BE836890A - PROCESS FOR MANUFACTURING DERIVATIVES OF ALCOXY ACID - 20 - ALCOYL - 16 - PROSTADIENOIQUE - Google Patents

Description

       

   <EMI ID = 1.1>

  
by the formula I:

  

 <EMI ID = 2.1>


  
OH 0

  
 <EMI ID = 3.1>

  
in which A represents -CH- or -C-; R and R, which can be

  
identical or different, each represents a hydrogen atom

  
 <EMI ID = 4.1>

  
tick or different, each represents a lower alkyl group and the non-toxic salts of these pharmacologically acceptable derivatives.

  
The compound of the present invention, that is to say the derivative

  
20-alkoxy-16-alkyl-prostadienoic acid represented by

  
 <EMI ID = 5.1>

  
hydroxy-protected prostadienoic acid derivative represented by formula II:

  

 <EMI ID = 6.1>


  
14

  
in which A, R, R and R have the same meaning as in

  
 <EMI ID = 7.1>

  
rents, each represent a hydrogen atom or a pro- group

  
 <EMI ID = 8.1>

  
being the protecting group for a hydroxy group and esterifying

  
then, if desired, the product.

  
In formula I, the lower alkyl group R, R, R

  
 <EMI ID = 9.1>

  
1 to 4 carbon atoms and practical examples of the alkyl group

  
are methyl group, ethyl group, propyl group,

  
isopropyl group, butyl group, isobutyl group, etc.

  
The dotted line linked to the cyclopentane ring represents <EMI ID = 10.1>

  
is positioned below the plane of the cyclopentane ring and the thick line linked to the cyclopentane ring represents a beta-steric configuration, i.e. the substituent is positioned above the plane of the cyclopentane ring. In addition, the wavy line linkage on the side of the chain represents a steric S configuration, steric R configuration, or a mixture thereof.

  
 <EMI ID = 11.1>

  
gene can provide pharmacologically acceptable non-toxic salts. Typical examples of these salts are salts of an alkali metal or an alkaline earth metal such as sodium, potassium, calcium, ammonium salts, etc. and salts of organic amines such as tetramethylammonium, dimethylamine, piperidine, monoethanolamine, and the like.

  
The conventionally known natural prostaglandins are unsaturated fatty acids having 20 carbon atoms and exhibit different physiological activities. Among the natural prostaglandins, prostaglandins E2 (PGE2) represented by the formula:

  

 <EMI ID = 12.1>


  
 <EMI ID = 13.1>

  

 <EMI ID = 14.1>


  
in which position 15 exhibits a steric S configuration are well known as derivatives of prostadienoic acid having different physiological activities. That is, prostaglandin E2 and prostaglandin F2a have physiological effects such as

  
contraction effect on smooth muscles of uterus, small intestine, etc., hypotensive effect and hypertensive effect, antilipolytic effect, effect against gastric secretions, <EMI ID = 15.1>

  
activity of blood platelets, an effect opposing the aggregation of platelets in the blood, an effect opposing the formation of thromboses, an effect increasing the proliferation of the epidermis, a stimulating effect on cornification, etc. , and hence are used to study, prevent and reduce various diseases or undesirable physiological conditions in humans and animals. For example, they are considered to be useful as agents for reducing or preventing atonic uterine hemorrhages after 'abortion or childbirth, as agents for inducing childbirth, as agent for termination of pregnancy, as agent for controlling ovulation, as hypotensive diuretic agent, as agent for treating thrombosis, as anti-asthma agent, as an agent against ulcers, as an agent against arteriosclerosis, etc.

  
However, it has been reported that a particularly important undesirable side effect, in particular a gastrointestinal side effect such as diarrhea, is frequently observed with the administration of natural prostaglandins.
(see Lancet - volume II, 536 (1971)).

  
Therefore, it is desired to have derivatives of prostadienoic acid having more intense physiological activities than natural prostaglandins without undesirable side effects.

  
Various studies have been carried out to satisfy these desires. For example, the derivative of alkyl-16- acid has been proposed.

  
 <EMI ID = 16.1>

  
 <EMI ID = 17.1>

  
 <EMI ID = 18.1>

  
of Japanese patent opened to the Public Inspectorate N [deg.] 19.549 / '73 '

  
 <EMI ID = 19.1>

  
doing so to fully satisfy the above mentioned purposes.

  
On the other hand, the new compound of the present invention,

  
 <EMI ID = 20.1>

  
having a structure in which the 16 position of the prostaglandi-

  
 <EMI ID = 21.1>

  
position 20 is substituted with a lower alkoxy group sufficiently satisfies the purposes mentioned above. Namely, the compound of the present invention has excellent effects such as <EMI ID = 22.1>

  
A pronounced anti-asthma when administered orally and has a lesser undesirable side effect with regard to diarrhea. Thus the compound of the present invention can be considered as an excellent drug.

  
As described above, the compound of the present invention is prepared from the hydroxy-protected prostadienoic acid represented by formula II and any group which does not cause any modification to the other parts of the compounds upon removal of the compound. protecting group can be used for protecting groups for hydroxy groups of R2 and R3 in formula II and it is preferable that the protecting group can be removed under mild condition. Examples of such protecting groups are a heterocyclic group such as a tetra group.

  
 <EMI ID = 23.1>

  
trimethylsilyl group; an acyl group such as an acetyl group,

  
a propionyl group, a benzoyl group, a p-phenylbenzoyie group, a trifluoroacetyl group, etc .; a hydrocarbon group such as a tert-butyl group, a trityl group, etc. ; and a carbonic acid ester residue such as a benzyloxycarbonyl group, an ethoxycarbonyl group, etc.

  
For the practical removal of the protecting group from the hydroxy group, suitable conditions are selected depending on the nature of the protecting group.

  
That is, when the protecting group for the hydroxy group is a heterocyclic group such as a tetrahydropyran-2-yl group, a tert-butyl group or a trityl group, the removal of the protecting group can be. carried out by treatment with an acid. Suitable acids used for this treatment are organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, etc., and mineral acids such as hydrochloric acid, acid. sulfuric, etc.

  
The acid treatment is carried out in a reaction solvent such as water, methanol, ethanol, tetrahydrofuran, dioxane or a mixture thereof. There is no limitation on the reaction temperature, but the work-up is usually carried out at room temperature or under heating.

  
When the protecting group for the hydroxy group is <EMI ID = 24.1>

  
benzoyl group, p-phenylbenzoyl group and trifluoroacetyl group, an acid or a base can be used for removing the protecting group but the use of a base is preferable. Preferred examples of the acid are mineral acids such as hydrochloric acid and sulfuric acid and preferred examples of the base are sodium hydroxide, hydroxide

  
of potassium, sodium carbonate and potassium carbonate. As the reaction solvent, water, methanol, ethanol, tetrahydrofuran, dioxane or a mixture thereof can be used.

  
When the protecting group for the hydroxy group is a trimethylsilyl group, removal of the protecting group is carried out by treating the compound with water. The water used may contain an acid or a base. Likewise, an organic solvent containing water such as tetrahydrofuran containing water, dioxane containing water, methanol containing water and

  
 <EMI ID = 25.1>

  
Also, when the protecting group for the hydroxy group is a residue of carbonic acid ester such as a benzyloxycarbonyl group, removal of the protecting group is effected by treatment with hydrobromic acid in acetic acid or by subjecting it to catalytic reduction.

  
Then, if desired, the product thus obtained is esterified

  
by a conventional method. For example, esterification can be carried out by treating the product with an equimolar or slightly excess amount of a lower diazoalkane such as a diazomethane, a diazoethane in an inert organic solvent such as diaxane, ether, etc. . under cooling.

  
In addition, in the case of the production of the compound of the present invention, the starting material of formula II in which

  
0

  
he

  
A is -C- is prepared by oxidizing it. compound of formula II in

  
 <EMI ID = 26.1>

  
where A is -C-, the oxidation product (A is -C- in formula II) can be used in the next reaction without isolation.

  
After completion of the reaction, the claimed compound is isolated or purified in the ordinary way. For example, it should

  
 <EMI ID = 27.1> <EMI ID = 28.1>

  
ne, etc.

  
In addition, the starting material of formula II is also a new compound and the production of the compound is illustrated below with reference to Examples.

  
Practical examples of the compounds of the present invention are given below:

  
 <EMI ID = 29.1> <EMI ID = 30.1>

  
The novel compound of the present invention can be used for various medicinal preparations containing it or containing salts thereof and can be administered in various ways, for example intravenously, orally or topically (including as an aerosol) into the vagina. or the nose. Perhaps the most important use of the compound of the present invention is as an anti-asthma agent by oral administration because of its physiological activity. For this purpose, suitable forms of the medicaments are: tablets, capsules, powders and syrups. The dose for clinical administration of the compound of the present invention is 0.05 - 5 mg / day.

  
The pharmacological activities of the compound of the present invention were tested by comparison with those of natural prostaglandin, methyl-16 derivative thereof and methoxy-20 derivative thereof. The results are shown in Table I.

  
Experimental procedure.

  
I. Antiasthmatic effects

  
i) Aerosol

  
Guinea pigs were placed in a chamber and sprayed for 10 sec. with an aerosol containing a solution of histamine (0.1%) and the onset of sternutations was recorded and animals, after a control time of 70-100 sec., were selected. These animals were sprayed for 15 sec. with an aerosol of the compounds tested, after 45 sec they were vaporized with histamine and observed for 3 min. If an animal did not sternute within 3 min. we decided that this animal was protected. The percentage of animals protected was determined.

  
ii) Oral route

  
Guinea pigs were sprayed for 10 sec. with histamine 30 min. after oral administration of the compounds tested and then observed for 3 min. The percentage of animals protected was determined.

  
II. Effects producing diarrhea.

  
Test compounds were administered orally to guinea pigs, the onset of diarrhea (loss or liquid feces) after 2 hours, 3 hours, 4 hours, 5 hours and the <EMI ID = 31.1>

  
diarrhea was determined.

  
III. Effects on bronchial resistance

  
Resistance in the lungs of guinea pigs has

  
 <EMI ID = 32.1>

  
 <EMI ID = 33.1>

  
of prostaglandins was expressed in terms of a protective effect against bronchoconstrictions caused by intravenous injection.

  
 <EMI ID = 34.1>

  
Guinea pigs anesthetized with urethane and artificially ventilated.

TABLE 1

  

 <EMI ID = 35.1>
 

  

 <EMI ID = 36.1>


  
(A): Effect producing diarrhea
(B): Effect on the resistance of the bronchi.

  
As is clear from the results shown in

  
 <EMI ID = 37.1>

  
thereof, which are compounds of the present invention, exhibit a potent anti-asthma effect both when administered in aerosol form and when administered by

  
 <EMI ID = 38.1>

  
exhibits some effect while methoxy-20-methyl-16-PGE2 exhibits a very potent anti-asthma effect. The fact that methoxy-20-methyl-16-PGE2 and its methyl ester exhibit a remarkable anti-asthma effect when administered orally is further supported by the fact that they give rise to a significant reduction in bronchial resistance. during intraduodenal administration.

  
Likewise, methoxy-20-methyl-16-PGE2 and its methyl ester <EMI ID = 39.1>

  
oral than methyl-16-PGE2 '

  
In addition, the fact that the value b / a is the most important

  
 <EMI ID = 40.1>

  
its methyl ester have, as shown in Table 1, a quite selective antiasthmatic activity.

  
 <EMI ID = 41.1>

  
higher physiological and less side effect than natural prostaglandin which is the basic body of the compounds of the present invention. In particular, since the compounds of the present invention have potent anti-asthma activity upon oral administration and cause less diarrhea, which is a side effect, they are selective anti-asthma agents.

  
Reference example 1:
a) To 60 ml of anhydrous dimethoxyethane, 685 mg of 50% oily sodium hydride was added in a stream of nitrogen and after having added dropwise to the mixture a solution of 3.8 g of <EMI ID = 42.1>

  
added dropwise to the mixture and the resulting mixture was then stirred for 90 minutes at room temperature.

  
After completion of the reaction, the reaction mixture was neutralized with dry ice powder and 200 ml of water was added thereto and the mixture was then saturated with sodium chloride. The resulting mixture was extracted 4 times, each time with 50 ml of methylene chloride. The extracts were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide 9.2 g of a.

  
 <EMI ID = 43.1>

  
furan.

  
b) After adding 3.78 g of sodium borohydride and 5.57 g of zinc chloride to 250 ml of anhydrous ether followed by an <EMI ID = 44.1>

  
crude in 100 ml of dry tetrahydrofuran was added dropwise to the mixture and the resulting mixture was then stirred for two hours at room temperature.

  
After completion of the reaction, the reaction mixture was neutralized with dry ice powder and 150 ml of water was added thereto and the resulting mixture was then extracted three times, each time with 50 ml of ether. . The extracts were combined, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide 7.7 g of crude product. The crude product was subjected to column chromatography on silica gel and then developed using a mixture of n-hexane and ethyl acetate as the eluting solution.

  
 <EMI ID = 45.1>

  
in a stream of nitrogen and after addition of 300 mg of carbonate

  
of potassium to the solution, the mixture was stirred for 3 hours at room temperature and then for one hour at 40 [deg.] C. The mixture was neutralized with acetic acid and the methanol was then removed by distillation under reduced pressure. To the residue containing crystals thus obtained was added 100 ml of water and after saturating the mixture with sodium chloride, the resulting mixture was extracted three times, each time with 50 ml of ethyl acetate. The extracts were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide the crude product.

   The product was subjected to column chromatography on silica gel and then developed using a mixture of methylene chloride and ethyl acetate as a solution <EMI ID = 46.1>

  
shape).

  
d) In 50 ml of anhydrous methylene chloride was dissolved <EMI ID = 47.1>

  
after adding to the solution 1.025 g of dihydro-2,3-pyrane and more than <1> <2> mg of p-toluene sulfonic acid monohydrate, and after stirring for 30 minutes at room temperature, it was added
30 ml of methylene chloride to the mixture. The methylene chloride layer formed was then collected, washed with a dilute aqueous solution of sodium bicarbonate and then with water,

  
 <EMI ID = 48.1> cooled to -60 [deg.] C with dry ice-cold acetone. 13.0 ml of a toluene solution containing <1>, 27 g of diisobutylaluminum hydride were then added dropwise to the solution in a stream of nitrogen and the mixture was stirred for 30 minutes at the same temperature. .

  
Then, after adding to the reaction mixture 15 ml of ethyl acetate, 7 ml of methanol, and 5 ml of water successively,
Further 70 ml of water was added to the mixture, whereby white precipitates were formed. After removing the precipitates by filtration, the filtrate was separated into an aqueous layer and an organic layer. The aqueous layer was extracted three times, each time with 50 ml of benzene, and the extracts and the organic layer were combined, washed with saturated aqueous sodium chloride solution and then with water, dried over sulfate. of anhydrous magnesium and concentrated under reduced pressure at a temperature below room temperature to provide 2.0463 g of

  
 <EMI ID = 49.1>

  
 <EMI ID = 50.1>
25 ml of anhydrous dimethyl sulfoxide in a stream of nitrogen and the

  
 <EMI ID = 51.1>

  
hour, until the evolution of hydrogen stops. The reaction mixture was then cooled to room temperature and then, after adding 4.5 g of carboxy-4-butyltriphenylphospho- bromide thereto.

  
 <EMI ID = 52.1>

  
in 15 ml of anhydrous dimethylsulfoxide was added to the mixture followed by stirring for one hour at room temperature.

  
After completion of the reaction, the reaction mixture was neutralized with dry ice powder and then a mixture of 150 ml of ethyl acetate and 70 ml of ether saturated with dry ice and ice water. , was added to the reaction mixture which was then shaken well. The resulting mixture formed separated into an aqueous layer and an organic layer, and the aqueous layer was extracted three times, each time with 30 ml of ethyl acetate. The extracts were combined with the organic layer and the resulting mixture was washed with ice-water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide 3.4 g of 9α-hydroxy-methoxy- acid. 20-methyl-16-bis

  
 <EMI ID = 53.1>

  
. The crude product was subjected to silica gel column chromatography and developed using a mixture of ethyl acetate and n-hexane as the eluting solution to provide <EMI ID = 54.1>

  
chloroform).

  
g) In 5 ml of ether, 153.8 mg of hydroxy-

  
 <EMI ID = 55.1>

  
(which was prepared in a proportion of 2.0 g of chronic anhydrous acid, 9.65 g of hydrous manganese sulfate, 2.13 ml of concentrated sulfuric acid and water to give a total volume of 50 ml

  
 <EMI ID = 56.1>

  
were then added to the mixture which was stirred for three hours.

  
 <EMI ID = 57.1>

  
 <EMI ID = 58.1>

  
to the reaction mixture and the mixture was extracted three times, each time with 30 ml of ether. The extracts were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide 143.5 mg of acid.

  
 <EMI ID = 59.1>

  
Reference example 2:
a) In 120 ml of dry methanol was dissolved 1.3 g of [hydroxy- <EMI ID = 60.1>

  
In addition to the solution of 196 mg of potassium carbonate, the mixture was stirred for three hours at room temperature and then for one hour at 40 [deg.] C in a stream of nitrogen. The mixture was neutralized with acetic acid and the methanol was removed by distillation under reduced pressure. The crystal-containing residue thus obtained was mixed with 100 ml of water and then, after saturating the mixture with sodium chloride, the resulting mixture was extracted three times, each time with 50 ml of ethyl acetate. The extracts were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide the desired crude product.

  
The crude product was subjected to column chromatography on developed silica gel using a mixture of methylene chloride and ethyl acetate as an elution solution for

  
 <EMI ID = 61.1>

  
0.561 g of 2,3-dihydro-pyran and 6.3 mg of p-toluenesulfonic acid were added to the solution and after stirring the mixture for
30 minutes at room temperature, 20 ml of methylene chloride was further added to the mixture. The methylene chloride layer was then collected, washed with dilute aqueous sodium bicarbonate solution and then water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to oven- <EMI ID = 62.1> cyclopenta [b] furan in a stream of nitrogen and after cooling the solution to -60 [deg.] C, 7.1 ml of a toluene solution containing 695 mg of diisobutylaluminum hydride was added dropwise. drop to the solution in a stream of nitrogen and the mixture was stirred for 30 minutes at the same temperature.

  
To the reaction mixture were then added 15 ml of ethyl acetate, 7 ml of methanol, and then 5 ml of water successively at the same temperature and then 50 µl of water was added to the mixture at room temperature, whereby white precipitates formed. The precipitates were removed by filtration and the filtrate separated into an aqueous layer and an organic layer. The aqueous layer was extracted three times each time with 50 ml of benzene and the extracts were combined with the organic layer. The mixture was washed with saturated aqueous sodium chloride solution and then water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure at a lower temperature.

  
 <EMI ID = 63.1>

  
[b] furan.

  
d) To 468 mg of 50% oily sodium hydride was added
15 ml of anhydrous dimethylsulfoxide in a stream of nitrogen and the mixture was stirred under heating at 70-75 [deg.] C for about

  
1 hour until the evolution of hydrogen stops. The reaction mixture was then cooled to room temperature and 2.25 g of

  
 <EMI ID = 64.1>

  
[b] furan in 10 ml of anhydrous dimethylsulfoxide, was added to the mixture and the resulting mixture was stirred for one hour at room temperature.

  
After completion of the reaction, the reaction mixture was neutralized with dry ice powder and a mixture of 150 ml of ethyl acetate and 70 ml of dry ether and cold water were. added to the mixture and the mixture was then shaken well. The resulting mixture separated into an aqueous layer and an organic layer. The aqueous layer was extracted three times, each time with 30 ml of ethyl acetate. The extracts were combined with the organic layer and the mixture was washed with ice-water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide 2.0 g of hydrcxy- acid.

  
 <EMI ID = 65.1>

  
chromatographed on a silica gel column developed using a mixture of ethyl acetate and n-hexane as elution solution to provide 0.8031 g of the desired product

  
 <EMI ID = 66.1>

  
e) In 5 ml of ether were dissolved 140.6 mg of acid <EMI ID = 67.1>

  
 <EMI ID = 68.1>

  
of a solution (prepared in a proportion of 2.0 g of anhydrous chromic acid, 9.65 g of hydrous manganese sulfate, 2.13 ml of concentrated sulfuric acid and water to obtain a total volume of

  
 <EMI ID = 69.1>

  
mixture which has been stirred for 3 hours at the same temperature.

  
After completion of the reaction, 10 ml of water was added to the reaction mixture and the mixture was extracted three times, each time with 30 ml of ether. The extracts were combined, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide 120.5 mg of 20-methoxy acid.

  
 <EMI ID = 70.1>

  
5 (cis) -13 (trans) -olque.

  
EXAMPLE 1

  
In 5 ml of a mixture of acetic acid, water and tetra-

  
 <EMI ID = 71.1>

  
 <EMI ID = 72.1>

  
according to Reference Example l- (f) and the solution was stirred during

  
 <EMI ID = 73.1>

  
After completion of the reaction, the solvents were removed by distillation under reduced pressure from the reaction mixture and the <EMI ID = 74.1>

  
of silica developed using a mixture of ethyl acetate and n-hexane as the eluting solution to provide 45.3 mg of acid

  
 <EMI ID = 75.1>

  
(trans) -oecious.

  
 <EMI ID = 76.1>

  
EXAMPLE 2

  
In 5 ml of a mixture of acetic acid, water and tetrahydrofuran (volume ratio 19: 11: 3) were dissolved 80.2 mg

  
 <EMI ID = 77.1>

  
reference 2- (d) and the solution was stirred for three hours at 40 [deg.] C &#65533; 2 [deg.] C. Then, by processing the resulting reaction mixture

  
in the same manner as in Example 1, 29.3 mg of acid was obtained

  
 <EMI ID = 78.1>

  
 <EMI ID = 79.1>

  
EXAMPLE 3

  
In 7 ml of a mixture of acetic acid, water and tetrahydrofuran (volume ratio: 19: 11: 3) was dissolved 143.5

  
 <EMI ID = 80.1>

  
1- (g) and the solution was stirred for 3 hours at

  
 <EMI ID = 81.1>

  
After completion of the reaction, the solvents were removed by distillation under reduced pressure from the reaction mixture, and the resulting residues were subjected to column chromatography on silica gel developed using a mixture of ethyl acetate and n-. hexane as elution solution to provide 67.8

  
 <EMI ID = 82.1>

  
methanol).

  
EXAMPLE 4

  
In 7 ml of a mixture of acetic acid, water and tetrahydrofuran (volume ratio: 19: 11: 3) were dissolved 120.5

  
 <EMI ID = 83.1>

  
Reference Example 2- (e) and the solution was stirred for

  
 <EMI ID = 84.1> <EMI ID = 85.1>

  
methanol)

  
Reference example 3

  
In 40 ml of dry dimethoxyethane were suspended
555 mg of 50% oily sodium hydride and, after addition to the

  
 <EMI ID = 86.1>

  
 <EMI ID = 87.1>

  
in 20 ml of dry dimethoxyethane at room temperature in a stream of nitrogen, the mixture was stirred for about an hour until the evolution of hydrogen ceased. Then a solution of

  
 <EMI ID = 88.1>

  
added to the mixture and the resulting mixture was further stirred for 90 minutes at room temperature.

  
After completion of the reaction, dry ice powder,
250 ml of methylene chloride and 200 ml of water were added to the reaction mixture and after shaking the mixture, the formed aqueous layer was separated from the organic solvent layer. The aqueous layer was extracted four times, each time with 40 ml of methylene chloride, and the extracts were combined, washed with water and dried. Then the solvent was removed from the mixture by distillation under reduced pressure and the residue formed was subjected to column chromatography on silica gel which was then developed using a mixture of ethyl acetate and n-hexane ( volume ratio: 1: 1) as an eluting solution to provide 4.692 g of a colorless oily product of [8-methoxy-

  
 <EMI ID = 89.1>

  
b) To 260 ml of dry ether were added 2.71 g of sodium borohydride and 4.9 g of anhydrous zinc chloride and, after stirring the mixture at room temperature for 1.5 hours, a solution <EMI ID = 90.1>

  
 <EMI ID = 91.1>

  
Dry was added to the mixture after which stirring was carried out for 2 hours at room temperature.

  
 <EMI ID = 92.1>

  
Gradually added to the reaction mixture, and then 200 ml of water was further added to the mixture followed by shaking. Then, the aqueous layer was separated from the organic layer. The aqueous layer was extracted five times, each time with 50 ml of ether, and the extracts were combined, washed with water and dried. The solvent was then removed by distillation under reduced pressure from the mixture obtained and the residue obtained was subjected to chromatography on a silica gel column developed using a mixture of ether and n-hexane (volume ratio:

  
 <EMI ID = 93.1>

  
3-hydroxy compound (R) of the desired product exhibiting a

  
 <EMI ID = 94.1>

  
products.

  
 <EMI ID = 95.1> <EMI ID = 96.1>

  
above and 315 mg of anhydrous potassium carbonate followed by stirring for five hours at room temperature. The reaction mixture was then neutralized with acetic acid and the solvent was removed by distillation under reduced pressure. The residue formed was mixed with 250 ml of ether and 50 ml of water then

  
 <EMI ID = 97.1>

  
separated into an agious layer and an organic layer. The aqueous layer was extracted twice, each time with 40 ml of ether. The extracts were combined with the organic layer. The mixture was washed with water, dried and the solvent was removed by distillation under reduced pressure. The obtained residue was subjected to silica gel column chromatography developed using chloroform as an eluting solution to remove methyl p-phenylbenzoate. Then by development using a mixture of methanol and chloroform (volume ratio: 1: 4)

  
 <EMI ID = 98.1> <EMI ID = 99.1>

  
 <EMI ID = 100.1> d) In 20 ml of dry methylene chloride, <EMI ID = 101.1> was dissolved

  
obtained in step (c) above and, after adding to the solution 510 mg of dihydro-2,3-pyran and 15 mg of p-toluenesulfonic acid monohydrate, the mixture was stirred for 15 minutes at Room temperature.

  
The reaction mixture was then washed twice with dilute aqueous sodium bicarbonate solution and then with water, dried and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography on silica gel developed using a mixture of ether and n-hcxanc (volume ratio: 1: 1) as the solution.

  
 <EMI ID = 102.1>

  
 <EMI ID = 103.1> e) In 40 ml of dry toluene were dissolved 458 mg of <EMI ID = 104.1>

  
 <EMI ID = 105.1>

  
from the solution to -60 [deg.] C in a stream of nitrogen, 2.1 ml of a toluene solution containing 205 mg of diisobutylaluminum hydride was added, after which stirring was carried out for
30 minutes. 0.5 ml of ethyl acetate, 0.10 ml of methanol and 2 ml of water were then added to the reaction mixture thus obtained successively at the same temperature as above, followed by shaking. Then, after filtering off the white precipitates formed, the filtrate layer was separated into an aqueous layer and an organic layer. The aqueous layer was extracted five times, each time with 30 ml of benzene, and the extracts were combined with the organic layer. After washing with water and drying, the solvent was removed from the mixture by

  
 <EMI ID = 106.1>

  
cyclopenta (b) colorless oily furan.

  
f) To 19S mg of 50% oily sodium hydride was added <EMI ID = 107.1>

  
was stirred under heating at 60 [deg.] C for about an hour until the evolution of hydrogen ceased. After cooling to room temperature, 930 mg of carboxy-4-butyltriphenylphosphonium bromide was added to the mixture and to the clear red solution as well.

  
 <EMI ID = 108.1>

  
[b] furan obtained in step (e) above in 5 ml of dry dimethylsulfoxide after which it was stirred for 2 hours at room temperature.

  
After completion of the reaction, the reaction mixture has

  
was dispersed in 150 ml of a mixture of ethyl acetate and ether
(volume ratio: 2: 1), saturated with dry ice and, after addition thereto with 70 ml of ice water followed by shaking, the resulting mixture separated into an aqueous layer and a layer. organic. The aqueous layer was extracted four times, each time with 50 ml of ethyl acetate, and the extracts were combined with the organic layer. The mixture was washed with water, dried, and the solvents were removed by distillation under reduced pressure. The obtained residue was subjected to column chromatography on silica gel developed using a mixture of ethyl acetate and n-hexane (volume ratio: 1: 2) as

  
 <EMI ID = 109.1>

  
above and to the solution was then slowly added 11 ml of a Jone's reagent (which was prepared in a proportion of 2.0 g of anhydrous chromic acid, 9.65 g of hydrous manganese sulfate, 2 , 13 ml of concentrated sulfuric acid and water to have a volume

  
 <EMI ID = 110.1>

  
brewed for 90 minutes at the same temperature.

  
After completion of the reaction, 50 ml of ether and 40 ml of a saturated aqueous solution of sodium sulfate were added to the reaction mixture after which shaking was carried out, and the resulting mixture thus formed was then separated into one. layer <EMI ID = 111.1>

  
four times, each time with 40 ml of ether, and the extracts were combined with the organic layer. After washing the mixture with water and drying, the solvent was distilled off under reduced pressure to provide 327 mg of methoxy-20-methyl-16- acid.

  
 <EMI ID = 112.1>

  
Reference example 4:
a) In 45 ml of dry dimethoxyethane were suspended 528 mg of oily 50% sodium hydride in a stream of nitrogen and after dropwise addition to the suspension of a solution of 2.93 g of phosphonate dimethyl- (methoxy-7-methyl-3-oxo-2) - <EMI ID = 113.1>

  
of dry dimethoxyethane, the mixture was stirred for 90 minutes at room temperature. Then a solution of 4.04 g of

  
 <EMI ID = 114.1>

  
More added dropwise to the mixture and the resulting mixture was stirred for 90 minutes at room temperature. After completion of the reaction, the reaction mixture was neutralized with dry ice powder and after addition of 150 ml of water and saturation with sodium chloride, the resulting mixture was extracted four times, each time with 50 ml of methylene chloride. These extracts were combined, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oily product was subjected to chromatography on a silica gel column developed using a mixture of ether and n-hexane (volume ratio: 3: 1) as the elution solution for

  
 <EMI ID = 115.1>

  
 <EMI ID = 116.1>

  
 <EMI ID = 117.1> sodium borohydride and 2.98 g of anhydrous zinc chloride and, after stirring for 90 minutes at room temperature, a

  
 <EMI ID = 118.1>

  
furan in 50 ml of dry tetrahydrofuran was added dropwise

  
 <EMI ID = 119.1>

  
ambient temperature.

  
 <EMI ID = 120.1>

  
neutralized with dry ice powder and, after addition of

  
150 ml of water, the resulting mixture was extracted three times, each time with 50 ml of ether. The extracts were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to provide 2.8 g of an oily product. Then, subjecting the oily product to silica gel column chromatography and developing it using a mixture of ether and n-hexane (volume ratio: 4: 1) as

  
 <EMI ID = 121.1>

  
chloroform).

  
c) In 40 ml of dry methanol, 1.21 g of [hydroxy- <EMI ID = 122.1> were dissolved

  
step (b) above and, after adding 169 mg of anhydrous potassium carbonate to the solution, the mixture was stirred for three hours at room temperature. Then, the obtained reaction mixture was neutralized with 147 mg of glacial acetic acid and the methanol was distilled off under reduced pressure. After adding 30 ml of water to the residue obtained and saturating with sodium chloride, the mixture was extracted three times, each time with 30 ml of ether. The extracts were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

   The oily product thus obtained was subjected to column chromatography on silica gel developed using a mixture of chloroform and ethyl acetate (volume ratio: 1: 4) as

  
 <EMI ID = 123.1>

  
chloroform).

  
d) In 13 ml of dry methylene chloride, <EMI ID = 124.1> was dissolved

  
 <EMI ID = 125.1>

  
2,3-dihydro-pyran and 4 mg of p-toluensulfonic acid monohydrate, the mixture was stirred for 30 minutes at room temperature.

  
 <EMI ID = 126.1>

  
of dilute aqueous sodium bicarbonate solution were added to the reaction mixture followed by shaking. The organic layer formed was separated, washed with water, dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under reduced pressure. The obtained residue was subjected to chromatography on a silica gel column developed using a mixture of ether and n-hexane (volume ratio:

  
1: 2) as an eluting solution to provide 869 mg of [8-methoxy-

  
 <EMI ID = 127.1>

  
[oily bjfurane.

  
e) In 40 ml of dry toluene, 555 mg of

  
 <EMI ID = 128.1>

  
cyclopenta [b] furan obtained in stage (d) in a stream of nitrogen and the solution was cooled to -60 [deg.] C with an acetone-dry ice mixture. Then 3.36 ml of a toluene solution containing 328-3 mg of diisobutylaluminum hydride was added dropwise to the solution in a stream of nitrogen and the mixture was then stirred for 30 minutes. Then 0.3 ml of ethyl acetate and then 0.3 ml. of methanol were added successively to the mixture at the same temperature and after raising the temperature to room temperature, 50 ml of water were added to the mixture, this

  
whereby white precipitates formed. The precipitates were removed by filtration and the filtrate was separated into an aqueous layer and an organic layer. The aqueous layer was extracted twice, each time with 50 ml of benzene and the extracts were obtained.

  
been combined with the organic layer. The mixture was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure at below room temperature to provide

  
 <EMI ID = 129.1>

  
 <EMI ID = 130.1>

  
 <EMI ID = 131.1>

  
 <EMI ID = 132.1>

  
heating the mixture to 60-65 [deg.] C, the mixture was stirred for about an hour until the evolution of hydrogen ceased. The <EMI ID = 133.1>

  
1.01 g of carboxy-4-butyltriphenylphosphonium bromide was added to the mixture. Then, to the clear red solution thus obtained,

  
 <EMI ID = 134.1>

  
[b] furan obtained in step (e) in 5 ml of dry dimethyl sulfoxide and the mixture was stirred for one hour at room temperature.

  
After completion of the reaction, the reaction mixture was neutralized with dry ice powder and then a mixture of
60 ml of ether and 30 ml of water saturated with dry ice was

  
additionally added to the mixture. The resulting mixture was then separated into one. aqueous layer and an organic layer and the aqueous layer

  
was extracted three times, each time with 30 ml of ethyl acetate. The extracts were combined with the organic layer and the mixture was washed with ice-water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel developed using a mixture of ethyl acetate and n-hexane (volume ratio: 1: 1) as the eluting solution to provide 262 mg.

  
 <EMI ID = 135.1>

  
 <EMI ID = 136.1>

  
Then 7.7 ml of a solution (which was prepared in a proportion of 2.0 g of anhydrous chromic acid, 9.65 g of hydrous manganese sulfate and 2.13 ml of concentrated sulfuric acid and 'water to have a total volume of 50 ml and pre-cooled down to 0 [deg.] C at
-5 [deg.] C) were added to the solution which was then stirred for 3 hours at the same temperature.

  
After completion of the reaction, 10 ml of water was added to the reaction mixture, and the mixture was then extracted three times, each time with 30 ml of ether. The extracts were combined, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 260 mg of methoxy acid.

  
 <EMI ID = 137.1>

  
 <EMI ID = 138.1>

  
To 7 ml of a mixture of acetic acid, water and tetrahydrofuran (volume ratio: 19: 11: 3) was added 327 mg of

  
 <EMI ID = 139.1>

  
reference 3 and the solution was stirred for two hours at

  
 <EMI ID = 140.1>

  
reaction mixture by distillation under reduced pressure and the obtained residue was subjected to column chromatography on silica gel developed using ethyl acetate as the eluting solution to provide 179 mg of dihydroxy-IIIa acid, 15 (S) -

  
 <EMI ID = 141.1>

  
EXAMPLE 6

  
In 4 ml of a mixture of acetic acid, water and tetrahydrofuran (volume ratio: 19: 11: 3) were dissolved

  
 <EMI ID = 142.1>

  
Reference Example 4 and the solution was stirred for 3 hours at 40 [deg.] C.

  
After completion of the reaction, the solvent was removed from the reaction mixture by distillation under reduced pressure, and the obtained residue was subjected to column chromatography on silica gel developed using ethyl acetate as the solution.

  
 <EMI ID = 143.1>

  
 <EMI ID = 144.1>

  
EXAMPLE 7

  
In 20 ml of ether were dissolved 124.6 mg of acid

  
 <EMI ID = 145.1>

  
and then an ether solution containing diazomethane was added dropwise to the solution until the mixture turned pale yellow, indicative of the end of the reaction. Then the solvent was removed from the reaction mixture by distillation under reduced pressure, and the obtained residue was subjected to silica gel column chromatography developed using a mixture of ethyl acetate and n-hexane as the solution of. elution to provide in the first fraction 40.6 mg of methyl ester <EMI ID = 146.1>


    

Claims (1)

1, - A process for the preparation of an alkoxy acid derivative- <EMI ID = 147.1> <EMI ID = 148.1> <EMI ID = 149.1> <EMI ID = 150.1> be identical or different, represent a hydrogen atom or <EMI ID = 151.1> or different each represent a lower alkyl group and its salts, characterized in that the protecting groups are removed <EMI ID = 152.1> represented by the formula: <EMI ID = 153.1> where A, R and R and R have the same meaning as below <EMI ID = 154.1> each feeling a hydrogen atom or a protecting group for the <EMI ID = 155.1> agent for the hydroxy group and then esterifies, if desired, the product obtained.