CA1131238A - Process for the preparation of bicyclic lactone diol derivatives - Google Patents
Process for the preparation of bicyclic lactone diol derivativesInfo
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- CA1131238A CA1131238A CA279,295A CA279295A CA1131238A CA 1131238 A CA1131238 A CA 1131238A CA 279295 A CA279295 A CA 279295A CA 1131238 A CA1131238 A CA 1131238A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
- C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
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Abstract
ABSTRACT OF THE DISCLOSURE
The preparation of certain racemic or optically active lactone diol derivatives is disclosed which derivatives are useful as itermediates in prostaglandin syntheses. These compounds may be represented by the structural formula I
The preparation of certain racemic or optically active lactone diol derivatives is disclosed which derivatives are useful as itermediates in prostaglandin syntheses. These compounds may be represented by the structural formula I
Description
23~
This invention relates to the pr~paration of certain racemic or optically active lactone diol derivatives, namely the racemic or optically active lactone diol derivatives o:E the structural formula I
O--C~
~ ~I) R10~ CH2 H
wherein, R represents acyl, hydrocarbon optionally containing also oxygen in the claim or silyl.
Thus, this invention provides for a process for preparing a racemic or optically active lactone diol derivative of the structural formula I
~0 O--C
~ (I) Rl`'o CH2-OH
wherein Rl represents acyl, hydrocarbon optionally containing also oxygen in the chain or silyl, which process comprises:
~a) reacting a racemic or optically active lactone diol of the structural formula II O-~C~
. ~
~II) .~'`~
with a trialkyl-silyl derivative of the structural formula IIII) , .
., . -- 1 --~;
`
~3~38 R2 Si R (III) ,~
,~
wherein R2, R3 and R4 each represent alkyl, and xl represents chloride, bromine or iodine or dialkyl-amino, then acylating the compound of the structural formula IV
~O--C~
~ ~IV) initally obtained, wherein R5 represents -SiR2R3R4, with a compound of structural formula (V) - o R6 .C ~x2 (V) or formula ~1 R7 - N = C = (VI) wherein R6 represents alkyl, aryl, substituted aryl or aralkyl, R7 represents alkyl, aryl or substituted aryl, and X represents chlorine or iodine and deblocking the primary hydroxyl of the lactone derivative of the structural formula VII O- C
~ (VII) '' ~: .
thus obtained wherein, R8 represents R6 -C0- or R7 -NH-C0- by acid hydrolysis; or (b) acylating the racemic or optically active lactone diol of the structural formula II with an ~cid halogenide of the structural formula V, reacting the compound of the structural formula IV, initially obtai.ned wherein R5 represents R6 -C0-, with a trialkyl silyl derivative of the structural formula III, then deblocking the primary hydroxyl group of the lactone derivative of the structural formula VIII ~0 C\
~ " (VIII) 9 '"" ~ 8 thus obtained, wherein R8 represents R6 -C0- and R9 represents -SiR R3R , by solvolysis carried out under alkaline condltions, or ~c) reacting the racemic or optically active lactone diol of the structural formula II with a benzyl halogenide of the structural formula IX
~ CH2 - X3 (IX) wherein X3 represents chlorine, bromine or iodine, reacting the compound of the struct-ural formula IV, initally obtained, wherein R5 represents ben~yl~
with a trialkyl-silyl derivative of the structural formula III, or with an , "
, .
~3~23~3 acid halogenide of the structural formula V, and then deblocking the primary hydroxyl of the lactone diol derivatives of the structural formula X
O--C~
~"' (X) R10'`"" C~12-Rll thus obtained J
wherein Rll represents benzyl, benzyloxy-carbonyl, trichloro-ethoxy-carbonyl, and R10 represents R6 -C0-, or -SiR2R3R4 by catalytic hydrogenation or with nascent hydrogen.
According to a preferred embodiment of process variant ~a) the secondary hydroxyl can be protected by aroyl, carbamoyl, preferably by p phenyl benzoyl, benzoyl, actyl, p phenyl, phenylcarbamoyl and the primer hydroxyl may be deblocked with acetic acid at a temperature no* exceeding 50C.
According to a preferred embodiment of process variant ~b) primaryhydroxyl is protected by alkanoyl or aroyl, preferably by benzoyl or acetyl, and the secunder hydroxyl by alkoxy-dialkyl-methyl such as methoxy-dimethyl methyl or ethoxy-methyl-methyl, and the primaryhyroxyl is solvolysed in a lower alkanol, in the presence of a base, preferably of potassium carbonate.
According to a preferred embodiment of process variant ~c) primaryhydroxyl is protected by benzyl, benzyloxy-carbonyl, or trichloroethoxy-carbonyl, and the secunder hydroxyl by phenyl-benzoyl, benzoyl, tetrahydropyranyl or silyl substituted by three identical or different Cl 6 alkyls. The primaryhydroxyl is deblocked by catalytic dehydrogenation achieved by nascent hydrogen generated from an acid by zinc, in the presence of a palladium catalyst under a hydrogen pressure of 3 atm.
: .
~3~3~
Among the entermediates employed in this invention are, for example 3,3a~,4,5,6,6a~-hexahydro-2-oxo-4~-trimethylsilyl-oxymethyl-5~-hydroxy-2H-cyclopenta[b]furane and 3,3a~,4,5,6,6a~-hexahydro-2-oxo-4~-trityloxymethyl-5~-hydroxy-2~1-cyclopenta[b]-furane which are novel compounds.
There are a lot of methods known in the art for the total synthesis of various prostaglandine analoges. In the known synthesis methods the way elaborated by E.J. Corey et al. takes a prominent part as regarding its ability to solve stereochemical problems, universality and importance [J. Amer. Chem.
Soc., 91, 5675 /1969/, ibid: 929 397 /1970/, ibid: 93, 1490 /1961/]. This method fUlfills also the requirements of the industrial production. The aimed product of the Corey synthesis is PGF2~9 which can be easily transformed into other pharmaceutically important natural prostaglandines, thus for example into PGEl, PGE2, PGEl , and PGEl~. The key-intermediate of the synthesis is the "Corey aldehyde" - wherein Rl represents p-phenyl-benzoyl or p-phenyl-carbamoyl-in which the four asymmetric carbon atoms have the same absolute and relative configuration as those of the PGF2~, and which contains both free or marked carbonyl functions serving for the preparation of the side-chains during the reaction, and the p-phenyl-benzoyl or p-phenyl-phenyl-carbamoyl hydroxyl-protecting groups, which are to control the stereoselective reduction of the C15-keto group. [J. Amer. Chem Soc. 9~, 8616 /1972/]. According to the synthesis "~orey aldehyde" and the other acyloxy lactone aldehydes of the structural formula XI ~z O--C
~ (XI) `
are prepared by oxydating acyloxy-lactones of the structural formula I~ wherein R represents acyl. The preparation of the compounds of the structural formula ~, :, :
: :
~ , , 1~3~38 I in this way, however, is extremely complicated, due to the high number of the reaction steps, and to the fact that the reagents are expensive and difficult to obtain.
Some other synthesis methods for the preparation of the compounds of the structural formula XI, I or of the compounds having similar field of application are to cope with similar difficulties ~See for example J. Amer.
Soc., 95, 6853 /1973/, J.C.S. Perkin I. 2796 /1973/). We have surprisingly found that the compounds of the structural formula I may be prepared by selective acylation of the racemic or optically active lactone diol of the structural formula II [~ II or ~ II].
Lactone diol of the structural formula II is a very convenient starting material, since it is readily available when prepared according to the cheap four-step synthesis disclosed in Tetrahedron Letters 4639-42 ~1976), using cyclopentadiene as starting substance. It should be noted that some representatives of the compounds of the structural formula I, for example the compound in which Rl is acetyl, can be prepared by partial deacetylation of the lactone diol diacetate of the structural formula XII
O--C~O
(XII) R10` CH2-R
wherein 20R and R each represent acetyl, this method, however, can not be extended to the preparation of the compounds of the structural formula I in general, and the acyl-migration taking place during the reaction has unfavourable consequences. It has been found that the primaryhydroxyl of the racemic or optically active lactone diol of the structural formula II can be subjected to a selective blocking reaction using . , , , ~ .
; ~'~ ,, .
~3~%3~3 various suitable reagents, and then the compound of the structural formula IV, initially obtainedJ in which R5 is a blocking group, can be protected on its free hydroxyl by any kind of acyl, for example p-phenyl-benzoyl, p-phenyl-phenyl-carbamoyl or of hydrocarbon, for e~ample tetrahydropyranyl. Finally the blocking group of the primaryhydroxyl is splitted off without attacking the ether or ester bond on the secondaryhydroxyl.
For the selective treatment of the primary and secondary hydroxyl of the compound of the structural formula II there is already a method known in the art [J. ~mer. Chem. Soc. 93 1491 /1971/], wherein as a bottom-note, without any experimental details the following procedure is suggested for solving the problem:
The primaryhydroxyl of the lactone diol of the structural formula ~-)-II is subjected to a selective trichloro-acetylating reaction, the second-aryhydroxyl of the hydroxyl-lactone trichloroacetate of the struc~ural formula IV obtained, wherein RS is trichloro-acetyl, is subseqently protected by tetrahydropyranyl, and then compound of the structural formula ~If obtained in the second step, in which Rl is tetrahydropyranyl and R5 is trichloroacetyl, is subjected to a saponification reaction. Thus tetrahydropyranyloxy-lactone-alcohol is obtained, which compound is within the scope o the structural formula I, and in which Rl represents tetrahydropyranyl.
The selective blocking of the primaryhydroxyl in the lactone diol is the decisive reaction step of our synthesis. Blocking can be achieved by various reactions, thus by acylation, alkylation and silylation. The regio-selectivity of the above reactions, however, is the function of the acylating, alkylating and silyla~ing agents applied and of the reaction conditions.
Generally the reaction results also in the production of secunder mono-acyl, mono-alkyl and mono-silyl side-products, which are~ however, easy to separate from the corresponding primarymain-products by column chromatography.
~ ':
..' -~ - 7 -~L~3~
What has been said above concerning the regioselectivity of the blocking reaction holds in respect of the acylating reactions carried out with 1 mole equivalent of acetic anhydride, acetyl chloride, benzoyl chloride or p-phenyl-benzoyl chloride in the presence of a base. The acylating reaction carried out by trichloroacetyl chloride did not prove to be absolutely regioselective, either, the aimed primarymono-acyl product was, however, easy to isolate by column chromatography in all of the above-mentioned cases.
Results obtained when etherifying the compound of the structural formula II were very similar. Thus, for example reacting the above compound with 1 mole equivalent of benzyl chloride mono-primarybenzylether of the structural formula IV, wherein R5 is benzyl, was obtained as a main product, together with the mono-secondary-benzyl ether of the structural formula I, wherein Rl represents benzyl, and with a small amount of the dibenzyl ether of the structural formula XII, wherein Rl and R5 each reprasent benzyl. ~
The case is similar when silylating the compound of the structural formula II with 1 mole equivalent of trimethylchloride sylane, in the presence of a base. Neither at 0C nor at room temperature could we achieve a 100%
selectivity in pyridine-dichloromethane solvent mixture and at 30-40%
completion of the reaction bothmono-sil,y~l ethers and the di-silyl ether were detected.
We have surprisingly found that with certain reagents under certain reaction conditions near 100% regioselectivity could be achieved for the blocking reaction of the primaryhydroxyl of the compound of the structural formula II. Thus silylating the racemic or optically active compound of the structural formula II with 1.0 to 1.1 mole equivalent of trimethylsilyl diethyl amine [Acta Chem. Acad. Sci. Hung., 58, 189 /1968/~ in acetonitrile at 0C, the reaction proceeds smoothly in some minutes, resulting in the mono-primary-silyl ether of the structural formula IV, in which R5 represents trimethyl , 3~3 silyl, besides mono-primary-silyl ether traces, which can be detected only chromatographically.
It should be noted that using 2 to 2.5 equivalents of the above reagent also the di-silyl ether can be produced in 30 to ~5 minutes.
Among the alkylating agents triphenyl-methyl chloride was found to be able to procluce a similarregio5elective reaction. When carrying out the tritylating reaction in pyridine, at room temperature, the crystalline mono-primary-triethyl ether of the structural formula IV, in which R5 is trityl, is obtained practically quantitatively.
The free secondaryhydroxyl of the compounds of the structural formula IV can be subjected to acylation or alkylation. The compounds of the structural formula IV preferably used in prostaglandine synthesis can be acylated in a manner known per se using a p-phenyl-benzoyl chloride or p-phenyl-isocyanate as acylating agents9 but also the tetrahydropyranyl ether of these compounds can be prepared employing 3,4-2H-dihydropyrane. Thus products of the structural formula XII are obtained, in which Rl and R5 represent different acyl, alkyl or silyl groups.
In the last step of our synthesis the primaryhydroxyl is deblocked by methods known per se. Care must be taken, however, that the reagents applied should not attack on the ester or other bond on the secondaryhydroxyl.
Trimethylsilyl and trityl are easily removable by hydrolysis effected under mild acid conditi~n, with heating. This last reaction step can be carried out also simultaneously with the separa*ion step following the acylation of the secondaryhydroxyl.
Should the primaryhydroxyl be blocked by acyl, for example acetyl or benzoyl, it is advisable to protect the secondaryhydroxyl by a protecting group resistant to a mild alkaline hydrolysis, thus for example by an ether type group, preferably by tetrahydropyranyl. When proceeding according to ~:~3~23~3 this method, the compounds of the structural formula XII, wherein Rl is hydrocarbon, for example tetrahydropyranyl or benzyl and R5 represents acyl, are treated with sodium alcoholate in an alcoholic medium, and thus compounds of the structural formula I are prepared.
The following Examples illustrate but do not limit the product and process of the present invention.
Example 1 (-)-3,3a~,4,5,6,6a~-hexahydro-4~-benzoyloxymethyl-5~-hydroxy -2H-cyclopentano[b]furane-2-on 354 mg (2moles) of levorotatory lactone diol of the structural formula II are dissolved in the mixture of 2 ml of dry pyridine and 10 ml of dichloro methane, the mixture is ice-cooled to 0C and the solution o~ 295 g ~2.1 mmoles) of benzoyl chloride in 5 ml of dichloro methane i5 added gradually. The proceedings of the reaction is followed by t.l.c. ~fter two hours the following spots are to be observed: spots corres-ponding to a small amount of the starting material, and to traces of the secondary monobenzoate (Rf = 0.34, ethyl acetate), respectively, but the main spot is to be found at Rf = 0.60 ~ethyl acetate), which corresponds to the primer monobenzoate. The reaction mixture is diluted with 30 ml of dichloromethane and is poured into 30 ml of 7% equeous sulfuric acid solution under ice-cooling, washed with 10 ml of 2.5% aqueous sodium bicarbonate solution and dried over magnesium sulfate. The solvent is then evaporated whereupon 550 mg of a colourless oil is obtained, which is chromatographed on 60 g of silica gel and eluated in 2:1 to 1:1 benzoyl-ethyl acetate solvent mixture, using the gradient eluating technique. Evaporating the fractions containing the main product 399 mg (72%) of the title monobenzoate are obtained which proved to be uniform according to the t.l.c. measurements.
[~]23 = -22 (c = 1.37, ethyl acetate) IR: 3400, 3010, 2920, 1770, 1710, 1600, 1590, 1450, 1265,1200, 1165, 1110, -, .
, 1065, 1030, 710 cm~l.
Example 2 (~)-3,3a~,4,5,6,6a~-hexahydro-4~-acetoxymethyl-5a-hydroxy-2H-cyclopentano[b]furane-2-on ~ ollowing the procedure set forth in the Example 1 but using 214.2 mg (2.1 mmoles) of acetic anhydride as acylating agent, 452 mg of a crude product are obtained, subjecting this product to column chromatography as described in the Example 1, 124 mg (58%) of the title primer monoacetate are obtained.
t.l.c. (on "Kieselgel nach Stahl"plate): Rf = 0.10 (benzene ethyl acetate 1:1);
0.42 (ethyl acetate); 0.61 ~ethyl acetate - methanol 6:1).
Example 3 ~ +)-3,3a~,4,5,6,6a~-hexahydro-4~-benzyloxymethyl-5a-hydroxy-2H-cyclopentano[b]furane-2-on 320 mg ~1.86 mmoles) of racemic lactone diol of the structural formula II are dissolved in 25 ml of acetone and 350 mg ~2.05 mmoles) of benzyl bromide and 290 mg of potassium carbonate are added. The reaction mixture is stirred at room temperature for 8 to 10 hours and the reaction is followed by t.l.c. The main spot is to be observed at Rf = 0.46 ~GF254 "Kiselgel nach Stahl" plate, ethyl acetate) which corresponds to the primer benzyl ether main product. The solvent is then evaporated, the residue taken up in ethyl acetate, washed subsequently wi-th water and brine, dried over magnesium sulfate and chromatographed on a chromatographic column made of 60 g of silica gel. The eluation is carried out with 2:1 to 1:1 mixture of benzene and ethyl acetate using the conventional gradient eluating technique.
The fractions containing the main product are pooled and evaporated to give the title compound in form of a pale-yellow oil.
IR: 3400 ~-OH), 1760 ~-CO-lactone), 1080 ~-CO-), 700, 7~0 ~-CH-) cm 1.
' ';~
~,~3~3~
Example 4 (+)-3,3a~,4,5,6,6a~-hexahydro-4~-benzoyloxymethyl-5~-tetrahydro-pyranyloxy-211-cyclopentano[b]furane-2-on 230 mg (0.83 mmoles) of levorotatory lactone diol primer monobenzoate of the general formula IV, in which R5 is benzoyl, are dissolved in 5 ml of dry benzene, 0.5 ml (5.5 mmoles) of 3,4-2H-dihydropyrane and 1 drop of phosphorous oxychloride are added. According ~o the t.l.c. measurements the reaction is completed within one hour. Thereafter four drops of triethyl amine and 5 ml of pentane are added and after 1 to 2 hours the resulted downy precipitate is filtered off. Upon removing the solvent on a rotatory evaporator under vacuo, 300 mg (100%) of the title compound is obtained as a colourless oil having the following physical characteristics:
Rf = 0.33 (on a GF254 "Kieselgel nach Stahl" plate, with benzene-ethyl acetate 3~
IR: 3010, 2910, 2850, 1770, 1710, 1600, 1260, 1160, 1110, 1070, 1030, 1010, 910, 710 cm~l.
Example 5 (-)-3,3a~,4,5,6,6a~-hexahydro-4~-hydroxymethyl-5~-tetrahydropyranyloxy-2H~cyclopentano[b]furane-2-on 300 mg (0.83 mmoles) of levor~atory lactone diol derivative of the structural formula XII, in which Rl represents tetrahydropyranyl and R5 represents benzoyl are dissolved in 5 ml of dry methanol and 2 ml of 0.5 M
methanolic solution of sodium methoxide are added.
According to the t.l.c. measurement the debenzoylating reac*ion is completed in 50 minutes. 1 ml of 1 M methanolic solution of acetic acid is then added and the solvent is removed on a rotatory evaporator, in vacuo.
The residue is dissolved in 15 ml. of ethyl acetate and the solution is subsequently washed with 3 ml of 5% sodium carbona~e solution, 2-fold 3 ml of ,' '. ~
~o~3~3~
water and 3 ml of brine, dried over sodium sulfate and evaporated. 201 mg (96%) of the title ~-) lactone diol secunder tetrahydropyranyl ether are obtained.
Physical properties: [N]D = -30.7 ~1 (c = 0.9~, methanol).
IR (max.): 3420, 2910, 1850, 1760, 1345, 1165, 1120, 1110, 1070, 1030, 1010 cm Rf = 0.20 (ethyl acetate), 0.~3 (6:1 ethyl acetate - methanol on a GR254 "Kieselgel nach Stahl" plate.
_ mple 6 (-)-3,3a~-4,5,6,6a~-hexahydro-4~-hydroxymethyl-5~-benzoyloxy-2H-cyclopentano~b]furane-2On 172 mg (l~noles) of levorotatory lactone diol of the structural formula II are dissolved in 5 ml of acetonitrile and 1.1 ml of 1 M solution of trimethyl silyl-diethyl-amine in acetonitrile and added dropwise, at room temperature, with stirring in 1 to 2 minutes. According to the t.l.c. measurement (benzene-ethyl acetate 1:1) the reaction is completed in 10 minutes. The main spot is found a~ Rf=0.36, but an other spot at Rf = 0.69 shows that also bis-silyl ether traces are present. The solvent and ~he formed diethyl amine is removed on a rotatory evaporator, under pressure of 12 to 15 torr, and at a temperature not exceeding 30C. The res~due i5 257 mg of a yellowish oil which is then dissolved in 5 ml of dichloro methane and the solution added to the mixture of 1 ml of dry pyridine and 162 mg ~1.15 mmoIes) of ben~oyl chloride at 0C
in 5 to 6 minutes. Af~er two hours of stirring the reaction mixture is poured into 10 ml of a 40% aqueous acetic acid solution, the container is washed out with 2 to 3 ml of dichloro methane, which is added to the reaction mixture, and then the mixture is allowed to stir for 30 to 35 minutes or shaken in a separating fumlel very intensively. The phases are separated, the aqueous phase is extracted with four 10 ml portions of dichloro methane and the combined organic extracts are washed to neutral in small portions, with 5% solution of sodium carbonate, and then dried over magnesium sulfate. Upon removing the . . .
~3~23~
solvent 240 mg of the title compound remain in form of a colourless oil, which can be turned into crystalline form upon stirring with a glass-stick.
After recrystallization from the mixture of ethyl aceta~e and hexane 210 mg ~76%) of lactone diol secunder-mono-benzoate are obtained, melting at 117 to 118C. [u] ~max): 3450, 2920, 1770, 1710, 1600, 1580, 1540, 1270, 1200, 1165, 1110, 1090, 1070, 1030, 710 cm 1, Example 7 ~ -)-3,3a~,4,5,6,6a~-hexahydro-4~-hydroxymethyl-5~-~p-phenyl-benzoyloxy)-2H-cyclopentano[b]furane-2-on The procedure set forth in the Example 6 is followed till the addition of the acylating agent. In the present Example the solution of 249 mg ~1.15 mmoles) of p-phenyl-benzoyl chloride in 2 ml of pyridine are added dropwise to the solution of the mono-primer-silyl ether in dichloro methane, at room temperature, in 5 to 6 minutes. The mixture is stirred for two hours and the proceedings of the reaction is controlled by t.l.c. The reaction mixture is then poured into 10 ml of a 40% aqueous solution of acetic acid, the container is washed with 2 to 3 ml of dichloro methane, which are then added to the reaction mixture. The mixture is vigorously stirred for 30-35 minutes, or is shaken in a separating funnel. After separating the phases the combined organic extracts are washed to neutral with 5% aqueous sodium carbonate solution, and are dried over magnesium sulfate. After removing the solvent 360 mg of a colourless oil are obtained, which are then recrystallized from the mixture of dichloro methane and hexane, giving 301 mg ~85%) of the title compound. The physical characteristics of the title compound are:
[~]D5 = -88.7~ (c=l.0, chloroform).
NMR (CDCL3): 7.0 to 8.0 (m, 7H, aromatic protons), 6.2 (m, 2H, aromatic protons), 4.85 (m, lH, -CH-0-), 4.5 (t, lH, -CH-0-), 1.85 to 2.7 (m, 9H).
. . .
~.~3~
Example 8 (-)-3,3a~,4,5,6,6a~-hexahydro-4~-hydroxymethyl-5~-(p-phenyl-phenylcarbamoyloxy)-2H-cyclopentano[b]furane-2-on The procedure set forth in the Example is followed till preparing the mono-primary-silyl ether. The obtained oil is taken up in 10 ml of dry tetrahydro furane and 223.2 g (1.2 mmoles) of p-phenyl-phenyl-isocyanate and 121 mg of triethyl amine are added subsequently. The reaction mixture is then stirred at room temperature for 5 hours, controlling the proceedings of the reaction by t.l.c. measurement. The obtained reaction mixture is poured into 10 ml of 40% aqueous acetic acid solution, the container is washed out with 2 to 3 ml of dichloro methane, and the washings being added to the reaction mixture it is stirred vigorously for 30 to 25 minutes. The phases are separated, the aqueous layer is extracted with four 10 ml portions of dichloro methane and the combined organic extracts are washed to neutral with 5% aqueous sodium carbonate solution, in small portions. The residue is dried over magnesium sulfate, the solvent is removed, 350 mg of a colourless oil are obtained. Recrystallization from the mixture of dichloromethane and hexane yields 295 mg of the title compound. Rf = 0.35 (ethyl acetate -hexane, on a GF254 "Kieselgel nach Stahl" plate).
Example 9 (-)-3, 3a~,4,5,6,6a~-hexahydro-4~-trityloxymethyl-5~-hydroxy-2H-cyclopentene[b]furane-2-on 303 mg (1.76 mmoles) of levorotatory lactone diol of the structural formula II are dissolved in 2 ml of dry pyridine and 502 mg (1.8 mmoles) of trityl chloride are added in one portion. The resulted orange solution is stirred for 20 to 40 hours, and thereafter 30 ml of 1 N ice-cooled hydrochloric acid 20 ml of ethyl acetate are added subsequently. The organic layer is separated, subsequently washed with 5 ml of 5% sodium bicarbonate solution ,j ,~
~.
:
; . , , ~:
::
z~
and 5 ml of brine and dried over sodium sulfate. The solvent is distilled off in vacuo on a rotatory evaporator and the obtained solid is taken up in 6 ml of ethyl acetate. Upon the addition of 7 to 15 ml of petrol ether a crystalline substance is obtained, whicll is identified as the title compound.
Yield: 668 mg ~91.5%). Physical characteristics: Rf = 0.71 (ethyl acetate), Rf = 0.58 (benzene-ethyl acetate 1:1) both on a GF254 "Kieselgel nach Stahl"
plate.
Melting point: 108 to 109C.
[~]D = -14.3 10.5 ~c 1.79, methanol) Example 10 (-)-3,3a~,4,5,6,6a~-hexahydro-4~-hydroxymethyl-5~-(p-phenyl-benzoyloxy)-2H-cyclopentano[b~furane-2-on 414 mg (1 mmoles) of the compound of the structural formula IV, in which R represents a trityl group, are dissolved in 6 ml of dichloro methane and 249 mg (1.15 mmoles) of p-phenyl-benzoyl chloride in 2 ml of dry pyridine are added dropwise to the solution. The reaction mixture is stir-red for two hours, whereas the proceedings of the reaction is followed by t.l.c. The reaction mixture is then poured into 10 ml of 80% aqueous acetic acid solution, the container is washed out wi~h 2 to 3 ml of dichloro methane and the mixture is stirred for 30 to 35 minutes at 60C. The organic and aqueous layers are separa~ed, the aqueous phase is extracted with four 10 ml portions of dichloro methane, and the combined organic solutions are washed to neutral with 5% sodium carbonate solution in small portions, and dried over magnesium sulfate. Upon removing the solvent 372 mg of a colourless oil are obtained. Recrystallization from the mixture of dichloro methane and hexane yields 303 mg of the title compound (87%) as a crystalline solid, which was found to be identical with the crystals obtained in Example 7.
~' ' -~3~
Example 11 ~ -)-3,3a~,4,5,6,6a~-hexahydro-4~-trimethylsilyloxy-methyl-5~-hydroxy-2H-cyclopentano[b]furane-2-on 167 mg (0.97 mmoles) of the levorotatory compound of the structural formula II are dissolved in 5 ml of acetonitrile at room temperature, and 1 ml of 1 M solution of trimethyl-silyl-diethylamine in acetonitrile are added with stirring. After a reaction period of 20 minutes the solvent is evaporated.
250 mg of a pale-yellow oil are obtained. Recrystallization from 1 ml of ether with addition of 3 to 5 ml of hexane yeilds 193 mg ~81.5%) of the title com-pound.
Melting point: 48.5 to 49.5 C [~]D = -26.9 ~c = 0.9 aceto nitrile) R~ = 0.70 ~ethyl acetate, 0.36 ~benzene - ethyl acetate 1:1).
It should be noted that the product may be recrystallized also from the mixture of benzene and hexane.
- 17 _ .i
This invention relates to the pr~paration of certain racemic or optically active lactone diol derivatives, namely the racemic or optically active lactone diol derivatives o:E the structural formula I
O--C~
~ ~I) R10~ CH2 H
wherein, R represents acyl, hydrocarbon optionally containing also oxygen in the claim or silyl.
Thus, this invention provides for a process for preparing a racemic or optically active lactone diol derivative of the structural formula I
~0 O--C
~ (I) Rl`'o CH2-OH
wherein Rl represents acyl, hydrocarbon optionally containing also oxygen in the chain or silyl, which process comprises:
~a) reacting a racemic or optically active lactone diol of the structural formula II O-~C~
. ~
~II) .~'`~
with a trialkyl-silyl derivative of the structural formula IIII) , .
., . -- 1 --~;
`
~3~38 R2 Si R (III) ,~
,~
wherein R2, R3 and R4 each represent alkyl, and xl represents chloride, bromine or iodine or dialkyl-amino, then acylating the compound of the structural formula IV
~O--C~
~ ~IV) initally obtained, wherein R5 represents -SiR2R3R4, with a compound of structural formula (V) - o R6 .C ~x2 (V) or formula ~1 R7 - N = C = (VI) wherein R6 represents alkyl, aryl, substituted aryl or aralkyl, R7 represents alkyl, aryl or substituted aryl, and X represents chlorine or iodine and deblocking the primary hydroxyl of the lactone derivative of the structural formula VII O- C
~ (VII) '' ~: .
thus obtained wherein, R8 represents R6 -C0- or R7 -NH-C0- by acid hydrolysis; or (b) acylating the racemic or optically active lactone diol of the structural formula II with an ~cid halogenide of the structural formula V, reacting the compound of the structural formula IV, initially obtai.ned wherein R5 represents R6 -C0-, with a trialkyl silyl derivative of the structural formula III, then deblocking the primary hydroxyl group of the lactone derivative of the structural formula VIII ~0 C\
~ " (VIII) 9 '"" ~ 8 thus obtained, wherein R8 represents R6 -C0- and R9 represents -SiR R3R , by solvolysis carried out under alkaline condltions, or ~c) reacting the racemic or optically active lactone diol of the structural formula II with a benzyl halogenide of the structural formula IX
~ CH2 - X3 (IX) wherein X3 represents chlorine, bromine or iodine, reacting the compound of the struct-ural formula IV, initally obtained, wherein R5 represents ben~yl~
with a trialkyl-silyl derivative of the structural formula III, or with an , "
, .
~3~23~3 acid halogenide of the structural formula V, and then deblocking the primary hydroxyl of the lactone diol derivatives of the structural formula X
O--C~
~"' (X) R10'`"" C~12-Rll thus obtained J
wherein Rll represents benzyl, benzyloxy-carbonyl, trichloro-ethoxy-carbonyl, and R10 represents R6 -C0-, or -SiR2R3R4 by catalytic hydrogenation or with nascent hydrogen.
According to a preferred embodiment of process variant ~a) the secondary hydroxyl can be protected by aroyl, carbamoyl, preferably by p phenyl benzoyl, benzoyl, actyl, p phenyl, phenylcarbamoyl and the primer hydroxyl may be deblocked with acetic acid at a temperature no* exceeding 50C.
According to a preferred embodiment of process variant ~b) primaryhydroxyl is protected by alkanoyl or aroyl, preferably by benzoyl or acetyl, and the secunder hydroxyl by alkoxy-dialkyl-methyl such as methoxy-dimethyl methyl or ethoxy-methyl-methyl, and the primaryhyroxyl is solvolysed in a lower alkanol, in the presence of a base, preferably of potassium carbonate.
According to a preferred embodiment of process variant ~c) primaryhydroxyl is protected by benzyl, benzyloxy-carbonyl, or trichloroethoxy-carbonyl, and the secunder hydroxyl by phenyl-benzoyl, benzoyl, tetrahydropyranyl or silyl substituted by three identical or different Cl 6 alkyls. The primaryhydroxyl is deblocked by catalytic dehydrogenation achieved by nascent hydrogen generated from an acid by zinc, in the presence of a palladium catalyst under a hydrogen pressure of 3 atm.
: .
~3~3~
Among the entermediates employed in this invention are, for example 3,3a~,4,5,6,6a~-hexahydro-2-oxo-4~-trimethylsilyl-oxymethyl-5~-hydroxy-2H-cyclopenta[b]furane and 3,3a~,4,5,6,6a~-hexahydro-2-oxo-4~-trityloxymethyl-5~-hydroxy-2~1-cyclopenta[b]-furane which are novel compounds.
There are a lot of methods known in the art for the total synthesis of various prostaglandine analoges. In the known synthesis methods the way elaborated by E.J. Corey et al. takes a prominent part as regarding its ability to solve stereochemical problems, universality and importance [J. Amer. Chem.
Soc., 91, 5675 /1969/, ibid: 929 397 /1970/, ibid: 93, 1490 /1961/]. This method fUlfills also the requirements of the industrial production. The aimed product of the Corey synthesis is PGF2~9 which can be easily transformed into other pharmaceutically important natural prostaglandines, thus for example into PGEl, PGE2, PGEl , and PGEl~. The key-intermediate of the synthesis is the "Corey aldehyde" - wherein Rl represents p-phenyl-benzoyl or p-phenyl-carbamoyl-in which the four asymmetric carbon atoms have the same absolute and relative configuration as those of the PGF2~, and which contains both free or marked carbonyl functions serving for the preparation of the side-chains during the reaction, and the p-phenyl-benzoyl or p-phenyl-phenyl-carbamoyl hydroxyl-protecting groups, which are to control the stereoselective reduction of the C15-keto group. [J. Amer. Chem Soc. 9~, 8616 /1972/]. According to the synthesis "~orey aldehyde" and the other acyloxy lactone aldehydes of the structural formula XI ~z O--C
~ (XI) `
are prepared by oxydating acyloxy-lactones of the structural formula I~ wherein R represents acyl. The preparation of the compounds of the structural formula ~, :, :
: :
~ , , 1~3~38 I in this way, however, is extremely complicated, due to the high number of the reaction steps, and to the fact that the reagents are expensive and difficult to obtain.
Some other synthesis methods for the preparation of the compounds of the structural formula XI, I or of the compounds having similar field of application are to cope with similar difficulties ~See for example J. Amer.
Soc., 95, 6853 /1973/, J.C.S. Perkin I. 2796 /1973/). We have surprisingly found that the compounds of the structural formula I may be prepared by selective acylation of the racemic or optically active lactone diol of the structural formula II [~ II or ~ II].
Lactone diol of the structural formula II is a very convenient starting material, since it is readily available when prepared according to the cheap four-step synthesis disclosed in Tetrahedron Letters 4639-42 ~1976), using cyclopentadiene as starting substance. It should be noted that some representatives of the compounds of the structural formula I, for example the compound in which Rl is acetyl, can be prepared by partial deacetylation of the lactone diol diacetate of the structural formula XII
O--C~O
(XII) R10` CH2-R
wherein 20R and R each represent acetyl, this method, however, can not be extended to the preparation of the compounds of the structural formula I in general, and the acyl-migration taking place during the reaction has unfavourable consequences. It has been found that the primaryhydroxyl of the racemic or optically active lactone diol of the structural formula II can be subjected to a selective blocking reaction using . , , , ~ .
; ~'~ ,, .
~3~%3~3 various suitable reagents, and then the compound of the structural formula IV, initially obtainedJ in which R5 is a blocking group, can be protected on its free hydroxyl by any kind of acyl, for example p-phenyl-benzoyl, p-phenyl-phenyl-carbamoyl or of hydrocarbon, for e~ample tetrahydropyranyl. Finally the blocking group of the primaryhydroxyl is splitted off without attacking the ether or ester bond on the secondaryhydroxyl.
For the selective treatment of the primary and secondary hydroxyl of the compound of the structural formula II there is already a method known in the art [J. ~mer. Chem. Soc. 93 1491 /1971/], wherein as a bottom-note, without any experimental details the following procedure is suggested for solving the problem:
The primaryhydroxyl of the lactone diol of the structural formula ~-)-II is subjected to a selective trichloro-acetylating reaction, the second-aryhydroxyl of the hydroxyl-lactone trichloroacetate of the struc~ural formula IV obtained, wherein RS is trichloro-acetyl, is subseqently protected by tetrahydropyranyl, and then compound of the structural formula ~If obtained in the second step, in which Rl is tetrahydropyranyl and R5 is trichloroacetyl, is subjected to a saponification reaction. Thus tetrahydropyranyloxy-lactone-alcohol is obtained, which compound is within the scope o the structural formula I, and in which Rl represents tetrahydropyranyl.
The selective blocking of the primaryhydroxyl in the lactone diol is the decisive reaction step of our synthesis. Blocking can be achieved by various reactions, thus by acylation, alkylation and silylation. The regio-selectivity of the above reactions, however, is the function of the acylating, alkylating and silyla~ing agents applied and of the reaction conditions.
Generally the reaction results also in the production of secunder mono-acyl, mono-alkyl and mono-silyl side-products, which are~ however, easy to separate from the corresponding primarymain-products by column chromatography.
~ ':
..' -~ - 7 -~L~3~
What has been said above concerning the regioselectivity of the blocking reaction holds in respect of the acylating reactions carried out with 1 mole equivalent of acetic anhydride, acetyl chloride, benzoyl chloride or p-phenyl-benzoyl chloride in the presence of a base. The acylating reaction carried out by trichloroacetyl chloride did not prove to be absolutely regioselective, either, the aimed primarymono-acyl product was, however, easy to isolate by column chromatography in all of the above-mentioned cases.
Results obtained when etherifying the compound of the structural formula II were very similar. Thus, for example reacting the above compound with 1 mole equivalent of benzyl chloride mono-primarybenzylether of the structural formula IV, wherein R5 is benzyl, was obtained as a main product, together with the mono-secondary-benzyl ether of the structural formula I, wherein Rl represents benzyl, and with a small amount of the dibenzyl ether of the structural formula XII, wherein Rl and R5 each reprasent benzyl. ~
The case is similar when silylating the compound of the structural formula II with 1 mole equivalent of trimethylchloride sylane, in the presence of a base. Neither at 0C nor at room temperature could we achieve a 100%
selectivity in pyridine-dichloromethane solvent mixture and at 30-40%
completion of the reaction bothmono-sil,y~l ethers and the di-silyl ether were detected.
We have surprisingly found that with certain reagents under certain reaction conditions near 100% regioselectivity could be achieved for the blocking reaction of the primaryhydroxyl of the compound of the structural formula II. Thus silylating the racemic or optically active compound of the structural formula II with 1.0 to 1.1 mole equivalent of trimethylsilyl diethyl amine [Acta Chem. Acad. Sci. Hung., 58, 189 /1968/~ in acetonitrile at 0C, the reaction proceeds smoothly in some minutes, resulting in the mono-primary-silyl ether of the structural formula IV, in which R5 represents trimethyl , 3~3 silyl, besides mono-primary-silyl ether traces, which can be detected only chromatographically.
It should be noted that using 2 to 2.5 equivalents of the above reagent also the di-silyl ether can be produced in 30 to ~5 minutes.
Among the alkylating agents triphenyl-methyl chloride was found to be able to procluce a similarregio5elective reaction. When carrying out the tritylating reaction in pyridine, at room temperature, the crystalline mono-primary-triethyl ether of the structural formula IV, in which R5 is trityl, is obtained practically quantitatively.
The free secondaryhydroxyl of the compounds of the structural formula IV can be subjected to acylation or alkylation. The compounds of the structural formula IV preferably used in prostaglandine synthesis can be acylated in a manner known per se using a p-phenyl-benzoyl chloride or p-phenyl-isocyanate as acylating agents9 but also the tetrahydropyranyl ether of these compounds can be prepared employing 3,4-2H-dihydropyrane. Thus products of the structural formula XII are obtained, in which Rl and R5 represent different acyl, alkyl or silyl groups.
In the last step of our synthesis the primaryhydroxyl is deblocked by methods known per se. Care must be taken, however, that the reagents applied should not attack on the ester or other bond on the secondaryhydroxyl.
Trimethylsilyl and trityl are easily removable by hydrolysis effected under mild acid conditi~n, with heating. This last reaction step can be carried out also simultaneously with the separa*ion step following the acylation of the secondaryhydroxyl.
Should the primaryhydroxyl be blocked by acyl, for example acetyl or benzoyl, it is advisable to protect the secondaryhydroxyl by a protecting group resistant to a mild alkaline hydrolysis, thus for example by an ether type group, preferably by tetrahydropyranyl. When proceeding according to ~:~3~23~3 this method, the compounds of the structural formula XII, wherein Rl is hydrocarbon, for example tetrahydropyranyl or benzyl and R5 represents acyl, are treated with sodium alcoholate in an alcoholic medium, and thus compounds of the structural formula I are prepared.
The following Examples illustrate but do not limit the product and process of the present invention.
Example 1 (-)-3,3a~,4,5,6,6a~-hexahydro-4~-benzoyloxymethyl-5~-hydroxy -2H-cyclopentano[b]furane-2-on 354 mg (2moles) of levorotatory lactone diol of the structural formula II are dissolved in the mixture of 2 ml of dry pyridine and 10 ml of dichloro methane, the mixture is ice-cooled to 0C and the solution o~ 295 g ~2.1 mmoles) of benzoyl chloride in 5 ml of dichloro methane i5 added gradually. The proceedings of the reaction is followed by t.l.c. ~fter two hours the following spots are to be observed: spots corres-ponding to a small amount of the starting material, and to traces of the secondary monobenzoate (Rf = 0.34, ethyl acetate), respectively, but the main spot is to be found at Rf = 0.60 ~ethyl acetate), which corresponds to the primer monobenzoate. The reaction mixture is diluted with 30 ml of dichloromethane and is poured into 30 ml of 7% equeous sulfuric acid solution under ice-cooling, washed with 10 ml of 2.5% aqueous sodium bicarbonate solution and dried over magnesium sulfate. The solvent is then evaporated whereupon 550 mg of a colourless oil is obtained, which is chromatographed on 60 g of silica gel and eluated in 2:1 to 1:1 benzoyl-ethyl acetate solvent mixture, using the gradient eluating technique. Evaporating the fractions containing the main product 399 mg (72%) of the title monobenzoate are obtained which proved to be uniform according to the t.l.c. measurements.
[~]23 = -22 (c = 1.37, ethyl acetate) IR: 3400, 3010, 2920, 1770, 1710, 1600, 1590, 1450, 1265,1200, 1165, 1110, -, .
, 1065, 1030, 710 cm~l.
Example 2 (~)-3,3a~,4,5,6,6a~-hexahydro-4~-acetoxymethyl-5a-hydroxy-2H-cyclopentano[b]furane-2-on ~ ollowing the procedure set forth in the Example 1 but using 214.2 mg (2.1 mmoles) of acetic anhydride as acylating agent, 452 mg of a crude product are obtained, subjecting this product to column chromatography as described in the Example 1, 124 mg (58%) of the title primer monoacetate are obtained.
t.l.c. (on "Kieselgel nach Stahl"plate): Rf = 0.10 (benzene ethyl acetate 1:1);
0.42 (ethyl acetate); 0.61 ~ethyl acetate - methanol 6:1).
Example 3 ~ +)-3,3a~,4,5,6,6a~-hexahydro-4~-benzyloxymethyl-5a-hydroxy-2H-cyclopentano[b]furane-2-on 320 mg ~1.86 mmoles) of racemic lactone diol of the structural formula II are dissolved in 25 ml of acetone and 350 mg ~2.05 mmoles) of benzyl bromide and 290 mg of potassium carbonate are added. The reaction mixture is stirred at room temperature for 8 to 10 hours and the reaction is followed by t.l.c. The main spot is to be observed at Rf = 0.46 ~GF254 "Kiselgel nach Stahl" plate, ethyl acetate) which corresponds to the primer benzyl ether main product. The solvent is then evaporated, the residue taken up in ethyl acetate, washed subsequently wi-th water and brine, dried over magnesium sulfate and chromatographed on a chromatographic column made of 60 g of silica gel. The eluation is carried out with 2:1 to 1:1 mixture of benzene and ethyl acetate using the conventional gradient eluating technique.
The fractions containing the main product are pooled and evaporated to give the title compound in form of a pale-yellow oil.
IR: 3400 ~-OH), 1760 ~-CO-lactone), 1080 ~-CO-), 700, 7~0 ~-CH-) cm 1.
' ';~
~,~3~3~
Example 4 (+)-3,3a~,4,5,6,6a~-hexahydro-4~-benzoyloxymethyl-5~-tetrahydro-pyranyloxy-211-cyclopentano[b]furane-2-on 230 mg (0.83 mmoles) of levorotatory lactone diol primer monobenzoate of the general formula IV, in which R5 is benzoyl, are dissolved in 5 ml of dry benzene, 0.5 ml (5.5 mmoles) of 3,4-2H-dihydropyrane and 1 drop of phosphorous oxychloride are added. According ~o the t.l.c. measurements the reaction is completed within one hour. Thereafter four drops of triethyl amine and 5 ml of pentane are added and after 1 to 2 hours the resulted downy precipitate is filtered off. Upon removing the solvent on a rotatory evaporator under vacuo, 300 mg (100%) of the title compound is obtained as a colourless oil having the following physical characteristics:
Rf = 0.33 (on a GF254 "Kieselgel nach Stahl" plate, with benzene-ethyl acetate 3~
IR: 3010, 2910, 2850, 1770, 1710, 1600, 1260, 1160, 1110, 1070, 1030, 1010, 910, 710 cm~l.
Example 5 (-)-3,3a~,4,5,6,6a~-hexahydro-4~-hydroxymethyl-5~-tetrahydropyranyloxy-2H~cyclopentano[b]furane-2-on 300 mg (0.83 mmoles) of levor~atory lactone diol derivative of the structural formula XII, in which Rl represents tetrahydropyranyl and R5 represents benzoyl are dissolved in 5 ml of dry methanol and 2 ml of 0.5 M
methanolic solution of sodium methoxide are added.
According to the t.l.c. measurement the debenzoylating reac*ion is completed in 50 minutes. 1 ml of 1 M methanolic solution of acetic acid is then added and the solvent is removed on a rotatory evaporator, in vacuo.
The residue is dissolved in 15 ml. of ethyl acetate and the solution is subsequently washed with 3 ml of 5% sodium carbona~e solution, 2-fold 3 ml of ,' '. ~
~o~3~3~
water and 3 ml of brine, dried over sodium sulfate and evaporated. 201 mg (96%) of the title ~-) lactone diol secunder tetrahydropyranyl ether are obtained.
Physical properties: [N]D = -30.7 ~1 (c = 0.9~, methanol).
IR (max.): 3420, 2910, 1850, 1760, 1345, 1165, 1120, 1110, 1070, 1030, 1010 cm Rf = 0.20 (ethyl acetate), 0.~3 (6:1 ethyl acetate - methanol on a GR254 "Kieselgel nach Stahl" plate.
_ mple 6 (-)-3,3a~-4,5,6,6a~-hexahydro-4~-hydroxymethyl-5~-benzoyloxy-2H-cyclopentano~b]furane-2On 172 mg (l~noles) of levorotatory lactone diol of the structural formula II are dissolved in 5 ml of acetonitrile and 1.1 ml of 1 M solution of trimethyl silyl-diethyl-amine in acetonitrile and added dropwise, at room temperature, with stirring in 1 to 2 minutes. According to the t.l.c. measurement (benzene-ethyl acetate 1:1) the reaction is completed in 10 minutes. The main spot is found a~ Rf=0.36, but an other spot at Rf = 0.69 shows that also bis-silyl ether traces are present. The solvent and ~he formed diethyl amine is removed on a rotatory evaporator, under pressure of 12 to 15 torr, and at a temperature not exceeding 30C. The res~due i5 257 mg of a yellowish oil which is then dissolved in 5 ml of dichloro methane and the solution added to the mixture of 1 ml of dry pyridine and 162 mg ~1.15 mmoIes) of ben~oyl chloride at 0C
in 5 to 6 minutes. Af~er two hours of stirring the reaction mixture is poured into 10 ml of a 40% aqueous acetic acid solution, the container is washed out with 2 to 3 ml of dichloro methane, which is added to the reaction mixture, and then the mixture is allowed to stir for 30 to 35 minutes or shaken in a separating fumlel very intensively. The phases are separated, the aqueous phase is extracted with four 10 ml portions of dichloro methane and the combined organic extracts are washed to neutral in small portions, with 5% solution of sodium carbonate, and then dried over magnesium sulfate. Upon removing the . . .
~3~23~
solvent 240 mg of the title compound remain in form of a colourless oil, which can be turned into crystalline form upon stirring with a glass-stick.
After recrystallization from the mixture of ethyl aceta~e and hexane 210 mg ~76%) of lactone diol secunder-mono-benzoate are obtained, melting at 117 to 118C. [u] ~max): 3450, 2920, 1770, 1710, 1600, 1580, 1540, 1270, 1200, 1165, 1110, 1090, 1070, 1030, 710 cm 1, Example 7 ~ -)-3,3a~,4,5,6,6a~-hexahydro-4~-hydroxymethyl-5~-~p-phenyl-benzoyloxy)-2H-cyclopentano[b]furane-2-on The procedure set forth in the Example 6 is followed till the addition of the acylating agent. In the present Example the solution of 249 mg ~1.15 mmoles) of p-phenyl-benzoyl chloride in 2 ml of pyridine are added dropwise to the solution of the mono-primer-silyl ether in dichloro methane, at room temperature, in 5 to 6 minutes. The mixture is stirred for two hours and the proceedings of the reaction is controlled by t.l.c. The reaction mixture is then poured into 10 ml of a 40% aqueous solution of acetic acid, the container is washed with 2 to 3 ml of dichloro methane, which are then added to the reaction mixture. The mixture is vigorously stirred for 30-35 minutes, or is shaken in a separating funnel. After separating the phases the combined organic extracts are washed to neutral with 5% aqueous sodium carbonate solution, and are dried over magnesium sulfate. After removing the solvent 360 mg of a colourless oil are obtained, which are then recrystallized from the mixture of dichloro methane and hexane, giving 301 mg ~85%) of the title compound. The physical characteristics of the title compound are:
[~]D5 = -88.7~ (c=l.0, chloroform).
NMR (CDCL3): 7.0 to 8.0 (m, 7H, aromatic protons), 6.2 (m, 2H, aromatic protons), 4.85 (m, lH, -CH-0-), 4.5 (t, lH, -CH-0-), 1.85 to 2.7 (m, 9H).
. . .
~.~3~
Example 8 (-)-3,3a~,4,5,6,6a~-hexahydro-4~-hydroxymethyl-5~-(p-phenyl-phenylcarbamoyloxy)-2H-cyclopentano[b]furane-2-on The procedure set forth in the Example is followed till preparing the mono-primary-silyl ether. The obtained oil is taken up in 10 ml of dry tetrahydro furane and 223.2 g (1.2 mmoles) of p-phenyl-phenyl-isocyanate and 121 mg of triethyl amine are added subsequently. The reaction mixture is then stirred at room temperature for 5 hours, controlling the proceedings of the reaction by t.l.c. measurement. The obtained reaction mixture is poured into 10 ml of 40% aqueous acetic acid solution, the container is washed out with 2 to 3 ml of dichloro methane, and the washings being added to the reaction mixture it is stirred vigorously for 30 to 25 minutes. The phases are separated, the aqueous layer is extracted with four 10 ml portions of dichloro methane and the combined organic extracts are washed to neutral with 5% aqueous sodium carbonate solution, in small portions. The residue is dried over magnesium sulfate, the solvent is removed, 350 mg of a colourless oil are obtained. Recrystallization from the mixture of dichloromethane and hexane yields 295 mg of the title compound. Rf = 0.35 (ethyl acetate -hexane, on a GF254 "Kieselgel nach Stahl" plate).
Example 9 (-)-3, 3a~,4,5,6,6a~-hexahydro-4~-trityloxymethyl-5~-hydroxy-2H-cyclopentene[b]furane-2-on 303 mg (1.76 mmoles) of levorotatory lactone diol of the structural formula II are dissolved in 2 ml of dry pyridine and 502 mg (1.8 mmoles) of trityl chloride are added in one portion. The resulted orange solution is stirred for 20 to 40 hours, and thereafter 30 ml of 1 N ice-cooled hydrochloric acid 20 ml of ethyl acetate are added subsequently. The organic layer is separated, subsequently washed with 5 ml of 5% sodium bicarbonate solution ,j ,~
~.
:
; . , , ~:
::
z~
and 5 ml of brine and dried over sodium sulfate. The solvent is distilled off in vacuo on a rotatory evaporator and the obtained solid is taken up in 6 ml of ethyl acetate. Upon the addition of 7 to 15 ml of petrol ether a crystalline substance is obtained, whicll is identified as the title compound.
Yield: 668 mg ~91.5%). Physical characteristics: Rf = 0.71 (ethyl acetate), Rf = 0.58 (benzene-ethyl acetate 1:1) both on a GF254 "Kieselgel nach Stahl"
plate.
Melting point: 108 to 109C.
[~]D = -14.3 10.5 ~c 1.79, methanol) Example 10 (-)-3,3a~,4,5,6,6a~-hexahydro-4~-hydroxymethyl-5~-(p-phenyl-benzoyloxy)-2H-cyclopentano[b~furane-2-on 414 mg (1 mmoles) of the compound of the structural formula IV, in which R represents a trityl group, are dissolved in 6 ml of dichloro methane and 249 mg (1.15 mmoles) of p-phenyl-benzoyl chloride in 2 ml of dry pyridine are added dropwise to the solution. The reaction mixture is stir-red for two hours, whereas the proceedings of the reaction is followed by t.l.c. The reaction mixture is then poured into 10 ml of 80% aqueous acetic acid solution, the container is washed out wi~h 2 to 3 ml of dichloro methane and the mixture is stirred for 30 to 35 minutes at 60C. The organic and aqueous layers are separa~ed, the aqueous phase is extracted with four 10 ml portions of dichloro methane, and the combined organic solutions are washed to neutral with 5% sodium carbonate solution in small portions, and dried over magnesium sulfate. Upon removing the solvent 372 mg of a colourless oil are obtained. Recrystallization from the mixture of dichloro methane and hexane yields 303 mg of the title compound (87%) as a crystalline solid, which was found to be identical with the crystals obtained in Example 7.
~' ' -~3~
Example 11 ~ -)-3,3a~,4,5,6,6a~-hexahydro-4~-trimethylsilyloxy-methyl-5~-hydroxy-2H-cyclopentano[b]furane-2-on 167 mg (0.97 mmoles) of the levorotatory compound of the structural formula II are dissolved in 5 ml of acetonitrile at room temperature, and 1 ml of 1 M solution of trimethyl-silyl-diethylamine in acetonitrile are added with stirring. After a reaction period of 20 minutes the solvent is evaporated.
250 mg of a pale-yellow oil are obtained. Recrystallization from 1 ml of ether with addition of 3 to 5 ml of hexane yeilds 193 mg ~81.5%) of the title com-pound.
Melting point: 48.5 to 49.5 C [~]D = -26.9 ~c = 0.9 aceto nitrile) R~ = 0.70 ~ethyl acetate, 0.36 ~benzene - ethyl acetate 1:1).
It should be noted that the product may be recrystallized also from the mixture of benzene and hexane.
- 17 _ .i
Claims (8)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a racemic or optically active lactone diol derivative of the structural formula I
(I) wherein R1 represents acyl, hydrocarbon optionally containing also oxygen in the chain or silyl, which process comprises:
(a) reacting a racemic or optically active lactone diol of the structural formula II
(II) with a trialkyl-silyl derivative of the structural formula III
(III) wherein R2, R3 and R4 each represent alkyl, and X1 represents chloride, bromine or iodine or dialkylamino, then acylating the compound of the structural formula IV
(IV) initially obtained, wherein R5 represents -SiR2R3R4, with a compound of the structural formula V
(V) or VI
R7 - N = C = O (VI) wherein R6 represents alkyl, aryl, substituted aryl or aralkyl, R7 represents alkyl, aryl or substituted aryl, and X2 represents chlorine or iodine and deblocking the primary hydroxyl of the lactone derivative of the structural formula VII
(VII) thus obtained wherein, R8 represents R6-CO- or R7-NH-CO-by acid hydrolysis; or (b) acylating the racemic or optically active lactone diol of the structural formula II with an acid halogenide of the structural formula V, reacting the compound of the structural formula IV, initially obtained wherein R5 represents R6-CO-, with a trialkyl silyl derivative of the structural formula III then deblocking the primary hydroxyl group of the lactone derivative of the structural formula VIII
(VIII) thus obtained, wherein R8 represents R6-CO-, and R9 represents -SiR2R3R4, by solvolysis carried out under alkaline conditions, or (c) reacting the racemic or optically active lactone diol of the structural formula II with a benzyl halogenide of the structural formula IX
(IX) wherein X represents chlorine, bromine or iodine, reacting the compound of the structural formula IV, initially obtained, wherein R5 represents benzyl, with a trialkyl-silyl derivative of the structural formula III, or with an acid halogenide of the structural formula V and then deblocking the primary hydroxyl of the lactone diol derivatives of the structural formula X
(X) thus obtained, wherein R11 represents benzyl, and R10 represents R6-CO-, or -SiR2R3R4, by catalytic hydrogenation or with nascent hydrogen.
(I) wherein R1 represents acyl, hydrocarbon optionally containing also oxygen in the chain or silyl, which process comprises:
(a) reacting a racemic or optically active lactone diol of the structural formula II
(II) with a trialkyl-silyl derivative of the structural formula III
(III) wherein R2, R3 and R4 each represent alkyl, and X1 represents chloride, bromine or iodine or dialkylamino, then acylating the compound of the structural formula IV
(IV) initially obtained, wherein R5 represents -SiR2R3R4, with a compound of the structural formula V
(V) or VI
R7 - N = C = O (VI) wherein R6 represents alkyl, aryl, substituted aryl or aralkyl, R7 represents alkyl, aryl or substituted aryl, and X2 represents chlorine or iodine and deblocking the primary hydroxyl of the lactone derivative of the structural formula VII
(VII) thus obtained wherein, R8 represents R6-CO- or R7-NH-CO-by acid hydrolysis; or (b) acylating the racemic or optically active lactone diol of the structural formula II with an acid halogenide of the structural formula V, reacting the compound of the structural formula IV, initially obtained wherein R5 represents R6-CO-, with a trialkyl silyl derivative of the structural formula III then deblocking the primary hydroxyl group of the lactone derivative of the structural formula VIII
(VIII) thus obtained, wherein R8 represents R6-CO-, and R9 represents -SiR2R3R4, by solvolysis carried out under alkaline conditions, or (c) reacting the racemic or optically active lactone diol of the structural formula II with a benzyl halogenide of the structural formula IX
(IX) wherein X represents chlorine, bromine or iodine, reacting the compound of the structural formula IV, initially obtained, wherein R5 represents benzyl, with a trialkyl-silyl derivative of the structural formula III, or with an acid halogenide of the structural formula V and then deblocking the primary hydroxyl of the lactone diol derivatives of the structural formula X
(X) thus obtained, wherein R11 represents benzyl, and R10 represents R6-CO-, or -SiR2R3R4, by catalytic hydrogenation or with nascent hydrogen.
2, A process according to claim 1 which comprises, when employing process (a), acylating an obtained compound of the structural formula IV, with a compound of the structural formula V or VI, wherein R6 is p-phenyl-phenyl, phenyl or methyl, R7 is p-phenyl-phenyl and X2 is chlorine or iodine, and deblocking the primary hydroxyl of the lactone derivative of the structural formula VII thus obtained, wherein R5 is -SiR2R3R4, wherein R2, R3 and R4 have the meaning as stated above, and R8 is p-phenylbenzoyl, benzoyl, acetyl or p-phenyl-phenylcarbamoyl, and thus preparing a compound of the structural formula I, in which R1 is p-phenylbenzoyl, benzoyl, acetyl or p-phenyl-phenylcarbamoyl.
3. A process according to claim 1, which comprises when employing process (b) acylating the racemic or optically active lactone diol of the structural formula II with an acid halogenide of the structural formula V, in which R6 is phenyl or methyl and X2 is chlorine or iodine.
4. A process according to claim 1 which comprises, when employing process (c) reacting a racemic or optically active lactone diol of the structural formula II with a benzyl halogenide.
5. A process according to claim 1 which comprises, when employing process (c) reacting an obtained compound of the structural formula IV, wherein R5 is benzyl, with a compound of the structural formula V, wherein R6 is phenylphenyl, or phenyl and X2 is chlorine or iodine, or with dihydropyrane or with a compound of the structural formula III
wherein R2, R3 and R4 are the same or identical and each stands for alkyl, and X1 is chlorine, bromine or iodine, or dialkyl amino, and removing by catalytic hydrogenation the protecting group from the primary hydroxyl of the compound of the structural formula X thus obtained, in which R11 is benzyl, R10 is phenylbenzoyl, benzoyl, tetrahydropyranyl or tri-alkyl silyl substituted by identical or different alkyls having 1 to 6 carbon atoms, thus preparing a compound of the formula I, in which R1 is phenyl benzoyl, benzoyl, tetrahydropyranyl or trialkyl silyl substituted by identical or different alkyls having 1 to 6 carbon atoms.
wherein R2, R3 and R4 are the same or identical and each stands for alkyl, and X1 is chlorine, bromine or iodine, or dialkyl amino, and removing by catalytic hydrogenation the protecting group from the primary hydroxyl of the compound of the structural formula X thus obtained, in which R11 is benzyl, R10 is phenylbenzoyl, benzoyl, tetrahydropyranyl or tri-alkyl silyl substituted by identical or different alkyls having 1 to 6 carbon atoms, thus preparing a compound of the formula I, in which R1 is phenyl benzoyl, benzoyl, tetrahydropyranyl or trialkyl silyl substituted by identical or different alkyls having 1 to 6 carbon atoms.
6. A process according to claim 1, wherein in said process (a) the acid hydrolysis is performed with acetic acid at a temperature below 50°C.
7. A process according to claim 1, wherein in said process (b) the solvolysis is performed in the presence of a lower alkanol and in the presence of a base.
8, A process according to claim 1, wherein in said process (c) the hydrogenation is performed with nascent hydrogen generated from zinc and an acid, in the presence of a palladium catalyst, under a hydrogen pressure of about 3 atmospheres.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB2232577A GB1579464A (en) | 1977-05-26 | 1977-05-26 | Processes for the preparation of lactonediol derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1131238A true CA1131238A (en) | 1982-09-07 |
Family
ID=10177565
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA279,295A Expired CA1131238A (en) | 1977-05-26 | 1977-05-27 | Process for the preparation of bicyclic lactone diol derivatives |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPS545965A (en) |
| CA (1) | CA1131238A (en) |
| GB (1) | GB1579464A (en) |
| SE (1) | SE431750B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109096320A (en) * | 2017-06-21 | 2018-12-28 | 黄冈鲁班药业股份有限公司 | The preparation method of lactone in benzoyl section |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3638762A1 (en) * | 1986-11-13 | 1988-05-26 | Schering Ag | RACEMAT CLEAVAGE OF 7 (ALPHA) -ACYLOXY-6SS-HYDROXY-METHYL-2-OXABICYCLO (3.3.0) OCTAN-3-ONES BY STEREO-SPECIFIC ENZYMATIC ACYLATE HYDROLYSIS |
| JP4358940B2 (en) * | 1999-08-26 | 2009-11-04 | 丸善石油化学株式会社 | Polymerizable compound and polymer having cyclohexanelactone structure |
-
1977
- 1977-05-24 SE SE7706083A patent/SE431750B/en not_active IP Right Cessation
- 1977-05-26 GB GB2232577A patent/GB1579464A/en not_active Expired
- 1977-05-27 CA CA279,295A patent/CA1131238A/en not_active Expired
- 1977-06-13 JP JP6976877A patent/JPS545965A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109096320A (en) * | 2017-06-21 | 2018-12-28 | 黄冈鲁班药业股份有限公司 | The preparation method of lactone in benzoyl section |
| CN109096320B (en) * | 2017-06-21 | 2021-04-16 | 黄冈鲁班药业股份有限公司 | Method for preparing benzoyl coriolide |
Also Published As
| Publication number | Publication date |
|---|---|
| SE7706083L (en) | 1978-11-25 |
| SE431750B (en) | 1984-02-27 |
| JPS545965A (en) | 1979-01-17 |
| GB1579464A (en) | 1980-11-19 |
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