USRE34935E - Method for preparing (+)-(2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5H-1,5-benzothiazepine-4-one and chlorinated derivatives thereof - Google Patents
Method for preparing (+)-(2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5H-1,5-benzothiazepine-4-one and chlorinated derivatives thereof Download PDFInfo
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- USRE34935E USRE34935E US08/053,855 US5385593A USRE34935E US RE34935 E USRE34935 E US RE34935E US 5385593 A US5385593 A US 5385593A US RE34935 E USRE34935 E US RE34935E
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- methoxyphenyl
- hydroxy
- acid
- compound
- benzothiazepine
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- 238000000034 method Methods 0.000 title claims description 16
- LHBHZALHFIQJGJ-CABCVRRESA-N (2s,3s)-3-hydroxy-2-(4-methoxyphenyl)-3,5-dihydro-2h-1,5-benzothiazepin-4-one Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](O)C(=O)NC2=CC=CC=C2S1 LHBHZALHFIQJGJ-CABCVRRESA-N 0.000 title description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims abstract description 19
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 229940098779 methanesulfonic acid Drugs 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 13
- CFXQEHVMCRXUSD-UHFFFAOYSA-N 1,2,3-Trichloropropane Chemical group ClCC(Cl)CCl CFXQEHVMCRXUSD-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 6
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical group ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 3
- 229910052801 chlorine Chemical group 0.000 claims description 3
- 229940117389 dichlorobenzene Drugs 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Chemical group 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- MVPPADPHJFYWMZ-IDEBNGHGSA-N chlorobenzene Chemical group Cl[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 MVPPADPHJFYWMZ-IDEBNGHGSA-N 0.000 claims 1
- VRVRGVPWCUEOGV-UHFFFAOYSA-N 2-aminothiophenol Chemical compound NC1=CC=CC=C1S VRVRGVPWCUEOGV-UHFFFAOYSA-N 0.000 abstract description 7
- CVZUMGUZDAWOGA-VHSXEESVSA-N methyl (2r,3s)-3-(4-methoxyphenyl)oxirane-2-carboxylate Chemical compound COC(=O)[C@@H]1O[C@H]1C1=CC=C(OC)C=C1 CVZUMGUZDAWOGA-VHSXEESVSA-N 0.000 abstract description 5
- MPWGGMIUPWSNEV-CVEARBPZSA-N methyl (2s,3s)-3-(2-aminophenyl)sulfanyl-2-hydroxy-3-(4-methoxyphenyl)propanoate Chemical compound S([C@H]([C@@H](O)C(=O)OC)C=1C=CC(OC)=CC=1)C1=CC=CC=C1N MPWGGMIUPWSNEV-CVEARBPZSA-N 0.000 abstract description 2
- 239000013067 intermediate product Substances 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 5
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- CUHUYVNPCQYRLG-DTWKUNHWSA-N (2r,3s)-3-(4-methoxyphenyl)oxirane-2-carboxylic acid Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@H](C(O)=O)O1 CUHUYVNPCQYRLG-DTWKUNHWSA-N 0.000 description 1
- KAANMZCKNKVSAA-CABCVRRESA-N (2s,3s)-8-chloro-3-hydroxy-2-(4-methoxyphenyl)-3,5-dihydro-2h-1,5-benzothiazepin-4-one Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](O)C(=O)NC2=CC=C(Cl)C=C2S1 KAANMZCKNKVSAA-CABCVRRESA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- TYRZAGMAVZESQX-UHFFFAOYSA-N 2-amino-5-chlorobenzenethiol Chemical compound NC1=CC=C(Cl)C=C1S TYRZAGMAVZESQX-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 150000004816 dichlorobenzenes Chemical class 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 150000002118 epoxides Chemical group 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 101150035983 str1 gene Proteins 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
Definitions
- the subject of the present invention is a method for preparing (+)-(2S,3S)-3-hydroxy-2-(4-methoxyphenyl-2,3-dihydro-5H-1,5-benzothiazepine-4-one, bearing optionally a chlorine atom on the aromatic ring.
- optically pure compounds are synthetic intermediates of compounds with therapeutic activities, such as (+)-(2S,3S)-3-acetyloxy-5-(2-dimethylaminoethyl)-2-(4-methoxyphenyl)-2,3-dihydro-5H-1,5-benzothiazepine-4-one and its chlorinated derivatives.
- the first step comprises reacting a 2-aminothiophenol derivative of general formula II with methyl (-). (2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate of formula III.
- a methyl (2S,3S)-3-[(2-aminophenyl)thio]-2-hydroxy-3-(4-methoxyphenyl)propionate derivative 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 ester of formula III is used in racemic form.
- the first step necessitates several hours of heating to 150°-160° 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.
- 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 is intermediate.
- 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);
- the starting ester of formula III is used in optically pure form. It is described in Japanese Patent Applications 145159/1986, 145160/1986 and 145174/1986.
- 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.
- the solvents to be used according to the invention are chlorinated organic solvents having a boiling point of more than 70° C. Examples of suitable solvents are 1,2,3-trichloropropane, dichlorobenzenes and, preferably, chlorobenzene.
- the catalyst used in the second step is selected from methanesulfonic acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, perchloric acid, paratoluenesulfonic acid.
- the preferred catalyst is methanesulfonic acid.
- 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.
- 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 150° C. for 3 hours (the reaction is completed after 2 hours).
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
2-Aminothiophenol is reacted with methyl (-)-(2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate, and the intermediate methyl (2S,3S)-3-[(2-aminophenyl)thio]-2-hydroxy-3-(4-methoxyphenyl)propionate is cyclized in the presence of methanesulfonic acid, in the same vessel and without isolating said intermediate product, using e.g. chlorobenzene as a solvent.
Description
.Iadd.
This application is a continuation-in-part of application Ser. No. 07/408,042, filed Sep. 14, 1989, now U.S. Pat. No. 5,013,835. .Iaddend.
The subject of the present invention is a method for preparing (+)-(2S,3S)-3-hydroxy-2-(4-methoxyphenyl-2,3-dihydro-5H-1,5-benzothiazepine-4-one, bearing optionally a chlorine atom on the aromatic ring.
These optically pure compounds are synthetic intermediates of compounds with therapeutic activities, such as (+)-(2S,3S)-3-acetyloxy-5-(2-dimethylaminoethyl)-2-(4-methoxyphenyl)-2,3-dihydro-5H-1,5-benzothiazepine-4-one and its chlorinated derivatives.
The reaction scheme is shown on the following page. In the formulae, X denotes hydrogen or chlorine.
The first step comprises reacting a 2-aminothiophenol derivative of general formula II with methyl (-). (2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate of formula III. A methyl (2S,3S)-3-[(2-aminophenyl)thio]-2-hydroxy-3-(4-methoxyphenyl)propionate derivative 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 150°-160° 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.
U.S. Pat. No. 4,416,819 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, likewise. ##STR1## describes the reaction of the latter with aminothiophenol of 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 is intermediate.
Thus it is clear that none of the known methods are suitable for economic industrial manufacture of the compounds of 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);
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 operating 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, 145160/1986 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. The solvents to be used according to the invention are chlorinated organic solvents having a boiling point of more than 70° C. Examples of suitable 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 further/more 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 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 of the cyclized compound (I), 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.
In an enameled, 25-liter reactor purged with nitrogen, are introduced 3 kg of methyl(-)-(2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate and 10 l of chlorobenzene, and the mixture is heated to 100° C. Heating is stopped, and a solution of 1900 g of 2-aminothiophenol in 1.51 of chlorobenzene is introduced in the space of 30 minutes, so as not to allow the temperature to exceed 120° C., and 3.5 l 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-1,5-benzothiazepine-4-one is obtained. Melting point: 200.3°-201.8° C. [α]D 20 =+114° (c=0.1; DMF).
In a 1 liter flask under an argon atmosphere are introduced 50 g of methyl (-)-(2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate and 350 ml of dichlorobenzene (a commercial mixture of o-, 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 150° C. for 3 hours (the reaction is completed after 2 hours).
The mixture is allowed to cool; 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-1,5-benzothiazepine-4-one are obtained. Melting point: 203°-204° C.
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 at 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 cool, 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-1,5-benzothiazepine-4-one are obtained. Melting point: 202.8°-204.1° C.
In the same way as in Example 1, the reaction between 2-amino-5-chlorothiophenol and methyl (-)-(2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate affords (+)-(2S,3S)-8-chloro-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5H-1,5-benzothiazepine-4-one. Melting point: 237°-241° C. [α]D 20 =+91.9° (c=0.1; DMF).
Claims (3)
1. A method for preparing a compound of the general formula (I) ##STR2## wherein X is hydrogen or chlorine, said method consisting essentially of: reacting a compound of the general formula (II) ##STR3## with a compound of formula (III) in optically pure levorotatory form ##STR4## to obtain an intermediate compound of general formula (IV) ##STR5## .[.; and then,.]. ; and then, without isolating said intermediate,
cyclizing the intermediate compound wherein said cyclization is effected in the presence of acid, and wherein said reacting and cyclizing steps are performed in the presence of .[.a solvent selected from the group consisting of chlorinated organic solvents that have boiling points greater than 70° C.]..Iadd.chlorobenzene. .Iaddend.
2. The method of claim 1, wherein X is hydrogen. .[.3. The method of claim 1, wherein the solvent is chlorobenzene..]. .[.4. The method of claim 1, wherein the solvent is a dichlorobenzene..]. .[.5. The method of claim 1,
wherein the solvent is 1,2,3-trichloropropane..]. 6. The method of claim 1, wherein said acid is methane-sulfonic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/053,855 USRE34935E (en) | 1989-01-11 | 1993-04-29 | Method for preparing (+)-(2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5H-1,5-benzothiazepine-4-one and chlorinated derivatives thereof |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8900246A FR2641535B1 (en) | 1989-01-11 | 1989-01-11 | PROCESS FOR THE PREPARATION OF (+) - (2S, 3S) -HYDROXY-3 (METHOXY-4 PHENYL) -2 DIHYDRO-2,3 5H-BENZOTHIAZEPINE-1,5 ONE-4 |
| FR8900246 | 1989-01-11 | ||
| US07/408,042 US5013835A (en) | 1989-01-11 | 1989-09-14 | Method of preparing (+)-(2S,3S)-3-hydroxy-2-(4-methoxyphenyl)2,3-dihydro-5H-1,5-benzothiazepine-4-one |
| US07/426,285 US5102998A (en) | 1989-01-11 | 1989-10-24 | Method for preparing (+)-(2s,3s)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5h-1,5-benzothiazepine-4-one and chlorinated derivatives thereof |
| US08/053,855 USRE34935E (en) | 1989-01-11 | 1993-04-29 | Method for preparing (+)-(2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5H-1,5-benzothiazepine-4-one and chlorinated derivatives thereof |
Related Parent Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US07/408,042 Continuation-In-Part US5013835A (en) | 1989-01-11 | 1989-09-14 | Method of preparing (+)-(2S,3S)-3-hydroxy-2-(4-methoxyphenyl)2,3-dihydro-5H-1,5-benzothiazepine-4-one |
| US07/426,285 Reissue US5102998A (en) | 1989-01-11 | 1989-10-24 | Method for preparing (+)-(2s,3s)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5h-1,5-benzothiazepine-4-one and chlorinated derivatives thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| USRE34935E true USRE34935E (en) | 1995-05-09 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US08/053,855 Expired - Lifetime USRE34935E (en) | 1989-01-11 | 1993-04-29 | Method for preparing (+)-(2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-5H-1,5-benzothiazepine-4-one and chlorinated derivatives thereof |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | USRE34935E (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5859241A (en) * | 1996-03-22 | 1999-01-12 | Dsm N.V. | Process for the preparation of a benzothiazepine |
Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4416819A (en) * | 1982-07-09 | 1983-11-22 | Tanabe Seiyaku Co., Ltd. | Process for preparing 1,5-benzothiazephine derivatives |
| US4420628A (en) * | 1981-02-27 | 1983-12-13 | Tanabe Seiyaku Co., Ltd. | Process for preparing threo-2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitrophenylthio)-propionic ester |
| US4438035A (en) * | 1981-12-07 | 1984-03-20 | Tanabe Seiyaku Co., Ltd. | Method of preparing benzothiazepine derivatives |
| EP0154838A1 (en) * | 1984-02-18 | 1985-09-18 | Tanabe Seiyaku Co., Ltd. | Novel 1,5-benzothiazepine derivatives, processes for preparing the same and pharmaceutical compositions |
| US4552695A (en) * | 1983-04-21 | 1985-11-12 | Shionogi & Co., Ltd. | Process for production of diltiazem hydrochloride |
| JPS61145160A (en) * | 1984-12-20 | 1986-07-02 | Nippon Chemiphar Co Ltd | Production of optically active propionic acid derivative |
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| JPS61145174A (en) * | 1984-12-20 | 1986-07-02 | Nippon Chemiphar Co Ltd | Production method of novel optically active epoxypropionate derivative |
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| US4885375A (en) * | 1988-05-18 | 1989-12-05 | Marion Laboratories, Inc. | Resolution of 3-(4-methoxyphenyl)glycidic acid with in situ conversion to alkyl esters |
| US5013835A (en) * | 1989-01-11 | 1991-05-07 | Synthelabo | Method of preparing (+)-(2S,3S)-3-hydroxy-2-(4-methoxyphenyl)2,3-dihydro-5H-1,5-benzothiazepine-4-one |
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Cited By (1)
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| US5859241A (en) * | 1996-03-22 | 1999-01-12 | Dsm N.V. | Process for the preparation of a benzothiazepine |
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