JPS60163842A - Preparation of prostaglandin e1 - Google Patents

Abstract

PURPOSE:To obtain efficiently the titled compound useful as a drug easily in high yield, by using an organotin hydride compound as a reducing agent, reducing selectively double bond at 7, 8 positions of DELTA<7>-prostaglandin E1. CONSTITUTION:Double bond at 7, 8 positions of a compound shown by the formula I [R<1> is H, or 1-10C alkyl; R<2> and R<3> are H, tri(1-7C)hydrocarbon-silyl, 2-7C acyl, etc.; R<4> is (substituted) 1-10C alkyl, (substituted) 5-7C cycloalkyl; in the formula II, E-configuration, or Z-configuration exists or both exist in any ratio; X is ethylene or trans vinylene], its 15-epimer, its enantiomer, or DELTA<7>-prostaglandin E1, a mixture of them in any blending ratio is selectively reduced with an organotin hydride compound, and, if necessary, a free radical initiator, and optionally deprotected and/or hydrolyzed to give the desired compund.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a novel method for producing prostaglandin E, which is useful as a pharmaceutical.

For more details, see △1-p-staglandin E1 class 7,8
The present invention relates to a method for producing prostaglandin EIs useful as pharmaceuticals by selectively reducing the double bond in position.

Prior Art A reaction system using Raney nickel or zinc-acetic acid is known as a method for reducing the double bonds at the 7 and 8 positions of Δ7-prostaglandin (described in JP-A-58-83670). .

This reaction produces prostaglandin E, which is useful as a pharmaceutical.
This is an excellent method for producing products such as . A particular difficulty with this reaction is that a side reaction in which the carbonyl group at position 9 is reduced tends to occur.

Purpose of the Invention The present inventors have conducted intensive research to find a more advantageous chemical synthesis method for prostaglandin E1 class.
The present invention was achieved by discovering that prostaglandin E1 can be easily obtained in high yield by selectively reducing the double bond at the position of the compound.

Therefore, the purpose of the present invention is to selectively reduce the double bonds at positions 7 and 8 of I-prostaglandin EI to efficiently obtain prostaglandin EI useful as a pharmaceutical. .

Structure and effects of the invention The manufacturing method of the present invention is based on the following formula [0 iR3 5- A compound represented by the following, its 15-shrimp form.

N-prostaglandin E, which is an enantiomer thereof or a mixture thereof in any proportion.

A compound represented by the following formula (3), characterized in that the double bond at position 7 of the group is selectively reduced, and then subjected to deprotection and/or hydrolysis reaction as necessary, and its 15-shrimp form .

This is a method for producing prostaglandin E, which is an enantiomer thereof or a mixture thereof in any proportion.

The production method of the present invention uses the compound of formula CI) having a double bond at the 7,86-position as described above,
This method produces μ-staglandin E1 by selectively reducing double bonds.

In the above formula [■], R1 is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.

Examples of the alkyl group having 1 to 10 carbon atoms include methyl,
Preferred examples include ethyl, propyl-9-isobutyl, butyl, t-butyl, pentyl, hexyl, heptyl, and octyl groups.

Particularly preferred as R' are a hydrogen atom and a methyl group.

R2 and R3 are the same or different, and are tri(CI-C
,) Hydrocarbon-based silyl group, a group that forms a 7-cetal bond with the oxygen atom of a hydroxyl group, or an acyl group having 2 to 7 carbon atoms.

)! Examples of the (C1-Ct) hydrocarbon-silyl group include trimethylsilyl, triethylsilyl, t-
Preferred examples include tri(C,-C,)alkylsilyl such as butyldimethylsilyl; diphenyl(C,-04)alkylsilyl or tribenzylsilyl such as t-butyldiphenylsilyl.

An example of a group that forms a 7-cetal bond with the oxygen atom of a hydroxyl group is 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 −
Examples include oxo-bicyclo[3°1.0]hex-4-yl group. Examples of the acyl group having 2 to 7 carbon atoms include acetyl, propionyl, n-butyryl, n
- Valeryl, cabroyl, benzoyl groups, etc. can be mentioned. Among these, R'' and R'' are 2-tetrahydropyranyl, 2-tetrahydrofuranyl, and 1-ethoxyethyl.

2-methoxy-2-propyl, (2-methoxyethoxy)methyl or 6,6-dimethyl-3-oxa-2-oxobicq [3,1,0':]hex-4-yl group is preferred.

It is to be understood that these silyl groups, groups forming an acetal bond, etc. are hydroxyl group-protecting groups.

These silyl groups.

The group forming an acetal bond, the acyl group, is easily removed under acidic to neutral conditions.

As R2 and R'', a 2-tetrahydropyranyl group or a t-butyldimethylsilyl group is particularly preferred.

R4 represents a substituted or unsubstituted furkyl group having carbon atoms #11 to #10 or a substituted or unsubstituted cycloalkyl group having carbon atoms #11 to #7. The unsubstituted alkyl group having 1 to 10 carbon atoms may be linear or branched, such as methyl, ethyl, propyl, and butyl.

,<n-hexyl, 2-methyl-1-hexyl, 2-methyl-2-hexyl.

Examples include n-heptyl, n-octyl and the like, preferably n-pentyl, n-hexyl, 2-methyl-9-1-hexyl, 2-methyl-2-hexyl and the like.

Substituents for the alkyl group having 1 to 10 carbon atoms include Hagen atoms such as fluorine, chlorine, and bromine; methoxy, ethoxy, n-propoxy, 1so-propoxy, n-butoxy, chromethoxy, 1dichloropmethoxy Alkoxy such as trifluoromethoxy; methoxycarbonyl, ethoxy, and lponyl.

Examples include alkoxycarbonyl groups such as butoxycarbonyl and hexyloxycarbonyl groups; and cycloalkyl groups such as cyclopentyl and cyclohexyl groups.

Examples of the unsubstituted cycloalkyl group having 5 to 7 carbon atoms include cyclopentyl and cyclohexyl groups. Examples of the substituent of the cycloalkyl group having 5 to 7 carbon atoms include the same substituents as described above. R4 is n-pentyl+2-
Methyl-1-hexyl, 2-methy10-2-hexyl, cyclopentyl, and cyclohexyl groups are preferred.

The present invention includes mixtures of the 15-shrimp form of the above formula CI), their enantiomers, and isomers thereof in arbitrary proportions.

Δ7-μ staglandin E represented by the above formula [0,
For example, as shown in the reaction formula below, 7-
The △1-boost taglandin E1 type of the above formula [engineering] is transferred via the hydropoxypμ staglandin E1 type.
, isomers regarding the double bond (△?) at the 8th position exist.

That is, they are 72 bodies and 7E bodies, and in the present invention, 72 bodies.
7E-isomer, 7E-isomer and mixtures thereof.

The method of the present invention is to selectively reduce the double bonds at positions 7 and 8 of the above formula [0 and lead to prostaglandin birds. That is, the corresponding compound of formula (5) can be easily obtained by reacting the compound of the above formula CI] with an organotin hydrogen compound. Examples of organic tin hydrogen compounds include tributyltin hydride, triphenyltin hydride,
Triethyltin hydride, tripropyltin hydride, etc. are used, and the amount thereof is usually 1 equivalent to 100 equivalents relative to the starting compound [0].

An equivalent amount is used, preferably 1 equivalent to 1000 equivalents. The reaction solvent may be an alcoholic solvent or the like if necessary, but a solventless reaction is generally preferred. In order to make the reaction proceed smoothly, a free radical initiator may be used (mainly α, α'-7zobisisobutyp nitrile, bis-t-butyl peroxide, etc., and the amount is adjusted depending on the starting material [0 Usually 0.01 equivalent to 10 equivalents,
Preferably it is 0.1 equivalent to 1 equivalent. Reaction temperature is 0°C
~200°C, preferably 30°C ~14°C
It is carried out in the range of 0°C. After completion of the reaction, prostaglandin E represented by the above formula (g) is separated and purified, for example, by directly subjecting the reaction solution to p-madography. The obtained product can be protected by a known method (E, J, Cor
ly S, J, Amen.

Chem, Soc, %, IJ, +6190 (1
972) and R, F, Newton'! z,
Tetrahedron Lett, 41.

3981 (1979)).

Also, if necessary, the ester group at position 1 may be hydrolyzed. Such hydrolysis can be carried out using an enzyme such as pig liver esterase. In this way, the desired Prustabrangin islands are produced.

The feature of the present invention is to selectively reduce the double bonds at positions 7 and 8 of compound [alpha]], and it is a useful method for synthesizing prostaglandin E1.

13- Preferred specific examples of such prostaglandin E, (PGE, ) are as follows.

(t) PGE+.

+21 (1711)−+ 7 ,20-dimethyl P
G&g(a) (17R)-17,20-minemethyl PG&.

+41 16 , 17 , 18 , 19 , 20-pentanol-15-cyclopentyl PGE.

(5116, 17, 18, 19, 20-pentanol-1
5-cyclohexyl PGE.

+61 +2,3-dehydro form of the compound of 11 to (5) +71 methyl ester of the compound of +1i to (6).

The method of the present invention will be explained below with reference to Examples.

Reference Example 1 OII + dl 7-hydroρoxyP in which eggplant flask
GE, methyl ester (di-THP) 167■=14
- Take (o, a 02 mmol) and add 2.51 m of dry dichloromethane and 220 m of 4-dimethylaminopyridine.
g (1,80 mm nA) was added. This was cooled in a water bath, and methane fluoronyl chloride 70 JIA! (0,
90 mmol) was added dropwise. The water bath was removed and the mixture was stirred at room temperature (24°0) for 11 hours. The reaction mixture was added to a saturated aqueous sodium hydrogen carbonate solution 151, shaken, and extracted with dichloromethane (10*(X3). The organic layer was washed with 10% hydrochloric acid and a saturated aqueous sodium chloride solution, and then extracted over anhydrous magnesium sulfate. Dry, 1A condensation, silica gel column chromatography (7I, hexane:
Ethyl acetate-4: 1) Separate with K, di-7゜8-
Dehydro PGE, methyl ester (di-THP form)
67.4+my (4z%) of methyl ester was obtained.

Smooth data Hnmr (CDCl5) δ: 6,72 (dt, J
= 7.8, 2.0Hz.

iH), I), s -5,1(m, 2H), 4
．． 8-4.5 (m, 2H), 4.3-3.2 (m, l
0H).

2.6-z, Q(m, 6H), 0.88(t, 3H)I
R: neat): 1743.1734.1653
m-'Mass (75eV, m/e): 534
(M+) Example 1゜7.8-dehydeq PGE, methyl ester 11゜15
- bis-tetrahydropyranyl ether 19■ (o, o
a 6 mmol) to tributyltin hydride 0.25
and 5 g of bis-t-butyl peroxide were added and stirred at 100-110'O for 10 minutes. It was cooled and directly subjected to silica gel chromatography (3I!+hexane:ethyl acetate -5:1→3:1) to obtain 15.2 mg (soti) of PGE, methyl ester 11°15-bis-tetrahydropyranyl ether. Ta.

TLC: Rf=0.41 (hexane: ethyl acetate-2:
1) IR (neat): 1743, eos, 860
aa-'NMR (δppm in CDCIm):
0.89 (t, 3H).

1.04-1.98 (m, 30H), 1.98-2.5
8 (m, 51F (), 2.76 (dd, IH).

3.68 (S, 3H), 3.30-4.35 (m.

sH), 4. yo(m, zH), s, 4z ~5.76
(m, 2H) Example λ 7.8-dehyde RPGE, methyl ester 11°15-
Bis-t-butyldimethylsilyl ether 47 Q (
0,062m+aol) and tributyltin hydride 0.
Add 75m, bis-1-butyl peroxide 1011
After adding g, stir at 100'OK for 1°. Cool to room temperature and add directly to the columnar mudcraffy (s, p,
PGE, methyl ester 11゜17-15-bis-1-butyldimethylsilyl ether 26.
axg (71%) was obtained.

IR: (neat):1y4s,xzsa,s3s,7
y4α-heavy NMR (δppm in CDC1,): o ~ 0.
2 (m, 12H), 0.89 (8, 18H).

0.7 ~ x, t (m, aH), ], i ~ a, o (m.

24H), 3.70 (S, 3H), 3.7-4.4 (m
, 2) I), s, 4-s, 7 (m, 2H) Example 3゜(178)-17,20-dimethyl-2,3゜7.8-
Dehydro PGE, methyl ester 11,15-bis-t
-11 tributyltin hydride was added to 80 mg of -butyldimethylsilyl ether, 1511 g of bis-t-butyl peroxide was added, and the mixture was stirred at 100 DEG 0 for 10 minutes. Cooled to room temperature and subjected to 18-direct column chromatography (10 g, hexane:ethyl acetate-30:1) to obtain (17S)-17,20
-Dimethyl-2,3-dehydro PGE1 methyl ester 11,15-bis-t-7' tildimethylsilyl ether 819 (10%) was obtained. In this case, a product in which the ketone at position 9 was reduced was not obtained.

NMR; (δppm in CDCl1.) 0-0.2
(m, 12H), 0.7-1.0 (m, zaH), o,
9~s, a(m, 2xH).

3.74 (S, 3H), 3.8~+, s (m.

2H), 5.4-5.8 (m, 2H), 5.84 (br
d, IH, J=16,0Hz), 7.02(dt, I
H, J = 16.0,7,0Hz) Example 4゜(178)-17,20-dimethyl-2,3-dehydro PGE, methyl ester 11.15-bis-t-butyldimethylsilyl ether 35㎜ Acetonitrile-4
7tI6 dissolved in 2d of hydrofluoric acid (20:l) solution,
After stirring for 25 minutes, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, overconcentrated, and subjected to silica gel column chromatography to obtain (1y 8 )-17,20-dimethyl-2,3
-dehydro PGE1 methyl ester 1711 g (l[5
172%).

NMR (δppm in CDC1a): 0.7~
1.0 (m, 6H), 1. (1-3.2 (m, zaH)
, a, 7z (s, aH), a, a~4.5 (m, 2H)
t 5.3-6.0 (rn, 3H).

6.96 (dtlH, J=16.0, 6.8Hz) Example & PGE Methyl Ester Bis-t-7'Tyldimethylsilyl Ether 60 m11? (t o μmol) in a mixture of tetrahydrofuran-water-acetic acid (X:1:a)
was dissolved in water and stirred at room temperature for 48 hours.

Toluene was added to the reaction solution and the solvent was distilled off under reduced pressure to obtain a product of 3.0 g (a, x β mol) (yield 80%).
) PGE, methyl ester was obtained.

Spectrum data Hnmr (CDC1,) δ: 5,6-5.4
(m, 2H); 4.2-3.8 (m, 2H), 3.
63 (s+, 3H).

2.7-1,0 (27H), 0.9 (t,
J=7Hz.

5H) IR (neat): 1750 cm-'Mass
(20 eV, m/s) a 68 (M+) This component was found to be identical to (-1-PGE, methyl ester standard) by PLC (WATER 86000A).

2l- JA8COIJV IDEC100, UV 210n
m, flow rate 1.5 d/m, 900 Psi, solvent:
Hexane: Tetrahydrofuran, Column Develos
il 100-5) Patent applicant Teijin Ltd. 22-

Claims (1)

[Claims] 1. △7- which is a compound represented by the following formula CI), its 15-form, its enantiomer, or a mixture thereof in any proportion.
It is characterized by selectively reducing the double bonds at the 7th and 8th positions of prostaglandin islands, and then subjecting them to debinding and/or hydrolysis reactions as necessary. compound, its 15-shrimp form. Prostaglandin E, which is its enantiomer or a mixture thereof in any proportion. manufacturing method of types. 2. The method for producing prostaglandins EI according to claim 1, which comprises selectively reducing by using an organotin hydrogen compound. 3. The method for producing prostaglandin E1 according to claim 1 or 2, wherein R1 in the above formula α] is a hydrogen atom or a methyl group. 4. In the above formula α], R4 is an n-pentyl group. Prostaglandin E according to any one of claims 1 to 3, which is a 2-methyl-1-hexyl group, a 2-methyl-2-hexyl group, a cyclopentyl group, or a cyclohexyl group. Manufacturing method. 5. The prostaglan according to any one of claims 1 to 4, wherein in the above formula [I] K, R1 and Rs are a 2-tetrahydropyranyl group or a t-butyldimethylsilyl group. Method for producing Gin E, etc.