JPS5883670A - Novel preparation of prostaglandin e1 and its kind - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an inhibitor of blood platelet aggregation, hypotensor by a short process in high yield, by reducing selectively a DELTA<7>-prostaglandin E, and, if necessary, deprotecting and/or hydrolyzing the reaction product. CONSTITUTION:A DELTA<7>-prostaglandin E shown by the formulaI(R<1> is H, 1-10C alkyl, or tri(1-6C)hydrocarbon-silyl; R<2> is 1-10C alkyl, 5-6-membered cycloalkyl; R<5> is H or methyl; R<3> and R<4> are OH-protecting group; A is a group of CH2CH2, a group of CH=CH, a group of C C) is subjected to catalytic reduction using a zinc reducing agent (zinc powder, zinc-silver, or zinc-copper), or Raney-nickel in an atmosphere of hydrogen. If necessary, the reaction product is deprotected and/or hydrolyzed, to give the desired compound shown by the formula II (R<31> and R<41> are H or OH-protecting group). The starting substance shown by the formulaIis obtained by reacting a compound shown by the formula III with a reactive derivative of an organic sulfonic acid in the presence of a basic compound.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an I+1 method for the production of Prostaclampin &a. For more details, see Δ-P B Staglandine E
, selectively reducing l or desorbing and removing the hydroxyl group from 7-hydro p-xyprostaglandin Ed,
The present invention relates to a novel production θξ of producing Prostaclampin & 4g by subsequent selective reduction.

Boostertag Kun9ine E is one of the l-type p-staglan gain and has an inhibitory effect on platelet aggregation.

It is a compound that has unique antihypertensive activities such as blood pressure lowering effects, and is a useful compound that has recently been used as a peripheral circulation treatment drug in the medical field.

M klZ K , i of conventional Prusta Blancain E,
・It is obtained by biosynthesis from (:) dihomo-8-lylunic acid (D, A, Dgp @t al +l
Bioebem, Biophym.

Aeta + Ilo, 204 (1964)) and the method using the method of intramolecular aldol reaction and optical resolution in the 11-nido p albin induction book (
E.J.

Car@y et al. +' J, Am@r, Chem, 8oe,
, 91, 53s (see s s 9)) Qil12
-Substituted-2-cyclopentene 7/114 isomer is attached with Michael organometallic compound (C, J, 8th et al.
J, Am5r, Chem, Soc,, 95.1a)
6(19)3) and A, F. Kluge et al., JACSl
, 92, 7821 (1971))・ψProtected Pros〉Grandin F@@F*
ey et al.* J, Am@r, Chem.

8@@,, 92.2586 (197G), $teru) etc. are known (J, B. Bindra et al. + Pros
taglandin 5yntheais +muscad
emic Prass (1977)-), however, in the biosynthetic method, the yield from the raw material dihomo-8,-lylunic acid is very low, and the purified waste from the by-product is The method of obtaining the starting material by chemical synthesis requires many steps to obtain the starting material.On the other hand, even if the starting material is easily obtained, the yield of σ Novrostaglampin E from such starting material is low. There are drawbacks such as very low performance.

In view of this point, the present inventor uses the advantageous Fy method for the chemical synthesis of prostaglandin E, namely (1) easily obtained starting materials. (1) The reaction process is short, +1
We conducted extensive research to find a Qhk method that has advantages such as a high total yield of lil.
7-1 Draw) Sibu-p Staclandine E Obtained in High Yield by One-Step Reaction from -2-Sic-Bentenone
We discovered that prostaglandins F4 can be easily obtained with low yields by removing the sled hydroxyl group to form perprostaglantin E, and then selectively converting the tr=N group. In other words, the method of the present invention selectively converts d-prostaglanti/E@ expressed by the following formula 0 to K
A method for producing prostaglandins represented by the following formula (4), and a method for producing prostaglandins represented by the following formula (4), which includes the following: 7-Hydop-xyprostagran “IinE” expressed by OR sound
fI! 4 was reacted with a single sulfonic acid reactivity #4 in the presence of a basic compound to obtain d-Prustabrandein (represented by the following formula OR4), which was then selectively reduced and further This is a method for producing p-staglandinnucle expressed by the following formula (1), in which steps are taken to remove the ambiguity and/or to perform the hydrolysis reaction as necessary.

The 7-hydroxyglostaglanines represented by the above formula 11 used in method t of the present invention are separately proposed by the Ministry of the Invention et al.
725 and Tokuchi An 55-81306), it can be easily prepared with a yield of 1 by a one-step reaction from 4-human 2-cyclopentenoid. In the above formula [11, 1t1 is a hydrogen atom, C, +C,. lower alkyl group or tri(C.

~CS) Hydrocarbon-covered with silyl group. Examples of such lower alkyl groups include methyl and ethyl.

Propyl, 7-tyl, hexyl, decyl, and benzyl groups are standard Gerao! ,)! j(CI-C4) Hydrocarbon-silyl group includes trimethylsilyl, triethylsilyl 11. ,
The t-pthyldimethylsilyl group is 4.

R1 represents a substituted or unsubstituted υJ C, -C10 furkyl group or a substituted or unsubstituted Q.5- to 6-membered dichlorofurkyl group. The unsubstituted σI C,% C,, realkyl group may be either 4-pronged or branched, such as pentyl, hexyl, 2-hexyl, 2-hexyl, etc.
-Methylhexyl, heptyl, octyl, etc., preferably pentyl.

Hexyl, 2-methylhexyl/1 group, etc. 7'l can be obtained. Examples of unsubstituted S to 6-membered Schiff groups include cyclopentyl and cyclopentyl groups.
6 Preferred examples of m1m in the true cycloalkyl group include methyl, ethyl, ethynyl, phenyl, phenoxy, trifluorofunyl, trifluoromethyl, methoxy, and ethoxy groups. Among these 4K”
is pentyl, hexyl, 2-methylhemoyl or (cycloalkyl group is preferred.

R1 and R' are the same or different and are water groups and pus groups, and such protecting groups include tri(C1-C,) swollen hydrogen-
Name a group that forms an acetal bond with a silyl group or a hydroxyl group or an oxygen group.

A tri(C1-C,) hydrocarbon-silyl group or a group similar to those mentioned above may be mentioned, and examples of the group forming a covalent τ acetal bond with the hydrane atom of the water group include, for example, methoxyethyl, 1-ethoxyethyl, 2-methoxy-2
-Propyl, 2-ethoxy-2-propyl, (2-methoxy)A)methyl2. benzyloxymethyl, 2-
Natrahydrofuranyl, 2-latrahydrofuranyl 6,6-dimethyl-3-oxa-2-oxohycyclo(s 1.o )hex-4-yl 4-gin is used. Among these holding groups, t-butyldimethylsilyl group, l-ethoxyethyl group, 2-methoxy2-propyl A+(2-methoxyethoxy)methyl group, and 2-natrahydropinonyl group are preferred.

The method of the present invention will start by eliminating and removing the hydroxyl group at the 7-position in the 7-hydro-p-staglandin EIlliK of the above formula I to derive the d-prostaglandin E of the above formula (2), i.e., Compound 2Q can be easily obtained by reacting the compound of formula 1 above with an organic sulfone w1f reactive enzyme conductor in the presence of a basic compound. As the basic compound used here, amines are preferable, and examples of such amines include 4-dimethyl 7-minovirine, triethylamine,
Examples include Shiitubu pvircyclohe1dylamine, improvir dimenalamine, diisopropylethylamine, and 4-dimethylaminopyridine is particularly preferred.
L. Examples of the reactive derivatives of organic sulfonic acids include organic sulfonic acid solides such as methanesulfonyl coulide and p-)luenesulfonyl chloride; and sulfonic anhydrides such as methanesulfonic anhydride.

The reactive derivative of organic sulfuric acid used is a5 to 10, preferably 2 to 10, based on the starting compound of the formula symbol.
It is used in the range of 3 ships, and basic compounds are used in the range of 1-10
The violet is preferably used in an amount of 4 to 6 equivalents.

The reaction temperature is 0 to 50℃, and the reaction temperature is 0 to 30℃.
The completion of the reaction can be confirmed by aging using thin 1-coomadography, etc., in which 1111 of the raw material compound is lost. The reaction time is usually o, s - t
It is o time. A solvent may be used to make the reaction proceed smoothly. Such solvents include, for example, dicou methane.

RProform, rH; , preferably jiku p
Lomethane is used.

The reaction product can be purified from the reaction mixture by conventional means, such as extraction, washing with water, drying, coomadography, etc.

The thus obtained dinosome (ti) represented by Ota
- prostaglandins 2) are then subjected to selective reduction. The methods used for selective reduction are as follows:
For example, reduction with a zinc-based reducing agent such as zinc powder 1M lead-chain, zinc-copper, or catalytic reduction with Raney nickel is preferably mentioned. When a zinc-based reducing agent is used, the reaction is carried out in the presence of glacial acetic acid. The amount of the zinc-based reducing agent used is 1916 di, preferably 1 to 1! The amount of glacial acetic acid is 1 to 200,
A solvent of preferably 2 to 0 S equivalents is used to allow the reaction to proceed smoothly. Examples of such solvents include methanol, ethanol, and butanol-based alcohols.
m: I'NL Dimethoxyethane, dimethylformamide, dimethylsulfate, phooxide, or a mixed solvent thereof is preferably used. Particularly preferably, methanol is used. On the other hand, Raney's catalytic reduction is hydrogen WI! Selective reduction is carried out downstream. The Raney nickel used in this case is ``C1~20 equivalent to the raw material,
Preferably, an amount of 1 to 1.0 m is used. A solvent is used to make the reaction proceed smoothly. As such a solvent, for example, alcohols such as methanol, ethanol, and methanol; dimethoxytaene, tetrahedral ethers, dinotylform 7j, and a mixed solvent thereof are preferably used. 41 is preferably methanol.

The product thus obtained is subjected to conventional methods such as extraction, washing with water, drying 1. It can be purified by p-mudography or the like. The protective groups for the hydroxyl groups at the 11th and 15th positions may be removed from the prepared product, if necessary.

Removal is accomplished, for example, by treating the product at room temperature in an acetic acid-water-de)p-hydrofuran mixture (3:1:1 to 3:!) (E, J).

('or@y et al., J, λm@r, ck@im, 8oc,
+94. s s s o (see l.12))
.

Furthermore, if necessary, the ester group at the 1-position may be hydrolyzed. Such hydrolysis can be carried out using an enzyme such as lipase.

In this way, the desired booster grandinnuku is manufactured.

A feature of the method of the present invention is that booster glandin can be easily obtained in relatively high yield from an easily obtained starting material (preserved 4-hydroxycyclobentenone) through only three reaction steps. It's possible.

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

Example 1 1. - eggplant flask Kdt-7-hydroxy PG & methyl ester (di-THP form) ti Mitsu (a30!
・Take l) and add dry dichloromethane zs- and 220% 4-dimethylaminopyridine (L I O!IIIEI@
1) was added. This was cooled in a water bath, and methanesulfonylcoolidof Oaj<0.9@rmr@l) was added dropwise. The water bath was removed and the mixture was stirred at room temperature (24°C) for 11 hours. The reaction mixture was diluted with saturated sodium bicarbonate aqueous solution 1
5 - Added to the solution, shaken and extracted with methane (
10ggX3).

The organic layer was washed with 10-hydrochloric acid and a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. ll1
[dispersed in silica gel column coomadography (tt, hexane:acetic acid ether = 42 l), #-%il
-dehydro PG)i.

Methyl ester (di-THP form) 67. a recommendation g(
42chi) was obtained.

Spectral data 'Hnmr (CDC4) δ: IL72 (dt# J
=7.8.

1 (Il'lz, I H), 5-11 11 (m
s 2H) e4s-ts (m, 2H), 43-12
(m, t.

H), zs-*o (m, sH), α5s (t.

5H) IR (neat): 1t4s, 1734.
Eye 11$3ffi'Mas4 (? 5 eV
, IQ/@): 5 3 4 (
M”) Example 2 dt-7,I-dehydro PG & methyl ester (di-
THP compound) izwg (iy4 mol) was dissolved in 1-methanol, and 4 drops of glacial acetic acid were added. This is zinc powder 35
While adding 0■ (43mm・l) in 3 times,
Separate the soldered zinc for 2 hours at °C,
Solution F was concentrated using a vacuum pump. The residue was dissolved in coulloform, insoluble materials were separated from P, and solution F was concentrated under reduced pressure. It was fractionated using silica gel column ρ1 Togelafy (s f, hexane:ethyl acetate = 4:1), and L3■ (!Ii
*) An oily substance was obtained.

The spectral data of this product were as follows.

'Hmmr (CDC4) a 2 N7 ~ l
L4 (m, 2H).

4@I (brl 2H), 42~! ! (s
m# ・H)Mass (75@Vl n%e)
: 4 s 4 (M+-to2) #) 4h is H-
A sample of the dx-THP substance of PG & methyl ester was mixed with silica gel TLCK (hexane: ethyl acetate = g
: 1).

Example 3 (TBDM8: t-methyldimethylsilicate)-
1 to 6-zohydro-7-hydroxy-ρoxy PGF.

Methyl ester (Bisu iun DM 8 bodies) gos (a
343 mmol) and 4-dimethylaminopyridine xz
Dissolve tg (to 4 mmol) in 4 m of dry dichloromethane and add 40 d of methanesulfonyl chloride (a 5
*■ol) m1ll! (~25°C) was added dropwise. 3
After stirring for 0 minutes, add 1 OILt (a I S
Add methanesul small nyl chloride of 1), 18
Stir for a minute. The reaction mixture was added to 20 ml of saturated aqueous heptammonium chloride solution, shaken, and the organic layer was separated. Extract the aqueous layer with dicouromethane (l・-X2)L,
The organic layers were combined and washed with 1O thihydrochloric acid. After drying over anhydrous magnesium sulfate, it was concentrated and subjected to silica gel column coomadography (1 oy, hexane:ether=
s: t) 4c, fractionate, and go to a-5? , @-fhi FpPG & methyl ester (bis-710M8 bodies) 12
4■ (619G) was obtained.

Spectral data 'Hnmr (CDC4) a: is 2
(br, IH)w! Ls” (m, 2
H) l 41 9 (me IH) 1 table・'
(br+ ”H) + l 5 * (s
+ lH) *L l' (bre ”H
) + L S 2-3 (me @ H)
.

*OL) (m) l00fJ a 8
(m), a O--al(m) 11i(meat): xzls, 1750.
*tsl.

1m21em→Mass (IS @V, m/m):
s * o (M”) Example 4 !- to methanol to a- (1,8-dehydro PG & methyl ester (bis-780M8 bodies) 17.4 increase (11
4μm@t), add 1/3 cup of Raney nickel W-2 and put it under a hydrogen balloon! I! The mixture was stirred at 19°C for 1 hour. After removing the catalyst using Celite, the P solution was condensed and fractionated using silica gel column coomadography (log, hexane:ether=s:i).
#-PGE, methyl ester (
8 bodies of Bis-780M) were obtained.

Spectral data 'Iinmr (CDC4) J: is-[4(m
e2H).

42-18 (m e 2 H), l 66 (s
s 3 H).

! 64 (dd, IH, Jgl, 2,1 a4Hz) *
24-1.11 (m, 4H), L7-1.0
(m) eLO-α Yi(1!1.21M), 0.
1~α0 (m)III(treat): l?
! 106@-' Collection Example 5 dl-PGE)+rux-ychill (bis-TBDMB body)
co@(lOjImlol) was dissolved in 11 ml of a mixture of tetrahydro7ran-water-acetic acid (1:l:3) and stirred for 4 hours at room temperature. Toluene was added to the reaction solution, and the solvent was removed under reduced pressure to obtain 10q of product.
#-PG & methyl ester of all1) (yield 80%) was obtained.

Spectral data 'I1mmr (CDC4) J: 16-14
(ah, 2H).

42-me (@, 21), ass (s, 3H).

friend! -10 (xtH), as (t, J=7Hz.

5R) 1R (meat): lt so511-1M
ass (2@@Vsnshi/e):
s s s (M”) This component was found to be identical to H-PGF and methyl ester standard by HPLC. (WATER85oooA.

Claims (1)

[Claims] A prostaglan represented by the following formula 1, characterized in that L is selectively reduced with the following formula I OR' and then subjected to a debinding and/or hydrolysis reaction as necessary. Method for producing tin E1 type. 2. A method for producing pronucgrandin islands according to claim 1, which comprises selective reduction by catalytic reduction with a zinc-based reducing agent or Raney nickel. The manufacturing method according to claim 1, which is a methino group or an ethyl group. Table Any one of Item 3 of No. IXJ of Patent No. 114, in which R■ is a pentyl group, hexyl group, 2-methylhexyl group, or cyclohexyl group in the above formula α''.
Method for producing Prostaclampin &amp; (5) The above symbol, R8 and R' are the same or different, 2-tetrahydropyranyl group, t-butyldimethylsilyl group, 1-ethoxyethyl group, 2-methoxyethyl group, 2-methoxyethyl group,
- The method for producing purustabrangaine sushi according to any one of claims 1 to 4, wherein the purupyl group or (2-methoxy"toxy)methyl group is a purupyl group or a (2-methoxy"toxy)methyl group. a The 7-hydropypstaclandine compound coated with the following formula is reacted with the reaction f4 knee conductor of a stable sulfonic acid in the presence of a basic compound to form a lower grip type mark. d-prostaclampin hl14, represented by oa', was obtained;
The above formula (
1) A method for producing prostaglandin &amp; 7. Range of hour hand ID water selectively reduced by catalytic reduction with zinc-based reducing agent or Raney nickel Item 6 1k
l! Method for producing Takano Pustaglandi/gI. a Reactivity of organic sulfonic acid - The conductor is mekunsulfoni! Lecroli F, P-) Ruensul 4, Nirku ρ□do or methanesulfonic anhydride Claim 6 or 7 JJ Distribution υ knob ρ Staglandine El #IO
) d construction method. Tortoise A patent in which the basic compound is an amine. I) A method for producing prostaglandins according to any one of Items 6 to 8. 1G In the above formula 1, RI is a hydrogen atom. , a methyl group or an ethyl group, (
- A method for producing Prostaclamp-in type h according to any one of the items. 11. In the above formula 1, W is a pentyl bracket, hex. Any one of the suite items 6 to 10, which is a 2-methylhexyl group, a 2-methylhexyl group, or a Schiff ρ group.
A method for producing ILc'nopustaglantein E, etc. 12 In the above formula, Rs and R4 are the same and < is different; methoxyethoxy) methyl group 1: In certain cases 1 - A method for producing prostachlaminin &amp;