CH622247A5 - Process for the preparation of prostaglandin A2 and of certain of its derivatives - Google Patents
Process for the preparation of prostaglandin A2 and of certain of its derivatives Download PDFInfo
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- CH622247A5 CH622247A5 CH840477A CH840477A CH622247A5 CH 622247 A5 CH622247 A5 CH 622247A5 CH 840477 A CH840477 A CH 840477A CH 840477 A CH840477 A CH 840477A CH 622247 A5 CH622247 A5 CH 622247A5
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- prostaglandin
- synthesis
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- 238000000034 method Methods 0.000 title description 12
- MYHXHCUNDDAEOZ-UHFFFAOYSA-N Prostaglandin A&2% Natural products CCCCCC(O)C=CC1C=CC(=O)C1CC=CCCCC(O)=O MYHXHCUNDDAEOZ-UHFFFAOYSA-N 0.000 title description 7
- MYHXHCUNDDAEOZ-FOSBLDSVSA-N prostaglandin A2 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1C=CC(=O)[C@@H]1C\C=C/CCCC(O)=O MYHXHCUNDDAEOZ-FOSBLDSVSA-N 0.000 title description 7
- 238000002360 preparation method Methods 0.000 title description 3
- -1 alkyl radical Chemical group 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 125000004430 oxygen atom Chemical group O* 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229940043279 diisopropylamine Drugs 0.000 description 3
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229940124630 bronchodilator Drugs 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003033 spasmogenic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
- C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
- C07C405/0033—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing sulfur
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
622 247 622,247
2 2
REVENDICATIONS
1. Procédé de préparation des produits de formule générale: 1. Process for the preparation of products of general formula:
(I) (I)
co2r dans laquelle R représente un atome d'hydrogène ou un radical alkyle ayant de 1 à 4 atomes de carbone, Ri représente un atome d'hydrogène ou un radicai méthyle, X représente un atome d'oxygène ou un radical méthylène et R2 représente un radical alkyle ayant de 1 à 4 atomes de carbone, caractérisé en ce que l'on traite, en présence d'une base forte, un produit de formule générale: co2r in which R represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, Ri represents a hydrogen atom or a methyl radical, X represents an oxygen atom or a methylene radical and R2 represents a alkyl radical having from 1 to 4 carbon atoms, characterized in that a product of general formula is treated, in the presence of a strong base:
formule dans laquelle A, R, Ri, R2 et X ont la signification précédente, produit de formule III que l'on chauffe pour obtenir le produit de formule I désiré. formula in which A, R, Ri, R2 and X have the preceding meaning, product of formula III which is heated to obtain the product of formula I desired.
i5 2. Procédé selon la revendication 1 de préparation du produit de formule: 2. Method according to claim 1 for preparing the product of formula:
0 0
(I') (I ')
caractérisé en ce que l'on traite le produit de formule: characterized in that the product of formula is treated:
0 0
I H. I I H. I
OH OH
35 35
dans laquelle R, Ri, R2 et X ont la signification précédente, par un produit de formule A—SO—Hai, dans laquelle A représente un radical méthyle, phényle ou paratolyle et Hai représente un atome d'halogène, pour obtenir un produit de formule: in which R, Ri, R2 and X have the above meaning, by a product of formula A — SO — Hai, in which A represents a methyl, phenyl or paratolyl radical and Hai represents a halogen atom, to obtain a product of formula:
(II') C02H (II ') C02H
40 par le chlorure de paratoluènesulfinyle en présence d'une base forte pour obtenir le produit de formule: 40 with paratoluenesulfinyl chloride in the presence of a strong base to obtain the product of formula:
produit que l'on chauffe pour obtenir le produit de formule l'désiré. product which is heated to obtain the product of the desired formula.
La présente invention a pour objet un nouveau procédé de préparation de la Prostaglandine A2 et de certains de ses dérivés, répondant à la formule générale: The subject of the present invention is a new process for the preparation of prostaglandin A2 and certain of its derivatives, corresponding to the general formula:
dans laquelle R représente un atome d'hydrogène ou un radical 55 alkyle ayant de 1 à 4 atomes de carbone, Ri représente un atome d'hydrogène ou un radical méthyle, X représente un atome d'oxygène ou un radical méthylène et R2 représente un radical alkyle ayant de 1 à 4 atomes de carbone. Ce procédé est caractérisé en ce que l'on traite, en présence d'une base forte, un produit de formule 60 générale: in which R represents a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, Ri represents a hydrogen atom or a methyl radical, X represents an oxygen atom or a methylene radical and R2 represents a alkyl radical having from 1 to 4 carbon atoms. This process is characterized in that, in the presence of a strong base, a product of general formula 60 is treated:
0 0
(II) (II)
3 3
622 247 622,247
dans laquelle R, Rl5 R2 et X ont la signification précédente, par un produit de formule A — SO — Hai, dans laquelle A représente un radical méthyle, phényle ou paratolyle et Hai représente un atome d'halogène, pour obtenir un produit de formule: in which R, Rl5 R2 and X have the above meaning, by a product of formula A - SO - Hai, in which A represents a methyl, phenyl or paratolyl radical and Hai represents a halogen atom, to obtain a product of formula :
0 5 0 5
(III) (III)
,C02R , C02R
(I') (I ')
02h 02h
-R, -R,
formule dans laquelle A, R, Rj, R2 et X ont la signification précédente, produit de formule III que l'on chauffe pour obtenir le produit de formule I désiré. formula in which A, R, Rj, R2 and X have the above meaning, product of formula III which is heated to obtain the desired product of formula I.
Les valeurs que peuvent représenter les substituants R et R2 sont choisies de préférence parmi les radicaux méthyle, éthyle, propyle, isopropyle, butyle, sec.-butyle ou tert.-butyle. The values which the substituents R and R2 may represent are preferably chosen from methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl or tert.-butyl radicals.
Le substituant Hai peut représenter notamment un atome de chlore, de brome ou d'iode. The Hai substituent can represent in particular a chlorine, bromine or iodine atom.
L'invention a plus particulièrement pour objet un procédé de préparation du produit de formule: The invention more particularly relates to a process for preparing the product of formula:
caractérisé en ce que l'on traite le produit de formule: characterized in that the product of formula is treated:
par le chlorure de paratoluènesulfinyle en présence d'une base forte pour obtenir le produit de formule: with paratoluenesulfinyl chloride in the presence of a strong base to obtain the product of formula:
(III') (III ')
OH OH
produit que l'on chauffe pour obtenir le produit de formule l'désiré. product which is heated to obtain the product of the desired formula.
La base forte, en présence de laquelle on transforme les produits de formule II ou II' en produits de formule III ou III' respectivement, est de préférence un mélange de diisopropylamine et de butyllithium. The strong base, in the presence of which the products of formula II or II 'are transformed into products of formula III or III' respectively, is preferably a mixture of diisopropylamine and butyllithium.
On peut cependant utiliser le butyllithium seul ou avec une autre base aminée telle que la diéthylamine. However, butyllithium can be used alone or with another amino base such as diethylamine.
On peut également utiliser le méthyllithium ou le phényllithium seuls ou avec la diéthylamine ou la diisopropylamine. Methyllithium or phenyllithium can also be used alone or with diethylamine or diisopropylamine.
On peut également utiliser l'hydrure de sodium dans le diméthyl-sulfoxyde. Sodium hydride can also be used in dimethyl sulfoxide.
La transformation par chauffage des produits de formule III ou III' en produits de formule I ou l'est effectuée de façon avantageuse dans un solvant organique à une température comprise de préférence entre 70 et 140° C. Le solvant que l'on utilise de préférence est le toluène, mais on peut également utiliser d'autres solvants organiques tels que le benzène ou le xylène. The transformation by heating of products of formula III or III 'into products of formula I or is carried out advantageously in an organic solvent at a temperature preferably between 70 and 140 ° C. The solvent which is used preferably toluene, but other organic solvents such as benzene or xylene can also be used.
Les produits de formule II, qui ne sont pas connus, peuvent être préparés selon le procédé décrit dans la demande de brevet français N° 2251323. The products of formula II, which are not known, can be prepared according to the process described in French patent application No. 2251323.
Les produits de formule I, obtenus selon le procédé de la présente invention et dans laquelle Ri représente un groupe méthyle et X un atome d'oxygène, sont décrits comme médicaments dans la demande de brevet français N° 2279390. Ils manifestent en pharmacologie des propriétés spasmogènes, bronchodilatatrices et hypotensives. The products of formula I, obtained according to the process of the present invention and in which R 1 represents a methyl group and X an oxygen atom, are described as medicaments in French patent application No. 2279390. They demonstrate properties in pharmacology spasmogenic, bronchodilator and hypotensive.
0 0
alc02C ' alc02C '
Les produits obtenus selon le procédé de la présente invention et dans laquelle Rx représente un atome d'hydrogène et X un atome d'oxygène sont utilisés comme intermédiaires dans le brevet belge 40 N° 807047 pour obtenir des produits présentant en pharmacologie des propriétés entre autres antihypertensives et bronchodilatatrices. The products obtained according to the process of the present invention and in which Rx represents a hydrogen atom and X an oxygen atom are used as intermediates in Belgian patent 40 No. 807047 to obtain products having properties in pharmacology among others antihypertensives and bronchodilators.
Les produits de formule I dans laquelle Rx représente un atome d'hydrogène et X représente un radical méthylène sont décrits dans 45 la demande de brevet néerlandais N° 7301094. The products of formula I in which Rx represents a hydrogen atom and X represents a methylene radical are described in 45 Dutch patent application No. 7301094.
Ces produits possèdent des propriétés analogues à celles des autres Prostaglandines; ils peuvent également être utilisés comme intermédiaires. These products have properties similar to those of other prostaglandins; they can also be used as intermediates.
50 Les autres produits de formule I sont mentionnés dans la publication japonaise J5 N° 0088.054. The other products of formula I are mentioned in Japanese publication J5 No. 0088.054.
Le procédé de l'invention permet notamment d'obtenir la Prostaglandine A2 dans des conditions plus satisfaisantes que celles que l'art antérieur permet de réaliser. The process of the invention makes it possible in particular to obtain prostaglandin A2 under conditions more satisfactory than those which the prior art makes it possible to achieve.
55 En effet: 55 Indeed:
a) Dans le brevet français N° 2104916, on a décrit un procédé de synthèse de la Prostaglandine A2 de formule I'. a) In French patent No. 2104916, a process for the synthesis of prostaglandin A2 of formula I 'has been described.
Cette synthèse est effectuée en huit stades à partir des produits de formule: This synthesis is carried out in eight stages from the products of formula:
^(CH2)nC02alci ^ (CH2) nC02alci
(B) (B)
622 TAI 622 TAI
formule dans laquelle ale représente un radical alcoyle inférieur et alci un radical alcoyle, n est un nombre entier égal à 2,3 ou 4 et m est un nombre entier égal à 3,4 ou 5. formula in which ale represents a lower alkyl radical and alci an alkyl radical, n is an integer equal to 2.3 or 4 and m is an integer equal to 3.4 or 5.
De plus, cètte synthèse comporte une étape nécessitant une séparation des deux isomères de formules: In addition, this synthesis includes a step requiring separation of the two isomers of formulas:
'CH. 'CH.
(CH. (CH.
(CH, (CH,
CH-; CH-;
•OH. •OH.
(CH9V -COpH (CH9V -COpH
et obtenus lors du traitement à chaud du produit de formule: and obtained during the hot treatment of the product of formula:
OCH OCH
^CH2)n-C02H ^ CH2) n-C02H
^(CH„) -CH., ^ (CH „) -CH.,
b) Dans le brevet français N° 2085654, on a décrit une synthèse en trois étapes de la dihydroprostaglandine A2 à partir des produits de formule B. b) In French patent No. 2085654, a three-stage synthesis of dihydroprostaglandin A2 has been described from the products of formula B.
Or, la présente invention décrit une synthèse de la Prostaglandine A2 en deux stades à partir de la dihydroprostaglandine A2. Cette synthèse est donc plus courte que celle décrite dans le brevet N° 2104916. En outre, elle est plus facile à mettre en œuvre, car elle permet d'éviter des séparations d'isomères. Enfin, la synthèse qui fait l'objet de la présente invention permet d'obtenir la Prostaglandine A2 avec un rendement global, à partir du produit B, supérieur. However, the present invention describes a synthesis of prostaglandin A2 in two stages from dihydroprostaglandin A2. This synthesis is therefore shorter than that described in patent No. 2104916. In addition, it is easier to implement, because it makes it possible to avoid separation of isomers. Finally, the synthesis which is the subject of the present invention makes it possible to obtain prostaglandin A2 with an overall yield, from product B, which is higher.
Sur un autre plan, le présent procédé présente également deux avantages importants par rapport à celui décrit dans «J.A.C.S.», 98,6 (1976) p. 83, procédé qui consiste à préparer la Prostaglandine A2 à partir d'un dérivé de la dihydroprostaglandine A2 par utilisation du chlorure de phénylesélényle. On another level, the present process also has two important advantages over that described in "J.A.C.S.", 98.6 (1976) p. 83, a process which consists in preparing prostaglandin A2 from a derivative of dihydroprostaglandin A2 by using phenyleelenyl chloride.
En effet, la synthèse décrite dans «J.A.C.S.» est effectuée en quatre étapes, alors que celle de la présente invention n'en comporte que deux. De plus, la synthèse décrite dans «J.A.C.S.» utilise un réactif toxique, alors que le réactif utilisé dans la présente synthèse ne l'est pas. Indeed, the synthesis described in "J.A.C.S." is carried out in four stages, while that of the present invention comprises only two. In addition, the synthesis described in "J.A.C.S." uses a toxic reagent, while the reagent used in this synthesis is not.
L'exemple suivant illustre l'invention. The following example illustrates the invention.
Exemple: Example:
Acide (8RS, 12SR, 15SR) (5Z, 13E) 9-oxo 15-hydroxyprosta-triène 5,10,13 oïque Acid (8RS, 12SR, 15SR) (5Z, 13E) 9-oxo 15-hydroxyprosta-triene 5,10,13 oic
Stade A: Acide (8RS, 12SR, 15SR) (5Z, 13E) 9-oxo 10-parato-luènesulfinyl 15-hydroxyprostadiène 5,13 oïque On introduit, sous gaz inerte, 363 mg de diisopropylamine dans 5 cm3 de glyme. On refroidit à — 78° C et introduit lentement 2,8 cm3 de butyllithium titrant 1,3N. On laisse revenir le mélange • à 0° C et après 15 mn à cette température, on refroidit de nouveau à —78° C et ajoute lentement 336 mg de l'acide (8RS, 12SR, 15SR) (5Z, 13E) 9-oxo 15-hydroxyprostadiène 5,13 oïque en solution dans 5 cm3 de glyme, puis 210 mg de chlorure de paratoluènesulfinyle. Stage A: Acid (8RS, 12SR, 15SR) (5Z, 13E) 9-oxo 10-parato-luenesulfinyl 15-hydroxyprostadiene 5.13 oic 363 mg of diisopropylamine in 5 cm3 of glyme are introduced under inert gas. Cooled to -78 ° C and slowly introduced 2.8 cm3 of butyllithium grading 1.3N. The mixture is allowed to return to 0 ° C. and after 15 minutes at this temperature, it is again cooled to -78 ° C. and slowly added 336 mg of the acid (8RS, 12SR, 15SR) (5Z, 13E) 9- 5.13 oic 15-hydroxyprostadiene oxo in solution in 5 cm3 of glyme, then 210 mg of paratoluenesulfinyl chloride.
On laisse 1 h à — 78° C, verse dans une solution saturée de phosphate monosodique, extrait à l'acétate d'éthyle, sèche et évapore à sec sous pression réduite. On obtient une huile jaune. The mixture is left for 1 hour at -78 ° C., poured into a saturated solution of sodium phosphate, extracted with ethyl acetate, dried and evaporated to dryness under reduced pressure. A yellow oil is obtained.
Stade B: Acide {8RS, 12SR, 15SR) (5Z, 13E) 9-oxo 15-hydroxy-prostatriène 5,10,13 oïque Stage B: Acid (8RS, 12SR, 15SR) (5Z, 13E) 9-oxo 15-hydroxy-prostatriene 5,10,13 oic
L'huile obtenue au stade précédent est mise en solution dans 5 cm3 de toluène et est chauffée 30 mn au reflux. On évapore à sec et Chromatographie l'huile obtenue sur gel de silice en utilisant un mélange benzène/acétate d'éthyle/acide acétique (60/40/1). The oil obtained in the previous stage is dissolved in 5 cm3 of toluene and is heated for 30 min at reflux. The oil obtained is evaporated to dryness and the oil obtained is chromatographed on silica gel using a benzene / ethyl acetate / acetic acid mixture (60/40/1).
On obtient 109 mg de produit attendu [Rf=0,5 (chloroforme/ méthanol/acide acétique: 95/5/5)] et récupère 145 mg de produit de départ. 109 mg of expected product are obtained [Rf = 0.5 (chloroform / methanol / acetic acid: 95/5/5)] and 145 mg of starting product is recovered.
4 4
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.40 .40
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R R
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR7620769A FR2357542A1 (en) | 1976-07-07 | 1976-07-07 | PROCESS FOR THE PREPARATION OF PROSTAGLANDIN A2 AND SOME OF ITS DERIVATIVES |
Publications (1)
Publication Number | Publication Date |
---|---|
CH622247A5 true CH622247A5 (en) | 1981-03-31 |
Family
ID=9175362
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CH840477A CH622247A5 (en) | 1976-07-07 | 1977-07-07 | Process for the preparation of prostaglandin A2 and of certain of its derivatives |
Country Status (13)
Country | Link |
---|---|
JP (1) | JPS537649A (en) |
BE (1) | BE856545A (en) |
CA (1) | CA1087614A (en) |
CH (1) | CH622247A5 (en) |
DE (1) | DE2730762A1 (en) |
DK (1) | DK303977A (en) |
FR (1) | FR2357542A1 (en) |
GB (1) | GB1538037A (en) |
HU (1) | HU178334B (en) |
IE (1) | IE45609B1 (en) |
LU (1) | LU77693A1 (en) |
NL (1) | NL7707458A (en) |
SE (1) | SE420091B (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU636675B2 (en) * | 1989-10-19 | 1993-05-06 | Teijin Limited | 2-substituted 2-cyclopentenone and carcinostatic agent and osteogenesis promoter containing the same as active ingredient |
US5338844A (en) * | 1989-10-19 | 1994-08-16 | Teijin Limited | 2-substituted-2-cyclopentenone compound and anticancer agent and bone formation accelerator comprising same as active ingredient |
ES2864167T3 (en) | 2015-03-09 | 2021-10-13 | Mitsubishi Gas Chemical Co | Diaminodicyclohexylmethane isomerization method |
-
1976
- 1976-07-07 FR FR7620769A patent/FR2357542A1/en active Granted
-
1977
- 1977-06-16 SE SE7706998A patent/SE420091B/en unknown
- 1977-06-20 HU HU77RO933A patent/HU178334B/en unknown
- 1977-07-05 NL NL7707458A patent/NL7707458A/en not_active Application Discontinuation
- 1977-07-06 IE IE1407/77A patent/IE45609B1/en unknown
- 1977-07-06 BE BE179126A patent/BE856545A/en not_active IP Right Cessation
- 1977-07-06 CA CA282,191A patent/CA1087614A/en not_active Expired
- 1977-07-06 LU LU77693A patent/LU77693A1/xx unknown
- 1977-07-06 DK DK303977A patent/DK303977A/en not_active Application Discontinuation
- 1977-07-07 JP JP8050777A patent/JPS537649A/en active Pending
- 1977-07-07 DE DE19772730762 patent/DE2730762A1/en not_active Withdrawn
- 1977-07-07 CH CH840477A patent/CH622247A5/en not_active IP Right Cessation
- 1977-07-07 GB GB28566/77A patent/GB1538037A/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
NL7707458A (en) | 1978-01-10 |
SE420091B (en) | 1981-09-14 |
LU77693A1 (en) | 1978-01-31 |
SE7706998L (en) | 1978-01-08 |
BE856545A (en) | 1978-01-06 |
FR2357542B1 (en) | 1979-07-06 |
HU178334B (en) | 1982-04-28 |
FR2357542A1 (en) | 1978-02-03 |
DE2730762A1 (en) | 1978-01-12 |
CA1087614A (en) | 1980-10-14 |
IE45609L (en) | 1978-01-07 |
JPS537649A (en) | 1978-01-24 |
IE45609B1 (en) | 1982-10-06 |
GB1538037A (en) | 1979-01-10 |
DK303977A (en) | 1978-01-08 |
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