DE2730762A1 - PROCESS FOR THE PRODUCTION OF PROSTAGLANDIN A LOW 2 AND CERTAIN DERIVATIVES OF ITSELVES - Google Patents
PROCESS FOR THE PRODUCTION OF PROSTAGLANDIN A LOW 2 AND CERTAIN DERIVATIVES OF ITSELVESInfo
- Publication number
- DE2730762A1 DE2730762A1 DE19772730762 DE2730762A DE2730762A1 DE 2730762 A1 DE2730762 A1 DE 2730762A1 DE 19772730762 DE19772730762 DE 19772730762 DE 2730762 A DE2730762 A DE 2730762A DE 2730762 A1 DE2730762 A1 DE 2730762A1
- Authority
- DE
- Germany
- Prior art keywords
- formula
- product
- iii
- products
- prostaglandin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
- 238000000034 method Methods 0.000 title claims description 14
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- BGKHCLZFGPIKKU-UHFFFAOYSA-N (13E,15S)-15-hydroxy-9-oxo-prosta-10,13-dienoic acid Natural products CCCCCC(O)C=CC1C=CC(=O)C1CCCCCCC(O)=O BGKHCLZFGPIKKU-UHFFFAOYSA-N 0.000 title description 3
- -1 alkyl radical Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 3
- DYYLCPSSSFWEEA-UHFFFAOYSA-N 4-methylbenzenesulfinyl chloride Chemical compound CC1=CC=C(S(Cl)=O)C=C1 DYYLCPSSSFWEEA-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims description 2
- HCBPHBQMSDVIPZ-UHFFFAOYSA-N methylcyclohexatriene Chemical compound CC1=CC=C=C[CH]1 HCBPHBQMSDVIPZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000000047 product Substances 0.000 description 28
- 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 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 150000003180 prostaglandins Chemical class 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-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
- 230000003182 bronchodilatating effect Effects 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
- 229940043279 diisopropylamine Drugs 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 239000003960 organic solvent Substances 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
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- VXDSLUMUNWTSDB-UHFFFAOYSA-N acetic acid;chloroform;methanol Chemical compound OC.CC(O)=O.ClC(Cl)Cl VXDSLUMUNWTSDB-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 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
- 238000006243 chemical reaction Methods 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
- 230000001077 hypotensive effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 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
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- WJCXADMLESSGRI-UHFFFAOYSA-N phenyl selenohypochlorite Chemical compound Cl[Se]C1=CC=CC=C1 WJCXADMLESSGRI-UHFFFAOYSA-N 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 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 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 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
- 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
Landscapes
- 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
Dr. F. Zumstein sen. - Dr. E. Assmann - Dr. R. Koenigsberger Dipl.-Phys. R. Holzbauer - Dipl.-Ing. F. Klingseiseti - Dr. F. Zumstein jun.Dr. F. Zumstein Sr. - Dr. E. Assmann - Dr. R. Koenigsberger Dipl.-Phys. R. Holzbauer - Dipl.-Ing. F. Klingseiseti - Dr. F. Zumstein jun.
KTO.-NR. 397997. BLZ 700 306 00ACCOUNT NO. 397997. BLZ 700 306 00
14/90/n
Cas 1752 D14/90 / n
Cas 1752 D
ROUSSEL-UCLAF, Pari s/FrankreichROUSSEL-UCLAF, Paris / France
Verfahren zur Herstellung des Prostaglandins A- und bestimmter Derivate desselbenProcess for the production of prostaglandin A- and certain derivatives thereof
Die vorliegende Erfindung betrifft ein neues Verfahren zur Herstellung von Prostaglandin A2 und bestimmten Derivaten desselben.The present invention relates to a new process for the preparation of prostaglandin A 2 and certain derivatives thereof.
Die Erfindung betrifft insbesondere ein Verfahren zur Herstellung von Produkten der allgemeinen Formel I:The invention relates in particular to a process for the preparation of products of the general formula I:
worinwherein
R ein Wasserstoffatom oder einen Alkylrest mit 1 bis 4 Kohlenstoffatomen bedeutet,R is a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms means,
R^ ein Wasserstoffatom oder einen Methylrest bedeutet,R ^ denotes a hydrogen atom or a methyl radical,
709882/1017709882/1017
-X--X-
X ein Sauerstoffatom oder einen Methylenrest bedeutet und R2 einen Alkylrest mit 1 bis 4 Kohlenstoffatomen bedeutet,X denotes an oxygen atom or a methylene radical and R 2 denotes an alkyl radical having 1 to 4 carbon atoms,
das dadurch gekennzeichnet ist, daß man in Anwesenheit einer starken Base ein Produkt der allgemeinen Formel II:which is characterized in that, in the presence of a strong base, a product of the general formula II:
IIII
>2> 2
worin R, R.., R2 und X die vorstehend angegebene Bedeutung besitzen, mit einem Produkt der Formel A-SO-HaI, worin A einen Methyl-, Phenyl- oder p-Tolylrest darstellt und Hai ein HaIogenatom bedeutet, behandelt, um ein Produkt der Formel III:wherein R, R .., R 2 and X have the meanings given above, treated with a product of the formula A-SO-Hal, wherein A is a methyl, phenyl or p-tolyl radical and Hal is a halogen atom a product of formula III:
IIIIII
-R,-R,
zu erhalten, worin A, R, R^, R- und X die vorstehend angegebene Bedeutung besitzen, welches Produkt der Formel III man erhitzt, um das gewünschte Produkt der Formel I zu erhalten.to obtain wherein A, R, R ^, R- and X are those given above Which product of the formula III is heated in order to obtain the desired product of the formula I is important.
Die Bedeutungen, die die Substituenten R und R2 annehmen können, sind unter den Methyl-, Äthyl-, Propyl-, Isopropyl-, Butyl-, sek.-Butyl- oder tert.-Butyl-Resten ausgewählt.The meanings which the substituents R and R 2 can assume are selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl radicals.
Der Substituent Hai kann ein Chlor-, Brom- oder Jodatom darstellen. The substituent Hai can represent a chlorine, bromine or iodine atom.
Die Erfindung betrifft insbesondere ein Verfahren zur Herstellung des Produkts der Formel I1:The invention relates in particular to a process for the preparation of the product of formula I 1 :
709882/1097709882/1097
OHOH
das dadurch gekennzeichnet ist, daß man das Produkt der Formel II1:which is characterized in that the product of the formula II 1 :
mit p-Toluolsulfinylchlorid in Anwesenheit einer starken Base behandelt, um das Produkt der Formel III1:treated with p-toluenesulfinyl chloride in the presence of a strong base to give the product of formula III 1 :
CO2H III1 CO 2 H III 1
zu erhalten, welches Produkt man erhitzt,- um das gewünschte Produkt der Formel I1 zu erhalten.to obtain which product is heated - in order to obtain the desired product of the formula I 1 .
Die starke Base, in deren Anwesenheit man die Produkte der Formel II oder II1 in Produkte der Formel III bzw. III1 überführt, ist vorzugsweise ein Gemisch von Diisopropylamin und Butyllithium.The strong base, in the presence of which the products of the formula II or II 1 are converted into products of the formula III or III 1 , is preferably a mixture of diisopropylamine and butyllithium.
Man kann indessen Butyllithium allein oder mit einer weiteren Stickstoffbase, wie Diethylamin, verwenden.However, butyllithium can be used alone or with an additional nitrogen base such as diethylamine.
709882/1087709882/1087
Gleichfalls kann man das Methyllithium oder das Phenyllithium allein oder mit Diäthylamin oder Diisopropylamin verwenden.Likewise, methyl lithium or phenyl lithium can be used alone or with diethylamine or diisopropylamine.
Man kann ebenfalls Natriumhydrid in Dirnethylsulfoxyd verwenden.Sodium hydride in dimethyl sulfoxide can also be used.
Die Umwandlung durch Erhitzen der Produkte der Formel III oder III1 in Produkte der Formel I oder I1 wird in einem organischen Lösungsmittel bei einer Temperatur vorzugsweise zwischen 70 und 140 C vorgenommen. Das Lösungsmittel, das man vorzugsweise verwendet, ist Toluol, wobei man jedoch auch andere organische Lösungsmittel, wie Benzol oder Xylol, verwenden kann.The conversion by heating the products of the formula III or III 1 into products of the formula I or I 1 is carried out in an organic solvent at a temperature preferably between 70 and 140.degree. The solvent which is preferably used is toluene, although other organic solvents such as benzene or xylene can also be used.
Die Produkte der Formel II, die nicht bekannt sind, können gemäß dem in der FR-PS 2 251 323 beschriebenen Verfahren hergestellt werden.The products of the formula II, which are not known, can be prepared according to the process described in French Pat. No. 2,251,323 will.
Die nach dem erfindungsgemäßen Verfahren erhaltenen Produkte der Formel I, worin R1 eine Methylgruppe bedeutet und X ein Sauerstoffatom darstellt, werden als Arzneimittel in der FR-PS 2 279 390 beschrieben. Sie zeigen in der Pharmakologie spasmogene, bronchodilatatorische und hypotensive Eigenschaften. The products of the formula I obtained by the process according to the invention, in which R 1 is a methyl group and X is an oxygen atom, are described as medicaments in FR-PS 2,279,390. In pharmacology, they show spasmogenic, bronchodilatory and hypotensive properties.
Die nach dem erfindungsgemäßen Verfahren erhaltenen Produkte, worin R^ ein Wasserstoffatom bedeutet und X ein Sauerstoffatom darstellt, werden als Zwischenprodukte in der BE-PS 807 verwendet, um Produkte zu erhalten, die in der Pharmakologie unter anderem anti-hypertensive und bronchodilatatorische Eigenschaften aufweisen.The products obtained by the process according to the invention, in which R ^ is a hydrogen atom and X is an oxygen atom represents, are used as intermediate products in BE-PS 807 to obtain products that are used in pharmacology have anti-hypertensive and bronchodilatory properties, among other things.
Die Produkte der Formel I, worin R. ein Wasserstoffatom bedeutet und X einen Methylenrest darstellt, werden in der NL-Patentanmeldung 73.01094 beschrieben.The products of the formula I in which R. is a hydrogen atom and X represents a methylene radical are described in NL patent application 73.01094.
Diese Produkte besitzen Eigenschaften, die denjenigen von anderen Pro s tag landinen analog sind, und sie können auch als* Zwischenprodukte verwendet werden.These products have properties that are analogous to those of other Pro s Taglandinen, and they can also be used as * Intermediate products are used.
7098I2/10S77098I2 / 10S7
Die weiteren Prodiakte der Formel I sind in der JA-Patentpublikation 50-088054 beschrieben.The other products of the formula I are in the JA patent publication 50-088054.
Das erfindungsgemäße Verfahren gestattet es insbesondere, das Prostaglandin A~ unter Bedingungen zu erhalten, die zufriedenstellender sind als diejenigen, die nach dem Stand der Technik erhalten werden können.The method according to the invention makes it possible in particular to obtain the prostaglandin A ~ under conditions which are more satisfactory are than those that can be obtained from the prior art.
Dies geht aus folgenden hervor:This can be seen from the following:
a) In der FR-PS 2 104 916 wurde ein Verfahren zur Synthese von Prostaglandin Ap der Formel I1 beschrieben.a) In FR-PS 2 104 916 a process for the synthesis of prostaglandin Ap of the formula I 1 was described.
Diese Synthese wird in 8 Stufen, ausgehend von Produkten der Formel:This synthesis is carried out in 8 steps, starting from products of the formula:
AIkO2CAIkO 2 C
durchgeführt, in der Alk einen niedrig-Alkylrest bedeutet und AIk1 einen Alkylrest darstellt, η eine ganze Zahl, nämlich 2, 3 oder 4,bedeutet und m eine ganze Zahl, nämlich 3, 4 oder 5, bedeutet.carried out in which Alk is a lower-alkyl radical and AIk 1 is an alkyl radical, η is an integer, namely 2, 3 or 4, and m is an integer, namely 3, 4 or 5.
Überdies enthält diese Synthese eine Stufe, die eine Tren nung der beiden Isomeren der Formeln:In addition, this synthesis contains a step that separates the two isomers of the formulas:
)0H) 0H
(CH2)n-C02H und(CH 2 ) n -C0 2 H and
08882/108708882/1087
die während der Behandlung in der Wärme des Produkts der Formel:which during treatment in the warmth of the product of the formula:
OCHOCH
(CH2)m-CH5 (CH 2 ) m -CH 5
erhalten werden, erforderlich macht.is required.
b) In der FR-PS 2 085 654 wurde eine Synthese in 3 Stufen des Dihydroprostaglandxns A2, ausgehend von Produkten der Formel B, beschrieben.b) In FR-PS 2 085 654 a synthesis in 3 stages of the dihydroprostaglandxn A 2 , starting from products of the formula B, was described.
Demgegenüber beschreibt die vorliegende Erfindung eine Synthese von Prostaglandin A„ in 2 Stufen, ausgehend von Dihydroprostaglandin A-· Diese Synthese ist somit kürzer als die in der FR-PS 2 104 916 beschriebene. Außerdem ist sie leichter durchführbar, da sie es gestattet, Trennungen von Isomeren zu vermeiden. Schließlich gestattet es die erfindungsgemäße Synthese, das Prostaglandin A_ mit einer überlegenen Gesamtausbeute, ausgehend vom Produkt B, zu erhalten.In contrast, the present invention describes a synthesis of prostaglandin A "in 2 stages, starting from dihydroprostaglandin A- · This synthesis is thus shorter than that described in FR-PS 2 104 916. It is also easier to carry out, as it makes it possible to avoid separations of isomers. Finally, the synthesis according to the invention allows starting the prostaglandin A_ with a superior overall yield from product B.
In anderer Hinsicht besitzt das erfindungsgemäße Verfahren ebenfalls zwei bedeutende Vorteile im Vergleich zu dem in J.A.C.S., 98_, 6 (1976), S. 83 beschriebenen Verfahren, das darin besteht, ein Prostaglandin Ap, ausgehend von einem Derivat des Dihydroprostaglandins A-, durch Verwendung von Phenylselenylchlorid herzustellen.In other respects, the inventive method has also two significant advantages compared to the method described in J.A.C.S., 98_, 6 (1976), p. 83, the consists in a prostaglandin Ap, starting from a derivative of dihydroprostaglandin A-, by using phenylselenyl chloride to manufacture.
In der Tat wird die in J.A.C.S. beschriebene Synthese in 4 Stufen durchgeführt, während diejenige der vorliegenden Erfindung nur zwei benötigt. Überdies verwendet die in J.A.C.S. beschriebene Synthese ein toxisches Reagens, während das beiIndeed, the J.A.C.S. synthesis described in 4 steps are carried out while that of the present invention requires only two. In addition, the J.A.C.S. synthesis described a toxic reagent, while that in
709882/1097709882/1097
der erfindungsgemäßen Synthese verwendete Reagens nicht toxisch ist.reagent used in the synthesis of the present invention is non-toxic is.
Das folgende Beispiel erläutert die Erfindung, ohne sie zu be schränken.The following example illustrates the invention without being restrict.
(8RS,12SR.15SR)(5Z.13E)-9-Oxo-15-hydroxy-prostatrien-5.10,13-säure (8RS, 12SR.15SR) (5Z.13E) -9-oxo-15-hydroxy-prostatrien-5.10,13- acid
Stufe A; (8RS.12SR.15SR)(5Z,13E)-9-0xo-10-p-toluolsulfinyl-15-hydroxy-prostadien-5,13-säureLevel A; (8RS.12SR.15SR) (5Z, 13E) -9-0xo-10-p-toluenesulfinyl-15-hydroxy-prostadiene-5,13-acid
Man bringt unter Inertgas 363 mg Diisopropylamin in 5 cm Glyme ein. Man kühlt auf -78°C ab und bringt langsam 2,8 cm Butyllithium mit einem Titer von l,3n ein. Man läßt das Gemisch auf O C zurückkehren und kühlt nach 15 Minuten bei dieser Temperatur erneut auf -78°C ab und fügt langsam 336 mg (8RS,12SR,15SR)(5Z,13E)-9-Oxo-15-hydroxy-prostadien-5,13-säure in Lösung in 5 cm Glyme und anschließend 210 mg p-Toluolsulfinylchlorid zu.363 mg of diisopropylamine are introduced into 5 cm under inert gas Glyme a. It is cooled to -78 ° C. and 2.8 cm of butyllithium with a titer of 1.3n is slowly introduced. The mixture is left return to O C and cool at this after 15 minutes Temperature again down to -78 ° C and slowly add 336 mg (8RS, 12SR, 15SR) (5Z, 13E) -9-oxo-15-hydroxy-prostadiene-5,13-acid in solution in 5 cm of glyme and then 210 mg of p-toluenesulfinyl chloride.
Man beläßt 1 Stunde bei -78°C, gießt in eine gesättigte Mononatriumphosphatlösung, extrahiert mit Äthylacetat, trocknet und dampft unter vermindertem Druck zur Trockne ein. Man erhält ein gelbes Öl.It is left for 1 hour at -78 ° C, poured into a saturated monosodium phosphate solution, extracted with ethyl acetate, dried and evaporated to dryness under reduced pressure. You get a yellow oil.
Stufe B; (8RS.12SR.15SR)(5Z.13E)-9-Oxo-15-hydroxy-prostatrien-5,1O%13-säureLevel B; (8RS.12SR.15SR) (5Z.13E) -9-Oxo-15-hydroxy-prostatrien-5.1O % 13-acid
Das in der vorstehenden Stufe erhaltene Öl wird in 5 cm Toluol in Lösung gebracht und 30 Minuten zum Rückfluß erwärmt. Man dampft zur Trockne ein und chromatographiert das erhaltene Öl an Siliciumdioxydgel, wobei man ein Benzol-Äthylacetat-Essigsäure-Gemisch (6θ/4θ/ΐ) verwendet.The oil obtained in the previous step is dissolved in 5 cm of toluene brought into solution and heated to reflux for 30 minutes. It is evaporated to dryness and the oil obtained is chromatographed on silica gel, using a benzene-ethyl acetate-acetic acid mixture (6θ / 4θ / ΐ) is used.
Man erhält 109 mg des erwarteten Produkts [Rf = 0,5 (Chloroform-Methanol-Essigsäure: 95/5/5)] und gewinnt 145 mg Ausgangsprodukt zurück. 709882/1097 · 109 mg of the expected product are obtained [Rf = 0.5 (chloroform-methanol-acetic acid: 95/5/5)] and 145 mg of starting product are recovered. 709882/1097
Claims (2)
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 |
|---|---|
| DE2730762A1 true DE2730762A1 (en) | 1978-01-12 |
Family
ID=9175362
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19772730762 Withdrawn DE2730762A1 (en) | 1976-07-07 | 1977-07-07 | PROCESS FOR THE PRODUCTION OF PROSTAGLANDIN A LOW 2 AND CERTAIN DERIVATIVES OF ITSELVES |
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 |
| WO2016143537A1 (en) | 2015-03-09 | 2016-09-15 | 三菱瓦斯化学株式会社 | Method of isomerizing diaminodicyclohexylmethane |
-
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 CA CA282,191A patent/CA1087614A/en not_active Expired
- 1977-07-06 IE IE1407/77A patent/IE45609B1/en unknown
- 1977-07-06 DK DK303977A patent/DK303977A/en not_active Application Discontinuation
- 1977-07-06 BE BE179126A patent/BE856545A/en not_active IP Right Cessation
- 1977-07-06 LU LU77693A patent/LU77693A1/xx unknown
- 1977-07-07 CH CH840477A patent/CH622247A5/en not_active IP Right Cessation
- 1977-07-07 JP JP8050777A patent/JPS537649A/en active Pending
- 1977-07-07 DE DE19772730762 patent/DE2730762A1/en not_active Withdrawn
- 1977-07-07 GB GB28566/77A patent/GB1538037A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FR2357542A1 (en) | 1978-02-03 |
| SE420091B (en) | 1981-09-14 |
| NL7707458A (en) | 1978-01-10 |
| JPS537649A (en) | 1978-01-24 |
| IE45609B1 (en) | 1982-10-06 |
| BE856545A (en) | 1978-01-06 |
| HU178334B (en) | 1982-04-28 |
| IE45609L (en) | 1978-01-07 |
| SE7706998L (en) | 1978-01-08 |
| GB1538037A (en) | 1979-01-10 |
| CA1087614A (en) | 1980-10-14 |
| CH622247A5 (en) | 1981-03-31 |
| FR2357542B1 (en) | 1979-07-06 |
| LU77693A1 (en) | 1978-01-31 |
| DK303977A (en) | 1978-01-08 |
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| 8139 | Disposal/non-payment of the annual fee |