IE63595B1 - Method of preparing (+)-(2s, 3s)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5h-1, 5-benzothiazepine-4-one and chlorinated derivatives thereof - Google Patents
Method of preparing (+)-(2s, 3s)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5h-1, 5-benzothiazepine-4-one and chlorinated derivatives thereofInfo
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- IE63595B1 IE63595B1 IE225890A IE225890A IE63595B1 IE 63595 B1 IE63595 B1 IE 63595B1 IE 225890 A IE225890 A IE 225890A IE 225890 A IE225890 A IE 225890A IE 63595 B1 IE63595 B1 IE 63595B1
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- methoxyphenyl
- benzothiazepine
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- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Description
The subject of the present invention is a method for preparing ( + ) -(2S, 3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro5H-1,5-benzothiazepine-4-one, bearing optionally a chlorine atom on the aromatic ring.
These optically pure compounds are intermediates for the synthesis of compounds with therapeutic activities, such as (+)~ (2S,3S) -3~acetyloxy-5~(2-dimethylaminoethyl)-2-(4-methoxyphenyl) -2,3-dihydro~5H-l,5-benzothiazepine-4-one.
The reaction scheme is shown on the following page. In the formulae, X represents a hydrogen or chlorine atom.
The first step comprises reacting a 2-aminothiophenol of general formula (II) with methyl (“)~(2R,3S)~2,3-epoxy”3~(4methoxyphenyl)propionate of formula (III). A methyl (2S,3S)~
3-[(2-aminophenyl)thio]~2-hydroxy~3-(4-methoxyphenyl)propionate of general formula (IV) is obtained via opening the epoxide ring.
The second step comprises the cyclization of this compound in the presence of an acid.
The reaction principles of each of the two steps are well known.
They are found, for example, in Chem. Pharm. Bull., 18, 2028-2037 (1970), where the ester of formula (III) is used in racemic form. The first step necessitates several hours of heating to 15O-16O°C, and after separation and purification of the ester of formula IV, the second step is performed by hydrolyzing this ester and cyclizing the acid obtained in the presence of sulfuric or acetic acid, in refluxing xylene.
United States Patent 4,116,819 describes the first step, where the (racemic) ester of formula (III) reacts with the aminothiophenol (II) in toluene after six hours of heating at reflux.
Japanese Patent Application 145160/1986, which describes the synthesis of the optically pure ester of formula (III),
OCH3
Scheme
(II)
(III)
OCH,
likewise describes the reaction of the latter with an aminothiophenol of general formula (II), under toluene reflux for 10 hours.
Finally, European Patent Application 0154838 describes, among others, a method that combines the two steps. The reactions are performed without solvent, requiring 16 hours of heating to 160°C, and furnishing a mixture of optical isomers of the final compound and its intermediate.
Thus it is clear that none of the known methods is suitable for economic industrial manufacture of the compounds of general formula (I), for various reasons; poor yields, elevated temperatures, the need to purify- the intermediate and/or final compounds, and long reaction times.
The present invention therefore proposes a method that overcomes the disadvantages of the known art, and affords the following advantages:
- the two reaction steps can be performed in the one and same reactor, so that emptying and cleaning it between the two steps, or using a second reactor, is unnecessary (for reasons of convenience, the two steps can be performed in separate reactors, but anyway it is not necessary to isolate the intermediate ester, so that the operation consists of a mere transfer of the whole reaction mixture);
~ the total yield is high compared with the yields of the known methods;
- energy consumption is reduced, in particular during the first step;
- the reaction times are short; and
- the final compound is pure.
The physico-chemical conditions of the method according to the invention, which make it possible to attain all the advantages listed above, are described below.
The starting ester of formula (III) is used in optically pure form. It is described in Japanese Patent Applications
145159/1986, 145160/1936 and 145174/1986.
The possibility of carrying out the two steps of the reaction in the same vessel, without evacuation or intermediate transfer to another vessel, is due to the selection of a unique solvent which is highly suitable for each of the steps.
Specific solvents for.each.of the two steps are naturally already known (dichloroethane, toluene, xylene, etc.), but they are different for each step and so do not permit the entire method to take place within the same reactor and, anyway, they make necessary to isolate the intermediate compound.
The solvents to be used according to the invention are chlorinated organic solvents having a boiling point of more than 70°C. Examples of such solvents are 1,2,3-trichloropropane, dichlorobenzenes and, preferably, chlorobenzene.
These solvents are not only - and unexpectedly - highly favorable to a good overall yield, but furthermore they are so efficient that the first step necessitates heating only for startup, because the exothermic nature of the reaction is sufficient for it to be maintained without adding external energy. This particular feature was entirely unforeseeable, because it had never been found with other solvents .
Additionally, the use of these solvents promotes the threoerythro selectivity of the first step. With other solvents, it is in fact found that an unfavorable mixture of diastereoisomers of general formula (IV) is obtained.
Another particular feature of the invention is due to the catalyst used in the second step. While it is known that cyclization takes place better in an acid medium (sulfuric or acetic), the catalyst to be used according to the invention is selected from methanesulfonic acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, perchloric acid, paratoluenesulfonic acid. The preferred catalyst is methanesulfonic acid.
These acids, which make it possible to obtain an excellent yield, are simple to add to the reaction medium as soon as the first step is completed.
The following examples provide a detailed illustration of the method according to the invention.
Example 1
In an enameled, 25-liter reactor purged with nitrogen, are introduced 3 kg of methyl (-) -(2R,3S)~2,3-epoxy-3-(4methoxyphenyl)propionate and 10 1 of chlorobenzene, and the mixture is heated to 1OO°C. Heating is stopped, and a solution of 1907 g of 2-aminothiophenol in 1.5 1 of chlorobenzene is introduced in the space of 30 minutes, so as not to allow the temperature to exceed 120°C, and 3.5 1 of chlorobenzene is also added to rinse the inlet funnel and the tubing.
The temperature is kept at approximately 115°C for a further 30 minutes, and then 37.5 ml of methanesulfonic acid is added, and the mixture is heated at reflux for 8 hours, with elimination of a mixture of methanol and chlorobenzene by distillation, in order not to allow the temperature to drop below 132°C (the boiling point of chlorobenzene).
The heating is stopped, the mixture is allowed to return to 20°C, it is chilled to 5°C for one hour, and the crystals formed are filtered, rinsed with chlorobenzene, and are dried in a vacuum at 100°C.
A yield of 3463 g of pure ( + ) -(2S,3S)~3-hydroxy-2~(4-methoxyphenyl)-2,3-dihydro-5H-l,5-benzothiazepine-4~one is obtained.
Melting point: 2 00.3-2 01.8°C. [α]θθ = +114° (c = 0.1;
DMF) .
Example 2
In a 1 liter flask under an argon atmosphere are introduced g of methyl (-) -(2R,3S)-2,3-epoxy-3~(4-methoxyphenyl)propionate and 350 ml of dichlorobenzene (a commercial mixture of ο-, m- and p-isomers) and the mixture is'heated at 115°C. Then, in the space of 30 minutes, so as not to allow the temperature to exceed 120°C, 31.8 g of 2-aminothiophenol are introduced.
The temperature is kept at 120°C for a further 30 minutes, and then 0.62 ml of methanesulfonic acid is added, and the mixture is heated at 15O°C for 3 hours (in fact the reaction is completed after 2 hours).
The mixture is allowed to return to ambient temperature, it is chilled to 5°C for one hour, and the crystals are filtered and washed with dichlorobenzene and dried in vacuo.
49.5 g of pure (+)-(2S,3S)-3-hydroxy-2-(4-methoxyphenyl)2.3- dihydro-5H-l,5—benzothiazepine-4-one are obtained. Melting point: 203-204°C.
Example 3
18.8 g of 2-aminothiophenol are added dropwise to a solution of 30 g of methyl (-) -(2R,3S)-2,3-epoxy~3-(4-methoxyphenyl)propionate in 200 ml of 1,2,3-trichloropropane heated to
110-115°C.
After 30 minutes 0.35 g of methanesulfonic acid is added, and the mixture is heated at 145-150°C for 6 hours.
The mixture is allowed to return to ambient temperature, then chilled and filtered, the crystals are washed with
1.2.3- trichloropropane, and dried in vacuo at 50°C.
33.8 g of pure ( + )“(2S,3S)”3-hydroxy-2---(4~methoxyphenyl)2.3- dihydro-5H-l,5—benzothiazepine-4-one are obtained.
Melting point: 202.8-204.1°C.
Example 4
In the same way as in Example 1, the reaction between 2-ami= no-5-chlorothiophenol and methyl (-)-(2R,3S)-2,3-epoxy~3-(4methoxyphenyl)propionate affords ( + )-(2S,3S) --8-chi or o-3hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5H-i,5-benzothiazepine-4-one.
Melting point: 237-241°C. [α]ρθ = +91-9° (c = 0.1; DMF).
z
Claims (9)
1. A process for the preparation of compounds of general formula (I) wherein X represents a hydrogen or chlorine atom, comprising first reacting a 2-aminothiophenol of general formula (II) wherein X is as defined above, with methyl (-) -(2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate of formula (III) and then cyclizing the intermediate compound, of general formula (IV) thus obtained in the presence of an acid, the process being characterized in that the two reaction steps are performed without isolation of the intermediate compound, by using a solvent selected from chlorobenzene, dichlorobenzenes and 1,2,3-trichloropropane.
2. A process according to claim 1, characterized in that X represents a hydrogen atom.
3. A process according to claim 1, characterized in that X represents a chlorine atom.
4. A process according to claim 1, characterized in that the solvent is chlorobenzene.
5. A process according to claim 1, characterized in that the solvent is a dichlorobenzene.
6. A process according to claim 1, characterized in that the solvent is 1,2,3-trichloropropane.
7. A process according to claim 1, characterized in that methanesulphonic acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulphonic acid, perchloric acid or paratoluenesulfonic acid is used to catalyse the cyclization of the intermediate compound of general formula (IV). β
8. » A process according to claim 1 for th® preparation of a compound of general formula (I) given and defined therein, substantially as hereinbefore described and exemplified.
9. A compound of general formula (I) given and defined in claim 1, whenever prepared by a process claimed in a preceding claim,
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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IE225890A IE63595B1 (en) | 1990-06-21 | 1990-06-21 | Method of preparing (+)-(2s, 3s)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5h-1, 5-benzothiazepine-4-one and chlorinated derivatives thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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IE225890A IE63595B1 (en) | 1990-06-21 | 1990-06-21 | Method of preparing (+)-(2s, 3s)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5h-1, 5-benzothiazepine-4-one and chlorinated derivatives thereof |
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IE63595B1 true IE63595B1 (en) | 1995-05-17 |
Family
ID=11033775
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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IE225890A IE63595B1 (en) | 1990-06-21 | 1990-06-21 | Method of preparing (+)-(2s, 3s)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5h-1, 5-benzothiazepine-4-one and chlorinated derivatives thereof |
Country Status (1)
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IE (1) | IE63595B1 (en) |
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1990
- 1990-06-21 IE IE225890A patent/IE63595B1/en not_active IP Right Cessation
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