US2836604A - Preparation of racemic santonin - Google Patents

Description

United 1 PREPARATION OF RACER lit: SANTONIN Yasuo Abe, Theda, Osaka, Tadats" tau, Kyoto, Hisashi Ishilrawa, Kobe, Talzuichi Milo, Amagasakl, Hyogo, Masao o mi, Iheda, ()saka, and Tadashi Togo, Ashiya, Hyogo, .fapan, assignors to Takecia Pharmaceutical industries, Ltd Higashi-ku, Osaka, Japan No Drawing. Application April 19, 1954 Selim No. 424,284

Claims priority, application Japan September 36 1953 6 Claims. (Cl. Zea-343s This invention relates to optically active and inactive stereoisomers of santonin.

The isomers have the common structure representable by the foltowing formula:

I I CH3 O Patented IE-lay T? ind The 4 racemates in the present invention are explained as follows:

(A) The optically inactive stereoisomeride consisting of equivalent amounts of ii id. it is design ted as racemic santonin C. a

(B) The optically inactive stereoisomeride consisting of equivalent amounts of ill and lid. It is designated as racemii santonin D.

(C) The optically inactive stereoisomeride consisting of equivalent amounts of H11 and Hid. It is designated as racemic oc-SflfllOHlH.

The iiy inactive stereoisorneride consisting of equivalent amounts of 1V1 and Did. It is designated as racemic ,B-santonin.

The 2 optically active isomers in the present invention are explained as follows:

(E) The optically active compound representable by the Formula Hid. it is designated as dextrorotatory ccsantonin'.

(F) The optically active compound representable by the Formula lVd. It is designated as dextrorotatory 18- santonin.

in general these compounds are almost insoluble in water, sparingly soluble in ether and petroleum, but they are soluble in a variety of hot organic solvents, such as methanol, ethanol, chloroform, ether, benzene, acetone and petroleum etc, and in aqueous solution of alkali.

These compounds as a whole show the absorption band characteristic of e,;3,[3-trisubstituted ot,fi-I1I1S8.tl1l2.td ketone in the ultra-violet region. They are effective as anthelmintic and in some of them the activity is almost equal to that of natural sautonin. Many of them are less toxic than natural santonin and some of them show half the toxicity of natural santonin.

By the action of sodium methylate in methanol all these compounds display the pink color characteristic of natural santonin, but the color reaction is rather weak in the case of santonin C or D.

Next, detailed explanations are made. on the individuals of the compounds.

(a) Racemic santonin C is recrystallized from methanol into colorless prisms, M. P. C. When subjected to dienone-phenol rearrangement by heating with 55% sulfuric acid at 50 C., it is converted into rac. u-desmotroposantonin, M. P. 198 C. The ultra violet spectrum of the compound has an absorption maximum at 247 my. (log 6 4.15) but it shows no such a characteristic shoulder in the vicinity of 270 ru as is seen in natural santonin.

(b) Racemic santonin D is recrystallized from methanol into colorless prisms, M. P. C. This compound has an absorption maximum at 245 m (10g 6 4.19)- When subjected to rearrangement with 55% sulfuric acid, it is converted into racemic B-desmotroposantonin, M. P. 232 C.

(c) Racemic a-santonin is recrystallized from methanol into colorless plates, M. P. 181 C. This compound has an absorption maximum at 241 m (log 4.28) and shows a shoulder in the vicinity of 270 m in accordance with those of natural santonin. The infra-red spectra of this compound also well accord with those of natural santonin. When subjected to clienone-phenol rearrangement by heating with 55% sulfuric acid at 50 C., it is converted into racemic a-desrnotroposantonin.

(d) Racemic S-santonin is recrystallized from methanol into colorless rhombic plates, M. P. 186 C. This compound has an absorption maximum at 242 m (log. e=4.19) and show a characteristic shoulder in the vicinity of 270 m n. The infra-red spectra of this compound well accord with those of natural santonin. Both the ccand B-santonins are racemates which correspond to natural 'a-santonin and natural fl-santonin, respectively. When spectra of this compound Well accordwith those of natural santonin. The specific rotatory power of this compound is [a] =+l68 (2% solution in alcohol) and it is the antipode of natural l-a-santonin. This compound is converted into d-a-desmotroposantorin through the dienone-phenol rearrangement.

(f) Dextrorotatory-fi-santonin or (+)-,8-santonin is recrystallized from methanol into colorless prisms, M. P.

215 C. The specific rotatory power of this compound is E J Q=+I37 (2% solution 'inchloroform) and it is the antipode of natural p-santonin. This compound is converted into d-fi-desmotroposantonin through the dienone-phenol rearrangement. e

'I 'he-methods'for manufacturing them are explained as follows: (a) Rac.-santonin C,-The l/iichaelcondensationof 3- keto'-4,9-dimethyl l,2,3,7,8,9-hexahydronapthalene vdiethylmethylmalonate in the presenceofsodium methylate gave rac.-diethyl (3-keto-4,9-dimethyl-1,2,3,5,6,7,8,9-octahydro-fi-naphthyl) -m ethyhnalonate, which, on alkaline hydrolysis (the free acid melts at 204 C. with decomposition) and subsequent decarboxylation, yielded a mixture of substituted propionic acids epimeric at C An isomer of v "racl-a-(3-keto-4,9-dimethyl-l,2,3,5,6,7,8,9-octahydro-' 6-napthyl)-pr opionic acid, M. P. 135 C. (designated as D-acid) was obtained by recrystallization from ethyl acetrite-petroleum. ether and subsequently from methanol- 'water. The mother liquors of the ethyl acetate-petroleum ether recrystallization were concentrated and the separating crystallinematerial was recrystallized from methanol-water to atford another. lSOlTEY'Of. the acid, M. 'P.

with

145 f C. (designated as C-acid). Bromination of C-acid gave the lactone of rad-a-('3-keto-2-bromo-4,9-dimethyl- S-hydroxy-1,2,3,5,,7,8,9-0ctahydro-6-naphthyl -propionic acid, M. P. 145 C. (dec.),.and this was dehydrobrominated vith boiling'collidine to rac.-santonin C, M. P. 180

(b Rac.-sqnt9nin D.-.-Rac.-santonin D was prepared from rac.-D-acid, M. R135? C., by the same procedure '.as describedon the;preceding experiment for rac.-santonin C via bromolactone D.(M..P. 143 C. dec.). This was recrystallized from "methanol to colorless prisms, M.P.190 C. g

(c) Racwfi-santoninf. To a solution of rac.-C- and -D- a'cidIin glacial acetic acid, selenium dioxide and a small amount of water was added and refluxed for 4 hours. 'The precipitating selenium was filtered off, and the filtrate was distilled ata reduced pressureIfIhe residue was ex- 'tracted with ether,'and theether extract was washed with sodium carbonate solution and water successively, and dried over anhydrous sodium sulfate. On evaporation of the ether, a crystalline material separated from the residue, which on recrystallization from methanol gave colorless prismsof rac.-;8-santonin, M. P. 186 C.

(d) Ram-oc-santofiinE-Ffom the mother liquor of rac.-

B-santonin, described in the preceding example, was obtained another crystalline product, viz., rac.-asantonin.

This was recrystallized from aqueous methanolas colorless rectangular plates, M; P. 181 C.

Resolution of this dienone-acid was effected via the brucine or quinone salt, and the laevo acid thus obtained was decarboxylated to an isomeric mixture of two optically active u-(3-l:eto-4,9-dimethyl-3,5,6,7,8,9-hexahydrov 6-naphthyl)-propionic acids epimeric at C This. material was boiled with selenium dixode in acetic acid for several hours. After precipitatingselenium was removed by filtration, and the solvent was evaporated to leave a crude mixture of 'diand d-p santonin.

When heated with methanolic potassium hydroxide,

the crude santonin isomers were changed to a mixture of the corresponding potassium-santoninates. The solution was acidified with hydrochloric acid, and d-u-santonin was obtained from the easily lactonizing part; as colorless rectangular plates, M. P. 172 C.

(7) d-e-Santonin 0r (+)-fl-sar zt0nin.The velocity of lactonization of d-jS-santoninic acid is slower than that of d-a-isomer. V

After d-a-santonin was removed in the manner described in Example 2, the acidified solution was warmed on the water bath affording d-p-santonin as colorless rhombic prisms, M. P. 215 C. a All melting points are uncorrected.

This invention also relates to a process for preparing racemic santonin D.

That is, hydrolysis of racemic a-(3 -keto-4,9-dimethyl- 1,2,3,5,6,7,8,9-octahydro-6-naphthyl)-propionic acid alkyl ester (V) prepared by the method given in Proceeding of the Japan Academy 28, 425 (1952) and J. Am. Chem. Soc. 75, 2567 (1953), gives anisorneric mixture, from which two isomers, racemic a-(3-keto-4,9-dimethyl-l,2,3,-

-5,6,7,8,9-octahydro-6-naphthyl)-propionic acid-A (VTa: designated as A-acid, M. P. 181 C.) and -B (VIb: desig-' nated as B-acid, M. .P. l20125 C), were crystallized. Exhaustive separation of the A and B acids leaves behind anacidic substance containinganother .acid, M. P. C. (Vldz' designated asv Dracid) and-halogenation of the substance by two moles of halogen or by the Wohl- Zieglers procedure for allyl halogenation with two moles of reagent yields racemic a-.(3-keto-4,9-dimethyl-2-halogeno-5-hydroxy-l,2,3,5, 6,7,8,9 octahydro 6 naphthyl)- propionic acid lactone (VII). v V a a As halogenating agent by the Wohl-Zieglers method are cited, for example, N-succinic imidobromide, N-phthalic' imidobromide, N-succinic imidochloride and N-phthalic.

imidochloride. v a

In the above mentioned halogenation of D-acidracemic a-(3-l eto-4,9-dimethyl-2,5-dihalogeno-l,2,3,5,6,7,8,9 octahydro-6-naphthyl)-propionic acid is isolated as an intermediate in some experiments, but treatment of this compound with a basic reagent such as carbonates of alkali and alkaline earth metal gives rise to the halogenolactone (VII) under splitting off the halogen at C with the hydrogen of the carboxyl atC as hydrogen halide.

0n the other hand, the C -halogeno-lactone (VII) is a also obtained by mono halogenation of D-acid (VId: M. P. 135 C.) to forma-(3-l;eto-4,9-dirnethyl-5-hydroxy- 1,2,3,5,6,7,8,9-octahydro-6-naphthyl)-propionic acid lactone. (VIII)'followed by halogenation at C Treatment of the halogenolactone (VII) with a basic reagent, for example, collidine, pyridine, piperidine, picoline, N,N-dialkylaniline, primary or secondary amine, silver oxide, carbonates and bicarbonates, of alkali and alkaline earth metal or neutral salts such as lithium chloride, magnesium chloride in dimethyl formamide, introduces a double bond between C and C producing the desired product, racemic santonin D. This product, M. P.

C., has absorption maximum at 245 na .(log

.C, 73.14; H, 7.37. p

The reactions in this invention are shown in the following scheme:

(V) OH:

(R=alkyl radical) O= (|]CH;

C O O R CH:

(V18) CH; (V (Vld) H O +CH: Y C O OH CCH3 I CH3 0-C 0 (VIII) (VII) CH;

i 0- 0-0 HI 0 E: C O (X =halogen) (IX) OH:

H O JCH:

a. at.

All melting points are uncorrected.

Example 1 Twenty-five grams of the mother liquors of rac.-A- and -B-acid (of. Proc. Japan Acad. 28, 425 (1952); I. Am. Chem. Soc. 75, 2567 (1953)), in 250 cc. of ether were agitated, and to this was gradually added a solution of 48 g. of bromine in 250 cc. of acetic acid at room temperature. The ether was removed under reduced pressure and the residue poured into a large quantity of water, extracted with ether, and the ether solution was Washed with water, sodium bicarbonate and water again. After being dried over sodium sulfate, the solution was concentrated to leave a small amount of ether. Filtration gave 0.7 g. of crystalline substance, which was recrystallized from methanol to afford the lactone of rac. lit-(3- keto-4,9-dimetl1yl-2-bromo-5-hydroxy-1,2,3,5,6,7,8,9-octahydro-6-naphtl1yl)-propionic acid (VII) as colorless plates, M. P. 180 C. dec.

A mixture of 0.7 g. of the above lactone and cc. of 'y-collidine was heated at 140-150 C. for an hour. The reaction mixture was cooled, taken up in ether, and the ether solution was washed with water, diluted sulfuric acid, water, sodium carbonate and Water by turns, dried and evaporated. The crystalline material was filtered and 6 recrystallized from methanol to furnish the lactone of rac. u-(3-keto-4,9-dimethyl-3,5,6,7,8,9-heXahydro-6-naphthyl) -propionic acid as prisms, M. P. 190 C., which was designated as rac.-santonin D (IX).

Example 2 To a suspended solution of 4 g. of rac.-D-acid in cc. of ether containing a few drops of hydrogen bromideacetic acid, was added dropwise a solution of 2.6 g. of bromine in 26 cc. of acetic acid. The solution was concentrated under reduced pressure and diluted with water. The separating solid was recrystallized from methanol to give 2.5 g. of the lactone of rac. a-(3-keto-4,9-dimethyl-5- hydroxy-l,2,3,5,6,7,8,9-octahydro-6-naphthyl) propionic acid D (VIII), M. P. 138 C.

A mixture of 2.5 g. of the lactone D (VIII) in 50 cc. of ether and 1.6 g. of bromine in 16 cc. of acetic acid was refluxed for 40 minutes on a water bath. After evaporating the ether, the residual solution was diluted to afford 1.0 g. of the lactone of rac. oc-(3-ii'.O-4,9dlmethyl-Z-bromo-S- hydroxy l,2,3,5,6,7,8,9 octahydro-- naphthyD-propionic acid D (VII) which was dehydrobrominated to rac.-santonin D (IX) in the same way as described in Example 1.

What is claimed is:

l. A method for the manufacture of a racemic santonin having a melting point of C. (uncorr.), which comprises subjecting the lactone of racemic u-(3-keto-4,9-dimethyl-Z-halogeno-S-hydroxyl ,2,3 ,5 ,6,7,8 ,9 octahydro-6- naphthyD-propionic acid to the action of a dehydrohalogenating agent selected from the group consisting of bases of the pyridine series and metal halides, whereby the 2- positioned halogen is split ofl and a double bond is formed between C and C 2. A method for the manufacture of a racemic santonin having a melting point of 190 C. (uncorr.), which coinprises subjecting racernic ix-(3-keto-4,9-dimethyl-1,2,35,- 6,7,8,9-octahydro-6-naphthyl)-propionic acid to the action of two equivalents of free halogen whereby the halogen is introduced at each of the 2- and 5-positions, and subjecting the product to the action of a dehydrohalogenating agent selected from the group consisting of bases of the pyridine series and metal halides whereby the halogen at C and the hydrogen of the carboxyl radical at C split off as hydrogen halide forming a lactone ring, and the halogen is split off at C forming a double bond between C and C 3. A method for the manufacture of a racemic santonin having a melting point of 190 C. (uncorr.), which comprises subjecting racemic x(3-keto-4,9-dimethyl-l,2,3,5,- 6,7,8,9-octahydro-6-naphthyl)-propionic acid to the action of one equivalent of free halogen whereby the halogen is introduced at the 5-position, subjecting the product to the action of a dehydrohalogenating agent selected from the group consisting of bases of the pyridine series and metal halides whereby the halogen at C and the hydrogen of the carboxyl radical at C split off as hydrogen halide forming a lactone ring, subjecting the product to the action or" one equivalent of free halogen whereby the halogen is introduced at C and subjecting the product to the action of a dehydrohalogenating agent selected from the group consisting of bases of the pyridine series and metal halides whereby the halogen at C is split ott and a double bond is formed between C and C 4. A process according to claim 1, wherein the dehydrohalogenating agent is 'y-collidine.

5. A process according to claim 2, wherein the halogen is bromine and the dehydrohalogenating agent is y-collidine.

6. A process according to claim 3, wherein the halogen is bromine and the dehydrohalogenating agent is 'y-collidine.

(References on following page) 7 f References Cited in the file of this patent Clemo et al.: J. Chem. Soc.', 1952, page.3 843.. Paranjape et al.: Current Science, v91. 12, pages 150- 151 1943).

Abe et al.: Chem. Abst vol. 48, page 1317 (1954), citing Proc. Jap. Acad., v01. 28, pages 425-8 (1952).

Abe et al.: Chem. Abst., vol. 48, pages 10706-10707 (1954), citing Proc. Jap. Acad;, vo1. 29, pages 113-114 Jap., v01. 72, pages 1339- 1342 (1952); r

Barnett: Stereochenfistry(l950), pages 3 to 26 '(Pitman and Sons, Ltd., London).

Fieser and'Fieser: OrganicChemistry (2d ed., 1950), pages 246-277. V

'Karrerz- Organic Chemistry (3rd., 1947), pp. 95-105.

Cohen: Organic Chemistry, part II (4th ed., .1923),

pages 194-9 (Longmans, Green and Co., London); Clemo et al.: Journ. Chem. See, 1934, pages 1343 -6.

Gunstone et al.: Journ. Chem. Soc, 1952, pages 1354- i J. A. C. S. 7 5, pages 2567-2571, June 5,

Claims (2)

1. 2. A METHOD FOR THE MANUFACTURE OF A RACEMIC SANTONIN HAVING A MELTING POINT OF 190*C. (UNCORR.), WHICH COMPRISES SUBJECTING RACEMIC A-(3-KETO-4,9-DIMETHYL-1,2,3,5,6,7,9-OCTAHYDRO-6-NAPHTHYL)-PROPIONIC ACID TO THE ACTION OF TWO EQUIVALENTS OF FREE HALOGEN WHEREBY THE HALOGEN IS INTRODUCED AT EACH OF THE 2- AND 5-POSITIONS, AND SUBJECTING THE PROCUCT TO THE ACTION OF A DEHYDROHALOGENATING AGENT SELECTED FROM THE GROUP CONSISTING OF BASES OF THE PYRIDINE SERIES AND METAL HALIDES WHEREBY THE HALOGEN AT C5 AND THE HYDROGEN OF THE CARBOXYL RADICAL AT C11 SPLIT OFF AS HYDROGEN HALIDE FORMING A LACTONE RING, AND THE HALOGEN IS SPLIT OFF AT C2 FORMING A DOUBLE BOND BETWEEN C1 AND C2,
2. 3. A METHOD FOR THE MANUFACTURE OF A REACEMIC SANTONIN HAVING A MELTING POINT OF 190*C. (UNCORR.), WHICH COMPRISES SUBJECTING RACEMIC A-(3-KETO-4,9-DIMETHYL-1,2,3,5,6,7,8,9-OCTAHYDRO-6-NAPHTHYL)-PROPIONIC ACID TO THE ACTION OF ONE EQUIVALENT OF FREE HALOGEN WHEREBY THE HALOGEN IS INTRODUCED AT THE 5-POSTION, SUBJECTING THE PRODUCT TO THE ACTION OF A DEHYDROHALOGENATING AGENT SELECTED FROM THE GROUP CONSISTING OF BASES OF THE PYRIDINE SERIES AND METAL HALIDES WHEREBY THE HALOGEN AT C5 AND THE HYDROGEN OF THE CARBOXYL RADICAL AT C11 SPLIT OFF AS HYDROGEN HALIDE FORMING A LACTONE RING, SUBJECTING THE PORDUCT TO THE ACTION OF ONE EQUIVALENT OF FREE HALOGEN WHEREBY THE HALOGEN IS INTRODUCED AT C2, AND SUBJECTING THE PRODUCT TO THE ACTION OF A DEHYDROHALOGENATING AGENT SELECTED FROM THE GROUP CONSISTING OF BASES OF THE PYRIDINE SERIES AND METAL HALIDES WHEREBY THE HALOGEN AT C2 IS SPLIT OFF AND A DOUBLE BOND IS FORMED BETWEEN C1 AND C2.