AP973A - 2-Azabicyclo {2.2.1} heptane derivatives preparation and application thereof. - Google Patents
2-Azabicyclo {2.2.1} heptane derivatives preparation and application thereof. Download PDFInfo
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- AP973A AP973A APAP/P/1997/001149A AP9701149A AP973A AP 973 A AP973 A AP 973A AP 9701149 A AP9701149 A AP 9701149A AP 973 A AP973 A AP 973A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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Abstract
Novel 1R 2-azabicyclo [2 . 2 .1] heptane derivatives of general formula (I) wherein Rx is an alkyl radical containing 1-4 carbon atoms and Ar is an optionally substituted phenyl or a-or (3-naphthyl radical, and preparation and application thereof. The novel products of general formula (I) are particularly useful for preparing adenosine agonists.
Description
2-AZABICYCLO[2,2,1]HEPTANE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION
The present invention relates to IR 2azabicyclo[2.2.1]heptane derivatives of general formula (I) :
atom radical or a radical
in which Rx represents an to their preparation and to their use.
In the general formula (I) R represents a hydrogen of general formula:
(Π) alkyl radical containing 1 to 4 carbon atoms and Ar represents a phenyl or a- or βnaphthyl radical optionally substituted by one or more identical or different atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, the alkoxy radical containing 1 to 4 carbon atoms or the nitro radical.
Preferably, Rx represents a methyl or ethyl radical and Ar represente a phenyl radical optionally substituted by one or more methyl or methoxy radicals.
AP/P/ 9 7/01149
AP 00973
More particularly still, Rx represents a methyl radical and Ar represents a phenyl radical.
According to the invention, the products of general formula (I) in which R represents a radical of general formula (II) can be obtained by bishydroxylation of a product of general formula:
in which Rx and Ar are defined as above.
The bishydroxylation is generally carried out by operating under the conditions described by V. VanRheenen et al., Tetrahedron Letters, 23., 19731976 (1976). More particularly, the oxidation can be carried out by means of potassium permanganate or of osmium tetroxide, the reaction being carried out in the presence of N-methylmorpholine oxide or of triethylamine oxide or of potassium ferricyanide (K3FeCNs) . The reaction is generally carried out in an aqueous/organic medium, such as a water/tert-butanol or water/acetone mixture.
The oxidizing agent should generally be chosen so that only the ,5,6-dihydroxy derivative in the exo form is formed.
The product of general formula (III)
AP!?! 9 7/01149
ΑΡ 00973 can be obtained by a Diels-Alder reaction between a homochiral amine of general formula:
ί) in which Rx and Ar are defined as above, in the form of 5 a salt, preferably with an inorganic acid such as hydrochloric acid, formaldehyde and cyclopentadiene, the reaction being- carried out under the conditions described by S.D. Larsen and P.A.. Grieco, J. Amer.
Chem. Soc., 107, 1768-1769 (1985).
The implementation of the process results, from a homochiral amine of R or S form, in a mixture of 2-diastereoisomers which, reacting in the same way in the subsequent bishydroxylation stage, should not necessarily be separated.
According to the invention, the product of general formula (I) in which R represents a hydrogen atom can be obtained by hydrogenolysis of a product of general formula (I), in which R represents a radical of general formula (II), by means of hydrogen in the presence of a catalyst such as palladium-on-charcoal, the reaction being carried out in an organic solvent such as an alcohol, for example methanol.
The IR isomer of general formula (I) in which
R represents a radical of general formula (II) can be isolated from a mixture of a product of general
AP// 9 7/01 149
AP 00973
-4formula (I) and of a product of general formula (I'):
wherein the R symbols represent a radical of general formula (II) as defined above; which process comprises the diastereoselective crystallization of a product of formula (I) in which R represents a radical of formula (II) as defined above, with an optically active organic ) acid in an appropriate organic solvent, such as Ldimethoxysuccinic acid, in an organic solvent chosen from aliphatic alcohols containing from 1 to 3 carbon atoms. Isopropanol is a suitable alcohol.
The products of general formula (I) are particularly useful for preparing the products which form the subject of United States Patent US 5,364,862 and which are agents which are active in the treatment of cardiovascular diseases, such as hypertension and myocardial ischaemia.
[1-S-[Ια,2β, 3β, 4α(S*)]]-4-[7-[[2-(3-Chloro-2thienyl)-1-ethylethyl]amino]-3H-imidazo[4,5-b]pyridin-3j yl)-N-ethyl-2,3-dihydroxycyclopentanecarboxamide of formula:
AP/P/ 9 7/01149
is of very particular advantage.
The products of general formula (I) are particularly useful for preparing the carbosugar of general formula:
AP 00973
I)
R-0
ΎΖ
NH-Gj (V)
O-R' in which R2 represents a carboxyl radical, an alkoxycarbonyl radical in which the alkyl part contains 1 to 4 carbon atoms, an N-alkylaminocarbonyl radical in which the alkyl part contains 1 to 4 carbon atoms, or a hydroxymethyl or alkoxymethyl radical, and R' and R, which are identical or different, represent a hydrogen atom, an aliphatic organic acid residue containing 2 to 4 carbon atoms, such as an acetyl or propionyl radical, or an aromatic acid residue, such as a benzoyl residue, or else R' and R together form a methylene radical, the carbon atom of which is optionally substituted by one or more identical or different radicals chosen from alkyl radicals containing 1 to 4 carbon atoms, which can together form an alicyclic radical containing 5 or
6 carbon atoms, or phenyl radicals, and Gx represents a hydrogen atom or a protecting group G2 for the amino functional group. More particularly, R2 represents an ethylaminocarbonyl or hydroxymethyl radical and R' and R together form an isopropylidene radical.
The carbosugar of general formula (V) constitutes one of the components of the structure of the products claimed in United States Patent US 5,364,862.
The carbosugar of general formula (V) can be
AP/P/ 97/01149
AP 00973 prepared from the product of general formula (I) in the following way.
The hydroxyl functional groups of the product of general formula (I) in which R represents a hydrogen atom or a radical of general formula (II) can be protected in the ester or acetal form in order to give a product of general formula:
in which R represents a hydrogen atom or a radical of general formula (II) and R'x and Rx, which are identical or different/ represent an aliphatic organic acid residue containing 2 to 4 carbon atoms, such as an acetyl or propionyl radical, or an aromatic acid residue, such as a benzoyl residue, or else R'x and Rx
Γ) together form a methylene radical, the carbon atom of , ) 15 which is optionally substituted by one or more identical or different radicals chosen from alkyl radicals containing 1 to 4 carbon atoms, which can together form an alicyclic radical containing 5 or 6 carbon atoms, or phenyl radicals.
The protection of the hydroxyl radicals is generally carried out under the usual esterification or acetalization conditions, for example by reacting with acetic or propionic acid in the presence of p-toluenesulphonic acid in an organic solvent such as
AP/P/ 9 7/01 149
AP 00973 an aromatic hydrocarbon, for example benzene or toluene, the water being separated off as it is formed, or by reacting with an aldehyde or with a ketone, optionally in the acetal form, in the presence of an acid, such as trifluoroacetic acid, in an organic solvent such as an aromatic hydrocarbon, for example benzene or toluene, at a temperature of between 50°C and the reflux temperature of .the reaction mixture.
The product of general formula (VI) in which 10 R represents a radical of general formula (II) can be converted to the product of general formula (VI) in which R represents a hydrogen atom by hydrogenolysis.
The hydrogenolysis is generally carried out by means of hydrogen, optionally under pressure, in the presence of a catalyst, such as palladium-on-charcoal, in an organic solvent such as an alcohol, for example methanol, ethanol or isopropanol, at a temperature of between 0 and 50°C.
The product of general formula (VI), which is a novel product, constitutes another subject of the present invention.
The product of general formula (VI) in which R represents a hydrogen atom can be converted to the product of general formula:
(ΥΠ)
7P/ 9 7/01149
El <
AP 00973 in which and R'1! are defined as above and G2 represents a protecting group for the amino functional group, by reaction with a suitable reagent which allows selective introduction of a protecting group.
The protecting groups are chosen from those which can subsequently be selectively removed. Mention may be made, among protecting groups which are particularly well suited, of the following radicals: chloroacetyl, methoxymethyl, 2,2,210 trichloroethoxycarbonyl, t-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, diphenylmethyl, trialkylsilyl, allyloxycarbonyl, benzyloxycarbonyl, in which the phenyl ring is optionally substituted by a halogen atom, by an alkyl radical containing 1 to 4 carbon atoms or by an alkyloxy radical containing 1 to 4 carbon atoms, or t-butoxycarbonyl. Mention may be made, among the other protecting groups which are ) particularly well suited, of those which are described /
J by T.W. Greene and P.G.M. Wuts, Protecting Groups in
Organic Synthesis, Chapter 7, 2nd edition, John Wiley & Sons (1991).
The t-butoxycarbonyl group is of very particular advantage.
The product of general formula (VII) in which
G2 represents a t-butoxycarbonyl radical can be obtained directly from a product of general formula (VI) in which R represents a radical of general formula (II) by simultaneous hydrogenolysis and tertAP/P/ 9 7/01149
ΑΡ 00973 butoxycarbonylation.
The reaction is generally carried out by simultaneously reacting hydrogen, in the presence of a catalyst such as palladium-on-charcoal, and di-t-butyl dicarbonate with a product of general formula (VI), the reaction being carried out in an organic solvent such as an alcohol, for example methanol, ethanol or isopropanol, at a temperature of between 0 and 50°C.
The product of general formula (VII) is a 10 novel product which constitutes another subject of the present invention.
The product of general formula (VII) is then oxidized to the product of general formula:
(vm)
AP/P/ 9 7/01149 in which R'lz R11! and G2 are defined as above.
The oxidation is generally carried out by means of ruthenium oxide (RuO4) , optionally generated in situ from a precursor such as RuO2 or RuCl3 in the presence of an oxidizing agent chosen from a periodate, such as sodium periodate, a hypochlorite, such as sodium hypochlorite or hypobromite, or a bromate, such as sodium bromate, or an organic tertiary amine oxide, such as N-methylmorpholine oxide or triethylamine oxide, the reaction being carried out in water or in a
AP 00973 homogeneous or heterogeneous aqueous/organic medium, such as a water/ethyl acetate mixture.
The oxidation can also be carried out by means of sodium hypochlorite alone (bleach) or by means of potassium permanganate or by means of sodium tungstate in the presence of an oxidizing agent, such as sodium hypochlorite, aqueous hydrogen peroxide solution or an alkyl hydroperoxide.
The product of general formula (VIII) can 10 also be obtained by oxidation of a product of general formula (VI) in which R represents a hydrogen atom under the conditions described above, followed by the protection of the nitrogen atom of the lactam obtained of general formula:
AP/P/ 9 7/01 149
ax) in which R'x and Rx are defined as above, by a protecting group as defined above.
The product of general formula (VIII) is a novel product which constitutes another subject of the present invention.
The product of general formula (VIII) can be converted into the product of general formula (V) under conditions appropriate to the nature of the Rz substituent which has to be introduced.
AP 00973
The product of general formula (V) in which R2 represents a carboxyl radical can be obtained by reaction of an inorganic base, such as sodium hydroxide, with the product of general formula (VIII), followed by replacement of the protecting group G2 by a hydrogen atom and optionally of the R'x and R! radicals by hydrogen atoms .
The product of general formula (V) in which R2 represents a carboxyl radical can be obtained by replacement of the protecting group G2 of the product of general formula (VIII) by a hydrogen atom, followed by reaction with an with an inorganic base, such as sodium hydroxide, and optionally by replacement of the R'x and R'1! radicals by hydrogen atoms.
The product of general formula (V) in which R2 represents an alkoxycarbonyl radical in which the alkyl part contains 1 to 4 carbon atoms can be obtained by ) reaction of an alkali metal alkoxide with the product
...) of general formula (VIII), followed by replacement of the protecting group G2 by a hydrogen atom and optionally of the R'x and Rx radicals by hydrogen atoms .
The product of general formula (V) in which R2 represents an alkoxycarbonyl radical in which the alkyl part contains 1 to 4 carbon atoms can be obtained by replacement of the protecting group G2 of the product of general formula (VIII) by a hydrogen atom, followed by reaction with an alkali metal alkoxide and optionally
AP/P/ 9 7/01149
AP 00973 by replacement of the R'x and Rx radicals by hydrogen atoms .
The product of general formula (V) in which R2 represents an N-alkylaminocarbonyl radical in which the alkyl part contains 1 to 4 carbon atoms can be obtained by reaction of an alkylamine with the product of general formula (VIII), followed [lacuna] replacement of the protecting group G2 by a hydrogen atom and optionally by replacement of the R'x and Rx radicals by hydrogen atoms.
The product of general formula (V) in which R2 represents an N-alkylaminocarbonyl radical in which the alkyl part contains 1 to 4 carbon atoms can be obtained by replacement of the protecting group G2 of the product of general formula (VIII) by a hydrogen atom, followed by reaction with an alkylamine and optionally by replacement of the R'x and Rx radicals by hydrogen ) atoms.
) The product of general formula (V) in which R2 represents a hydroxymethyl radical can be obtained by reaction of a reducing agent such as a borohydride, for example sodium or potassium borohydride, with the product of general formula (VIII), followed by replacement of the protecting group G2 by a hydrogen atom and optionally of the R'x and Rx radicals by hydrogen atoms .
The product of general formula (V) in which R2 represents a hydroxymethyl radical can be obtained by
AP/P/ 9 7/01 149
AP Ο Ο 9 7 3 replacement of the protecting group G2 of the product of general formula (VIII) by a hydrogen atom, followed by reaction with a reducing agent such as a borohydride, for example sodium or potassium borohydride, and by optional replacement of the R'x and R'y radicals by hydrogen atoms.
The product of general formula (V) can be used under the conditions described in United States Patent US 5,364,862 to produce therapeutically active )
products.
The following examples illustrate the present invention.
EXAMPLE 1
A solution of 20 g of a-S-methylbenzylamine 15 (165 mmol) in 60 cm3 of water, the pH of which is adjusted to 6.10 by addition of 17 cm3 of 36% (w/v) hydrochloric acid, is introduced, under an argon
)) atmosphere, into a 250 cm3 three-necked round-bottomed
Λ..Ζ
J flask equipped with a reflux condenser and a stirring system. After cooling to 5°C, 20 cm3 of a 37% (w/v) aqueous formaldehyde solution are added. The mixture is stirred for 5 minutes at 5°C and then 21.8 g of cyclopentadiene (330 mmol) are added. The mixture is stirred for 16 hours between -5 and 0°C. The aqueous phase is separated by settling and then washed with cm3 of pentane. Neutralization is carried out to pH =
8.0 by addition of concentrated sodium.hydroxide solution. Extraction is then carried out with 2 times
AP/P/ 9 7/01 149
AP 00973 cm3 of ethyl acetate. The aqueous phase is brought to pH = 11 by addition of concentrated sodium hydroxide solution and then extracted with 2 times 70 cm3 of ethyl acetate. The organic phases are combined, then washed with 2 times 50 cm3 of water and then dried over sodium sulphate. After filtering and concentrating to dryness under reduced pressure, 33.10 g of 2-(a-Smethylbenzyl) -2-azabicyclo [2,2., 1] hept-5-ene are obtained in the form of a slightly yellow oil.
)
- 10 12 g of N-methylmorpholine oxide, in 32 cm3 of water, and then, slowly, 6.3 cm3 of a 2.5% (w/v) solution of osmium tetroxide (OsO4) in tert-butanol are added, at a temperature in the region of 25°C, to a 500 cm3 three-necked round-bottomed flask equipped with a reflux condenser and a stirring system and containing a solution of 20 g of 2-(α-S-methylbenzyl)-2azabicyclo[2,2,1]hept-5-ene (75.34 mmol) in 220 cm3 of 'j) tert-butanol. The mixture is stirred for 2 hours at a ) temperature in the region of 20°C and then for 3 hours at 65°C. After evaporation of the tert-butanol under reduced pressure, the residue is taken up in 350 cm3 of isopropanol. After concentrating to dryness under reduced pressure, 24 g of cis-5,6-dihydroxy-2-(a-Smethylbenzyl)-2-azabicyclo[2,2,1]heptane are obtained in the form of an oil. By crystallization from cyclohexane, 14 g of 5R,6S-dihydroxy-2-(a-Smethylbenzyl)-2-azabicyclo[2,2,1]heptane are obtained with an isomeric purity of greater than 95%.
AP/P/ 9 7/01 149
AP 00973
The N.M.R. spectrum, determined in deuterated chloroform, shows the following chemical shifts (δ):
1.21 (3H, d), 1.38 (IH, d) , 1.59 (IH, d) , 2.22 <2H, m) , 2.45 (IH, dd), 2.95 (IH, s), 3.39 (IH, q), 3.78 (IH,
d), 3.90 (IH, d), 7.28 (5H, m).
EXAMPLE 2
31.7 g of 2,2-dimethoxypropane (304 mmol) and then, slowly, 13 g of trifluoroacetic acid (114 mmol) are added to a 500 cm3 three-necked round-bottomed )
flask, equipped with a reflux condenser and a stirring system, containing a solution of 18.4 g of 5R,6Sdihydroxy-2-(α-S-methylbenzyl)-2azabicyclo[2,2,1]heptane (76 mmol) in 130 cm3 of toluene. The mixture is heated for 4 hours 10 minutes at 65°C. After cooling to 30°C and concentrating on a rotary evaporator in order to remove the toluene, the excess 2,2-dimethoxypropane and some of the
1) trifluoroacetic acid, the reaction mixture is taken up j
) in dichloromethane and is then neutralized by addition of 100 cm3 of 2N sodium hydroxide solution. After separating by settling, drying the organic phase over sodium sulphate, filtering, treating with decolouring charcoal (30 g) for 30 minutes at reflux of the dichloromethane, filtering through clarcel and concentrating to dryness under reduced pressure, 18.8 g of 5R,'6S-isopropylidenedioxy-2- (α-S-methylbenzyl) -2azabicyclo[2,2,1]heptane are obtained, the structure of which is confirmed by the proton N.M.R. spectrum which,
AP/P/ 9 7/01 149
AP 00973 determined in deuterated chloroform, shows the following chemical shifts (δ): 1.22 (3H, d), 1.23 (6H, s), 1.31 (IH, d), 1.57 (IH, d), 2.08 (IH, d), 2.34 (IH, broad s), 2.45 (IH, dd), 3.06 (IH, s), 3.40 (IH, q),
4.09 (IH, d), 4.19 (IH, d), 7.26 (5H, m).
0.5 g of 5% by weight palladium-on-charcoal, g of 5R,6S-isopropylidenedioxy-2-(α-S-methylbenzyl)2-azabicyclo[2,2,1]heptane, 3.98 g of ditert-butyl dicarbonate and 36 cm3 of methanol are introduced into a
250 cm3 three-necked round-bottomed flask equipped with a stirring system. The apparatus is purged with argon and then with hydrogen and is then placed under a hydrogen atmosphere at 25°C. The reaction is continued for 5 hours, a purge with hydrogen being carried out every quarter of an hour in order to remove the carbon dioxide gas formed.
After filtering through clarcel and y concentrating to dryness under reduced pressure, 4.84 g z
) of 5R,6S-isopropylidenedioxy-2-(tert-butoxycarbonyl)-220 azabicyclo[2,2,1]heptane are obtained, the structure of which is confirmed by the N.M.R. spectrum which, determined in d6-dimethyl sulphoxide, shows the following chemical shifts (δ): 1.16 (s, 3H), 1.28 (s,
3H), 1.32 (s, IH), 1.34 (s, 3H), 1.65 (d, IH), 2.38 (m,
IH), 2.65 (d, IH), 2.99 (m, IH), 3.84 (m, IH), 3.94 (d, IH), 4.16 (d, IH).
270 mg of 5R,6S-isopropylidenedioxy-2-(tertbutoxycarbonyl) -2-azabicyclo [2 , 2 , 1] heptane (1 mmol) and
AP/P/ 9 7/01 149
AP 00973
0 mg of RuO2-H2O (0.3 equivalent) are introduced into a 3 0 cm3 tube. 10 cm3 of ethyl acetate and 720 mg of water (40 equivalents) are added. 2.14 g of sodium periodate (10 equivalents) are then added and the tube is hermetically sealed. The tube is agitated for 16 hours at 50°C. The reaction mixture is filtered through clarcel and then extraction is carried out with 2 times 20 cm3 of ethyl acetate. The organic phases are dried over sodium sulphate. After filtering and concentrating to dryness under reduced pressure, 245 mg of a solid are obtained, which solid contains 68% of 5R,6Sisopropylidenedioxy-2-(tert-butoxycarbonyl)-2azabicyclo[2,2,1]heptane-3-one and 32% of starting material. The structure of the product obtained is confirmed by the N.M.R. spectrum which, determined in d6 dimethyl sulphoxide, shows the following chemical shifts (δ): 1.38 (9H, s), 1.23 (3H, s), 1.33 (3H, s),
Λ 1.85 (1H, d), 1.93 (1H, d), 2.69 (1H, s) , 4.24 (1H, s) , j 4.41 (1H, d), 4.51 (1H, d).
EXAMPLE 3
1.47 g of 5R,6S-isopropylidenedioxy-2(tert-butoxycarbonyl)-2-azabicyclo[2,2,1]heptane-3-one, in solution in 10 cm3 of anhydrous toluene, and then approximately 0.7 cm3 of ethylamine are introduced into a 25 cm3 autoclave equipped with magnetic stirring. The autoclave is closed and is heated at a temperature of between 90 and 100°C for 21 hours. After cooling, the toluene is evaporated and the residue is taken up in
AP/P/ 9 7/01 149 .9
ΑΡ 00973 cm3 of dichloromethane and 10 cm3 of water. After separating by settling, the organic phase is washed with 10 cm3 of water. The combined aqueous layers are washed with 10 cm3 of dichloromethane. The combined organic phases are washed with 10 cm3 of a saturated sodium chloride solution and then dried over sodium sulphate. After filtering and concentrating to dryness under reduced pressure, 1.58 g of a product are obtained, which product contains 95% of 2R,3S10 isopropylidenedioxy-4-R-tert-butoxycarbonylamino-l-δε thylaminocarbonylcyclopentane, the structure of which is confirmed by the N.M.R. spectrum which, determined in d6 dimethyl sulphoxide, shows the following chemical shifts: 0.95 (t, 3H), 1.14 (s, 3H), 1.31 (s, 12H), 1.55 (m, 1H), 2.11 (m, 1H), 2.64 (m, 1H), 3.00 (qi, 2H),
3.77 (m, 1H), 4.23 (m, 1H), 4.54 (m, 1H), 7.07 (d, 1H), 8.12 (t, 1H).
1.22 g of 2R,3S-isopropylidenedioxy-4Rtert-butoxycarbonylamino-1S20 ethylaminocarbonylcyclopentane and 10 cm3 of dichloromethane are introduced into a 25 cm3 roundbottomed flask. 0.85 g of trifluoroacetic acid is added, with magnetic stirring, at a temperature in the region of 25°C. After stirring for 6 hours and concentrating to dryness, 1.16 g of 2R,3Sisopropylidenedioxy-4R-amino-ISethylaminocarbonylcyclopentane trifluoroacetate are obtained, the structure of which is confirmed by the
AP/P/ 9 7/01 149
AP 00973
N. M.R. spectrum which, determined in d6 dimethyl sulphoxide, shows the following chemical shifts: 0.79 (t, 3H), 1.03 (S, 3H), 1.19 (s, 3H), 1.42 (m, 1H), 2.05 (m, 1H), 2.52 (m, 1H), 2.89 (qi, 2H), 3.04 (m, 1H),
4.16 (m, 1H).
EXAMPLE 4
A solution of 0.5 mmol of a mixture (78/22 in moles) of 5R,6S-dihydroxy-2-(α-S-methylbenzyl)-2azabicyclo[2,2,1]heptane and of 5S,6R-dihydroxy-2-(a-S) methylbenzyl)-2-azabicyclo[2,2,1]heptane and of
O. 5 mmol of L-dimethoxysuccinic acid in 1 cm3 of isopropanol is stirred for 24 hours at a temperature varying from 25°C at the start to 5°C. The crystals obtained are separated by filtration and dried. 110 mg of 5R,6S-dihydroxy-2-(a-S-methylbenzyl)-2azabicyclo[2,2,1]heptane are thus obtained with an enantiomeric excess of 97%.
) The mixture (78/22 in moles) of 5R,6S) dihydroxy-2- (or-S-methylbenzyl) -220 azabicyclo[2,2,1]heptane and of 5S,6R-dihydroxy-2-(a-Smethylbenzyl)-2-azabicyclo[2, 2,1]heptane can be obtained in the following way:
4.12 g of N-methylmorpholine oxide in 11 cm3 of water, and then, slowly, 360 μΐ of a 2.5% (w/v) solution of osmium tetroxide (OsO4) in tert-butanol are added, at a temperature in the region of 25°C, to a
250 cm3 three-necked round-bottomed flask, equipped with a reflux condenser and a stirring system, containing a
AP/P/ 9 7/01 149
AP 00973 solution of 7 g of 2-(α-S-methylbenzyl)-2azabicyclo[2,2,1]hept-5-ene (35 mmol) in 70 cm3 of tertbutanol. The mixture is stirred for 1 hour at a temperature in. the region of 20°C and then for 4 hours at 65°C. After evaporating the tert-butanol under reduced pressure, the residue is taken up in 150 cm3 of isopropanol. After concentrating to dryness under reduced pressure, 8.27 g of of a product are obtained, the proton N.M.R. spectrum of which shows that it is )
composed of a mixture (78/22 in moles) of 5R,6Sdihydroxy-2- (a-S-methylbenzyl) -2azabicyclo[2,2,1]heptane and of 5S,6R-dihydroxy-2-(a-Smethylbenzyl)-2-azabicyclo[2,2,1]heptane.
EXAMPLE 5
568 mg of 5R,6S-isopropylidenedioxy-2-(tertbutoxycarbonyl) -2-azabicyclo[2,2,1] heptane-3-one and 10 cm3 of a 70% (by weight) aqueous ethylamine solution
Λ are introduced into a Berghoff tube. The tube is ) heated for 4 hours at 60°C with agitation. After cooling, the excess triethylamine and the water are removed under reduced pressure. After drying under reduced pressure, 650 mg of 2R,3S-isopropylidenedioxy4-R-tert-butoxycarbonylamino-l-Sethylaminocarbonylcyclopentane are thus obtained with a yield of 98%, the structure of which is confirmed by the proton N.M.R. spectrum and the optical rotation of which is [a] d° = 15.0 (c = 1, methanol).
AP/P/ 9 7/01149
275 μΐ of trifluoroacetic acid are added to a
AP 00973 solution of 200 mg of 2R,3S-isopropylidenedioxy-4-Rtert-butoxycarbonylamino-1 - S ethylaminocarbonylcyclopentane in 1.6 cm3 of anhydrous dichioromethane. The mixture is stirred overnight at a temperature in the region of -5°C. The reaction mixture is poured into 4 cm3 of 2.5N aqueous sodium hydroxide solution. The organic layer is concentrated under reduced pressure at a temperature of less than 25°C.
125 mg of a product are thus obtained, which product is dissolved in 0.5 cm3 of tetrahydro furan. 70 mg of benzoic acid are added to this solution. After cooling the solution obtained to a temperature in the region of 0°C, the crystals obtained are separated by filtration and washed with pentane. 138 mg of 2R,3S15 is opropy1idenedioxy-4 R-amino-1S ethylaminocarbonylcyclopentane benzoate are thus obtained.
EXAMPLE 6
J) 90 μΐ of trifluoroacetic acid are added to a solution of 167 mg of5R,6S-isopropylidenedioxy-2{tert-butoxycarbonyl)-2-azabicyclo[2,2,1]heptane-3-one in 1 cm3 of dichioromethane cooled to 0°C. The temperature is allowed to return to 23°C over 40 minutes and then the mixture is stirred for 22 hours at this temperature. 90 μΐ of trifluoroacetic acid are again added and then the mixture is stirred for a further 1 hour at a temperature of 23°C. After evaporating under reduced pressure, 123 mg of 5R,6SAP/P/ 9 7/01 149
AP 00973 isopropylidenedioxy-2-azabicyclo[2,2,1]heptane-3-one are obtained, the purity of which, determined by high performance liquid chromatography, is in the region of 92% and the structure of which is confirmed by the proton N.M.R. spectrum.
A solution of 10 g of 5R,6Sisopropylidenedioxy-2-azabicyclo[2,2,1]heptane-3-one in 100 cm3 of a 70% (by weight) aqueous triethylamine solution is heated at 110°C for 20 hours under )
autogenous pressure. After cooling, the excess triethylamine is removed under reduced pressure and then washing is carried out with dichloromethane in order to remove the unreacted starting material. The aqueous layer is then concentrated and dried. 10.54 g of 2R,3S-isopropylidenedioxy-4R-amino-lS-ethyl5aminocarbonylcyclopentane are thus obtained.
Claims (18)
1. ' IR 2-azabicyclo[2.2.1]heptane derivatives of general formula (I):
in which R represents a hydrogen atom or a radical of formula-.
R, ^Ar 01) in which Rx represents an alkyl radical containing 1 to 4 carbon atoms and Ar represents a phenyl or a- or β-naphthyl radical optionally substituted by one or more identical or different atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, the alkoxy radical containing 1 to 4 carbon atoms or the nitro radical.
2. 2-azabicyclo[2.2.1]heptane derivatives according to claim 1 for which Rx represents a methyl or ethyl radical and Ar represents a phenyl radical optionally substituted by one or more methyl or methoxy radicals.
3. 2-azabicyclo[2.2.1]heptane derivatives according to claim 1 for which Rx represents a methyl radical and Ar represents a phenyl radical.
ΑΡ/Γ7 9 7/01 14 9
AP 00973
4. Process for the preparation of a product according to one of claims 1, 2 or 3 for which R represents a radical of general formula (II) characterized in that a bi'shydroxylation is carried out
5 on a product of general formula:
;;
in which Rx and Ar are defined as in one of claims 1, 2 or 3.
5. Process according to claim 4,
10 characterized in that the bishydroxylation is carried out by means of potassium permanganate or of osmium tetroxide, the reaction being carried out in the presence of N-methylmorpholine oxide or of triethylamine oxide or of potassium ferricyanide
15 (K3FeCNs) .
6. Process for the preparation of a product according to claim 1 for which R represents a hydrogen atom, characterized in that a product according to one of claims 1, 2 or 3 is treated with hydrogen in the
20 presence of a catalyst such as palladium on a support, the reaction being carried out in an organic solvent chosen from aliphatic alcohols containing 1 to 3 carbon atoms .
7. Process for the preparation of a product
API?! 9 7/01 149
ΑΡ 00973
for which the R symbols 5 represent a radical of general formula (II), characterised in that the
I ' diastereoselective crystallization of the product of general formula (I.) for which ,R represents a radical of general formula (II) is carried out with an optically
10 active acid, such as L-dimethoxysuccinic acid, the crystallization being carried out in an organic solvent chosen from aliphatic alcohols containing 1 to 3 carbon atoms .
8. Process for the preparation of a product
15 of general formula:
O
ΑΡ/Γ/ 97/01149
AP 00973
-25ain which R\ and R'^, which are identical or different, represent an aliphatic organic acid residue containing 2 to 4 carbon atoms, such as an acetyl or propionyl radical, or an aromatic acid residue, such as a benzoyl residue, or else R'x and R’1! together form a methylene radical, the carbon atom of which is optionally
AF* 0 0 9 7 3 substituted by one or more identical or different radicals chosen from alkyl radicals containing 1 to 4 carbon atoms, which can together form an alicyclic radical containing 5 or 6 carbon atoms, or phenyl
5 radicals, and G2 represents a protecting group for an amino radical, characterized in that:
a) the hydroxyl functional groups of a product according to one of claims 1, 2 or 3 are protected
10 under the usual esterification or acetalization conditions in order to obtain a product of general formula:
in which R'i and R’1! are defined as above and R is defined as in one of claims 1, 2 or 3, /
) 15 b) the product of general formula (VI) is converted into the product of general formula:
AP/P/ 97 / 0 1 149 in which R'x and R11! are defined as above and G2 represents a protecting group for the nitrogen atom, by either
20 i) hydrogenolysis of a product of general
AP 00973 formula (VI) in which R represents a radical of general formula (II) and reaction with a reagent which allows a protecting group for the nitrogen atom to be introduced, it being possible for the hydrogenolysis 5 and the protection of the nitrogen atom to be carried out simultaneously, or else ii) reaction of a product of general formula (VI) in which R represents a hydrogen atom with a reagent which allows a protecting group for the
10 nitrogen atom to be introduced, then
c) the product of general formula (VII) is oxidized to the product of general formula (VIII).
9. Process according to claim 8, characterized in that the protection of the hydroxyl
15 functional groups of a product according to one of claims 1, 2 or 3 is carried out by means of an aliphatic acid containing 2 to 4 carbon atoms or of an aldehyde or of a ketone, optionally in acetal form, in the presence of an acid in an inert organic solvent at
20 a temperature between 50°C and the reflux temperature of the reaction mixture.
10. Process according to claim 8, characterized in that hydrogenolysis is carried out by means of hydrogen in the presence of a catalyst such as
25 palladium-on-charcoal and the protection of the nitrogen atom is carried out under the usual conditions for protection, depending on the nature of the protecting group.
AP/P/ 9 7/01 149
AP 00973
11. Process according to claim 8, characterized in that, when G2 represents a tertbutoxycarbonyl radical, the simultaneous hydrogenolysis and protection are carried out by simultaneously
5 reacting hydrogen in the presence of a catalyst, such as palladium-on-charcoal, and di-tert-butyl dicarbonate in an aliphatic alcohol containing 1 to 3 carbon atoms at a temperature of between 0 and 50°C.
12. Process according to claim 8,
10 characterized in that the oxidation of the product of general formula (VII) is carried out by means of ruthenium oxide (RuO4) , optionally generated in situ in the presence of an oxidizing agent.
13. Process for the preparation of a product
15 of general formula:
(VIII)
AP/P/ 9 7/01149 in which R'x and Rx and G2 are defined as in claim 8, characterized in that a product of general formula:
N-R (VI) in which R'x and Rx are defined as in claim 8 and R
AP 00973 represents a hydrogen atom, is oxidized under the conditions of claim 11 and then the nitrogen atom of the lactam obtained is protected under the conditions of claim 10.
14. A product of general formula:
(VUI) in which R'x and Rx, which are identical or different, represent an aliphatic organic acid residue containing 2 to 4 carbon atoms, such as an acetyl or propionyl radical, or an aromatic acid residue, such as a benzoyl
10 residue, or else R'-l and R'1! together form a methylene radical, the carbon atom of which is optionally substituted by one or more identical or different radicals chosen from alkyl radicals containing 1 to 4 carbon atoms, which can together form an alicyclic
15 radical containing 5 or 6 carbon atoms, or phenyl radicals, and G2 represents a protecting group for an amino radical.
15. A product of general formula:
(VI)
AP/P/ 9 7/01149 in which R represents a hydrogen atom or a radical of general formula (II) as defined in one of claims 1, 2 or 3 and R'x and Rx, which are identical or different, represent an aliphatic organic acid residue containing 2 to 4 carbon atoms, such as an acetyl or propionyl radical, or an aromatic acid residue, such as a benzoyl residue, or else R'x and Rx together form a methylene radical, the carbon atom of which is optionally substituted by one or more identical or different radicals chosen from alkyl radicals containing 1 to 4 carbon atoms, which can together form an alicyclic radical containing 5 or 6 carbon atoms, or phenyl radicals.
16. A product of general formula:
N-G, (VII) in which R'x and Rx, which are identical or different,
15 represent an aliphatic organic acid residue containing 2 to 4 carbon atoms, such as an acetyl or propionyl radical, or an aromatic acid residue, such as a benzoyl residue, or else R'x and Rx together form a methylene radical, the carbon atom of which is optionally
20 substituted by one or more identical or different radicals chosen from alkyl radicals containing 1 to 4 carbon atoms, which can together form an alicyclic radical containing 5 or 6 carbon atoms, or phenyl radicals, and G2 represents a protecting group for the
AP/P/ 9 7/01 149
AP 00973 amino functional group.
17. Process for the preparation of a product of general formula:
R.
NH-G (V)
R-0
0-R'
..)
..)
..)
..) in which R2 represents a carboxyl radical, an alkoxycarbonyl radical in which the alkyl part contains 1 to 4 carbon atoms, an N-alkylaminocarbonyl radical in which the alkyl part contains 1 to 4 carbon atoms, or a hydroxymethyl or alkoxymethyl radical, and R' and R, which are identical or different, represent a hydrogen atom or an aliphatic organic acid residue containing 2 to 4 carbon atoms, such as an acetyl or propionyl radical, or an aromatic acid residue, such as a benzoyl residue, or else R' and R together form a methylene radical, the carbon atom of which is optionally substituted by one or more identical or different radicals chosen from alkyl radicals containing 1 to 4 carbon atoms, which can together form an alicyclic radical containing 5 or 6 carbon atoms, or phenyl radicals, and Gx represents a hydrogen atom or a protecting group G2 for the amino functional group, characterized in that, depending on the nature of the R2 radical which it is desired to obtain, an inorganic base, an alkali metal alkoxide, an alkylamine or an alkali metal borohydride is reacted with a product of
AP/P/ 9 7/01 149
AP 00973 general formula :
(vm) in which R'x, Rx and G2 are defined as above, and then optionally the R'x and R x radicals and the protecting group G2 are replaced by hydrogen atoms.
18. Process for the preparation of a product of general formula:
R.
NH-G (V)
R-0
O-R·
3 10
3 10 in which R2 represents a carboxyl radical, an alkoxycarbonyl radical in which the alkyl part contains 1 to 4 carbon atoms, an N-alkylaminocarbonyl radical in which the alkyl part contains 1 to 4 carbon atoms, or a hydroxymethyl or alkoxymethyl radical, and R' and R, which are identical or different, represent a hydrogen atom or an aliphatic organic acid residue containing 2 to 4 carbon atoms, such as an acetyl or propionyl radical, or an aromatic acid residue, such as a benzoyl residue, or else R' and R together form a methylene radical, the carbon atom of which is optionally substituted by one or more identical or different radicals chosen from alkyl radicals containing 1 to
APiP! 97/01 149
AP 00973
4 carbon atoms, which can together form an alicyclic radical containing 5 or 6 carbon atoms, or phenyl radicals, and Gx represents a hydrogen atom or a protecting group G2 for the amino functional group,
5 characterized in that the protecting group G2 of a product of general formula:
in which R'x, Rx and G2 are defined as above, is replaced by a hydrogen atom, the product obtained is then reacted, depending on the nature of the R2 radical
10 which it is desired to obtain, with an inorganic base, an alkali metal alkoxide, an alkylamine or an alkali metal borohydride, and then the R'x and Rx radicals are optionally replaced by hydrogen atoms.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9506353A FR2734822B1 (en) | 1995-05-30 | 1995-05-30 | NEW 2-AZABICYCLO (2.2.1) HEPTANE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION |
PCT/FR1996/000793 WO1996038447A1 (en) | 1995-05-30 | 1996-05-28 | 2-azabicyclo[2.2.1]heptane derivatives, preparation and application thereof |
Publications (2)
Publication Number | Publication Date |
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AP9701149A0 AP9701149A0 (en) | 1998-01-31 |
AP973A true AP973A (en) | 2001-06-08 |
Family
ID=9479463
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Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
APAP/P/1997/001149A AP973A (en) | 1995-05-30 | 1996-05-28 | 2-Azabicyclo {2.2.1} heptane derivatives preparation and application thereof. |
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KR (1) | KR100488393B1 (en) |
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AP (1) | AP973A (en) |
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US4954504A (en) * | 1986-11-14 | 1990-09-04 | Ciba-Geigy Corporation | N9 -cyclopentyl-substituted adenine derivatives having adenosine-2 receptor stimulating activity |
US5063233A (en) * | 1986-11-14 | 1991-11-05 | Ciba-Geigy Corporation | N9 -cyclopentyl-substituted adenine derivatives useful as adenosine receptor agonists |
US4803272A (en) * | 1987-02-24 | 1989-02-07 | E. I. Du Pont De Nemours And Company | S-modified adenosyl-1,8-diamino-3-thiooctane derivatives |
US5561134A (en) * | 1990-09-25 | 1996-10-01 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Compounds having antihypertensive, cardioprotective, anti-ischemic and antilipolytic properties |
GB9301000D0 (en) * | 1993-01-20 | 1993-03-10 | Glaxo Group Ltd | Chemical compounds |
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Non-Patent Citations (2)
Title |
---|
CHEM. PHARM. BULL. 1991, 39 (5), 1112-1122 * |
TETRAHEDRON LETT. 1989, 30 (13), 1645-1648 * |
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