JP3313174B2 - Method for producing E-type prostaglandins or esters thereof - Google Patents

Description

[Detailed description of the invention]

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for selectively converting the triple bond into a cis double bond by reducing E-type prostaglandins or their esters having a triple bond in the α chain.

[0002]

2. Description of the Related Art As a general method for producing a compound having a cis carbon-carbon double bond, a method of reducing a compound having a carbon-carbon triple bond using a Lindlar catalyst is known.

[0003]

However, in this method, in addition to compounds having cis carbon-carbon double bonds, compounds having trans carbon-carbon double bonds and saturated compounds are by-produced. , it has been difficult to obtain high-purity cis-olefins. In addition, there is a risk of fire when using this method.

[0004]

Means for Solving the Problems As a result of intensive studies aimed at solving the above-mentioned problems, the present inventors have found that E-type prostaglandins having a triple bond in the α chain or esters thereof Alternatively, by using a divalent palladium complex or complex salt as a catalyst and reducing with formic acid, it was found that a compound having a cis double bond in the α chain can be produced selectively, in good yield, and easily, thus completing the present invention. .

[0005] That is, the present invention provides the formula

[0006]

[In the formula, R is a hydrogen atom and has 1 to 4 carbon atoms.
is an alkyl group or an optionally substituted allyl group, R ⁴ and R ⁵ are the same or different and represent a hydrogen atom or a hydroxyl-protecting group, A, R ⁶ and R ⁷ are resistant to reduction reaction. Any group that does not participate, B indicates a carbon-carbon single bond or any group that does not participate in the reduction reaction, and Y indicates a vinylene group. Formula characterized by reducing E-type prostaglandins represented by ] or an ester thereof with formic acid in the presence of a 0-valent or divalent palladium complex or complex salt

[0008]

(In the formula, R' represents a hydrogen atom when R is a hydrogen atom or an optionally substituted allyl group; when R is an alkyl group having 1 to 4 carbon atoms, have the same meanings, and A, B, Y, R ⁴ , R ⁵ , R ⁶ and R ⁷ have the same meanings as defined above). The method.

In the present invention, the alkyl group having 1 to 4 carbon atoms is a linear or branched group such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group and t-butyl group. A chain alkyl group. An optionally substituted allyl group is represented by the formula _-CH2 -CR1= ^CR2R3 (wherein ^R1 and ^{R2 are} the same or different and represent ^a hydrogen atom or a lower alkyl group, R ³ represents a hydrogen atom, a lower alkyl group, an alkenyl group or an aryl group.

[0011]

Groups represented by the following can be mentioned.
Here, when a compound of formula (I) in which R is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms is subjected to this reaction, a compound of formula (II) in which R' is a group corresponding to R is obtained. However, when a compound of formula (I) in which R is an allyl group is subjected to this reaction, hydrogenolysis of the allyl group occurs simultaneously with reduction of the triple bond of the α chain, resulting in A compound of (II) is obtained. The hydroxyl-protecting group is one commonly used in the field of prostaglandins, such as t-butyldimethylsilyl group, triethylsilyl group, phenyldimethylsilyl group, t-butyldiphenylsilyl group, tetrahydropyranyl group, tetrahydrofuranyl group. Nil group, methoxymethyl group, ethoxyethyl group, benzyl group and the like. R ⁴ and R ⁵ are a hydrogen atom or a hydroxyl-protecting group, and of these, a t-butyldimethylsilyl group is preferred.

In the reduction reaction of the present invention, the α-chain triple bond of E-type prostaglandins or esters thereof is selectively reduced with formic acid using a zero- or divalent palladium complex or complex salt as a catalyst. The triple bond is cis-2
It is a reaction that converts to a heavy bond. Therefore, any of A, B, ^R6 and ^R7 may be used as long as they do not participate in this reaction (however, B may represent a carbon-carbon single bond). To give an example of these, A and B
Examples include linear alkylene groups having 1 to 7 carbon atoms (e.g., methylene, ethylene, trimethylene, tetramethylene, hexamethylene, heptamethylene groups, etc.), 3 to 9 carbon atoms, A linear alkenylene group of [e.g. the formula

[0014]

(Wherein, n1 represents an integer of ₁ to 5, n2 represents an integer of ₁ to ₄ , n3 represents an integer of 1 to 6, etc.)], chain A linear alkylene group having 2 to 8 carbon atoms having one oxygen atom or sulfur atom interposed therein [for example, the formula

[0016]

(wherein X represents an oxygen atom or a sulfur atom, n ₄ represents an integer of 1 to 5, and n ₅ represents an integer of 1 to 7), etc.], the formula

[0018]

( _In the formula, n6 and _n7 are the same or different and represent an integer of 1 to 3.) The group represented by the formula

[0020]

(wherein n ₈ and n ₉ are the same or different and represent an integer of 1 to 3). Examples of R ⁶ include a hydrogen atom, methyl group, ethyl group and vinyl group. R ⁷ is, for example, a linear or branched alkyl group or alkenyl group having 1 to 10 carbon atoms (e.g., pentyl group, hexyl group, 1-methylhexyl group,
2-methylhexyl group, 1,1-dimethylhexyl group,
2-pentenyl group, 5-hexenyl group, etc.), cycloalkyl groups having 3 to 10 carbon atoms (e.g., cyclopentyl group, cyclohexyl group, cycloheptyl group, etc.),
An alkyl group having 1 to 4 carbon atoms (e.g., cyclopentylmethyl group, cyclohexylmethyl group, 2-cyclopentylethyl group, 3 −
cyclopentylpropyl group, 3-cyclohexylpropyl group, 4-cyclopentylbutyl group, benzyl group, phenoxymethyl group, 2-phenylethyl group, 4-phenylbutyl group, etc.), phenyl group and the like.

The zerovalent or divalent palladium complex or complex salt includes, for example, tris(dibenzylideneacetone)dipalladium(0)chloroform, bis(dibenzylideneacetone)palladium(0), tetrakis(triphenylphosphine)palladium(0) ), bis(acetylacetonate)palladium(II), dichlorobis(benzonitrile)palladium(II), dichlorobis(acetonitrile)palladium(II), dichlorobis(triphenylphosphine)palladium(II), π-allylpalladium(II) Chloride complexes, palladium chloride, lithium tetrachloropalladate, palladium acetate, and the like. The amount of these used is 0.0 relative to the compound of formula (I) as a starting material.
1 to 0.5 equivalents. The amount of formic acid to be used is 1 equivalent to an excess amount relative to the compound of formula (I) as a starting material.

In the present invention, it is preferable to add phosphines, except when phosphines are already coordinated to the "zero-valent or divalent palladium complex or complex salt". Phosphines include, for example, triethylphosphine, tributylphosphine, triphenylphosphine, tri(p-tolueneoxy)phosphine, triethoxyphosphine, bis(diphenylphosphino)ethane, bis(diphenylphosphino)propane, bis(diphenylphosphino) ) butane, bis(diphenylphosphino)ferrocene, and the like. In addition, if necessary, organic amines as a base (e.g., triethylamine, tributylamine, diethylamine, diisopropylamine, ethylamine, propylamine, butylamine, piperidine, pyrrole, pyrrolidine, morpholine, N-methylmorpholine, dimethylaniline, pyridine, O -methylethanolamine, aniline, piperazine, etc.) or ammonia can be added in an appropriate amount. Furthermore, if necessary, solvents [ethers (e.g. dioxane, tetrahydrofuran, tetrahydropyran, diethyl ether, diglyme etc.), esters (e.g. ethyl acetate, methyl acetate, valerolactone etc.), amides (e.g. N,N-dimethylformamide ,
N-methylpyrrolidone, etc.), dimethylsulfoxide, etc.] can be added. The reaction temperature is 0°C to the reflux temperature of the solvent, preferably room temperature to 100°C.

Of the compounds of the formula (II) produced according to the present invention, compounds in which the hydroxyl group is protected [compounds of the formula (II) in which R ⁴ and R ⁵ are groups other than hydrogen atoms] can be It can be easily deprotected to produce a prostaglandin E type compound (or derivative thereof) that is useful for treating various diseases including peripheral circulatory disorders.

[0025]

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to selectively and easily
It has become possible to produce E-type prostaglandins having a cis double bond in the α chain or esters thereof in a short period of time and at high yields.

[0026]

[Examples] The present invention will be described in more detail below with reference to examples.
explain. Example(2Z,17S)-2,3-didehydro-17,20-
Dimethyl-PGE 1 11,15-bis(t-butyldimethylsilyl ether)
l) Production of methyl ester Formic acid (31 μl, 0.7 mmol) and triethyla
tetrahydrofuran (83 μl, 0.6 mmol)
tris(dibenzylideneacetone) solution (2 ml)
n) dipalladium(0) chloroform complex (21m
g, 0.02 mmol) and triphenylphosphine
(20 μl, 0.08 mmol) was added, and the mixture was stirred at room temperature for 10 minutes.
Stir for a while. In this, (17S)-2,2,3,3-
tetradehydro-17,20-dimethyl-PGE₁ 1
1,15-bis(t-butyldimethylsilyl ether)
Methyl ester (123.8mg, 0.2mmol)
tetrahydrofuran solution (2 ml) of n-hexane
After extraction with San, the organic layer was dried over anhydrous magnesium sulfate.
Dried. After filtration, the crude product was obtained by concentrating the filtrate under reduced pressure.
The product was subjected to silica gel column chromatography (n-hexa
(n:ether = 20:1) to give the title compound 9
9.7 mg was obtained.¹H-NMR (CDCl₃, 300M
Hz) δppm; 0.02 and 0.05 (2s, 1
2H), 0.73-0.99 (m, 24H), 1.01
~2.01 (m, 16H), 2.11 ~ 2.27 (m,
3H), 2.35-2.52 (m, 1H), 2.63
(dd, J=6.8 Hz, 18.1 Hz, 1 H),3.
71 (s, 3H), 4.00-4.10 (m, 1H),
4.12-4.25 (m, 1H), 5.47-5.54
(m, 2H), 5.77 (d, J=11.6Hz, 1
H), 6.24 (dt, J=7.5Hz, 11.6H
z, 1H)

Continuation of front page (51) Int.Cl. ⁷ identification code FI B01J 31/24 B01J 31/24 X // C07B 61/00 300 C07B 61/00 300 C07M 9:00 C07M 9:00 (72) Inventor Gumi Kazuya 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Toru Tanami 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Ken Muto Tokyo 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Naoya Ono 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Jun Goto Takada, Toshima-ku, Tokyo 3-24-1 Taisho Pharmaceutical Co., Ltd. (56) References JP-A-5-255128 (JP, A) JP-A-59-152370 (JP, A) JP-A-54-130504 (JP, A) JP-A-54-132507 (JP, A) JP-A-5-238964 (JP, A) JP-A-5-310689 (JP, A) (58) Researched field (Int. Cl. ⁷ , DB name) C07C 405 /00 504 B01J 31/04 B01J 31/22 B01J 31/24 C07B 61/00 300 C07M 9:00 CASREACT (STN)

Claims (2)

(57) [Claims] [Claim 1] Formula [Chemical 1] [In the formula, R represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an optionally substituted allyl group;
⁴ and R ⁵ are the same or different and represent a hydrogen atom or a hydroxyl-protecting group, A, R ⁶ and R ⁷ represent any group that does not participate in the reduction reaction, and B represents a carbon-carbon single bond or a reduction Any group that does not participate in the reaction is shown, and Y is a vinylene group. ], E-type prostaglandins or esters thereof represented by formula [Chemical 2] , characterized by reducing with formic acid in the presence of a 0-valent or divalent palladium complex or complex salt (In the formula, R' represents a hydrogen atom when R is a hydrogen atom or an optionally substituted allyl group, and when R is an alkyl group having 1 to 4 carbon atoms, the same and A, B, Y, R ⁴ , R ⁵ , R ⁶ and R ⁷ have the same meanings as defined above). 2. The production method according to claim 1, wherein the reaction is carried out in the presence of a phosphine compound together with a 0-valent or divalent palladium complex or complex salt.