IT9021525A1 - PROCEDURE FOR THE PREPARATION OF VULPECOLIC ACID. - Google Patents
PROCEDURE FOR THE PREPARATION OF VULPECOLIC ACID. Download PDFInfo
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- IT9021525A1 IT9021525A1 IT021525A IT2152590A IT9021525A1 IT 9021525 A1 IT9021525 A1 IT 9021525A1 IT 021525 A IT021525 A IT 021525A IT 2152590 A IT2152590 A IT 2152590A IT 9021525 A1 IT9021525 A1 IT 9021525A1
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- Prior art keywords
- acid
- formula
- vulpecolic
- alpha
- derivative
- Prior art date
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- 239000002253 acid Substances 0.000 title claims description 13
- 238000000034 method Methods 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical group CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- -1 alkali metal hypochlorite Chemical class 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 150000001451 organic peroxides Chemical class 0.000 claims description 4
- 239000003495 polar organic solvent Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 238000006735 epoxidation reaction Methods 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Inorganic materials Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229940099352 cholate Drugs 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 description 1
- OUTUZEBQXNEVGY-UHFFFAOYSA-N 5,5-diethyl-1,3-diazinane-2,4,6-trione;4-(dimethylamino)-1,5-dimethyl-2-phenylpyrazol-3-one Chemical compound CCC1(CC)C(=O)NC(=O)NC1=O.O=C1C(N(C)C)=C(C)N(C)N1C1=CC=CC=C1 OUTUZEBQXNEVGY-UHFFFAOYSA-N 0.000 description 1
- 241000289672 Trichosurus vulpecula Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 201000001883 cholelithiasis Diseases 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 208000001130 gallstones Diseases 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 description 1
- 229960001661 ursodiol Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Descrizione dell'invenzione industriale Description of the industrial invention
La presente invenzione riguarda la preparazione dell'acido 1 -alfa, 3-alfa,7-alfa-triidrossi-5-beta-colan-24-oico, noto anche come acido vulpecolico, e più specificamente un procedimento per la sua sintesi in modo industrialmente vantaggioso. The present invention relates to the preparation of 1-alpha, 3-alpha, 7-alpha-trihydroxy-5-beta-colan-24-oic acid, also known as vulpecolic acid, and more specifically a process for its synthesis in a manner industrially advantageous.
L’acido vulpecolico, avente formula: Vulpecolic acid, having the formula:
( I ) (I)
è stato isolato e descritto per la prima volta nel 1986 (Sum P.Lee e coll., Journal of Lipid Research, vol.28, 1987, pag.19-31) al pari di alcuni suoi derivati ed è stato reperito nella bile di un marsupiale australiano (Trichosurus vulpecula). was isolated and described for the first time in 1986 (Sum P. Lee et al., Journal of Lipid Research, vol. 28, 1987, pages 19-31) like some of its derivatives and was found in the bile of an Australian marsupial (Trichosurus vulpecula).
Questo acido appartiene alla categoria degli acidi biliari e presenta caratteristiche e proprietà analoghe a quelle dell’acido ursodesossicolico, in particolare per quanto riguarda il trattamento della calcolosi biliare, colesterolica e della dispepsia epatobiliare. This acid belongs to the category of bile acids and has characteristics and properties similar to those of ursodeoxycholic acid, in particular as regards the treatment of gallstones, cholesterol and hepatobiliary dyspepsia.
Naturalmente non è ipotizzabile un suo sfruttamento terapeutico se la produzione di questo acido dovesse avvenire per estrazione del prodotto naturale dalla cistifellea del predetto marsupiale. Of course, its therapeutic exploitation is not conceivable if the production of this acid were to take place by extraction of the natural product from the gallbladder of the aforementioned marsupial.
Scopo principale della presente invenzione è quello di fornire un procedimento di sintesi per la preparazione dell'acido vulpecolico in modo industrialmente vantaggioso. The main object of the present invention is to provide a synthesis process for the preparation of vulpecolic acid in an industrially advantageous way.
A tale scopo il procedimento della presente invenzione prevede gli stadi di: For this purpose, the process of the present invention provides for the stages of:
I THE
(a) epossidazione del 3-oxo,l ,2-coIen,7-acetossi,24-metil-oato di formula (a) epoxidation of 3-oxo, 1,2-coIen, 7-acetoxy, 24-methyl-oate of formula
II ) II)
con idrato di un metallo alcalino ed acqua ossigenataod un perossido organico od un ipoclorito di metallo alcalino, in un solvente organico polare; with hydrate of an alkali metal and hydrogen peroxide or an organic peroxide or an alkali metal hypochlorite, in a polar organic solvent;
(b) idrogenazione del composto epossidato risultante di formula (b) hydrogenation of the resulting epoxidized compound of formula
(III ) con ottenimento del derivato recante un sostituente ossidrilico in posizione 1 -alfa, di formula (III) obtaining the derivative bearing a hydroxyl substituent in the 1-alpha position, of formula
(c) reazione del composto (IV) con diborano in rapporto molare di 3 ad l,a bassa temperatura e sotto atmosfera inerte, con ottenimento del derivato biossidrilato nella posizioni I -alfa e 3-alfa,di formula (c) reaction of compound (IV) with diborane in a molar ratio of 3 to 1, at low temperature and under an inert atmosphere, with the obtainment of the dihydroxy derivative in the I-alpha and 3-alpha positions, of formula
(d) reazione del derivato (V) con idrato di metallo alcalino ed isolamento dell’acido vulpecolico di formula (I). (d) reaction of the derivative (V) with alkali metal hydrate and isolation of the vulpecolic acid of formula (I).
Per quanto riguarda il composto di partenza di formula (II) esso può essere preparato secondo il metodo descritto da Masahiko e coll., Chem.Pharm.BuIL, 34(7), 2890-9, 1986. As regards the starting compound of formula (II) it can be prepared according to the method described by Masahiko et al., Chem.Pharm.BuIL, 34 (7), 2890-9, 1986.
Nello stadio (a) del procedimento, come perossido organico si intende un composto scelto tra acido peracetico, acido perbenzoico ed acido trifluoroacetico, mentre con solvente organico polare si intende un solvente scelto tra acido formico, acido acetido, acqua, alcooli alifatici inferiori e loro miscele. In step (a) of the process, organic peroxide means a compound selected from peracetic acid, perbenzoic acid and trifluoroacetic acid, while with polar organic solvent it is meant a solvent selected from formic acid, acetid acid, water, lower aliphatic alcohols and their blends.
Dallo schema che segue è possibile apprezzare prontamente i diversi stadi attraverso i quali si svolge il procedimento di sintesi della presente invenzione,! cui aspetti particolari appariranno più chiaramente dall’esempio che segue, avente ovviamente titolo puramente esemplificativo. From the following diagram it is possible to readily appreciate the different stages through which the synthesis process of the present invention takes place. whose particular aspects will appear more clearly from the following example, obviously having a purely illustrative title.
Esempio Example
(a) Metil l,2-alfa-epossi-3-oxo-7-acetossi-24-colato (III) (a) Methyl 1,2-alpha-epoxy-3-oxo-7-acetoxy-24-cholate (III)
Una soluzione di 1 grammo di 3-oxo-l,2-colen-7-acetossi-24-metil-oato (II) in 35 mi di metanolo viene trattata con 0,25 mi si idrossido di sodio in soluzione metanolica al 10% ed 1,6 mi di a* ^0% Per una notte sotto agitazione. A solution of 1 gram of 3-oxo-1,2-colen-7-acetoxy-24-methyl-oate (II) in 35 ml of methanol is treated with 0.25 ml of sodium hydroxide in 10% methanolic solution and 1.6 ml of a * 0% for one night under stirring.
Il prodotto che precipita viene filtrato e lavato con matanolo freddo. L’epossido viene eluito con esano/benzene (80/20) attraverso una colonna di allumina neutra. The precipitating product is filtered and washed with cold matanol. The epoxide is eluted with hexane / benzene (80/20) through a neutral alumina column.
Si cristallizza da etere dietilico il derivato del titolo (p.m.:460,59) con resa del 70% del teorico. The title derivative (m.p.:460.59) is crystallized from diethyl ether with a yield of 70% of the theoretical.
Analisi elementare per 21 40 6 Elementary analysis for 21 40 6
calcolato: C 70,40%; H 8,75% calculated: C 70.40%; H 8.75%
trovato: C 70,91%; H 8,57% found: C 70.91%; H 8.57%
(b) Metil-l,aIfa-idrossi-3-oxo-7-acetossi-5, beta-colato (IV) (b) Methyl-1, alpha-hydroxy-3-oxo-7-acetoxy-5, beta-cholate (IV)
250 mg del composto (III) vengono sciolti in una miscela di 8 mi di tetraidrofurano e 4 mi di etanolo e si idrogena su 30 mg di Pd/C al 5%.Quando non si ha ulteriore assorbimento di idrogeno si separa il catalizzatore per filtrazione e si porta a secco sotto vuoto.il residuo viene eluito su allumina neutra con esano/benzene (80/20) e si cristallizza da diclorometano ottenendo il derivato del titolo (p.m„'462,61) con resa del 55% d.t. 250 mg of compound (III) are dissolved in a mixture of 8 ml of tetrahydrofuran and 4 ml of ethanol and hydrogen on 30 mg of 5% Pd / C. When there is no further hydrogen absorption, the catalyst is separated by filtration and it is dried under vacuum. The residue is eluted on neutral alumina with hexane / benzene (80/20) and crystallizes from dichloromethane to obtain the derivative of the title (m.p. 462.61) with a yield of 55% of theory.
Aanalisi elementare per C27H42°6: Elemental analysis for C27H42 ° 6:
calcolato: C 70,10%; H 9,15% calculated: C 70.10%; H 9.15%
trovato: C 70,95%; h 9,08% found: C 70.95%; h 9.08%
(c) Metil-l,alfa-3,alfa-diidrossi-7-acetossi-5,beta-colato (V) (c) Methyl-1, alpha-3, alpha-dihydroxy-7-acetoxy-5, beta-cholate (V)
200 mg di composto (IV) vengono sciolti in tetraidrofurano contenente diborano in un rapporto molare di 3:1 e si agita per 150 minuti a 0°Csotto atmosfera di ^.La soluzione di reazione viene quindi evaporata sotto vuoto ed il residuo viene eluito con diclorometano su allumina neutra. 200 mg of compound (IV) are dissolved in tetrahydrofuran containing diborane in a molar ratio of 3: 1 and stirred for 150 minutes at 0 ° C under an atmosphere. The reaction solution is then evaporated under vacuum and the residue is eluted with dichloromethane on neutral alumina.
Si cristallizza infine da diclorometano ottenendo il derivato del titolo (p.m.:464,62) Finally, it crystallizes from dichloromethane obtaining the derivative of the title (p.m.:464.62)
Analisi per C27H44°6‘ Analysis for C27H44 ° 6 '
calcolato: C 69,79%; H 9,54% calculated: C 69.79%; H 9.54%
trovato: C 70,05%; H 9,15% found: C 70.05%; H 9.15%
(d) acido vulpecolico (I) (d) vulpecolic acid (I)
10 grammi del derivato (V) vengono portati a ricadere per 8 ore in 200 mi di una soluzione di idrato sodico al 10% Si filtra e si secca sotto vuoto a 50°C. Si cristallizza da etanolo al 50% ottenendo l'acido vulpecolico desiderato (p.m.:42ó,58) con punto di fusione di I50-I52°C. 10 grams of the derivative (V) are refluxed for 8 hours in 200 ml of a 10% sodium hydrate solution. It is filtered and dried under vacuum at 50 ° C. It crystallizes from 50% ethanol obtaining the desired vulpecolic acid (m.p.:42ó.58) with a melting point of 150-152 ° C.
Analisi elementare per C24H40°5 H2O: Elemental analysis for C24H40 ° 5 H2O:
calcolato: C 67,57%; H 9,92% calculated: C 67.57%; H 9.92%
trovato: C 67,41%; H 9,83% found: C 67.41%; H 9.83%
Resta inteso che i reagenti nonché i singoli stadi sono sucettibile di variazioni e modifiche che rientrano nelle conoscenze e capacità del chimico esperto. It is understood that the reagents as well as the individual stages are susceptible to variations and modifications which are within the knowledge and ability of the skilled chemist.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT02152590A IT1243726B (en) | 1990-09-20 | 1990-09-20 | Process for the preparation of vulpecholic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT02152590A IT1243726B (en) | 1990-09-20 | 1990-09-20 | Process for the preparation of vulpecholic acid |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| IT9021525A0 IT9021525A0 (en) | 1990-09-20 |
| IT9021525A1 true IT9021525A1 (en) | 1992-03-20 |
| IT1243726B IT1243726B (en) | 1994-06-21 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IT02152590A IT1243726B (en) | 1990-09-20 | 1990-09-20 | Process for the preparation of vulpecholic acid |
Country Status (1)
| Country | Link |
|---|---|
| IT (1) | IT1243726B (en) |
-
1990
- 1990-09-20 IT IT02152590A patent/IT1243726B/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| IT1243726B (en) | 1994-06-21 |
| IT9021525A0 (en) | 1990-09-20 |
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