CA1052801A - Tetrahydrofurane derivatives and production thereof - Google Patents
Tetrahydrofurane derivatives and production thereofInfo
- Publication number
- CA1052801A CA1052801A CA202,705A CA202705A CA1052801A CA 1052801 A CA1052801 A CA 1052801A CA 202705 A CA202705 A CA 202705A CA 1052801 A CA1052801 A CA 1052801A
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- Canada
- Prior art keywords
- tetrahydro
- furyl
- prepared
- octanoic acid
- product obtained
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Furan Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
This invention relates to therapeutically active 2,5-tetrahydrofurane derivatives, wherein the substituent in the 2-position is a group ROOC-(CH2)7, in which R is hydrogen or lower alkyl, the 5-substituent being an alkyl of alkenyl group of 4 to 13 carbon atoms, which may be substituted with an oxygen atom or, a hydroxy group and/or a lower alkyl group at the third carbon atom, counted from the furane ring, and to the production thereof.
This invention relates to therapeutically active 2,5-tetrahydrofurane derivatives, wherein the substituent in the 2-position is a group ROOC-(CH2)7, in which R is hydrogen or lower alkyl, the 5-substituent being an alkyl of alkenyl group of 4 to 13 carbon atoms, which may be substituted with an oxygen atom or, a hydroxy group and/or a lower alkyl group at the third carbon atom, counted from the furane ring, and to the production thereof.
Description
1(~5'~
'rhiS i nVeJl~ ll rC~ es to ~,5 tct-r,~hy(lrorlJr~3r!e derivatives and to -their pro~Juction.
~rhe tetrahydrofllrane deriva-tives of the invcnt;on are represented by the formula:
1! 2 ~ ~ o~
wllerein R1 represellts hydrogen or a lower alkyl group, each of R2 alld R3 represents hydrogen, or R2 and R together represent a urther bond between the two carbon atoms, R4 represents hydrogen or a lower alkyl group and R5 is hydroxy or R4 and R5 together represent an oxygen atom, and R represents a C5Hll groua.
The compounds of the invention have useful biological properties combined with low toxicity. Thus, they have a controlling effect upon the activity of the sympathetic nervous system, giving new possibilities for the treatment of hyperpiesis.
Further, they have a luteolytic effect which is of interest in controlling the rut, or as abortives, in mammals.
The following schemes of reaction illustrate the production of the compounds of the invention:
(CH3)2CO,p-toluenesolufonic acid CH300C(CH2)7 ~ ~ C~H 3 78 \OCH3 CH3ooc(cH2) ~ ~CHO
~ ' llDS'~
1l Cl-13 (Cl~2) 4CC 2 3 2 __ Cl~3()(~(, (( il2) 7- t ~-~J~ 5 11 81~ fJ om I _ III
NaBH
Cll 300C ( Cll 2 ) 7~ ~ CH--ClICllOHC51il 1 91%
IV
`IV OH 7~ l100C ( CH 2 ) 7~--Cll=CllCllOllC 5H 11 IV 112, F~aNi CH300C (C~I2) 7~ CH2Cl~2cllOHcsHI
95%
VI
VI 95%~ HOOC (CH2) 7~ CH2CH2CHOHC5H
VII
III H2 ~ 8aNi CH300C (CH2) 7~CH2CH2cOc5H11 VIII
V1II ~ HOOC (CH2) 7~cH
105;~8~
TMCS, IIMDS ~1~ 3--~ i OOC ( CH ~ ) 7 CH ~C~ (JC 5~
I X ~ ~ LC H 3~ r ~ ~
1- CH3MgBr OH
X 2 . H30 I~OOC (CH2) 7 CH2CH2-1-C5 82% fi^om IX ~ 1~ CH
OH
BF3~ (C2H5) 20,CH30H CH300C (CH2) 7 CH2CH
XI 98~ ~ CH3 XII
~0 The starting materials for the production of the compounds of the invention are tetrahydrofurane derivatives of the formula:
Rl--O~C- (CH2)~ CHO
wherein Rl is as hereinbefore defined.
The said starting materials are new compounds, which can be produced e.g. from the 8- (5-dimethoxymethyl-tetrahydro-2-furyl)-octanoic acid methyl ester known from our copending application No. 166,252 filed March 16, 1973.
The starting aldehydes are condensed with the appro-priate alkane-2-one, e.g. 2-heptanone, possibly in the form of its dimethylphosphonic acid dimethyl ester, resulting in the formation of a 3-oxo-1-alkenyl group at the 5-position of the tetrahydrofurane ring, and optionally hydrogenating 1[)5~8~1 the double bond, re(lucing ~ k(to (~ro1~p to a hydro~.y ~roup, or transforming the keto ~roup into hydroycn and a 10Wer ~lkyl grolip by a Grignard reaction.
When Rl represents hydrogen in -the resulting compound, the carboxyl group may subsequently be esterified to yicld esters of the invention, or, if ~he resulting compound is an ester, it may be saponified to yield the corresponding acid.
The introduction of the side chain in 5-position is preferably carried out at room temperature in solution in an alkanol, e.g. methanol or ethanol.
Suitable catalysts for the hydrogenation are Raney nickel, Raney copper, and noble metal catalysts, e.g. palladium.
The following examples are illustratives of the pro-duction of the present compounds, the various compounds being identified by the numbering in the above schemes of reaction.
Example 1 A. 8-(5-Formyl-tetrahydro-2-furyl)-octanoic acid methyl ester (II) 8-(5-Dimethoxymethyl-tetrahydro-2-furyl)-octanoic 2Q acid methyl ester (I) (1.51 g, 0.00500 mole), _-toluene-sulfonic acid (30 mg), and acetone (50 ml) were stirred and heated for about 6 hours in such a way that every 30 minutes about 30 ml of the acetone were distilled off, and a similar new portion of acetone was added to the reaction mixture. The reaction was followed by thin layer chromatography (tlc). After cooling, sodium bicarbonate (0.1 g) was added, and the suspension was stirred for 1 105~
hour. After fi]trcltion, t:l-e solv(nt ~.,s r(~ ov(d by he(~ting on ~
~ater bath (60C, 10 mm llg), and -t'ne rcs;dual ye]lc~w oil (1.45 y) was purified by distillation, giving 1.00 g (78%) of II as a colourless oil, bo o5 119-122C, nD 1.4603.
Calculated for C14 24 4 Found : C 65.4 H 9.6 B. 8-[5-(3-Oxo-l-octenyl)-tetrahydro-2-furyl]-octanoic acid metllyl ester , . . , .. .. ,, , . _ ~ .
50QO sodium hydride in mineral oil (1.11 g, n.o230 mole) lO ~ s suspellded in 1,2-dimethoxyethane (115 ml). At 15C and under ~ic~orous stirring (2-oxoheptyl)-phosphonic acid dimethyl ester (5.11 g, 0.0230 mole) in dimethoxyethane (23 ml) was added drop-wise over a period of 15 minutes. The reaction mixture contain-ing a ~hite, voluminous precipitate was stirred for 1 hour at room temperature. A solution of crude II (7.20 g), prepared from I (7.55 g, 0.0250 mole), in 1,2-dimethoxyethane (46 ml) was added dropwise over a period of 15 minutes to the stirred reaction mixture, maintained below 25DC. The resulting turbid, yellow solution was stirred at room temperature for 2 hours. The solvent was distilled off from a water bath (40C, 10 mm Hg). The oily residue was dissolved in ether (230 ml), washed with cold 10%
aqueous sodium chloride (60 + 60 + 60 ml) and cold water (60 +
60 ml), and dried over sodium sulfate. After filtration, the solvent was removed from a water bath (60C, 10 mm Hg). The residual light tea-coloured oil (9.60 g) was distilled under nitrogen to give 7.15 g (81%) of III as a light yellowish oil, bo o5 160-190C, nD 1.4712.
For analysis 1.00 g of III (bo o5 160-190C) was pu-105'~
rified by chrolnal-o~ral~hy on sil;r-a gel (ether - l;yro;ne (b 50~C) 1:1 as eluent) to givc 0.80 y of a lighl ye]]ow oil.
Distillation (185-l90~C, 0.03 nun 7ig) yielded 0.62 g of III as a light yellowish oil, nD 1.4756.
Calcul~ted for C21l~36 4 ( Found : C 71.8 H 10.2 E~ample 2 8-[5-(3-l~ydroxy-1-octenyl)-tetrahydro-2-furyl]-octanoic ac~d metllyl ester III (3.17 g, O.Q0900 mole) was dissolved in methanol (75 ml) and sodium tetrahydroborate (1.7 g, 0.045 mole) was added at 0C with stirring. The stirring was continued for 1 hour. During this time the temperature was slowly raised to room temperature. The colourless solution was poured into ice-water (250 ml) and extracted with ether (100 + 50 + 50 ml). The com~ined ethereal extracts were washed with water (50 + 25 + 25 ml), dried over magnesium sulfate, and evaporated from a water bath (50C, 10 mm Hg). The obtained light yellowish oil (3.38 g) was distilled under reduced pressure to give 2.90 g (91~) of IV
as a colourless oil, bo o5 175-188C, -D 1.4699.
For analysis 0.72 g of IV (bc o5 175-188C) was purified by chromatography on silica gel (ether-ligroine(b.<50C) 1:1 as eluent) to give 0.65 g of a colourless oil. Distillation (185-190C, 0.05 mm Hg) yielded 0.55 g of IV as a colourless oil, nD 1.4711.
Calculated for C21H38O4 (354.5):C 71-1 H 10-8 Found :C 71.3 H 10.8 ~.os~
Example 3 8-[5-(3-liyd~oxy-1-oc~enyl)~tetrahydro--2-fl~ry1]-ocl-.Jn~ic a-;d _ . _ _ . _ _ . _ . _ . _ _ _ _ . _ ,, , .. _ .., , , , . . , _ . .. . .
IV (1.77 g, 0.00500 mole), meth,lnol(20 ml), ~nd 20%
aqueous potassium carbonate (10 ml) were stirred and heated under reflux or 90 minutes. The methanol was removed from a ~ater bath (60C, 100 mm Hg). The residue was ~iluted with water (25 ml) and washed with ether (25 ml). The resulting clear solution was acidified to pH 5-6 with acetic acid. The resulting emulsion was extracted with ether (25 + 25 ml). The com~ined ethereal extracts were dried over sodium sulfate and evaporated from a water bath (60C, 1 mm Hg) to give 1.60 g (94%) of V as a colourless oil, -D 1.4778.
For analysis, 1.60 g of V (-D 1.4778) was purified by chromatography on silica gel (ether - ligroine (b.<50C) 2:1 as eluent) to give 1.30 g of a colourless oil. Distillation (190-195~C, 0.04 mm Hg) yielded 1.04 g of V as a colourless oil, nD 1.4790.
Calculated for C20H36O4 (340.5): C 70-5 H 10-7 Found : C 70.3 H 10.7 Example 4 8-l5-(3-Hydroxyoct l)-tetrahydro-2-furyl]-octanoic Y
acid methyl ester IV (1.77 g, 0.00500 mole), methanol (50 ml), and Raney nickel (1 g) were shaken under hydrogen at a pressure of 70 atmospheres for 24 hours at room temperature. After filtra-tion, the solvent was remo~ed from a water bath (60~C, 10 mm Hg).
Ether (50 ml) was added to the residue, and the turbid, colour-less solution was filtered. The lOS'~
ethereal so]ntion was e~<~po~ed to ~lryr,ess from ~ -"<~f-r b~h (60C, 10 mm l~g). The r-sidual c1ear, colourlcss oi] (1 90 g) was distilled under reduced pressure to give 1.69 y (95%) of VI as a colourless oil, b 5 160-172C, nD 1.4625.
For analysis, 1.50 g of VI (bo o5 160-172C) was pul-ified by chromatography on silica gel (e~her - liyroine (b.<
50C) 1:1 as eluent) to give 1.20 g of a colourless oil. Dis-tillation under xed~lced pressure gave 1.05 g of VI as a colour-less oil, bo 1 175-176C, nD 1.4630.
Calclllated for C21H40 4 ( Found : C 70.8 H 11.3 Example 5 8-[5-(3-Hydroxyoctyl)-tetrahydro-2-furyl]-octanoic acid VI (1.78 g, 0.00500 mole), methanol (20 ml), and 20%
aqueous potassium carbonate (10 ml) were stirred and heated under reflux for 90 minutes. The methanol was removed from a water bath (60C, 100 mm Hg). The residue was diluted with water (25 ml) and washed with ether (25 ml). The resulting clear solution was acidified to pH 5-6 with acetic acid. An emulsion was formed, which was extracted with ether (25 + 25 ml).
The combined ethereal extracts were dried over sodium sulfate and evaporated from a water bath ~60C, 1 mm Hg) to give 1.62 g (95~) of VII as a light yellowish oil, -D 1.4682.
For analysis, 1.62 g of VII (-D 1.4682) was purified ~y chromatography on silica gel (ether - ligroine (b.<50C) 2:1 as eluent) to give 1.20 g of a light yellowish oil.
Distillation (180-190C, 0.03 mm Hg) yielded 0.85 g of VII
1(~5'~8(~
as a li~ht yellowish oil, which solidif;ed OJl standing M.p. 32-33C, nD 1.4713.
Calculated for C20 38 4 ( Found : C 69.9 H 11.1 Example 6 8-[5-(3-Oxooctyl)-tetrahydro-2-furyl]-octanoic acid methyl ester III (3.52 ~. 0.0100 mole), methanol (50 ml), and Raney nickel (0.5 g) were stirred under hydrogen at a pressure of 1 a~mosphere, until absorption stopped. After filtration, the solvent was removed from a water bath (60C, 10 mm Hg). The residual light yellowish oil (3.60 g) was distilled under reduced pressure to give 3.01 g (85%) of VIII as a light yellow-ish oil, bo o3 165-176C~ nD5 1-4608-For analysis, 3.01 g of VIII (bo o3 165-176C) was purified by chromatography on silica gel (ether - ligroine (b.<5C~C) 1:2 as eluent) to give 2.06 g of a colourless oil.
Distillation under reduced pressure gave 1.95 g of VIII as a colourless oil, bo o3 172-174C, nD 1-4600-Calculated for C21 38 4 ( Found : C 71.0 H 10.9 Example 7 8-[5-(3-Oxooctyl)-tetrahydro-2-furyl]-octanoic acid VIII (1.77 g, 0.00500 mole), methanol (20 ml), and 20~ aqueous potassium carbonate (10 ml) were stirred and heated under reflux for 2,5 hours. The methanol was removed from a water bath (60C, 100 mm Hg). The residue was diluted with water (25 ml) and washed with ether (25 ml). The 105'~80~
resulting clear solution was acidified 1o pl~ 5~6 with acetic acid. The emulsion being formed was extrac1:ed with ether ~25 +
25 ml). The combined ethereal extracts were dried over sodium sulfate and evaporated from a water bath (6CC, 1 rnm Hg). The yellowish, oily residue of IX (1.60 g, 94%) solidified by standing. M.p. 26-28C, _~ 1.4673.
For analysis, 1.60 g of IX (m.p. 26-28C) was purified by chromatography on silica gel (ether - ligroine (b.C50C) 1:1 as eluent) to give 1.30 g of a light yellowish oil. Distillation under reduced pressure yielded 0.88 g of IX as a light yellowish oil, which solidified by standing, bo o5 200-202C, m.p. 31-32C, n2D5 1 4686.
Calculated for C20H36O4 (340.5) : C 70.5 H 10-7 Found : C 70.5 H 10.7 Example 8 _-[5-(3-Hydroxy-3-methyloctyl)-tetrahydro-2-furyl]-octanoic acid IX (6.30 g, 0.0185 mole), hexamethyldisilazane (HMDS) (12 ml), trimethylchlorosilane (TMCS) (6 ml), and pyridine (40 ml) were mixed and kept overnight at room temperature. The resulting white suspension was evaporated to dryness (50C, 10 mm Hg). Ether (100 ml) was added, and the suspension was filtered. The resulting clear, yellow solution of X was cooled to 0C, and methylmagnesium bromide in ether (3.8N, 8.0 ml, 0.030 mole) was added dropwise during 20 minutes. After stirring for 2 hours at room temperature, the white suspension being formed was poured into a mixture of cold hydrochloric acid (0.25N, 140 ml) and ether (50 ml). The ethereal phase was separated, and 5~
the aqueous layer was extracted with ether (50 + 25 ml~, The combined ethereal extracts were washed with water (50 ml) and dried over sodium sulfate. The solvent was removed ~rom a water bath (60C, 10 mm Hg), and the re-sidual light yellowish oil (7,40 g) was distilled under reduced pressure to give 5.40 g (82%) of XI as a light yellowish oil, bo o8 203-210C, nD5 1.4710, For analysis, 1.50 g of XI (bo o8 203-210C) ~as pu-rified by chromatography on silica gel (ether - ligroine lo (b,< 50C) 1:1 as eluent) to give 1,10 g of a light yel-lowish oil. Distillation (190-200C, 0.05 mm Hg) yielded 1.00 g of XI as a light yellowish oil, nD5 1,4725, Calculated for C21H4004 (356,5): C 70,7 H 11-3 Found : C 70.5 H 11.2 Example 9 8-/~-(3-Hydroxy-3-methyloctyl~-tetrahydro-2-furyl7-octanoic acid methyl ester (XII) XI (1.78 g, 0.00500 mole), methanol (25 ml), and ethyl ether-borontrifluoride complex (0.1 ml) were stirred and heated under reflux for 1 hour. After cooling, the re-action mixture was poured into ice - water (200 ml) and extracted with ether (50 + 50 + 25 ml)0 The combined ethe-real extracts were washed with cold 2% aqueous sodium hy-drogen carbonate (50 ml) and water (50 ml~. The ethereal solution was dried over sodium sulfate and evaporated to dryness from a water bath (60C, 10 mm Hg). The residual yellowish oil (1.95 g) was distilled under reduced pres-sure to give 1.82 g (98%) of XII as a colourless oil, bo o3 160-170C, nD5 1.46250 For analysis, 1.80 g of VII (bo o3 160-170C) was pu-105'~
rified by chromatoyrdphy on sil;ca yel (ct:hcr-]iyroine (b.<5G~C) 1:1 as eluent) to give 1.00 g of a colourlcss oil. Distill~tiGn (150-160C, 0.05 mm llg) yielded 0.75 g of XII as a colourless oil, n2~5 1.4640.
Calculated for C22H42O4 (370.6) : C 71.3 H 11-4 Found : C 71.1 H 11.4.
'rhiS i nVeJl~ ll rC~ es to ~,5 tct-r,~hy(lrorlJr~3r!e derivatives and to -their pro~Juction.
~rhe tetrahydrofllrane deriva-tives of the invcnt;on are represented by the formula:
1! 2 ~ ~ o~
wllerein R1 represellts hydrogen or a lower alkyl group, each of R2 alld R3 represents hydrogen, or R2 and R together represent a urther bond between the two carbon atoms, R4 represents hydrogen or a lower alkyl group and R5 is hydroxy or R4 and R5 together represent an oxygen atom, and R represents a C5Hll groua.
The compounds of the invention have useful biological properties combined with low toxicity. Thus, they have a controlling effect upon the activity of the sympathetic nervous system, giving new possibilities for the treatment of hyperpiesis.
Further, they have a luteolytic effect which is of interest in controlling the rut, or as abortives, in mammals.
The following schemes of reaction illustrate the production of the compounds of the invention:
(CH3)2CO,p-toluenesolufonic acid CH300C(CH2)7 ~ ~ C~H 3 78 \OCH3 CH3ooc(cH2) ~ ~CHO
~ ' llDS'~
1l Cl-13 (Cl~2) 4CC 2 3 2 __ Cl~3()(~(, (( il2) 7- t ~-~J~ 5 11 81~ fJ om I _ III
NaBH
Cll 300C ( Cll 2 ) 7~ ~ CH--ClICllOHC51il 1 91%
IV
`IV OH 7~ l100C ( CH 2 ) 7~--Cll=CllCllOllC 5H 11 IV 112, F~aNi CH300C (C~I2) 7~ CH2Cl~2cllOHcsHI
95%
VI
VI 95%~ HOOC (CH2) 7~ CH2CH2CHOHC5H
VII
III H2 ~ 8aNi CH300C (CH2) 7~CH2CH2cOc5H11 VIII
V1II ~ HOOC (CH2) 7~cH
105;~8~
TMCS, IIMDS ~1~ 3--~ i OOC ( CH ~ ) 7 CH ~C~ (JC 5~
I X ~ ~ LC H 3~ r ~ ~
1- CH3MgBr OH
X 2 . H30 I~OOC (CH2) 7 CH2CH2-1-C5 82% fi^om IX ~ 1~ CH
OH
BF3~ (C2H5) 20,CH30H CH300C (CH2) 7 CH2CH
XI 98~ ~ CH3 XII
~0 The starting materials for the production of the compounds of the invention are tetrahydrofurane derivatives of the formula:
Rl--O~C- (CH2)~ CHO
wherein Rl is as hereinbefore defined.
The said starting materials are new compounds, which can be produced e.g. from the 8- (5-dimethoxymethyl-tetrahydro-2-furyl)-octanoic acid methyl ester known from our copending application No. 166,252 filed March 16, 1973.
The starting aldehydes are condensed with the appro-priate alkane-2-one, e.g. 2-heptanone, possibly in the form of its dimethylphosphonic acid dimethyl ester, resulting in the formation of a 3-oxo-1-alkenyl group at the 5-position of the tetrahydrofurane ring, and optionally hydrogenating 1[)5~8~1 the double bond, re(lucing ~ k(to (~ro1~p to a hydro~.y ~roup, or transforming the keto ~roup into hydroycn and a 10Wer ~lkyl grolip by a Grignard reaction.
When Rl represents hydrogen in -the resulting compound, the carboxyl group may subsequently be esterified to yicld esters of the invention, or, if ~he resulting compound is an ester, it may be saponified to yield the corresponding acid.
The introduction of the side chain in 5-position is preferably carried out at room temperature in solution in an alkanol, e.g. methanol or ethanol.
Suitable catalysts for the hydrogenation are Raney nickel, Raney copper, and noble metal catalysts, e.g. palladium.
The following examples are illustratives of the pro-duction of the present compounds, the various compounds being identified by the numbering in the above schemes of reaction.
Example 1 A. 8-(5-Formyl-tetrahydro-2-furyl)-octanoic acid methyl ester (II) 8-(5-Dimethoxymethyl-tetrahydro-2-furyl)-octanoic 2Q acid methyl ester (I) (1.51 g, 0.00500 mole), _-toluene-sulfonic acid (30 mg), and acetone (50 ml) were stirred and heated for about 6 hours in such a way that every 30 minutes about 30 ml of the acetone were distilled off, and a similar new portion of acetone was added to the reaction mixture. The reaction was followed by thin layer chromatography (tlc). After cooling, sodium bicarbonate (0.1 g) was added, and the suspension was stirred for 1 105~
hour. After fi]trcltion, t:l-e solv(nt ~.,s r(~ ov(d by he(~ting on ~
~ater bath (60C, 10 mm llg), and -t'ne rcs;dual ye]lc~w oil (1.45 y) was purified by distillation, giving 1.00 g (78%) of II as a colourless oil, bo o5 119-122C, nD 1.4603.
Calculated for C14 24 4 Found : C 65.4 H 9.6 B. 8-[5-(3-Oxo-l-octenyl)-tetrahydro-2-furyl]-octanoic acid metllyl ester , . . , .. .. ,, , . _ ~ .
50QO sodium hydride in mineral oil (1.11 g, n.o230 mole) lO ~ s suspellded in 1,2-dimethoxyethane (115 ml). At 15C and under ~ic~orous stirring (2-oxoheptyl)-phosphonic acid dimethyl ester (5.11 g, 0.0230 mole) in dimethoxyethane (23 ml) was added drop-wise over a period of 15 minutes. The reaction mixture contain-ing a ~hite, voluminous precipitate was stirred for 1 hour at room temperature. A solution of crude II (7.20 g), prepared from I (7.55 g, 0.0250 mole), in 1,2-dimethoxyethane (46 ml) was added dropwise over a period of 15 minutes to the stirred reaction mixture, maintained below 25DC. The resulting turbid, yellow solution was stirred at room temperature for 2 hours. The solvent was distilled off from a water bath (40C, 10 mm Hg). The oily residue was dissolved in ether (230 ml), washed with cold 10%
aqueous sodium chloride (60 + 60 + 60 ml) and cold water (60 +
60 ml), and dried over sodium sulfate. After filtration, the solvent was removed from a water bath (60C, 10 mm Hg). The residual light tea-coloured oil (9.60 g) was distilled under nitrogen to give 7.15 g (81%) of III as a light yellowish oil, bo o5 160-190C, nD 1.4712.
For analysis 1.00 g of III (bo o5 160-190C) was pu-105'~
rified by chrolnal-o~ral~hy on sil;r-a gel (ether - l;yro;ne (b 50~C) 1:1 as eluent) to givc 0.80 y of a lighl ye]]ow oil.
Distillation (185-l90~C, 0.03 nun 7ig) yielded 0.62 g of III as a light yellowish oil, nD 1.4756.
Calcul~ted for C21l~36 4 ( Found : C 71.8 H 10.2 E~ample 2 8-[5-(3-l~ydroxy-1-octenyl)-tetrahydro-2-furyl]-octanoic ac~d metllyl ester III (3.17 g, O.Q0900 mole) was dissolved in methanol (75 ml) and sodium tetrahydroborate (1.7 g, 0.045 mole) was added at 0C with stirring. The stirring was continued for 1 hour. During this time the temperature was slowly raised to room temperature. The colourless solution was poured into ice-water (250 ml) and extracted with ether (100 + 50 + 50 ml). The com~ined ethereal extracts were washed with water (50 + 25 + 25 ml), dried over magnesium sulfate, and evaporated from a water bath (50C, 10 mm Hg). The obtained light yellowish oil (3.38 g) was distilled under reduced pressure to give 2.90 g (91~) of IV
as a colourless oil, bo o5 175-188C, -D 1.4699.
For analysis 0.72 g of IV (bc o5 175-188C) was purified by chromatography on silica gel (ether-ligroine(b.<50C) 1:1 as eluent) to give 0.65 g of a colourless oil. Distillation (185-190C, 0.05 mm Hg) yielded 0.55 g of IV as a colourless oil, nD 1.4711.
Calculated for C21H38O4 (354.5):C 71-1 H 10-8 Found :C 71.3 H 10.8 ~.os~
Example 3 8-[5-(3-liyd~oxy-1-oc~enyl)~tetrahydro--2-fl~ry1]-ocl-.Jn~ic a-;d _ . _ _ . _ _ . _ . _ . _ _ _ _ . _ ,, , .. _ .., , , , . . , _ . .. . .
IV (1.77 g, 0.00500 mole), meth,lnol(20 ml), ~nd 20%
aqueous potassium carbonate (10 ml) were stirred and heated under reflux or 90 minutes. The methanol was removed from a ~ater bath (60C, 100 mm Hg). The residue was ~iluted with water (25 ml) and washed with ether (25 ml). The resulting clear solution was acidified to pH 5-6 with acetic acid. The resulting emulsion was extracted with ether (25 + 25 ml). The com~ined ethereal extracts were dried over sodium sulfate and evaporated from a water bath (60C, 1 mm Hg) to give 1.60 g (94%) of V as a colourless oil, -D 1.4778.
For analysis, 1.60 g of V (-D 1.4778) was purified by chromatography on silica gel (ether - ligroine (b.<50C) 2:1 as eluent) to give 1.30 g of a colourless oil. Distillation (190-195~C, 0.04 mm Hg) yielded 1.04 g of V as a colourless oil, nD 1.4790.
Calculated for C20H36O4 (340.5): C 70-5 H 10-7 Found : C 70.3 H 10.7 Example 4 8-l5-(3-Hydroxyoct l)-tetrahydro-2-furyl]-octanoic Y
acid methyl ester IV (1.77 g, 0.00500 mole), methanol (50 ml), and Raney nickel (1 g) were shaken under hydrogen at a pressure of 70 atmospheres for 24 hours at room temperature. After filtra-tion, the solvent was remo~ed from a water bath (60~C, 10 mm Hg).
Ether (50 ml) was added to the residue, and the turbid, colour-less solution was filtered. The lOS'~
ethereal so]ntion was e~<~po~ed to ~lryr,ess from ~ -"<~f-r b~h (60C, 10 mm l~g). The r-sidual c1ear, colourlcss oi] (1 90 g) was distilled under reduced pressure to give 1.69 y (95%) of VI as a colourless oil, b 5 160-172C, nD 1.4625.
For analysis, 1.50 g of VI (bo o5 160-172C) was pul-ified by chromatography on silica gel (e~her - liyroine (b.<
50C) 1:1 as eluent) to give 1.20 g of a colourless oil. Dis-tillation under xed~lced pressure gave 1.05 g of VI as a colour-less oil, bo 1 175-176C, nD 1.4630.
Calclllated for C21H40 4 ( Found : C 70.8 H 11.3 Example 5 8-[5-(3-Hydroxyoctyl)-tetrahydro-2-furyl]-octanoic acid VI (1.78 g, 0.00500 mole), methanol (20 ml), and 20%
aqueous potassium carbonate (10 ml) were stirred and heated under reflux for 90 minutes. The methanol was removed from a water bath (60C, 100 mm Hg). The residue was diluted with water (25 ml) and washed with ether (25 ml). The resulting clear solution was acidified to pH 5-6 with acetic acid. An emulsion was formed, which was extracted with ether (25 + 25 ml).
The combined ethereal extracts were dried over sodium sulfate and evaporated from a water bath ~60C, 1 mm Hg) to give 1.62 g (95~) of VII as a light yellowish oil, -D 1.4682.
For analysis, 1.62 g of VII (-D 1.4682) was purified ~y chromatography on silica gel (ether - ligroine (b.<50C) 2:1 as eluent) to give 1.20 g of a light yellowish oil.
Distillation (180-190C, 0.03 mm Hg) yielded 0.85 g of VII
1(~5'~8(~
as a li~ht yellowish oil, which solidif;ed OJl standing M.p. 32-33C, nD 1.4713.
Calculated for C20 38 4 ( Found : C 69.9 H 11.1 Example 6 8-[5-(3-Oxooctyl)-tetrahydro-2-furyl]-octanoic acid methyl ester III (3.52 ~. 0.0100 mole), methanol (50 ml), and Raney nickel (0.5 g) were stirred under hydrogen at a pressure of 1 a~mosphere, until absorption stopped. After filtration, the solvent was removed from a water bath (60C, 10 mm Hg). The residual light yellowish oil (3.60 g) was distilled under reduced pressure to give 3.01 g (85%) of VIII as a light yellow-ish oil, bo o3 165-176C~ nD5 1-4608-For analysis, 3.01 g of VIII (bo o3 165-176C) was purified by chromatography on silica gel (ether - ligroine (b.<5C~C) 1:2 as eluent) to give 2.06 g of a colourless oil.
Distillation under reduced pressure gave 1.95 g of VIII as a colourless oil, bo o3 172-174C, nD 1-4600-Calculated for C21 38 4 ( Found : C 71.0 H 10.9 Example 7 8-[5-(3-Oxooctyl)-tetrahydro-2-furyl]-octanoic acid VIII (1.77 g, 0.00500 mole), methanol (20 ml), and 20~ aqueous potassium carbonate (10 ml) were stirred and heated under reflux for 2,5 hours. The methanol was removed from a water bath (60C, 100 mm Hg). The residue was diluted with water (25 ml) and washed with ether (25 ml). The 105'~80~
resulting clear solution was acidified 1o pl~ 5~6 with acetic acid. The emulsion being formed was extrac1:ed with ether ~25 +
25 ml). The combined ethereal extracts were dried over sodium sulfate and evaporated from a water bath (6CC, 1 rnm Hg). The yellowish, oily residue of IX (1.60 g, 94%) solidified by standing. M.p. 26-28C, _~ 1.4673.
For analysis, 1.60 g of IX (m.p. 26-28C) was purified by chromatography on silica gel (ether - ligroine (b.C50C) 1:1 as eluent) to give 1.30 g of a light yellowish oil. Distillation under reduced pressure yielded 0.88 g of IX as a light yellowish oil, which solidified by standing, bo o5 200-202C, m.p. 31-32C, n2D5 1 4686.
Calculated for C20H36O4 (340.5) : C 70.5 H 10-7 Found : C 70.5 H 10.7 Example 8 _-[5-(3-Hydroxy-3-methyloctyl)-tetrahydro-2-furyl]-octanoic acid IX (6.30 g, 0.0185 mole), hexamethyldisilazane (HMDS) (12 ml), trimethylchlorosilane (TMCS) (6 ml), and pyridine (40 ml) were mixed and kept overnight at room temperature. The resulting white suspension was evaporated to dryness (50C, 10 mm Hg). Ether (100 ml) was added, and the suspension was filtered. The resulting clear, yellow solution of X was cooled to 0C, and methylmagnesium bromide in ether (3.8N, 8.0 ml, 0.030 mole) was added dropwise during 20 minutes. After stirring for 2 hours at room temperature, the white suspension being formed was poured into a mixture of cold hydrochloric acid (0.25N, 140 ml) and ether (50 ml). The ethereal phase was separated, and 5~
the aqueous layer was extracted with ether (50 + 25 ml~, The combined ethereal extracts were washed with water (50 ml) and dried over sodium sulfate. The solvent was removed ~rom a water bath (60C, 10 mm Hg), and the re-sidual light yellowish oil (7,40 g) was distilled under reduced pressure to give 5.40 g (82%) of XI as a light yellowish oil, bo o8 203-210C, nD5 1.4710, For analysis, 1.50 g of XI (bo o8 203-210C) ~as pu-rified by chromatography on silica gel (ether - ligroine lo (b,< 50C) 1:1 as eluent) to give 1,10 g of a light yel-lowish oil. Distillation (190-200C, 0.05 mm Hg) yielded 1.00 g of XI as a light yellowish oil, nD5 1,4725, Calculated for C21H4004 (356,5): C 70,7 H 11-3 Found : C 70.5 H 11.2 Example 9 8-/~-(3-Hydroxy-3-methyloctyl~-tetrahydro-2-furyl7-octanoic acid methyl ester (XII) XI (1.78 g, 0.00500 mole), methanol (25 ml), and ethyl ether-borontrifluoride complex (0.1 ml) were stirred and heated under reflux for 1 hour. After cooling, the re-action mixture was poured into ice - water (200 ml) and extracted with ether (50 + 50 + 25 ml)0 The combined ethe-real extracts were washed with cold 2% aqueous sodium hy-drogen carbonate (50 ml) and water (50 ml~. The ethereal solution was dried over sodium sulfate and evaporated to dryness from a water bath (60C, 10 mm Hg). The residual yellowish oil (1.95 g) was distilled under reduced pres-sure to give 1.82 g (98%) of XII as a colourless oil, bo o3 160-170C, nD5 1.46250 For analysis, 1.80 g of VII (bo o3 160-170C) was pu-105'~
rified by chromatoyrdphy on sil;ca yel (ct:hcr-]iyroine (b.<5G~C) 1:1 as eluent) to give 1.00 g of a colourlcss oil. Distill~tiGn (150-160C, 0.05 mm llg) yielded 0.75 g of XII as a colourless oil, n2~5 1.4640.
Calculated for C22H42O4 (370.6) : C 71.3 H 11-4 Found : C 71.1 H 11.4.
Claims (22)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the production of 2,5-tetrahydrofurane derivatives of the formula I
wherein R1 represents hydrogen or a lower alkyl group, each of R2 and R3 represents hydrogen, or R2 and R3 together represent a further bond between the carbon atoms, R4 represents hydrogen, or a lower alkyl group, R5 is hydroxy or R4 and R5 together represent an oxygen atom, and R6 represents a C5H11 group which comprises condensing an aldehyde of the formula II
wherein R1 is as above defined, with the appropriate 2-oxoalkane of the formula R6-COCH3 wherein R6 is as above or 2-oxo-alkylphos-phonate of the formula where R6 is as above and Alk is alkyl to establish a 3-oxo-1-alkenyl group in 5-position at the tetrahydrofurane ring, in the resulting compound, when R2 and R3 are required to be hydrogen catalytically hydrogenating the double bond when R4 is required to be hydrogen and R5 hydroxy reducing the keto group to a hydroxy group, and when R4 is required to be lower alkyl and R5 hydroxy converting the keto group into a lower alkyl group by a Grignard reaction.
wherein R1 represents hydrogen or a lower alkyl group, each of R2 and R3 represents hydrogen, or R2 and R3 together represent a further bond between the carbon atoms, R4 represents hydrogen, or a lower alkyl group, R5 is hydroxy or R4 and R5 together represent an oxygen atom, and R6 represents a C5H11 group which comprises condensing an aldehyde of the formula II
wherein R1 is as above defined, with the appropriate 2-oxoalkane of the formula R6-COCH3 wherein R6 is as above or 2-oxo-alkylphos-phonate of the formula where R6 is as above and Alk is alkyl to establish a 3-oxo-1-alkenyl group in 5-position at the tetrahydrofurane ring, in the resulting compound, when R2 and R3 are required to be hydrogen catalytically hydrogenating the double bond when R4 is required to be hydrogen and R5 hydroxy reducing the keto group to a hydroxy group, and when R4 is required to be lower alkyl and R5 hydroxy converting the keto group into a lower alkyl group by a Grignard reaction.
2. A process as claimed in claim 1 in which the reduction is effected with sodium borohydride and the Grignard reagent is a lower alkyl magnesium halide.
3. A process as claimed in claim 1 in which when in the product obtained R is hydrogen and R1 is required to be lower alkyl esterifying the product obtained.
4. A 2,5-tetrahydrofurane derivative of formula I given in claim 1 where R1,R2,R3,R4, R5 and R6 areas in claim 1 when prepared by the process as claimed in Claim 1, 2 or 3 or an obvious chemical equivalent thereof.
5. A process as claimed in claim 1 which comprises reacting 8-(5-formyl-tetrahydro-2-furyl)-octanoic acid methyl ester in 1,2-dimethoxy ethane with a reaction mixture prepared by admixing a sodium hydride in mineral oil suspended in 1,2-dimethoxy ethane and (2-oxoheptyl)-phosphonic acid dimethyl ester.
6. 8-[5-(3-Oxo-1-octenyl)-tetrahydro-2-furyl]-octanoic acid methyl ester when prepared by the process as claimed in claim 5 or an obvious chemical equivalent thereof.
7. A process as claimed in claim 5 in which the product obtained is treated with sodium tetrahydroborate in methanol.
8. 8[5-(3-Hydroxy-1-octenyl)-tetrahydro-2-furyl]-octanoic acid methyl ester when prepared by the process as claimed in claim 7 or an obvious chemical equivalent thereof.
9. A process as claimed in claim 7 in which the product obtained is refluxed in methanol with aqueous potassium carbonate.
10. 8-[5-(3-Hydroxy-1-octenyl)-tetrahydro-2-furyl]-octanoic acid when prepared by the process as claimed in claim 9 or an obvious chemical equivalent thereof.
11. A process as claimed in claim 7 in which the product obtained is hydrogenated in methanol in the presence of Raney nickel.
12. 8-[5-(3-Hydroxyoctyl)-tetrahydro-2-furyl]-octanoic acid methyl ester when prepared by the process as claimed in claim 11 or an obvious chemical equivalent thereof.
13. A process as claimed in claim 11 in which the product obtained is refluxed in methanol with aqueous potassium carbonate.
14. 8-[5-(3-Hydroxyoctyl)-tetrahydro-2-furyl]-octanoic acid when prepared by the process as claimed in claim 13 or an obvious chemical equivalent thereof.
lS. A process as claimed in claim 5 in which the product obtained is hydrogenated in methanol in the presence of Raney nickel.
16. 8-[5-(3-Oxooctyl)-tetrahydro-2-furyl]-octanoic acid methyl ester when prepared by the process as claimed in claim 15 or an obvious chemical equivalent thereof.
17. A process as claimed in claim 15 in which the product obtained is refluxed in methanol with aqueous potassium carbonate.
18. 8?5-(3-Oxooctyl)-tetrahydro-2-furyl]-octanoic acid when prepared by the process as claimed in claim 17 or an obvious chemical equivalent thereof.
19. A process as claimed in claim 17 in which the product obtained is mixed with hexamethyldisilazane and trichloromethylchloro silane a pyridine and the mixture treated with methyl magnesium bromide in ether.
20. 8?5-(3-Hydroxy-3-methyloctyl)-tetrahydro-2-furyl]-octanoic acid when prepared by the process as claimed in claim 19 or an obvious chemical equivalent thereof.
21. A process as claimed in claim 19 in which the product obtained is refluxed in methanol with an ethyl ether boron trifluoride complex.
22. 8?5-(3-Hydroxy-3-methyloctyl)-tetrahydro-2-furyl]-octanoic acid methyl ester when prepared by the process as claimed in claim 21 or an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB2924173A GB1466256A (en) | 1973-06-20 | 1973-06-20 | 2,5-substituted furans and their production |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1052801A true CA1052801A (en) | 1979-04-17 |
Family
ID=10288383
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA202,705A Expired CA1052801A (en) | 1973-06-20 | 1974-06-18 | Tetrahydrofurane derivatives and production thereof |
| CA202,704A Expired CA1053686A (en) | 1973-06-20 | 1974-06-18 | Furane derivatives and production thereof |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA202,704A Expired CA1053686A (en) | 1973-06-20 | 1974-06-18 | Furane derivatives and production thereof |
Country Status (13)
| Country | Link |
|---|---|
| JP (2) | JPS5032165A (en) |
| BE (2) | BE816570A (en) |
| CA (2) | CA1052801A (en) |
| DD (2) | DD112755A5 (en) |
| DE (2) | DE2429247A1 (en) |
| DK (2) | DK329874A (en) |
| FI (2) | FI187374A (en) |
| FR (2) | FR2234301B1 (en) |
| GB (1) | GB1466256A (en) |
| IL (2) | IL45065A (en) |
| NL (2) | NL7408199A (en) |
| NO (2) | NO742235L (en) |
| SE (2) | SE7408097L (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0390857A4 (en) * | 1987-12-15 | 1991-04-17 | The Trustees Of Princeton University | Transgenic testing systems for mutagens and carcinogens |
-
1973
- 1973-06-20 GB GB2924173A patent/GB1466256A/en not_active Expired
-
1974
- 1974-06-18 CA CA202,705A patent/CA1052801A/en not_active Expired
- 1974-06-18 CA CA202,704A patent/CA1053686A/en not_active Expired
- 1974-06-19 FI FI1873/74A patent/FI187374A/fi unknown
- 1974-06-19 NL NL7408199A patent/NL7408199A/xx not_active Application Discontinuation
- 1974-06-19 FR FR7421232A patent/FR2234301B1/fr not_active Expired
- 1974-06-19 BE BE145629A patent/BE816570A/en unknown
- 1974-06-19 DE DE2429247A patent/DE2429247A1/en active Pending
- 1974-06-19 DD DD179281A patent/DD112755A5/xx unknown
- 1974-06-19 IL IL45065A patent/IL45065A/en unknown
- 1974-06-19 NL NL7408200A patent/NL7408200A/xx not_active Application Discontinuation
- 1974-06-19 FI FI1874/74A patent/FI187474A/fi unknown
- 1974-06-19 SE SE7408097A patent/SE7408097L/xx unknown
- 1974-06-19 DE DE2429248A patent/DE2429248A1/en active Pending
- 1974-06-19 FR FR7421231A patent/FR2234302B1/fr not_active Expired
- 1974-06-19 SE SE7408096A patent/SE7408096L/xx unknown
- 1974-06-19 JP JP49069267A patent/JPS5032165A/ja active Pending
- 1974-06-19 BE BE145628A patent/BE816569A/en unknown
- 1974-06-19 NO NO742235A patent/NO742235L/no unknown
- 1974-06-19 IL IL45066A patent/IL45066A/en unknown
- 1974-06-19 DD DD179283A patent/DD113356A5/xx unknown
- 1974-06-19 NO NO742234A patent/NO742234L/no unknown
- 1974-06-19 JP JP49069266A patent/JPS5032164A/ja active Pending
- 1974-06-20 DK DK329874A patent/DK329874A/da unknown
- 1974-06-20 DK DK329674A patent/DK329674A/da unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO742234L (en) | 1975-01-13 |
| FR2234301B1 (en) | 1978-09-22 |
| IL45065A0 (en) | 1974-09-10 |
| FR2234302A1 (en) | 1975-01-17 |
| FR2234301A1 (en) | 1975-01-17 |
| FR2234302B1 (en) | 1978-12-01 |
| IL45066A0 (en) | 1974-09-10 |
| DE2429248A1 (en) | 1975-01-16 |
| SE7408096L (en) | 1974-12-23 |
| BE816569A (en) | 1974-10-16 |
| DD112755A5 (en) | 1975-05-05 |
| FI187374A (en) | 1974-12-21 |
| JPS5032165A (en) | 1975-03-28 |
| CA1053686A (en) | 1979-05-01 |
| JPS5032164A (en) | 1975-03-28 |
| BE816570A (en) | 1974-10-16 |
| DK329874A (en) | 1975-02-10 |
| NO742235L (en) | 1975-01-13 |
| GB1466256A (en) | 1977-03-02 |
| SE7408097L (en) | 1974-12-23 |
| DK329674A (en) | 1975-02-10 |
| IL45065A (en) | 1978-06-15 |
| NL7408200A (en) | 1974-12-24 |
| DD113356A5 (en) | 1975-06-05 |
| NL7408199A (en) | 1974-12-24 |
| DE2429247A1 (en) | 1975-01-16 |
| FI187474A (en) | 1974-12-21 |
| IL45066A (en) | 1977-07-31 |
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