CN100341850C - Salts of demethyl phencynonate isomer and N-para-methyl-phenyl-sulfuryl glutamic acid optical isomer and their preparing method and use - Google Patents
Salts of demethyl phencynonate isomer and N-para-methyl-phenyl-sulfuryl glutamic acid optical isomer and their preparing method and use Download PDFInfo
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Abstract
The present invention relates to salt (-) III. (+) IV or (+) III. (-) IV and a preparation method thereof. The salt is formed by demethyl benzene ring pelargonic ester (2'-phenyl-2'-cyclopentyl-2'-glycolic acid-9 alpha-(3-azabicyclo (3, 3, 1) dinonyl) ester) optical isomers and chiral acid. The salt is a key intermediate for preparing benzene ring pelargonic ester (2'-phenyl-2'-cyclopentyl-2'-glycolic acid-9 alpha-(N-methyl-3-azabicyclo (3, 3, 1) dinonyl) ester) optical isomers. The optical purity of the obtained benzene ring pelargonic ester optical isomers is higher than 98%.
Description
Technical field
The present invention relates to optically pure demethyl benzene ring pelargonate (2 '-phenyl-2 '-cyclopentyl-2 '-oxyacetic acid-9 α-[3-azabicyclo (3,3,1) ninth of the ten Heavenly Stems] ester) optical isomer and N-salt that the Methyl benzenesulfonyl glutamic acid optical isomer is formed and preparation method thereof, described salt be the preparation benzene ring pelargonate (2 '-phenyl-2 '-cyclopentyl-2 '-oxyacetic acid-9 α-[N-methyl-3-azabicyclo (3,3,1) ninth of the ten Heavenly Stems] ester) key intermediate of optical isomer.
Background technology
Phencynonate hydrocloride (phencynonate hydrocloride, 2 '-cyclopentyl-2 '-phenyl-2 '-oxyacetic acid-9 α-[N-methyl-3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] ester hydrochloride, its structure is as shown in the formula shown in the I)
Be a kind of selectivity anticholinergic agent, the clinical control various motion sicknesses such as carsick, seasick that are used for.CN1089838A and US6028198 disclose the purposes of phencynonate hydrocloride as anti-motion sickness (carsickness, ship, machine etc.) medicine; CN97125424.9, GB2297255 and ES549796A disclose the preparation method of phencynonate hydrocloride; WO02067933 disclose phencynonate hydrocloride treatment Parkinson's disease/syndromic purposes with and treatment or alleviate the purposes of vertigo acute attacks such as Meniere and positional vertigo.
In the molecular structure of phencynonate hydrocloride, contain the chiral carbon atom that α-phenyl-α-cyclopentyl-Alpha-hydroxy replaces, so have a pair of optical isomer, clinical application at present be its raceme form.Preliminary study shows, left-handed benzene ring pelargonate is the active isomer of cholinolytic effect, than high about two orders of magnitude of dextrorotatory form, trembling that the anti-methylarecaidin of left-handed benzene ring pelargonate causes is stronger respectively 18 times and 21 times than dextrorotatory form with secretion to rat brain m receptor avidity for levo form.
Split Method is to prepare the most frequently used method of chiral drug optical isomer.Its ultimate principle is, with racemic modification to be split and specific optical activity reagent effect, form the salt of diastereomer, utilize the dissolubility difference of the salt of two kinds of diastereomers then, method by recrystallization is separated, and obtains the single enantiomer of optical purity.
Benzene ring pelargonate is a basic cpd, therefore can split its optical isomer of preparation with chiral acid such as tartrate, amygdalic acid etc.But discover, uncle's N structure alkalescence of benzene ring pelargonate a little less than, be difficult to and acid resolution reagent salify.And take preparation demethyl benzene ring pelargonate earlier, and making it and the resolution reagent salify, methylating after the fractionation obtains the optical isomer of corresponding benzene ring pelargonate again, and then effect is better.Applicant's a Chinese patent application 200410029596.4 relates to demethyl benzene ring pelargonate and its production and use, but does not wherein relate to optically active demethyl benzene ring pelargonate and preparation method thereof.
Therefore, need the effective preparation approach of searching as the demethyl phencynonate optical isomer of the key intermediate of synthetic phencynonate optical isomer.
Summary of the invention
The purpose of this invention is to provide raw material and be easy to get, the key intermediate that relates in the method for reaction conditions gentleness, synthetic demethyl phencynonate optical isomer that stereoselectivity is high and this method.
The applicant is through discovering repeatedly, and conventional tartrate, amygdalic acid etc. all can not effectively split the demethyl benzene ring pelargonate, uses the preferred N-of chiral acid amino acid then can split the demethyl benzene ring pelargonate effectively to Methyl benzenesulfonyl L-glutamic acid.Therefore, form demethyl phencynonate optical isomer and N-the salt of Methyl benzenesulfonyl glutamic acid optical isomer is become key step in the demethyl benzene ring pelargonate mesotomy process.
Therefore, one aspect of the present invention relates to preparation optically pure demethyl phencynonate optical isomer and the N-method to the salt of Methyl benzenesulfonyl glutamic acid optical isomer.
Another aspect of the present invention relates to the salt that optically pure demethyl phencynonate optical isomer and N-form the Methyl benzenesulfonyl glutamic acid optical isomer, and they can be represented by following formula (-) III (+) IV and (+) III (-) IV:
Of the present inventionly relate in one aspect to salt that above-mentioned optically pure demethyl phencynonate optical isomer and N-form the Methyl benzenesulfonyl glutamic acid optical isomer is used to prepare phencynonate optical isomer as intermediate purposes again.
According to the present invention, above-mentioned formula (-) III (+) IV and (+) III (-) IV salt can obtain by following synthetic route:
At benzene; toluene; in the hexanaphthene equal solvent; under 70-100 ℃; make 2; 2; 2-trichlorine methylamino ethoxy acyl chlorides heated 4-8 hour with the mixture of benzene ring pelargonate raceme; the back adds the Zn powder; slough 2; 2; 2-trichlorine methylamino ethoxy acyl chlorides; obtain demethyl benzene ring pelargonate (III), make the single enantiomer salify of demethyl benzene ring pelargonate (III) and N-p-toluenesulfonyl L-glutamic acid, filter; collecting precipitation; to precipitate and use methyl alcohol; ethanol; Virahols etc. are solvent recrystallization (3～5 times) repeatedly under 50～80 ℃, simultaneously mother liquor are recycled, and obtain optically pure demethyl phencynonate optical isomer and N-salt (-) III (+) IV and (+) III (-) IV to the Methyl benzenesulfonyl glutamic acid optical isomer respectively.
After formula (-) III (+) IV that obtains and (+) III (-) IV salt alkalize respectively with 5～10% KOH or NaOH solution, obtain the individual isomer (IIIa/IIIb) of optically pure N-demethyl benzene ring pelargonate, the latter can obtain optically pure benzene ring pelargonate enantiomer (Ia/Ib) through methylation reaction again.
The reaction scheme that above-mentioned preparation formula (-) III (+) IV and (+) III (-) IV salt also further obtain optically pure benzene ring pelargonate enantiomer can be illustrated as follows:
The chiral acid N-that uses in the said synthesis route can be made by optically active L-glutamic acid (biochemical reagents are available from Beijing chemical reagents corporation) and Tosyl chloride reaction the optical isomer of Methyl benzenesulfonyl L-glutamic acid.
Specifically, optically pure demethyl phencynonate optical isomer and N-may further comprise the steps salt (-) III (+) IV of Methyl benzenesulfonyl glutamic acid optical isomer and the preparation method of (+) III (-) IV:
(a) adopt 2,2,2-trichlorine methylamino ethoxy acyl chlorides and Zn powder make the raceme of benzene ring pelargonate slough the n-formyl sarcolysine base, obtain the demethyl benzene ring pelargonate;
(b) make demethyl benzene ring pelargonate that step (a) obtains and wherein a kind of single enantiomer salify of N-p-toluenesulfonyl L-glutamic acid, filter collecting precipitation, behind the recrystallization, obtain demethyl phencynonate optical isomer and N-salt (-) III (+) IV or (+) III (-) IV repeatedly to the Methyl benzenesulfonyl glutamic acid optical isomer;
(c) with the mother liquor evaporate to dryness after filtering in the step (b), corresponding (+)-demethyl phencynonate optical isomer or (-)-demethyl phencynonate optical isomer of obtaining in alkalization back;
(d) (+)-demethyl benzene ring pelargonate that step (c) is obtained or (-) demethyl benzene ring pelargonate again with the another kind of single enantiomer salify of N-p-toluenesulfonyl L-glutamic acid, then corresponding salt (+) III (-) IV or (-) III (+) IV that obtains demethyl phencynonate optical isomer and N-to the Methyl benzenesulfonyl glutamic acid optical isomer.
Further, after (-) III (+) IV of obtaining or (+) III (-) IV carried out alkalinisation treatment respectively, the corresponding single enantiomer that obtains optically pure N-demethyl benzene ring pelargonate, and then can obtain corresponding phencynonate optical isomer, and the optical purity of thus obtained phencynonate optical isomer is greater than 98%.
Embodiment
Specify the present invention with embodiment below, these embodiment should not be construed as the limitation of the present invention that goes up in all senses.
Embodiment 12 '-cyclopentyl-2 '-phenyl-2 '-oxyacetic acid-9 α-[N-(2,2,2-trichlorine ethoxy acetyl)-3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] ester (II) synthetic
With 10g (25mmol) 2 '-cyclopentyl-2 '-phenyl-2 '-oxyacetic acid-9 α-[3-methyl-3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] ester hydrochloride (I) is added in the 80mL ether, the dropping ammonia alkalization, make I change into free alkali and be dissolved in the ether, washing, dry back pressure reducing and steaming ether; In residue, add anhydrous 20mL benzene, evaporated under reduced pressure; Triplicate.At last free alkali is dissolved in the 30mL dry-out benzene, in this solution, adds 8.3g 2,2,2-trichlorine methylamino ethoxy acyl chlorides adds Anhydrous potassium carbonate 300mg again in the solution of 20mL benzene, and stirring heating is 5 hours in 85 ℃ of oil baths, cooling back elimination solid is with the filtrate decompression evaporate to dryness.With ether 40mL dissolution residual substance, use weak ammonia and water washing successively, after the Anhydrous potassium carbonate drying, the pressure reducing and steaming solvent gets the sticking jelly formula II compound of the little yellow transparent of 12.2g, yield 94%.Ultimate analysis: C
24H
30NO
5Cl
3: theoretical value %:C 55.56, and H 5.83, and N 2.70; Experimental value %:C 54.62, H 5.86, and N 2.73.Mass spectrum (FAB) m/z (%) 518 (M
+-1,14.67), 317 (18.00), 175 (100.00).
Embodiment 22 '-cyclopentyl-2 '-phenyl-2 '-oxyacetic acid-9-[3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] preparation of ester (III)
11g (21mmol) formula II compound is dissolved among the ethyl acetate 30mL, adds the acetic acid solution of 25mL90%, add the 7g zinc powder several times under stirring, keep 50 ℃ of temperature; After adding zinc powder, in 40 ℃ of stirred in water bath heating 2 hours.Add the 90%25mL acetic acid solution again, the 5g zinc powder.In 50 ℃ of stirred in water bath heating 12 hours.Silica gel thin-layer detects, and reacts complete substantially.The elimination solid is used washing with alcohol.Merging filtrate, evaporated under reduced pressure adds ether 150mL, with the alkalization of 5% sodium hydroxide solution, makes free alkali be dissolved in ether.Tell the ether layer, wash with water to neutrality, behind anhydrous magnesium sulfate drying, the pressure reducing and steaming solvent gets little yellow solid, uses recrystallizing methanol, gets 5.3g colourless crystallization formula III compound, yield 73%, fusing point 124-126 ℃.Ultimate analysis C
21H
29NO
3, theoretical value %:C 73.44, and H 8.51, and N 4.08; Experimental value %:C 73.49H 8.66, N 3.96.
1H-NMR：δ(ppm，CD
3Cl)，7.70(m，2H)，7.31(m，3H)，4.63(s，1H)，3.86(s，1H)，2.96-3.19(m，5H)，2.16(m，1H)，2.00(m，1H)，1.90(s，1H)，1.32-1.69(m，14H)。
Embodiment 3 L-(+)-N-are to the preparation of Methyl benzenesulfonyl L-glutamic acid [(+) IV]
14.7g (0.1mol) L-(+)-L-glutamic acid is dissolved among the sodium hydroxide 100m of 2N, about 70 ℃ with heating in water bath, adds p-methyl benzene sulfonic chloride 22.8g (0.12mol) more than half an hour approximately under stirring in batches.Constantly dropping sodium solution keeps pH 〉=9, keeps 70 ℃ of reactions of temperature to stir one hour.Be cooled to room temperature, cryosel is bathed and to be cooled to below 0 ℃, drips concentrated hydrochloric acid to the pH=3.Divide three extractions with the 300ml ethyl acetate, extraction liquid merges, reflux, and activated carbon decolorizing filters.The Calcium Chloride Powder Anhydrous drying is filtered, and washs siccative with anhydrous ethyl acetate.Concentrated solution is to 80ml, and crystallization is separated out in the cryosel cooling, obtains 27.7g (+) IV compound, yield 92%.[α]
D 20=+22.6 ° (room temperature, ethyl acetate, c=1.10), fusing point: 130-132 ℃.
Embodiment 4 D-(-)-N-are to the preparation of Methyl benzenesulfonyl L-glutamic acid [(-) IV]
With reference to the method for embodiment 3, obtain (-) IV compound by D-(-)-L-glutamic acid and p-methyl benzene sulfonic chloride reaction.[α]
D 20=-22.5 ° (room temperature, ethyl acetate, c=1.20), fusing point: 130-132 ℃.
Embodiment 5 (-)-2 '-cyclopentyl-2 '-phenyl-2 '-oxyacetic acid-9-[3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] preparation of ester (IIIa)
With 6.8g (0.02mol) 2 '-cyclopentyl-2 '-phenyl-2 '-oxyacetic acid-9-[3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] ester (III) raceme compound dissolution is in 200mL50 ℃ of dehydrated alcohol, the dehydrated alcohol ((+) IV) that drips 6.0g (0.02mol) (+)-N-p-toluenesulfonyl L-glutamic acid is solution (50mL).After dropwising, reaction solution is chilled to room temperature, and placement is spent the night.Filter, collecting precipitation, its be (-)-2 '-cyclopentyl-2 '-phenyl-2 '-oxyacetic acid-9-[3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] ester (+)-N-is to Methyl benzenesulfonyl base glutaminate (-) III (+) IV.The salt of gained is stablized until optical value with ethyl alcohol recrystallization (10mL/g), repeated recrystallization step.
Gained salt is placed the 180mL anhydrous diethyl ether, add the alkalization of 5% potassium hydroxide solution, separate ether layer, washing, the dried recovered ether, obtain (-)-2 '-cyclopentyl-2 '-phenyl-2 '-oxyacetic acid-9-[3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] ester (IIIa) 1.7g, the rate of recovery 50%.[α]
D 20=-13.8 ° (room temperature, ethanol, c=0.4), fusing point: 138-139 ℃.
Embodiment 6 (+)-2 '-cyclopentyl-2 '-phenyl-2 '-oxyacetic acid-9-[3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] preparation of ester (IIIb)
With preparation (-)-2 among the embodiment 5 '-cyclopentyl-2 '-phenyl-2 '-oxyacetic acid-9-[3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] ester (+)-N-mother liquor evaporate to dryness that Methyl benzenesulfonyl base glutaminate (-) III (+) IV is obtained; with obtain after the 5% potassium hydroxide solution alkalization crude product (+)-2 '-cyclopentyl-2 '-phenyl-2 '-oxyacetic acid-9-[3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] ester; use (-)-N-p-toluenesulfonyl L-glutamic acid ((-) IV) for preparing as embodiment 4 as resolution reagent again; method according to embodiment 5; obtain (+)-2 '-cyclopentyl-2 '-phenyl-2 '-oxyacetic acid-9-[3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] ester (-)-N-is to Methyl benzenesulfonyl base glutaminate (+) III (-) IV; after repeated recrystallization step value to optical value is stablized; alkalization and separate obtain optically pure (+)-2 '-cyclopentyl-2 '-phenyl-2 '-oxyacetic acid-9-[3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] ester (IIIb) 1.9g, the rate of recovery 55%.[α]
D 20=+13.5 ° (room temperature, ethanol, c=0.4), fusing point: 138-139 ℃.
The preparation of embodiment 7 (-)-2 '-cyclopentyl-2 '-phenyl-2 '-oxyacetic acid-9 α-[3-methyl-3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] ester hydrochloride (Ia)
With 0.97g (2.8mmol) (-)-2 '-cyclopentyl-2 '-phenyl-2 '-oxyacetic acid-9-[3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] ester (IIIa) is dissolved in the 30mL dehydrated alcohol mixing solutions with the 8mL anhydrous diethyl ether, add 0.2mL (3.2mmol) methyl iodide and 1g Anhydrous potassium carbonate, after the stirring at room 3 hours, append the 0.5mL methyl iodide, continue to stir 12 hours, filter, filtrate decompression reclaims solvent, ether dissolution residue, washing and drying, reclaim solvent and obtain colourless viscous liquid, add 5mL 2N hydrochloric acid soln and make it salify, ice bath left standstill 3 hours, obtain formula Ia compound, output 0.98g, productive rate 89%, fusing point: 209-210 ℃.[α]
D 20=-12.1 ° of (room temperature, CHCl
3, c=0.3).
1H-NMR：δ(ppm，CD
3Cl)，10.99(s，1H)，7.64(m，2H)，7.35(m，3H)，4.98(s，1H)，3.75(m，2H)，2.98-3.02(m，4H)，2.88(s，3H)，2.28(s，1H)，2.07(s，1H)，1.94(m，2H)，1.29-1.62(m，12H)。
The preparation of embodiment 8 (+)-2 '-cyclopentyl-2 '-phenyl-2 '-oxyacetic acid-9 α-[3-methyl-3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] ester hydrochloride (Ib)
With reference to the method for embodiment 7, (+)-2 '-cyclopentyl-2 '-phenyl-2 '-oxyacetic acid-9-[3-azabicyclo (3.3.1) ninth of the ten Heavenly Stems] ester (IIIb) obtains formula Ib compound with iodomethane reaction.Fusing point: 209-210 ℃.[α]
D 20=+11.9 ° of (room temperature, CHCl
3, c=0.3).
1H-NMR：δ(ppm，CD
3Cl)，10.87(s，1H)，7.64(m，2H)，7.35(m，3H)，5.00(s，1H)，3.73-3.82(m，2H)，2.97-3.01(m，4H)，2.89(s，3H)，2.27(s，1H)，2.06(s，1H)，2.00(m，2H)，1.33-1.70(m，12H)。
Claims (5)
1, the salt of optically pure (-)-demethyl benzene ring pelargonate and L-(+)-p-toluenesulfonyl L-glutamic acid, it is expressed from the next:
2, the salt of optically pure (+)-demethyl benzene ring pelargonate and D-(-)-p-toluenesulfonyl L-glutamic acid, it is expressed from the next:
3, the preparation method of salt (-) III (+) IV of claim 1 or 2 described optically pure demethyl phencynonate optical isomer and p-toluenesulfonyl glutamic acid optical isomer and (+) III (-) IV comprises:
(a) adopt 2,2,2-trichlorine methylamino ethoxy acyl chlorides and Zn powder make the raceme of benzene ring pelargonate slough the n-formyl sarcolysine base, obtain the demethyl benzene ring pelargonate;
(b) make demethyl benzene ring pelargonate that step (a) obtains and wherein a kind of single enantiomer salify of N-p-toluenesulfonyl L-glutamic acid, filter collecting precipitation, behind the recrystallization, obtain demethyl phencynonate optical isomer and N-salt (-) III (+) IV or (+) III (-) IV repeatedly to the Methyl benzenesulfonyl glutamic acid optical isomer;
(c) with the mother liquor evaporate to dryness after filtering in the step (b), corresponding (+)-demethyl phencynonate optical isomer or (-)-demethyl phencynonate optical isomer of obtaining in alkalization back;
(d) (+)-demethyl benzene ring pelargonate that step (c) is obtained or (-) demethyl benzene ring pelargonate again with the another kind of single enantiomer salify of N-p-toluenesulfonyl L-glutamic acid, then corresponding salt (+) III (-) IV or (-) III (+) IV that obtains demethyl phencynonate optical isomer and N-to the Methyl benzenesulfonyl glutamic acid optical isomer.
4, the method for claim 3, wherein optically pure first phencynonate optical isomer and the N-of going obtains by 3-5 recrystallization the salt of Methyl benzenesulfonyl glutamic acid optical isomer in the step (b).
5, claim 1 or 2 described compounds are as the purposes of the intermediate of preparation phencynonate optical isomer.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1089838A (en) * | 1993-10-22 | 1994-07-27 | 中国人民解放军军事医学科学院毒物药物研究所 | The syndromic pharmaceutical composition of a kind of control motion sickness |
| CN1182738A (en) * | 1997-12-09 | 1998-05-27 | 中国人民解放军军事医学科学院毒物药物研究所 | Method for preparing benzene ring nonyl ester |
| CN1312074A (en) * | 2001-02-28 | 2001-09-12 | 中国人民解放军军事医学科学院毒物药物研究所 | New application of benzene ring pelargonate hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1089838A (en) * | 1993-10-22 | 1994-07-27 | 中国人民解放军军事医学科学院毒物药物研究所 | The syndromic pharmaceutical composition of a kind of control motion sickness |
| CN1182738A (en) * | 1997-12-09 | 1998-05-27 | 中国人民解放军军事医学科学院毒物药物研究所 | Method for preparing benzene ring nonyl ester |
| CN1312074A (en) * | 2001-02-28 | 2001-09-12 | 中国人民解放军军事医学科学院毒物药物研究所 | New application of benzene ring pelargonate hydrochloride |
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Effective date of registration: 20110816 Address after: 100850 Taiping Road, Beijing, Haidian District, No. 27 Co-patentee after: Hainan Sihuan Pharmaceutical Co.,Ltd Patentee after: Institute of Poisonous Substance and Medicine of Military of Military academy of medical sciences of Address before: 100850 Taiping Road, Beijing, Haidian District, No. 27 Patentee before: Institute of Poisonous Substance and Medicine of Military of Military academy of medical sciences of |
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Owner name: HAINAN SIHUAN PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: HAINAN SIHUAN PHARMACEUTICAL CO.,LTD Effective date: 20140107 Owner name: BEIJING SIHUAN PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: INSTITUTE OF POISONOUS SUBSTANCE AND MEDICINE OF MILITARY OF MILITARY ACADEMY OF MEDICAL SCIENCES OF Effective date: 20140107 |
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Effective date of registration: 20140107 Address after: 101114 Beijing city Tongzhou District Zhangjiawan Town Qi Shanzhuang East Village Patentee after: Beijing Sihuan Pharmaceutical Co., Ltd. Patentee after: Hainan Fourth Ring Pharmaceutical Co., Ltd. Address before: 100850 Taiping Road, Beijing, Haidian District, No. 27 Patentee before: Institute of Poisonous Substance and Medicine of Military of Military academy of medical sciences of Patentee before: Hainan Sihuan Pharmaceutical Co.,Ltd |
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Address after: 101114 Beijing city Tongzhou District Zhangjiawan Town Qi Shanzhuang East Village Patentee after: Beijing Sihuan Pharmaceutical Co., Ltd. Patentee after: Hainan Sihuan Pharmaceutical Co.,Ltd Address before: 101114 Beijing city Tongzhou District Zhangjiawan Town Qi Shanzhuang East Village Patentee before: Beijing Sihuan Pharmaceutical Co., Ltd. Patentee before: Hainan Fourth Ring Pharmaceutical Co., Ltd. |