CA1054593A - Bufatrienolide rhamnoside ethers and a process for their preparation - Google Patents
Bufatrienolide rhamnoside ethers and a process for their preparationInfo
- Publication number
- CA1054593A CA1054593A CA000228894A CA228894A CA1054593A CA 1054593 A CA1054593 A CA 1054593A CA 000228894 A CA000228894 A CA 000228894A CA 228894 A CA228894 A CA 228894A CA 1054593 A CA1054593 A CA 1054593A
- Authority
- CA
- Canada
- Prior art keywords
- proscillaridin
- process according
- methylether
- prepared
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000000034 method Methods 0.000 title claims description 30
- -1 rhamnoside ethers Chemical class 0.000 title description 5
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 title description 3
- MYEJFUXQJGHEQK-ALRJYLEOSA-N Proscillaridin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C=C2CC[C@H]3[C@@]4(O)CC[C@H](C5=COC(=O)C=C5)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1 MYEJFUXQJGHEQK-ALRJYLEOSA-N 0.000 claims abstract description 34
- 229930190098 proscillaridin Natural products 0.000 claims abstract description 34
- 229960003584 proscillaridin Drugs 0.000 claims abstract description 34
- MYEJFUXQJGHEQK-UHFFFAOYSA-N proscillaridin A Natural products OC1C(O)C(O)C(C)OC1OC1C=C2CCC3C4(O)CCC(C5=COC(=O)C=C5)C4(C)CCC3C2(C)CC1 MYEJFUXQJGHEQK-UHFFFAOYSA-N 0.000 claims abstract description 34
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical group COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 7
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 7
- 239000012312 sodium hydride Substances 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 230000001035 methylating effect Effects 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- CWLNAJYDRSIKJS-UHFFFAOYSA-N triethoxymethoxyethane Chemical compound CCOC(OCC)(OCC)OCC CWLNAJYDRSIKJS-UHFFFAOYSA-N 0.000 claims description 2
- 230000011987 methylation Effects 0.000 claims 5
- 238000007069 methylation reaction Methods 0.000 claims 5
- 239000000126 substance Substances 0.000 claims 4
- 239000001257 hydrogen Substances 0.000 claims 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 239000002904 solvent Substances 0.000 claims 2
- AHJWSRRHTXRLAQ-UHFFFAOYSA-N tetramethoxymethane Chemical compound COC(OC)(OC)OC AHJWSRRHTXRLAQ-UHFFFAOYSA-N 0.000 claims 2
- 230000003197 catalytic effect Effects 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 239000000376 reactant Substances 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- 206010019280 Heart failures Diseases 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- RLAHWVDQYNDAGG-UHFFFAOYSA-N Methanetriol Chemical compound OC(O)O RLAHWVDQYNDAGG-UHFFFAOYSA-N 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
- RKWPZPDLTYBKCL-RVZGXXANSA-N meproscillarin Chemical compound O[C@@H]1[C@H](O)[C@@H](OC)[C@H](C)O[C@H]1O[C@@H]1C=C2CC[C@H]3[C@@]4(O)CC[C@H](C5=COC(=O)C=C5)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1 RKWPZPDLTYBKCL-RVZGXXANSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- RXCVUXLCNLVYIA-UHFFFAOYSA-N orthocarbonic acid Chemical compound OC(O)(O)O RXCVUXLCNLVYIA-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J19/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 by a lactone ring
- C07J19/005—Glycosides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Cardiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Heart & Thoracic Surgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
A B S T R A C T
Proscillaridin-2',3'-orthoester-4'-methylether or proscillaridin 2',3'-orthocarbonate-4'-methylether derivatives of formula I
I
in which R1 represents an alkyl group containing from 1 to 4 carbon atoms and R2 represents a hydrogen atom, or an alkoxy group containing from 1 to 4 carbon atoms. These compounds find application in the treatment of cardiac insufficiency.
Proscillaridin-2',3'-orthoester-4'-methylether or proscillaridin 2',3'-orthocarbonate-4'-methylether derivatives of formula I
I
in which R1 represents an alkyl group containing from 1 to 4 carbon atoms and R2 represents a hydrogen atom, or an alkoxy group containing from 1 to 4 carbon atoms. These compounds find application in the treatment of cardiac insufficiency.
Description
-` 1054593 The present invention relates to bufatrienolide rhamnoside ethers and to a process for their preparation.
Proscillaridin 4'-methylether is ~nown, and, has good pharmacologi-cal properties which make it very suitable for the treatment of cardiac in-sufficiency. However, known processes for preparing this compound produce comparatively low yields. Thus, it is known that proscillaridin can be methy-lated and from the mixture of ethers thus obtained, a small yield of the 4'-methylether is isolated. Alternatively, proscillaridin can be converted into its 2',3'-acetonide, which can then be methylated. The isopropylidene residue is then separated. The yield obtained by using this process is about 25 %.
; It has now been found that certain bufatrienolide rhamnoside ethers can be produced more readily and in greater yields. Moreover, on ~; account of their enteral resorption characteristics, they are very suitable for the treatment of cardiac diseases.
According to the present invention, there is provided compounds of the general formula I
o~3 ' ¦ I
~/; )H
CH30 0 / ~J
X
in which Rl represents an alkyl group containing from 1 to 4 carbon atoms and R2 represents a hydrogen atom or an alkoxy group containing from 1 to 4 carbon atoms.
According to the present invention there is also provided a `:
: ' 1054593 `: :
process for the production of a proscillaridin-2',3'-orthoester-4'- :
methylether or proscillaridin-2',3'-orthocarbonate-4'-methylether, conform- ~ :
ing to the general formula O~
CH30 o ~Y ~
' O O ~ ' in which Rl represents an ethyl group containing from 1 to 4 carbon atoms and R2 represents a hydrogen atom or an alkoxy group containing from 1 to 4 carbon atoms, which comprises methylating a corresponding 4'-hydroxy com-pound of the formula:-O
0~
~ II
~\ /~/~ ''- ' l ¦ OH -: :~
OH O ~ ~ . . . .
1~
.
\~/
'. : :
O ,:
.
lOS4593 in whLch Rl and R2 are as previously defined.
The starting of formula II is itself prepared by the reacting proscillaridin with a compound of the formula: CR10)3 CR2J wherein Rl and R2 have the same significance as stated above.
The reaction of proscillaridin with (R10)3 CR2 is effected in a suitable polar aprotic organic solvent, such as dioxan, tetrahydrofuran, ethylene glycol dimethylether or diethylene glycol dimethylether, with a tri--- alkylorthoester~ which is preferably trimethyl or triethyl orthoformate ~
~ i orthoa~ or with a tetraalkyl orthocarbonate, preferably tetramethyl or tetraethyl orthocarbonate, and traces of an inorganic or organic acid, such as, for example, hydrochloric acid or p-toluene-sulphonic acid. The crude product thus obtained, after conventional working up in an identical manner to that described in the literature for proscillaridin 2',3'-acetonide, is methylated in dimethylformamide utilising methyl iodide and an inorganic or organic base, preferably sodium hydride or barium hydroxide.
The invention will be further described, with reference to the ~-~
following non-limitative Examples.
Proscillaridin 2',3'-ethylorthoformate 4'-methylether.
To a solution of proscillaridin (5.3 g. 10 mMol) in an hydrous tetrahydrofuran ~25 ml) is added triethylorthoformate (5 ml) and p-toluene-sulphonic acid ~5 mg). The reaction mixture is stirred for 15 minutes at room temperature~ and is then treated with ethyl acetate (100 ml) and is shaken out with a saturated aqueous sodium bicarbonate solution ~30 ml). The organic phase is washed with water, dried over sodium sulphate and evaporated in vacuo. There is thus obtained 6.5 g of crude proscillaridin 2',3'-ethylortho-formate. The crude product is dissolved in dimethylformamide (50 ml), treated with methyl iodide (10 ml) and a substantially 55% suspension of sodium hydride in oil (4 g) and stirred for one hour at room temperature. Ethyl acetate is used for working-up the mixture, the organic phase then being repeatedly shaken out with water, dried over sodium sulphate and concentrated in vacuo. The residue is subjected to chromatography on kiesel gel using a 2 : 1 mixture of methylene chloride and ethyl acetate as eluant.
There is thus obtained 3.5 g of pure proscillaridin 2', 3'-ethyl-orthoformate 4'-methylether, which represents 58% of the theoretical yield.
The product, in amorphous form, has a melting point of 120 to 125C and an [alD of - 74. (c = 0.5 chloroform). The compound has an Rf-value of 0.37 (thin layer chromatography on kiesel gel completed plates 60 R254 made by the firm E. Merck, Darmstadt; the eluant being a 2 : 1 mixture of methylene chlor-; 10 ide and ethyl acetate chamber saturation, flow path lS cm). The compound has an empirical formula of C34H4809 and a molecular weight of 600.7.
Elementary Analysis Calculated C 67.98% H 8.05%
Found C 68.0% H 8.3 %
Example 2 :~, Proscillaridin 2',3'-methYlorthoformate 4'-methvlether. ~ -., ~
In a manner analogous to that described in Example 1, starting ! .`.
`~ from proscillaridin (1.0 g) and the methyl ester of orthoformic acid (1.0 ml), there is obtained 0.45 g. of pure proscillaridin 2',3i-methylorthoformate 4'-methylether (41 % of the theoretical yield). Melting point: 108 to 113C (in amorphous form) [~]20 : _ 78 (c = 0.5 chloroform) f-value : 0.32 (conditions as in Example 1) Empirical Formula: C33 Molecular Weight: 586.7 Elementary Analysis:
; Calculated C 67.55% H 7.90%
Found C 67.6 % H 8.1 %
- Example 3 Proscillaridin 2',3'-dimethylorthocarbonate 4'-methylether ;
In a manner analogous to that described in Example 1, by utilizing 1.0 g proscillaridin and 1.5 ml of the methyl ester of orthocarbonic acid, _ 4 _ ,.
, .
lOS4S93 0.41 g of pure proscillaridin 2',3'-dimethylorthocarbonate 4'-methylether (36% of the theoretical yield) is obtained. Rf-value 0.36 (conditions as in Example l)
Proscillaridin 4'-methylether is ~nown, and, has good pharmacologi-cal properties which make it very suitable for the treatment of cardiac in-sufficiency. However, known processes for preparing this compound produce comparatively low yields. Thus, it is known that proscillaridin can be methy-lated and from the mixture of ethers thus obtained, a small yield of the 4'-methylether is isolated. Alternatively, proscillaridin can be converted into its 2',3'-acetonide, which can then be methylated. The isopropylidene residue is then separated. The yield obtained by using this process is about 25 %.
; It has now been found that certain bufatrienolide rhamnoside ethers can be produced more readily and in greater yields. Moreover, on ~; account of their enteral resorption characteristics, they are very suitable for the treatment of cardiac diseases.
According to the present invention, there is provided compounds of the general formula I
o~3 ' ¦ I
~/; )H
CH30 0 / ~J
X
in which Rl represents an alkyl group containing from 1 to 4 carbon atoms and R2 represents a hydrogen atom or an alkoxy group containing from 1 to 4 carbon atoms.
According to the present invention there is also provided a `:
: ' 1054593 `: :
process for the production of a proscillaridin-2',3'-orthoester-4'- :
methylether or proscillaridin-2',3'-orthocarbonate-4'-methylether, conform- ~ :
ing to the general formula O~
CH30 o ~Y ~
' O O ~ ' in which Rl represents an ethyl group containing from 1 to 4 carbon atoms and R2 represents a hydrogen atom or an alkoxy group containing from 1 to 4 carbon atoms, which comprises methylating a corresponding 4'-hydroxy com-pound of the formula:-O
0~
~ II
~\ /~/~ ''- ' l ¦ OH -: :~
OH O ~ ~ . . . .
1~
.
\~/
'. : :
O ,:
.
lOS4593 in whLch Rl and R2 are as previously defined.
The starting of formula II is itself prepared by the reacting proscillaridin with a compound of the formula: CR10)3 CR2J wherein Rl and R2 have the same significance as stated above.
The reaction of proscillaridin with (R10)3 CR2 is effected in a suitable polar aprotic organic solvent, such as dioxan, tetrahydrofuran, ethylene glycol dimethylether or diethylene glycol dimethylether, with a tri--- alkylorthoester~ which is preferably trimethyl or triethyl orthoformate ~
~ i orthoa~ or with a tetraalkyl orthocarbonate, preferably tetramethyl or tetraethyl orthocarbonate, and traces of an inorganic or organic acid, such as, for example, hydrochloric acid or p-toluene-sulphonic acid. The crude product thus obtained, after conventional working up in an identical manner to that described in the literature for proscillaridin 2',3'-acetonide, is methylated in dimethylformamide utilising methyl iodide and an inorganic or organic base, preferably sodium hydride or barium hydroxide.
The invention will be further described, with reference to the ~-~
following non-limitative Examples.
Proscillaridin 2',3'-ethylorthoformate 4'-methylether.
To a solution of proscillaridin (5.3 g. 10 mMol) in an hydrous tetrahydrofuran ~25 ml) is added triethylorthoformate (5 ml) and p-toluene-sulphonic acid ~5 mg). The reaction mixture is stirred for 15 minutes at room temperature~ and is then treated with ethyl acetate (100 ml) and is shaken out with a saturated aqueous sodium bicarbonate solution ~30 ml). The organic phase is washed with water, dried over sodium sulphate and evaporated in vacuo. There is thus obtained 6.5 g of crude proscillaridin 2',3'-ethylortho-formate. The crude product is dissolved in dimethylformamide (50 ml), treated with methyl iodide (10 ml) and a substantially 55% suspension of sodium hydride in oil (4 g) and stirred for one hour at room temperature. Ethyl acetate is used for working-up the mixture, the organic phase then being repeatedly shaken out with water, dried over sodium sulphate and concentrated in vacuo. The residue is subjected to chromatography on kiesel gel using a 2 : 1 mixture of methylene chloride and ethyl acetate as eluant.
There is thus obtained 3.5 g of pure proscillaridin 2', 3'-ethyl-orthoformate 4'-methylether, which represents 58% of the theoretical yield.
The product, in amorphous form, has a melting point of 120 to 125C and an [alD of - 74. (c = 0.5 chloroform). The compound has an Rf-value of 0.37 (thin layer chromatography on kiesel gel completed plates 60 R254 made by the firm E. Merck, Darmstadt; the eluant being a 2 : 1 mixture of methylene chlor-; 10 ide and ethyl acetate chamber saturation, flow path lS cm). The compound has an empirical formula of C34H4809 and a molecular weight of 600.7.
Elementary Analysis Calculated C 67.98% H 8.05%
Found C 68.0% H 8.3 %
Example 2 :~, Proscillaridin 2',3'-methYlorthoformate 4'-methvlether. ~ -., ~
In a manner analogous to that described in Example 1, starting ! .`.
`~ from proscillaridin (1.0 g) and the methyl ester of orthoformic acid (1.0 ml), there is obtained 0.45 g. of pure proscillaridin 2',3i-methylorthoformate 4'-methylether (41 % of the theoretical yield). Melting point: 108 to 113C (in amorphous form) [~]20 : _ 78 (c = 0.5 chloroform) f-value : 0.32 (conditions as in Example 1) Empirical Formula: C33 Molecular Weight: 586.7 Elementary Analysis:
; Calculated C 67.55% H 7.90%
Found C 67.6 % H 8.1 %
- Example 3 Proscillaridin 2',3'-dimethylorthocarbonate 4'-methylether ;
In a manner analogous to that described in Example 1, by utilizing 1.0 g proscillaridin and 1.5 ml of the methyl ester of orthocarbonic acid, _ 4 _ ,.
, .
lOS4S93 0.41 g of pure proscillaridin 2',3'-dimethylorthocarbonate 4'-methylether (36% of the theoretical yield) is obtained. Rf-value 0.36 (conditions as in Example l)
Claims (25)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the production of a proscillaridin-2',3'-orthoester-4'-methylether or proscillaridin-2',3'-orthocarbonate-4'-methylether, conforming to the general formula:
I
in which R1 represents an alkyl group containing from 1 to 4 carbon atoms and R2 represents a hydrogen atom, or an alkoxy group containing from 1 to 4 carbon atoms, which comprises methylating a corresponding 4'-hydroxy com-pound of the formula:
II
in which R1 and R2 are as previously defined.
I
in which R1 represents an alkyl group containing from 1 to 4 carbon atoms and R2 represents a hydrogen atom, or an alkoxy group containing from 1 to 4 carbon atoms, which comprises methylating a corresponding 4'-hydroxy com-pound of the formula:
II
in which R1 and R2 are as previously defined.
2. Process according to claim 1 in which the starting material of formula II is prepared by reacting proscillaridin with a compound of the formula (R1O)3 CR2 wherein R1 and R2 are as defined in claim 1.
3. Process according to claim 1 for production of a proscillaridin-2',-3'-orthoester-4'-methylether or a proscillaridin-2',3'-orthocarbonate-4'-methylether conforming to the general formula I
I
wherein R1 represents an alkyl group containing one to four carbon atoms and R2 represents hydrogen, or an alkoxy group containing one to four carbon atoms, which comprises reacting proscillaridin with a compound of formula (R1O)3 CR2, in which R1 and R2 have the above meanings, and thereafter methylating the product in the 4'-position.
I
wherein R1 represents an alkyl group containing one to four carbon atoms and R2 represents hydrogen, or an alkoxy group containing one to four carbon atoms, which comprises reacting proscillaridin with a compound of formula (R1O)3 CR2, in which R1 and R2 have the above meanings, and thereafter methylating the product in the 4'-position.
4. Proscillaridin-2',3'-orthoester-4'-methylethers and proscillaridin-2',3'-orthocarbonate-4'-methylethers whenever prepared by the process of claim 1, 2 or 3 or by an obvious chemical equivalent thereof.
5. Process according to claim 1, 2 or 3 in which the methylation in the 4'-position is effected by reaction with methyl iodide in the presence of sodium hydride or barium hydroxide.
6. Process according to claim 1, 2 or 3 in which the methylation in the 4'-position is effected by reaction with methyl iodide in the presence of sodium hydride using dimethylformamide as solvent.
7. Process according to claim 2 in which the reaction of proscillari-din with a compound of the formula (R1O)3 CR2 is effected in a polar aprotic organic solvent and in the presence of catalytic amount of an inorganic or organic acid.
8. A process according to claim 7 in which the solvent is dioxan, tetrahydrofuran, ethylene glycol dimethylether or diethylene glycol dimethyl-ether.
9. A process according to claim 7 in which the inorganic or organic acid is hydrochloric or p-toluene-sulphonic acid.
10. A process according to claim 7, 8 or 9 in which the reactant of formula (R1O)3 CR2 is trimethyl orthoformate, triethyl orthoformate, tetramethyl orthocarbonate or tetraethyl orthocarbonate.
11. A process according to claim 1, 2 or 3 in which R1 is methyl and R2 is hydrogen.
12. A process according to claim 1 in which proscillaridin 2',3'-methyl-orthoformate 4'-methylether is prepared by methylating proscillaridin 2',3'-methylorthoformate.
13. A process according to claim 12 in which the methylation is effect-ed by reaction with methyl iodide in the presence of sodium hydride.
14. A process according to claim 12 in which the proscillaridin 2', 3'-methylorthoformate is prepared by reacting proscillaridin with trimethyl orthoformate.
15. Proscillaridin 2',3'-methylorthoformate 4'-methylether whenever prepared by the process of claim 12, 13 or 14 or by an obvious chemical equivalent thereof.
16. A process according to claim 1, 2 or 3 in which R1 is ethyl and R2 is hydrogen.
17. A process according to claim 1 in which proscillaridin 2',3'-ethylorthoformate 4'-methylether is prepared by methylating proscillaridin 2',3'-ethylorthoformate.
18. A process according to claim 17 in which the methylation is effected by reaction with methyl iodide in the presence of sodium hydride.
19. A process according to claim 17 in which the proscillaridin 2'-3'-ethylorthoformate is prepared by reacting proscillaridin with triethylortho-formate.
20. Proscillaridin 2',3'-ethylorthoformate 4'-methylether whenever prepared by the process of claim 17, 18 or 19 or by an obvious chemical equivalent thereof.
21. A process according to claim 1, 2 or 3 in which R1 is methyl and R2 is methoxy.
22. A process according to claim 1 in which proscillaridin 2',3'-dimethylorthocarbonate 4'-methylether is prepared by methylating proscill-aridin 2'-3'-dimethoxyorthocarbonate.
23. A process according to claim 22 in which the methylation is affected by reaction with methyl iodide in the presence of sodium hydride.
24. A process according to claim 22 in which the proscillaridin 2', 3'-dimethylorthocarbonate is prepared by reacting proscillaridin with tetramethyl orthocarbonate.
25. Proscillaridin 2',3'-dimethylorthocarbonate 4'-methylether, when-ever prepared by the process of claim 22, 23 or 24 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2427976A DE2427976C2 (en) | 1974-06-10 | 1974-06-10 | Proscillaridin ethers, processes for their preparation and pharmaceuticals containing them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1054593A true CA1054593A (en) | 1979-05-15 |
Family
ID=5917784
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000228894A Expired CA1054593A (en) | 1974-06-10 | 1975-06-09 | Bufatrienolide rhamnoside ethers and a process for their preparation |
Country Status (13)
| Country | Link |
|---|---|
| JP (1) | JPS518274A (en) |
| AT (1) | AT349160B (en) |
| BE (1) | BE829998A (en) |
| CA (1) | CA1054593A (en) |
| CH (1) | CH594701A5 (en) |
| DD (1) | DD120018A5 (en) |
| DE (1) | DE2427976C2 (en) |
| FI (1) | FI751725A (en) |
| FR (1) | FR2273549A1 (en) |
| GB (1) | GB1461051A (en) |
| NL (1) | NL7506825A (en) |
| SE (1) | SE7506571L (en) |
| ZA (1) | ZA753082B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5348332A (en) * | 1976-10-15 | 1978-05-01 | Hitachi Ltd | Remote supervisory control system for dam gate |
| JPS58142654U (en) * | 1982-03-23 | 1983-09-26 | 光武 量 | Magnetic water heating device that uses wind and water power |
| JPS58149719U (en) * | 1982-03-31 | 1983-10-07 | 日本ハ−ゼン株式会社 | Medical stereoscopic observation device |
| JPS60168434A (en) * | 1984-02-13 | 1985-08-31 | 佐藤 富男 | Apparatus for measuring heart cavity ratio |
| JPH067708U (en) * | 1992-06-30 | 1994-02-01 | トノクラ医科工業株式会社 | Cardiac / thoracic ratio measuring device |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1910207C3 (en) * | 1969-02-28 | 1978-04-13 | Knoll Ag, 6700 Ludwigshafen | Process for their manufacture |
| BE759830A (en) * | 1969-12-06 | 1971-06-03 | Hoechst Ag | DI-ALKYL-ORTHOCARBONATES OF HETEROSIDES IN 3 OF CARDENOLIDES AND BUFADIENOLIDES |
| DE2063406C3 (en) * | 1970-12-23 | 1978-05-03 | C.H. Boehringer Sohn, 6507 Ingelheim | Acyl derivatives of proscillaridin A, process for their preparation and preparations containing them |
| DE2217404C3 (en) * | 1972-04-11 | 1982-02-11 | Gödecke AG, 1000 Berlin | New cardiac cardenolide rhamnosides |
-
1974
- 1974-06-10 DE DE2427976A patent/DE2427976C2/en not_active Expired
-
1975
- 1975-04-24 GB GB1695275A patent/GB1461051A/en not_active Expired
- 1975-05-13 ZA ZA00753082A patent/ZA753082B/en unknown
- 1975-05-15 FR FR7515222A patent/FR2273549A1/en active Granted
- 1975-06-06 CH CH728275A patent/CH594701A5/xx not_active IP Right Cessation
- 1975-06-06 DD DD186504A patent/DD120018A5/xx unknown
- 1975-06-09 NL NL7506825A patent/NL7506825A/en not_active Application Discontinuation
- 1975-06-09 CA CA000228894A patent/CA1054593A/en not_active Expired
- 1975-06-09 SE SE7506571A patent/SE7506571L/en unknown
- 1975-06-09 AT AT436475A patent/AT349160B/en not_active IP Right Cessation
- 1975-06-09 BE BE157130A patent/BE829998A/en not_active IP Right Cessation
- 1975-06-10 FI FI751725A patent/FI751725A/fi not_active Application Discontinuation
- 1975-06-10 JP JP50070096A patent/JPS518274A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| NL7506825A (en) | 1975-12-12 |
| DE2427976C2 (en) | 1985-12-12 |
| FI751725A (en) | 1975-12-11 |
| JPS518274A (en) | 1976-01-23 |
| DD120018A5 (en) | 1976-05-20 |
| SE7506571L (en) | 1975-12-11 |
| CH594701A5 (en) | 1978-01-31 |
| BE829998A (en) | 1975-12-09 |
| FR2273549B1 (en) | 1979-07-06 |
| AT349160B (en) | 1979-03-26 |
| FR2273549A1 (en) | 1976-01-02 |
| DE2427976A1 (en) | 1976-01-02 |
| JPS61357B2 (en) | 1986-01-08 |
| ATA436475A (en) | 1978-08-15 |
| ZA753082B (en) | 1976-04-28 |
| GB1461051A (en) | 1977-01-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Debost et al. | Selective preparation of mono-and diacetals of d-mannitol | |
| CN107235967B (en) | The synthesis technology of anti-tumor drug Tegafur | |
| CA1054593A (en) | Bufatrienolide rhamnoside ethers and a process for their preparation | |
| CN115485268A (en) | Synthesis of vinyl protected alcohol intermediates | |
| US4613666A (en) | Neplanocin A derivatives | |
| NO752493L (en) | ||
| US4322412A (en) | Anthracycline glycosides, their preparation, use and compositions thereof | |
| CA1148945A (en) | Vindesine synthesis | |
| US3998999A (en) | Process for preparing pyrazomycin and pyrazomycin B | |
| CN108047179B (en) | Fullerene dihydrofuran compound and preparation method thereof | |
| US4528372A (en) | N-Phthalidyl-5-fluorouracils | |
| SU1251806A3 (en) | Method of producing 7-substituted 9a-methoxymitosane | |
| SU826957A3 (en) | Method of preparing 11-beta-oxy-18-methylsteroids of estrane series | |
| IE43088B1 (en) | Cardenolide glycosides and methods of making the same | |
| US5091411A (en) | Pseudo-primycin complexes, components and acid addition salts thereof as well as a process for the preparation of same | |
| US4908464A (en) | Process for the production of 1,3,2-oxazaphosphorinanes | |
| Lin et al. | Synthesis of Some Isocoumarin Derivatives | |
| RO108792B1 (en) | 8-fluoroantracyclinglicozide derivates, preparation process therefor and intermediary compounds | |
| KR100487992B1 (en) | Sulfur derivatives of 2'-Fluoro-5-methyl-β-L-arabinopuranosyluridine | |
| JPS5934194B2 (en) | Method for producing heterocyclic compounds | |
| SU388000A1 (en) | METHOD OF OBTAINING | |
| JPH0220638B2 (en) | ||
| CA1117103A (en) | Peruvoside derivative and method for producing same | |
| Noorzad et al. | Heterocyclic amino sugar derivatives: Part VII. Synthesis of 2-deoxy-2-methylamino-d-gulose and of its 4-methyl 4, 6-dimethyl ethers | |
| CA1057737A (en) | Proscillaridine derivatives and processes for the production thereof |