JPS596872B2 - prostaglandin - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing prostaglandin-like compounds.

More specifically, the present invention relates to a method for producing prostaglandin compounds useful as synthetic intermediates for pharmaceuticals. Prostaglandins are widely distributed in animal tissues, are secreted in vivo, and are known as lipid-soluble substances that affect smooth muscle contraction, blood pressure, lipid metabolism, platelet aggregation, etc. in minute amounts.

Therefore, they are useful as medicines such as antihypertensive diuretics, antithrombotic agents, bronchodilators, anti-inflammatory agents, labor stimulants, abortion agents, and arteriosclerosis preventive agents. Natural prostaglandins have a basic skeletal structure shown by the formula, and are divided into PGE groups, PGF groups, and PGA groups based on the structure of the five-membered carbon ring as shown below.
classified into groups.

This is further explained by the position of the double bond in the side chain.
-1 group (trans-△13), PG-2 group (cis-△5)
trans-1 △13) and PG-3 group (cis-1 △5, trans-△13, cis-1 △17).

Various types of prostaglandins, which are generated due to differences in the ring structure or the position of the double bond, each exhibit specific pharmacological effects. Although many methods are known for chemically synthesizing prostaglandins, one of the main methods is a method in which a side chain at the C-12 position of a five-membered ring is formed by a Wittig reaction. This method is explained by Il.
E. J. The present inventors have previously made partial improvements to these methods and synthesized prostaglandin-like compounds with better effects. However, when these methods are applied, the cost of the Wittig reagent is very high. From the above viewpoint, the present inventors first formed an ethenylformyl group -CH=CH-CHO by the Wittig reaction, and planned a synthetic method to obtain a prostaglandin-like compound by reacting this with various organometallic reagents, As a result of various studies, the present invention was completed.

According to this method, it is possible to save the raw material for changing the hydrocarbon side chain below the C-16 position, and furthermore, compared to the previous method, the reduction of the carbonyl at the C-15 position can be omitted. . Furthermore, since the completion of the side chain portion below the C-16 position is accomplished by the Grignard reaction, it has the advantage of being able to form a wider range of derivatives than the Wittig reaction.

There are two types of prostaglandins: a natural type and a racemic type (i.e., a mixture of the natural type and an equal amount of enantiomers), and the prostaglandin referred to in the method of the present invention includes both of these types. . That is, according to the present invention, an alicyclic aldehyde represented by the general formula (wherein R1 represents a 2-tetrahydropyranyl group, a 2-tetrahydrofuranyl group, or a 1-ethoxyethyl group), and an alicyclic aldehyde represented by the general formula R2MgX
Grignard reagent () (R2 has 4 to 4 carbon atoms)
8, where X represents bromine, iodine or chlorine), a prosthetic compound represented by the general formula (wherein R1 and R2 have the same meanings as above) can be obtained. Grandin compounds can be produced.

The alicyclic aldehyde (1), which is the raw material of the present invention, is produced by the following route from 2-oxa-3-oxo-hydroxymethyl-J-A-acetoxysbicyclo[3.3.O]octane. thus manufactured.

(In the formula, R1 has the same meaning as above.) The above lactone () is already a known compound, and the racemic type has been published in the Journal of the American Chemical Society No. 1 (J. Am. Chem. SOc.). 91
Volume 5675 page (1969), the natural type is Comrade No. 9
It is described in Volume 2, page 397 (1970).

When racemic or natural acetyl alcohol is used, a racemic or natural prostaglandin compound can be obtained from each. The lactone (2) is hydrolyzed with a common hydrolysis reagent and then acidified or hydrolyzed with a weak alkali in an anhydrous alcohol solvent to form the diol (V). When diol (V) is acetylated under mild conditions, the primary alcohol ()1* is acetylated to become acetyl alcohol ()9. Acetyl alcohol () in a solvent inert to the reaction, dihydropyran,
Reaction of dihydrofuran or ethyl vinyl ether with a catalytic amount of an acid condensing agent such as p-toluenesulfonic acid gives acetyl ether (). Acetyl ether 5
Le () is hydrolyzed to become hydroxyether () in the same way as lactone (). Furthermore, among the hydroxy ethers (), those in which R1 is 2-tetrahydropyranyl were synthesized by Ichi Shu Korey et al. by the method shown below [Journal of the American Journal]. Chemical Society 1 (J.Am.Chem.
．． SOc) Vol. 93, p. 1490 (1971)]. It is selectively oxidized to obtain alicyclic aldehyde of general formula () in high yield.

This and formyl methylene dimethyl phenyl phosphorane of formula (X) produced according to the route shown below were mixed in methyl dichloride (at 0°C for about 40 hours) to form a compound of general formula (1). An alicyclic aldehyde is obtained, which has already been synthesized by the present inventors.The Grignard reagent of the general formula () used as the other raw material is prepared by combining . It can be obtained from magnesium metal.

The reaction between this compound and the alicyclic aldehyde of general formula (1) is a so-called Grignard reaction, and can be easily carried out according to a method known per se. In other words, the general formula (
Dissolve the alicyclic aldehyde in 1) in ether, and slowly add the Grignard reagent of general formula () dissolved in ether. After stirring at 5° C. for 1 hour, a saturated aqueous solution of ammonium chloride is added and hydrolyzed to obtain the desired prostaglandin compound of the general formula ().

The hydroxyl group formed at this time has both α-1 coordination and β-1 coordination, but the two can be separated using a silica gel column or the like, if desired. Alternatively, the final product can be separated and purified by carrying out subsequent steps as a mixture. The compounds obtained by the method of the present invention can be used as common intermediates for synthesizing useful compounds with altered side chains of PGF,a, PGF2a, PGE, PGE2.

Next, from the compound obtained by the method of the present invention, PGF2
a, PGFl.

, dihydroPGFla, PGE, PGEl, dihydroPGEl, PGA2, PGA1, dihydroPGA1 and their side chain substituted products are shown below.
(In the formula, R1 and R2 are the same as above, R3 is a 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, or 1-ethoxyethyl group, and X and Y are -CH2C
H2- or -CH-CH-) As shown in this reaction formula, a compound of general formula () is mixed with dihydropyran, dihydrofuran, ethyl vinyl ether and a catalytic amount of an acid condensing agent in a solvent inert to the reaction. , for example with p-toluenesulfonic acid to form compound (XII).

Among these compounds (X), one in which R1 and R3 are tetrahydropyranyl groups and R2 is an n-pentyl group was synthesized by Ichi Shu Korey et al. [Journal.
of the American Chemical Society (J
．． Am. Chem. SOc) Volume 92, page 397 (197
0 years)]. Also, R1 and R3 are the same as above, and R2 is 1 (R)
Methylpentyl or 1(S)-methylpentyl has already been synthesized by the present inventors.

(JP-A-48-54068) Various prostaglandins and their analogous compounds can be obtained from these compounds by the methods described in the above-mentioned literature.

That is, when this compound () is reduced with diisobutylaluminum hydride in an inert solvent, lactol (X
IV) is obtained.

Further, by condensing this compound (X) with 4-carboxy-n-butylidene triphenylphosphorane by Wittig reaction, cacilebonic acid (XVI) is obtained. When this compound (X) is catalytically reduced using a relatively weakly active catalyst, such as various forms of palladium nickel, only the cis double bond is saturated to form the compound (XM[). Further, when catalytic reduction is performed using a highly active catalyst such as platinum oxide, all double bonds are saturated to form the compound (XVl). Compound (X) (XVl) and (
X) is an aqueous solution of an organic acid such as acetic acid or an inorganic acid such as hydrochloric acid by adding, if necessary, a water-miscible organic solvent such as methanol, ethanol, or tetrahydrofuran;
When hydrolysis is carried out at room temperature or under heating, the compound (XI
X) i.e. PGF2a, PGFiO, dihydro PG
Fl. and compounds similar to them are synthesized. Compounds (X) (X) and (X) are then oxidized with a mild oxidizing agent such as chromic acid oxidation by various methods to obtain compound (XX).

When this compound (XX) is hydrolyzed under the above-mentioned acidic conditions, compounds ○αD, that is, PGEl, PGE2, dihydro PGE, and compounds similar thereto are obtained.
When compound (XXI) is treated under more acidic conditions than in the case of hydrolysis, compound (XX[I), that is, PG
Al, PGA2, dihydroPGAl and similar compounds are obtained. The PG analogues thus obtained can be further converted into derivatives with respective characteristics by various methods currently known for prostaglandins.

For example, when treated with an equivalent amount of base or organic amine,
forming a metal salt or organic amine salt of a PG-like compound;
Becomes easily soluble in water. It also forms clathrate compounds with molecules capable of forming clathrate compounds, such as cyclodextrins, and becomes stable prostaglandins. Esters are prepared by (1) esterification with diazoalkyl; (4) reaction with alcohol or thiol using synchhexylcarbodiimide as a condensing agent; (1i1) First, tertiary amine and pivaloyl halide or alkyl sulfonyl halide. is added to form a mixed acid anhydride, and then an alcohol is reacted (Japanese Patent Publication No. 49-2076
No. 6, same. No. 4924911).

In addition, the carboxyl group of prostaglandin is converted to alcohol by converting the methyl ester of PGE into an oxime, as shown in Japanese Patent Publication No. 13332/1983.
Next, it is reduced with lithium aluminum hydride to form an oxime alcohol, and then the oxime is hydrolyzed to obtain the desired alcohol. Further, a 11-desoxy PGEl-like compound can be obtained by converting the 15-position hydroxyl group of PGAs into a trialkylsilyl ether, subjecting them to catalytic reduction, and then hydrolyzing them. Next, the present invention will be explained in more detail with reference to the following examples.

Example 1 2-oxa-3-oxo-16-(2-formyl-1
amylmagnesium bromide synthesized by a conventional method by dissolving 560 g of cisbicyclo[3.3.O]octane in 207 n1 of anhydrous ether 3.15 ml of an ether solution (0.7 molar concentration) was gradually added dropwise while maintaining the temperature at 5°C.

After further stirring at 5° C. for 1 hour, 30 ml of a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with 100 ml of ether. The ether layer was washed with saturated brine, dried, and concentrated under reduced pressure. The residue was separated using a silica gel column using ether: ethyl acetate: n-hexane (2:1:1) as the elution solvent, and 2-oxa-3-oxo-16sine 1-
(3α-hydroxy-1 trans octenyl) 1 J A 1 (2-tetrahydropyranyloxy) 1 cisbicyclo[3.3.0] octane and its side chain hydroxyl isomer, 1407 ng and 150 T, respectively! Zg (total yield: 41%) was obtained as a colorless oil 1. Infrared absorption spectrum (hereinafter abbreviated as R) (liquid film method) α body: 3450
, 292012840, 1765, 1180, 1130
11075, 10201970? -1 (the β-form is almost the same) 2 nuclear magnetic resonance spectrum (hereinafter NM
(abbreviated as R) (deuterated chloroform) α form: δ = 5.54-5
．． 19 (2H, multiplet), 5.03-4.64 (1H,
multiplet), 4.64-4,37 (1H1 multiplet), 4.
22-2.98 (4H, multiplet), 2.80 (1H, singlet, two-line) (almost the same for the β-form) TLC [Ethyllivenzene acetate (1:4)] α-form: Rf = 0.33 , β form: Rf-0.27 The alicyclic aldehyde used in this example was synthesized as follows.

This 2-oxa-3-
Dissolve 957 oxo-16-hydroxymethyl-J-Anchieacetoxysbicyclo[3.3.O]octane in 750 ml of anhydrous methanol, and dissolve 65 y of potassium carbonate.
The mixture was stirred at room temperature for 1 hour, then neutralized with hydrochloric acid while cooling on ice, the resulting crystals were filtered off, and the solution was concentrated under reduced pressure. After washing the residue with ethanol and then ethyl acetate,
After complete drying, 2-oxa-3-oxo-16syn-hydroxymethyl-J-A-hydroxycisbicyclo[3.3.0]octane was obtained, 4 white powdery crystals, yield 62y (yield 81%), melting point 119°C. IR (KBr
tablet method): 3350, 2970-2880, 17401
1480, 1440, 14101138011335,
1305, 1270, 1205, 1100110801
10601104011020, 10001975? −
1 NMR (deuterated chloroform + deuterated dimethyl sulfoxide)
: δ-5.1.0 to 4.60 (1H1 multiplet), 4,2
9 (2H, singlet), 4.13-3.77 (1H, multiplet), 3.38 (2H, doublet) TLC [methylrimethanol dichloride (20:1)]: Rf-0 .27 Next, the obtained diol 627 was dissolved in 700 ml of anhydrous pyridine, cooled to -40°C, acetic anhydride 37y was added dropwise, and -
Stir at 40--20°C for 5 hours and at 0°C overnight.

Pyridine was distilled off under reduced pressure, dissolved in 500 ml of ethyl acetate, 100 ml of sodium hydrogen sulfate was added, stirred vigorously, filtered under reduced pressure, the ▲ solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. Purification was performed using benzene:ethyl acetate (1:3) as the elution solvent to obtain 2-oxa-3-oxo-acetoxymethyl-J-A-hydroxybicyclo[3.3.O]octane.
67 (yield 68%), colorless needle crystals, melting point 36~
37℃0R (KB abuse agent): 3450, 29601177
5, 174011420, 1370112501119
0, 1120, 1090110401980CTII-
1NMR (deuterated chloroform): δ = 5.15-46 (1
H, multiplet), 4.3 to 3.75 (3H, multiplet), 3
．． 50 (1H, singlet), 2.02 (3H, singlet) TLC [methyllimethanol dichloride (20:1)]:R
f-0.50 Next, 21.57 ml of this acetyl alcohol was dissolved in 260 ml of methyl dichloride to give 12.5 ml of dihydropyran.
57 and P-toluenesulfonic acid 0.26y were added and stirred at room temperature for 20 minutes.

Next, after neutralizing with an aqueous sodium hydrogen carbonate solution, it was diluted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure.
-Oxo-6-acetoxymethyl-J-A-1 (2
'-tetrahydropyranyloxy)cisbicyclo[3.
3.70] Octane 287 was obtained (yield 98%) as a colorless oil.

IR (liquid film method): 2950-2840, 1775, 17
4011465, 144011390-1340112
4011180, 1140-1120, 1080110
401980? -1NMR (deuterochloroform): δ-5
．． 2-4.72 (1H1 multiplet), 4.72-4.30
(1H1 multiplet), 4.7-3.2 (5H, multiplet),
2.01 (3H, singlet) TLC [methylrimethanol dichloride (20:1)] Rf-0.74 Next, 16.47 of this acetyl ether was dissolved in 200 ml of anhydrous methanol, and 22.8 V of potassium carbonate was added. The mixture was stirred at room temperature for 30 minutes, then neutralized with hydrochloric acid while cooling on ice, the resulting crystals were separated (▲), and the liquid (▲) was concentrated under reduced pressure.

The residue was extracted with ethyl acetate, dried and concentrated under reduced pressure, and then purified using ethyl acetate on a silica gel column to obtain 10.9y (yield 78%) of hydroxyether as a colorless oil. IR (liquid film method): 3450, 2920,
2850, ~2300, 1780~173011460
11440, 13801135011305, 1240
, 1180, 107011030, 1020, 9701
950CTI1-1NMR (deuterochloroform): δ=5
．． 13-4.74 (1H1 multiplet), 4,74-4.3
5 (1H1 multiplet), 4.0-3.3 (6H, multiplet)
, 2.92-2.32 (3H1 multiplet), 2.32-1
．． 80 (3H, multiplet), 1.80-1.08 (6H,
Multiplet) TLC [ethyl acetate]: Rf-0.42 Next, add pyridine 4 to 300 ml of methyl dichloride.

Dissolve 35ml of chromic anhydride and 2.74y of chromic anhydride,
The mixture was stirred at 5° C. for 15 minutes to form a chromic acid-pyridine complex.

Next, add 10y of dry Celite and cool to 5-0°C, add the solution of 6d of methyl dichloride containing 700w of hydroxyether obtained above, stir at 0°C for 15 minutes, then add 10y of acidic sodium sulfite. After stirring for an additional 10 minutes, the mixture was filtered, and the r solution was concentrated under reduced pressure, dissolved in 20 ml of methyl dichloride, and immediately used in the subsequent step without purification. Trimethylphenylphosphonium bromide 2.
327 was suspended in 15d of anhydrous tetrahydrofuran, and O
After gradually adding 10 ml of a 1.0 molar n-butyllithium ether solution while keeping the temperature at 0.degree. C., and stirring for 20 minutes, transparent yellow methylene dimethylphenylphosphorane was produced.

When this solution was added to a mixed solution of 2.4 ml of ethyl formate and 10 Tf11 of anhydrous tetrahydrofuran, a large amount of white solid precipitated at that moment, but after stirring for an additional 30 minutes, it became a cloudy mixed solution. To this, add 25 ml of 1N monohydrochloric acid aqueous solution at 0°C and 15 ml of ether at 0°C, separate the aqueous layer, gradually add 3N caustic soda aqueous solution at 0°C, and extract several times with 20TIII of methyl dichloride at 0°C. did.
The methyl dichloride layers were combined, washed once with ice water, dried over magnesium sulfate, concentrated at below 0°C to a solvent volume of 20 ml, and stored at -78°C. These reactions were carried out while keeping the temperature below 0°C. The formed formyl methylene dimethyl phenyl phosphorane is easily decomposed and cannot be stored for more than 20 hours. Then 2-
oxa-3-oxo-16-formyl-J-A-1 (
2-tetrahydropyranyloxy)-cisbicyclo[3
・3・O] Octane 432 was dissolved in 20 ml of methyl dichloride and heated at 0°C to half the amount of the methyl dichloride solution of formyl methylene dimethyl phenyl phosphorane synthesized earlier.
m1 was added. After stirring at 0° C. for 15 hours, the remaining 10 ml was added and further stirred for 8 hours. Formyl methylene dimethyl phenyl phosphorane, freshly synthesized from 700 η of trimethyl phenyl phosphonium bromide, was added again in the same manner as before, and the mixture was stirred at 0° C. for an additional 15 hours. After concentrating the reaction mixture solution at 0°C or lower, it was purified using a silica gel column using methylrimethanol dichloride (200:1) as an elution solvent to obtain 2-oxa-3-oxo-6-syn-1, the raw material of the present invention. (2-formyl-1
Trans-ethenyl)-J-A-1(2tetrahydropyranyloxy)-cisbicyclo[3.3.0]octane 2907r19 was obtained as a colorless oil, yield 61%0.
R (liquid film method): 29301177011685, 135
0, 1173, 1120, 1070, 10301967
? -1NMR (deuterated chloroform): δ-9.78 to 9.
27 (1H, double line), 6.

90~6.41 (1H1 double line - [wa d line), 6.31~
5.78 (1H, double line - [d line), 5.17-4,3
5 (2H, multiplet), 4.35-3.14 (3H1 multiplet), 314-1.99 (6H, multiplet) Example 2 2-oxa-3-oxo-6syn-(3-hydroxy −
4-methyl-1 transoctenyl)7anti-1(2-
Tetrahydropyranyloxy)-cisbicyclo[3.3
・0] Synthesis of octane 2-oxa-3-oxo-6-(2-formyl-1-trans-ethenyl)-J-A-(2-tetrahydropyranyloxy)-cisbicyclo[3.3.O ] Octane 560η to anhydrous ether 20m
1 and then add an ether solution of 2-hexyl-magnesium bromide synthesized by a conventional method (0.
65 molar concentration) was gradually added dropwise while maintaining the temperature at 5°C.

After further stirring at 5° C. for 1.5 hours, 30 ml of a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with 100 ml of ether. The ether layer was washed with saturated brine, dried, and concentrated under reduced pressure. The residue was separated using a silica gel column using ether:acetic acid:n-hexane (2:1:1) as the elution solvent, and 2-oxa-3-oxo-16syn-(3α
-Hydroxy-4-methyl-1-transoctenyl)-
117 W! 9 and 132W (total yield: 34%) were obtained as colorless oils. IR (liquid film method) alpha form: 3400, 2960, 2840, 177011
18011140, 1080, 1040, 980Crf
L-1 [β-form is almost the same] NMR (deuterated chloroform) α-form: δ-5.61 to 5.04 (2H1 multiplet), 5
．． 04-4,75 (1H1 multiplet), 4.62-4.

37 (1H, multiplet), 4,20-3,00 (4H1 multiplet), 1.82-0.60 (19H1 multiplet) [β-form is almost the same] TLC [ethyllivenzene acetate (1:
4) [α-form: Rf-0.31, β-form: Rf-0.25] Next, using the compound obtained by the present invention, an important compound that can produce natural prostaglandins and their analogous compounds. A method for producing the intermediate is shown as a reference example.

Reference example 1 2-oxa-3-oxo-16-[3α-hydroxy-1-transoctenyl]-J-(2-tetrahydropyranyloxy)-cisbicyclo[3.3.0]octane 2.1y was dissolved in 30ml of methyl dichloride, 870η of dihydropyran and 30T11 of p-toluenesulfonic acid.
g and stirred at room temperature for 20 minutes.

Next, it was neutralized with hydrogenated sodium hydroxide solution, extracted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure to obtain 2-oxa-3-oxo-16-syn-1 [
3α-(2-tetrahydropyranyloxy)-1 transoctenyl]-J-A-1(2-tetrahydropyranyloxy)-cisbicyclo[3.3.0]octane was prepared as a colorless oil by 2,66 times ( Yield: 100%). IR
(Liquid film method): 2950, 2860, 1775, 1740
11660, 1440113501126011200
, 1040, 10801980 礪-1 NMR (deuterochloroform): δ = 5.74 to 5.32 (2H, multiplet),
4.82-4.59 (2H, multiplet), 4.28-3.
68 (5H, multiplet), 3.68-3630 (2H, multiplet) TLC [methylrimethanol dichloride (20:1)
]: Rf=0.83 Reference example 2 2-oxa-3-oxo-16-[3α-hydroxy-4-methyl-1-transoctenyl]-J-A-1 (
2-tetrahydropyranyloxy)-cisbicyclo[3
・3・O] Octane 1.877 was reacted and post-treated in the same manner as in Reference Example 1 to produce 2-oxa-3-oxo-6syn[3α-(2-tetrahydropyranyloxy)-4
-Methyl-1 trans octenyl]-J-A-1 (2-
Tetrahydropyranyloxy)-cisbicyclo[3.3
・O] Octane as a colorless oil 2,32y (yield 9
9%) obtained.

IR (liquid film method): 2950, 2860, 1780, 14
60, 14401138011240, 1180-11
30, 1030, 980CTIL-1 NMR (deuterochloroform): δ = 5.64 to 5.22 (2H1 multiplet),
5.16-4,68 (2H, multiplet), 4.25-3.
86 (5H, multiplet), 3.

86-3,24 (2H1 multiplet)

Claims (1)

[Claims] 1 General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] (R_
1 represents a 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, or 1-ethoxyethyl group), and an alicyclic aldehyde represented by the general formula R_2MgX (R_2 is a straight or branched chain having 4 to 8 carbon atoms A general formula characterized by reacting a Grignard reagent represented by an alkyl group (X represents bromine, iodine or chlorine) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [III] (R
_1 and R_2 have the same meanings as above).