WO2023181054A1 - Improved process for synthesis of benazepril intermediate - Google Patents
Improved process for synthesis of benazepril intermediate Download PDFInfo
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- WO2023181054A1 WO2023181054A1 PCT/IN2023/050237 IN2023050237W WO2023181054A1 WO 2023181054 A1 WO2023181054 A1 WO 2023181054A1 IN 2023050237 W IN2023050237 W IN 2023050237W WO 2023181054 A1 WO2023181054 A1 WO 2023181054A1
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- benzazepin
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- 238000000034 method Methods 0.000 title claims abstract description 34
- 230000015572 biosynthetic process Effects 0.000 title claims description 6
- 238000003786 synthesis reaction Methods 0.000 title claims description 6
- XPCFTKFZXHTYIP-PMACEKPBSA-N Benazepril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XPCFTKFZXHTYIP-PMACEKPBSA-N 0.000 title abstract description 12
- 229960004530 benazepril Drugs 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 239000002904 solvent Substances 0.000 claims abstract description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 21
- 239000000203 mixture Substances 0.000 claims abstract description 18
- 239000000706 filtrate Substances 0.000 claims abstract description 12
- 238000010438 heat treatment Methods 0.000 claims abstract description 9
- 239000011541 reaction mixture Substances 0.000 claims abstract description 5
- 238000004064 recycling Methods 0.000 claims abstract description 5
- 230000000707 stereoselective effect Effects 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 229940078552 o-xylene Drugs 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- 229940113088 dimethylacetamide Drugs 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- -1 tertbutyl ethyl acetate Chemical compound 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 abstract description 9
- JGHYNVSYTNERGK-GUYCJALGSA-N (3s)-3-[[(1s)-1-phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one Chemical compound C1([C@@H](N[C@@H]2C(NC3=CC=CC=C3CC2)=O)C)=CC=CC=C1 JGHYNVSYTNERGK-GUYCJALGSA-N 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 7
- 230000006340 racemization Effects 0.000 description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 238000004296 chiral HPLC Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RQEUFEKYXDPUSK-ZETCQYMHSA-N (1S)-1-phenylethanamine Chemical compound C[C@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 description 1
- AYQMNFRCBKOMIA-UHFFFAOYSA-N 1-benzazepin-2-one Chemical compound O=C1C=CC=C2C=CC=CC2=N1 AYQMNFRCBKOMIA-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000010949 in-process test method Methods 0.000 description 1
- 229940080268 lotensin Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B55/00—Racemisation; Complete or partial inversion
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- the present invention relates to a process for preparation of intermediates of Benazepril and more to an improved process for preparation of Benazepril intermediate (3S)-3- [[( 1 S)- 1 -phenylethyl] amino] -1,3 ,4,5-tetrahydro- 1 -benzazepin-2-one.
- Benazepril (A) and its pharmaceutically active salt is an ACE inhibitor and is marketed as Lotensin. It is used for high blood pressure, heart failure and diabetic kidney disease and is chemically named as 2-[(3S)-3-[((lS)-l-ethoxycarbonyl-3- phenyl-propyl)amino]-2-oxo-4,5-dihydro-3H- 1-benzazepin- 1-yl] acetic acid.
- the desired (S,S) product is collected by filtration.
- the literature reports diastereomeric ratio (99:1) with 93% yield when the reaction is carried out in mineral oil at 140°C for 16 hours.
- CN102250004B reports solventless reaction method for higher conversion rate.
- the object of present invention is to provide an improved process for synthesis of Benazepril intermediate, (3S)-3-[[(lS) -1 -phenylethyl] amino]-l, 3, 4, 5 -tetrahydro -
- Another object of the present invention is to provide racemization of undesired isomer (3R)-3-[[(lS)-l-phenylethyl]amino]-l,3,4,5-tetrahydro-l-benzazepin-2-one and re-use in the reaction, which improves yields and makes the process cost-effective.
- the predefined solvent in step (i) is an acetate solvent selected from ethyl acetate, isopropyl acetate, tertbutyl ethyl acetate and methyl acetate.
- the predefined temperature in step (i) is 50-90°C, preferably at 55-80°C and more preferably at 60- 70°C.
- the (IR) isomer is the mixture of (R) and (S) isomer having ratio in the range of 70:30 - 90:10.
- the predefined solvent in step (iv) is selected from o-xylene, Toluene, dimethyl formamide and dimethyl acetamide.
- the predefined temperature in step (iv) is 120-160°C, preferably at 130-150°C and more preferably at 135-145°C. DETAILED DESCRIPTION OF THE INVENTION
- the present invention relates to an improved process for the stereo- specific preparation of Benazepril intermediate (3S)-3-[[(lS)-l-phenylethyl]amino]-l, 3,4,5- tetrahydro-l-benzazepin-2-one of formula (IS).
- the process for preparation of Benazepril intermediate compound of Formula (IS) includes the following steps: i) heating the compound of Formula (I) (3RS)-[[(lS)-l-phenylethyl]amino]- l,3,4,5-tetrahydro-l-benzazepin-2-one at a predefined temperature in a predefined solvent;
- step (i) recovering the racemic compound obtained in step (iv) by distilling the solvent of previous step under vacuum and recycling by adding the racemic compound to step (i).
- the predefined temperature is
- the predefined solvent in step (i) is an acetate solvent selected from ethyl acetate, isopropyl acetate, tertbutyl ethyl acetate and methyl acetate.
- the (IR) isomer of step (iii) is a mixture of (IR):(IS) isomer in the ratio of 70:30 - 90:10.
- the predefined temperature in step (iv) is 120-160°C, preferably at 130-150°C, particularly at 135-145°C.
- the heating in step (iv) is done to obtain 50:50 mixture of compounds of formulae (IR) and (IS).
- the predefined solvent in step (iv) is selected from o-xylene, Toluene, dimethyl formamide and dimethyl acetamide.
- Example 1 is set forth herein below and are illustrative of different amounts and types of reactants and reaction conditions that can be utilized in practicing the disclosure. It will be apparent, however, that the disclosure can be practiced with other amounts and types of reactants and reaction conditions than those used in the examples, and the resulting devices various different properties and uses in accordance with the disclosure above and as pointed out hereinafter.
- Example 1 is set forth herein below and are illustrative of different amounts and types of reactants and reaction conditions that can be utilized in practicing the disclosure. It will be apparent, however, that the disclosure can be practiced with other amounts and types of reactants and reaction conditions than those used in the examples, and the resulting devices various different properties and uses in accordance with the disclosure above and as pointed out hereinafter.
- Example 1 is set forth herein below and are illustrative of different amounts and types of reactants and reaction conditions that can be utilized in practicing the disclosure. It will be apparent, however, that the disclosure can be practiced with other amounts and types of reactants and reaction conditions than those used in the examples
- the compound of formula (I) is charged to ethyl acetate and the mixture is heated to 60-70°C for at least 1-2 hours.
- the undesired (IR) isomer solubilizes in the solvent and the desired (IS) isomer is separated by filtration.
- the desired isomer (IS) is analyzed for the amount of undesired isomer (IR) content. If the (IR) content is more than 0.1%, then the residue is again charged to fresh ethyl acetate and heated to 60- 70°C for at least 1-2 hours.
- the filtrate is distilled out completely under vacuum at 80-85°C and undesired isomer (IR) is isolated.
- the undesired isomer (IR) obtained is the mixture of (IR) and (IS) isomer.
- the ratio of (IR):(1S) is 70:30 to 90:10.
- o-xylene was charged to the mass obtained and heated at 135- 145 °C till the racemic compound (I) with 50:50 ratio of (S):(R) is obtained.
- the racemic isomer (I) obtained is isolated by complete distillation of o-xylene under vacuum below 80°C. The racemic isomer is recycled in the step (I).
- the temperature of the mixture was raised to 60-65°C and stirred for about 1 hour.
- the mass was gradually cooled to 25-30°C and further to 5-10°C.
- the suspension was filtered and the wet solid was washed with chilled ethyl acetate (100 ml).
- the solid obtained was suck dried and further dried under vacuum at 50-55°C for 6-7 hours to obtain the compound (IS) (3S)-3-[[(lS)-l-phenylethyl]amino]-l,3,4,5-tetrahydro-l- benzazepin-2-one (41 g).
- the filtrate was kept aside for recovery of undesired isomer.
- the process of the present invention is economically feasible due to the racemization and recycling of the undesired isomer.
- the process avoids use of resolving agent and hence it avoids salt making and breaking which reduces time cycle of the reaction. Due to ease of handling operations, the process is suitable for large scale production.
Abstract
The present invention relates to an improved process for the preparation for the stereo-specific preparation of Benazepril intermediate (3S)-3-[[(1S)-1- phenylethyl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one of formula (IS). The steps include: heating the compound of Formula (I) (3RS)-[[(1S)-1-phenylethyl]amino]- 1,3,4,5-tetrahydro-1-benzazepin-2-one at a predefined temperature in a predefined solvent followed by separating undissolved desired isomer of formula (IS) from the reaction mixture of step (i); recovering the R-isomer of formula (IR) from the filtrate followed by distilling the filtrate to isolate the compound of R-isomer of formula (IR); racemizing R-isomer of formula (IR) to form racemic mixture of formula (I) and recovering the racemic compound obtained in step (iv) by distilling the solvent of previous step under vacuum and recycling by adding the racemic compound to step (i).
Description
“IMPROVED PROCESS FOR SYNTHESIS OF BENAZEPRIL
INTERMEDIATE”
FIELD OF THE INVENTION
The present invention relates to a process for preparation of intermediates of Benazepril and more to an improved process for preparation of Benazepril intermediate (3S)-3- [[( 1 S)- 1 -phenylethyl] amino] -1,3 ,4,5-tetrahydro- 1 -benzazepin-2-one. BACKGROUND OF THE INVENTION
Benazepril (A) and its pharmaceutically active salt is an ACE inhibitor and is marketed as Lotensin. It is used for high blood pressure, heart failure and diabetic kidney disease and is chemically named as 2-[(3S)-3-[((lS)-l-ethoxycarbonyl-3- phenyl-propyl)amino]-2-oxo-4,5-dihydro-3H- 1-benzazepin- 1-yl] acetic acid.
(3 S )-3 - [[( 1 S )- 1 -phenylethyl] amino] -1,3 ,4,5-tetrahydro- 1 -benzazepin-2-one of formula (IS) is a key intermediate of Benazepril and is represented as formula (I) below:
Various processes are known in literature for the preparation of this intermediate. The synthesis of (3S)-3-[[(lS)-l-phenylethyl]amino]-l,3,4,5-tetrahydro- l-benzazepin-2-one is reported in a research article titled “Asymmetric Synthesis of N- Substituted r-Aminobenzlactam via Crystallization-Induced Asymmetric Transformation of Covalent Diastereomer” by Shi eh et.al.. The process involves suspending diastereoisomer in a non-polar solvent and heated to 140-160°C. The reaction mixture was diluted with cyclohexane and the mixture was cooled to room temperature. The desired (S,S) product is collected by filtration. The literature reports diastereomeric ratio (99:1) with 93% yield when the reaction is carried out in mineral oil at 140°C for 16 hours. CN102250004B reports solventless reaction method for higher conversion rate.
The racemic (3RS)-3-[[(lS)- 1 -phenylethyl] amino]- 1,3,4, 5-tetrahydro-l -benzazepin-2- one obtained from previous stage is heated to 130-160°C and in the molten state the undesired isomer is converted to the desired isomer and the yield reported is 70-80%.
The benazepril intermediate discussed above is most critical to prepare as it has two chiral centres and both having S-configuration. The process by Shieh et.al has some practical impediments. When the processof Shiel et.al was replicated by person skilled in art, it was observed that after the addition of cyclohexane the reaction mass became hard. (3S)-3-[[(lS)- 1 -phenylethyl] amino]- 1,3,4, 5-tetrahydro-l -benzazepin-2- one being insoluble in mineral oil as well as in cyclohexane became very thick slurry. It was observed that after cooling it stuck to the walls of reactor. Also, it does not yield diasteromeric ratio as claimed. Thus the process is not feasible and scalable for large scale production due to lack of operational ease.
In the racemization process of undesired isomer (IR) to (I) as reported in CN102250004B, racemization is achieved. However, as the process is solventless, the decomposition of the compound was observed at higher temperature such as 160°C. Due to decomposition, the yield loss is observed.
Due to the above-mentioned technical difficulties of the processes cited in prior art, there is a need to develop a process that is feasible for higher scale production. Further, there is a need of a process that is environmental friendly and has operational ease.
Objects of the invention
The object of present invention is to provide an improved process for synthesis of Benazepril intermediate, (3S)-3-[[(lS) -1 -phenylethyl] amino]-l, 3, 4, 5 -tetrahydro -
1-benzazepin- 2-one, which is industrially feasible and applicable.
Another object of the present invention is to provide racemization of undesired isomer (3R)-3-[[(lS)-l-phenylethyl]amino]-l,3,4,5-tetrahydro-l-benzazepin-2-one and re-use in the reaction, which improves yields and makes the process cost-effective.
SUMMARY OF THE INVENTION
A process for stereospecific synthesis of [(3S)-3-[((lS)-l-ethoxycarbonyl-3- phenyl-propyl)amino]-2-oxo-4,5-dihydro-3H-l-benzazepin-l-yl]acetic acid of formula (I), that includes the steps of heating the compound of Formula (I) (3RS)-[[(1S)-1- phenylethyl]amino]-l,3,4,5-tetrahydro-l-benzazepin-2-one at a predefined temperature in a predefined solvent; separating undissolved desired isomer of formula (IS) from the reaction mixture of step (i) by filtration; recovering the R-isomer of formula (IR) from the filtrate followed by distilling the filtrate to isolate the compound of R-isomer of formula (IR); racemizing R-isomer of formula (IR) by heating the isomer at a predefined temperature in a predefined solvent to form racemic mixture of formula (I); and recovering the racemic compound obtained in step (iv) by distilling the solvent of previous step under vacuum and recycling by adding the racemic compound to step (i). The predefined solvent in step (i) is an acetate solvent selected from ethyl acetate, isopropyl acetate, tertbutyl ethyl acetate and methyl acetate. The predefined temperature in step (i) is 50-90°C, preferably at 55-80°C and more preferably at 60- 70°C. The (IR) isomer is the mixture of (R) and (S) isomer having ratio in the range of 70:30 - 90:10. The predefined solvent in step (iv) is selected from o-xylene, Toluene, dimethyl formamide and dimethyl acetamide. The predefined temperature in step (iv) is 120-160°C, preferably at 130-150°C and more preferably at 135-145°C.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the stereo- specific preparation of Benazepril intermediate (3S)-3-[[(lS)-l-phenylethyl]amino]-l, 3,4,5- tetrahydro-l-benzazepin-2-one of formula (IS).
Formula (IS)
The foregoing objects of the present invention are accomplished and the problems and shortcomings associated with the prior art, techniques and approaches are overcome by the present invention as described below in the preferred embodiments.
All materials used herein were commercially purchased as described herein or prepared from commercially purchased materials as described herein.
Although specific terms are used in the following description for sake of clarity, these terms are intended to refer only to particular structure of the invention selected for illustration in the drawings and are not intended to define or limit the scope of the invention.
References in the specification to “preferred embodiment” means that a particular feature, structure, characteristic, or function described in detail thereby omitting known constructions and functions for clear description of the present invention.
In an embodiment of the present invention, an improved process for the preparation of compound of formula (IS), is disclosed.
Formula (IS) The process for preparation of Benazepril intermediate compound of Formula (IS) includes the following steps: i) heating the compound of Formula (I) (3RS)-[[(lS)-l-phenylethyl]amino]- l,3,4,5-tetrahydro-l-benzazepin-2-one at a predefined temperature in a predefined solvent;
Formula (I) ii) separating undissolved desired isomer of formula (IS) from the reaction mixture of step (i) by filtration; iii) recovering the R-isomer of formula (IR) from the filtrate followed by distilling the filtrate to isolate the compound of R-isomer of formula (IR);
iv) racemizing R-isomer of formula (IR) by heating the isomer at a predefined temperature in a predefined solvent to form racemic mixture of formula (I); and
Formula CD v) recovering the racemic compound obtained in step (iv) by distilling the solvent of previous step under vacuum and recycling by adding the racemic compound to step (i). In accordance with this embodiment, in step (i) the predefined temperature is
50-90°C, preferably at 55-80°C; particularly at 60-70°C. The predefined solvent in step (i) is an acetate solvent selected from ethyl acetate, isopropyl acetate, tertbutyl ethyl acetate and methyl acetate. The (IR) isomer of step (iii) is a mixture of (IR):(IS) isomer in the ratio of 70:30 - 90:10. The predefined temperature in step (iv) is 120-160°C, preferably at 130-150°C, particularly at 135-145°C. The heating in step (iv) is done to obtain 50:50 mixture of compounds of formulae (IR) and (IS). The predefined solvent
in step (iv) is selected from o-xylene, Toluene, dimethyl formamide and dimethyl acetamide.
Only a few examples and implementations are disclosed. Variations, modifications, and enhancements to the described examples and implementations and other implementations can be made based on what is disclosed.
Examples are set forth herein below and are illustrative of different amounts and types of reactants and reaction conditions that can be utilized in practicing the disclosure. It will be apparent, however, that the disclosure can be practiced with other amounts and types of reactants and reaction conditions than those used in the examples, and the resulting devices various different properties and uses in accordance with the disclosure above and as pointed out hereinafter.
Example 1
The compound of formula (I) is charged to ethyl acetate and the mixture is heated to 60-70°C for at least 1-2 hours. The undesired (IR) isomer solubilizes in the solvent and the desired (IS) isomer is separated by filtration. The desired isomer (IS) is analyzed for the amount of undesired isomer (IR) content. If the (IR) content is more than 0.1%, then the residue is again charged to fresh ethyl acetate and heated to 60- 70°C for at least 1-2 hours.
The filtrate is distilled out completely under vacuum at 80-85°C and undesired isomer (IR) is isolated. The undesired isomer (IR) obtained is the mixture of (IR) and (IS) isomer. The ratio of (IR):(1S) is 70:30 to 90:10. o-xylene was charged to the mass obtained and heated at 135- 145 °C till the racemic compound (I) with 50:50 ratio of (S):(R) is obtained. The racemic isomer (I) obtained is isolated by complete distillation of o-xylene under vacuum below 80°C. The racemic isomer is recycled in the step (I).
3-bromo-l,3,4,5-tetrahydro-l-benzazepin-2-one (100 gm) was charged to propylene glycol (100 ml) and stirred for 10-15 minutes at 30-35°C. (S)-(-)alpha- methylbenzylamine (55.36 gm) was charged and the temperature was raised to 105-
110°C and the mixture was stirred for about 4 hours.
The mass was gradually cooled to 75-80°C and isopropyl alcohol (50 ml) was added gradually over 60-70 minutes. Water (125 ml) was charged gradually to the mass at 40-45°C over 2-3 hours. The mixture was stirred for 15-20 minutes. The mass was cooled to 30-35°C and stirred for 1-1.5 hours. The mass was filtered and the solid was washed with water (2x100 ml). The solid was suck dried under vacuum at room temperature and (3RS)- [[( 1 S)- 1 -phenylethyl] amino] - 1 ,3,4,5-tetrahydro- 1 -benzazepin- 2-one (105 gm) was formed.
Example 3
Preparation of (3S)-3-ll( lS)-l-Dhenylethyl]amino]-l,3,4,5-tetrahydro-l- in-2-one (IS)
(3RS)-3-[[(lS)-l-phenylethyl]amino]-l,3,4,5-tetrahydro-l-benzazepin-2-one (100 gm) was charged to ethyl acetate (200 ml) at 30-35°C. The mixture was heated to 60-70°C and stirred for 1 hour. The mass was cooled to 25-30°C and further cooled to 5-10°C. The mass was stirred for about 1 hour at 5-10°C. The mass was filtered and the precipitate was washed with ethyl acetate (100 ml). The solid obtained was suck dried well under vacuum and the solid was charged to ethyl acetate (500 ml) at 25-30°C. The temperature of the mixture was raised to 60-65°C and stirred for about 1 hour. The mass was gradually cooled to 25-30°C and further to 5-10°C. The suspension was filtered and the wet solid was washed with chilled ethyl acetate (100 ml). The solid obtained was suck dried and further dried under vacuum at 50-55°C for 6-7 hours to obtain the compound (IS) (3S)-3-[[(lS)-l-phenylethyl]amino]-l,3,4,5-tetrahydro-l- benzazepin-2-one (41 g). The filtrate was kept aside for recovery of undesired isomer.
Chiral HLPC: (IS) isomer: 99.73% and (IR) isomer: 0.27%
Example 4
Ethyl acetate (500 ml) was charged to (3S)-3-[[(lS)-l-phenylethyl]amino]- l,3,4,5-tetrahydro-l-benzazepin-2-one isolated in example 2 at 25-30°C. The mixture was stirred for 15-20 minutes. The mixture was heated to 60-65°C and then stirred for
1-2 hours. The mixture was gradually cooled to 25-30°C and further to 5-10°C. The suspension was filtered and washed with chilled ethyl acetate (100 ml). The solid obtained was suck dried and further dried under vacuum at 50-55°C for 6-7 hours to obtain the compound (IS) (3S)-3-[[(lS)-l-phenylethyl]amino]-l,3,4,5-tetrahydro-l- benzazepin-2-one. The filtrate was kept aside for recovery of undesired isomer.
Chiral HPLC: (IS) isomer: 99.94% and (IR): 0.06%
Example 5
Recovery of (3R)-3-ll(lS)-l-Dhenylethyllaminol-l,3,4,5-tetrahydro-l-benzazeDin-
2-one
The filtrate obtained in example 3 and 4 containing ethyl acetate was distilled under vacuum completely to isolate (3R)-3-[[(lS)-l-phenylethyl] amino]-l, 3,4,5- tetrahydro -1-benzazepin -2-one.
Chiral HPLC: (IR) isomer: 70% and (IS): 30%
Example 6
of (I) by racemization of (3R)-3-rr(lS)-l-DhenylethyHaminol-l, 3,4,5-
1 -benzazepin -2-one (IR) o-xylene (200 ml) was added to the recovered (3R)-3-[[(lS)-l- phenylethyl]amino]-l,3,4,5-tetrahydro-l-benzazepin-2-one in example 5. The temperature was raised to 135-145°C and the mass was stirred for 6-8 hours. The sample was submitted for in process analysis. The result of the analysis was as follows: Chiral HPLC: (IR) isomer: 60% and (IS): 40%
The heating of the reaction mass at 135-145°C was continued till the limit of (R)-isomer (NMT 50) is achieved. The mass was cooled to 75-80°C. o-xylene was distilled under vacuum. The isolated (3RS)-[[(lS)-l-phenylethyl]amino]-l, 3,4,5- tetrahydro-l-benzazepin-2-one (I) was recyled in process as explained in example 3.
In the context of the present invention, the process of the present invention is economically feasible due to the racemization and recycling of the undesired isomer. The process avoids use of resolving agent and hence it avoids salt making and breaking which reduces time cycle of the reaction. Due to ease of handling operations, the process is suitable for large scale production.
The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching.
The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable
others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.
It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the spirit or scope of the present invention.
Claims
1. A process for stereospecific synthesis of [(3S)-3-[((lS)-l-ethoxycarbonyl-3-phenyl- propyl)amino]-2-oxo-4,5-dihydro-3H-l-benzazepin-l-yl]acetic acid of formula (I),
Formula (IS) comprising: i) heating the compound of Formula (I) (3RS)-[[(lS)-l-phenylethyl]amino]-l, 3,4,5- tetrahydro-l-benzazepin-2-one at a predefined temperature in a predefined solvent; ii) separating undissolved desired isomer of formula (IS) from the reaction mixture of step (i) by filtration; iii) recovering the R-isomer of formula (IR) from the filtrate followed by distilling the filtrate to isolate the compound of R-isomer of formula (IR); iv) racemizing R-isomer of formula (IR) by heating the isomer at a predefined temperature in a predefined solvent to form racemic mixture of formula (I); and v) recovering the racemic compound obtained in step (iv) by distilling the solvent of previous step under vacuum and recycling by adding the racemic compound to step (i).
2. The process as claimed in claim 1, wherein the predefined solvent in step (i) is an acetate solvent selected from ethyl acetate, isopropyl acetate, tertbutyl ethyl acetate and methyl acetate.
3. The process as claimed in claim 1, wherein the acetate solvent is ethyl acetate.
4. The process as claimed in claim 1, wherein the predefined temperature in step (i) is 50-90°C, preferably at 55-80°C and more preferably at 60-70°C.
5. The process as claimed in claim 1, wherein (IR) isomer is the mixture of (R) and (S) isomer having ratio in the range of 70:30 - 90:10.
6. The process as claimed in claim 1, wherein the predefined solvent in step (iv) is selected from o-xylene, Toluene, dimethyl formamide and dimethyl acetamide.
7. The process as claimed in claim 1, wherein the predefined temperature in step (iv) is 120-160°C, preferably 130- 150°C and more preferably 135-145°C.
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Citations (3)
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WO2003003972A2 (en) * | 2001-05-18 | 2003-01-16 | Scinopharm Taiwan, Ltd. | Kinetic resolution of a intermediate useful in the production of benazepril and analogues thereof |
CN102250004B (en) * | 2010-05-17 | 2014-03-26 | 江苏英力科技发展有限公司 | Preparation method of 3-[(1-(1S)-phenylethyl) amino]-2,3,4,5-tetrahydro-2-oxo-1H-(3S)-benzazepine |
WO2015007897A1 (en) * | 2013-07-19 | 2015-01-22 | Lek Pharmaceuticals D.D. | Method of racemisation of undesired enantiomers |
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WO2003003972A2 (en) * | 2001-05-18 | 2003-01-16 | Scinopharm Taiwan, Ltd. | Kinetic resolution of a intermediate useful in the production of benazepril and analogues thereof |
CN102250004B (en) * | 2010-05-17 | 2014-03-26 | 江苏英力科技发展有限公司 | Preparation method of 3-[(1-(1S)-phenylethyl) amino]-2,3,4,5-tetrahydro-2-oxo-1H-(3S)-benzazepine |
WO2015007897A1 (en) * | 2013-07-19 | 2015-01-22 | Lek Pharmaceuticals D.D. | Method of racemisation of undesired enantiomers |
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