THE ALKALOID OF CHIN-SHIH-HU

THE

ALKALOID

BY K. K. CHEN (From

the Lilly

OF CHIN-SHIH-HU AND

A. LING

Research Laboratories,

(Received for publication,

CHEN Indianapolis)

July 25, 1935)

1 We are indebted to Mr. E. J. Hughes for his assistance in the alkaloidal assay of our specimen. 653

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Chin-shih-hu is a Chinese medicinal herb and has been extolled chiefly as a tonic and antipyretic (1). The specimens obtained from the Chinese wholesale drug housesconsist of the dried stems only, the roots, leaves, and flowers having been eliminated. The plant grows among rocks in the mountainous regions of southwestern China, and blooms during the summer months. Occasionally, it is cultivated for ornamental purposes. The botanical identification of chin-shih-hu, as with many other Chinese drugs, is still in question. According to Stuart (2), it is Dendrobium nobile, family of Orchidaceae, but in “Botanical nomenclature” (3), it is classified as Dendrobium moniliforme. It is certain, however, that chin-shih-hu comprises a group of several species, as will be shown below. Scientific work on this traditional drug was initiated by Suzuki, Keimatsu, and Ito (4-6) who isolated a new alkaloid named dendrobine, m.p. 134’. They presented evidence that the principle is a tertiary base having a methyl group and a la&one ring. During the past 3 years we have had an opportunity to study the Szechuan variety of chin-shih-hu, purchased in Shanghai. The dried stems, golden yellow in color, and approximately 26 cm. in length, are tied in small bundles. As viewed after cutting, they are solid in structure. There are nodes at definite intervals. The internodes near the tip measure on the average 2.3 cm., and those near the root 3.6 cm. By the usual method of extraction, the presence of alkaloids was clearly demonstrated. The sample showed a content of 0.52 per cent total alkaloids when assayed according to the U.S.P. procedure for belladonna leaves’ (7).

654

Chin-Shih-Hu

EXPERIMENTAL

A quantity of 25 kilos of the powdered drug was percolated with methanol until exhausted. The percolate was distilled under diminished pressure to a syrup, then diluted with 2.5 per cent hydrochloric acid, strained through cheese-cloth, and filtered. The acid solution was concentrat,ed to one-half its volume under a vacuum, and treated with 10 per cent sodium hydroxide until it


The alkaloid dendrobine can be easily isolated in crystalline form by the method to be described in a later section. Our process utilizing sodium hydroxide and isopropyl alcohol appears to give better yields than that of Suzuki, Keimatsu, and Ito (4). The results of combustion analyses and molecular weight determinations suggest the empirical formula C~H2602N, which completely agrees with the revised formula of the Japanese workers (6). A series of eleven salts and derivatives, seven of which are new, has been prepared, and their analytical data, wherever available, also support the validity of the proposed formula. Incidentally, the melting points of the hydrochloride, hydriodide, and methiodide are much higher than those reported by Suzuki and Keimatsu (5). The pharmacological action of dendrobine will be reportedelsewhere. It suffices here to say that the alkaloid has a slight antipyretic action in rabbits, and, in moderate doses, a depressor action in etherized cats. It inhibits isolated rabbit intestine but contracts isolated guinea pig uterus. The minimal lethal dose of dendrobine hydrochloride by intravenous injection has been determined to be 20 mg. per kilo in mice and rats, 22 in guinea pigs, and 17 in rabbits. In the course of our work, a sample of the Kweichow variety of chin-shih-hu was made available to us. These stems were longer than those of the Saechuan variety, the average length being 36.6 cm.; otherwise their appearance was almost the same. By the application of our method, however, we failed to isolate any dendrobine, although we obtained evidence of the presence of a different alkaloid. Owing to the small amount existing in the plant, this latter alkaloid has not been separated in pure form. This substantiates our contention that the chin-shih-hu of commerce consists of several species. Suzuki, Keimatsu, and Ito (4, 8) had a similar experience with their various samples.

K. K. Chen and A. L. Chen

655

AnaZysis~-C~~H~a0~N Calculated. Found.

C 72.95, H 9.57, N 5.32, mol. wt. 263 “ 73.10, “ 9.57, “ 5.51, “ “ 250 “ 72.92, “ 9.60, “ 5.47, “ “ 254

Dendrobine hydrochloride, C1,jH2502NfHCI, was prepared by dissolving the alkaloid in alcohol and adding to it an excess of 5 per cent hydrochloric acid. The whole was evaporated to dryness under a fan, and the residue was dissolved in isopropyl altiohol. When this solution was chilled in an ice mixture and ether was added, the hydrochloride crystallized out at once. The salt forms colorless,fine thin plates, melts sharply at 193” (corrected), and has a specific rotation of [cr]:’ = - 40.3” in water. If it is contaminated with a slight impurity, there will be no definite melting point but a decomposition point above 240’. This is probably what Suzuki and Keimatsu obtained. The hydrochloride is very soluble * All the analyses and molecular weight determinations (Rast) reported in this paper were made by Dr. Ing. A. Schoeller, Berlin-Schmargendorf, Germany.


became distinctly alkaline. The whole was repeatedly extracted with a chloroform-ether mixture in the proportion of 4 : 1. Upon evaporation to almost dryness, the residue was stirred vigorously with a small volume of isopropyl alcohol and quickly filtered by suction. This removed a great portion of the impurity. The semicrystalline mass was dissolved in hot isopropyl alcohol and decolorized with charcoal. When the solution was chilled in an ice mixture, dendrobine crystallized out in colorless prisms. Purification was effected by recrystallizing several times from the same solvent. A total of 47.8 gm. of the alkaloid with a sharp melting point was obtained. Dendrobine melts at 136” (corrected) and has a specific rotation of [cy]? = -52” in alcohol. It sublimes gradually above 50”. It is soluble in ether, acetone, chloroform, methyl, ethyl, and isopropyl alcohols, but is insoluble in water. It forms heavy precipitates with Mayer’s and Wagner’s reagents, and produces with phosphotungstic acid a milky turbidity, which soon disappears but reappears u,pon standing. It gives no color reactions with concentrated mineral acids in the cold. From the following data, the empirical formula GeH2602N is proposed.

656 in water insoluble

Chin-Shih-Hu and alcohol in ether.

but less soluble

Analysis-CleHzsOtN .HCl Calculated, Cl 11.83;

found,

in isopropyl

Cl 11.40,

alcohol,

and

11.36

Analysis-C,,H,sOzN

.HI Calculated,

I 32.17;

found,

I 32.18,

32.22

Dendrobine nitrate, ClaH2602N. HNOa, was prepared in a similar manner to the hydrochloride, and recrystallized from absolute ethyl alcohol upon the addition of ether. It forms polygonal prisms, melts at 198.5-199” (corrected), and has a specific rotation of [(Y]:‘.~ = -30.2” in water. It is soluble in water, alcohol, and acetone. Dendrobine sulfate, (C16H2502N)2 .HzSOd, was formed by suspending the alkaloid in water and adding 10 per cent sulfuric acid until the particles were dissolved and the solution became acid to litmus. After evaporation to dryness under a fan the residue was taken up in hot acetone. The sulfate crystallized out on standing in a refrigerator. It forms large prisms, melts at 178” (corrected), and has a specific rotation of [cy] iE = -36.7” in water. It is soluble in water and alcohol, but insoluble in ether. Dendrobine oxalate, (C16H2602N)2. CzH,04, was made by dissolving the alkaloid in a small volume of alcohol and adding a 10 per cent solution of oxalic acid until acid to litmus. After evaporation to dryness under a fan, the mass was dissolved in hot acetone and chilled in a refrigerator. Well formed needles appeared at once after the addition of a few drops of water. The oxalate melts at


Dendrobine hydrobromide, C&H&2N. HBr, was made in the same manner as the hydrochloride, except that the purification and recrystallization were carried out in an ethyl alcohol-ether mixture. This salt forms large prisms, melts at 259-259.5” (corrected), and has a specific rotation of [a] i” = - 34.3” in water. It is soluble in water and alcohol but insoluble in ether. Dendrobine hydriodide, CLHzsOzN. HI, was prepared by the same method as the hydrobromide. It crystallizes in needles, melts at 284-284.5” (corrected), and has a specific rotation of [a] i” = -29” in water. It is soluble in water, less soluble in alcohol, and insoluble in ether.

K. K. Chen and A. L. Chen

Analysis-ClsHzsOzN

. CHJ Calculated,

I 31.33;

found,

I 31.15

Dendrobine uurichtoride, C16H2r,02N. HAuCL, was easily prepared by dissolving a sufficient amount of the alkaloid in dilute hydrochloric acid and adding to it a solution of chloroauric acid. A precipitate was at once formed. The product was purified and Dendrobine aurichloride forms recrystallized in dilute alcohol. golden rosettes, melts at 183-184” (corrected), and is more soluble in alcohol than in water. AnaZysis-C,sH2~0~N

.HAuCld Calculated, Au 32.70;

3 We are indebted to Dr. paring dendrobine methiodide,

found,

A. M. VanArendonk aurichloride, and

Au 32.91 for his assistance platinichloride.

in pre-


137-138” (corrected) and has a specific rotation of [a]$?,5 = - 50.8” in alcohol. It is soluble in alcohol, acetone, and ether, but insoluble in water. Dendrobine picrate, G6HZ602N. CsH307N3, was prepared by dissolving the alkaloid in alcohol and acidifying the solution with picric acid. Upon the addition of ether the salt was promptly precipitated out. It was purified and recrystallized from a mixture of isopropyl and ethyl alcohols. The picrate forms yellow prisms and melts at 210” (corrected) with decomposition. It is soluble in chloroform and acetone, but less soluble in ethyl and isopropyl alcohols, ether, and water. Dendrobine jlavianate, C16H2602N. CloHsOsN&, was obtained in the same manner as the picrate. It crystallizes in yellow rosettes of feathery needles, decomposes at 212’ (corrected), and is soluble in alcohol, acetone, and chloroform. Dendrobine methiodide,3 C&H2502N. CH& was prepared by dissolving the base in methyl alcohol and adding to it methyl iodide. The whole was refluxed for 23 hours. Upon evaporation, yellowish orange needles were formed. It was purified in a mixture of butyl alcohol and ether. Dendrobine methiodide crystallizes in fine rosettes, melts at 246’ (corrected), and has a specific rotation of [a] F = -28.8” in alcohol. It is soluble in ethyl, isopropyl, and butyl alcohols and water, but slightly soluble in ether. The compound apparently decomposes in solution upon standing.

658

Chin-Shih-Hu

Dendrobine plutinichloride, (C1eH2602N)2. HzPtCls, was formed by the interaction of the base with chloroplatinic acid in alcohol. After chilling, the mass was filtered, and purified from hot water. The platinichloride crystallizes in fine, orange-colored clusters, melts at 283” (corrected), and is relatively more soluble in water than in alcohol. Calculated,

Pt 20.34; found Pt 20.96, 21.16

The Szechuan variety of the Chinese drug chin-shih-hu contains an average of 0.52 per cent total alkaloids. A method has been described for the isolation and crystallization of the alkaloid, dendrobine, C&H2602N. A series of eleven salts and derivatives has been prepared and characterized-the hydrochloride, the hydrobromide, the hydriodide, the nitrate, the sulfate, the oxalate, the picrate, the flavianate, the methiodide, the aurichloride, and the platinichloride. The Kweichow variety of chin-shih-hu yields no dendrobine. BIBLIOGRAPHY

1. 2. 3. 4. 5. 6. 7. 8.

Li, S. C., Pentsao Kang Mu, chap. 20 (1596). Stuart, G. A., Chinese materia medica, Shanghai, 147 (1911). Botanical nomenclature, Shanghai, 330 (1917). Suzuki, H., Keimatsu, I., and Ito, M., J. Phurm. Sot. Japan, 62, 162 (abst., German), 996 (orig., Japanese) (1932). Suzuki, H., and Keimatsu, I., J. Pharm. Sot. Japan, 62, 133 (abst., German), 1049 (orig., Japanese) (1932). Suzuki, H., Keimatsu, I., and Ito, M., J. Pharm. Sot. Japan, 64, 138 (abst., German), 302 (orig., Japanese) (1934). The pharmacopmia of the United States of America, tenth decennial revision, Philadelphia, 74 (1926). Suzuki, H., Keimatsu, I., and Ito, M., J. Pharm. Sot. Japan, 64, 146 (abst., German), 996 (orig., Japanese) (1934).


SUMMARY

THE ALKALOID OF CHIN-SHIH-HU K. K. Chen and A. Ling Chen J. Biol. Chem. 1935, 111:653-658.

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THE ALKALOID OF CHIN-SHIH-HU

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