CA1105484A - 1,3-dicarbonyl compounds and process for their preparation - Google Patents
1,3-dicarbonyl compounds and process for their preparationInfo
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Abstract
ABSTRACT OF THE DISCLOSURE
1,3-Dicarbonyl compounds and process for their preparation of the general formula
1,3-Dicarbonyl compounds and process for their preparation of the general formula
Description
This invention relates to novel 1,3-dicarbonyl compo~mds and a novel process for their preparation.
More specifically, this invention relates to a process for preparing 1,3-dicarbonyl compounds which comprises reacting an ~ unsaturated carbonyl compound with an organic copper lithium compound to introduce an organic group into the ~-posit-ion of the carbonyl compound, and then reacting the product with an organic carboxylic acid halide or an organic carboxylic acid anhydride to introduce an acyl group into the ~-position of the carbonyl compcund; and to novel 1,3-dicarbonyl compounds obtained by this process.
It is an object of this invention to provide novel 1,3-dicarbonyl compounds useful as medicines, agricultural chemicals, perfumes and intermediates of these, and a novel process for preparing these compounds.
Another object of this inven~ion is ~o provide a novel process for preparing 1,3-dicarbonyl compounds in high yields from ~,~-unsaturated carbonyl compounds.
Still another object of this invention is to provide novel 2-acyl-3-substituted-cyclopentan- or -cyclohexan-l-ones use-ful as medicines, agricultural chemicals, perfumes, and their intermediates, and aprocess for their preparation.
Other objects and ad~antagesof this invention will be-come apparent from the following description.
According to this invention, there is provided a process for preparing 1,3-dicarbonyl compounds of the following formula - ~ ^~
,8~
R4-- C C C O ( RB lC--where~n ~ represents an a~kyl group o 1 to 12 carbon at~ms, which may be subst~tuted by a protacted hydroxyl group; R2 and R4 rapresa~t a hydrogen abom; R3 represents a hydLogen atcm or an al~yl group of 1 bo 12 carbon abQms, which may bs substltuted by a p~tectRd hydroxyl g~cupi R~
represents an aL~yl grQup of 1 to 12 carhon a~om~ o~ a phenyl group, each of which may be substituted by a carboxyl o~ low~r akkoxycarbonyl yroup; and ~ represents an alkyl, alken~l or alk~nyl group, each of which has up to 12 carbon atons and may be subst~tuted b~ a p.~otectel hydroxyl group; and Rl and R3 may addataonally togathar rep~esent an alk~lene group o 2 to 4 aarbcn atoms, ~hiah may be substituted by a prQtected hydroxyl group, or the h~dro~yzed campounds thereo ~hich camprises ~1) reacting an ~ unsaturated cæbon~l ccmpo~nd of ~he ollowing formula R3 R2 R~
R~ C - C C - 0 whe,rein ~ , R2, R3 and R~ are the same as delned abc~e, with an organic copp~r lithium campcun~ o the ollow.mg orm~1a Cu~)nLi~2 n ~II) wherein ~ is ~he same as deined abcve, Y represents a moncvalent anion, and n is 1 or 2, and when n is 2, the t~10 ~ grcu~s are ad~ntacal or different~
with the p~c~iso that ~ an the case o n being 1, and at 13ast one o~ ~
graups in the case of n beang 2, are alkyls or alken~ls contain~g at least 2 t~8 ~
carbon atoms an~ up to 12 ca~bon atoms, and ma~ be substltut~l by a protectel hydLoxyl g~oup, ln th~ p~esence of an aprot~c lnert organlc solven-t;
~ 2) reactmg the r3actio~ product with an acid halide o.r acid anhydride derlved fron an c~ganic car~oxylic acid of the following formula ~ - COOH (III) whe.reLn ~ ls the sa~e as defin~d ab we; and ~ 3) iE ~scessa~y, t~eatmg the reaction prcduct ~i~h water o~
an a~ueous solution o~ a st~ong electrolyte to h~d~olyze 1~.
Thus, the prccess o this ~nvention ls cha-racterized ln th~t 10 substi~u~nts are successively ~introduced. Ln-to the ~-F~sition and the X-position of the ~ unsaturated ca~onyl canpour~l, a~ in p~rticular, an ac~l group ls mtroduced into the ~-pos~tion.
Methods cc~ising Lntroduc~ng a rnethyl group into ~e ~-position of an ~,3-unsatu~ated ca~l~on~ camFound, ar~d t~ a~et~ating th3 resulting product have pre~lously been kn~n, and ~3 oll~irlg litera~re references reFort that ~n such methods, O-acetylation o the carbon~ cc~pound occurs dc~n~nantly.
1) E. Piers et al., "Jou~ oE the P~srican Ch~cal Societ:y", 93, 5113 ~1971).
More specifically, this invention relates to a process for preparing 1,3-dicarbonyl compounds which comprises reacting an ~ unsaturated carbonyl compound with an organic copper lithium compound to introduce an organic group into the ~-posit-ion of the carbonyl compound, and then reacting the product with an organic carboxylic acid halide or an organic carboxylic acid anhydride to introduce an acyl group into the ~-position of the carbonyl compcund; and to novel 1,3-dicarbonyl compounds obtained by this process.
It is an object of this invention to provide novel 1,3-dicarbonyl compounds useful as medicines, agricultural chemicals, perfumes and intermediates of these, and a novel process for preparing these compounds.
Another object of this inven~ion is ~o provide a novel process for preparing 1,3-dicarbonyl compounds in high yields from ~,~-unsaturated carbonyl compounds.
Still another object of this invention is to provide novel 2-acyl-3-substituted-cyclopentan- or -cyclohexan-l-ones use-ful as medicines, agricultural chemicals, perfumes, and their intermediates, and aprocess for their preparation.
Other objects and ad~antagesof this invention will be-come apparent from the following description.
According to this invention, there is provided a process for preparing 1,3-dicarbonyl compounds of the following formula - ~ ^~
,8~
R4-- C C C O ( RB lC--where~n ~ represents an a~kyl group o 1 to 12 carbon at~ms, which may be subst~tuted by a protacted hydroxyl group; R2 and R4 rapresa~t a hydrogen abom; R3 represents a hydLogen atcm or an al~yl group of 1 bo 12 carbon abQms, which may bs substltuted by a p~tectRd hydroxyl g~cupi R~
represents an aL~yl grQup of 1 to 12 carhon a~om~ o~ a phenyl group, each of which may be substituted by a carboxyl o~ low~r akkoxycarbonyl yroup; and ~ represents an alkyl, alken~l or alk~nyl group, each of which has up to 12 carbon atons and may be subst~tuted b~ a p.~otectel hydroxyl group; and Rl and R3 may addataonally togathar rep~esent an alk~lene group o 2 to 4 aarbcn atoms, ~hiah may be substituted by a prQtected hydroxyl group, or the h~dro~yzed campounds thereo ~hich camprises ~1) reacting an ~ unsaturated cæbon~l ccmpo~nd of ~he ollowing formula R3 R2 R~
R~ C - C C - 0 whe,rein ~ , R2, R3 and R~ are the same as delned abc~e, with an organic copp~r lithium campcun~ o the ollow.mg orm~1a Cu~)nLi~2 n ~II) wherein ~ is ~he same as deined abcve, Y represents a moncvalent anion, and n is 1 or 2, and when n is 2, the t~10 ~ grcu~s are ad~ntacal or different~
with the p~c~iso that ~ an the case o n being 1, and at 13ast one o~ ~
graups in the case of n beang 2, are alkyls or alken~ls contain~g at least 2 t~8 ~
carbon atoms an~ up to 12 ca~bon atoms, and ma~ be substltut~l by a protectel hydLoxyl g~oup, ln th~ p~esence of an aprot~c lnert organlc solven-t;
~ 2) reactmg the r3actio~ product with an acid halide o.r acid anhydride derlved fron an c~ganic car~oxylic acid of the following formula ~ - COOH (III) whe.reLn ~ ls the sa~e as defin~d ab we; and ~ 3) iE ~scessa~y, t~eatmg the reaction prcduct ~i~h water o~
an a~ueous solution o~ a st~ong electrolyte to h~d~olyze 1~.
Thus, the prccess o this ~nvention ls cha-racterized ln th~t 10 substi~u~nts are successively ~introduced. Ln-to the ~-F~sition and the X-position of the ~ unsaturated ca~onyl canpour~l, a~ in p~rticular, an ac~l group ls mtroduced into the ~-pos~tion.
Methods cc~ising Lntroduc~ng a rnethyl group into ~e ~-position of an ~,3-unsatu~ated ca~l~on~ camFound, ar~d t~ a~et~ating th3 resulting product have pre~lously been kn~n, and ~3 oll~irlg litera~re references reFort that ~n such methods, O-acetylation o the carbon~ cc~pound occurs dc~n~nantly.
1) E. Piers et al., "Jou~ oE the P~srican Ch~cal Societ:y", 93, 5113 ~1971).
2) P. I.. Stotter et al., "J~;~nal o organ~a ~mlst;ry"
38, 2576 ~1973).
38, 2576 ~1973).
3) R. K. Bcec~nan, Jr., "Journal of organic C~nis~ry"~
38, 4~50 ~1973).
The reerence 1) reF~ts t;hat enol acetate o the ollow~ng o~u1a
38, 4~50 ~1973).
The reerence 1) reF~ts t;hat enol acetate o the ollow~ng o~u1a
4 -OTHP
AcO
Cll~
CAc denotes CH3CO_, and THP denotes a tetrahydropyranyl group) was obtained in a yield of 88~ by reacting an ~,~-uns~turated ketone of the follotling formula. OTHP
C~13 ~ith litllium dimethylcuprate, and reacting the resulting produc~ with acetyl chloride.
The reference 2) reports that by reacting an ~3~-unsaturated ketone of the following formula ~ ~
(two R groups both represent atoms or methyl groups) with lithium dimethylcuprate ~LiMe2Cu), and reacting the resulting product ~ith an excess of acetic anhydride ~Ac2O), a compound of the following formula - ~Ac (R is the same as defined in formula ~3), and Ac represents CH3CC;~
was obtained in a yield of 90% ~R=H), and 92% [R=~CH3).
The reference 3) contains almost the same disclosure as the reference 1).
Furthermore, James A. Marshall et al., "Jou~nal of the ~nerican Chemi.cal Society", 91 648 (1969) [reference 4)] discloses that enol aceta~e of the following formula 1 ~
OAc Cfi) CH
3 Ac=CH3CO-was obtained in a yield of 30% by reacting an a,~-unsa~urated ketone of the following formula CH
~/~
I l v ~ o ~5) with methylmagn~sium iodide, a Crignard reagent, in the presence of a copper salt, and then reacting the resulting product with acetyl chloride.
As far as the applicants are aware, there has been no other report than those in the above-cited literature references 1) to 4) regarding ~he alkylation and acylation of ~ unsaturated carbonyl compounds. These references commonly disclose that by methylating the ~-position of the above carbonyl compound and then acetylating the product, O-acetylation of the carbonyl compound occurs donminantly.
Our investigations however led to the discovery tha~ when an ~ unsaturated carbonyl compound such as cyclohex-2- en-l-one is reacted with an organic copper lithium compound to introduce an organic group contain-ing at least 2 carbon atoms into the ~-position of the unsaturated carbonyl compound, subsequent acylation of the resulting product unexpectedly results in the predominan~ C-acylation of its ~-position.
For example, according to our investigations, 2-acetyl-3-e~llyl cyclohexan-l-one of the following formula o o " "CCH3 tIV-I) was obtained in a yield of 72% by reacting cyclohex-2-en-1--one of the following formula O
~ (I-l) with lithium diethylcuprate to introduce an ethyl group into its ~-position, and reacting the resulting reacting mixture with acetyl chloride, as shown hereinbelow in Example 3.
The invention will be described in greater detail bclow.
In the present invention, the ~ unsa~urated carbonyl compound of formula (I) is first reacted with organic copper lithium compound of formula ~II) (first step). This first step will be described in detail.
[FIRST STE~
-Unsaturated Carbonyl Compounds (I) In the above formula *~I), Rl, R2, R3 and R4 are identical or different and represent a hydrogen atom or a monovalent organic group, and the organic groups may be linked to each other to form rings.
Examples of the monovalent organic group are saturated hydrocarbon groups and unsaturated hydrocarbon groups which may contain a substituent not reactive with the organic copper lithium compounds, such as alkoxy, aryloxy, siloxy~ carboxy, acyloxy or carbonyl (keto, formyl). Preferred monovalellt organic groups are those containing 1 to 30 carbon atoms, and the rings formed by ~he organic groups are preferably 5- to 7-membered.
Typical examples of the ~ unsaturated carbonyl compound of formula (I) are given below.
I-l-A~ Compounds wherein Rl and R3 ~or R~) are linked to form a ring:-~a) 6-Membered Compounds Cyclohex-2-en-1-one, 2-methylcyclohex-2~en-1-one, 3-methylcyclohex-2-en-1-one, isophorone, carvone, 2,3-dimethylcyclohex~2-en~l~one, 2-oxo~ ethyl-A3 octalin, 1 -oxo-~2~oc~alin, 4-estren-3,17-dione, 1(5)-androsten-3,17~dione, and
AcO
Cll~
CAc denotes CH3CO_, and THP denotes a tetrahydropyranyl group) was obtained in a yield of 88~ by reacting an ~,~-uns~turated ketone of the follotling formula. OTHP
C~13 ~ith litllium dimethylcuprate, and reacting the resulting produc~ with acetyl chloride.
The reference 2) reports that by reacting an ~3~-unsaturated ketone of the following formula ~ ~
(two R groups both represent atoms or methyl groups) with lithium dimethylcuprate ~LiMe2Cu), and reacting the resulting product ~ith an excess of acetic anhydride ~Ac2O), a compound of the following formula - ~Ac (R is the same as defined in formula ~3), and Ac represents CH3CC;~
was obtained in a yield of 90% ~R=H), and 92% [R=~CH3).
The reference 3) contains almost the same disclosure as the reference 1).
Furthermore, James A. Marshall et al., "Jou~nal of the ~nerican Chemi.cal Society", 91 648 (1969) [reference 4)] discloses that enol aceta~e of the following formula 1 ~
OAc Cfi) CH
3 Ac=CH3CO-was obtained in a yield of 30% by reacting an a,~-unsa~urated ketone of the following formula CH
~/~
I l v ~ o ~5) with methylmagn~sium iodide, a Crignard reagent, in the presence of a copper salt, and then reacting the resulting product with acetyl chloride.
As far as the applicants are aware, there has been no other report than those in the above-cited literature references 1) to 4) regarding ~he alkylation and acylation of ~ unsaturated carbonyl compounds. These references commonly disclose that by methylating the ~-position of the above carbonyl compound and then acetylating the product, O-acetylation of the carbonyl compound occurs donminantly.
Our investigations however led to the discovery tha~ when an ~ unsaturated carbonyl compound such as cyclohex-2- en-l-one is reacted with an organic copper lithium compound to introduce an organic group contain-ing at least 2 carbon atoms into the ~-position of the unsaturated carbonyl compound, subsequent acylation of the resulting product unexpectedly results in the predominan~ C-acylation of its ~-position.
For example, according to our investigations, 2-acetyl-3-e~llyl cyclohexan-l-one of the following formula o o " "CCH3 tIV-I) was obtained in a yield of 72% by reacting cyclohex-2-en-1--one of the following formula O
~ (I-l) with lithium diethylcuprate to introduce an ethyl group into its ~-position, and reacting the resulting reacting mixture with acetyl chloride, as shown hereinbelow in Example 3.
The invention will be described in greater detail bclow.
In the present invention, the ~ unsa~urated carbonyl compound of formula (I) is first reacted with organic copper lithium compound of formula ~II) (first step). This first step will be described in detail.
[FIRST STE~
-Unsaturated Carbonyl Compounds (I) In the above formula *~I), Rl, R2, R3 and R4 are identical or different and represent a hydrogen atom or a monovalent organic group, and the organic groups may be linked to each other to form rings.
Examples of the monovalent organic group are saturated hydrocarbon groups and unsaturated hydrocarbon groups which may contain a substituent not reactive with the organic copper lithium compounds, such as alkoxy, aryloxy, siloxy~ carboxy, acyloxy or carbonyl (keto, formyl). Preferred monovalellt organic groups are those containing 1 to 30 carbon atoms, and the rings formed by ~he organic groups are preferably 5- to 7-membered.
Typical examples of the ~ unsaturated carbonyl compound of formula (I) are given below.
I-l-A~ Compounds wherein Rl and R3 ~or R~) are linked to form a ring:-~a) 6-Membered Compounds Cyclohex-2-en-1-one, 2-methylcyclohex-2~en-1-one, 3-methylcyclohex-2-en-1-one, isophorone, carvone, 2,3-dimethylcyclohex~2-en~l~one, 2-oxo~ ethyl-A3 octalin, 1 -oxo-~2~oc~alin, 4-estren-3,17-dione, 1(5)-androsten-3,17~dione, and
5-pregnen-3~-ol-7,20-dione acetate.
~b) 5-Membered Compounds Cyclopent-2-en-1-one, 3,4-dimethylcyclopent-2-en-1-one, 3,4,4-trimethylcyclopent-2~en-1-one, 2-methylcyclopent-2-en-1-one, 3-methylcyclopent-2-en-1-one, 4-methylcyclopent-2-en-1-one, 3-isopropylcyclopent-2-en-1-one, 2,3,4-trime~hylcyclopent-2-en-1-one, 4-isopropyl-2,3-dimethylcyclopent-2-en-1-one, 3-ethyl-2-methylcyclopent-2-en-1-one, 2,3-dimethylcyclopent-2-en-1-one, 3-methyl-2-amylcyclopent-2-en-l-one, 1~8)-hydroinden-2-one, 8~9)-hydroinden-1-one, 2-hydroinden-1-one, and 4-t-butyldimethylsiloxycyclopent-2-en-1-one.
(c) 7-Membered Compounds Cyclohept-2-en-1-one, 2-methylcyclohept-2-en-1-one, and 3,7-dimethylcyclohept-2-en-1-one.
I-l-B. Compounds wherein Rl and R2 are linked to form a ring:-2-Methylenecyclopen~an-l-one, 2-methylenecyclohexan--1-one, and 2-propylidenecycloheptan-1-one.
I-l-C. Compounds wherein R2 and R3 ~or R4) are linked to form a ring:-1-Acetylcyclopentene~
l-cyclopentene aldehyde, l-acetylcyclohexene, l-cyclohexene aldehyde, and l-acetylcycloheptene.
I-l-D. Linear compounds ~herein R1, R2, R3 and R4 are not linked to each other:-Methyl vinyl ketone, ethyl vinyl ketone~
n-propyl vinyl ketone, n-butyl vinyl ketone, isobutyl vinyl ketone, n-amyl vinyl ketone, methyl iscpropenyl kstone, sthyl isopropenyl ketone, 2-ethyl-1-hexen-3-one, 3-penten-2-one~
3-hexen-2-one, 3-hepten-2-one, 4-hexen-3-one, 7-methyl-5-octen-4-one, 5 J 5-dimethyl-3-hexen-2-one, 4-methyl-3-penten-2-one, 5-methyl-4-hexen-3-one, 5-ethyl-4-hepten~3-one, 8~
3-methyl-3~penten-2~one, 3_methyl-3_hepten-2-one, 3-n-propyl-3-hexen-2~one, 3,4-dimethyl 3-penten~2-one, 4,5-dlmethyl-4-penten-3-one, 2,4,5-trimethyl-4-hexen-3-one, acrolein, crotonaldehyde, methacrolein, 2-methyl-2-butenal, and 2,3-dimethyl-2-butenal.
I-2. Organic copper lithium comp~unds (II) According to the process of this inventionJ the ~ unsaturated carbonyl compound (I) is reacted with the organic copper lithium compound of the formula CU(RB)nLiY2_n (II) wherein the symbols are the same as defined above and when n is 2, the above formula will become Cu(RB)2.Li (II'), in the presence of an aprotic inert organic solvent. It is presumed that as a result of this, the following reactions of formula (L) or (M), for example, take place.
~ ~ CU(Rg)2Li ~ ~ CuLiRB ~L) O
~3 ~ Cu(RB)2Li ~ ~ CuLiRB
(M) O O
s RB in formula (II) abo~e is suitably a saturated or unsaturated hydrocarbon residue which may contain an ether linkage. Especially preferred RB groups are monovalent saturated or unsaturated hydrocarbon residues containing 2 to 20 carbon a~oms which may contain an ether linkage.
Examples of RB in formula (II) are alkyl, alkenyl, aralkyl, aralkenyl, aralkynyl, alkoxyalkyl, alkoxyalkenyl, and alko.~yalkynyl groups. Preferred RB groups are monovalent organic residues containing 2 to 20 carbon atoms. Examples of Y are chlorine, bromine, iodineg and cyano group.
The organic copper lithium compound can be easily prepared by reacting a corresponding organic lithium compound Witll a cuprous salt in an inert medium in an atmosphere of nitrogen. At this time, the organic lithium compound is not limited to one species, but two different organic lithium com-pounds may be reacted with the cuprous salt stepwise or simul-taneously to form an organic copper lithium compound having two different RB groups.
Examples of suitable organic lithium compounds are shown below.
Alkyllithiums ~2 1) Ethyllithium ~2-2~ n-Propyllithium (2-3) i-Propyllithium ~2-4) n-Butyllithium ~2-5) t-Butyllithium (?~6~ n-Pentyllithium (2-7) n-Hexyllithium ~2-8) Cyclohexyllithium ~2-9) n-Heptyllithium (2-10) n-Octyllithium C2-ll) n-Nonyllithium Alkenyllithiums (2-12) Vinyllithium ~2-13) l-Lithio-prop-cis-l-ene (2-14) l-Lithio-prop-trans-l-ene ~2-15) 1-Lithio-oct-cis-5-ene ~2-16) l-Lithio-oct-trans-l-ene (2-17) l-Lithio-oct-cis-l-ene (2-18) 1-Lithio-oct-trans-l-cis-5-diene _kyny l l i tlli ~uns 2-19) 1-Lithio-oct-5-yne (2-20) l-Lithio-but-l-yne (2-21) l-Lithio-pent-l-yne (2-22) l-Li~hio-hex-l-yne ~2-23) l-Lithio-hep-l-yne ~2-24) l-Lithio-oct-l-yne Aralkyllithiums (2-25) 1-Lithio-8-phenyl-octene Aralkenyllithi~ns (2-26) 1-(2-Thenyl)-vinyllithium (2-27) 1-Lithio-8-phenyl-oct-trans-1-ene (2-28) 1-Lithio-8-phenyl-oct-cis-1-ene Aralkynyllithiums (2-29) 1-Lithio-8-phenyl-oct-5-yne Alkoxyaralkyllithiums (2-30) 1-Lithio-3-tetrahydropyranyloxy-octane (2-31) 1-Lithio-bis(3,7-tetrahydropyranyloxy) - oetane Alkoxyalkenylll iums ~2-32) 1-Lithio-3-tetrahydropyranyloxy-oct-trans-1-ene ~2-3~) 1-Lithio-bis(3,7-tetrahydropyranyloxy)-oct-trans-1-ene (2-34) 1-Lithio-3-tetrahydropyranyloxy-oct-trans-1-cis-5-diene Alkoxyalk~lyllithiums ~ 2-35) 1-Lithio-3-(~-ethoxy~-ethoxy-oct-5-yne Siloxyallcenyllithium_ (2-36) l-Lithio-~-t-butyldimethylsiloxy-oct-trans-l-ene.
The cuprous salts that can be reacted with the org~mic lithium compounds to form ~he organic copper lithium compounds (II) may, for example, be cuprous chloride, cuprous bromide, cuprous iodide, and cuprous cyanide.
One specific example of preparing the organic copper lithium compound from the organic lithium compound and the cuprous salt comprises reacting the organic lithium compound wi~h the cuprous salt at ro~m temperature to - 78C for several hours, for example, at --78C for 0.5 hour, using an inert medium such as a hydrocarbon (e.g., pentane, hexane or heptane) or an ~her ~e.g., diethyl ether~ -tetrahydrofuran, dioxane, or dimethoxyethane).
The compound of the formula LII] may be used as a complex with a trivalent phosphorous compound such as trialkylphosphines ~e.g., triethy-lphosphine or tri-n-butylphosphine~, trialkyl phosphites (e.g., trimethyl phosphite, triisopropyl phosphite, or tri-n-bu~yl phosphite) or tri-phenylphosphine, Frequently, the use of the complex ends to gire an increased yield of the final product.
-1~-~ ccording to the process of this invention, the ~
unsaturated carbonyl compound is ~irs~ reacted with the above organic copper lithium compo~md in the presence of an aprotic organic medium~
The ~,~-unsaturated carbonyl compound and the organic copper lithium compound are reacted stoichiometrically. Usually, the ~,~-unsaturated carbonyl compound is used in a proportion of 0.5 to 2 mols, pre~erably 0.8 to 1.2 mols, per mol of the organic copper lithium compound.
The reaction temperature is -78C to about 50C.
It is sufficient, however, that the reaction is performed at room temperature for 10 minutes to 2 hours. The reaction proceeds sufficiently even when the temperature is lower than the above-specified range, for example, when it is -100 C.
The reaction is carried out in the presence of an aprotic organic medium which is liquid at the reackion temperature and not reactive with the reaction reagents. Such aprotic inert organic media includes a variety of aprotic inert liquid media including nitrogen-containing, sulfur-containing or oxygen-~0 containing aprotic polar organic solvents. Examples of these organic media are saturated hydrocarbons such as pentane, hexane, heptane or cyclohexane, aromatic hydrocarbons such as benzene, toluene or oxylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or diethylene glycol dimethyl ether, hexamethylphosphoric triamide, N,N-dimethylformamide, N,N-di-methylacetamide, dimethyl sulfoxide, sulfolane and N-methylpyr-rolidone. Inert solvents such as pentane which are used to produce the organic copper lithium compounds can be used dir0ctly as such aprotic organic solvents. In this case, the starting ~ unsaturated carbonyl compound ~I) is added to the reaction system in which the organic copper lithium compound has been prepared.
[SECOND STEP]
II-l. Reaction agent in the second step;-According to the process of this invention, ~he reac-tion product obtained by the reaction in the first step is reacted with an acid anhydride or an acid halide derived from an organic carboxylic acid having the following ~ormula RA-COOH (III) whercin RA is a monovalent orgc~nic group, in the presence of an aprotic inert organic solvent, preferably in the co-presence of a nitrogen-containing, sulfur-containing or oxygen-con~aining aprotic organic solvent to form the desired 1,3-dicarbonyl compound of formula (IV) (second step).
Suitable RA groups are those containing 1 to 20 carbon atoms.
The acid halides are especially suitable as the reaction agent in the second step.
Suitable acid halides or acid anhydrides derived from the organic carboxylic acids of formula ~III) are acid halides of the following formula R'A-COX (III-A~
wherein R'A is a monovalent organic group containing 1 to 20 carbon atoms, and X is a halogen atom, or acid anhydrides of the following formulae `':
R'A--c " (III-B) o ~ col ~
A ~ C~ c) 'O
wherein R'A is a monovalent organic group containing 1 to 20 carbon atoms, and R"A is a divalent organic group containing 2 to 20 carbon atoms.
The acid halides of formula ~III-A) are especially preferred.
O the acid halides, acid chlorides are preferred because they have sufficient reactivity and are readily available.
Of these, acid halides or acid anhydrides of the fol-lowing formulae X-C-Z-COOR (III-A') Q
o ~ C~Z-COOR (III-B') C,-Z-COOR
~Yherein Z is a divalent saturated or unsaturated hydrocarbon residue containing 1 to 19 carbon atoms;
R is hydrogen atom or a saturated or unsaturated hydrocarbon residue containing 1 to 8 carbon atoms;
and X is a halogen atom, are preferred. The acid halides of formula (III-A') are especial-ly preferred.
~ ~5~ k Specific examples of these acid halides and acid an-hydrides are shown below.
II-l-A. Acid Halides Acetyl chloride, acetyl bromide, acetyl iodide, acetyl fluoride, propionyl chloride, propionyl bromide, n-butyryl chloride, isobutyryl chloride, n-valeryl chloride, isovaleryl chloride, n-caproyl chloride, enanthoyl chloride, capryloyl chloride, pelargonoyl chloride, caprinoyl chloride, undecanoyl chloride, lzuroyl chloride, tridecanoyl chloride, myristoyl chloride, pentadecanoyl chloride, palmitoyl chloride, margaroyl chloride, stearoyl chloride, cyclopropanecarboxylic acid chloride, cyclopenkanecarboxylic acid chloride, cyclohexanecarboxylic acid chloride, ~ ?~
:
trimethylacetyl chloride, diethylacetyl chloride, t-butylacetyl chloride, acryloyl chloride, crotonyl chloride, methacryloyl chloride, 4-methyl-2-pentenoic acid chloride, 10-undecenoyl chloride, oleyl chloride, benzoyl chloride, benzoyl bromide, phenylacetyl chloride, p-methylbenzoyl chloride, ~-phenylpropionyl chloride, cinnamoyl chloride, p-bromobenzoyl chloride, o-chlorobenzoyl chloride, methoxyacetyl chloride, p-methoxybenzoyl chloride, p-acetylbenzoyl chloride, 2-furoyl chloride, ~-thienoyl chloride, 2-thienylacetyi chloride, nicotinoyl chloride, methoxalyl chloride, ethoxyalyl chloride, ~-carbomethoxypropionyl chloride, r- carboethoxybutyryl chloride, ~-carboethoxyvaleroyl chloride, -~-carbocthoxycaproyl chloride, ~-carboethoxyvaleroyl chloride, ~-carboethoxyenanthoyl chloride, ~-carboethoxycaprylyl chloride, o-carbomethoxybenzoyl chloride, m-carbomethoxybenzoyl chloride, p-carbomethoxyben~oyl chloride, cyanoacetyl chloride, oxalyl chloride, oxalyl bromide, succinoyl chloride, adipoyl chloride, 1,4-cyclohexanedicarboxylic acid chloride, ph~haloyl chloride, isophthaloyl chloride, and terephthaloyl chloride, II-l-B. Acid Anhydrides Acetic anhydride, propionic anhydride, n-butyric anhydride, n-valeric anhydride, n-caproic anhydride, enanthoic anhydride, n-caprylic anhydride, pilargonic anhydride, n-capric anhydride, undecanoic anhydride, lauric anhydride, tridecanoic anhydride, myristic anhydride, pentadecanoic anhydride, palmitic anhydride, margaric anhydride, stearic anhydride, isobutyric anhydride isovaleric anhydride, cyclobutanecarboxylic anhydride, cycohexanecalboxylic anhydride, crotonic anhydride, oleic anhydride, vaccenic anhydride, linoleic anhydrid~, linolenic anhydride, benzoic anhydride phenylacetic anhydride, o-toluic anhydride, m-toluic anhydride, p-toluic anhydride, p-methoxybenzoic anhydride, p-bromobenzoic anhydride, p-chlorobenzoic anhydride, ~-naphthenic anhydride, diphenylacetic anhydride, succinic anhydride, glutaric anhydride, cis-1,2-cyclobutanedicarboxylic anhydride~
1,2-cyclohexanedicarboxylic anhydride, 5-norbornene-2,3-dicarboxylic anhydride, maleic anhydride, and phthalic an~ydride.
The acid halides and acid anhydrides that can be used in this invention are~ of course, not limited to the above-illustrated species.
II-2. Reaction Conditions in the Second Step tC-Acylation):-The reaction of the reaction product of the first step ~ith the above acid halide or anhydride is carried out in an aprotic inert solvent. Alternatively, it can be carried out advantageously in an aprotic inert solvent in the co-presence of a Lewis acid and/or an aprotic polar organic compound, and this method often brings about an appreciable increase in yield.
Examples of the aprotic inert solvent are hydrocarbons such as pentane, hexane, heptane, cyclohexane, benzene, toluene or xylene, which have already been described with regard to the - first step, and algo ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, t~iethylene glycol dimethyl ether, or diethylene glycol dimethyl ether. Examples of the Lewis acid are aluminum fluoride, aluminum chloride, aluminum bromide, ~luminum iodide, boron trifluoride, boron trichloride, boron tribromide, zinc chloride, zinc bromide, stannic chloride, stannic bromide, ferric chloride, ti~anium tetrachloride, or ~ntimony trifruoride.
Examples of the aprotic polar compo~md used together ~ith the aprotic inert solvent in performing the second-step reaction of this invention include hexamethylphosphoric triamide, N,N-dimethyl~ormamide, dimethyl sulfo*ide, formaldehyde dimethyl mercaptal S-oxide, sulfolane, N-methylpyrrolidone, ~e~ramethyl-urea, acetonitrile, nitrobenzene, dimethylcyanamide, tetra-5~
methylethylenediamine, tetraethylethylenediamine, triethylene-diamine, triethylamine, pyridine, ~,~'-dipyridyl, 1,5-diaza-bicyclo [4,3-0]-5-nonene, and 1,5-diazabicyclo [5,4,0]-5-undecene.
The reaction can be preferably carried ou* by bringing the reaction product o~ the first step into intimate contact ~ith the acid halide or anhydride in the presence of the above solvent at a temperature of -78C to about 50C.
Preferably, the above solvent is used in a total amount of about 0.8 to about 100 mol times, preferably about 10 to 50 mol times, the amount of the ~,~-unsaturated carbonyl compound as a starting material in the first step. The amount of the solvent, however, is not limited to this preferred range~
The acid anhydride or acid halide as a reaction agent c.~l be used in an amount of about 0.5 to about 10 mol times, preferably 0.8 to 5 mol times, the amount of the starting ~
unsaturated carbonyl compound. The amount of the Lewis acid optionally used is not more than 5 molar times the amount of the acid anhydride or acid halide.
The reaction proceeds sufficiently at a temperature of not more than 50C, pr~ferably 0 to 40C, more p:referably 10 to 30C, for 0,5 to about 30 hours.
The 1,3-dicarbonyl compound of formula ~IV) is separated and purified in the following manner after the reaction.
The reaction product is treated with water or an aqueous solution of a strong electroiyte for about 0.1 to 1 hou-r to hydrolyze it, and neutralized i~ desired. The product so treated is then extracted with ether such as diethyl ether, a saturated hydrocarbon such as pentane or hexane, an aromatic hydrocarbon such as benzene or toluene, or a halogenated hydrocarbon such as -methylene chlorideor chloroform. The organic phase extracted is sufficiently ~Yashed with water or an aqueous solution of a strong electrolyte, or if desired, with a dilute acid, thoroughly dried with anhydrous sodilum sulfate, and concentrated to obtain a crude product. The crude product is purified by distillation or column chromatography to afford highly pure 1,3-dicarbonyl compounds of formula ~IV).
The process of this invention described above can thus give 1,3-dicarbonyl compounds of formula ~IV).
Of the 1,3-dicarbonyl compounds prepared by the pres-ent invention 2-acyl-3-substituted cyclopentan-l-ones of the follol~ing formula.
Il ,0, H ~ ~-R~A ~IV-a) H R'B
where:in Q is a hydrogen atom, a hydroxyl group~ or a protected hydroxyl group; R'A is a monovalent organic group containing 1 to 20 carbon atoms; and R'B is a monovalent organic group containing 2 to 20 carbon atoms, especially those of the following formula Il O
H ~ ~ C-Z-COOR ~IV-B) R'B
-2~-wherein Q and R'B are the same as defined in formula (IV-A) above; Z is a divalent saturated or unsaturated hydrocarbon residue containing l to l9 carbon atoms;
and R is a hydrogen atom or a satura~ed or unsatura~ed hydrocarbon residue containing 1 to 8 carbon atoms, and 2-acyl-3-substitut~d cyclohexan-l-ones of the ollowing formula ~ C- R ' A
Q ~ ~ ~IV-C) wherein Q is a hydrogen atom, a hydroxyl group, or a protected hydroxyl group; R'A is a monvalent organic group containing l to 20 carbon atoms; and R'B is a monovalent organic group containing 2 to 20 carbon atoms, especially those of the following formula 11 o H ~ C-Z-COOR
H ~ IV-D) ~ H B
wherein Q and R'B are the same as defined in formula ~IV-C); Z is a divalent saturated or unsaturated hydrocarbon residue containing l to 19 carbon atoms;
and R is a hydrogen atom or a saturated or unsaturated hydrocarbon residue containing 1 to 8 carbon atoms, are novel compounds, and are useful :Eor preparing medicines, agricultural chemicals, perfumes etc.
Furthermore, 2-acyl-3-substituted cyclopentan-l-ones of the following formllla o ii O
~1 ~
~C-Z'-COOR
( I V- E ) Q R B
Q is a hydrogen atom, a hydroxyl ~roup or a protected hydroxyl group; Z' is a divalent sa~uratod or unsa~urated hydrocarbon re-s.idue cont~ining 5 to 10 carbon atoms; and R"~ is a satura~ed or ~msaturated hydrocarbon residue containing 8 to 20 carbon atoms, which may contain 1 to 3 hydroxyl groups or protected hydroxyl groups, are novol compol~ds and oxo analogs of prostaglandin El having various important physiological effects such as smooth muscle shrinking activity, hypotensive activity, bronchodila~ing activity, or activity for inhibiting liberation of fatty acids.
The following ~xamples illustrate -the present invention in greater detail~
(a) Preparation of Organic Copper Lithium Compound To 2 ml of anhydrous diethyl ether was added 136 mg (2 mmol) of l-pentyne, and 1.5 ml (2 mmol) of a 1~3 M ether solution of methylli-thium was added dropwise at 0C in an atmosphere of nitrogen. The mixture was then stirred for 15 minutes 9 and the resul-ting solution was added to 1 ml, of anhydrous diethyl e-ther con-tainlng 380 mg (2 mmol) o~ cuprous iodide~ and the mix-ture was stirred at 0C for 15 minutes to afford an ar~ydrous die-th-yl ether solution of copper pen-tylide~
On the other hand 9 736 mg (2 mmol) of 3-t butyl-dimethylsiloxy-l-iodo-trans-l-octene was added to 2 ml. of anhydrous hexane, and 1.4 ml. (2 mmol) of a 1.4 M hexane solution of n-butyllithium was added. The mixture was stirred at -78C for 30 minutes in an atmosphere of nitrogen to afford an anhydrous hexane solution of 3-t--butyldimethyl-siloxy-l-lithio-trans-1-octene. The resulting solution was added clropwise to the anhydrous diethyl e-ther solution of copper pentylide obtained previously9 and the mixture was stirred at 78C for 30 minutes to afford a solu-tion of an organic copper lithium compound of the following formula C3H7C - C(C5H11C,HCH CH)CuLi, osi(cH3)2-t-cL~Hg (b) ~-Alkyla-tion and a-Acylation A solution of 164 mg (2 mmol) of cyclopent-2-en-l-one in 1 ml. of diethyl ether was added to -the solu-tion of the organic copper lithium compound prepared in ~a) above, and the mixture was stirred at -78C for 30 minutes (3-alkylation). Then9 a solution of 1.2L~ g (6 mmol) of w,carboethoxycaproyl chloride in a mixture of 3 ml. of of diethyl ether and 10 ml. of te-trahydrofurang and the mixture was stirred at room temperature for 3 hours (~-acylation).
(c) Separation and Purification of -the Reaction Product The tetrahydrofuran was removed a-t reduced pressure from the reaction mixture obtained in (b) above, and an aqueous solution of ammonium chloride containing a small amount of ammonia was added. The mixture was stirred, and extracted with petroleum ether. The petroleum ether phase was washed thoroughly wi-th water9 and then with an aqueous solution of sodium chloride9 dried with anhydrous sodium sulfa-te9 and concentrated to afford l.L~2 g of a crude reaction product. The crude product was subJected to column chromato graphy (carrier9 silica gel9 developing solvent, a 1.2 (volume) mixture of diethyl ether and petroleum ether)9 and again purified by preparative thin-layer chromatography to afford a purified product (liquid) in an amount of 100 mg (d) Identification of -the Reaction Produc-t The purified product gave the following spectral data.
, characteristic absorptions (cm~l) at- 1730, 1720, 1630, 1170 7 1030, 830, and 770 (carbo~
tetrachloride9 ~(ppm))o 0.08 (6H9 silyl me-thyl group) 0.93 (12H9 t-bu-tyl group, and me-thyl group of side chain) lo 29 (3H9 methyl group of ethyl ester) 1.3 - 1.8 (16H9 methylene group) 2.1 - 2.6 (7H9 me-thylene and me-thine groups adjacent; to carbonyl or olefin group) about 3.6 (2H9 methine group to which siloxy group is attached9 and methine group of ~diketone) 4.16 (2H9 me-thylene group of ethyl ester) 5.4 - 5.7 (2H9 olefin proton) (70 eVy m/e)o 494 (M+) 9 479 (M-CH3)9 449 (M-OC2H5)9 L~37 (M-C4Hg).
~ Y~ _ ^r~ h (developing solvento9 ~ether/n-hexane)~
Rf = 0.4~
G ci:~g~gl3s~ ~L ~Stati.onary phase9 JXR sillcone 10%, 1 m, the -temperature elevated from 150 to 260C at a rate of 10C/min):
Retention time 20 minu-tes 17 seconds From the above data 9 the resulting product was identified as an ethyl ester of 15--t~bu-tyldlme-thylsiloxy-~ 29 -~ 9~ ~
7-oxo-11-deoxypros-taglandin El.
It was ascertained from the gas chromatographic analysis of the crude reaction product that -the yield of -this product was about 26%.
The ethyl ester so obtained was dissolved in a mixture consisting of 2 ml of acetic acid, 1 ml of water and 1 ml of tetrahydrofuran 9 and the mixture stirred at room temperature for 20 hours. Then9 it was concentrated to afford about 80 mg of a crude product. The crude product was subjected to preparative -thin-layer chromatography (develop-ing solvent. diethyl ether) 9 and a fraction having an Rf of 0.38 was separated to afford 10 mg of a liquid purified product. This product gave the following spectral data.
Infrared absorp-tion (liquid film) 9 characteristic absorptions at (cm 1), 34509 1730 9 1710 9 16359 1170 9 1030 9 and 975.
Nuclear magnetic ~esonance absor~tion (deutero-chloroform9 ~(ppm))0 0.89 (3H7 me-thyl group of side chain) 1.2 - 1.8 (16H90 me-thylene group) 201 ~ 2.7 (7H9 methylene and methine groups adjacent to carbonyl or olefin group) 1,24 (3H9 methyl group of ethyl ester) 4.13 (2H9 methylene group of et~yl ester) 3,5 - 4,2 (3H 9 me-thine group to which alcohol is boncled, proton of alcohol9 or me-thine group of ~-diketone) 3,5 _ 4.2 (2H9 olefin proton) Mass aralysis (m/e)~
362 ~M~H209 70 eV)~
380 (M~ 9 70 eV and lleV~ a direct inle-t method) ~ (developing solvent 9 ether):
Rf = 3.~8 From the above data9 this product was identified as an ethyl ester of` 7-oxo-11-deoxyprostaglandin El-Example 2 (a) Preparation of Organic Copper Lithium Compound To 2 ml of anhydrous diethyl ether were added 82 mg (1.2 mmol) of 1 pentyne9 and 0.95 ml (1.2 mmol) of a 1,3 M ether solution of methyllithium. The mixture was stirred at 0~ for 15 minutes in an atmosphere of nitrogen.
The solution was added to 1 ml of anhydrous diethyl ether containing 230 mg (1~2 mmol) of cuprous iodide9 and the mixture was stirred at 0C for 15 minutes in an atmosphere of nitrogen to afford an anhydrous diethyl ether solution of copper pentylide.
On -the other hand9 442 mg (1.2 mmol) of 3-t-butyldimethylsiloxy~ iodo-trans-l-octene was added to 2 ml of anhydrous hexane9 and 1 ml (1~2 mmol) of a 1.2 M hexane solution of n-butyllithium was added. The mix-ture was stirred at -78C for 30 minu-tes in an atmosphere of nitro~en to afford an anhydrous hexane solution of 3-t-butyldime-thylsiloxy-~ thio-trans-l~octene. The resul-ting solution was added dropwise to the anhydrous diethyl ether solution of copper pen-tylide prepared previously~ and the mixture was stirred at -78C for ~0 minutes in an atmosphere of nitrogen to afford a solution of an organic copper lithium compound of the following formula C3H7C C(C5H11CHC~I CH) u OSi(CH3)2 t~C4H9 (b) ~-~lkylatlon and a~Acylation A solution of 212 mg (] mmol) of 4-t-bu-tyldimethyl-siloxycyclopent-2-en-1-one in 1 ml of die-thyl ether was added to the solution of -the organlc copper lithium cornpound prepared in (a) above 9 and t;he mixture stirred at -78C
for 30 minutas (~alkylation). During this time~ the reac-tion solution turned from yellow to light yellow via orange. Then9 to the resulting solu-tion was added ~ solu-tion of 1.03 g (5 mmol) of ~-carboethoxycaproyl chloride in a mixture consisting of 5 ml of -tetrahydrofuran and 2 ml of hexamethylphosphoric triamide (HMPA) 3 and the mixture was stirred a-t room temperature for 1 hour (~-acylation).
~0 The reaction solution turned brown.
(c) Separation and Purifica-tion of the Reaction Produc-t The tetrahydrofuran was removed at reduced pressure from the reaction mixture obtained in (b) above 3 and -then an aqueous solu-tion of ammonium chloride was added~ The mixture was then neutralized wi-th soclium bicarbonate (whereby the pH changed from 1 -to 6)~ and extrac-ted wi-th petroleum ether. The petroleurn ether phase was washed thoroughly with water and then with an aqueous solution of sodium chloride, dried with anhydrous sodium sulfate9 and concentrated to afford 1.29 g of a crude reaction produc-t.
The crude product was subjected to column chromatography (carrier9 silica gel9 developing solvent, ethyl e-ther) to afford 970 mg of a purified reaction product (luquid), The product was further purified by preparative -thin-layer chromatography9 and identified.
0 (d) Identi~ica-tion of the Reac-tion Product The above purified product gave the foll.owing spectral data.
Infrared absorption (liquid film), characteristic absorptions at (cm 1)~
1730~ 16359 8409 775 (70 eV9 m/e)~
624 (M+9 detected at 11 eV)9 609 (M-CH3)9 579 (M-OC2H5) 9 567 (M-C4Hg)p 492 (M-HOSi (CH3)2 t-C~Hg) ~ r (developing solventp diethyl e-ther)O
Rf - 0~54 G55 chromato~p~ (stationary phase9 OV-l 15%9 2m9 280C):
Retention time9 6 minu-tcs 50 seconds (carbon tetrachloride9 ~ (ppm)) 0.08 (12H9 si].ylmethyl group) 0.93 (21H9 -t-bu-tyl group9 and methyl group of side chain) 1.29 ~3H; methyl group of ethyl ester) 1.3 - 1.8 (14H; methylene group) 2.1 - 2.6 (7H; methylene and methine groups adjacent to carbonyl or olefin group) about 3~6 (3H; methyl group to which siloxy group is bonded, and methine group of ~-diketone) 4.16 (~H; methylene group of ethyl ester) 5.4 - 5.7 (2~l; olefin proton) From the above data, this product was identified as an ethyl ester of 7-oxo-11,15-bis~t-butyldimethyl-siloxy)prostaglandin El.
530 mg of the above ethyl ester was dissolved in a mixture consisting of 60 ml of acetic acid and 20 ml of water. The mixture was stirred at room temperature for 18 hours, and concen~rated to afford 691 mg of a crude product. The crude product was subjected to preparative thin-layer chromatography (developing solvent, diethyl ether), and 156 mg of a fraction was collected. This fraction was further subjected to pre-parative thin-layer chromatography ~developing solvent, diethyl ether) to afford 35 mg of a purified product (in a yield of 16% based on the crude product).
This pure product gave the following spectral data.
Infrared absorption (liquid film), characteristic absorptions ~cm~l) a~:
- 3~ -~i 5~
3400 9 1730 9 17159 1635 9 11809 103^9 975.
Nuclea~ i ~ (deutero-chloroform9 (~ (ppm)) 0.90 (3H9 methyl group of side chain) 1.24 (3H9 methyl group of ethyl ester) 1,2 1.8 (14H9 methylene group) 2.1 - 2.7 (7H9 me-thylene and methine groups ad~acent to carbonyl or olefin group) abou-t 2,6 (2H9 alcohol pro-ton) 2.8 - 3.7 (3H9 methine group bonded -to alcohol 9 and methine group of ~-diketone) 4.07 (2H9 methylene group of e-thyl ester) 5.4 - 5.7 (2H9 olefin proton).
Mass analysis (direct inlet method9 lleV9 m/e)~
396 (M~9 slightly appreciable)9 378 (M-H20)9 368 (M-28)9 ~60 (M-H20 x 2) T n~ chromat~a~
Rf = 0.08 (e-thyl ether.) Rf = 0.34 (ethyl acetate) From the above data, -this product was identified as an ethyl ester of 7 oxoprostaglandin ~1O
Exam~
To 25 ml of ar~ydrous die-thyl ether was added 950 mg (5 mmol) of cuprous iodi.de9 and -the mixture was cooled to -78C in an 2tmosphere o~ ni-trogen. To -the solution was added 17 ml (10 mmol) of a 0.58 M e-ther solu-tion of ethyllithium, and the mixture s-tirred for 30 minutes (the preparation of li-thium diethylcuprate).
Then9 a solution of 480 mg (5 mmol) ofccyclohex-2-en-1-one in 1 ml of ether was added dropwise 9 and the mixt-lre was stirred at -7~C for 30 mlnu-tes (~-alkylation). A mixture consisting of 2.2 g (2~ mmol) of acetyl chloride 9 2 ml of hexamethyl phosphoric triamide (HMPA) and 10 ml of -tetra-hydrofuran was added to the mixture. The mix-ture was continuously stirred ~or one hour while raising the tempe-rature gradually to roorn temperature (a-acetylation). The resulting reaction mixture was evaporated at reduced pressure by means of a rotary evaporator to remove the tetrahydrofuran from it. An aqueous solu-tion of sodium bicarbonate was added to the concentrated mixture to hydrolyze and neutralize i-t. The mixture was then ex-trac-ted with ether. The ethereal phase was washed thoroughly with water9 dried with anhydrous sodium sulfate9 and concentrated to ~f~ord 1.26 g o~ a crude product. When this crude product was analyzed by -thin-layer chroma-tography, a spot capable of being colored brown with a methanol solution of ferric chloride was seen a-t an R~ of 0.65 (developing solvent9 diethyl ether). ~ fraction corresponding -to this spot was separa-ted by prepara-tive thin-layer chromatography (developing solven-t9 diethyl e-ther) to afford 605 mg of a liquid. This liquid product ga-ve -the following spectral data9 and was identified as 2 acetyl-3-ethylcyclohexan-1-one. The amount of 605 mg corresponded to 3.6 mmol~ and -the yield was '72 %.
Thin-la~r~c~ L~E~e~ (d~Yeloping solvent, diethyl ether)o Rf = 0.65 l~f~ b~a~ng~L (liquid filmp cm 1).
3400 9 1720 9 1690, 1600 (CGl 9 (ppm))~
0.93 (3H 9 methyl group~
2.07 (3~9 methyl group of acetyl group) 1.3 - 2.5 (9H9 methylene group) 16.10 (lH9 methine group between ketone ~roups) ~ y~}~_(70 eV 9 m/e)O
168 (molecular ion) Example 4 To 20 ml of anhydrous diethyl e-ther were added 1.9 g (10 mmol) of cuprous iodide and 2.0 g (10 mmol of tri-n-butylphosphine 9 and the mix-ture was stirred at room 2~ temperature for about 30 minutes in an atmosphere of nitrogen. The mixture was then cooled to -78C, and 12.8 mg (20 mmol) of a 15 Yc by weight hexane solution of n-butyl-lithium was added 9 followed by s-tirring for 30 minutes.
Then~ a solution of 700 mg (10 mmol) of methyl vinyl ketone in 10 ml of ether was added) and the mixture stirred at -78C
for 1 hour. Then, 5 ml of .hexamethylphosphoric triamide was added~ and the mixture was stirred at room -tempera-ture for about mo minutes, Furthermore 9 a solution of 3053 g (25 mmol) of benzoyl chloride in 20 ml of ether was added, and the mixture was stirred at room terrlperature for one hour, After the reaction9 50 ml of a saturated ammoniac aqueous solution of ammonium chloride was added, and the mixture stirred at room temperature for about 30 minutes.
The mixture was post-treated (pH 4)9extracted with ether9 washed, and dried with anhydrous sodium sulfate. The dried product was concentrated to afford 12.326 g of a crude product. The crude product was purified by column chromatography (silica gel).
There was obtained 1.198 g (~.2 mmol) of 3-benzoyl-2-oc-t~none in a yield of 52%, This product gave the following spectral data.
Infrared absorption ~liquid film9 cm 1)~
3050, 1720 9 16~0 9 1600 9 15809 710 9 690 ~5 Nuclear mag~tic resonance absor~tion (carbon tetrachloride, ~ (ppm)) 0.90 (3H9 methyl group) 1.1 - 1.9 (8H9 methylene group) 2.02 (3H~ methyl group of methyl ketone) 7.2 - 7~5 (3H, proton of benzene ring) 7.7 - 8,1 (2H9 proton of benzene ring) Mass analysis (m/e).
232 (molecular ion) ~E ~
To 10 ml c,f ~nhydrous diethyl ether was added 380 mg (2 mmol) of cuprous iodide, and the mixture was cooled to -78C in an atmosphere of nitrogen. Then, 3 ml (4 mmol) of a 1.33 M hexane solution of n-butyllithiurn was added to the resulting solution9 and the mixture stirred ~or 30 minutes. A solution of 252 mg (2 mmol) o~ n-amyl vinyl ketone in 0.5 ml of ether was added, and the mixture stirred at -78C for one hour~ Furthermore9 a mixture consisting of 800 mg (6 rnmol) of n-caproyl chloride 9 O. 5 ml of hexamethylphosphoric triamide and ~ ml o~ ether was added to -the mixture, and the mixture was continuously stirred for 2 hours while raising the tempera-turé gradually to room temperature. Then, an aqueous solution of sodium bicarbonate was added to the mix-ture to hydroly~e and neutralize it. The neutralized mixture wns extracted with ~ther. The resulting ethereal phase was thoroughly washed with water 7 dried with anhydrous sodium sulfate, arld concen-trated to afford 510 mg of a crude product. The crude product was subjected to preparative thin-layer chromatography (developing solvent~ a 1O2 mixture of n-hexane and ether), to afford 250 mg of a liquid capable of being colored by addition of ferric chloride.
This liquid product gave the ~ollowing spectral data, and was identified as 7-n-pentyltridecane-6,8-dione, The amount of 250 mg corresponded to 0.89 rnmol9 and the yield was 44%.
nfrared ab~E~ (]iquid film9 cm 1) 335~, 1720, 16909 1600 Nuclear magnetic resonance absorption (CClL~9 (ppm))o 0.87 (9H9 CH3) 1.20 (20H9 -CH2-) 2 40 (4Ef~ ~CH2- adjacent to C=0) ~ 39 -16.10 (lH9 CH between two ketone groups) y~}~ (70 eV9 m/e)-282 (molecular ion) Example 6 In the same way as in ~xample 49 12.9 ml (20 mmol) of a 15 % by weight hexane solution of n-butyllithium was reacted for one hour with a solution of 960 mg (10 mmol) of 2-cyclohexenone in 10 ml of ether in the presence of 1,9 g (10 mmol) of cuprous iodide and 2.0 g (10 mmol) of tri-n-butylphosphine. Then9 5 ml of hexamethylphosphoric triamide was added, and th~ mixture was s+irred for about 10 minutes. Further9 a solution of ~,93 g (50 mmol) of acetyl chloride in 20 ml of ether was added gradually to the mixture a-t -78C9 and after the addition 9 the mix-tura was stirred con-tinuously for 1 hour a-t room -temperature.
After the reaction, the reaction product was post-treated9 extracted9 washed9 and dried in the same way as in Example 4 to afford 6.384 g of a crude product. The crude product was purified by distillation at r~duced pressure. There were obtained 40 mg (0.3 mmol) of 3-n-butylcyclohexanone as A by-product in a yield of 3 %, and 1.578 g (8~1 mmol) of 2-acetyl-3-n-butylcyclohexanone as a main product in a yield o~` 81%~ The produc-t gave the following spectral data4 Infrared ab ~E~ (liquid filmJ cm l)o ~ (carbon te-trachloride, ~(ppm))o o,gO (3~9 -C~3) 2.10 (3H9 -CH3 of CH~C0-) 1.1 - 2.4 (13H9 -CH2-) 16.13 (lH9 CH between two ketone groups) Mass analys~s (70 eV9 m/e)o 5~ 196 (molecular ion) . .
_ample 7 In the same way as in ~xample 49 15.3 ml (20 mmol)of a 1.31 M hexane solution of n-butyllithium was reacged with a solution of 960 mg (10 mmol) of 2-cyclohexe-r~one in 5 ml of ether at -78C for 30 minutes in the presence of 3.90 g (10 mmol) of tri-n-butylphosphine-copper (I) iodide complex. ThenJ a mixture consisting of 4 ml (56 mmol) of acetyl chlorideg 5 ml of hexamethylphosphoric triamide and lQ ml of ether was rapidly added 9 and the mixture was stirred for 4 hours while gradually raising the temperature to room temperature, After the reaction9 the reaction product was post-treated 9 extracted, washed5 and dried in the same way as in Example 4 to afford 5.48 g of a crude product. The crude produc-t was purified by distillation at reduced pressure to afford l.81 g of 2-acetyl~3-n-butylcyclohexanone (boiling point 64 - 66C/
0.06 mmHg, 92%).
Example 8 To 20 ml of anhydrous diethyl ether was added 1.9 g (10 mmol) of cupr;ous iodide9 and at -78C in an atmosphere of nitrogen9 12.8 ml (20 mmol) of a 15 % by weight hexane solution of n-butylli-thium was added, The ~ixture was stirred for 30 minutes9 and then9 960 mg (10 mmol) of 2-cyclohexenone was added. The mixture was further stirred for one hour. Then9 3.93 g (50 mmol) of acetyl chloride was added 9 and the mixture was stirred for 2 hours at room -temperature. After the reac-tion9 the reaction product was post-treated, extracted9 washed9 and dried in the same way as in Example 4 -to afford 2.662 g of a crude product. The crude product was purified by column chromatography (sillca gel) to afford 56 mg (0.4 mmol) of 3 n-butylcyclohexanone as a by-produc-t in a yield of 4~0 and 1.103 g (5.6 mmol) of 2-acetyl-3-n-butylcyclvhexanone as a main product in a yield of 560~'.
Example 9 In the same way as in Example 49 1208 ml (20 mmol) of a 15 % by weight hexane solution of n-butyllithium was reacted with 960 mg (10 mmol) of a solu-tion of 960 mg (10 mmol) of 2-cyclohexenone in 10 ml of ether for one hour in the presence of 1.9 g (10 mmol) of cuproua iodido and 2.0 g (10 mmol) of tri-n-butylphosphone. Then, 5 ml of hexamethylphosphoric triamide was added~ and -the mixture stirred for about 10 minutes. Furthermore 9 a solu-tion of 5.1 g (50 mmol) of acetic anhydride in 20 ml of e-ther was added, and -the mixture was stirred for an ad~itional 2~5 hours at room tempera-ture. After the reaction9 -the reaction product was post-trea-ted, extracted 9 washed, and dried in the same way as in Example 4 to afford 2.285 g of a crude product. The crude product was purified by column chromato-graphy to afford 81 mg (0,5 mmol) of 3-n~butylcyclohexan~ne as a by-product in a yield of 5% 9 and 98 mg (0.5 mmol) of 2-acetyl-3-n-butylcyclohexanone as a -product in a yield of 5%.
In the same way as in ~xample 49 12.8 ml (20 mmol) of a 15 % by weight hexane solution of n-butyllithium was reacted with a solution of 960 mg (10 mmol) of 2-cyclohexenone in 10 ml of ether at -78C for 1 hour with stirring in the presence of 1.9 g (10 mmol) of cuprous iodide ~nd 2.0 g (10 mmol) of tri-n-butylphosphine. Then9 5 ml of hexamethylphosphoric triamide was added, and the mixture was further stirred for about 10 minutes~ The resulting solution was added dropwise a-t 0C to a solution prepared by adding 2.66 g (20 mmol) of aluminum chloride and 2.04 g (20 mmol) of acetic anhydride to 20 ml of anhydrous diethyl ether, and stirring the mixture for about 30 minutes at 0C in an atmosphere of nitrogen. The mixture was stirred ~`or an addi-tional 2 hours at room temperature, and -then9 post~treated9 extracted, washed and dried in the same way as in ~xample 4 to afford 9.251 g of a crude product~
The crude product was distilled at reduced pressure to a~ford 564 mg (3.7 mmol) of 3-n-butylcyclohexanone as a by-product in a yield of 37% and 364 mg (1.9 mmol) of 2-ace-tyl-3-n-butylcyclohexanone as a product in a yield of 19%.
~ E~
To 30 ml of anhydrous dietllyl ether were added 1.5 g (10 mmol) of cuprous bromide and 2.5 g (20 mmol) of 5q~
trimethyl phosphite 9 an~ the ri~ixture stirred for about l hour at room temperature in an atmosphere of ni-tr~gen.
The mixture was cooled to -78C9 and. 12.8 ml (20 mmol) of a 15 % by weight hexane solution of n-butyllithium was added9 followed by further stirring the mixture for ~0 minutes. Then9 960 mg (lO mmol) of 2-cyclohexenone was ~dded and reacted for l hour. ~fter the reaction9 5 ml of -tetrarr.ethylenediamine was added, ard the mixture was stirred for about lO minutes. The resulting solution was added dropwise at 0C to a solution prepared by adding 2.84 g (20 mmol) of a boron trifluoride-diethyl ether complex a~ld 2.04 g (20 mmol) of acetic anhydride to 20 ml of a.nhydrous diethyl ether9 and stirring the mixture at 0C for about 30 minutes in an atmosphere of nitrogen.
Then, the mixture was stiri~ed for an additional 3 hours at room temperature9 and then9 post-treated9 extracted 9 washed with d.ilute hydrochloric acid, and driecl in the same way as in Example 4 to &fford 5.432 g of a crude productO
The crude product was purified by distillation at reduced pressure -to afford 370 mg (2 4 mmol) of 3-n-butylcyclohexa-none in a yield of 24% and 170 mg (0.9 mmol) of 2-acetyl-3-n-butylcyclohexanone in a yield of 9%.
xample 12 To ~0 ml of anhydrous diethyl ether were added 3.8 g (20 mmol) of cuprous iodide and 400 g (20 mmol) of tri-n-butylphosphine, and the mixture was stirred for about l hour a-t room ternperature in an atmosphere of nitrogen and then cooled to -78C. Then 9 25.6 ml (40 mmol) of a - 4~ -~ `~
15 % by weight hexane solutiGn of n-butyllithiu~ was added 7 and the rnixture was stirred for 30 minutes 9 and 1.92 g (20 mmol) of 2-cyclohexenone was added The mixture was further stirred for 1 hour at -78C~ Then, 5 ml of hexamethylphosphoric tiramide was added 9 and the mix-ture was stirred for about 10 minutes. Phthalic anhydrid~
(2.6 g, 20 mmol) was further ~dded 9 and the mixture was stirred for 3 hours at room temperature. After the reaction, a solution of 4 g (100 rnmol) o~ sodiu~. hydroxide in 50 ml of water was added, and the rnixture was stirred for about 1 hour. It was extracted with ether 9 washed 9 and dried to af~ord 6.22 g of a crude product. The crude product was distilled to afford 1.62 g (10.5 mmol) of 3 n-butylcyclohexanone in a yield O F 53%.
On the other hand 9 the aqueous phas~ aftar -the ether ex-traction was acidified with hydrochloric acid9 extracted with ethyl acetate9 washed9 and dried to afford 7.645 g of a crude product The crude product was purified by column chromatography (silica gel)~ and recrystallized from a mixture of ethyl acetate and chloroforrn to afford 700 mg (23 mmol) of o-(2-oxo-6-n-butylcyclohexyl) carbonyl-benzoic acid in a yield of 12%. This product gave the following spectral data, Infr ~ (liquid film9 cm l)o around 30009 1690 ~ (deutero~
chloroform9 d` (ppm))~
.90 (3H9 ~CH3) . 1.0 ~ 1.6, 2.1 - 2.6 (141I, -CH2-) 7.4 - 7.7~ 7~7 - 8.1 (4H9 proton of benzene ring) around 10,2 (lH; proton of carboxylic acid), disppeared upon treatment with heavy water) Mass analysis (70 eV 9 m/e)0 302 (molecular ion) xample 13 In the same way as in Example 4 9 12.8 ml (20 mmol) of a 15 % by weight hexane solution of n-butyllithium was reacted with a solution of 820 ml (10 mmol) of 2-1~ cyclopentenone in 10 ml of ether for 1 hour in -the presence of 1,9 g (10 mmol) of cuprou~ iodide and 200 g (10 mmol) of tri-.n-butylphosphine. Theng 5 ml of hexamethylphosphoric triamide ~as added9 and the mix-ture was s-tirred for about 10 minutes. A solution of 3.93 g (50 mmol)of acetyl chloride in 20 ml of ether wa~ added gradually at -78C, and then9 the mixture stirred for 1 hour at room -temperature~ After the reaction9 the produc-t was post-treated9 extracted9 washed and dried in the same way as in Example 4 -to afford 10.781 g of a crude produc-t. The crude produc-t was purified by distillation at reduced pressure to afford 459 mg (3,3 mmol) of 3~n-butylcyclopentanone in a yield of 335~ and 698 mg (3,8 mmol) of 2-acetyl-3--butylcyclopentanone in a yield o~ 38%. The latter product gave the following spectral data.
(liquid film9 cm 1)~
17409 1710, 1650 9,~ G,L~ ~____sonance absor -tion (carbon tetrachloride, ~(ppm)):
_ 46 --0.9~ (3H9 -CH3) 1.1 ~ 1.7 (llH~ -~H2-) 2.00 (3H; -CH3 of CH3C0-) ~ Q~ (70 eV, m/e)O
182 (molecular ion) 5:~L~ le To 10 ml of anhydrous diethyl ether was added 950 ml (5 mmol) of cuprous iocdide, and at 0C in an atmosphere of nitrogen9 7.8 ml (10 mmol) of a 1.30 M ether solution of methyllithium was added9 folll~wed by stirring for 15 minutes.
Then9 a solution of 480 mg (5 mmol) of cyclohex-2~en-1-one in 1 ~1 of ether was added dropwise to the mixture 9 and the stirring was continued for 1 hour at O~C. Then, a mixture consisting of 106 g (20 mmol) of acetyl chloride, 1 ml of hexamethylphosphoric triamide and 3 ml of ether was added 9 and the mixture was stirred for 2 hours whlle raising the temperature gradually tc) room temperature. An aclueous solution of sodium bicarbona-te was added to neutralize -the reaction mixture, and lt was -then extracted with e-ther.
The resulting ethereal phase was thoroughly washed with water. dried with anhydrous sodium sulfate7 and concent-rated to afforcl 800 mg of a crude product. The crude product was subjected to preparative thin-layer chromatography -to afford ~70 mg of a liquid, This liquid product corres-ponded in gas chromatogram~ infrared absorp-tion spectrwn~
nuclear magnetic resonance spectrum and mass spectrum with 1-acetoxy-3-methylcyclohex-1-ene prepared ~y reac-ting 3-methylcyclohexan-l-one with acetic anhydride in t,he presence f~
of perchloric acid9 and was thus identifiecl as l-acetoxy-3-methylcyclohex-l~eneO
The amount of 670 mg corraspGnded -to L-.3 mmol and -the yield was 86Q/Q.
Gas-chromatographic and various spectral analyses of the crude product showed -that there was no appreciable formation of 2-acetyl-3-methylcyclohexanone.
~b) 5-Membered Compounds Cyclopent-2-en-1-one, 3,4-dimethylcyclopent-2-en-1-one, 3,4,4-trimethylcyclopent-2~en-1-one, 2-methylcyclopent-2-en-1-one, 3-methylcyclopent-2-en-1-one, 4-methylcyclopent-2-en-1-one, 3-isopropylcyclopent-2-en-1-one, 2,3,4-trime~hylcyclopent-2-en-1-one, 4-isopropyl-2,3-dimethylcyclopent-2-en-1-one, 3-ethyl-2-methylcyclopent-2-en-1-one, 2,3-dimethylcyclopent-2-en-1-one, 3-methyl-2-amylcyclopent-2-en-l-one, 1~8)-hydroinden-2-one, 8~9)-hydroinden-1-one, 2-hydroinden-1-one, and 4-t-butyldimethylsiloxycyclopent-2-en-1-one.
(c) 7-Membered Compounds Cyclohept-2-en-1-one, 2-methylcyclohept-2-en-1-one, and 3,7-dimethylcyclohept-2-en-1-one.
I-l-B. Compounds wherein Rl and R2 are linked to form a ring:-2-Methylenecyclopen~an-l-one, 2-methylenecyclohexan--1-one, and 2-propylidenecycloheptan-1-one.
I-l-C. Compounds wherein R2 and R3 ~or R4) are linked to form a ring:-1-Acetylcyclopentene~
l-cyclopentene aldehyde, l-acetylcyclohexene, l-cyclohexene aldehyde, and l-acetylcycloheptene.
I-l-D. Linear compounds ~herein R1, R2, R3 and R4 are not linked to each other:-Methyl vinyl ketone, ethyl vinyl ketone~
n-propyl vinyl ketone, n-butyl vinyl ketone, isobutyl vinyl ketone, n-amyl vinyl ketone, methyl iscpropenyl kstone, sthyl isopropenyl ketone, 2-ethyl-1-hexen-3-one, 3-penten-2-one~
3-hexen-2-one, 3-hepten-2-one, 4-hexen-3-one, 7-methyl-5-octen-4-one, 5 J 5-dimethyl-3-hexen-2-one, 4-methyl-3-penten-2-one, 5-methyl-4-hexen-3-one, 5-ethyl-4-hepten~3-one, 8~
3-methyl-3~penten-2~one, 3_methyl-3_hepten-2-one, 3-n-propyl-3-hexen-2~one, 3,4-dimethyl 3-penten~2-one, 4,5-dlmethyl-4-penten-3-one, 2,4,5-trimethyl-4-hexen-3-one, acrolein, crotonaldehyde, methacrolein, 2-methyl-2-butenal, and 2,3-dimethyl-2-butenal.
I-2. Organic copper lithium comp~unds (II) According to the process of this inventionJ the ~ unsaturated carbonyl compound (I) is reacted with the organic copper lithium compound of the formula CU(RB)nLiY2_n (II) wherein the symbols are the same as defined above and when n is 2, the above formula will become Cu(RB)2.Li (II'), in the presence of an aprotic inert organic solvent. It is presumed that as a result of this, the following reactions of formula (L) or (M), for example, take place.
~ ~ CU(Rg)2Li ~ ~ CuLiRB ~L) O
~3 ~ Cu(RB)2Li ~ ~ CuLiRB
(M) O O
s RB in formula (II) abo~e is suitably a saturated or unsaturated hydrocarbon residue which may contain an ether linkage. Especially preferred RB groups are monovalent saturated or unsaturated hydrocarbon residues containing 2 to 20 carbon a~oms which may contain an ether linkage.
Examples of RB in formula (II) are alkyl, alkenyl, aralkyl, aralkenyl, aralkynyl, alkoxyalkyl, alkoxyalkenyl, and alko.~yalkynyl groups. Preferred RB groups are monovalent organic residues containing 2 to 20 carbon atoms. Examples of Y are chlorine, bromine, iodineg and cyano group.
The organic copper lithium compound can be easily prepared by reacting a corresponding organic lithium compound Witll a cuprous salt in an inert medium in an atmosphere of nitrogen. At this time, the organic lithium compound is not limited to one species, but two different organic lithium com-pounds may be reacted with the cuprous salt stepwise or simul-taneously to form an organic copper lithium compound having two different RB groups.
Examples of suitable organic lithium compounds are shown below.
Alkyllithiums ~2 1) Ethyllithium ~2-2~ n-Propyllithium (2-3) i-Propyllithium ~2-4) n-Butyllithium ~2-5) t-Butyllithium (?~6~ n-Pentyllithium (2-7) n-Hexyllithium ~2-8) Cyclohexyllithium ~2-9) n-Heptyllithium (2-10) n-Octyllithium C2-ll) n-Nonyllithium Alkenyllithiums (2-12) Vinyllithium ~2-13) l-Lithio-prop-cis-l-ene (2-14) l-Lithio-prop-trans-l-ene ~2-15) 1-Lithio-oct-cis-5-ene ~2-16) l-Lithio-oct-trans-l-ene (2-17) l-Lithio-oct-cis-l-ene (2-18) 1-Lithio-oct-trans-l-cis-5-diene _kyny l l i tlli ~uns 2-19) 1-Lithio-oct-5-yne (2-20) l-Lithio-but-l-yne (2-21) l-Lithio-pent-l-yne (2-22) l-Li~hio-hex-l-yne ~2-23) l-Lithio-hep-l-yne ~2-24) l-Lithio-oct-l-yne Aralkyllithiums (2-25) 1-Lithio-8-phenyl-octene Aralkenyllithi~ns (2-26) 1-(2-Thenyl)-vinyllithium (2-27) 1-Lithio-8-phenyl-oct-trans-1-ene (2-28) 1-Lithio-8-phenyl-oct-cis-1-ene Aralkynyllithiums (2-29) 1-Lithio-8-phenyl-oct-5-yne Alkoxyaralkyllithiums (2-30) 1-Lithio-3-tetrahydropyranyloxy-octane (2-31) 1-Lithio-bis(3,7-tetrahydropyranyloxy) - oetane Alkoxyalkenylll iums ~2-32) 1-Lithio-3-tetrahydropyranyloxy-oct-trans-1-ene ~2-3~) 1-Lithio-bis(3,7-tetrahydropyranyloxy)-oct-trans-1-ene (2-34) 1-Lithio-3-tetrahydropyranyloxy-oct-trans-1-cis-5-diene Alkoxyalk~lyllithiums ~ 2-35) 1-Lithio-3-(~-ethoxy~-ethoxy-oct-5-yne Siloxyallcenyllithium_ (2-36) l-Lithio-~-t-butyldimethylsiloxy-oct-trans-l-ene.
The cuprous salts that can be reacted with the org~mic lithium compounds to form ~he organic copper lithium compounds (II) may, for example, be cuprous chloride, cuprous bromide, cuprous iodide, and cuprous cyanide.
One specific example of preparing the organic copper lithium compound from the organic lithium compound and the cuprous salt comprises reacting the organic lithium compound wi~h the cuprous salt at ro~m temperature to - 78C for several hours, for example, at --78C for 0.5 hour, using an inert medium such as a hydrocarbon (e.g., pentane, hexane or heptane) or an ~her ~e.g., diethyl ether~ -tetrahydrofuran, dioxane, or dimethoxyethane).
The compound of the formula LII] may be used as a complex with a trivalent phosphorous compound such as trialkylphosphines ~e.g., triethy-lphosphine or tri-n-butylphosphine~, trialkyl phosphites (e.g., trimethyl phosphite, triisopropyl phosphite, or tri-n-bu~yl phosphite) or tri-phenylphosphine, Frequently, the use of the complex ends to gire an increased yield of the final product.
-1~-~ ccording to the process of this invention, the ~
unsaturated carbonyl compound is ~irs~ reacted with the above organic copper lithium compo~md in the presence of an aprotic organic medium~
The ~,~-unsaturated carbonyl compound and the organic copper lithium compound are reacted stoichiometrically. Usually, the ~,~-unsaturated carbonyl compound is used in a proportion of 0.5 to 2 mols, pre~erably 0.8 to 1.2 mols, per mol of the organic copper lithium compound.
The reaction temperature is -78C to about 50C.
It is sufficient, however, that the reaction is performed at room temperature for 10 minutes to 2 hours. The reaction proceeds sufficiently even when the temperature is lower than the above-specified range, for example, when it is -100 C.
The reaction is carried out in the presence of an aprotic organic medium which is liquid at the reackion temperature and not reactive with the reaction reagents. Such aprotic inert organic media includes a variety of aprotic inert liquid media including nitrogen-containing, sulfur-containing or oxygen-~0 containing aprotic polar organic solvents. Examples of these organic media are saturated hydrocarbons such as pentane, hexane, heptane or cyclohexane, aromatic hydrocarbons such as benzene, toluene or oxylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or diethylene glycol dimethyl ether, hexamethylphosphoric triamide, N,N-dimethylformamide, N,N-di-methylacetamide, dimethyl sulfoxide, sulfolane and N-methylpyr-rolidone. Inert solvents such as pentane which are used to produce the organic copper lithium compounds can be used dir0ctly as such aprotic organic solvents. In this case, the starting ~ unsaturated carbonyl compound ~I) is added to the reaction system in which the organic copper lithium compound has been prepared.
[SECOND STEP]
II-l. Reaction agent in the second step;-According to the process of this invention, ~he reac-tion product obtained by the reaction in the first step is reacted with an acid anhydride or an acid halide derived from an organic carboxylic acid having the following ~ormula RA-COOH (III) whercin RA is a monovalent orgc~nic group, in the presence of an aprotic inert organic solvent, preferably in the co-presence of a nitrogen-containing, sulfur-containing or oxygen-con~aining aprotic organic solvent to form the desired 1,3-dicarbonyl compound of formula (IV) (second step).
Suitable RA groups are those containing 1 to 20 carbon atoms.
The acid halides are especially suitable as the reaction agent in the second step.
Suitable acid halides or acid anhydrides derived from the organic carboxylic acids of formula ~III) are acid halides of the following formula R'A-COX (III-A~
wherein R'A is a monovalent organic group containing 1 to 20 carbon atoms, and X is a halogen atom, or acid anhydrides of the following formulae `':
R'A--c " (III-B) o ~ col ~
A ~ C~ c) 'O
wherein R'A is a monovalent organic group containing 1 to 20 carbon atoms, and R"A is a divalent organic group containing 2 to 20 carbon atoms.
The acid halides of formula ~III-A) are especially preferred.
O the acid halides, acid chlorides are preferred because they have sufficient reactivity and are readily available.
Of these, acid halides or acid anhydrides of the fol-lowing formulae X-C-Z-COOR (III-A') Q
o ~ C~Z-COOR (III-B') C,-Z-COOR
~Yherein Z is a divalent saturated or unsaturated hydrocarbon residue containing 1 to 19 carbon atoms;
R is hydrogen atom or a saturated or unsaturated hydrocarbon residue containing 1 to 8 carbon atoms;
and X is a halogen atom, are preferred. The acid halides of formula (III-A') are especial-ly preferred.
~ ~5~ k Specific examples of these acid halides and acid an-hydrides are shown below.
II-l-A. Acid Halides Acetyl chloride, acetyl bromide, acetyl iodide, acetyl fluoride, propionyl chloride, propionyl bromide, n-butyryl chloride, isobutyryl chloride, n-valeryl chloride, isovaleryl chloride, n-caproyl chloride, enanthoyl chloride, capryloyl chloride, pelargonoyl chloride, caprinoyl chloride, undecanoyl chloride, lzuroyl chloride, tridecanoyl chloride, myristoyl chloride, pentadecanoyl chloride, palmitoyl chloride, margaroyl chloride, stearoyl chloride, cyclopropanecarboxylic acid chloride, cyclopenkanecarboxylic acid chloride, cyclohexanecarboxylic acid chloride, ~ ?~
:
trimethylacetyl chloride, diethylacetyl chloride, t-butylacetyl chloride, acryloyl chloride, crotonyl chloride, methacryloyl chloride, 4-methyl-2-pentenoic acid chloride, 10-undecenoyl chloride, oleyl chloride, benzoyl chloride, benzoyl bromide, phenylacetyl chloride, p-methylbenzoyl chloride, ~-phenylpropionyl chloride, cinnamoyl chloride, p-bromobenzoyl chloride, o-chlorobenzoyl chloride, methoxyacetyl chloride, p-methoxybenzoyl chloride, p-acetylbenzoyl chloride, 2-furoyl chloride, ~-thienoyl chloride, 2-thienylacetyi chloride, nicotinoyl chloride, methoxalyl chloride, ethoxyalyl chloride, ~-carbomethoxypropionyl chloride, r- carboethoxybutyryl chloride, ~-carboethoxyvaleroyl chloride, -~-carbocthoxycaproyl chloride, ~-carboethoxyvaleroyl chloride, ~-carboethoxyenanthoyl chloride, ~-carboethoxycaprylyl chloride, o-carbomethoxybenzoyl chloride, m-carbomethoxybenzoyl chloride, p-carbomethoxyben~oyl chloride, cyanoacetyl chloride, oxalyl chloride, oxalyl bromide, succinoyl chloride, adipoyl chloride, 1,4-cyclohexanedicarboxylic acid chloride, ph~haloyl chloride, isophthaloyl chloride, and terephthaloyl chloride, II-l-B. Acid Anhydrides Acetic anhydride, propionic anhydride, n-butyric anhydride, n-valeric anhydride, n-caproic anhydride, enanthoic anhydride, n-caprylic anhydride, pilargonic anhydride, n-capric anhydride, undecanoic anhydride, lauric anhydride, tridecanoic anhydride, myristic anhydride, pentadecanoic anhydride, palmitic anhydride, margaric anhydride, stearic anhydride, isobutyric anhydride isovaleric anhydride, cyclobutanecarboxylic anhydride, cycohexanecalboxylic anhydride, crotonic anhydride, oleic anhydride, vaccenic anhydride, linoleic anhydrid~, linolenic anhydride, benzoic anhydride phenylacetic anhydride, o-toluic anhydride, m-toluic anhydride, p-toluic anhydride, p-methoxybenzoic anhydride, p-bromobenzoic anhydride, p-chlorobenzoic anhydride, ~-naphthenic anhydride, diphenylacetic anhydride, succinic anhydride, glutaric anhydride, cis-1,2-cyclobutanedicarboxylic anhydride~
1,2-cyclohexanedicarboxylic anhydride, 5-norbornene-2,3-dicarboxylic anhydride, maleic anhydride, and phthalic an~ydride.
The acid halides and acid anhydrides that can be used in this invention are~ of course, not limited to the above-illustrated species.
II-2. Reaction Conditions in the Second Step tC-Acylation):-The reaction of the reaction product of the first step ~ith the above acid halide or anhydride is carried out in an aprotic inert solvent. Alternatively, it can be carried out advantageously in an aprotic inert solvent in the co-presence of a Lewis acid and/or an aprotic polar organic compound, and this method often brings about an appreciable increase in yield.
Examples of the aprotic inert solvent are hydrocarbons such as pentane, hexane, heptane, cyclohexane, benzene, toluene or xylene, which have already been described with regard to the - first step, and algo ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, t~iethylene glycol dimethyl ether, or diethylene glycol dimethyl ether. Examples of the Lewis acid are aluminum fluoride, aluminum chloride, aluminum bromide, ~luminum iodide, boron trifluoride, boron trichloride, boron tribromide, zinc chloride, zinc bromide, stannic chloride, stannic bromide, ferric chloride, ti~anium tetrachloride, or ~ntimony trifruoride.
Examples of the aprotic polar compo~md used together ~ith the aprotic inert solvent in performing the second-step reaction of this invention include hexamethylphosphoric triamide, N,N-dimethyl~ormamide, dimethyl sulfo*ide, formaldehyde dimethyl mercaptal S-oxide, sulfolane, N-methylpyrrolidone, ~e~ramethyl-urea, acetonitrile, nitrobenzene, dimethylcyanamide, tetra-5~
methylethylenediamine, tetraethylethylenediamine, triethylene-diamine, triethylamine, pyridine, ~,~'-dipyridyl, 1,5-diaza-bicyclo [4,3-0]-5-nonene, and 1,5-diazabicyclo [5,4,0]-5-undecene.
The reaction can be preferably carried ou* by bringing the reaction product o~ the first step into intimate contact ~ith the acid halide or anhydride in the presence of the above solvent at a temperature of -78C to about 50C.
Preferably, the above solvent is used in a total amount of about 0.8 to about 100 mol times, preferably about 10 to 50 mol times, the amount of the ~,~-unsaturated carbonyl compound as a starting material in the first step. The amount of the solvent, however, is not limited to this preferred range~
The acid anhydride or acid halide as a reaction agent c.~l be used in an amount of about 0.5 to about 10 mol times, preferably 0.8 to 5 mol times, the amount of the starting ~
unsaturated carbonyl compound. The amount of the Lewis acid optionally used is not more than 5 molar times the amount of the acid anhydride or acid halide.
The reaction proceeds sufficiently at a temperature of not more than 50C, pr~ferably 0 to 40C, more p:referably 10 to 30C, for 0,5 to about 30 hours.
The 1,3-dicarbonyl compound of formula ~IV) is separated and purified in the following manner after the reaction.
The reaction product is treated with water or an aqueous solution of a strong electroiyte for about 0.1 to 1 hou-r to hydrolyze it, and neutralized i~ desired. The product so treated is then extracted with ether such as diethyl ether, a saturated hydrocarbon such as pentane or hexane, an aromatic hydrocarbon such as benzene or toluene, or a halogenated hydrocarbon such as -methylene chlorideor chloroform. The organic phase extracted is sufficiently ~Yashed with water or an aqueous solution of a strong electrolyte, or if desired, with a dilute acid, thoroughly dried with anhydrous sodilum sulfate, and concentrated to obtain a crude product. The crude product is purified by distillation or column chromatography to afford highly pure 1,3-dicarbonyl compounds of formula ~IV).
The process of this invention described above can thus give 1,3-dicarbonyl compounds of formula ~IV).
Of the 1,3-dicarbonyl compounds prepared by the pres-ent invention 2-acyl-3-substituted cyclopentan-l-ones of the follol~ing formula.
Il ,0, H ~ ~-R~A ~IV-a) H R'B
where:in Q is a hydrogen atom, a hydroxyl group~ or a protected hydroxyl group; R'A is a monovalent organic group containing 1 to 20 carbon atoms; and R'B is a monovalent organic group containing 2 to 20 carbon atoms, especially those of the following formula Il O
H ~ ~ C-Z-COOR ~IV-B) R'B
-2~-wherein Q and R'B are the same as defined in formula (IV-A) above; Z is a divalent saturated or unsaturated hydrocarbon residue containing l to l9 carbon atoms;
and R is a hydrogen atom or a satura~ed or unsatura~ed hydrocarbon residue containing 1 to 8 carbon atoms, and 2-acyl-3-substitut~d cyclohexan-l-ones of the ollowing formula ~ C- R ' A
Q ~ ~ ~IV-C) wherein Q is a hydrogen atom, a hydroxyl group, or a protected hydroxyl group; R'A is a monvalent organic group containing l to 20 carbon atoms; and R'B is a monovalent organic group containing 2 to 20 carbon atoms, especially those of the following formula 11 o H ~ C-Z-COOR
H ~ IV-D) ~ H B
wherein Q and R'B are the same as defined in formula ~IV-C); Z is a divalent saturated or unsaturated hydrocarbon residue containing l to 19 carbon atoms;
and R is a hydrogen atom or a saturated or unsaturated hydrocarbon residue containing 1 to 8 carbon atoms, are novel compounds, and are useful :Eor preparing medicines, agricultural chemicals, perfumes etc.
Furthermore, 2-acyl-3-substituted cyclopentan-l-ones of the following formllla o ii O
~1 ~
~C-Z'-COOR
( I V- E ) Q R B
Q is a hydrogen atom, a hydroxyl ~roup or a protected hydroxyl group; Z' is a divalent sa~uratod or unsa~urated hydrocarbon re-s.idue cont~ining 5 to 10 carbon atoms; and R"~ is a satura~ed or ~msaturated hydrocarbon residue containing 8 to 20 carbon atoms, which may contain 1 to 3 hydroxyl groups or protected hydroxyl groups, are novol compol~ds and oxo analogs of prostaglandin El having various important physiological effects such as smooth muscle shrinking activity, hypotensive activity, bronchodila~ing activity, or activity for inhibiting liberation of fatty acids.
The following ~xamples illustrate -the present invention in greater detail~
(a) Preparation of Organic Copper Lithium Compound To 2 ml of anhydrous diethyl ether was added 136 mg (2 mmol) of l-pentyne, and 1.5 ml (2 mmol) of a 1~3 M ether solution of methylli-thium was added dropwise at 0C in an atmosphere of nitrogen. The mixture was then stirred for 15 minutes 9 and the resul-ting solution was added to 1 ml, of anhydrous diethyl e-ther con-tainlng 380 mg (2 mmol) o~ cuprous iodide~ and the mix-ture was stirred at 0C for 15 minutes to afford an ar~ydrous die-th-yl ether solution of copper pen-tylide~
On the other hand 9 736 mg (2 mmol) of 3-t butyl-dimethylsiloxy-l-iodo-trans-l-octene was added to 2 ml. of anhydrous hexane, and 1.4 ml. (2 mmol) of a 1.4 M hexane solution of n-butyllithium was added. The mixture was stirred at -78C for 30 minutes in an atmosphere of nitrogen to afford an anhydrous hexane solution of 3-t--butyldimethyl-siloxy-l-lithio-trans-1-octene. The resulting solution was added clropwise to the anhydrous diethyl e-ther solution of copper pentylide obtained previously9 and the mixture was stirred at 78C for 30 minutes to afford a solu-tion of an organic copper lithium compound of the following formula C3H7C - C(C5H11C,HCH CH)CuLi, osi(cH3)2-t-cL~Hg (b) ~-Alkyla-tion and a-Acylation A solution of 164 mg (2 mmol) of cyclopent-2-en-l-one in 1 ml. of diethyl ether was added to -the solu-tion of the organic copper lithium compound prepared in ~a) above, and the mixture was stirred at -78C for 30 minutes (3-alkylation). Then9 a solution of 1.2L~ g (6 mmol) of w,carboethoxycaproyl chloride in a mixture of 3 ml. of of diethyl ether and 10 ml. of te-trahydrofurang and the mixture was stirred at room temperature for 3 hours (~-acylation).
(c) Separation and Purification of -the Reaction Product The tetrahydrofuran was removed a-t reduced pressure from the reaction mixture obtained in (b) above, and an aqueous solution of ammonium chloride containing a small amount of ammonia was added. The mixture was stirred, and extracted with petroleum ether. The petroleum ether phase was washed thoroughly wi-th water9 and then with an aqueous solution of sodium chloride9 dried with anhydrous sodium sulfa-te9 and concentrated to afford l.L~2 g of a crude reaction product. The crude product was subJected to column chromato graphy (carrier9 silica gel9 developing solvent, a 1.2 (volume) mixture of diethyl ether and petroleum ether)9 and again purified by preparative thin-layer chromatography to afford a purified product (liquid) in an amount of 100 mg (d) Identification of -the Reaction Produc-t The purified product gave the following spectral data.
, characteristic absorptions (cm~l) at- 1730, 1720, 1630, 1170 7 1030, 830, and 770 (carbo~
tetrachloride9 ~(ppm))o 0.08 (6H9 silyl me-thyl group) 0.93 (12H9 t-bu-tyl group, and me-thyl group of side chain) lo 29 (3H9 methyl group of ethyl ester) 1.3 - 1.8 (16H9 methylene group) 2.1 - 2.6 (7H9 me-thylene and me-thine groups adjacent; to carbonyl or olefin group) about 3.6 (2H9 methine group to which siloxy group is attached9 and methine group of ~diketone) 4.16 (2H9 me-thylene group of ethyl ester) 5.4 - 5.7 (2H9 olefin proton) (70 eVy m/e)o 494 (M+) 9 479 (M-CH3)9 449 (M-OC2H5)9 L~37 (M-C4Hg).
~ Y~ _ ^r~ h (developing solvento9 ~ether/n-hexane)~
Rf = 0.4~
G ci:~g~gl3s~ ~L ~Stati.onary phase9 JXR sillcone 10%, 1 m, the -temperature elevated from 150 to 260C at a rate of 10C/min):
Retention time 20 minu-tes 17 seconds From the above data 9 the resulting product was identified as an ethyl ester of 15--t~bu-tyldlme-thylsiloxy-~ 29 -~ 9~ ~
7-oxo-11-deoxypros-taglandin El.
It was ascertained from the gas chromatographic analysis of the crude reaction product that -the yield of -this product was about 26%.
The ethyl ester so obtained was dissolved in a mixture consisting of 2 ml of acetic acid, 1 ml of water and 1 ml of tetrahydrofuran 9 and the mixture stirred at room temperature for 20 hours. Then9 it was concentrated to afford about 80 mg of a crude product. The crude product was subjected to preparative -thin-layer chromatography (develop-ing solvent. diethyl ether) 9 and a fraction having an Rf of 0.38 was separated to afford 10 mg of a liquid purified product. This product gave the following spectral data.
Infrared absorp-tion (liquid film) 9 characteristic absorptions at (cm 1), 34509 1730 9 1710 9 16359 1170 9 1030 9 and 975.
Nuclear magnetic ~esonance absor~tion (deutero-chloroform9 ~(ppm))0 0.89 (3H7 me-thyl group of side chain) 1.2 - 1.8 (16H90 me-thylene group) 201 ~ 2.7 (7H9 methylene and methine groups adjacent to carbonyl or olefin group) 1,24 (3H9 methyl group of ethyl ester) 4.13 (2H9 methylene group of et~yl ester) 3,5 - 4,2 (3H 9 me-thine group to which alcohol is boncled, proton of alcohol9 or me-thine group of ~-diketone) 3,5 _ 4.2 (2H9 olefin proton) Mass aralysis (m/e)~
362 ~M~H209 70 eV)~
380 (M~ 9 70 eV and lleV~ a direct inle-t method) ~ (developing solvent 9 ether):
Rf = 3.~8 From the above data9 this product was identified as an ethyl ester of` 7-oxo-11-deoxyprostaglandin El-Example 2 (a) Preparation of Organic Copper Lithium Compound To 2 ml of anhydrous diethyl ether were added 82 mg (1.2 mmol) of 1 pentyne9 and 0.95 ml (1.2 mmol) of a 1,3 M ether solution of methyllithium. The mixture was stirred at 0~ for 15 minutes in an atmosphere of nitrogen.
The solution was added to 1 ml of anhydrous diethyl ether containing 230 mg (1~2 mmol) of cuprous iodide9 and the mixture was stirred at 0C for 15 minutes in an atmosphere of nitrogen to afford an anhydrous diethyl ether solution of copper pentylide.
On -the other hand9 442 mg (1.2 mmol) of 3-t-butyldimethylsiloxy~ iodo-trans-l-octene was added to 2 ml of anhydrous hexane9 and 1 ml (1~2 mmol) of a 1.2 M hexane solution of n-butyllithium was added. The mix-ture was stirred at -78C for 30 minu-tes in an atmosphere of nitro~en to afford an anhydrous hexane solution of 3-t-butyldime-thylsiloxy-~ thio-trans-l~octene. The resul-ting solution was added dropwise to the anhydrous diethyl ether solution of copper pen-tylide prepared previously~ and the mixture was stirred at -78C for ~0 minutes in an atmosphere of nitrogen to afford a solution of an organic copper lithium compound of the following formula C3H7C C(C5H11CHC~I CH) u OSi(CH3)2 t~C4H9 (b) ~-~lkylatlon and a~Acylation A solution of 212 mg (] mmol) of 4-t-bu-tyldimethyl-siloxycyclopent-2-en-1-one in 1 ml of die-thyl ether was added to the solution of -the organlc copper lithium cornpound prepared in (a) above 9 and t;he mixture stirred at -78C
for 30 minutas (~alkylation). During this time~ the reac-tion solution turned from yellow to light yellow via orange. Then9 to the resulting solu-tion was added ~ solu-tion of 1.03 g (5 mmol) of ~-carboethoxycaproyl chloride in a mixture consisting of 5 ml of -tetrahydrofuran and 2 ml of hexamethylphosphoric triamide (HMPA) 3 and the mixture was stirred a-t room temperature for 1 hour (~-acylation).
~0 The reaction solution turned brown.
(c) Separation and Purifica-tion of the Reaction Produc-t The tetrahydrofuran was removed at reduced pressure from the reaction mixture obtained in (b) above 3 and -then an aqueous solu-tion of ammonium chloride was added~ The mixture was then neutralized wi-th soclium bicarbonate (whereby the pH changed from 1 -to 6)~ and extrac-ted wi-th petroleum ether. The petroleurn ether phase was washed thoroughly with water and then with an aqueous solution of sodium chloride, dried with anhydrous sodium sulfate9 and concentrated to afford 1.29 g of a crude reaction produc-t.
The crude product was subjected to column chromatography (carrier9 silica gel9 developing solvent, ethyl e-ther) to afford 970 mg of a purified reaction product (luquid), The product was further purified by preparative -thin-layer chromatography9 and identified.
0 (d) Identi~ica-tion of the Reac-tion Product The above purified product gave the foll.owing spectral data.
Infrared absorption (liquid film), characteristic absorptions at (cm 1)~
1730~ 16359 8409 775 (70 eV9 m/e)~
624 (M+9 detected at 11 eV)9 609 (M-CH3)9 579 (M-OC2H5) 9 567 (M-C4Hg)p 492 (M-HOSi (CH3)2 t-C~Hg) ~ r (developing solventp diethyl e-ther)O
Rf - 0~54 G55 chromato~p~ (stationary phase9 OV-l 15%9 2m9 280C):
Retention time9 6 minu-tcs 50 seconds (carbon tetrachloride9 ~ (ppm)) 0.08 (12H9 si].ylmethyl group) 0.93 (21H9 -t-bu-tyl group9 and methyl group of side chain) 1.29 ~3H; methyl group of ethyl ester) 1.3 - 1.8 (14H; methylene group) 2.1 - 2.6 (7H; methylene and methine groups adjacent to carbonyl or olefin group) about 3~6 (3H; methyl group to which siloxy group is bonded, and methine group of ~-diketone) 4.16 (~H; methylene group of ethyl ester) 5.4 - 5.7 (2~l; olefin proton) From the above data, this product was identified as an ethyl ester of 7-oxo-11,15-bis~t-butyldimethyl-siloxy)prostaglandin El.
530 mg of the above ethyl ester was dissolved in a mixture consisting of 60 ml of acetic acid and 20 ml of water. The mixture was stirred at room temperature for 18 hours, and concen~rated to afford 691 mg of a crude product. The crude product was subjected to preparative thin-layer chromatography (developing solvent, diethyl ether), and 156 mg of a fraction was collected. This fraction was further subjected to pre-parative thin-layer chromatography ~developing solvent, diethyl ether) to afford 35 mg of a purified product (in a yield of 16% based on the crude product).
This pure product gave the following spectral data.
Infrared absorption (liquid film), characteristic absorptions ~cm~l) a~:
- 3~ -~i 5~
3400 9 1730 9 17159 1635 9 11809 103^9 975.
Nuclea~ i ~ (deutero-chloroform9 (~ (ppm)) 0.90 (3H9 methyl group of side chain) 1.24 (3H9 methyl group of ethyl ester) 1,2 1.8 (14H9 methylene group) 2.1 - 2.7 (7H9 me-thylene and methine groups ad~acent to carbonyl or olefin group) abou-t 2,6 (2H9 alcohol pro-ton) 2.8 - 3.7 (3H9 methine group bonded -to alcohol 9 and methine group of ~-diketone) 4.07 (2H9 methylene group of e-thyl ester) 5.4 - 5.7 (2H9 olefin proton).
Mass analysis (direct inlet method9 lleV9 m/e)~
396 (M~9 slightly appreciable)9 378 (M-H20)9 368 (M-28)9 ~60 (M-H20 x 2) T n~ chromat~a~
Rf = 0.08 (e-thyl ether.) Rf = 0.34 (ethyl acetate) From the above data, -this product was identified as an ethyl ester of 7 oxoprostaglandin ~1O
Exam~
To 25 ml of ar~ydrous die-thyl ether was added 950 mg (5 mmol) of cuprous iodi.de9 and -the mixture was cooled to -78C in an 2tmosphere o~ ni-trogen. To -the solution was added 17 ml (10 mmol) of a 0.58 M e-ther solu-tion of ethyllithium, and the mixture s-tirred for 30 minutes (the preparation of li-thium diethylcuprate).
Then9 a solution of 480 mg (5 mmol) ofccyclohex-2-en-1-one in 1 ml of ether was added dropwise 9 and the mixt-lre was stirred at -7~C for 30 mlnu-tes (~-alkylation). A mixture consisting of 2.2 g (2~ mmol) of acetyl chloride 9 2 ml of hexamethyl phosphoric triamide (HMPA) and 10 ml of -tetra-hydrofuran was added to the mixture. The mix-ture was continuously stirred ~or one hour while raising the tempe-rature gradually to roorn temperature (a-acetylation). The resulting reaction mixture was evaporated at reduced pressure by means of a rotary evaporator to remove the tetrahydrofuran from it. An aqueous solu-tion of sodium bicarbonate was added to the concentrated mixture to hydrolyze and neutralize i-t. The mixture was then ex-trac-ted with ether. The ethereal phase was washed thoroughly with water9 dried with anhydrous sodium sulfate9 and concentrated to ~f~ord 1.26 g o~ a crude product. When this crude product was analyzed by -thin-layer chroma-tography, a spot capable of being colored brown with a methanol solution of ferric chloride was seen a-t an R~ of 0.65 (developing solvent9 diethyl ether). ~ fraction corresponding -to this spot was separa-ted by prepara-tive thin-layer chromatography (developing solven-t9 diethyl e-ther) to afford 605 mg of a liquid. This liquid product ga-ve -the following spectral data9 and was identified as 2 acetyl-3-ethylcyclohexan-1-one. The amount of 605 mg corresponded to 3.6 mmol~ and -the yield was '72 %.
Thin-la~r~c~ L~E~e~ (d~Yeloping solvent, diethyl ether)o Rf = 0.65 l~f~ b~a~ng~L (liquid filmp cm 1).
3400 9 1720 9 1690, 1600 (CGl 9 (ppm))~
0.93 (3H 9 methyl group~
2.07 (3~9 methyl group of acetyl group) 1.3 - 2.5 (9H9 methylene group) 16.10 (lH9 methine group between ketone ~roups) ~ y~}~_(70 eV 9 m/e)O
168 (molecular ion) Example 4 To 20 ml of anhydrous diethyl e-ther were added 1.9 g (10 mmol) of cuprous iodide and 2.0 g (10 mmol of tri-n-butylphosphine 9 and the mix-ture was stirred at room 2~ temperature for about 30 minutes in an atmosphere of nitrogen. The mixture was then cooled to -78C, and 12.8 mg (20 mmol) of a 15 Yc by weight hexane solution of n-butyl-lithium was added 9 followed by s-tirring for 30 minutes.
Then~ a solution of 700 mg (10 mmol) of methyl vinyl ketone in 10 ml of ether was added) and the mixture stirred at -78C
for 1 hour. Then, 5 ml of .hexamethylphosphoric triamide was added~ and the mixture was stirred at room -tempera-ture for about mo minutes, Furthermore 9 a solution of 3053 g (25 mmol) of benzoyl chloride in 20 ml of ether was added, and the mixture was stirred at room terrlperature for one hour, After the reaction9 50 ml of a saturated ammoniac aqueous solution of ammonium chloride was added, and the mixture stirred at room temperature for about 30 minutes.
The mixture was post-treated (pH 4)9extracted with ether9 washed, and dried with anhydrous sodium sulfate. The dried product was concentrated to afford 12.326 g of a crude product. The crude product was purified by column chromatography (silica gel).
There was obtained 1.198 g (~.2 mmol) of 3-benzoyl-2-oc-t~none in a yield of 52%, This product gave the following spectral data.
Infrared absorption ~liquid film9 cm 1)~
3050, 1720 9 16~0 9 1600 9 15809 710 9 690 ~5 Nuclear mag~tic resonance absor~tion (carbon tetrachloride, ~ (ppm)) 0.90 (3H9 methyl group) 1.1 - 1.9 (8H9 methylene group) 2.02 (3H~ methyl group of methyl ketone) 7.2 - 7~5 (3H, proton of benzene ring) 7.7 - 8,1 (2H9 proton of benzene ring) Mass analysis (m/e).
232 (molecular ion) ~E ~
To 10 ml c,f ~nhydrous diethyl ether was added 380 mg (2 mmol) of cuprous iodide, and the mixture was cooled to -78C in an atmosphere of nitrogen. Then, 3 ml (4 mmol) of a 1.33 M hexane solution of n-butyllithiurn was added to the resulting solution9 and the mixture stirred ~or 30 minutes. A solution of 252 mg (2 mmol) o~ n-amyl vinyl ketone in 0.5 ml of ether was added, and the mixture stirred at -78C for one hour~ Furthermore9 a mixture consisting of 800 mg (6 rnmol) of n-caproyl chloride 9 O. 5 ml of hexamethylphosphoric triamide and ~ ml o~ ether was added to -the mixture, and the mixture was continuously stirred for 2 hours while raising the tempera-turé gradually to room temperature. Then, an aqueous solution of sodium bicarbonate was added to the mix-ture to hydroly~e and neutralize it. The neutralized mixture wns extracted with ~ther. The resulting ethereal phase was thoroughly washed with water 7 dried with anhydrous sodium sulfate, arld concen-trated to afford 510 mg of a crude product. The crude product was subjected to preparative thin-layer chromatography (developing solvent~ a 1O2 mixture of n-hexane and ether), to afford 250 mg of a liquid capable of being colored by addition of ferric chloride.
This liquid product gave the ~ollowing spectral data, and was identified as 7-n-pentyltridecane-6,8-dione, The amount of 250 mg corresponded to 0.89 rnmol9 and the yield was 44%.
nfrared ab~E~ (]iquid film9 cm 1) 335~, 1720, 16909 1600 Nuclear magnetic resonance absorption (CClL~9 (ppm))o 0.87 (9H9 CH3) 1.20 (20H9 -CH2-) 2 40 (4Ef~ ~CH2- adjacent to C=0) ~ 39 -16.10 (lH9 CH between two ketone groups) y~}~ (70 eV9 m/e)-282 (molecular ion) Example 6 In the same way as in ~xample 49 12.9 ml (20 mmol) of a 15 % by weight hexane solution of n-butyllithium was reacted for one hour with a solution of 960 mg (10 mmol) of 2-cyclohexenone in 10 ml of ether in the presence of 1,9 g (10 mmol) of cuprous iodide and 2.0 g (10 mmol) of tri-n-butylphosphine. Then9 5 ml of hexamethylphosphoric triamide was added, and th~ mixture was s+irred for about 10 minutes. Further9 a solution of ~,93 g (50 mmol) of acetyl chloride in 20 ml of ether was added gradually to the mixture a-t -78C9 and after the addition 9 the mix-tura was stirred con-tinuously for 1 hour a-t room -temperature.
After the reaction, the reaction product was post-treated9 extracted9 washed9 and dried in the same way as in Example 4 to afford 6.384 g of a crude product. The crude product was purified by distillation at r~duced pressure. There were obtained 40 mg (0.3 mmol) of 3-n-butylcyclohexanone as A by-product in a yield of 3 %, and 1.578 g (8~1 mmol) of 2-acetyl-3-n-butylcyclohexanone as a main product in a yield o~` 81%~ The produc-t gave the following spectral data4 Infrared ab ~E~ (liquid filmJ cm l)o ~ (carbon te-trachloride, ~(ppm))o o,gO (3~9 -C~3) 2.10 (3H9 -CH3 of CH~C0-) 1.1 - 2.4 (13H9 -CH2-) 16.13 (lH9 CH between two ketone groups) Mass analys~s (70 eV9 m/e)o 5~ 196 (molecular ion) . .
_ample 7 In the same way as in ~xample 49 15.3 ml (20 mmol)of a 1.31 M hexane solution of n-butyllithium was reacged with a solution of 960 mg (10 mmol) of 2-cyclohexe-r~one in 5 ml of ether at -78C for 30 minutes in the presence of 3.90 g (10 mmol) of tri-n-butylphosphine-copper (I) iodide complex. ThenJ a mixture consisting of 4 ml (56 mmol) of acetyl chlorideg 5 ml of hexamethylphosphoric triamide and lQ ml of ether was rapidly added 9 and the mixture was stirred for 4 hours while gradually raising the temperature to room temperature, After the reaction9 the reaction product was post-treated 9 extracted, washed5 and dried in the same way as in Example 4 to afford 5.48 g of a crude product. The crude produc-t was purified by distillation at reduced pressure to afford l.81 g of 2-acetyl~3-n-butylcyclohexanone (boiling point 64 - 66C/
0.06 mmHg, 92%).
Example 8 To 20 ml of anhydrous diethyl ether was added 1.9 g (10 mmol) of cupr;ous iodide9 and at -78C in an atmosphere of nitrogen9 12.8 ml (20 mmol) of a 15 % by weight hexane solution of n-butylli-thium was added, The ~ixture was stirred for 30 minutes9 and then9 960 mg (10 mmol) of 2-cyclohexenone was added. The mixture was further stirred for one hour. Then9 3.93 g (50 mmol) of acetyl chloride was added 9 and the mixture was stirred for 2 hours at room -temperature. After the reac-tion9 the reaction product was post-treated, extracted9 washed9 and dried in the same way as in Example 4 -to afford 2.662 g of a crude product. The crude product was purified by column chromatography (sillca gel) to afford 56 mg (0.4 mmol) of 3 n-butylcyclohexanone as a by-produc-t in a yield of 4~0 and 1.103 g (5.6 mmol) of 2-acetyl-3-n-butylcyclvhexanone as a main product in a yield of 560~'.
Example 9 In the same way as in Example 49 1208 ml (20 mmol) of a 15 % by weight hexane solution of n-butyllithium was reacted with 960 mg (10 mmol) of a solu-tion of 960 mg (10 mmol) of 2-cyclohexenone in 10 ml of ether for one hour in the presence of 1.9 g (10 mmol) of cuproua iodido and 2.0 g (10 mmol) of tri-n-butylphosphone. Then, 5 ml of hexamethylphosphoric triamide was added~ and -the mixture stirred for about 10 minutes. Furthermore 9 a solu-tion of 5.1 g (50 mmol) of acetic anhydride in 20 ml of e-ther was added, and -the mixture was stirred for an ad~itional 2~5 hours at room tempera-ture. After the reaction9 -the reaction product was post-trea-ted, extracted 9 washed, and dried in the same way as in Example 4 to afford 2.285 g of a crude product. The crude product was purified by column chromato-graphy to afford 81 mg (0,5 mmol) of 3-n~butylcyclohexan~ne as a by-product in a yield of 5% 9 and 98 mg (0.5 mmol) of 2-acetyl-3-n-butylcyclohexanone as a -product in a yield of 5%.
In the same way as in ~xample 49 12.8 ml (20 mmol) of a 15 % by weight hexane solution of n-butyllithium was reacted with a solution of 960 mg (10 mmol) of 2-cyclohexenone in 10 ml of ether at -78C for 1 hour with stirring in the presence of 1.9 g (10 mmol) of cuprous iodide ~nd 2.0 g (10 mmol) of tri-n-butylphosphine. Then9 5 ml of hexamethylphosphoric triamide was added, and the mixture was further stirred for about 10 minutes~ The resulting solution was added dropwise a-t 0C to a solution prepared by adding 2.66 g (20 mmol) of aluminum chloride and 2.04 g (20 mmol) of acetic anhydride to 20 ml of anhydrous diethyl ether, and stirring the mixture for about 30 minutes at 0C in an atmosphere of nitrogen. The mixture was stirred ~`or an addi-tional 2 hours at room temperature, and -then9 post~treated9 extracted, washed and dried in the same way as in ~xample 4 to afford 9.251 g of a crude product~
The crude product was distilled at reduced pressure to a~ford 564 mg (3.7 mmol) of 3-n-butylcyclohexanone as a by-product in a yield of 37% and 364 mg (1.9 mmol) of 2-ace-tyl-3-n-butylcyclohexanone as a product in a yield of 19%.
~ E~
To 30 ml of anhydrous dietllyl ether were added 1.5 g (10 mmol) of cuprous bromide and 2.5 g (20 mmol) of 5q~
trimethyl phosphite 9 an~ the ri~ixture stirred for about l hour at room temperature in an atmosphere of ni-tr~gen.
The mixture was cooled to -78C9 and. 12.8 ml (20 mmol) of a 15 % by weight hexane solution of n-butyllithium was added9 followed by further stirring the mixture for ~0 minutes. Then9 960 mg (lO mmol) of 2-cyclohexenone was ~dded and reacted for l hour. ~fter the reaction9 5 ml of -tetrarr.ethylenediamine was added, ard the mixture was stirred for about lO minutes. The resulting solution was added dropwise at 0C to a solution prepared by adding 2.84 g (20 mmol) of a boron trifluoride-diethyl ether complex a~ld 2.04 g (20 mmol) of acetic anhydride to 20 ml of a.nhydrous diethyl ether9 and stirring the mixture at 0C for about 30 minutes in an atmosphere of nitrogen.
Then, the mixture was stiri~ed for an additional 3 hours at room temperature9 and then9 post-treated9 extracted 9 washed with d.ilute hydrochloric acid, and driecl in the same way as in Example 4 to &fford 5.432 g of a crude productO
The crude product was purified by distillation at reduced pressure -to afford 370 mg (2 4 mmol) of 3-n-butylcyclohexa-none in a yield of 24% and 170 mg (0.9 mmol) of 2-acetyl-3-n-butylcyclohexanone in a yield of 9%.
xample 12 To ~0 ml of anhydrous diethyl ether were added 3.8 g (20 mmol) of cuprous iodide and 400 g (20 mmol) of tri-n-butylphosphine, and the mixture was stirred for about l hour a-t room ternperature in an atmosphere of nitrogen and then cooled to -78C. Then 9 25.6 ml (40 mmol) of a - 4~ -~ `~
15 % by weight hexane solutiGn of n-butyllithiu~ was added 7 and the rnixture was stirred for 30 minutes 9 and 1.92 g (20 mmol) of 2-cyclohexenone was added The mixture was further stirred for 1 hour at -78C~ Then, 5 ml of hexamethylphosphoric tiramide was added 9 and the mix-ture was stirred for about 10 minutes. Phthalic anhydrid~
(2.6 g, 20 mmol) was further ~dded 9 and the mixture was stirred for 3 hours at room temperature. After the reaction, a solution of 4 g (100 rnmol) o~ sodiu~. hydroxide in 50 ml of water was added, and the rnixture was stirred for about 1 hour. It was extracted with ether 9 washed 9 and dried to af~ord 6.22 g of a crude product. The crude product was distilled to afford 1.62 g (10.5 mmol) of 3 n-butylcyclohexanone in a yield O F 53%.
On the other hand 9 the aqueous phas~ aftar -the ether ex-traction was acidified with hydrochloric acid9 extracted with ethyl acetate9 washed9 and dried to afford 7.645 g of a crude product The crude product was purified by column chromatography (silica gel)~ and recrystallized from a mixture of ethyl acetate and chloroforrn to afford 700 mg (23 mmol) of o-(2-oxo-6-n-butylcyclohexyl) carbonyl-benzoic acid in a yield of 12%. This product gave the following spectral data, Infr ~ (liquid film9 cm l)o around 30009 1690 ~ (deutero~
chloroform9 d` (ppm))~
.90 (3H9 ~CH3) . 1.0 ~ 1.6, 2.1 - 2.6 (141I, -CH2-) 7.4 - 7.7~ 7~7 - 8.1 (4H9 proton of benzene ring) around 10,2 (lH; proton of carboxylic acid), disppeared upon treatment with heavy water) Mass analysis (70 eV 9 m/e)0 302 (molecular ion) xample 13 In the same way as in Example 4 9 12.8 ml (20 mmol) of a 15 % by weight hexane solution of n-butyllithium was reacted with a solution of 820 ml (10 mmol) of 2-1~ cyclopentenone in 10 ml of ether for 1 hour in -the presence of 1,9 g (10 mmol) of cuprou~ iodide and 200 g (10 mmol) of tri-.n-butylphosphine. Theng 5 ml of hexamethylphosphoric triamide ~as added9 and the mix-ture was s-tirred for about 10 minutes. A solution of 3.93 g (50 mmol)of acetyl chloride in 20 ml of ether wa~ added gradually at -78C, and then9 the mixture stirred for 1 hour at room -temperature~ After the reaction9 the produc-t was post-treated9 extracted9 washed and dried in the same way as in Example 4 -to afford 10.781 g of a crude produc-t. The crude produc-t was purified by distillation at reduced pressure to afford 459 mg (3,3 mmol) of 3~n-butylcyclopentanone in a yield of 335~ and 698 mg (3,8 mmol) of 2-acetyl-3--butylcyclopentanone in a yield o~ 38%. The latter product gave the following spectral data.
(liquid film9 cm 1)~
17409 1710, 1650 9,~ G,L~ ~____sonance absor -tion (carbon tetrachloride, ~(ppm)):
_ 46 --0.9~ (3H9 -CH3) 1.1 ~ 1.7 (llH~ -~H2-) 2.00 (3H; -CH3 of CH3C0-) ~ Q~ (70 eV, m/e)O
182 (molecular ion) 5:~L~ le To 10 ml of anhydrous diethyl ether was added 950 ml (5 mmol) of cuprous iocdide, and at 0C in an atmosphere of nitrogen9 7.8 ml (10 mmol) of a 1.30 M ether solution of methyllithium was added9 folll~wed by stirring for 15 minutes.
Then9 a solution of 480 mg (5 mmol) of cyclohex-2~en-1-one in 1 ~1 of ether was added dropwise to the mixture 9 and the stirring was continued for 1 hour at O~C. Then, a mixture consisting of 106 g (20 mmol) of acetyl chloride, 1 ml of hexamethylphosphoric triamide and 3 ml of ether was added 9 and the mixture was stirred for 2 hours whlle raising the temperature gradually tc) room temperature. An aclueous solution of sodium bicarbona-te was added to neutralize -the reaction mixture, and lt was -then extracted with e-ther.
The resulting ethereal phase was thoroughly washed with water. dried with anhydrous sodium sulfate7 and concent-rated to afforcl 800 mg of a crude product. The crude product was subjected to preparative thin-layer chromatography -to afford ~70 mg of a liquid, This liquid product corres-ponded in gas chromatogram~ infrared absorp-tion spectrwn~
nuclear magnetic resonance spectrum and mass spectrum with 1-acetoxy-3-methylcyclohex-1-ene prepared ~y reac-ting 3-methylcyclohexan-l-one with acetic anhydride in t,he presence f~
of perchloric acid9 and was thus identifiecl as l-acetoxy-3-methylcyclohex-l~eneO
The amount of 670 mg corraspGnded -to L-.3 mmol and -the yield was 86Q/Q.
Gas-chromatographic and various spectral analyses of the crude product showed -that there was no appreciable formation of 2-acetyl-3-methylcyclohexanone.
Claims (19)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing 1,3-dicarbonyl compounds of the following formula (IV) wherein R1 represents an alkyl group of 1 to 12 carbon atoms, which may be substituted by a protected hydroxyl group; R2 and R4 represent a hydrogen atom; R3 represents a hydrogen atom or an alkyl group of 1 to 12 carbon atoms, which may be substituted by a protected hydroxyl group; RA ropresents an alkyl group of 1 to 12 carbon aboms or a phenyl group, each of which may be sub-stituted by a carboxyl or lower alkoxycarbonyl group; and RB represents an alkyl, alkenyl or alkynyl group, each of which has up to 12 carbon atoms and may be substituted by a protected hydroxyl group; and R1 and R3 may additional-ly together represent an alkylene group of 2 to 4 carbon atoms, which may be substituted by a protected hydroxyl group, or the hydrolyzed compounds thereof which comprises (1) reacting an ?,.beta.-unsaturated carbonyl compound of the following formula (I) wherein R1, R2, R3 and R4 are the same as defined above, with an organic copper lithium compound of the following formula Cu(RB)nLiY2-n (II) wherein RB is the same as defined above, Y represents a monovalent anion, and n is 1 or 2, and when n is 2, the two RB groups are identical or different, with the proviso that RB in the case of n being 1, and at least one of RB groups in the case of n being 2, are alkyls or alkenyls containing at least 2 carbon atoms and up to 12 carbon atoms, and may be substituted by a protected hydroxyl group, in the presence of an aprotic inert organic solvent;
(2) reacting the reaction product with an acid halide or acid anhydride derived from an organic carboxylic acid of the following formula RA - COOH (III) wherein RA is the same as defined above; and (3) if necessary, treating the reaction product with water or an aqueous solution of a strong electrolyte to hydrolyze it.
(2) reacting the reaction product with an acid halide or acid anhydride derived from an organic carboxylic acid of the following formula RA - COOH (III) wherein RA is the same as defined above; and (3) if necessary, treating the reaction product with water or an aqueous solution of a strong electrolyte to hydrolyze it.
2. The process of claim 1 wherein said .alpha.,.beta.-unsaturated carbonyl compound of formula (I) is a compound of the following formula (I-A) wherein Q is a hydrogen atom or a protected hydroxyl group.
3. The process of claim 1 wherein said .alpha.,.beta.-unsaturated carbonyl compound of formula (I) is a compound of the following formula (I-B) wherein Q is a hydrogen atom or a protected hydroxyl group.
4. The process of claim 1 wherein said acid halide or acid anhydride derived from the compound of formula (III) is a compound of the following formula RACOX (III-A) wherein RA is as defined in claim 1, and X is a halogen atom, or a compound of the formulae (III-B) or (III-C) wherein RA is as defined in claim 1, and R"A represents an alky-lene group of 2 to 12 carbon atoms.
5. The process of claim 1 wherein said two reactions (1) and (2) are carried out respectively in a nitrogen-containing, sulfur-containing or oxygen-containing, aprotic inert organic medium.
6. The process of claim 1 wherein said two reactions (1) and (2) are carried out at a temperature of -78°C to 50°C.
7. 2-Acyl-3-substituted cyclopentan-1-ones of the formula wherein RA and RB are as defined in claim 1 and Q represents a hydrogen atom or a protected hydroxyl group whenever prepared by the process of claim 2 or by an obvious chemical equivalent thereof.
8. Process according to claim 1 wherein said .alpha.,.beta.-unsatur-ated carbonyl compound of formula I is a compound of the formula (I-A) wherein Q represents a hydrogen atom or a protected hydroxyl group, and the organic carboxylic acid of formula III is of the formula ROOC - Z - COOH
wherein Z represents an alkylene group of 1 to 12 carbon atoms or a phenylene group, and R is a hydrogen atom or a lower alkyl group.
wherein Z represents an alkylene group of 1 to 12 carbon atoms or a phenylene group, and R is a hydrogen atom or a lower alkyl group.
9. 2-Acyl-3-substituted cyclopentan-1-ones of the formula wherein R, RB, Q and Z are as defined in claims 1 and 8, when-ever prepared by the process of claim 8 or by an obvious chemi-cal equivalent thereof.
10. Process according to claim 1 wherein said .alpha.,.beta.-unsatur-ated carbonyl compound of formula I is a compound of the formula (I-B) wherein Q represents a hydrogen atom or a protected hydroxyl group, and the organic carboxylic acid of formula III is of the formula ROOC - Z - COOH
wherein Z represents an alkylene group of 1 to 12 carbon atoms or a phenylene group, and R is a hydrogen atom or a lower alkyl group.
wherein Z represents an alkylene group of 1 to 12 carbon atoms or a phenylene group, and R is a hydrogen atom or a lower alkyl group.
11. 2-Acyl-3-substituted cyclohexan-1-ones of the formula wherein R, RB, Q and Z are as defined in claims 1 and 10, when-ever prepared by the process of claim 10 or by an obvious chemi-cal equivalent thereof.
12. Process according to claim 1 wherein said .alpha.,.beta.-unsatur-ated carbonyl compound of formula I is a compound of the formula wherein Q represents a hydrogen atom or a protected hydroxyl group, the organic copper lithium compound is of the formula Cu(R"B)nLiY2-n wherein R"B is an alkyl, alkenyl or alkynyl group of 8 to 12 carbon atoms which may contain one hydroxyl group or one pro-tected hydroxyl group, Y represents an anion and n is 1 or 2, and the organic carboxylic acid has the formula ROOC - Z' - COOH
wherein R represents a hydrogen atom or a lower alkyl group and Z' represents an alkylene group of 5 to 10 carbon atoms or a phenylene group.
wherein R represents a hydrogen atom or a lower alkyl group and Z' represents an alkylene group of 5 to 10 carbon atoms or a phenylene group.
13. 2-Acyl-3-substituted cyclopentan-1-ones of the formula (IV-E) wherein Q, R, R"B and Z' are as defined in claim 12 whenever prepared by the process of claim 12 or by an obvious chemical equivalent thereof.
14. Process for the preparation of an ethyl ester of 7-oxo-11-deoxy-prostaglandin-E1 which comprises reacting together an organic copper-lithium compound of the formula cyclopent-2-en-1-one and .omega.-carboethoxycaproyl chloride, and hydrolyzing the thus obtained product by means of aqueous acetic acid.
15. 7-Oxo-11-deoxy-prostaglandin E1 ethyl ester whenever prepared by the process of claim 14 or by an obvious chemical equivalent thereof.
16. Process for the preparation of an ethyl ester of 7-oxo-prostaglan-din E1 which comprises reacting together an organic copper lithium compound of the formula 4-t-butyl-dimethyl-siloxycyclopent-2-en-1-one, and .omega.-carboethoxy-caproyl chloride, and hydrolyzing the thus obtained product with aqueous acetic acid.
17 7-Oxoprostaglandin E1 ethyl ester, whenever prepared by the process of claim 16 or by an obvious chemical equivalent thereof.
18. Process for the preparation of 2-acyl-3-substituted cyclo-alkan-1-ones chosen from the group consisting of:
(a) cyclopentan-1-ones of the formula wherein RA and RB are as defined in claim 1, and Q represents a hydrogen atom or a protected hydroxyl group, and (b) cyclohexan-1-ones of the formula wherein Q and RB are as defined above, Z represents an alkylene group of 1 to 12 carbon atoms or a phenylene group, and R represents a hydrogen atom or a lower alkyl group, which process comprises:
(A) when a cyclopentan-1-one is required (i) reacting an .alpha.,.beta.-unsaturated carbonyl compound of formula with an organic copper lithium compound of the formula Cu(RB)nLiY(2-n) wherein RB is as defined above and Y and n as defined in claim 1;
(ii) reacting the reaction product with an acid halide or acid anhydride derived from an organic carboxylic acid of the formula RA - COOH, wherein RA is as defined above; or (B) where a cyclohexan-1-one is required (i) reacting an un-saturated .alpha.,.beta.-carbonyl compound of the formula with an organic copper lithium compound of the formula Cu(RB)nLiY(2-n) wherein RB, Y and n are as defined above;
(ii) reacting the reaction product with an organic carboxylic acid of the formula ROOC-Z-COOH, wherein R and Z are as defined above; and (C) if necessary, treating the reaction product with water or an aqueous solution of a strong electrolyte to hydrolyse it.
(a) cyclopentan-1-ones of the formula wherein RA and RB are as defined in claim 1, and Q represents a hydrogen atom or a protected hydroxyl group, and (b) cyclohexan-1-ones of the formula wherein Q and RB are as defined above, Z represents an alkylene group of 1 to 12 carbon atoms or a phenylene group, and R represents a hydrogen atom or a lower alkyl group, which process comprises:
(A) when a cyclopentan-1-one is required (i) reacting an .alpha.,.beta.-unsaturated carbonyl compound of formula with an organic copper lithium compound of the formula Cu(RB)nLiY(2-n) wherein RB is as defined above and Y and n as defined in claim 1;
(ii) reacting the reaction product with an acid halide or acid anhydride derived from an organic carboxylic acid of the formula RA - COOH, wherein RA is as defined above; or (B) where a cyclohexan-1-one is required (i) reacting an un-saturated .alpha.,.beta.-carbonyl compound of the formula with an organic copper lithium compound of the formula Cu(RB)nLiY(2-n) wherein RB, Y and n are as defined above;
(ii) reacting the reaction product with an organic carboxylic acid of the formula ROOC-Z-COOH, wherein R and Z are as defined above; and (C) if necessary, treating the reaction product with water or an aqueous solution of a strong electrolyte to hydrolyse it.
19. 2-Acyl-3-substituted cycloalkan-1-ones chosen from the group consisting of:
(a) cyclopentan-1-ones of the formula wherein RA and RB are as defined in claim 1, and Q represents a hydrogen atom or a protected hydroxyl group, and (b) cyclohexan-1-ones of the formula wherein Q and RB are as defined above, Z represents an alkylene group of 1 to 12 carbon atoms or a phenylene group, and R represents a hydrogen atom or a lower alkyl group; whenever prepared by the process of claim 18 or by an obvious chemical equivalent thereof.
(a) cyclopentan-1-ones of the formula wherein RA and RB are as defined in claim 1, and Q represents a hydrogen atom or a protected hydroxyl group, and (b) cyclohexan-1-ones of the formula wherein Q and RB are as defined above, Z represents an alkylene group of 1 to 12 carbon atoms or a phenylene group, and R represents a hydrogen atom or a lower alkyl group; whenever prepared by the process of claim 18 or by an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA221,362A CA1105484A (en) | 1975-03-06 | 1975-03-06 | 1,3-dicarbonyl compounds and process for their preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA221,362A CA1105484A (en) | 1975-03-06 | 1975-03-06 | 1,3-dicarbonyl compounds and process for their preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1105484A true CA1105484A (en) | 1981-07-21 |
Family
ID=4102443
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA221,362A Expired CA1105484A (en) | 1975-03-06 | 1975-03-06 | 1,3-dicarbonyl compounds and process for their preparation |
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| Country | Link |
|---|---|
| CA (1) | CA1105484A (en) |
-
1975
- 1975-03-06 CA CA221,362A patent/CA1105484A/en not_active Expired
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