CA1146571A - Process for the preparation of xanthone derivatives - Google Patents
Process for the preparation of xanthone derivativesInfo
- Publication number
- CA1146571A CA1146571A CA000345339A CA345339A CA1146571A CA 1146571 A CA1146571 A CA 1146571A CA 000345339 A CA000345339 A CA 000345339A CA 345339 A CA345339 A CA 345339A CA 1146571 A CA1146571 A CA 1146571A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- compound
- effected
- group
- carbon atoms
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
- C07D311/82—Xanthenes
- C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
- C07D311/86—Oxygen atoms, e.g. xanthones
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pyrane Compounds (AREA)
- Diaphragms For Electromechanical Transducers (AREA)
- Peptides Or Proteins (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE:
The present invention relates to a process for the preparation of compounds of general formula I, (1) wherein R represents a hydrogen atom or an alkyl radical contain-ing from 1 to 9 carbon atoms and R1 represents an alkyl radical containing from 1 to 5 carbon atoms, which comprises cyclising a compound of formula II,
The present invention relates to a process for the preparation of compounds of general formula I, (1) wherein R represents a hydrogen atom or an alkyl radical contain-ing from 1 to 9 carbon atoms and R1 represents an alkyl radical containing from 1 to 5 carbon atoms, which comprises cyclising a compound of formula II,
Description
1~46571 This invention relates to a novel process for preparing xanthone derivatives of interest in the treatment of allergic conditions.
According to thc present invention, there is provided a process for the preparation of compounds of general formula I, o Rl-S ~ COOH (I) ~ ~ O
R
wherein R represents a hydrogen atom or an alkyl radical con-taining from 1 to 9 carbon atoms and Rl represents an alkyl radical containiny from 1 to 5 carbon atoms, which comprises cyclising a compound of formula II, o " R OOC
~ ~ COOR2 (II) Ar wherein R and Rl are as defined above, Ar represents an aryl group and R2 and R3, which may be the same or different, each represents an esterifying group and if required, hydrolysing the resulting compound to obtain the corresponding free acid.
The compounds of general formula I are described in British Patent Specification No. 1,518,083 in the name of the applicants. As indicated therein they possess interesting anti-allergic activity and are, in particular, of importance in the treatment of allergic asthma and bronchial asthma of allergic origin. According to the present invention, these compounds may be prepared in good yields, using relatively stable intermediates and avoiding the use of azides in the formation of the sulphonimi--1- ~
1~46571 doyl radicals. In general, R preferably represents an n-hexyl radical and Rl preferably represents a methyl radical. Ar pre-ferably represents a monocyclic aryl group having 6 to 10 carbon atoms, ~.g. a phenyl group which may carry substituents such as C1 4 alkyl groups e.g. methyl groups. The ~-totyl group is pre-ferred, In the compound of formula II, R2 and R3 may, for example, each represent an alkyl group containing from 1 to 3 carbon atoms; an aryl, e.g. nitrophenyl group; an aralkyl, e.g.
nitrobenzyl group; or a dialkylaminoalkyl, e.g. dimethylamino~
ethyl, group. According to a preferred embodiment the esterifying groups R2 and R3 are such as to enable the compound of formula II to be obtained in a crystallised form so as to facilitate the preparation of pure compound of formula II.
Cyclisation of the compound of formula II is conveniently effected by means of a strong acid such as, for example, poly-phosphoric or concentrated sulphuric acid, in which case hydrolysis to the free acid of formula I generally takes place simultaneously or, for example, on addition of water. Where, however, a cor-responding ester and/or arylsulphonimidoyl derivative is thefinal product of the cyclisation reaction, hydrolysis to the free acid of formula I may take place in a separate stage according to conventional methods, e.g. by heating in acidic or basic solu-tion. Preferred temperatures for the cyclisation are from 100 to 150C.
The compound of formula II may be obtained, if desired, by reacting a compound of formula III, R1 S ~ (III) .~
SO R
~r wherein R, Rl and Ar are as hereinbefore defined, with a compound of formula IV, (IV) Hal wherein R2 and R3 are as hereinbefore defined and Hal represents a chlorine, bromine or iodine atom, in the presence of a weak base and of metallic copper or a copper oxide, preferably in the form of a powder. The weak base may, for example, be an alkali metal carbonate e.g. sodium or potassium carbonate. The reaction is preferably effected under reflux.
The compound of formula III may be prepared, for example, by hydrolysis of a compound of formula V, O
Rl S ~ (V) ~ ~ 0-R4 N
Ar wherein R, Rl and Ar are as hereinbefore defined and R4 represents an acyl group, for example a group of formula -CO-X where X repre-sents an alkyl group containing from 1 to 3 carbon atoms or a phenyl ~roup. Hydrolysis is preferably effected by means of an aqueous solution of a weak base such as, for example, an alkali metal carbonate, e.g. sodium carbonate, and preferably at the boil-ing point of the reaction mixture.
The compound of formula V may be formed, if desired, by oxidation of a compound of formula VI, Rl--S ~
~ ~ O-R4 S2 R (VI) 11~6S71 wherein R, Rl, R4 and Ar are as hereinbefore defined, e.g. using a periodate such as sodium metaperiodate, preferably in the pre-sence of ruthenium (IV) oxide, or a peroxide oxidising agent.
~- The oxidation is preferably effected in the presence of an organic solvent for the compound of formula VI, such as, for example, a halogenated hydrocarbon e.g. dichloromethane. Periodates will normally be used in aqueous solution, in which case a 2-phase solvent system may be present.
The compound of formula VI may itself be obtained, if desired, by reacting a compound of formula VII, Rl-S ~
R 0-R4 (VII) wherein R, Rl and R4 are as hereinbefore defined, with a reagent of the formula ArSO2N + where Ar has the above meaning and M
represents an alkali metal atom, advantageously chloramine T
Cl (~-totyl-SO2N < +). The reaction is preferably effected in the presence of an organic solvent, most preferably an alkanol such as e.g. isopropanol.
The compound of formula VIJ may in turn be prepared, for example, by reacting a compound of formula VIII, Rl-S (VIII) ~ OH
wherein R and Rl are as hereinbefore defined, with an appropriate acylating agent, for example an acid halide or anhydride. Thus, for example when R4 in the compound of formula VII represents a group of formula -CO-X wheLe X is as hereinbefore defined, the acylating agent may be a compound of formula Z-CO-X where Z repre-~6571 sents a chlorine or bromine atom, or a compound of formula(X-CO)2O. The reaction of the compound of formula VIII with the acylating agent is preferably effected in the presence of an anhydrous organic solvent such as, for example pyridine.
The following non-limiting Examples serve to illustrate the invention.
Example 1 5-Hexyl-7-~S-meth~lsulphonomidoyl)xanthone-2~carboxylic acid Step A: 2-hexyl-4-(methylthio)~henyl benzoate _____ _________ ______ ___ __________ A solution of 2-hexyl-4-(methylthio)phenol (75 g) in pyridine (225 ml) was stirred with benzoyl chloride (100 g~ at room temperature for two hours. Water (450 ml~ was then added thereto and the resultant mixture was stirred for 1 hour. The product thus formed was filtered off, washed with water and dried to give 2-hexyl-4-(methylthio)phenyl benzoate (110 g, 100 %) as a colourless, crystalline solid, m.p. 57-58.
Step B 2-hexyl-4-(S-methyl-N-tosyls_l~h mldo~l)eh_nyl_b~a_oa~e The 2-hexyl-4-(methylthio)phenyl benzoate obtained in step A (50 g) was added over 15 min. to a stirred solution of chloramine-T (43 g) in isopropanol (IL) at 50. After stirring for 15 min. the suspension obtained was filtered, cooled to 0C
and crystallisation induced. The product thus formed was filtered off and dried to give 2-hexyl-4-(S-methyl-N-tosylfulphimidoyl) phenyl benzoate (63 g, 83%) as a colourless crystalline solid, m.p.
111-112.
Step C: 2-hexyl-4-~S-methyl-N-tosylsulphonlmidoyl)~henyl benzoate A solution of the 2-hexyl-4-(S-methyl-N-tosylsulphimi-doyl)phenyl benzoate obtained in step B (50 g) in dichloromethane (250 ml) was stirred vigorously with ruthenium (IV) oxide (100 mg) and aqueous sodium periodate (50 ml, 10% w/v). A pale green emulsion was formed which darkened considerably after a few minu-tes when the periodate had been consumed. The process was repeat-ed with four successive quantities of aqueous sodium periodate (50 ml, 10% w/v), the time taken to reprecipitate the cataIyst increasing on each occasion. The total weight of sodium periodate used was 25 g.
The organic layer was separated and the aqueous layer extracted with dichloromethane (lO0 ml). The combined organic solutions were washed with water, dried (MgSO4) and evaporated under reduced pressure to give a colourless oil which was used directly in the next step.
The catalyst may be recovered by filtering the reaction mixture. The oil can be crystallised if required by trituration in IMS to give a colourless, crystalline solid, m.p. 90-91.
steP D: 2-hexyl-4-(S-methyl-N-tosylsulphonimidoyl)~henol The oil from the previous step was dissolved in methanol (250 ml) and the solution obtained was mixed with aqueous sodium ; carbonate (lO~, 500 rnl) and heated with stirring at 60 for 3 hours, whereupon a clear solution was obtained. The solution was treated at room temperature with hydrochloric acid (20%, lO0 ml) and the product thus formed extracted with chloroform. Evaporation of the solvent under reduced pressure and trituration of the residue with 40-60 petrol gave 2-hexyl-4-(S-methyl-N- tosylsulpho-nimidoyl)phenol (40 g, 97% over two steps1 as a colourless crys-talline solid, m.p. lO9-110.
Step E: dimethyl 4- ~-hexyl-4-(S-methyl-N-tosylsul~honimidoylL-E?henxYllsoE~hthalate A mixture of the 2-hexyl-4-(S-methyl-N-tosylsulphonimi-doyl)phenol obtained in the previous step (20 g), dimethyl 4-bromoisophthalate (15 g~, potassium carbonate (lO g), copper powder - (l g), nitrobenzene (lO0 ml) and toluene (50 ml) was stirred under nitrogen and heated slowly to 160 while some of the toluene 6S~l (approx. 25 ml) was distilled out to dry the mixture. The tem-perature was maintained at 160 for 2 hours and then the remainder of the solvent was distilled off under reduced pressure. The cooled residue was dissolved in dichloromethane (400 ml) and the solution obtained was filtered and evaporated under reduced pressure. The residue was dissolved in ether (250 ml) and induced to crystallise by cooling the solution obtained to 0. The solid was filtered off, washed with ether,and dried to give dimethyl 4- ~2-hexyl-4-(S-methyl-N-tosylsulphonimidoyl)phenoxy~isophthalate (15.7 g, 53~), as a light brown crystalline solid, m.p. 124-126 .
The filtrate was evaporated to dryness and the residue triturated in 40-60 petrol to give a second crop of crude product (6.8g) in need of further purification.
~E_~: 5-hexyl-7-1S-methylsulPhonimidoyl)xanthone-2-carboxyli~
acid _ _ __ A solution of the dimethyl 4-L2-hexyl-4-(S-methyl-N-tosylsulphonimidoyl)phenoxy~isophthalate obtained in the previous step (5 g) in concentrated sulphuric acid (25 ml) was heated at ,120 for 1 hour, cooled a little and poured with vigorous stirring into water (250 ml). The solid thus precipitated was filtered off, washed with water and recrystallised form methanol to give 5-hexyl-7-(S-methylsulphonimidoyl)xanthone-2-carboxylic acid (2.5 g, 74.9%).
ExamPle 2 5-hexYl-7-(s-methylsulphonimidoyl)xanthone-2-carboxylic acid ~E_~: 2-hexyl-4-~methylthio)phenyl acetate A solution of 2-hexyl-4-(methylthio)phenol (6.6 g) in pyridine (36 ml) and acetic anhydride (18 ml) was stirred overnight at room temperature and then poured into water. The mixture obtained was extracted with ether. The organic extract was washed with dilute hydrochloric acid, sodium bicarbonate solution and 1~4~i571 ~.
finally with water then evaporated to dryness. 2-hexyl-4-(methyl-thio)phenyl acetate was obtained as a pale yellow oil (7.45 g, 95~).
Step B: 2-hexyl~4-(S-methyl-N-tosylsulehimidoyl)~henyl acetate _____ ____ ______ ______-_ ____ __ ___ _ _ _ _________ ~
A solution of the 2-hexyl-4-(methylthio)phenyl acetate obtained in the previous step (5 g) and chIoramine-T trihydrate (6.5 g) in dioxan (250 ml) and water (125 ml) was stirred for five hours, then evaporated to dryness leaving a red viscous oil (11 g).
The residue was chromatographed on a silica gel column eluting with chloroform and collecting 50 ml fractions. Fractions (3)-(6) gave pure 2-hexyl-4-(S-methyl-N-tosylsulphimidoyl)phenyl acetate as a colourless viscous oil which solidified to a white crystalline solid upon triturating with ice-cold petrol (60-80) (5 g, 61~, m,p. 62-5).
steP C. 2-hexyl-4-~S-methyl-N-tosylsul~honimidoyl)~henyl acetate _____ ____ ______ _______ ____ ________ _ ___ _________ A solution of the 2-hexyl-4-(S-methyl-N-tosylsulphimi-doyl)phenyl acetate obtained in the previous step (l g) in dichlo-romethane (40 ml) was treated with a solution of sodium meta-periodate ~1 g) in water and soluble ruthenium (IV) oxide (5 mg)~20 The resultant mixture was stirred for 30 mins, then a further 5 mg of ruthenium oxide and 0.3 g metaperiodate were added thereto.
Stirring was continued for a further 15 mins, then the organic layer was separated, filtered and evaporated to dryness. The residue was chromatographed on a silica gel column eluting with ethyl acetate. FractionS (2)-(3) gave pure 2-hexyl-4-(S-methyl-N-tosylsulphonimidoyl)phenyl acetate as a colourless viscous oil which solidified on cooling (0.88 g, 85~).
Step D: 2-hexyl-4-1S-methyl-N-tosylsul~honimidoylL~henol A suspension of the oily 2-hexyl-4-(S-methyl-N-tosyl-sulphonimidoyl)phenyl acetate obtained in the previous step (0.8 g) in saturated sodium carbonat~ solution (30 ml) and ethanol (15 ml) 1~46571 was stirred at 50 for 15 mins, afterwhich time all the oil had dissolved. The resultant solution was poured into waterl acidified with conc. hydrochloric acid and extracted with ether. Evaporation of the solvent gave 2-hexyl-4-(S-methyl-N-tosylsuphonimidoyl) phenol as a white oil which solidified to a white crystalline solid upon triturating with ether/petrol ~60-80; (0.65 g, 90% m.p.
107 9) SteP E. dimethyl 4-12-hexyl-4-(S-methyl-N-tosylsul~honimidoylL-____ __________ ___________ _ _____ ___ _ ______ _ _ phenoxy~-iso~hthalate _____ _____ ________ A solution of the 2-hexyl-4-(S-methyl-N-tosylsulphoni-midoyl)phenol obtained in the previous step (0.4 g) and dimethyl bromoisophthalate (0.3g) in nitrobenzene (lO ml) was dried azeo-tropically by the addition and distillation of benzene. The re-sultant solution was treated with copper powder (50 mg~ and anhy-drous potassium carbonate (0.4 g) and stirred for 2 hours at 160 under a stream of dry nitrogen gas. The mixture thus obtained was cooled, diluted with chloroform, filtered and the solvent was evaporated off under high vacuum leaving a red/brown viscous oil.
Trituration of the oil with petrol (60-80) caused it to solidify to a buff crystalline solid which was the required dimethyl 4-L2-hexyl-4-(S-methyl-N-tosylsulphonimidoyl)-phenoxy~-isophthalate (0.53 g, 90~). The product was obtained as a white crystalline solid after passage through a short silica gel column eluting with chloroform (m.p. 115-7).
Step F- methyl-5-hexyl-7-(S-methylsulphonimidoyl)xanthone-2-____ _______ ___________ ____ ________ _____________ carboxylate _ _ _ _ _ _ _ _ _ _ A solution of the dimethyl 4-~2-hexyl-4-(S-methyl-N-tosYlsulphonimidoyl)-phenoxy~-isophthalate obtained in the previous step (0.2 g) in polyphosphoric acid (4ml) was stirred at 80 for ten minutes and the temperature gradually increased to 120. The resultant dark red viscous reaction mixture was stirred a further 1~46571 1 1/2 hours at 120 and then cooled and poured into water to give a yellow viscous oil which was extracted into ethyl acetate.
The product thus obtained (0.11 g) was a mixture of methyl 5-hexyl-7-(S-methylsulphonimidoyl)-xanthone-2-carboxylate and the corres-ponding acid (shown by tlc and NMR spectra). The ester was obtained pure by column chromatography on silica gel eluting with ethyl acetate and collecting 50 ml fractions. Fractions (9)-(12) gave the pure methyl 5-hexyl-7-(S-methylsulphonimidoyl)xanthone-2-car-boxylate as a white crystalline solid.
SteP G: 5-hexyl-7-lS-methylsulphonimidoyl)xanthone-2-carboxyllc acid _ _ _ _ A solution of the methyl 5-hexyl-7-(S-methylsulphonimi-doyl)xanthone-2-carboxylate obtained in the previous step~(0.1 g) in ethanol (5 ml) ans water (1 ml) was treated with 0.2 N sodium hydroxide solution (2.7 ml) an~ the resultant mixture was refluxed for 1 hour. Afker cooling, the solution obtained was acidified with 2 N hydrochloric acid solution. 5-hexyl-7-(S-methylsulphoni-midoyl)xanthone-2-carboxylic acid separated out as a white solid 20 and was filtered off and washed well with water. (0.09 g, 93~, m.p. 193-4).
According to thc present invention, there is provided a process for the preparation of compounds of general formula I, o Rl-S ~ COOH (I) ~ ~ O
R
wherein R represents a hydrogen atom or an alkyl radical con-taining from 1 to 9 carbon atoms and Rl represents an alkyl radical containiny from 1 to 5 carbon atoms, which comprises cyclising a compound of formula II, o " R OOC
~ ~ COOR2 (II) Ar wherein R and Rl are as defined above, Ar represents an aryl group and R2 and R3, which may be the same or different, each represents an esterifying group and if required, hydrolysing the resulting compound to obtain the corresponding free acid.
The compounds of general formula I are described in British Patent Specification No. 1,518,083 in the name of the applicants. As indicated therein they possess interesting anti-allergic activity and are, in particular, of importance in the treatment of allergic asthma and bronchial asthma of allergic origin. According to the present invention, these compounds may be prepared in good yields, using relatively stable intermediates and avoiding the use of azides in the formation of the sulphonimi--1- ~
1~46571 doyl radicals. In general, R preferably represents an n-hexyl radical and Rl preferably represents a methyl radical. Ar pre-ferably represents a monocyclic aryl group having 6 to 10 carbon atoms, ~.g. a phenyl group which may carry substituents such as C1 4 alkyl groups e.g. methyl groups. The ~-totyl group is pre-ferred, In the compound of formula II, R2 and R3 may, for example, each represent an alkyl group containing from 1 to 3 carbon atoms; an aryl, e.g. nitrophenyl group; an aralkyl, e.g.
nitrobenzyl group; or a dialkylaminoalkyl, e.g. dimethylamino~
ethyl, group. According to a preferred embodiment the esterifying groups R2 and R3 are such as to enable the compound of formula II to be obtained in a crystallised form so as to facilitate the preparation of pure compound of formula II.
Cyclisation of the compound of formula II is conveniently effected by means of a strong acid such as, for example, poly-phosphoric or concentrated sulphuric acid, in which case hydrolysis to the free acid of formula I generally takes place simultaneously or, for example, on addition of water. Where, however, a cor-responding ester and/or arylsulphonimidoyl derivative is thefinal product of the cyclisation reaction, hydrolysis to the free acid of formula I may take place in a separate stage according to conventional methods, e.g. by heating in acidic or basic solu-tion. Preferred temperatures for the cyclisation are from 100 to 150C.
The compound of formula II may be obtained, if desired, by reacting a compound of formula III, R1 S ~ (III) .~
SO R
~r wherein R, Rl and Ar are as hereinbefore defined, with a compound of formula IV, (IV) Hal wherein R2 and R3 are as hereinbefore defined and Hal represents a chlorine, bromine or iodine atom, in the presence of a weak base and of metallic copper or a copper oxide, preferably in the form of a powder. The weak base may, for example, be an alkali metal carbonate e.g. sodium or potassium carbonate. The reaction is preferably effected under reflux.
The compound of formula III may be prepared, for example, by hydrolysis of a compound of formula V, O
Rl S ~ (V) ~ ~ 0-R4 N
Ar wherein R, Rl and Ar are as hereinbefore defined and R4 represents an acyl group, for example a group of formula -CO-X where X repre-sents an alkyl group containing from 1 to 3 carbon atoms or a phenyl ~roup. Hydrolysis is preferably effected by means of an aqueous solution of a weak base such as, for example, an alkali metal carbonate, e.g. sodium carbonate, and preferably at the boil-ing point of the reaction mixture.
The compound of formula V may be formed, if desired, by oxidation of a compound of formula VI, Rl--S ~
~ ~ O-R4 S2 R (VI) 11~6S71 wherein R, Rl, R4 and Ar are as hereinbefore defined, e.g. using a periodate such as sodium metaperiodate, preferably in the pre-sence of ruthenium (IV) oxide, or a peroxide oxidising agent.
~- The oxidation is preferably effected in the presence of an organic solvent for the compound of formula VI, such as, for example, a halogenated hydrocarbon e.g. dichloromethane. Periodates will normally be used in aqueous solution, in which case a 2-phase solvent system may be present.
The compound of formula VI may itself be obtained, if desired, by reacting a compound of formula VII, Rl-S ~
R 0-R4 (VII) wherein R, Rl and R4 are as hereinbefore defined, with a reagent of the formula ArSO2N + where Ar has the above meaning and M
represents an alkali metal atom, advantageously chloramine T
Cl (~-totyl-SO2N < +). The reaction is preferably effected in the presence of an organic solvent, most preferably an alkanol such as e.g. isopropanol.
The compound of formula VIJ may in turn be prepared, for example, by reacting a compound of formula VIII, Rl-S (VIII) ~ OH
wherein R and Rl are as hereinbefore defined, with an appropriate acylating agent, for example an acid halide or anhydride. Thus, for example when R4 in the compound of formula VII represents a group of formula -CO-X wheLe X is as hereinbefore defined, the acylating agent may be a compound of formula Z-CO-X where Z repre-~6571 sents a chlorine or bromine atom, or a compound of formula(X-CO)2O. The reaction of the compound of formula VIII with the acylating agent is preferably effected in the presence of an anhydrous organic solvent such as, for example pyridine.
The following non-limiting Examples serve to illustrate the invention.
Example 1 5-Hexyl-7-~S-meth~lsulphonomidoyl)xanthone-2~carboxylic acid Step A: 2-hexyl-4-(methylthio)~henyl benzoate _____ _________ ______ ___ __________ A solution of 2-hexyl-4-(methylthio)phenol (75 g) in pyridine (225 ml) was stirred with benzoyl chloride (100 g~ at room temperature for two hours. Water (450 ml~ was then added thereto and the resultant mixture was stirred for 1 hour. The product thus formed was filtered off, washed with water and dried to give 2-hexyl-4-(methylthio)phenyl benzoate (110 g, 100 %) as a colourless, crystalline solid, m.p. 57-58.
Step B 2-hexyl-4-(S-methyl-N-tosyls_l~h mldo~l)eh_nyl_b~a_oa~e The 2-hexyl-4-(methylthio)phenyl benzoate obtained in step A (50 g) was added over 15 min. to a stirred solution of chloramine-T (43 g) in isopropanol (IL) at 50. After stirring for 15 min. the suspension obtained was filtered, cooled to 0C
and crystallisation induced. The product thus formed was filtered off and dried to give 2-hexyl-4-(S-methyl-N-tosylfulphimidoyl) phenyl benzoate (63 g, 83%) as a colourless crystalline solid, m.p.
111-112.
Step C: 2-hexyl-4-~S-methyl-N-tosylsulphonlmidoyl)~henyl benzoate A solution of the 2-hexyl-4-(S-methyl-N-tosylsulphimi-doyl)phenyl benzoate obtained in step B (50 g) in dichloromethane (250 ml) was stirred vigorously with ruthenium (IV) oxide (100 mg) and aqueous sodium periodate (50 ml, 10% w/v). A pale green emulsion was formed which darkened considerably after a few minu-tes when the periodate had been consumed. The process was repeat-ed with four successive quantities of aqueous sodium periodate (50 ml, 10% w/v), the time taken to reprecipitate the cataIyst increasing on each occasion. The total weight of sodium periodate used was 25 g.
The organic layer was separated and the aqueous layer extracted with dichloromethane (lO0 ml). The combined organic solutions were washed with water, dried (MgSO4) and evaporated under reduced pressure to give a colourless oil which was used directly in the next step.
The catalyst may be recovered by filtering the reaction mixture. The oil can be crystallised if required by trituration in IMS to give a colourless, crystalline solid, m.p. 90-91.
steP D: 2-hexyl-4-(S-methyl-N-tosylsulphonimidoyl)~henol The oil from the previous step was dissolved in methanol (250 ml) and the solution obtained was mixed with aqueous sodium ; carbonate (lO~, 500 rnl) and heated with stirring at 60 for 3 hours, whereupon a clear solution was obtained. The solution was treated at room temperature with hydrochloric acid (20%, lO0 ml) and the product thus formed extracted with chloroform. Evaporation of the solvent under reduced pressure and trituration of the residue with 40-60 petrol gave 2-hexyl-4-(S-methyl-N- tosylsulpho-nimidoyl)phenol (40 g, 97% over two steps1 as a colourless crys-talline solid, m.p. lO9-110.
Step E: dimethyl 4- ~-hexyl-4-(S-methyl-N-tosylsul~honimidoylL-E?henxYllsoE~hthalate A mixture of the 2-hexyl-4-(S-methyl-N-tosylsulphonimi-doyl)phenol obtained in the previous step (20 g), dimethyl 4-bromoisophthalate (15 g~, potassium carbonate (lO g), copper powder - (l g), nitrobenzene (lO0 ml) and toluene (50 ml) was stirred under nitrogen and heated slowly to 160 while some of the toluene 6S~l (approx. 25 ml) was distilled out to dry the mixture. The tem-perature was maintained at 160 for 2 hours and then the remainder of the solvent was distilled off under reduced pressure. The cooled residue was dissolved in dichloromethane (400 ml) and the solution obtained was filtered and evaporated under reduced pressure. The residue was dissolved in ether (250 ml) and induced to crystallise by cooling the solution obtained to 0. The solid was filtered off, washed with ether,and dried to give dimethyl 4- ~2-hexyl-4-(S-methyl-N-tosylsulphonimidoyl)phenoxy~isophthalate (15.7 g, 53~), as a light brown crystalline solid, m.p. 124-126 .
The filtrate was evaporated to dryness and the residue triturated in 40-60 petrol to give a second crop of crude product (6.8g) in need of further purification.
~E_~: 5-hexyl-7-1S-methylsulPhonimidoyl)xanthone-2-carboxyli~
acid _ _ __ A solution of the dimethyl 4-L2-hexyl-4-(S-methyl-N-tosylsulphonimidoyl)phenoxy~isophthalate obtained in the previous step (5 g) in concentrated sulphuric acid (25 ml) was heated at ,120 for 1 hour, cooled a little and poured with vigorous stirring into water (250 ml). The solid thus precipitated was filtered off, washed with water and recrystallised form methanol to give 5-hexyl-7-(S-methylsulphonimidoyl)xanthone-2-carboxylic acid (2.5 g, 74.9%).
ExamPle 2 5-hexYl-7-(s-methylsulphonimidoyl)xanthone-2-carboxylic acid ~E_~: 2-hexyl-4-~methylthio)phenyl acetate A solution of 2-hexyl-4-(methylthio)phenol (6.6 g) in pyridine (36 ml) and acetic anhydride (18 ml) was stirred overnight at room temperature and then poured into water. The mixture obtained was extracted with ether. The organic extract was washed with dilute hydrochloric acid, sodium bicarbonate solution and 1~4~i571 ~.
finally with water then evaporated to dryness. 2-hexyl-4-(methyl-thio)phenyl acetate was obtained as a pale yellow oil (7.45 g, 95~).
Step B: 2-hexyl~4-(S-methyl-N-tosylsulehimidoyl)~henyl acetate _____ ____ ______ ______-_ ____ __ ___ _ _ _ _________ ~
A solution of the 2-hexyl-4-(methylthio)phenyl acetate obtained in the previous step (5 g) and chIoramine-T trihydrate (6.5 g) in dioxan (250 ml) and water (125 ml) was stirred for five hours, then evaporated to dryness leaving a red viscous oil (11 g).
The residue was chromatographed on a silica gel column eluting with chloroform and collecting 50 ml fractions. Fractions (3)-(6) gave pure 2-hexyl-4-(S-methyl-N-tosylsulphimidoyl)phenyl acetate as a colourless viscous oil which solidified to a white crystalline solid upon triturating with ice-cold petrol (60-80) (5 g, 61~, m,p. 62-5).
steP C. 2-hexyl-4-~S-methyl-N-tosylsul~honimidoyl)~henyl acetate _____ ____ ______ _______ ____ ________ _ ___ _________ A solution of the 2-hexyl-4-(S-methyl-N-tosylsulphimi-doyl)phenyl acetate obtained in the previous step (l g) in dichlo-romethane (40 ml) was treated with a solution of sodium meta-periodate ~1 g) in water and soluble ruthenium (IV) oxide (5 mg)~20 The resultant mixture was stirred for 30 mins, then a further 5 mg of ruthenium oxide and 0.3 g metaperiodate were added thereto.
Stirring was continued for a further 15 mins, then the organic layer was separated, filtered and evaporated to dryness. The residue was chromatographed on a silica gel column eluting with ethyl acetate. FractionS (2)-(3) gave pure 2-hexyl-4-(S-methyl-N-tosylsulphonimidoyl)phenyl acetate as a colourless viscous oil which solidified on cooling (0.88 g, 85~).
Step D: 2-hexyl-4-1S-methyl-N-tosylsul~honimidoylL~henol A suspension of the oily 2-hexyl-4-(S-methyl-N-tosyl-sulphonimidoyl)phenyl acetate obtained in the previous step (0.8 g) in saturated sodium carbonat~ solution (30 ml) and ethanol (15 ml) 1~46571 was stirred at 50 for 15 mins, afterwhich time all the oil had dissolved. The resultant solution was poured into waterl acidified with conc. hydrochloric acid and extracted with ether. Evaporation of the solvent gave 2-hexyl-4-(S-methyl-N-tosylsuphonimidoyl) phenol as a white oil which solidified to a white crystalline solid upon triturating with ether/petrol ~60-80; (0.65 g, 90% m.p.
107 9) SteP E. dimethyl 4-12-hexyl-4-(S-methyl-N-tosylsul~honimidoylL-____ __________ ___________ _ _____ ___ _ ______ _ _ phenoxy~-iso~hthalate _____ _____ ________ A solution of the 2-hexyl-4-(S-methyl-N-tosylsulphoni-midoyl)phenol obtained in the previous step (0.4 g) and dimethyl bromoisophthalate (0.3g) in nitrobenzene (lO ml) was dried azeo-tropically by the addition and distillation of benzene. The re-sultant solution was treated with copper powder (50 mg~ and anhy-drous potassium carbonate (0.4 g) and stirred for 2 hours at 160 under a stream of dry nitrogen gas. The mixture thus obtained was cooled, diluted with chloroform, filtered and the solvent was evaporated off under high vacuum leaving a red/brown viscous oil.
Trituration of the oil with petrol (60-80) caused it to solidify to a buff crystalline solid which was the required dimethyl 4-L2-hexyl-4-(S-methyl-N-tosylsulphonimidoyl)-phenoxy~-isophthalate (0.53 g, 90~). The product was obtained as a white crystalline solid after passage through a short silica gel column eluting with chloroform (m.p. 115-7).
Step F- methyl-5-hexyl-7-(S-methylsulphonimidoyl)xanthone-2-____ _______ ___________ ____ ________ _____________ carboxylate _ _ _ _ _ _ _ _ _ _ A solution of the dimethyl 4-~2-hexyl-4-(S-methyl-N-tosYlsulphonimidoyl)-phenoxy~-isophthalate obtained in the previous step (0.2 g) in polyphosphoric acid (4ml) was stirred at 80 for ten minutes and the temperature gradually increased to 120. The resultant dark red viscous reaction mixture was stirred a further 1~46571 1 1/2 hours at 120 and then cooled and poured into water to give a yellow viscous oil which was extracted into ethyl acetate.
The product thus obtained (0.11 g) was a mixture of methyl 5-hexyl-7-(S-methylsulphonimidoyl)-xanthone-2-carboxylate and the corres-ponding acid (shown by tlc and NMR spectra). The ester was obtained pure by column chromatography on silica gel eluting with ethyl acetate and collecting 50 ml fractions. Fractions (9)-(12) gave the pure methyl 5-hexyl-7-(S-methylsulphonimidoyl)xanthone-2-car-boxylate as a white crystalline solid.
SteP G: 5-hexyl-7-lS-methylsulphonimidoyl)xanthone-2-carboxyllc acid _ _ _ _ A solution of the methyl 5-hexyl-7-(S-methylsulphonimi-doyl)xanthone-2-carboxylate obtained in the previous step~(0.1 g) in ethanol (5 ml) ans water (1 ml) was treated with 0.2 N sodium hydroxide solution (2.7 ml) an~ the resultant mixture was refluxed for 1 hour. Afker cooling, the solution obtained was acidified with 2 N hydrochloric acid solution. 5-hexyl-7-(S-methylsulphoni-midoyl)xanthone-2-carboxylic acid separated out as a white solid 20 and was filtered off and washed well with water. (0.09 g, 93~, m.p. 193-4).
Claims (32)
1. A process for the preparation of compounds of general formula I:
(I) wherein R represents a hydrogen atom or an alkyl radical contain-ing from 1 to 9 carbon atoms and R1 represents an alkyl radical containing from 1 to 5 carbon atoms ,which comprises cyclising a compound of general formula II
(II) wherein R and R1 are as defined above, Ar represents an aryl group and R2 and R3, which may be the same or different, each represents an esterifying group and if required, by hydrolysing the resulting compound to obtain the corresponding free acid.
(I) wherein R represents a hydrogen atom or an alkyl radical contain-ing from 1 to 9 carbon atoms and R1 represents an alkyl radical containing from 1 to 5 carbon atoms ,which comprises cyclising a compound of general formula II
(II) wherein R and R1 are as defined above, Ar represents an aryl group and R2 and R3, which may be the same or different, each represents an esterifying group and if required, by hydrolysing the resulting compound to obtain the corresponding free acid.
2. A process as claimed in claim 1, wherein R represents an n-hexyl radical.
3. A process as claimed in claim 1 or 2, wherein R1 represents a methyl radical.
4. A process as claimed in claim 1 wherein, in the compound of formula II, Ar represents a monocyclic aryl group having from 6 to 10 carbon atoms.
5. A process as claimed in claim 4 wherein, in the compound of formula II, Ar represents a phenyl group optionally substituted by one or more C1-4 alkyl groups.
6. A process as claimed in claim 5 wherein, in the compound of formula II, Ar represents a p-tolyl group.
7. A process as claimed in claim 1 wherein in the compound of formula II, R2 and R3, which may be the same or dif-ferent, each represents an alkyl group containing from 1 to 3 carbon atoms or an aryl, aralkyl or dialkylaminoalkyl group.
8. A process as claimed in claim 7 wherein, in the compound of formula II, R2 and R3, which may be the same or dif-ferent, each represents a nitrophenyl, nitrobenzyl or dimethylamino-ethyl group.
9. A process as claimed in claim 1, wherein cyclisation is effected by means of a strong acid.
10. A process as claimed in claim 9, wherein the strong acid is polyphosphoric or concentrated sulphuric acid.
11. A process as claimed in claim 1, 9 or 10, wherein the cyclisation is effected at temperatures of from 100° to 150°C.
12. A process as claimed in claim 1, in which the acid of formula I is formed by hydrolysis during the cyclisation step or by addition of water.
13. A Process as claimed in claim 1, 9 or 10, in which the product of the cyclisation step is subjected to hydrolysis in a separate stage.
14. A process as claimed in claim 1, wherein the compound of formula II is obtained by reacting a compound of general for-mula III:
(III) wherein R, R1 and Ar are as defined in claim 1, with a compound of general formula IV:
(IV) wherein R2 and R3 are as defined in claim 1 and Hal represents a chlorine, bromine or iodine atom, in the presence of a weak base and of metallic copper or a copper oxide.
(III) wherein R, R1 and Ar are as defined in claim 1, with a compound of general formula IV:
(IV) wherein R2 and R3 are as defined in claim 1 and Hal represents a chlorine, bromine or iodine atom, in the presence of a weak base and of metallic copper or a copper oxide.
15. A process as claimed in claim 14, wherein the metal-lic copper or copper oxide is in the form of a powder.
16. A process as claimed in claim 14 or 15, wherein the weak base is an alkali metal carbonate.
17. A process as claimed in claim 14, wherein the reaction of the compound of formula III with the compound of formula IV is effected under reflux.
18. A process as claimed in claim 14, wherein the com-pound of formula III is obtained by hydrolysing a compound of general formula V, (V) wherein R represents a hydrogen atom or an alkyl radical containing from 1 to 9 carbon atoms; R1 represents an alkyl radical containing from 1 to 5 carbon atoms; Ar represents an aryl group and R4 re-presents an acyl group.
19. A process as claimed in claim 18 wherein, in the compound of formula V, R4 represents a group of formula -CO-X
where X represents an alkyl group containing from 1 to 3 carbon atoms or a phenyl group.
where X represents an alkyl group containing from 1 to 3 carbon atoms or a phenyl group.
20. A process as claimed in claim 18, wherein hydrolysis of the compound of formula V is effected by means of an aqueous solution of a weak base.
21. A process as claimed in claim 20, wherein hydrolysis of the compound of formula V is effected by means of an aqueous solution of an alkali metal carbonate.
22. A process as claimed in claim 18, 20 or 21, wherein the hydrolysis of the compound of formula V is effected under reflux.
23. A process as claimed in claim 18, wherein the compound of formula V is obtained by oxidizing a compound of general for-mula VI:
(VI) wherein R, R1, Ar and R4 are as defined in claim 18.
(VI) wherein R, R1, Ar and R4 are as defined in claim 18.
24. A process as claimed in claim 23, wherein oxidation is effected by means of a periodate or a peroxide oxidising agent.
25. A process as claimed in claim 24, wherein oxidation is effected by means of sodium metaperiodate in the presence of ruthenium (IV) oxide.
26. A process as claimed in claim 23, 24 or 25, wherein the oxidation is effected in the presence of a halogenated hydro-carbon as solvent.
27. A process as claimed in claim 23, wherein the com-pound of formula VI is obtained by reacting a compound of general formula VII:
(VII) wherein R represents a hydrogen atom or an alkyl radical contain-ing from 1 to 9 carbon atoms; R1 represents an alkyl radical con-taining from 1 to 5 carbon atoms and R4 represents an acyl group, with a reagent of formula wherein Ar represents an aryl radical and M represents an alkali metal atom.
(VII) wherein R represents a hydrogen atom or an alkyl radical contain-ing from 1 to 9 carbon atoms; R1 represents an alkyl radical con-taining from 1 to 5 carbon atoms and R4 represents an acyl group, with a reagent of formula wherein Ar represents an aryl radical and M represents an alkali metal atom.
28. A process as claimed in claim 27, wherein the reagent of formula is chloramine T.
29. A process as claimed in claim 27 or 28, wherein the reaction of the compound of formula VII with the reagent of formula is effected in the presence of an alkano] as solvent.
30. A process as claimed in claim 27, wherein the com-pound of general formula VII is obtained by reacting a compound of general formula VIII:
(VIII) wherein R and R1 are as defined in claim 27, with an appropriate acylating agent.
(VIII) wherein R and R1 are as defined in claim 27, with an appropriate acylating agent.
31. A process as claimed in claim 30, wherein the acylat-ing agent is an acid halide or anhydride.
32. A process as claimed in claim 30 or 31, wherein the reaction of the compound of formula VIII with the acylating agent is effected in the presence of an anhydrous organic solvent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7904649 | 1979-02-09 | ||
| GB7904649 | 1979-02-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1146571A true CA1146571A (en) | 1983-05-17 |
Family
ID=10503083
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000345339A Expired CA1146571A (en) | 1979-02-09 | 1980-02-08 | Process for the preparation of xanthone derivatives |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0016665B1 (en) |
| JP (1) | JPS55108867A (en) |
| AT (1) | ATE967T1 (en) |
| AU (1) | AU531013B2 (en) |
| CA (1) | CA1146571A (en) |
| DE (1) | DE3060348D1 (en) |
| DK (1) | DK145948C (en) |
| ES (1) | ES8102115A1 (en) |
| FI (1) | FI800392A (en) |
| GB (1) | GB2042540B (en) |
| HU (1) | HU180552B (en) |
| IE (1) | IE49389B1 (en) |
| IL (1) | IL59046A (en) |
| PT (1) | PT70795B (en) |
| ZA (1) | ZA80141B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL47519A (en) * | 1974-07-09 | 1979-03-12 | Roussel Uclaf | 7-sulphinimidoyl(sulphimidoyl)-xanthone-2-carboxylic acid derivatives, their preparation and pharmaceutical compositions containing them |
| JPS5850225B2 (en) * | 1976-01-01 | 1983-11-09 | ルセル・ユクラフ | Novel xanthones, their salts and esters, and pharmaceuticals comprising these compounds |
| SE445346B (en) * | 1978-03-03 | 1986-06-16 | Roussel Uclaf | SET TO PREPARE 7-SULPHONIMIDOYL-XANTON-2-CARBOXYLIC ACID DERIVATIVE |
-
1979
- 1979-12-27 IL IL59046A patent/IL59046A/en unknown
-
1980
- 1980-01-08 HU HU808033A patent/HU180552B/en unknown
- 1980-01-10 ZA ZA00800141A patent/ZA80141B/en unknown
- 1980-01-30 DE DE8080400146T patent/DE3060348D1/en not_active Expired
- 1980-01-30 EP EP80400146A patent/EP0016665B1/en not_active Expired
- 1980-01-30 AT AT80400146T patent/ATE967T1/en not_active IP Right Cessation
- 1980-02-07 PT PT70795A patent/PT70795B/en not_active IP Right Cessation
- 1980-02-08 GB GB8004291A patent/GB2042540B/en not_active Expired
- 1980-02-08 CA CA000345339A patent/CA1146571A/en not_active Expired
- 1980-02-08 AU AU55350/80A patent/AU531013B2/en not_active Ceased
- 1980-02-08 JP JP1376980A patent/JPS55108867A/en active Granted
- 1980-02-08 ES ES488385A patent/ES8102115A1/en not_active Expired
- 1980-02-08 FI FI800392A patent/FI800392A/en not_active Application Discontinuation
- 1980-02-08 DK DK54180A patent/DK145948C/en not_active IP Right Cessation
- 1980-02-08 IE IE250/80A patent/IE49389B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HU180552B (en) | 1983-03-28 |
| IL59046A0 (en) | 1980-03-31 |
| ATE967T1 (en) | 1982-05-15 |
| GB2042540B (en) | 1982-11-24 |
| AU5535080A (en) | 1980-08-14 |
| DE3060348D1 (en) | 1982-06-24 |
| IE49389B1 (en) | 1985-10-02 |
| EP0016665B1 (en) | 1982-05-05 |
| IE800250L (en) | 1980-08-09 |
| AU531013B2 (en) | 1983-08-04 |
| DK145948B (en) | 1983-04-25 |
| DK54180A (en) | 1980-08-10 |
| DK145948C (en) | 1983-09-26 |
| ES488385A0 (en) | 1980-12-16 |
| GB2042540A (en) | 1980-09-24 |
| ZA80141B (en) | 1981-02-25 |
| FI800392A (en) | 1980-08-10 |
| ES8102115A1 (en) | 1980-12-16 |
| JPS55108867A (en) | 1980-08-21 |
| PT70795A (en) | 1980-03-01 |
| IL59046A (en) | 1985-03-31 |
| PT70795B (en) | 1981-06-11 |
| EP0016665A1 (en) | 1980-10-01 |
| JPH0144710B2 (en) | 1989-09-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6013828A (en) | Processes and intermediates useful to make antifolates | |
| US4788282A (en) | Deprotection of allylic esters and ethers | |
| US4658055A (en) | Method for manufacture of 7-(2,5-dioxocyclopentyl)heptanoic acid derivative | |
| CA1146571A (en) | Process for the preparation of xanthone derivatives | |
| EP1116719B1 (en) | 3-(1-Hydroxy-pentylidene)-5-nitro-3H-benzofuran-2-one, a process for the preparation thereof and the use thereof | |
| US4225524A (en) | Steroid derivatives and process for preparing the same | |
| KR910003617B1 (en) | Process for the preparation of quinolene and naphthyridone-carboxylic acids | |
| US5070212A (en) | Intermediates useful for the synthesis of delphinidin chloride | |
| US4079065A (en) | Process for the production of 2H-cyclopenta (b) furan-2-one compounds | |
| PL118827B1 (en) | Method of manufacture of tricyclicdiketone | |
| US5892057A (en) | Preparation of sulfo-N-hydroxysuccinimide salts | |
| CA1126282A (en) | Process for the preparation of xanthone derivatives | |
| EP0183348A1 (en) | Process for the preparation of 8-halo-5,6-dialkoxyquinazoline -2,4-diones and their salts | |
| US6090168A (en) | Processes and intermediates useful to make antifolates | |
| JP4148550B2 (en) | 5-Amino-1-cyclopropyl-4-oxoquinoline-3-carboxylic acid derivative and process for producing the same | |
| US4242267A (en) | Process for preparing 5-alkyl-7-(S-alkyl-sulfonimidoyl)-xanthone-2-carboxylic acids | |
| US4234491A (en) | Steroid synthesis process using mixed anhydride | |
| KR810001251B1 (en) | Process for preparing 3-(tetrazol-5-yl)-1-azaxanthon derivatives | |
| CA1254228A (en) | Method of producing the p-chlorophenol ester of p- chlorophenoxyisobutyric acid | |
| CA1066291A (en) | 3-formyl-4-methyl-2,6-dihydroxypyridine and a process for its preparation | |
| CN111253405A (en) | Preparation method of biapenem intermediate | |
| KR910001999B1 (en) | Process for the preparation of benzoyl maleic acid derivative | |
| JPS60152469A (en) | Preparation of cis-diester derivative | |
| KR910002154B1 (en) | 3-pyrroline derivatives and their preparation | |
| US4219488A (en) | Process for preparing steroidal [16α,17-b]naphthaleno-21-carboxylic acid esters |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |