JPS60193964A - 6-hydroxyiminoprostaglandin e1 and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is H, 1-10C alkyl, phenyl, 3- 10C cycloalkyl, etc.; R<2> and R<3> are H, tri(1-7C)hydrocarbon-silyl, or together with O of OH form an acetal bond; R<4> is H, methyl or vinyl; R<5> is 3-8C alkyl, phenyl, 1-6C alkoxy, etc.; X is single bond or methylene). EXAMPLE:dl-(15RS)-11,15-bis( t-butyldimethylsilyl )-6-hydroxyiminoprostaglandin E1 methyl ester. USE:Useful as pharmaceutical and their synthetic intermediate. PREPARATION:The compound of formula I can be prepared by carrying out the conjugated addition reaction of the compound of formula II [R<21> is tri(1-7C)hydrocarbon-silyl, etc.] with an organic copper compound, reacting the reaction product with the compound of formula III (R<11> is 1-10C alkyl, etc.), converting the nitro group to hydroxyimino group, and if necessary, subjecting the reaction product to the deprotection, hydrolysis, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to 6-hydroxyiminoprostaglandin E,
and its manufacturing method. More specifically, the present invention describes novel 6-hydroxy p-ximino prostaglandin islands useful as pharmaceuticals and intermediates thereof, and 4-substituted-2
- Conjugate addition of organocopper compounds to cyclopentenones,
The present invention relates to a method for producing 6-hydroxy-p-ximino prostaglandin E1 at once using a key step of capturing the enlate generated in the system with a nitroolefin and then converting the nitro group into a hydroxyimino group. .

Prior art 6 - Oxoprostaglandin activation is pstacyclinic/
It is known as an in vivo active metabolite of prostacyclin (C, P, Qu
illey et al., J.P. Journal, Ono, Pharmacology, Vol. 57, pp. 273-276! 1979, 'P, Y., Wong et al., a-p.

Journal, Op, 7 Humacogy, Volume 60, 245
~248 pages, 1979; C,N.

B e rry et al.,]]7-? =y agy, vol. 26,
pp. 324-330, 11183; R, J, Grif
fiths et al.

Pritish, Journal, Op., F7-Macopsy, vol. 79, pp. 149-155.

(1983). Furthermore, some analogs of the above compounds are known to have not only platelet aggregation inhibiting and blood pressure lowering effects, but also excellent anti-ulcer effects (Japanese Patent Application Laid-Open No. 53-84
Publication No. 942.

JP-A No. 54-44639, 4+) JP-A No. 11555-
(See Publication No. 141465, Japanese Patent Application Laid-Open No. 1987-74660)
It has also been reported that it has a cell-protecting effect (
Unexamined Japanese Patent Publication No. 111 (No. 58-164512 9% Unexamined Japanese Patent Publication No. 58-164512)
203911, JP-A-58-203964). Prostacyclin has a half-life of activity of about a few minutes at physiological pH, and there is a problem with its stability as a drug, but the above-mentioned 6-oxoprostyllandin E is more stable than prostacyclin ( C,P,
For this reason, the application of 6-oxoprostaglandin islands and their analogs to pharmaceuticals is expected.

Purpose of the Invention The present inventors, with the intention of converting such useful 6-oxoprostaglandin islands and their analogues into pull drugs, have conducted extensive research into derivatives thereof, and have discovered 6-oxoprostaglandin as a compound that meets the purpose. We have successfully synthesized a new 6-hydroxyimino prostaglandin E, which is a human-xyiminated 6-position of grandin E, and also synthesized the present 6-hydroxyiminoprostaglandin E, as shown as a reference example described below. The present invention was also achieved by discovering that staglandin E is a synthetic intermediate for 6-oxoprostaglandin E.

Therefore, an object of the present invention is to provide novel compounds such as 6-hydroxyiminoprostaglandin E as prodrugs and synthetic intermediates, and a method for producing the same.

Structure and Effects of the Invention The present invention provides 6-substituted p-staglandin E, which is a compound represented by the following formula CI), its enantiomer, or a mixture thereof in any proportion.

In the above formula CI), X represents a single bond or a methylene group. Therefore, when X represents a single bond, the above formula CI) means 6-hydroxyiminop-staglandin F4 represented by the following formula [1'], and when X represents a methylene group, the above formula C
I) is 15-deoxy-16 represented by the following formula ['']
-HydroiI-C6-Hydo-p-ximinoprostaglandin E.

R1 is a hydrogen atom, a C1-CIO alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C, ~C
1° cycloalkyl group, substituted or unsubstituted phenyl CC, ~C,) alkyl group.

or - represents an equivalent cation.

Examples of the alkyl group of CI""CIO include methyl, ethyl, n-propyl+1so-propyl, n-dutyl, and tert-butyl.

n-pentyl, n-hexinocy, n-heptyl.

Straight chain or branched ones such as n-octyl, n-nonyl and n-decyl can be mentioned.

Examples of substituents for the directly substituted or unsubstituted phenyl group include a halogen atom, a hydroxy group, and c! ~q7cipoxy group, C2-C4 alkyl group which may be substituted with a halogen atom, C1-C4 which may be substituted with a halogen atom
C4 alkoxy group? Nitrile group, carboxyl group or (
CI-Q) Alkoxycarbonyl group and the like are preferred.

The halogen atom is preferably fluorine, chlorine or bromine, particularly fluorine or chlorine.

Examples of the acyl group include acetoxy, propionyloxy, n-butyryloxy+1so-butyryloxy, n-valeryloxy, igo-valeryloxy, cabroyloxy, enantyloxy or pesozoyloxy. be able to.

Examples of the C3-C, furkyl group which may be substituted with halogen include methyl, ethyl, n-propyl, 180-propyl+1-methyl, chloromethyl, dichloromethyl,
Preferred examples include p-methyl and the like. Examples of the q-C4 alkoxy group optionally substituted with hapgen include methoxyethoxy, n-
Preferred examples include propoxy+igo-p-boxy, n-butoxy, poly-promethoxyradichloro-p-methoxy, and trifluoromethoxy. (C,
~c4) Examples of the alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, hexyloxycarbonyl, and the like.

The substituted phenyl group can have 1 to 3, preferably 1 substituent as described above.

Substituted or unsubstituted C8-CIO dichlorofurkyl groups include saturated or unsaturated C, -Cl01, preferably ra to, particularly preferably q groups, substituted with the same substituents as mentioned above or unsubstituted; For example, cyclopropyl-9-cyclopentyl, Schiff-1-hexyl, Schiff-hexenyl-cycloheptyl-9-cyclooctyl-9-cyclodecyl, and the like can be mentioned.

The substituted or unsubstituted phenyl CC, -c-furkyl group includes benzyl, α-7enethyl, substituted with the same substituent as mentioned above or unsubstituted phenyl group,
Examples include β-phenethyl.

Examples of monoequivalent cations include ammonium cations such as NHa++ tetramethylammonium, monomethy/L-ammonium, dimethylammonium, trimethylammonium, benzylammonium, phenethyl ammonium, morpholinium cation, monoethanol ammonium, piperidinium cation; Ten,
Alkali metal cations such as K0; 1/2Ca” +
1/2 Mg! +* ”/2Zn” + 1/3A7”
Divalent or trivalent metal cations such as 10 and the like can be mentioned.

As R1, a hydrogen atom I C, -C8° furkyl group or a single cation is preferable.

W and Hs are the same or different, hydrogen atom +)
') (C1-C,) Translation Hydrogen A group that forms an acetal bond with the oxygen atom of a silyl group or hydroxyl group.

tri(01-q)R as hydrogensilyl group) L such as trimethylsilyl, triethylsilyl.

Tri(C) such as t-butyldimethylsilyl group.

-C4)alkylsilyl, diphenyl(C,P-04)alkylsilyl such as t-butyldiphenylsilyl, or tribenzylsilyl, etc. can be mentioned as preferred.

Examples of groups that form an acetal bond with the oxygen atom of a hydroxyl group include methoxymethyl-1-ethoxyethyl,
2-methoxy-2-propyl, 2-ethoxy-2-bouvil, (2-methoxyethoxy)methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-detrahydrofuranyl or 6,6-dimethyl-3-oxa -2-oxobicyclo(3,1,0)hex-4-yl group may be mentioned. Among these, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 1-ethoxyethyl, 2-methoxy-2-propyl, (2-methoxyethoxy)methyl or 6,6-dimethyl-3-oxa-2-oxobicyclo( 3,1,0)hex-4-yl group is particularly preferred.

Among these, W or R3 is a hydrogen atom, tri(
C, ~C4) alkylsilyl group, diphenyl (CIA-
C4) alkylsilyl group + 27 trahydrobilanyl group,
2-tetrahydrofuranyl group,! -ethoxyethyl group,
2-ethoxy-2-propyl group, (2-methoxyethoxy)methyl group, 6,6-dimethyl-3-oxa-2
-oxo-bicyclo (a,t,o)hex-4-yl group is preferred.

In the above formula (1) (including (CI') and (u')), W represents a hydrogen atom, a methyl group, or a vinyl group.

In the above formula (1) (CI') (including one C1), R is a straight chain or branched chain C, ~C, which may contain an oxygen atom, a furkyl group; an optionally substituted phenyl group; Phenoxy group or C8-CIO dichlorofurkyl group; or C8-C6 alkoxy & 1i1
．． represents a straight or branched chain C3-CI alkyl group substituted with an optionally substituted phenyl group, a phenoxy group, or a C,-ClO cycloalkyd group;

Straight chain or ti-branched @ which may contain oxygen atoms
Pseudo~C8 alkyl group and text is 2-methoxyethyl, 2-
Ethoxyethyl, propyl.

Butyl, pentyl, hexyl, heptyl, octyl, 1
-Methyl-1-butyl, 2-methyl-1-butyl, 2-
Methylhexyl, 2-methyl-2-hexyl, 2-hexyl, l,1-dimethylpentyl group, preferably 2-methoxyethyl, butyl, pentyl, hexyl.

4- or (~-methylhexyl, 2-hexyl, 1
-Methyl-1-butyl group, 4? Preferred is a butyl group.

The optionally substituted phenyl group and phenoxy group may be substituted with the substituents listed as the substituents for the substituted phenyl group of R1. Further, as the optionally substituted C1-C, cycloalkyl group, a saturated or unsaturated C1-CIO which is substituted with the same substituent as mentioned above or is unsubstituted, preferably to -Cy +
Particularly preferred are C, C, cycloalkyl groups such as cyclopropyl, cyclopentyl, cuclohexyl, cyclohexenyllasic Iybutyl! cyclooctyl,
Examples include cyclodecyl group.

C3-C, phenoxy group, phenyl group optionally substituted with 5, phenoxy group or C1-C,0 cyclo+:+
Straight chain or branched chain C1- substituted with a furkyl group
C, -C among the alkyl groups.

Examples of the alphyl group include methoxy, ethoxy, p-p-boxy, isop-1-boxy, butoxy, t-p-boxy,
Examples include hexyloxy group, and the optionally substituted phenyl group and phenoxy group include those mentioned above as they are. Q = C+. As the dichlorofurkyl group, the above-mentioned ones can be preferably mentioned as they are, and as the straight chain or branched @C, ~C, furkyl group, methyl, ethylgubu pvir + 1so-propyl, gutyl, 1so-butyl, 5ee-notyl ,
Examples include t-butyl and pentyl groups, and the substituent may be bonded to any position thereof.

Further, in the compound represented by the above formula (J), the steric configuration of the substituent bonded to the cyclopentanone ring is natural prostaglandin E.

It is a particularly useful stereoisomer because it has the same configuration as CI, but in the present invention, its mirror image, the following formula CI
) ent C) It also includes mixtures in arbitrary proportions. Also OR”,
Since the carbon substituted by R4 and W is an asymmetric carbon, there are two types of optical isomers, and the present invention includes any of the optical isomers or a mixture thereof in any proportion.

Further, the hydroxyimino group at the 6-position has two types of geometric isomers, syn form and anti form, but in this production method, it is produced as a mixture of approximately the same amount of geometric isomers.

6- represented by the above formula CI) provided by the present invention
Preferred specific examples of the p-staglandin E1 group include the compounds shown below.

CI) A specific example of a compound in which X is a single bond (the prostaglandin island is PGE).

It is abbreviated as . ) 01) 6-Hydroxyimino-PGE.

02) 16-Methyl-6-hydro p-ximine 7PGE.

03) 16-methyl-6-hydroxyimino-pGE+ 04) l2-methyl-6-hydroxyimino-p
G & Q5) I8-Methyl-6-hydro-ximino-pGE.

06) 19-Methyl-6-hydroxy μximino-P
G EI Q7) 20-Methyl-6-hydroxyimino-PGEl o8) 20-ethyl-6-hydroxyimino-PGE
.

09) 20-propyl-6-hydroxyimino-PG
El 10) 16-ethyl-6-hydroxyimino-PGE
+ 11) 17-ethyl-6-hydroxyimino-PGF4 12) 16, 16-dimethyl-6-hydroxyimino-PGE.

l11) 16117-dimethyl-6-hydroxyimino-PGE.

14) se, 20-dimethyl-6-hydroxyimino-PGE.

15) 17,20-dimethyl-6-hydro-p-ximino-PGE.

16) 16,16.20-)dimethyl-6-hydroxyimino-PGE.

17) 17-Methyl-20-ethyl-6-hydroxyimino PG E.

1s) t7,20-diethyl-6-hydroxyimino-PGE4 19) 15-cyclopentyl-ω-pentanol-6-hydroxyimino-PGE.

20) 15-Cyclohexyl-ω-pentanol-6-hydroxyimino-PGE.

21) 15-(2,3-diethyl)cyclopropyr-
ω-penta/ru-6-hydroxyimino-PGE.

22) 15-(2,2-dimethyl)cyclopentyl-
ω-pentanol-6-hydroxyimino-PGE.

23) 15-(4-t-butyl)cyclohexyl ω
-Pentano-6-hydroxyimino PGB.

24) 16-cyclopentyl-ω-tetratrue 6-hydroxyquimitwo PG E.

25) 16-cyclopentyl-ω-trinor-C-hydroxyimino-PG E.

26) 17-cyclopentyl-ω-tree true 6-
Hydroxyimino-PGE.

27) 18-cyclopentyl-ω-dinol-6-hydroxyimie/-PGE.

28) 16-cyclohexyl-ω-teFlanol-6-hydroxyimino-PGE.

29) 16-cyclohexyl-ω-trinor-6-hydro-p-ximino-PGE.

3G) 17-Cyclohexyl-ω-trinor-6-hydro-p-ximino-PGE.

31) 18-cyclohexyl-ω-dinol-6-hydro-p-ximino-PGE.

32) 16-cyclooctyl-〇-tetwonoru6-
Hydroximino-PGE.

33) 18-Cyclobuvir-ω-dinol-6-hydro p-xy-imino-PGE.

34) 19-Sykρp-Pyroω-True 6-Hydoxyimino-PGE.

3B) 18-oxa-6-hydro-p-ximino-P
G.E.

36) 16-phenyl-ω-tetratrue 6-hydrokiquimitwo PG E.

37) sy-phenyl-ω-trinor-6- and droxyimino-PGE.

38) 16-phenoxy-ω-tetratrue 6-hydro p
Kisii Mino-P G E.

39) Methyl esters of the compounds of 01) to 38) 411) Ethyl esters of the compounds of 01) to 38) 41) Sodium salts of the compounds of ol) to 38) 42) Hydroxyl groups of the compounds of 01) to 41) 11th place and 1st
Examples thereof include, but are not limited to, ethers in which the 5-position is substituted with a t-7' methyldimethylsilyl group and/or a 2-tetrahydropyranyl group. Also included are the 15-shrimp forms of compounds 01) to 42) and their enantiomers.

(If) A specific example of a compound having an xhz methylene group (Prustabrangin E is PGE).

It is abbreviated as . ) 51) 15-deoxy-16-hydrokey 6-hydro p
Xiimino-PGE.

52) ts-deoxy-16-hydroxy-px-18-oxa-6-hydroxyimino-PGE.

5B) 18+19+20-trinor-15-deoxy-16-hydroxy-17-phenoxy-6-hydroxyimino-PGE.

54) 15-thioxy-16-hydro p-xy-20-methyl-6-hydro p-ximino-PGE.

55), 15-deoxy-16-hydroxy-17,2
0-dimethyl-6-hydroxy cyimino-PGE.

56) 17 + 18 + 19 + 20-tetratrue 15-deoxy-16-hydroxy 16-cyclopentyl-6-hydro p-ximino-PGE.

57) 17,18,19,20-tetratrue 15-deoxy-16-hydroxy-16-cyclohexyl-6-hydroxyimino P G E1 58) 15-deoxy-16-hydropx-16-methyl-6-hydroxyimino -PGE.

59) 1B-deoxy-16-hydroxy-16-methyl-18-oxa-6-hydroxyimino PG E.

60) 18,19.20-)Linol-15-deoxy-16-hydroxy-17-phenoxy-16-methyl-6-hydroxyimino PG E.

61) 1B-deoxy-16-hydroxy-16,20
-dimethyl-6-hydroxyimino PG E.

62) 15-deoxy-16-hydroxy-16,17
, 20-) samethyl-6-hydro-p-ximino-PGE.

63) 17 + 18 + 19 + 20-tetratrue-15-deoxy-16-hydroxy-16-cyclopentyl-16-methyl-6-hydroxyimino-PGE.

64) 17,18,l9,20-tetratrue-1s-deoxy-16-hydroxy-p-xy-16-cyc-1-hexyl-16-methyl-6-hydro-p-ximino-PCB.

65) 15-deoxy-16-hydroxy-16-vinyl-6-hydro-p-ximino-PGE.

66) 15-deoxy-16-hydropxy-16-pinyl-18-oxa-6-hydroxyimino-PGE.

67) 18.19.20-) Linol- 15-deoxy-16-hydro poxy -17-phenoxy16-pinyl -6-Hydroxyimino PGF.

6g) 15-deoxy-16-hydroxy-20-methyl-16-vinyl-6-hydro-p-ximino-PG Karasu 69) 15-deoxy-16-human-xy 17.20
-dimethyl-16-vinyl-6-hydro p-ximino-PG island 70) 17,18,19,20-tetratrue 15-deoxy-16-hydroxy-16-cyclopentyl-16-vinyl-6-hydro! Xiimino-PGE.

71) 17118119 * 20-tetrano/l-
-15-deoxy-16-hydroxy-16-cyclohexyl-16-vinyl-6-hydroxyimino PG E.

72) Enantiomers of compounds of 51) to 71) 73) 51
)~72) Methyl ester of the compound 74) Ethyl ester of the compound 61)~72)? ! 1) Sodium 76) of compounds 51) to 72)
Hydroxyl groups (11th and 16th positions) of compounds 51) to 74)
Examples include, but are not limited to, ethers in which is bound by a t-tutyldimethylsilyl group and/or a 2-tetrahydropyranyl group. Also included are the 15-shrimp forms of compounds 61) to 76) and their enantiomers.

The 6-hydro-ximinoprostaglandin avian of the present invention represented by the above formula CI) is a 4-substituted-2-cyclobentenone represented by the following formula (U) 0R" or its enantiomer, or any of them A mixture of the proportions of an organic lithium compound represented by the following formula (III) 4 OR"1 and the following formula [Support CuQ
...Song/Song [■] A conjugate addition reaction is carried out with an organic copper compound obtained from a copper compound represented by the following formula (), and then a nitroolefin represented by the following formula () is reacted, and then the nitro group is converted into a hydroxyimino group. Convert and more must! By subjecting it to deprotection and/or hydrolysis and/or salt-forming reaction according to Prostaglandin E1 class can be produced.

The 4-substituted-2-cyclobentenones are known substances and are easily available. In the formula, as understood from the definition, R" is the one obtained by removing the hydrogen atom from the definition of R1, and is the same as that described above for the specific example of R1. The synthesis of this compound is described in the literature Tetrahedron + V
Reference is made to OL, 32.1713 (1976).

Similarly to R'', R'' in the organolithium compound of formula [■] is defined by removing the hydrogen atom from the definition of R''.

Q in the copper compound of formula (ff) is a halogen atom such as chlorine, fluorine, or bromine; a C8-C, alkoxy group such as methoxy, ethoxy, or p-boxy group; phenoxy group: phenylthio group; dimethylamino, diethylamino, diethylamino represents a di(C,S-C.)furkyl7ξ group; or a cyano group.

In order to obtain an organocopper compound from an organolithium compound of formula (m) and a copper compound of formula (IV), for example, documents G, H, P
o5ner l Organic Reaction+
Vol, 19, 1 (1972) + Tetr
ahedron IAJtt-+ 21 + 1247
(198G) etc. are considered as references.

In the 2) p-olefins of formula [■], R'' is the definition of R1 with the hydrogen atom and -equivalent cation removed, and such compounds are described in the literature Journal of Ame.
rjcan Chemical 5ociety, 9
8, 4679 (1976).

The 4-substituted-2-cyclobentenones and the organocopper compound are stoichiometrically reacted in equimolar amounts;
-0.5 per mole of substituted-2-cyclobentenones
The organic copper compound is used in an amount of 2.0 to 2.0 mol, particularly preferably 1.1 to 1.3 mol.

The reaction temperature is 120℃~θ℃, preferably 10℃
A temperature range of about -30°C is adopted. The reaction time varies depending on the reaction temperature, but is usually about 1 at -78°C to -20°C.
A time reaction is sufficient.

The reaction is carried out in the presence of an organic medium. An inert, non-ptonic organic medium that is liquid at the reaction temperature and does not react with the reaction reagents is used.

Examples of such aprotic polar solvents include saturated hydrocarbons such as pentane, hexane, and hebutane; aromatic hydrogen ash such as benzene, toluene, and xylene; diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol. Ether solvents such as dimethyl ether; other hexamethylphosphoric triamide (HMP) I
N,N-dimethylformamide (DMF), NlN-
Examples include so-called aprotic polar solvents such as dimethyl 7-ceto-7mide (DMAC), dimethylsulfoxidrasulfolane, and N-methylpyrrolidone, and it is also possible to use a mixed solvent of two or more solvents. Further, as the non-butonic inert organic medium, the inert medium used for producing the organocopper lithium compound can also be used as it is. That is, in this case, #4-ff conversion-2 was added to the reaction system in which the organic steel lithium compound was produced.
-The reaction may be carried out by adding cyclobentenones. The amount of organic medium used is sufficient as long as it allows the reaction to proceed smoothly, and is usually 1 to 100 times the volume of the raw materials, preferably 2 to 30 times the volume of the raw materials.

The reaction is preferably carried out in an atmosphere of nitrogen or argon gas. In addition, when carrying out the reaction, a trivalent phosphorus compound such as trialkylphosphine (e.g., triethylphosphine) is used.

The reaction is preferably carried out in the presence of tri-n-butylphosphine, etc.), trialkyl phosphites (e.g., trimethyl phosphite, triethyl phosphite, triisopropyl phosphite, tri-n-butyl phosphite, etc.). )! Preference is given to using J-n-butylphosphine.

In the method of the present invention, [4-[
It is assumed that an alkenyl group, which is the organic group of the organocopper compound, is added to the 3-position of the substituted-2-cyclobentenone, and an anion is generated at the 2-position, forming a so-called conjugated addition elerate. Ru. By reacting the nitroolefins defined by the above formula (V) with this conjugation processing route, the 6-nidoR prostaglandin Eln conductor with which the nitroolefins have reacted is present in the reaction system. (7sietro salt intermediate) is assumed to be produced.

The reaction of Nido-olefins may be carried out by diluting the above-mentioned non-propylene organic medium in a reaction system in which the 4-@substituted-2-cyclobentenone 1lAlc conjugate addition is carried out with the shoulder machine steel compound. This is carried out by adding (2) p-olefins represented by formula (V).

Mosquito p-olefins react with erulate produced by conjugate addition in stoichiometrically equimolar amounts, but usually,
-2-cyclobentenones 1 replaced with the initially used 4-1
0.5 to 2.0 times mole, particularly preferably 0
．． It is carried out using 8 to 1.2 molar amounts.

The reaction temperature is -120°C to 0°C, preferably -0°C to -
A temperature range of 30 degrees Celsius is adopted.

The reaction time varies depending on the reaction temperature, but is usually between -78°C and -4°C.
A reaction time of about 1 hour at 0°C is sufficient.

In the method of the present invention, 1lth
4-@'4Q% - An alkenyl group, which is the organic group of the organolithium compound, is added to the 3-position of the -2-cyclobentenone, and an anion is generated at the 2-position. It is assumed that it is in the form of a so-called acinitro salt in which the α-position of the nido group (position 6 in prostaglandin nomenclature) becomes an anion through Michael addition. The most important feature of the method of the present invention is that the acinitro salt intermediate produced by the above-mentioned two-step reaction (so-called three-component ligation reaction) is directly subjected to the next reaction to convert the nitro group into a hydroxyimino group. 4-substituted-2-
A three-step reaction is carried out using cyclobentenones without any isolation operation during the process, and 6-hydroxyiminoprostaglandin birds represented by the above formula (Vl) are produced.

Next, a reaction for converting the acyni)p group of the 7sietro salt intermediate into a hydroxyimino group will be described. Generally, the reaction of converting a nitro group into an oxo group is called a NEF reaction, and it is known that the reaction intermediate of this conversion reaction is an acinitrone salt. As reaction conditions for such a conversion reaction, (1) a method using an acid, (2) a method using a reducing agent, and (3) a method using an oxidizing agent are known.
Among these methods, in the method using a reducing agent, the 7-sinitro salt passes through the hydroxyimino form and is further reduced to be converted to an oxo group, thereby completing the Nef reaction. (e.g., J., E., McMurry et al.
J, Org.

References include Ch@m, 38, 4367 (1973). ) The present inventors conducted extensive research with the aim of efficiently obtaining the hydroxyimino form that is generated during the process. As a result of intensive research, the reaction from the 7sietro salt to the hydroxyimino form is more effective than the reaction from the human-xyimino form to the oxy form. The synthesis of 6-hydroxyiminopus taglandins EI of the present invention was achieved by discovering that the process proceeds quickly under mild conditions. The reaction conditions will be described below.

In the present invention, a reducing agent is used in the reaction of converting the acyni)p salt intermediate to the hydroxyimino compound. Examples of such reducing agents include low-valent metal compounds having reducing power such as trivalent titanium compounds, divalent vanadium compounds, and divalent Kudim compounds. It is particularly preferably used.

As the trivalent titanium compound, commercially available titanium trichloride aqueous solutions can be used as they are. However, if the reaction is carried out using only an aqueous titanium trichloride solution, the pH of the reaction system will be less than 1, resulting in strongly acidic conditions, which is not preferable. Therefore, in order to control the pH to around neutrality (pH 4 to 7, preferably around 6), a buffer salt is usually added to carry out the above reaction. Such buffer salts include, for example, sodium formate/ammonium acetate, sodium acetate! Examples include potassium acetate, sodium conolinate, sodium citrate, sodium tartrate, sodium phthalate, sodium phosphate, potassium disodium phosphate, potassium dipotassium phosphate, etc., but ammonium acetate is particularly preferred. .

Titanium trichloride is used in a molar amount of 1 to 20 times, preferably 2 to 15 times, preferably 3 to 10 times, based on the nitroolefin of formula (V). The amount of buffer salt used varies depending on the type of buffer salt and the amount of titanium trichloride used, and is determined while observing changes in pH. For example, when using ammonium acetate, the amount of titanium trichloride used is
When twice the molar amount is used, the pH of the reaction solution is adjusted to around 6.

In order to make the reaction proceed smoothly, K is preferably added to the reaction system with a relatively water-soluble organic medium, such as ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane, and dioxane, or methanol and ethanol. Examples include alcoholic solvents such as propyl alcohol, acetone, tNsN-dimethylformamithraacetic acid, and the like.

This reaction involves the conversion of the acyl)E salt to the oxo form.
-- Since the hydroxyimino compound, which is an intermediate of the reduction reaction, is efficiently obtained, the reaction is carried out at a reaction temperature of 9 reaction times.

Although it varies depending on the amount of reducing agent used, solvent + pH, etc., the reaction temperature is usually -40°C to 50°C.

Preferably, the reaction is carried out in the range of θ°C to 20°C, and the reaction time varies depending on the reaction conditions such as the reaction temperature and the amount of reducing agent + pH. If the reaction is followed by analytical means such as thin-layer chromatography, the reaction is more likely to occur than K. The end point of 0°C is determined.
It will be completed in 1 to 3 hours.

After the reaction, the resulting product is separated from the reaction solution and purified by conventional means. For example, extraction.

This can be done by washing, chromatography, or a combination of these.

In this way, the hydroxyl group of the compound represented by formula CI) is protected, and an ester of the carboxylic acid at the 1-position is obtained. Since the production method of the present invention uses a reaction that proceeds stereospecifically, a compound having the configuration represented by the above formula [1] can be obtained from a starting material having the configuration represented by the above formula (II). From the enantiomer of the formula CI), the enantiomer of the formula CI) represented by the formula (I) ant can be obtained.

Among the thus obtained compounds represented by the above formula CI), compounds in which the hydroxyl group is protected and the carboxylic acid at the 1st position is an ester form have two oxo groups (6-position carboxylic acid) present in the same molecule. Since one of the two (6) and 9) is in the form of an oxime, it is necessary as an intermediate to lead to other derivatives using this compound as a starting material. Furthermore, it is a useful derivative as an intermediate that can be converted into 6-oxygen p-staglandins, which are important as pharmaceuticals, through reduction or hydrolysis reactions.

Furthermore, the compound in which the hydroxyl group obtained here is a gas film, and the carbo/acid at the 1st position is an ester, can then be released as needed! t&! It can be subjected to hydrolysis or salt-forming reactions.

Removal of the hydroxyl protecting group (R2 and/or R8) is
In the case where the bonding group is a group that forms a 7-cetal bond with the oxygen atom of the hydroxyl group, 9 for example, acetic acid, a pyridinium salt of p-toluenesulfonic acid, or a cation exchange resin, etc. are used as a catalyst, such as water, tetrahydrofuran, ethyl This reaction is suitably carried out using ether, dioxane, 7cetone+7cetonitrile, etc. as the reaction solvent. The reaction is usually -78℃~
The temperature range is +50°C for 10 minutes to 3 days.

Further, when the protecting group is ) U (C, ~C,) hydrogen enzylide silyl group, for example, acetic acid, tetrabutylammonium fluoride, cesium fluoride.

Hydrofluoric acid! The reaction is carried out using hydrogen fluoride-pyridine as a catalyst in the reaction solvent described above at the same temperature and for a similar period of time.

The removal of the protecting group (R') of the carboxyl group, that is, the hydrolysis reaction, is carried out using an enzyme such as lipase or esterase in water or a solvent containing water at a temperature range of -10°C to +60°C for 10 minutes to 24 hours. It is done to some extent.

According to the present invention 91HC, the carboxyl group-containing compound produced by the above-mentioned hydrolysis reaction is then further subjected to a salt-forming reaction, if necessary, to give the corresponding carboxylate.

The salt formation reaction itself is known, and carboxylic acid is [%
amount of potassium hydroxide! Basic compounds such as sodium hydroxide and sodium carbonate, or 71) Limethylamine, monoethanolamine, and morpholine! A neutralization reaction is carried out in a conventional manner.

6-hydroxyiminoprostaglandin avian represented by the above formula (I), produced by the above method, and a compound represented by the Shimohi formula [■] in which R' + RF is a hydrogen atom, and its enantiomer or a mixture thereof in any proportion, 6-hydroxyiminoprostaglandin E, has interesting physiological activity,
It is also a useful derivative as a boodrug of 6-oxypurstabrandin E, which is extremely useful as a pharmaceutical agent such as a platelet aggregation inhibitor, an antiulcer agent, a vasodilator, an antihypertensive agent, and a therapeutic agent for cytotoxicity.

Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example 1 a-(t)-a-t-butyldimethylsilyloxy-
1-Iodo-1-octene (2,161m5.8.mm
0A! ) in ether solution (50m+7) K1.9M t-butyllithium in pentane solution (6,111J).

lt, 6 mmol) was added at -78°C and stirred for 2 hours.

This solution 1 (cuprous oxide (1,111*5.8mm
oj) Tributylphosphine (2,351, 11,6m
Add an ether solution (10m+4) of -78
The mixture was stirred at ℃ for 1 hour. Add μm4-t-butyldimethylsilyloxy-2-cyclobentenone (1,12
1t 5.3 mmol) in ether solution (10 ml)
was added and stirred at -78°C for 15 minutes and at -40°C for 30 minutes. Then methyl 6-nitro-6-hebutenoate (1
. Then add tetrahydrofuran (sosu), then vinegar i
17 ammonium (8,71 + 114 mmoj) aqueous solution (1001aj) and 25% titanium trichloride aqueous solution (12
114,19rmnoJ) was added and stirred at 0°C for 3 hours. After distilling off tetrahydrofuran under reduced pressure, 1, hexane was added, and the mixture was washed with an aqueous ammonium chloride solution, 1 brine, and dried (Mg5o4) + III M Shite'! , 131
A crude product was obtained. This was subjected to silica gel column chromatography (hexane: ethyl acetate; 9:1 → 1:2).
FC was applied to separate the product, d/-(15R8)-11
, 15-biX(butyldimethylsilyl)-6-nitroprostaglandin E1 methyl ester (948M1
51 *1.48mmoJ, 289G) *dl (
15R8) -11,'15-bis(t-butyldimethylsilyl)-6-oxyp-staglandin B, methyl ester (1221 apm 0.22 mmo7 +l
4%)-both intended l#-(15R8)-11.

15-bis(t-7'tyldimethylsilyl)-6-hydroxyiminoprostaglandin E1 methyl ester (
s s 51n9.1.1 o mmoA! +2t
q! r) was obtained.

NMR (CDα, δ(p)); 0.03 (12H+S) + 0.87 (21H) + 1
．． 1-1.8 (12H+m) 2.0-2.7 (10H,
m), 3.64 (3HI8) 13.8-4.3 (2Ht
mL 5.4-5.7 (2H+m).

IR (liquid film, ff1).

3370+1740+1250110801961)+
870.835.775° FD-MS; 625 (M+), 568 (M-57).

By the same operating procedure as in this example, (38) −
@) 11.15- from -3-t-butyldimethylsilyloxy-1-iodo-1-octene and (4R)-4-t-butyldimethylsilyloxy-2-cyclobentenone
Bis(t-butyldimethylsilyl)-6-hydroxyiminoprostaglandin methyl ester (35%) was obtained. Each spectrum completely matched that of the eight specimens.

Example 2 11.15-bis(1-butyldimethylsilyl)-6-hydropoxyimi7 prostaglandin E obtained in Example 1, methyl ester (313IQ + 0.5 mm
o7) was dissolved in acetonitrile (zoIRt), 0.4-pyridine and then hydrogen fluoride-pyridine (9.8m) were added thereto, and the mixture was stirred at room temperature for 2 hours. The organic layer obtained was washed with brine, dried over magnesium WL acid, concentrated under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 1 :
4) to 6-hydroxy p-ximinop-staglandin E1 methyl ester (151"P+0.38 mmoA
'+76%).

NMR(CDCls + δ(μ)); 0.87(
3) 1+t)+ 1.1 ~ 1.8(12H+m)+
2.0~2-2-7(12H13,64(3HIS)+
3. s ~4.3(2H+m)+5.4 ~s, 7(
2H+m).

IR (liquid film + CI).

3350.1740, 1650.11?5,980°F
D-MS; 397 (M+).

Example 3 By exactly the same method as Example 1 (as 1s S)
-@ -3-t-'7'Tyldimethylsilyloxy-5
-Methyl-1-iodo-1-nonene (1,2e I,
3. a mmolI) and (4R)-4-t-butyldimethylsilyloxy-2-cyclobentenone (s a
O# 12.5 mmo/), then methyl 6-nitoq
-6-hebutenony) (46gM912.5mmo/
), and then 25-titanium trichloride aqueous solution (9,3y, 1s mmo/ ) was added to the reaction solution, and ammonium acetate (6,941, 17,4 mmalt) was added to 231
An aqueous solution of 17 dissolved in water and tetrahydrofuran (11
5N) and stirred at room temperature for 2.5 hours. After the reaction is completed, Example! Similar post-processing.

11,15-bis(1-butyldimethylsilyl)-17(S), 20-dimethyl-6-
Oxoprostaglandin E, methyl ester (554
11940,87mn101 + 35'%) together with the target 11.15-bis(t-butyldimethylsilyl)-17C~, 20-dimethyl-6-hydro-p-ximinoprostaglandin island mer+j-ster (540a
p, 0.83 mmo/, 33%) was obtained.

NMR (CDα, I δ(wa)); −0,03(1
2H+8)+0.90(24HL 1.1~1.7(
13H+m)+1.8~2.7(10H+m)+3
．． 67 (3H+S) +3.85~4.40 (2H+m
) + 5.4~5.65 (2H+m) +6.8~7
．． 35 (disappeared with IH+bs+DtO).

IRC liquid film 1cII) # 335011740+125211090+965+8
35.772,675゜MS (20eV) p 696 (M'Bu) +521 +504 +464
+115° Example 4 11.15-bis(1-butyldimethylsilyl)-17(S, 2G-dimethyl-6 obtained in Example 3)
-Hydo p-ximinop p-staglandin island methyl ester (127#, 0.19 mmoJ) was desilylated in exactly the same manner as in Example 2, and post-treatment 1 separation was performed to obtain 17@), 20-dimethyl-6-hydro pxiimi7 prostaglandin E.

Methyl ester (5111g+ 0.12 mmoj+
+63'j) was obtained.

(a) B-82,7° (CO, 2g, Moon)
NMR (CDα8.δ(騨)); 0.8-1.0(6H+m) + 1.1-1.7(i
aH+m) 11.8-2.7 (12H+m) + 3
．． 64 (3H+8) *3, 7~4.3 (2H+m)
Is, 3-5.7 (2I(+m).

IRC liquid film, mercenary); 3350.1740, 1650.1175, 977゜M
S (20eV); 408 (M-OR), 1190,372゜Example 5 #-@-4-methyl-4-trimethylsilyloxy-! -Iodo-1-octene (1,1211+3.3mmo7) and (4R)-
4-t-dityldimethylsilyloxy-2-cyclobentenone (636K, 3.0mmoJ), then methyl 6-nitro-6-hebutenoate (617Mg+3-
3 mm01), and then a 25-titanium trichloride aqueous solution (22.5m, a6m) was added to the resulting reaction solution.
mo/ ) and ammonium acetate (1s, sg, 21
An aqueous solution prepared by dissolving 751 of 6 mmoljt) in water and tetrahydrofuran (15011 J) were added, and the mixture was stirred at 0°C for 5 hours. After the reaction was completed, the same treatment and column separation as in Example 1 were performed to obtain (16R8)-15-deoxy-11.
-t-Butyldimethylsilyl-16-methyl-16-trimethylsilyloxy-6-hydroxyiminoprostaglandin methyl ester (663"9 + 1.1
1 mm0J + 37%) t' was obtained.

NMR (CDCII + a (11”)); o,
oa(sl(,S), 0.09(9H9S)+0.8
7(12H)+1.11(3H9S)t 1.1 ~1
．． 7(10H*m)*1.8~2.7(12H+m)+
3.63(3H+S)+3.8~4.2(IH+m)
+6.2''-5,6 (2H+m).

IRC liquid film, σ); 3360.1740,1250,1080,970°8
60. 835. 775° FD-MS; 897 (M+) + 540 (M 57).

Example 6 (16R8)-1s-deoxy- obtained in Example 5
11-4-7'Tyldimethylsilyl-16-methyl-1
6-trimethylsilyloxy-6-hydroxyimifupp staglandin methyl nisdel (a o o wg
. (17
7W + 0.43 mmo7, 86%).

NMR (CDCjtm + a (p)); 0.9
0(3H+t)+ 1.13(3H+S)t 1.2~
1.7(10H+m)+2.0~2.8(14I(+n
1) I: t, 5a (ant8) 13.8-4.4 (I
H+m) I 5.3-5, 7 (2H+m).

IRC liquid film, a); 3410.1740.1245.1080,970°7
30° FD-MS; 41 s (M”>.

Claims (1)

[Scope of Claims] 1. 6-hydroxyiminoprostaglandin islands which are a compound represented by the following formula [1], its mirror body, or a mixture thereof in any proportion. 2. 6- according to claim 1, wherein X is a single bond
Hydrop-ximinoprho-staglandin islands. 6-hydroxyiminoprostaglandin E according to claim 1, wherein λ X is a methylene group. - equivalent cation, 6-hydro-p-ximinop-staglandin E1 according to any one of claims 1JJ to 3. a lt and R3 are the same or different hydrogen atoms, t')
(CI”-C4) alkylsilyl group, diphenyl CC
, ~C4) alkylsilyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, J-ethoxyethyl group, 2-ethoxy-2-pyl group, (2-methoxyethoxy)methyl group, or 6, 6-cymethyl-3-
6-hydroxyiminoprostaglandin E according to any one of claims 1 to 4, which is an oxa-2-oxybicyc+y (3,1,0)hex-4-yl group. . (I R1 is a butyl group, a pentyl group, a 1-methyl-1-
Butyl group, 2-methyl-1-butyl group. The 6-hydroxyiminoprostaglandin bird according to any one of claims 1 to 5, which is a cyclopentyl group, a cyclohexyl group, or a phenyl group. 7. 6-Hydo-p-ximinoptastalandin avian according to any one of claims 1 to 6, wherein &W is a hydrogen atom.Claim 1, wherein &W is a methyl group. Section ~ 6th
The 6-hydroxyiminoprostaglandin bird according to any one of the above items. 9. Claims 1 to ge in which R' is a vinyl group
6-hydroxyiminoprostaglandin E according to any one of the above items. lO 4-substituted-2-cyclobentenones represented by the following formula (n) ()R11 or their enantiomers, or mixtures thereof in arbitrary proportions, with an organolithium compound represented by the following formula [river] (IV) Cu
A conjugate addition reaction is carried out with an organic copper compound obtained from a copper compound represented by Q...[1v], and then the following formula () represents an L-kyl group. The following formula ( Vl) A method for producing 6-hydroxyiminoprostaglandin E, which is a compound represented by "0R,OR", its enantiomer, or a mixture thereof in any proportion.1. 6 of Claim 10 which converts into a hydroxyimino group
- A method for producing hydroxyiminop-staglandin E1. 12. The method for producing 6-hydroxyiminoprostaglandins Et according to claim 10, which is carried out by adding a buffer salt to the reaction medium. 1λ The method for producing 6-hydroxyiminoprostaglandins and the like according to claim 11 or 12, wherein the trivalent titanium compound is titanium trichloride. 14. Claims for carrying out in an organic medium containing water [6-hydro p according to any one of items 10 to 13]
A method for producing p-staglandin E, etc. 15. 6- of claim 14, wherein the organic medium is a medium containing an ether-based or alcohol-based solvent.
A method for producing hydroxyiminoprostaglandin E.