3-ol, ~0.4 g of 1-(3,4-dihydroxyphenyl)-3-nonanol was obtained.
Nuclear magnetic resonance spectra (in CDC13, TMS
internal standard, ppm):
0.8-1.9(15H), 2.55(2H), 3.60(1H), 6.4-6.8(3H) , : ~

:, ~2~
5~
Exa~ple 3 Cx2- ~ OH

~=CHe(cH2)scH3 CH2cH2C(CH2~5C 3 : Using 0.2 g of 10% palladium-carbon as catalyst~
0.5 g of 1-~3~4~ibenzyloxyphenyl)-1-nonen-3-one was catalytically reduced in a ~ixture of l0 ml of methanol and lO ml of ethyl acetate until the absorption of hydrogen stopped. Then, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography and eluted with a mixture of toluene and ethyl acetate (10 : 1) to provide 0.2 g of white crystals of l-~3,4-dihydroxyphenyl)-3-nonanone.
Melting point 50 - 53C~
: Elemental analysis for Cl~H22O3:
C H
Calculated: 71.97~ 8.86%
Found: 71.66% 8.77 Example 4 : OCH2 ~ OH OH

H

C}l=cHc(cH2)llcH3 ~CH2CH2 (CH2?11 3 cH2CHzC~(CH2~llCH3 : : . (a3 (b) ~7.~

~ , , ` 1, ~ j : `. .

In a mi~ture of 30 ml of ethyl acetate and 5 ml of ethanol ~as dissolved 1.5 g OL 1- ( 3,4-dibenzylo~y-phenyl)-l-pentadecen-3-one andthe compound was catalytically reduced using 0.2 g of 10~ pallaclium-carbon as a catalyst until the ahsorption of hydrogen stopped. Then, the catalyst ~7as filtered off and the filtrate was concentrated under reduced pressure. The residue was applied to silica gel (80 ml) column chromatography and eluted ~,7ith a mixture of toluene and ethyl acetate ~10 : 1) to provide 0.55 g of white crystals of 1-(3,4-dihydroxyphenyl)-3-penta-decanone (a) as the eluate first merging from the column. Melting point 67 - 6ac.

Elemental analysis for C21H3403:

C H
Calculated: 75041%10.24%
Found: 75.12% 10.38%
After the elution of 1-(3r4-dihydroxyphenyl)-3-pentadecanone was over, further elution was carried out with toluene to provide 0.1 g of 1-~,4-dlhvdroxyphenyl)-3-pentadecanol (b) as a white crystals.
Melting polnt 63 - 64C.

: :

:.

, ,:, . .

Elemental analysis for C21H36O3:
C H
Calculated: 74.95~ 10.78 ~ound: 74.88% 10.81~
By following the procedure as in Example 4, the compounds in following Examples 5 to 8 were prepared.
Example 5 (Using the compound obtained in Reference Example 4) OH
OH

CH CH ~IH(Ca ) H
ta) 1-(3,4-Dihydroxyphenyl)-4-ethyl-3-octanone (a).
Oily product.

::

: ~ :

:: :

' ~Z~i6~a~

Nuclear magnetic resonance spectra (in CDCl3, TMS
internal standard, ppm):
0.6-1.8(14H), 2.3(1H), 2.67(4H)9 6u4 6.8(3H) OH
(b) ~OH

CP.2 C~2 CH CH ( C~; ) 3 CH3 1-(3,4-Dihydroxyphenyl)-4-ethyl-3-octanol (b).
Oily product.
Nuclear magnetic resonance spectra (in CDCl3, TMS
internal standard, ppm):
0.85 (6H), 1.1 1.9(llH), 2.67(2H), 3.63(lH), 6 . 4-6 . 7 ( 3~l).

, ~

~2~
5~

Example 7 (~sing the compo~nd o~tained in Re,e~ence r~ample 6) OH
OH
O
CH2cH~c(c~-~)4cH3 (a) 1-(3,4-~ihydro~yphenyl)-3-octanone (a).
Meltins point ;3 - 55 C.
: ~ Ele~ental analysis for Cl~H20O3:
C H
: ~ ~ Calculated: 71.16% 8.~3~
Found: 70.87~ 8.7~%

. , , : , J

:-~

:

~9L6~

~ OH
~ IOH
CH2CH2CH(cH2)4c 3 (b) 1-(3,4-Dlhydroxyphenyl)-3-octanol (b).
Oily product.
Nuclear magnetic resonance spectra (in CDC13, TMS
internal standard, ppm)~
r O ~ 9 ( 311 ) r 1 ~ 9 ( 1 OH ~ ~ 2.6(2~1), 3.65(lH), 6.5-6 ~ 9 ( 3~
Example 8 (Using the compound obtained in Reference Example 7) OH
,~ OH
O
CH2cHzc ( cH2 ~ 6 cH3 (a) 1-(3,4-Dihydroxyphenyl)-3-decanone (a) : ~ : Uelting point 65 - 66C.
Elemental~analysis for C16H243 C ~ H
: Calculated: 72.:69P5 9.15%
Found: 72.42% 9.48~

, OH
OH
OH
CH2cH2~H(cH2)6cH3 (b) 1-~3,4-Dihydroxyphenyl)-3-decanol (b).
Oily product.
Nuclear maynetic resonance spectra (in CDC13, TMS
internal standard, ppm):
0.9(3H), 1.1-1.9(14H), 2.6(2H), 3.65(1H), 6.5-6.9(3M).
By ~ollowing the procedure as in E.cample 1, the compounds of following Examples 9 to 11 were prepared.
: Example 9 : :
: ~ OCE~2 ~ ~ :
f oCH24~ OH

CH=CH ICH(cH2)7cH3CH2CH2~H(CH2)7c 3 ~H OH

: ~ 1-(3,4-Dihydroxyphenyl)-3-undecanol. .
Uelting point 45 - 47C.
Elemental analysis for C17H283 : Calculated: 72.82~s ;10.06~
:: ~: ::: : :: : ~ :: :
~ : Found: 72.76%:: 10.29%

:
:
.,,.
~: ' :` ' , 6~

Example 10 CH = CHCH ( CH2 ) 8CH3 CH2 CH2 Cj H ( CH2 ) 8 3 OH ~
1-(3,4-Dihydroxyphenyl)-3-dodecanol.
Melting point 53 - 55 C.
Elemental analysis for C18H30O3:
C H
Calculated: 73.43% 10.27%
Found: 73.48~ 10.47%
Example 11 ~20C~Uz~

CH=CHCH CH(CH ) CH CH2CH2CH CH(CH~)~,CH3 OE~ CH3 3 1-~3,4-Dihydroxyphenyl)-4-methyl-3-nonanol.
Oily product.
Nuclear magnetic resonance spectra (in CDC13, l'MS
internal standard, ppm)O
0.7-1.3(17H), 2.58(2H), 3.55(1H), 6.5-6.9(3H), By following the same procedure as in Example 3, the compound of following Example 12 was prepared.
~: :
:

: :

:: ` :
.. r . ~

,`

.

Exam21e 12 OCH2 ~ OH
OCH2 ~ ~ OH

CH=CHCC~(CH2)3CH3 CH~CH2CCH(CH2)3CH3 1-(3,4-Dihydroxyphenyl)-4-methyl-3-octanone.

Oily product.

Nuclear magnetic resonance spectra (in CDC13, TMS

internal standard. ppm):

0.6-1.8(12H), 2.5(1H), 2.74(4H), 6.4-6.i3(3H) Example 13 OCH2 ~ OH
OCEI~ ~f)EI

' CH2IH(CH2)7CH3 CH2CH(CH2)7CH3 OH H

In 10 ml of ethanol was dissolved 0.5 g of 1-(3,4-dibenzyloxyphenyl)-2-decanol and the compound was catalytically reduced using 0.2 g of 10% palladium-atomospheric ; carbon at room temperature and under / until the absorption of hydrogen stopped. After the reaction was over, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to provide 0.28 g~of~l-(3,4-dlhydroxyphenyl)-2-decanol . Oily product.
Nuclear magnetic resonance spectra (ln CDC13, TMS
internal standard, ppm):
; 0-89(3Hj -CH3), 1.1~1.7(14H, -(CH2)7-), 1.62 (2H, CH2 - j, 3 . 7 4 ( 1H, -CH ( OEI ) - ), 6 . 4 -6 . 9 ( 3H, E~l of benzene ' , - ~2~

ring~

Example 14 ~Oc~12~ ~0~

CH2C(Cltl2)8CH3 CH2C(CH2)~CH3 By fQllowing the same procedure as in Example 13 using 0.3 g of 1-(3/4-dibenzyloxyphenyl~-2-undecanone, 140 mg of 1-(3,4-dihydroxyphenyl)-2-undecanone was obtained. Oily product.
Nuclear magnetic resonance spectra (in CDC13, TMS
internal standard, ppm):
0.86(3H, -CH3), 1.0-1.7(14EI, -(CH2)7-), 2.47(2H, -CH2-), 3.56(2H, -CH2-), 6.6-6.9(3H, H of benzene ring) Example 15 :
~CH2 ~ OH
OCH2 ~ _ ~ OH

CH2CH=CHC(CH2)5CH3 CH2CH2CH2CH(CH2)5CH3 :
By following the same procedure as in Example 4 uslng 0.3 g of 1-(3~4-dibenzyloxyphenyl)-2-decen-4-one,0.1 g of~l-(3,4-dihydroxyphenyl)-4-decanol was obtained~
Oily product.

Wuclear magnetic resonance spectra (in CDC13, TMS
internal standardj ppm): ~ ~

~; 0~36(3H, -CH3), 1.1-1.8(14H~, 1.48~2H, -CH2-), ~: ~ , ,, : :
'~"

:

. . .

6~

OH
3.61(1H, -CH-), 6.4-6.8(3H, H of benzene ring).
Example 16 OCH~ ~ OH
OCH2 ~ ~ OH

CH21CH(cH2)~c 3 CH2CH(c~2)6c 3 By following the same procedure as in Example 13 using 0.5 g of 1-(3,4-dibenz~loxyphenyl)-2-nonanol, 0.27 g of 1-(3,4-dihydroxyphenyl)-2-nonanol was obtained. Oily product.

Nuclear magnetic resonance spectra (in CDC13, TMS
internal standard, ppm):
0.89(3H, -CH3), 1.1-1.7(12H, -(CH2)6-), 1.62(2H, -CH2-), 3.75(1H, -CH~OH)-), 6.4-6.9~3H, H of benzene ring).

Example 17 ~CH2 ~ OH
OCH2 ~ ~ OH

: CH2-1CH(CE2j8CH3 CH21H(CH2)8c~3 By following the same procedure as in Exa~ple 13 uslng;0.5 g of~ 3,4-dibenzyloxyphenyl)-2-undecanol, :~ ~
0.29~g of 1-(3,4-dihydroxyphenyl)-2-undecanol~was o~tained. Meltinq point 56 - 58C.

~ ' ;:

Elemental analysls for Cl7H28O3:
C H
Calculated: 72~82% 10.06 Found:72.70% 10.26%
Example 18 OCH2 ~ OH

~CH2~ > ~~
OH QN ~

By following the same procedure as in Example 13 using 0.15 g of 2-(3,4-dibenzyloxyphenyl)-l-cyclo-hexyl-l-ethanol, 0.06 g oE 2-t3,4-dihdyroxyphenyl)-l-cyclohexyl-l-ethanol was obtained. Meltirlg point : 106 - 108C.
Elemental analysis for Cl~H20O3:
C H
Calculated: 71.16% 8.53 Found:70.99% 8.61%
Example I9 C~2 ~ :OH
OC~12~ ~ ~OH

2 2 H CH!I(CHz):4CH3 ;:(CN2)4C(cHz)4cH3 By oIlowIng the~same procqdure as In ExampIe 4 usIng 0.:54 g oP:I-~3,~4-dibenzyloxyphenyI)-3-decen-;S-one~
:0.28 g;of 1-(3,4-dIhydroxyphenyI)-S-decanone was : .v., :
: ''~:`' ~ :

:
' ~: , , ` , ' obtained. Melting point 76 - 78C.
Elemental analysis for Cl6H24O3:
C H
Calculated: 72.14~ 9.84%
Found: 72.18~ 9.75%
Example 20 CH2 ~ OH
OCN2 ~ ~ OH

(CH2)7C CH3 (CH2)7CCH3 By following the same procedure as in Example 13 using 0.3 g of 9-(3,4-dibenzyloxyphenyl)-2-nonanone, 0.16 g of 9-(3,4-dihydroxyphenyl)-2-rlonanone was obtained. Oily product.
Nuclear magnetic resonance spectra (in CDC13, TMS
internal standardj ppm):
1.0-1.80(10H), 2.16(3~), 2.30-2.60(4~), 6.50-6.90(3H).
; Example 21 OH OH

OH
(cH2)4c(cH~)~cH3 (CH2)4c~(c~2)4cH3 ; In 1.5 ml of methanol was dissolved 150 mg of l~(3,4~-dihydroxyphenyl)-S~decanone and 20 mg of sodium borohydride was added to the~solution under ice~cooling followed by stirring for 30 minute3~ Then, the;soivent : ::

.

~!L2~

was distilled off :Erom the reaction mixture and after adding 10 ml of water to the residue thus for;ned, the product was extracted with ether.
The extract was drled ~ anhydrous magnesium sulfate and the solvent was distilled off to provide white crystals of l-~3,4-dihydroxyphenyl~-5-decanol, which was collected by filtration with the addition of n-hexane. Yield 117mgO

Elemental analysis for C16H26O3~
C H
Calculated: 72.14~ 9.84 Found:72.13~ 9.75 Example 22 OCH2~ OH
OCH2~ ~ OU

CH=cHcH-lcH(cH2)3Gu3CH2CH2CH-CH~CH~)3CH3 Using 0.1 g of 10% palladium-carbon as catalyst, 560 mg of 1-(3,4-dibenzyloxyphenyl)-3-methoxy-4-methyl-l-octene was catalytically reduced in a mixture of 5 ml of methanol and 5 ml of ethyl acetate until the ~absorption of hydrogen stopped. Thereafter, the catalyst ~las filtered off and the filtrate was :
concentrated under reduced perssure to provide 330 mg of oily 1-~3,4-dihydroxyphenyl)-3-methoxy-4-methyl-octane.

~ ~ Nuclear magnetic resonance spectra ~in CDCl~ TMS
: : :

;

~Z~66~

internal standard9 ppm):

0.7-1.9(5H), 2,52~2H), 3.05(1H), 3.40(3H), 6.5-6.9(3H).

OCH2 ~ OH
~2~ ~

CH ( CH2 ) 10 CH2 ~ ( CH2 ) 11 OH
H

In 40 ml of acetic acid was dissolved 4.4 9 of 11-benzyloxy-1-~3,4-dibenzyloxyphenyl)-1-undecanol and the compound was catalytically reduced in the presence of 1 g of 10~ palladium-carbon at room temperature and under atmospheric pressure until the absorption of hydrogen stopped~ After the reaction was over, the catalyst was filtered off and after addlng 300 ml of watér to the filtrate, the product was extracted twice each time with 70 ml of ethyl acetate. The extract was washed with water, dried over anyhydrous magnesium ~ulfate, and then the solvent was distilled off to provide a solid product. The solid product was recrystallized from 10 ml of a mixture of ethyl ac~tate and toluene (1:1) to provide 1.~ 9 of 11-(3,4-dihydroxyphenyl)-1-undecanol.
Melting point 92 - 93C.
Elemental analys~s for C17H28~3 C H
; Calculated: 72.82~ 10.06 Found: 73.06% 10.29 : ~

~9 By following the procedure as in Example 23, the compounds of followiny Examples 24 and 25 A, B were perpared.
Example 24 (U~ing the compound obtained in Reference Example 18 step (b)) OH
OH

(CH2 ) 130H
13-(3,4-Dihydroxyphenyl)-l-tridecanol Melting point 93 - 95 C~
Elemental analysis for ClgH3203:
- C H
Calculated: 73.98% 10~46%
Found: 73.73% 10.75 Example 25 ~ ~
(Using the compound obtained in Reference Example 19 A
step (b)) OH
; ~ QH

(C~2)gOH
9-(3,4-Dihydroxyphenyl)-l-nonanol Melting point 89 - 91C.
: EIemental analysis for C15H243 C H
Calculated: 71.39~ 9.59~
Found: 71.12% 9.80%

:: :

~Z~6~

. Example 25 B

(Using the compound obtained in Reference Example 19 B step (b)) OH
OH

(CH2 ) loOH

10-(3,4-Dihydroxyphenyl)-l-decanol.
Melting point 89 - 91C.
Elemental analysis ~or C16H26O3:

C H
Calculated: 72.14% 9.84%
Found: 71.96~ 10.11 Example 26 (Using the compound obtained in Reference Example 20) OH
~ OCH3 (CH2 ) llOH
By following the procedure as in Example 23, (4-hydroxy-3~methoxyphenyl)-1-undecanol was obtained. Melting point 72 - 74C.
:Elemental analysis for C18H30O3:
: C~ H
Calculated: 73.33% 10.27%

Foond: ~ ~73 09% 10.26%

: ~
:

"' Example 2 7 OH
OCOC~.3 ~OCOCX3 CH= CllG ( CH2 ) 5 CH3 CH=CHC ( CH2 ) 5 C-~13 In 10 ml of methanol was dissolved 830 mg of 1-(3,4-diacetoxyphenyl)-1-nonen-3-one andafter adding 7.5 ml of an aqueous 1 N-sodium hydroxide solution to the solution, the mixture was stirred for 30 minutes at room temperatuxe. Then, the reaction mixtu.re was ice-cooled and after adding thereto 25 ml of water, the mixture was acidi~ied with the addition of 5 ml of an aqueous lN-hydrochloric acid solution to form crystals, which were collected by f.~ltration and washed with water to provide 580 mg of 1-(3,4-dihydroxy-phenyl)-l-nonen-3-one. Melting point 114 - 115C.
; Elemental analysis for C15H20O3:
C H
Calculated: 72.55~ 8.12%
Found: 72.32~ 8.23%

~: :
:
~ ~ .

\

72 ~ 6~) Example 28 0~

OCY.3 CH'CHCCH ( CH., ) 3CH3 A hydrochlor~c acid-acidified aqueous solution obtained by following the same procedure as in Example 27 using 1.0 9 of 1-(3,4-diacetoxyphenyl)-4-methyl-1-octen-3-one, was extracted twice each time with 20 ml of ether. The extract was washed with water, dried over anhydrous ~agnesium sulfate, and concentrated under reduced pressure to provide 0.7 9 of oily 1-(3,4-dihydroxyphenyl)

-4 methyl-1-octen-3-one.
Nuclear magnetic resonance spectra (in CDC13, TMS in~ernal standard, ppm):
0.88t3H), 1~05-1.9~9H), 2.85(1H), 6.59-7.7(5H) - Example 29 ~o~
~Y ~ 3 ~; :
By followi~ng the same procedure as in Example 28 using 1.0 g of t3,4-diacetoxyphenyl)-4-methyl~l nonen~3-one, 0.7 9 of 1-(3, 4~-dlhydr~oxyp~henyl)-4-methyl-l-nonen-3-one was oDtalned as an oil.
Nu;c~lear magnetic resonance spectra (in CDCl3, TMS ;nternal standard~, ppm) ~, 0.88(3H), 1.05-l.9(llH), 2.84(1H), 6.59-7.7(5H) Example 30 OH
~3 OH

CH=CHC ( CH2 ) 6CH3 By following the same procedure as in Example 27 using 0.25 g of 1-(3,4-diacetoxyphenyl)-1-decen-3-one, 0.14 g of 1-(3,4-dihydroxyphenyl)-1-decen-one was obtained. Melting point 116 - 118C.
Elemental analysis for C16H22O3:
C H
Calculated: 73.25% 8.45%
Found: 73.30~ 8.71%
Example 31 : OCH2 ~ pH
' ~CH2 4~

11 (CH ) CCH, C~ (CH2)6CCH3 2 /
~ ~ O

: Using 0.5 g of 10% palladium-carbon, 3.2 g o~ 1-(3,~4-dibenzyloxyphe~nyl)-1,8-nonanedlone wascatalytically reduced in a mixture~of 50 ml of ethanol and l.S ml of an~;aqu ous 5% perchloric acid~ solution at room tempsrature and under /pressure until the absorption of hydrogen stopped~. ~ After the resctlon was over, the catslyst:was filtered off and~the ~iltrate was ,~
"" ' ~ ' ' ' ' . . . `
' ~ .

74 3~ 6~

concentrated under reduced pressu'e. The residue was applied to silica gel (50 ml) column chromatography and eluted with a mixture of toluene and ethyl acetate l4 : 1). The crystals thus obtained were recrystallized from a mixture of toluene and n-hexane to provide l-(3,4-dihydro~yphenyl)-8-nonanone.
Melting point 73 - 75 C.
Elemental analysis for C15H22O3:
C H
Calculated: 71.97% 8.86%
Found: 71~91~ 9.12 Example 32 OH
~0~1 ( 2)7 3 By following the same procedure as in Example 31 using 780 mg of 1-(3,4-dibenzyloxyphenyl)-1,8-nonanediol, 210 mg of 1-(3,4-dihydroxyphenyl~-8-nonanol ~.~as obtained.
Melting poi.nt 53 - 61C.
Nuclear magnetic resonance spectra (in CDC13, TMS, ppml .
1.0-1.8(15H)/ 2.4812H), 3.84(1H), 6.5-6.9(3H) :

:~qL6~ ~

Example 33 OH
~OH

( CH2 ) 8 1CHCH3 OH

By following the same procedure as in Example 31 using 1 g of 1-(3,4-dibenzyloxyphenyl)-1,9-decanedlol, 340 mg of 1-13,4-dihydroxyphenyl)-9-decanol `was obtained. Melting point 43 - 46C.
Nuclear magnetic resonance spectra (in CDC13, ~MS, Ppm):
1.05-1.8(17H), 2.50(2H), 3.86(1H), 6.5-6.9(3H).
Example 34 , ~
~ ~ OH
:' : ~ 11 (C~2)7 CH2CH3 . . :
~: , ' By following the same procedure as in Example 31 using 2 g of 1-(3,4~dibenzyloxyphenyl)-1,8-decanedion as a raw material, 200 mg of 1-(3,4-dihydroxyphenyl)-S-decanone wasobtalned. Melting point 76 - 73C.
Nuclear magnetic resonance spectra (in CDC13, T~IS, .
ppm):

1.04(3H), 1.0-1.8(10H), 2.2-2.6~6H), 6.5-6.9(3H).

`:: : : : : :

~` ~
r ~

~.., 7s Example 35 OH
Oh (C~2 ) 8CC~3 By following the same procedure as in Example 1 using 1.02 g of 1-(3,4-dibenzyloxyphenyl)-1-decen-9-one as a raw material, 450 mg of 1-(3,4-dihydroxyphenyl)-9-decanone was obtained. Melting point 74- 76 C
Nuclear magnetic resonance spectra (in CDC13, TMS, ppm):
1.05-1.8(12H), 2.1(3H), 2.3-2~2(4H), 6.5-6.8(3H).
Example 36 ~H O~

3 ~ OC~3 C~l CE C ( C~r ) C~ C'~ C~ C~ ( C ) C~

by following the same procedure as in Example 4 using 1.2 g of 1-(4-benzyloxy-3-methoxyphenyl)-1-nonen-3-one as a raw material, 660 mg of 1-(4-hydroxy-3-methoxyphenyl)-3-nonanone (a) as an oil and 120 mg of 1-(4-hydroxy-3-methoxyphenyl)-3-nonanol p (b) as an oil were obtained.
Nuclear magnetic resonance spectra (in CDC13, TMS, ppm) of compound (a):

.:

~ ' ' .

.

6~

0.9(3H), loO ~ 1.8(8H), 2.4(2H), 2.5 - 3.0(4H), 3.88(3H)~
6.5 - 7.0(3H) Nuclear magnetic resonance spectra (in CDC13~ TMS, ppm) of compound (b):
0.9(3H), 1.0 - 2.0(12H)~ 2.5 - 2.8(2H), 3.4 - 3.8(1H), 3.88(3H~, 6.6 - 7.0(3H).
Example 37 OH
~, O'n /3 C...,,C~2~ C(C~.,7),C~'3 C~' By following the same procedure as in Example 1 using 1.4 g of 1-(3,4-dibenzyloxyphenyl)-3-methyl-3-nonanol, 0.7 9 of 1-(3,4-dihydroxyphenyl)-3-methyl-3-nonanol was obtained. Melting point 81 - 83 C.
Elemental analysis for C16H263:
O H
Calculated:72.14~ 9.84 Found: 71.96~ 10.06 Example 38 G~
C~
~ . ~ ~ r~

By following the same procedure as in Example 1 using 0.2 9 of 3-(3,4-dibenzyloxyphenyll-1-cyclohexyl-~ ,~, ~ , ., i ..~," " ~,, , " ,, : ' 66~

1-propanol was obtained. Melting point 118 - 119~ C.
Elemental analysis for C15H223:
C H
Calculated 71.97~ 8.86g ~ Found: 71.85~ 8.95%
; Example 39 O~ OH

r~ ~ O~HCH
OHC~ 3 1 l 1 3 C~.z C~.~ CHC~ ( C-~2 ) 3 C'~3 C~2 C~ C~C~ ~ C~2 ~ 3 ~ -3 To a solution of 0.5 9 of 1-(3,4-dihydroxyphenyl)-4-methyl-3-octanol obtained in Example 1 in 20 ml of acetic acid was added ; dropwise a mixture of 0.37 g of bromine and 2 ml of acetic acid and after the color of bromine disappeared, the solvent was distilled off under reduced pressure. The residue thus formed was extracted with ethyl acetate. The extract was ~ashed with waterJ
dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was applied to silica gel column chromatography and eluted with a mixture of toluene and ethyl acetate (2:1) to provide 0.5 9 of 1-(2-bromo-4,5-dihydroxyphenyl)-4-methyl-3-octanol.
Melti~ng point 68 - 71 C.

` ~ :
: ; :

~ ~ , , ..,...,. :.,,.., ~:

' ~2~
~9 Elemental analysis for Cl~H23O3Br C H Br Calculated: 54.39% 7.00% 24~12 Found: 54.12~ 7.12% 24.40%

Example 40 (Tablet) 11-(3,4-Dihydroxyphenyl)-l-undecanol (hereinafter, is referred to as l'ALT-118") 50 mg Lactose 113 mg Cone starch 28 mg Hydroxypropyl cellulose 4 mg C~lcium c~rboxy~lethyl cellulose 4 mg Magnesium stearate 1 mg total 200 mg After uniformly mixing 50 g of ALT-118, 113 g of lactose and 28 g of cone starch, 40ml of a10% (~I/V~
aqueous solution of hydroxypropyl cellulose was added to the mixture and the resultant mixture was granulated by : a wet granulation method. The granules thus obtained : : calcium : ~ were mixed with 4 g of/carboxymethyl cellulose and 1 g of magnesiu~ stearate and the mixture was press-tableted : ~ into tablets (200 mg per tablet).
~ : : :: : :
:Examp:le 41 ~ :

Caps~lle) ~ ~

ALT-118: ; ~: 50 mg ;

Crystalline cellulose 20 mg Crystal1ine lactose ~ ~ ~ 129 mg Magnesium~stearate :~~ 1 mg total 2~ mg ~ , :
;:''''' :

'~ ' .
'' :

~z~

The above components each in an amount 1,000 times ~he foregoing amount were mixed and then filled in gelatin capsule to provide capsules (200 mg per capsule).
Example 42 (Inhalation) After dissolving 0.1 9 of ALT-118 in about 90 ml of mixture of ethanol, propylene glycol and purified water (30:10:60 in weight ratio)~ the volume of the solution was adjusted to 100 ml using the aforesaid mixture and 10 ml each of the solution was filled in a definite container followed by sealing to provide an inhalation.

.

Claims (15)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process of producing a catechol derivative represented by general formula (I):

(I) wherein R1 represents a hydrogen atom; R2 represents a hydrogen atom or a halogen atom; X represents a straight chain or branched alkylene group having 1 to 15 carbon atoms or a vinylene group; Y represents a carbonyl group or a group represented by (wherein R3 and R4, which may be the same or different, each represents a hydrogen atom or a lower alkyl group); and Z represents a hydrogen atom, a straight chain or branched alkyl group having 1 to 15 carbon atoms or a cycloalkyl group; the sum of the carbon atoms of said X and Z being at least 7, which comprises reducing and/or hydrolyzing, or halogenating a compound represented by general formula (II):

(II) wherein R' represents an easily removable protective group for hydroxyl group; R1' represents an easily removable protective group for hydroxy group; R2 has the same signi-ficance as defined above, X' represents a straight chain or branched alkylene group having 1 to 15 carbon atoms, an alkenylene group represented by formula -(CH2)m'CH=CH-(wherein m' is 0 or an integer of 1 to 13), a group represented by formula -?-(CH2)m"- (wherein m" is an integer of 1 to 14) or a group represented by formula (m" has the same significance as defined above); said -(CH2)m'- and -(CH2)m"- in the above formulae may have branch; Y' represents a carbonyl group or a group represented by (R3' and R4, which may be the same or different, each represents a hydrogen atom or a lower alkyl group; said R3' may mean a protective group for hydroxy group); and Z has the same significance as defined above; the sum of the carbon atoms of said X' and Z
being at least 7.

2. The process as claimed in claim 1, wherein the reduction of the carbonyl group in the compound of formula (II) into a hydroxymethylene group or a methylene group, the reduction of the alkenylene group into an alkylene group, the removal of the protective group for hydroxy group, and the halogenation of the benzene group are performed in an optional order.

3. The process as claimed in claim 1, wherein the reduction of the carbonyl group in the compound of formula (II) into a hydroxymethylene group or a methylene group, the reduction of the alkenylene group into an alkylene group, and the removal of the protective group for hydroxy group are simultaneously performed.

4. The process as claimed in claim 3, wherein the reductions and the removal of the protective group are per-formed by a catalytic reduction using a palladiumcarbon catalyst.

5. A process according to claim 1 for the preparation of 11-(3,4-dihydroxyphenyl)-1-undecanol, wherein X is a decanylene group, Y is a group represented by and Z and R2 are each a hydrogen atom.

6. A process according to claim 1 for the preparation of 10-(3,4-dihydroxyphenyl)-1-decanol, wherein X is a nonany-lene group, Y is represented by the group , and Z and R2 are each a hydrogen atom.

7. A process according to claim 1 for the preparation of 1-(3,4-dihydroxyphenyl)-3-undecanol, wherein X is a methylene group, Y is represented by the group , Z is a octyl group and R2 is a hydrogen atom.

8. A process according to claim 1 for the preparation of 9-(3,4-dihydroxyphenyl)-2-nonanone, wherein X is a heptanylene group, Y is a carbonyl group, Z is a methyl group and R2 is an atom.

9. A process according to claim 1 for the preparation of 1-(3,4-dihydroxyphenyl)-4-methyl-3-octanol, wherein X is a methylene group, Y is represented by the group , Z is a 1-methyl-pentyl group and R2 is a hydrogen atom.

10. A catechol derivative represented by the formula:
wherein R1 represents a hydrogen atom; R2 represents a hydrogen atom or a halogen atom; X represents a straight chain or branched alkylene group having 1 to 15 carbon atoms or a vinylene group; Y represents a carbonyl group or a group represented by (wherein R3 and R4, which may be the same or different, each represents a hydrogen atom or a lower alkyl group) and Z represents a hydrogen atom, a straight chain or branched alkyl group having 1 to 15 carbon atoms or a cycloalkyl group; the sum of the carbon atoms of said X and Z being at least 7.

11. The compound 11-(3,4-dihydroxyphenyl)-1-undecanol.

12. The compound 10-(3,4-dihydroxyphenyl)-1-decanol.

13. The compound 1-(3,4-dihydroxyphenyl)-3-undecanol,

14. The compound 9-(3,4-dihydroxyphenyl)-2-nonanone.

15. The compound 1-(3,4-dihydroxyphenyl)-4-methyl-3-octanol.