JPH0580468B2 - - Google Patents

Description

Detailed Description of the Invention <Industrial Application Field> The present invention is directed to the production of 9-deoxo-9-hydroxymethyl-6-oxoprostaglandin E ₁ , which is an important intermediate for the synthesis of isocarbacyclines. Regarding manufacturing methods. More details: 5, 5, 6, 6
-Tetradehydro-9-deoxo-9-methylene prostaglandin E ₉ -deoxo-9-hydroxymethyl-6- is subjected to hydroboration and subsequent oxidation reaction, followed by deprotection reaction if necessary. This invention relates to a method for producing oxoprostaglandin E type ₁ . <Prior art> Prostacyclin is a local hormone produced primarily in the inner walls of arteries in living organisms.
It is an important factor that regulates the cell functions of the living body due to its strong physiological activities, such as platelet aggregation inhibitory activity and vasodilatory activity, and attempts are being made to directly provide this substance as a medicine. [P. J. Lewis & J. O. Grady, “Clinical Pharmacology of Prostacyelin” Raven Press, New York,
N.Y.), 1981]. However, natural prostacyclin has an enol ether bond in its molecule that is highly susceptible to hydrolysis, so it is easily deactivated under neutral or acidic conditions.
As a drug, it is not a desirable compound due to its chemical instability. For this reason, chemically stable synthetic prostacyclin derivatives that have the same physiological activity as natural prostacyclin are being intensively investigated at home and abroad. Among them, derivatives in which the oxygen atoms at the 6,9-positions of prostacyclin are replaced with methylene groups, that is, 9
(0) Methanoprostacyclin (carbacyclin) is known as a brostacyclin with sufficient chemical stability [DRMortons “Prostacyclin” G.R. Bain & Niss Bergström (JR
Vane and S. Bergstrom), Editions, Raven Press, New York (Eds, Raven
Press, N, Y), 1979, pp31-41] It is expected to be used as a drug. But this 6,9(0)-
The biological activity of methanoprostacyclin is weaker than that of natural prostacyclin, and the selectivity of its action cannot be said to be specific, so it cannot necessarily be said to be a preferable compound. On the other hand, Ikegami et al. and the present inventors have discovered a derivative (isocarbacyclin) in which the 6,9-position oxygen atoms of prostacyclin are substituted with a methine group, that is, a -CH= group, and its biological activity is similar to that of natural prostacyclin. [Ikegami et al., Tetrahedron et al.
Letters (Tetrahedron Lett.), 24 , 3493
(1983), Japanese Patent Publication No. 59-137445]. On the other hand, regarding the synthesis method of isocarbacycline, the following methods are known in addition to the above-mentioned documents. (i) Above: (1) Chemistry Letters (Chem.Lett.),
1984, 1069, (2) Tetrahedron Letters
Lett.), 24 , 3497 (1983), (3) JP-A-59-210044, (4) Journal of the Chemical Society, Chemical Communication (J.
CSChem.Commun.), 1984 , 1602. (ii) Shibasaki et al.: (1) Tetrahedron Letters
Lett.), 25 , 5897 (1984), (2) Tetrahedron Letters.
Lett.), 25 , 1067 (1984), (iii) Kojima et al.: (1) Chemical and Pharmaceutical Bulletin (Chem.Pharm.
Bull.), 32 , 2866 (1984), (2) JP-A-60-28943. However, the synthesis methods described in these documents require many steps to obtain the starting material, and even if the starting material is easily obtained, many steps are required to reach isocarbacycline, and the synthesis method is It has various drawbacks, such as extremely difficult isomer separation during the process. Therefore _, the present inventors conducted intensive studies to develop a new method for synthesizing _such ^{isocarbacyclines} . Substituted phenyl group, substituted or unsubstituted
It represents a _C3 - _C10 cycloalkyl group or a substituted or unsubstituted phenyl ( _C1 - _C2 ) alkyl group, ^R21 and ^R31 are the same or different, and a hydrogen atom,
represents a tri(C ₁ to _{C 7} ) hydrocarbon silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, R ⁴ represents a hydrogen atom, a C ₁ to C ₁₀ alkyl group, a vinyl group or an ethynyl group, R ⁵ is a straight or branched chain that may contain an oxygen atom
_C3 - _C10 alkyl group; straight chain or branched _C3 - _C10
Alkenyl group; linear or branched _C3 - _C10 alkynyl group; optionally substituted _C3 - _C10 cycloalkyl group; optionally substituted phenyl group;
an optionally substituted phenoxy group; or an optionally substituted phenyl group, an optionally substituted phenoxy group, or an optionally substituted phenoxy group;
represents a straight-chain or branched _C1 - _C5 alkyl group substituted with a _C3 - _C10 cycloalkyl group, and n
represents 0 or 1. ] 9-deoxo- which is a compound represented by, its stereoisomer or a mixture of them in any proportion
We have discovered an excellent new synthetic route for isocarbacycline [ ] shown by [Reaction formula-1] using 9-hydroxymethyl-6-oxoprostaglandin E type ₁ as a starting material, and have filed a separate application. [C] [C] [C] [In the above formula [], the definitions of R ⁴ and R ⁵ are the same as R ⁴ and R ⁵ in the above formula [], and R ¹² , R ₂₂ ,
The definition of R ₃₂ is R ₁₁ , R 21 , R ₂₁ ,
Same as R ₃₁ . In the above formula [], R ⁴ ,
The definition of R ⁵ is the same as R ⁴ and R ⁵ in the above formula [],
The definitions of R ₁₃ , R ₂₃ and R ₃₃ are respectively in the above formula []
Same as R ₁₁ , R ₂₁ , R ₃₁ . ] 9-Deoxo-9-hydroxymethyl- represented by the above formula [] which is the starting material for the above synthesis method
6-Oxoprostaglandin E ₁ can be obtained, for example, by the method of Ikegami et al. [Tetrahedron Letters, Vol. 24, p. 3493,
1983; see JP-A-59-137445], prostaglandin E type ₂ [] can be synthesized as a starting material by the method shown in the reaction formula (reaction formula-2) below. [Chemical] [Chemical] [Chemical] [Chemical] [Chemical] The definitions of R ¹ , R ² , R ³ , ¹¹ , R ²¹ , R ³¹ , R ⁴ , and R ⁵ n are the same as in the above formula. 9-BBN represents 9-borabicyclo[3.3.1]nonane and DBN represents 1,5-diazabicyclo[4.3.0]non-5-ene. ] However, the method (reaction formula-2) has many steps,
There was a desire to establish a more effective synthetic method. In addition, 9-deoxo-9-hydroxymethyl-6-oxoprostaglandin E type ₁ represented by the above formula [] can be prepared by the following method (reaction formula-3) separately filed by the present inventors. -Oxoprostaglandin E It can also be synthesized using Class ₁ [X] as a starting material. [Chemical structure] [Chemical structure] [Chemical structure] [The definitions of R ¹ , R ² , R ³ , ¹¹ , R ²¹ , R ³¹ , R ⁴ , and R ⁵ n are the same as in the above formula. ] However, in the method of (reaction formula-3), 6-oxo-prostaglandin E ₁ represented by the above formula [X] is methylenated to produce 6-oxo-9-methylenes represented by the above formula []. It is difficult to suppress the regioselectivity of methylenation in the reaction to obtain
As a result, 6-oxo-9-methylenes represented by the above formula [], and 9-deoxo-9-hydroxymethyl-6 represented by the above formula []
-The yield of oxoprostaglandin E type ₁ is low;
Improvement was desired. <Problems to be Solved by the Invention> The present inventors have developed a new and simple synthesis method for 9-deoxo-9-hydroxymethyl-6-oxoprostaglandin E type ₁ , which is a raw material for the synthesis of such isocarbacyclines. As a result of intensive research to develop,
The present invention was achieved by discovering a new synthetic route. <Means for Solving _the Problems> That is ^, _the present invention has the following formula:
Represents a _C3 - _C10 cycloalkyl group or a substituted or unsubstituted phenyl ( _C1 - _C2 ) alkyl group, ^R2 and ^R3 are the same or different, and a hydrogen atom,
represents a tri(C ₁ to _{C 7} ) hydrocarbon silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, R ⁴ represents a hydrogen atom, a C ₁ to C ₁₀ alkyl group, a vinyl group or an ethynyl group, R ⁵ is a straight or branched chain that may contain an oxygen atom
_C3 - _C10 alkyl group; straight chain or branched _C3 - _C10
Alkenyl group; linear or branched _C3 - _C10 alkynyl group; optionally substituted _C3 - _C10 cycloalkyl group; optionally substituted phenyl group;
an optionally substituted phenoxy group; or an optionally substituted phenyl group, an optionally substituted phenoxy group, or an optionally substituted phenoxy group;
represents a straight-chain or branched _C1 - _C5 alkyl group substituted with a _C3 - _C10 cycloalkyl group, and n
represents 0 or 1. 5,5,6,6 which is a compound represented by, its stereoisomer or a mixture of them in any ratio
-Tetradehydro-9-deoxo-9-methylene prostaglandin E Type ₁ is subjected to hydroboration and subsequent oxidation reaction, and if necessary, deprotection reaction is carried out. ] [In the formula, R ¹¹ is a C ₁ to C ₁₀ alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted phenyl group.
It represents a _C3 - _C10 cycloalkyl group or a substituted or unsubstituted phenyl ( _C1 - _C2 ) alkyl group, ^R21 and ^R31 are the same or different, and a hydrogen atom,
represents a tri(C ₁ to _{C 7} ) hydrocarbon silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, R ⁴ represents a hydrogen atom, a C ₁ to C ₁₀ alkyl group, a vinyl group or an ethynyl group, R ⁵ is a straight or branched chain that may contain an oxygen atom
_C3 - _C10 alkyl group; straight chain or branched _C3 - _C10
Alkenyl group; straight chain or branched C ₃ - C ₁₀ alkynyl group; optionally substituted cycloalkyl group; optionally substituted phenyl group; optionally substituted phenoxy group; or substituted optional phenyl group, optionally substituted phenoxy group, or optionally substituted C ₃ to _{C 10}
It represents a straight chain or branched _C1 - _C5 alkyl group substituted with a cycloalkyl group, and n represents 0 or 1. Provided is a method for producing 9-deoxo-9-hydroxymethyl 6-oxoprostaglandin E ₁ , which is a compound represented by the formula, its stereoisomer, or a mixture thereof in any proportion. In the above formulas [] and [], R ¹ and R ¹¹ are C ₁ to
It represents a _C10 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted _C3 - _C10 cycloalkyl group, or a substituted or unsubstituted phenyl ( _C1 - _C2 ) alkyl group. Examples of C ₁ to _{C 10} alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n
-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and other linear or branched ones. . Substituents for substituted or unsubstituted phenyl groups include, for example, halogen atoms, hydroxy groups, C _2
-C7 acyloxy group, C1-C4 alkyl group optionally substituted with a halogen atom, _C1 - _C4 alkoxy group optionally substituted with a halogen atom, nitrile group, carboxyl group, or ( _C1 - _C4 alkyl group optionally substituted with _a halogen atom) C ₆ ) alkoxycarbonyl group and the like are preferred. The halogen atom is preferably fluorine, chlorine or bromine, particularly fluorine or chlorine. Examples of the _C2 - _C7 acyloxy group include acetoxy, propionyloxy, n
-butyryloxy, iso-butyryloxy, n-
Valeryloxy, iso-valeryloxy, caproyloxy, enantyloxy or benzoyloxy and the like can be mentioned. Examples of the _C1 - _C4 alkyl group optionally substituted with halogen include methyl, ethyl, n-propyl, iso-propyl, n-butyl, chloromethyl,
Preferred examples include dichloromethyl and trifluoromethyl. Preferred examples of the _C1 - _C4 alkoxy group which may be substituted with halogen include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, chloromethoxy, dichloromethoxy, trifluoromethoxy, etc. be able to.
Examples of the ( _C1 - _C6 ) alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl,
Examples include butoxycarbonyl, hexyloxycarbonyl, and the like. The substituted phenyl group has 1 to 3 substituents as described above.
, preferably one. Substituted or unsubstituted _C3 - _C10 cycloalkyl groups include saturated or unsaturated _C3 substituted or unsubstituted with the same substituents as mentioned above;
_-C10 , preferably _C5 - _C6 groups, such as cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclodecyl, etc. may be mentioned. Examples of the substituted or unsubstituted phenyl ( _C1 - _C2 ) alkyl group include benzyl, α-phenethyl, and β-phenethyl, in which the phenyl group is substituted with the same substituent as mentioned above or unsubstituted. R ¹ and R ¹¹ are particularly preferably C ₁ to C ₁₀ alkyl groups. R ² and R ³ are the same or different, and R ²¹ and R ³¹ are also the same or different, and are a group that forms an acetal bond with a hydrogen atom, a tri(C ₁ -C ₇ ) hydrocarbon silyl group, or an oxygen atom of a hydroxyl group. represents. As a tri(C ₁ - C ₇ ) hydrocarbon silyl group,
For example, trimethylsilyltriethylsilyl, t-
Tri(C ₁ -C ₄ ) such as butyldimethylsilyl group
For example, trimethylsilyl, alkylsilyl, di(C ₁ -C ₄ )alkylphenylsilyl such as dimethylphenylsilyl, diphenyl(C ₁ -C ₄ )alkylsilyl or triphenylsilyl such as t-butyldiphenylsilyl, Preferred examples include tribenzylsilyl group. Particularly preferred is t-butyldimethylsilyl group. Groups that form an acetal bond with the oxygen atom of a hydroxyl group include, for example, methoxymethyl, 1-ethoxyethyl, 2-methoxy-2-propyl, 2
-ethoxy-2-propyl, (2-methoxyethoxy)methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl or 6,6-dimethyl-3-oxa-2-oxobicyclo[3.1.0]hex -4-yl group may be mentioned. Among these, 2-tetrahydropyranyl group is particularly preferred. In the above formulas [] and [], R ⁴ represents a hydrogen atom, a C ₁ -C ₁₀ alkyl group, a vinyl group or an ethynyl group. As a _C1 to _C10 alkyl group,
The same groups mentioned for R ¹ and R ¹¹ can be mentioned.
Particularly preferred is a methyl group. Among these, particularly preferred as R ⁴ are a hydrogen atom and a methyl group. In the above formulas [] and [], R ⁵ is a straight chain or branched chain C ₃ which may contain an oxygen atom.
_C10 alkyl group; straight chain or branched _C3 - _C10 alkenyl group; straight-chain or branched _C3 - _C10 alkynyl group; optionally substituted _C3 - _C10 cycloalkyl group; unsubstituted an optionally substituted phenyl group; an optionally substituted phenoxy group; an optionally substituted phenyl group, an optionally substituted phenoxy group, or an optionally substituted C ₃
- Represents a straight-chain or branched _C1 - _C5 alkyl group substituted with a _C10 cycloalkyl group. Straight-chain or branched _C3 - _C10 alkyl groups which may contain an oxygen atom include 2-methoxyethyl, 2-ethoxyethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, 1-methyl pentyl, 1-methylhexyl,
1,1-dimethylpentyl, 2-methylpentyl, 2-methylhexyl, 5-methylhexyl,
2,5-dimethylhexyl group etc., preferably butyl, pentyl, hexyl, (R)- or (S)- or (RS)-1-methylpentyl, (R)- or (S)- or ( RS)-2
-Methylhexyl group. As the C ₃ to C ₁₀ alkenyl group, 2-butenyl group,
2-pentenyl group, 3-pentenyl group, 2-hexynyl, 4-hexyl, 2-octynyl, 5-cenyl group, 4-hexenyl group, 2-methyl-4-hexenyl group, 2,6-dimethyl-5-heptenyl Examples include groups. C ₃ to C ₁₀ alkenyl groups include 2-butynyl,
Examples include 2-pentynyl, 3-pentynyl, 2-hexydecynyl, 1-methyl-3-pentynyl, 1-methyl-3-hexynyl, 2-methyl-4-hexynyl, and the like. Examples of the optionally substituted _C3 - _C10 cycloalkyl group include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, ( _C1 - _C5 ) alkylcyclopentyl group, ( _C1 - _C4 ) Alkylcyclohexyl group, dimethylcyclopentyl group, dimethylcyclohexyl group, chlorocyclopentyl group, bromocyclohexyl group, iodocyclopentyl group, fluorocyclohexyl group, etc., but cyclopentyl group and cyclohexyl group are preferable. Examples of substituents for the optionally substituted phenyl group and the optionally substituted phenoxy group include a halogen atom, a hydroxy group, a _C3 to _C7 acyloxy group, and a _C1 optionally substituted with a halogen atom.
_-C4 alkyl group, _C1 - _C4 alkoxy group optionally substituted with a halogen atom, nitrile group, carboxyl group, or ( _C1 - _C6 ) alkoxycarbonyl group are preferred. The halogen atom is preferably fluorine, chlorine or bromine, particularly fluorine or chlorine. Examples of the _C2 - _C7 acyloxy group include acetoxy, propionyloxy, n-butyryloxy, iso-butyryloxy, n-valeryloxy, iso-valeryloxy, caproyloxy,
Mention may be made of enantyloxy or benzoyloxy. Examples of the _C1 - _C4 alkyl group optionally substituted with halogen include methyl, ethyl,
Preferred examples include n-propyl, iso-propyl, n-butyl, chloromethyl, dichloromethyl, trifluoromethyl and the like.
Examples of the C ₁ -C ₄ alkoxy group which may be substituted with halogen include methoxy, ethoxy, n
-proboxy, iso-propoxy, n-butoxy,
Preferred examples include chloromethoxy, dichloromethoxy, trifluoromethoxy and the like. Examples of the ( _C1 - _C6 ) alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl, and the like. The substituted phenyl group or substituted phenoxy group can have 1 to 3, preferably 1 substituent as described above. An optionally substituted phenyl group, an optionally substituted phenoxy group, a straight chain or branched C ₁ to C ₅ alkyl group substituted with an optionally substituted C ₃ to C ₁₀ cycloalkyl group As the optionally substituted phenyl group and the optionally substituted phenoxy group, the above-mentioned ones can be preferably mentioned as they are. C ₃
As the ~C ₁₀ cycloalkyl group, the above-mentioned ones can be preferably mentioned as they are, and as the substituent, the same ones as those of the above-mentioned substituted phenyl group and substituted phenoxy group can be mentioned. Straight chain or branched chain _C1 - _C5 alkyl groups include methyl, ethyl,
Examples include propyl, iso-propyl, butyl, iso-butyl, sec-butyl, t-butyl, pentyl, and the like, and the substituent may be bonded to any position thereof. Among these, R ⁵ is butyl, pentyl,
1-methylpentyl, 2-methylhexyl, cyclopentyl, cyclohexyl, 2,6-dimethyl-5-heptenyl, 1-methyl-3-pentenyl, 1-methyl-3-hexynyl are preferred. In the compounds represented by the above formulas [] and [], n represents 0 or 1. When n=0, the following formula [-1] [In the formula, the definitions of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are the same as in the above formula. ] and the following formula [-1] [In the formula, the same definitions of R ¹¹ , R ²¹ , R ³¹ , R ⁴ , and R ⁵ apply. ] Formula [-2] [In the formula, the definitions of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are the same as in the above formula. ] and the following formula [-2] [In the formula, the definitions of R ¹¹ , R ²¹ , R ³¹ , R ⁴ and R ⁵ are the same as in the above formula. represents either one of the non-natural configurations at position 15 represented by or a mixture thereof in any proportion. In particular, when R ⁴ is a hydrogen atom, the above formula [−
1] and the natural configuration at position 15 represented by the above formula [-1] are preferred. When n=1, it also represents the (R)-configuration, (S)-configuration at the 16th position, and a mixture thereof in any proportion. 5,5,6,6-tetradehydro-9-deoxo-9-methylene prostaglandin E ₁ represented by the above formula [] and 9-deoxo-9-hydroxymethyl-6 represented by the above formula []
-Oxo-prostaglandin E class ₁ 8th and 9th
The configurations at positions 1, 11, 12 and the Δ ¹³ -double bond are particularly useful stereoisomers because they are natural prostaglandin types, but in the present invention, the configurations at each position are It also includes stereoisomers due to different stereoisomers or mixtures thereof in arbitrary proportions. 5,5,6,6-tetradehydro-9-deoxo-9-methylene prostaglandin E type ₁ represented by the above formula [] used as a raw material in the present invention is the following formula [] [Chemical] [wherein, ^R14 is a _C1 - _C10 alkyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted
Represents a _C3 - _C10 cycloalkyl group or a substituted or unsubstituted phenyl ( _C1 - _C2 ) alkyl group, ^R24 and ^R34 are the same or different, and a hydrogen atom,
represents a tri(C ₁ to _{C 7} ) hydrocarbon silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, R ⁴ represents a hydrogen atom, a C ₁ to C ₁₀ alkyl group, a vinyl group or an ethynyl group, R ⁵ is a straight or branched chain that may contain an oxygen atom
_C3 - _C10 alkyl group; straight chain or branched _C3 - _C10
Alkenyl group; linear or branched _C3 - _C10 alkynyl group; optionally substituted _C3 - _C10 cycloalkyl group; optionally substituted phenyl group;
an optionally substituted phenoxy group; or an optionally substituted phenyl group, an optionally substituted phenoxy group, or an optionally substituted phenoxy group;
represents a straight-chain or branched _C1 - _C5 alkyl group substituted with a _C3 - _C10 cycloalkyl group, and n
represents 0 or 1. ] 5,5,6,6 which is a compound represented by, its stereoisomer or a mixture of them in any ratio
- Methylenating agent prepared from tetradehydroprostaglandin E type ₁ with titanium tetrachloride-zinc-dibromomethane [L.Lom-
bardo et al., Tetrahedron Lettera, vol. 23, p. 4293, 1982.
] or by methylenation using other methylenating agents. 5,5,6,6-tetrahydroprostaglandin E ₁ represented by the above formula [] was prepared according to the method of Noyori et al. [R. Noyori et al.
Journal of the American Chemical
Society (J.Amer.Chem.Soc.), vol. 107,
3348 pages, 1985] (Reaction formula-4), it can be easily obtained by carrying out a three-component ligation reaction. [Chemical formula] [Chemical formula] [In the formula, the definitions of R ¹⁴ , R ²⁴ , R ³⁴ , R ⁴ , R ⁵ , and n are the same as in the above formula. ] 5,5,6,6-tetradehydro-9-deoxo-9-methylene prostaglandin E type ₁ represented by the above formula [] is subjected to hydroboration and subsequent oxidation reaction, and if necessary, By performing a deprotection reaction, 9-deoxo-9-hydroxymethyl-6 represented by the above formula []
- Oxoprostaglandin E type ₁ can be obtained. The hydroboration reaction and the subsequent oxidation reaction can be carried out by conventional techniques (organic reaction).
Reactions), Volume 13, Chapter, John Wiley & Sons
Inc.) New York, 1963; New Experimental Chemistry Course, Synthesis and Reactions of Organic Compounds, pp. 497-505, see Maruzen et al.). Hydroboration reagents include monoalkylboranes such as thexylborane ((CH ₃ ) ₂ CHC(CH ₃ ) ₂ BH ₂ ), monosubstituted borane such as monochloroborane, and dicyamylborane ((CH ₃ ) ₂ CHCH(CH ₃ )
BH), 9-borabicyclo[3.3.1]nonane (9-
BBN), dialkylboranes such as dicyclohexylborane and diisopinocamphenylborane, disubstituted borane such as catecholborane and cyhaloborane, and diborane (B ₂ H ₆ ), borane-tetrahydrofuran complex, borane-dimethylsulfide complex etc. can be used. Preferably, monosubstituted borane is used, more preferably monoalkylborane, and particularly preferably thexylborane. The oxidizing agent used in the oxidation reaction following hydroboration is H ₂ O ₂ −
NaOH, trimethylamine oxide, air oxidation, etc. can be used. Particularly preferred is _{H2O2 -} NaOH. The amount of hydroboration reagent used is stoichiometrically equal for monosubstituted borane with respect to 5,5,6,6-tetradehydro-9-deoxo-9-methylene prostaglandin E class ₁ . The reaction proceeds in moles. Usually, monosubstituted borane is used in an amount of 0.5 to 5 times the mole, preferably 0.8 to 2 times the mole of the raw material compound. In the case of di-substituted borane, the reaction proceeds stoichiometrically at twice the mole relative to the starting compound. Usually 1 to 10 times the mole, preferably
Use 1.6 to 6 times the mole. In the case of unsubstituted borane such as diborane, the reaction proceeds stoichiometrically at 2/3 times the mole relative to the starting compound. Usually 0.3 to 5 times the mole, preferably 0.5 to 2 times the mole. The reaction temperature is about -100°C to 50°C, preferably about -20°C to room temperature. The reaction time varies depending on the reaction temperature and is usually about 10 minutes to 20 hours, preferably about 30 minutes to 5 hours. The reaction is usually carried out in the presence of an organic medium. The medium used is an inert aprotic organic medium that does not react with the reaction reagent, preferably an ether solvent such as tetrahydrofuran, diethyl ether, diglyme, triglyme, etc., with tetrahydrofuran being particularly preferred. The alkylborane produced by the hydroboration reaction is usually not isolated, but is oxidized by adding an oxidizing agent directly to the reaction system to form the above formula []
This leads to the alcohol form represented by . When using hydrogen peroxide as an oxidizing agent, a base such as sodium hydroxide is used at the same time. Hydrogen peroxide can be used at any concentration, but a concentration of around 30% is commonly used. The amount of hydrogen peroxide used depends on the hydroboration reagent used.
The amount is 0.5 to 50 times by mole, preferably 3 to 10 times by mole.
Sodium hydroxide can be used as such or as an aqueous solution. Generally, an aqueous solution having a concentration of 1 to 10 normal is used. The amount used is 0.5 to 50 times the mole of the hydroboration reagent, preferably 3 to 10 times the mole. The reaction temperature at this time is 0℃~
The temperature is 100°C, preferably 40°C to 70°C. The reaction time is 5 minutes to 5 hours, preferably 20 minutes to 1 hour. When trimethylamine oxide is used as an oxidizing agent, it is usually 0.5 to 50 times the mole of the hydroboration reagent, preferably 3 to 50 times the mole of the hydroboration reagent.
Use 10 times the molar amount. The product thus obtained can be taken out from the reaction system as a crude product by quenching, extraction, etc. in accordance with a conventional method. The crude product can be purified, if desired, by purification means such as column chromatography, thin layer chromatography, liquid chromatography, recrystallization, or the like. The product thus obtained is further subjected to a deprotection reaction if necessary, but the removal of the protecting group of the hydroxyl group (deprotection reaction) is performed in the case where the protecting group is a group that forms an acetal bond with the oxygen atom of the hydroxyl group. ,
For example, acetic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, cation exchange resin, etc. are used as catalysts, and for example, water, methanol, ethanol, or tetrahydrofuran, ethyl ether, dioxane, acetone, etc. in the coexistence of water, methanol, ethanol, etc. This reaction is preferably carried out using acetonitrile or the like as a reaction solvent. The reaction temperature is usually -78°C to +80°C for about 10 minutes to 3 days. When the protecting group is a tri(C ₁ -C ₇ ) hydrocarbon group, it is treated with an acid such as acetic acid, p-trienesulfonic acid, or pyridinium p-toluenesulfonate as a catalyst in the above reaction solvent at the same temperature. Alternatively, use a fluorine-based reagent such as tetrabutylammonium fluoride, cesium fluoride, hydrofluoric acid, hydrogen fluoride-pyridine, etc., and use tetrahydrofuran, ethyl ether, dioxane, acetone, acetonitrile, etc. as a reaction solvent as described above. This is preferably carried out at the same temperature and for a similar period of time. The deprotected product thus obtained can also be isolated and purified using the same conventional separation means as described above. <Effect of the invention> The thus obtained 9 expressed by the above formula []
-Deoxo-9-hydroxymethyl-6-oxoprostaglandin E class ₁ is an important class of isocarbacyclines that are useful as they have strong platelet aggregation, vasodilation, cell protection, and anti-ulcer effects. It is useful as a synthetic intermediate. <Examples> The present invention will be described in detail with reference to Examples below, but the present invention is not limited thereto. Example 1 5,5,6,6-tetradehydro-9-deoxo-9-methylene prostaglandin E _1bis-
(t-Butyldimethylsilyl ether) methyl ester (compound 1) 200 mg (0.34 mmol) was dissolved in 3.5 ml of tetrahydrofuran, and then -
Cooled to 60°C. 1.43 ml (12 mmol) of 2,3-dimethyl-2-butene and 6 ml of tetrahydrofuran were added to another flask, and the mixture was heated at -10°C under a nitrogen atmosphere.
1M-borane-tetrahydrofuran complex (BH ₃ -THF) in tetrahydrofuran solution 10
ml and stirred at room temperature for 4 hours to prepare a thexylborane solution. This thexylborane solution 0.64ml
Add the solution of the above (compound 1) dropwise and incubate at -60℃ for 30 minutes.
After stirring for 20 minutes at 0℃, add 0.37 ml of 5N sodium hydroxide solution, then 35% hydrogen peroxide solution.
0.35 ml was added and stirred at 50°C for 30 minutes. A saturated aqueous ammonium chloride solution was added, and after extraction twice with ethyl acetate, the organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. When the obtained residue was separated and purified by silica gel column chromatography, (9S)-9-deoxo-9-hydroxymethyl-
115 mg (yield 54%) of 6-oxoprostaglandin E ₁ 11,15-bis(t-butyldimethylsilyl ether) methyl ester (compound 2) was obtained. NMR (δppm, _CDCl3 ): 0.75-1.0 (21H), 1.0-2.5 (m, 23H), 2.9-3.3 (1H, br, OH), 3.4-4.2 (m, 4H), 3.67 (s, 3H) , 5.40 (m, 2H) IR (cm ^-1 , neat): 3470, 1742, 1720, 1460, 1255 mass (FD, m/e): 608 (m H ₂ O), 569, 551 Example 2 ] (9S)-16,17,18,19,20-pentanol-9-deoxo-15- was obtained by reacting (compound 3) with thexylborane and then NaOH-H ₂ O ₂ in the same manner as in Example 1. Cyclopentyl-9-hydroxymethyl-6-oxoprostaglandin
E ₁ 11,15-bis(t-butyldimethylsilyl ether) methyl ester (compound 4) with a yield of 50%
I got it from NMR (δppm, CDCl ₃ ): 0.8-1.0 (18H), 1.0-2.5 (m, 24H), 3.4-4.2 (m, 4H), 3.65 (s, 3H), 5.40 (m, 2H) IR (cm ^{- 1} , neat): 3480, 1740, 1720, 1460, 1255 Example 3 [Chemical formula] In the same manner as in Example 1, (compound 5) was reacted with thexylborane and then NaOH-H ₂ O ₂ to form (9S , 17S)-9-deoxo-9-hydroxymethyl-17,20-dimethyl-6-oxoprostaglandin E ₁ 11,15-bis(t-butyldimethylsilyl ether) methyl ester (compound 6) at 42% Obtained in yield. NMR (δppm, CDCl ₃ ): 0.75-1.0 (24H), 1.0-2.5 (m, 24H), 3.4-4.2 (m, 4H), 3.65 (s, 3H), 5.40 (m, 2H) IR (cm ^{- 1} , neat): 3470, 1742, 1720, 1460, 1260 Reference example 1 [Chemical formula] 5,5,6,6-tetradehydroprostaglandin E ₁ bis-(t-butyldimethylsilyl ether) methyl ester (compound 7 ) 1.33g (2.25
mmol) in 30 ml of methylene chloride, and under ice-cooling, zinc-dibromomethane-titanium tetrachloride was dissolved.
Add an appropriate amount of methylenating agent (see Tetrahedron Letters, Vol. 23, p. 4293, 1982) prepared according to the method of Lombardo et al., and check for disappearance of the raw material by thin layer chromatography (TLC) while stirring at room temperature. did. Since the raw material did not disappear, the above methylenating agent was further added and the mixture was stirred at room temperature, and the raw material disappeared by TLC (the reaction time was 45 minutes in total). The above reaction mixture was added to 150 ml of saturated sodium bicarbonate solution, filtered through Celite, and extracted twice with n-hexane. The combined organic layers were washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off to obtain 1.2 g of residue. When this was purified by silica gel column chromatography, 2
% ethyl acetate-n-hexane eluate contained 928 mg (yield 70%) of 5,5,6,6-tetrahydro-9-
Deoxo-9-methylene prostaglandin E ₁
Bis-(t-butyldimethylsilyl ether) methyl ester (Compound 1) was obtained. NMR (δppm, CDCl ₃ ): 0.75-1.0 (21H), 3.67 (3H, s), 3.6-4.3 (2H, m), 4.8-5.2 (2H, br), 5.3-5.7 (2H, m) IR ( cm ^-1 , neat): 2960, 2940, 2860, 1740, 1458, 1428, 1250, 1112, 1000, 965, 835, 773 Reference Example 2 Compound 8 was converted to methylene in the same manner as in Reference Example 1. 16,17,18,19,20-pentanol-5,5,6,6-tetradehydro-9-
Deoxo-15-cyclopentyl-9-methylene prostaglandin E _1bis- (t-butyldimethylsilyl ether) methyl ester (compound 3)
Obtained with a yield of 75%. NMR (δppm, CDCl ₃ ): 0.75-1.0 (18H), 3.66 (3H, s), 3.6-4.3 (2H, m), 4.8-5.2 (2H, br), 5.3-5.7 (2H, m) Reference example 3 [Chemical formula] By methyleneating (Compound 9) in the same manner as in Reference Example 1, (17S)-5,5,6,6-
Tetradehydro-9-deoxo-17,20-dimethyl-9-methylene prostaglandin E _1bis-
(t-butyldimethylsilyl ether) methylsilyl ether) methyl ester (compound 5) at 80
% yield. NMR (δppm, _CDCl3 ): 0.75-1.1 (24H), 3.66 (3H, s), 3.5-4.3 (2H, m), 4.8-5.2 (2H, br), 5.3-5.7 (2H, m)

Claims (1)

[Claims] 1 The following formula [] [Chemical formula] In the formula, R ¹ is a C ₁ to _{C 10} alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted C ₃
~ _C10 cycloalkyl group, or substituted or unsubstituted phenyl ( _C1 - _C2 ) alkyl group,
R ² and R ³ are the same or different and represent a hydrogen atom, a tri(C ₁ -C ₇ ) hydrocarbon silyl group, or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, and R ⁴ is a hydrogen atom, C ₁ - Represents a C ₁₀ alkyl group, vinyl group or ethynyl group, and R ⁵ is a straight chain or branched chain C ₃ to C ₁₀ that may contain an oxygen atom.
Alkyl group; straight-chain or branched _C3 - _C10 alkenyl group; straight-chain or branched _C3 - _C10 alkynyl group; optionally substituted _C3 - _C10 cycloalkyl group; an optionally substituted phenyl group; an optionally substituted phenoxy group; an optionally substituted phenyl group, an optionally substituted phenoxy group, or an optionally substituted C ₃ -
Represents a straight chain or branched C ₁ -C ₅ alkyl group substituted with a C ₁₀ cycloalkyl group, where n is 0
Or 1. ] 5,5,6,6 which is a compound represented by, its stereoisomer or a mixture of them in any proportion
-Tetradehydro-9-deoxo-9-methylene prostaglandin E Type ₁ is subjected to hydroboration and subsequent oxidation reaction, and if necessary, deprotection reaction is carried out. ] In the formula, R ¹¹ is a C ₁ to C ₁₀ alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted phenyl group.
It represents a _C3 - _C10 cycloalkyl group or a substituted or unsubstituted phenyl ( _C1 - _C2 ) alkyl group, ^R21 and ^R31 are the same or different, and a hydrogen atom,
represents a tri(C ₁ to _{C 7} ) hydrocarbon silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, R ⁴ represents a hydrogen atom, a C ₁ to C ₁₀ alkyl group, a vinyl group or an ethynyl group, R ⁵ is a straight or branched chain that may contain an oxygen atom
_C3 - _C10 alkyl group; straight chain or branched _C3 - _C10
Alkenyl group; linear or branched _C3 - _C10 alkynyl group; optionally substituted _C3 - _C10 cycloalkyl group; optionally substituted phenyl group;
an optionally substituted phenoxy group; or an optionally substituted phenyl group, an optionally substituted phenoxy group, or an optionally substituted phenoxy group;
Represents a straight chain or branched C ₁ -C ₅ alkyl group substituted with a C ₁ -C ₁₀ cycloalkyl group, and n
represents 0 or 1. ] A method for producing 9-deoxo-9-hydroxymethyl-6-oxoprostaglandin E ₁ , which is a compound represented by the above, its stereoisomer, or a mixture thereof in any proportion. 2. The method for producing 9-deoxo-9-hydroxymethyl-6-oxoprostaglandin E ₁ according to claim 1, wherein the hydroboration reagent is a monoalkylborane. 3.9 of Claim 1 or 2, wherein the hydroboration reagent is thexylborane
-Deoxo-9-hydroxymethyl-6-oxoprostaglandin E Type ₁ manufacturing method. 4. 9-deoxo-9 according to any one of claims 1 to 3, wherein R ¹ is a methyl group.
-Production method of hydroxymethyl-6-oxoprostaglandin E type ₁ . 5 R ² and R ³ are tri(C ₁ to _{C 7} ) hydrocarbon silyl groups,
or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, claims 1 to 4.
9-deoxo-9-hydroxymethyl-6-oxoprostaglandin according to any one of paragraphs
E Class ₁ manufacturing method. 9-9 according to any one of claims 1 to 5, wherein 6 R ⁴ is a hydrogen atom or a methyl group.
A method for producing deoxo-9-hydroxymethyl-6-oxoprostaglandin E type ₁ . 7 R ⁵ is n-butyl group, n-pentyl group, 2-
Claims 1 to 6 which are methylhexyl group, cyclopentyl group, or cyclohexyl group
9-deoxo-9-hydroxymethyl-6-oxoprostaglandin according to any one of paragraphs
E Class ₁ manufacturing method.