CN114609290B - HPLC-UV detection method for purity of Pa Luo Weide intermediate - Google Patents
HPLC-UV detection method for purity of Pa Luo Weide intermediate Download PDFInfo
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- 238000000825 ultraviolet detection Methods 0.000 title claims abstract description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 156
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 48
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000012535 impurity Substances 0.000 claims abstract description 20
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000004202 carbamide Substances 0.000 claims abstract description 16
- 238000010828 elution Methods 0.000 claims abstract description 11
- 239000007788 liquid Substances 0.000 claims abstract description 9
- 239000012488 sample solution Substances 0.000 claims abstract description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000013557 residual solvent Substances 0.000 claims abstract description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 21
- 239000000523 sample Substances 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 238000001514 detection method Methods 0.000 claims description 15
- 239000012071 phase Substances 0.000 claims description 8
- QKAHKEDLPBJLFD-UHFFFAOYSA-N 6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione Chemical compound O=C1OC(=O)C2C1C2(C)C QKAHKEDLPBJLFD-UHFFFAOYSA-N 0.000 claims description 7
- MSPJNHHBNOLHOC-UHFFFAOYSA-N 3,3-dimethylcyclopropane-1,2-dicarboxylic acid Chemical compound CC1(C)C(C(O)=O)C1C(O)=O MSPJNHHBNOLHOC-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 43
- 239000000243 solution Substances 0.000 abstract description 14
- 239000002904 solvent Substances 0.000 abstract description 12
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000006243 chemical reaction Methods 0.000 abstract description 4
- 239000007864 aqueous solution Substances 0.000 abstract description 3
- 238000000926 separation method Methods 0.000 abstract description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 239000007858 starting material Substances 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 3
- 241001678559 COVID-19 virus Species 0.000 description 2
- 241000711573 Coronaviridae Species 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- DRMNZTFLOOSXIN-ZXZARUISSA-N (1r,5s)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione Chemical compound O=C1NC(=O)[C@@H]2[C@H]1C2(C)C DRMNZTFLOOSXIN-ZXZARUISSA-N 0.000 description 1
- BGOMFPZIMJCRDV-UHFFFAOYSA-N 6,6-dimethyl-3-azabicyclo[3.1.0]hexane Chemical compound C1NCC2C(C)(C)C21 BGOMFPZIMJCRDV-UHFFFAOYSA-N 0.000 description 1
- 208000025721 COVID-19 Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- NDOGLIPWGGRQCO-UHFFFAOYSA-N hexane-2,4-dione Chemical compound CCC(=O)CC(C)=O NDOGLIPWGGRQCO-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- LIENCHBZNNMNKG-OJFNHCPVSA-N nirmatrelvir Chemical compound CC1([C@@H]2[C@H]1[C@H](N(C2)C(=O)[C@H](C(C)(C)C)NC(=O)C(F)(F)F)C(=O)N[C@@H](C[C@@H]3CCNC3=O)C#N)C LIENCHBZNNMNKG-OJFNHCPVSA-N 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940125675 paxlovid Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 238000010408 sweeping Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
- G01N2030/342—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient fluid composition fixed during analysis
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Investigating Or Analysing Biological Materials (AREA)
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Abstract
The invention discloses an HPLC-UV detection method for purity of Pa Luo Weide intermediate, which comprises the steps of dissolving the intermediate with acetonitrile to prepare a sample solution containing 2mg of the intermediate per 1mL of acetonitrile, dissolving urea with acetonitrile to prepare a limit solution containing 0.005mg of urea per 1mL of acetonitrile, dissolving acetic acid with acetonitrile to prepare a limit solution containing 0.005mg of acetic acid per 1mL of acetonitrile, respectively taking 1 mu L of the solution, injecting the solution into a liquid chromatograph, recording a chromatogram, and detecting purity, impurity content and solvent residue of the intermediate; the method adopts a hydrophilic chromatographic column which well retains the strong polar compounds, a phosphoric acid aqueous solution/acetonitrile reversed phase chromatographic system and gradient elution for separation, can rapidly detect the purity of key intermediates, effectively separate main components from known impurities and residual solvents, monitor the reaction of the intermediates and ensure the smooth production of production workshops.
Description
Technical Field
The invention belongs to a high performance liquid chromatography (High Performance Liquid Chromatography, HPLC) method, in particular to a method for detecting purity, impurity content and residual solvent limit of a Pa Luo Weide intermediate by using HPLC.
Background
Pampers Luo Weide is the first oral drug to treat the new crown by approval. Currently, new coronaviruses (COVID-19) caused by the new coronavirus (SARS-CoV-2) are still spreading worldwide, and Pa Luo Weide (Paxlovid) is an inhibitor of the major protease 3CL of SARS-CoV-2, an essential viral enzyme, required for processing precursor proteins into functional products.
Named (1R, 5S) -6,6-dimethyl-3-azabicyclo [3.1.0]]hexane-2,4-dione with structural formulaMolecular formula C 7 H 9 NO 2 As a key intermediate for synthesizing the starting material of pampers Luo Weide, the purity, the content of related substances and the solvent residue need to be controlled in the process of producing the starting material of the target compound pampers Luo Weide.
The synthesis of the intermediate is a very key step in the process of directionally synthesizing the target compound Pa Luo Weide initial raw material, and the purity, the content of related substances and the solvent residual quantity are an important index for monitoring the reaction degree of the intermediate in a production workshop, so that the separation of the intermediate, impurities and solvents is of great significance to the reaction control in the production process of the Pa Luo Weide initial raw material.
Disclosure of Invention
The invention aims to provide an HPLC-UV method for detecting the purity of key intermediates, the content of related substances and the residual quantity of solvents in the process of preparing the Pa Luo Weide starting material.
The technical scheme adopted by the invention for solving the technical problems is as follows: an HPLC-UV detection method for the purity of the Pa Luo Weide intermediate comprises the following steps: YMC-Pack ODS-AQ,150×4.6mm,3 μm C18 column, column temperature 25 ℃; mobile phase: the water phase is 0.05% (v/v) phosphoric acid aqueous solution, the organic phase is acetonitrile, and the flow rate is 1.0 mL/min; elution procedure: gradient elution; sample introduction disc temperature: 5 ℃; detection wavelength: 200nm and 240nm; comprises the following steps
(1) Taking the structural formula asDissolving the sample with acetonitrile to prepare a sample solution containing about 2mg of the intermediate per 1mL of acetonitrile;
(2) Taking a proper amount of urea, dissolving a sample with acetonitrile, and secondarily diluting to prepare a limit solution containing about 0.005mg of urea per 1mL of acetonitrile;
(3) Taking a proper amount of acetic acid, dissolving a sample with acetonitrile, and secondarily diluting to prepare a limit solution containing about 0.005mg of acetic acid per 1mL of acetonitrile;
(4) And (3) respectively taking the solutions in the steps (1), (2) and (3), injecting the solutions into a liquid chromatograph according to a sample injection volume of 1 mu L, finishing intermediate detection, and recording chromatograms, thereby detecting the purity, impurity content and solvent residue of the intermediate.
Further, the chromatographic column is a C18 chromatographic column which has better hydrophilicity for strong polar compounds.
Further, the gradient elution is to firstly elute with 10% acetonitrile for 7.5min, then to raise the acetonitrile gradient to 75%, for 9.5min, then to rinse with 75% acetonitrile for 3min, and finally to adjust back to the initial ratio of 10% acetonitrile with 0.01min, and to equilibrate for 4.5min.
Further, the detection wavelength of 200nm is used for quantifying unknown impurities, urea, caronic acid, toluene and acetic acid, and the detection wavelength of 240nm is used for quantifying acetic anhydride and caronic anhydride.
Further, the liquid chromatograph is a Thermo Ultimate 3000/VC, DAD detector.
The beneficial effects of the invention are as follows:
the invention adopts YMC-Pack ODS-AQ,150 x 4.6mm,3 mu m C column, short column, small particle size and high column efficiency, which not only improves the separation efficiency of chromatographic peaks, but also can effectively shorten analysis time.
According to the invention, acetonitrile is selected to dissolve the sample, so that water is avoided being used as a sample dissolving solvent, and the stability of the sample solution is effectively improved.
The sample injection volume of the invention is 1 mu L, the volume is prevented from being adjusted as much as possible, and the solvent effect caused by adopting a pure organic phase as a solvent for dissolving samples is effectively improved by the sample injection volume of 1 mu L.
The invention adopts the same HPLC-UV method to control related substances and solvent residues of the intermediate, breaks through the general rule of the conventional GC control of the solvent residues, effectively reduces the number of methods and improves the analysis and detection efficiency.
The invention calculates the purity of the intermediate and the content of related substances by adopting a percentage area method, controls urea and acetic acid by adopting a limit method, and has simple and convenient established method and can effectively improve the analysis and detection efficiency.
According to the invention, 2 wavelengths are adopted for monitoring related substances controlled in the intermediate, 200nm is adopted for unknown impurities, urea, caronic acid, toluene and acetic acid, 240nm is adopted for acetic anhydride and caronic anhydride, when the content is calculated, the percentage area of the caronic acid is about multiplied by 8.5, the percentage area of the acetic anhydride is about multiplied by 5.1, whether the evaluation of acetic acid and urea exceeds the limit (0.25%), other impurities directly take the percentage area as the content thereof, the calculation mode is simple and convenient, and the analysis efficiency is effectively improved.
The method can simply and rapidly measure the purity of the intermediate, the content of related substances and the size of the residual solvent, and solves the problem of reaction monitoring of the intermediate in the production process.
Drawings
FIG. 1 is a sample of pure water of comparative example 1 of the present invention: acn=2: 8 (v/v) solution stability HPLC fold;
FIG. 2 is a graph showing the elution HPLC of YMC Pack ODS-AQ 1. Mu.L of comparative example 2 of the present invention.
Detailed Description
The invention will be further described with reference to the drawings and the specific examples.
The applicant finds that the intermediate and impurities and residual solvent thereof can be effectively separated by using a hydrophilic C18 chromatographic column which is better for retaining a strong polar compound and taking phosphoric acid aqueous solution/acetonitrile as a mobile phase system for gradient elution, and the specificity is strong, so that the purity of the intermediate, the impurity content and the residual solvent size can be accurately measured, and therefore, the method for detecting the purity of the intermediate in the preparation process of the key starting material of the novel crown drug by HPLC-UV is provided.
The HPLC-UV detection method for the purity of the intermediate ((1R, 5S) -6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2, 4-dione) in the preparation process of the starting material (6, 6-dimethyl-3-azabicyclo [3.1.0] hexane) can be realized according to the following method:
(1) A suitable amount of intermediate was taken and the sample was dissolved in acetonitrile to prepare a sample solution containing about 2mg of intermediate per 1mL of acetonitrile.
(2) An appropriate amount of urea was taken, the sample was dissolved in acetonitrile and diluted again to prepare a limiting solution containing about 0.005mg of urea per 1mL of acetonitrile.
(3) An appropriate amount of acetic acid was taken, the sample was dissolved in acetonitrile and diluted again to prepare a limiting solution containing about 0.005mg of acetic acid per 1mL of acetonitrile.
(5) And (3) respectively taking the solutions in the steps (1), (2) and (3), injecting the solutions into a liquid chromatograph according to a sample injection volume of 1 mu L, finishing intermediate detection, and recording chromatograms, thereby detecting the purity, impurity content and solvent residue of the intermediate.
Wherein the detection conditions are as follows:
high performance liquid chromatograph: thermo Ultimate 3000, DAD detector.
Chromatographic column: YMC-Pack ODS-AQ,150×4.6mm,3 μm.
Mobile phase: 0.05% (v/v) H 3 PO 4 in H 2 O (channel one), ACN (channel two).
Elution procedure: eluting with 10% acetonitrile for 7.5min, then increasing acetonitrile gradient to 75% for 9.5min, rinsing with 75% acetonitrile for 3min, and finally adjusting back to the initial ratio of 10% acetonitrile for 0.01min and balancing for 4.5min.
Detection wavelength: 200nm (unknown impurities, urea, caronic acid, toluene, acetic acid), 240nm (acetic anhydride, caronic anhydride).
Flow rate: 1.0mL/min.
Column temperature: 25 ℃.
Sample injection volume: 1 mul.
Sample introduction disc temperature: 5 ℃.
Comparative example 1
Instrument and conditions:
high performance liquid chromatograph: thermo Ultimate 3000, DAD detector.
Chromatographic column: YMC-Pack ODS-AQ,150×4.6mm,3 μm.
Mobile phase: 0.1% (v/v) H 3 PO 4 in H 2 O (channel one), ACN (channel two).
Elution procedure: eluting with 15% acetonitrile for 1.5min, then raising the acetonitrile gradient to 80%, taking 7min, washing with 80% acetonitrile for 3min, and finally adjusting back to 15% acetonitrile with 0.1min, and balancing for 4min.
Detection wavelength: and (5) full sweeping.
Flow rate: 1.0mL/min.
Column temperature: 30 ℃.
Sample injection volume: 1 mul.
The experimental steps are as follows: the intermediate 2 produced (known impurity 1 of intermediate) was taken as a solid, 25mg, placed in a 5mL volumetric flask, and acetonitrile was added: water = 8:2 (v/v) was dissolved and diluted to a scale, and shaken well to prepare a sample solution for development of the method.
Taking the sample solution, performing high performance liquid chromatography under the conditions, and recording a chromatogram. As a result, in FIG. 1, peak No. 1 is intermediate 1 (known impurity 2 of intermediate), peak No. 2 is intermediate 2 (known impurity 1 of intermediate), and it can be seen from the figure that the solution of known impurity intermediate 2 to be controlled by intermediate is unstable under this condition.
Comparative example 2
Instrument and conditions:
high performance liquid chromatograph: thermo Ultimate 3000, DAD detector.
Chromatographic column: YMC-Pack ODS-AQ,150×4.6mm,3 μm.
Mobile phase: 0.05% (v/v) H 3 PO 4 in H 2 O (channel one), ACN (channel two).
Elution procedure: eluting with 10% acetonitrile for 7.5min, then increasing acetonitrile gradient to 75% for 9.5min, rinsing with 75% acetonitrile for 3min, and finally adjusting back to the initial ratio of 10% acetonitrile for 0.01min and balancing for 4.5min.
Detection wavelength: 200nm (unknown impurities, urea, caronic acid, toluene, acetic acid), 240nm (acetic anhydride, caronic anhydride).
Flow rate: 1.0mL/min.
Column temperature: 25 ℃.
Sample injection volume: 1 mul.
Sample introduction disc temperature: 5 ℃.
The experimental steps are as follows: a suitable amount of intermediate was taken and the sample was dissolved in acetonitrile to prepare a sample solution containing about 2mg of intermediate per 1mL of acetonitrile.
Taking the sample solution, performing high performance liquid chromatography under the conditions, and recording a chromatogram. The results are shown in figure 2, the peak No. 1 is urea, the peak No. 2 is acetic acid, the peak No. 3 is acetic anhydride, the peak No. 4 is caronic anhydride, the peak No. 5 is intermediate, the peak No. 6 is caronic anhydride, the peak No. 7 is toluene, under the condition, the intermediate is completely separated from each impurity by baseline, the peaks are symmetrical, and the main peak of the intermediate is about 6.89 min.
The above embodiments are merely illustrative of the principles of the present invention and its effectiveness, and some practical embodiments, and variations and modifications may be made by those skilled in the art without departing from the inventive concept, which are all within the scope of the present invention.
Claims (3)
1. An HPLC-UV detection method of pampers Luo Weide intermediate purity, characterized in that the detection conditions are:
chromatographic column: YMC-Pack ODS-AQ,150×4.6mm,3 μm C18 column, column temperature 25 ℃;
mobile phase: the water phase is 0.05% v/v phosphoric acid water solution, the organic phase is acetonitrile, and the flow rate is 1.0 mL/min;
elution procedure: gradient elution: eluting with 10% acetonitrile for 7.5min, then raising the acetonitrile gradient to 75% for 9.5min, then washing with 75% acetonitrile for 3min, and finally adjusting back to the initial ratio of 10% acetonitrile with 0.01min, and balancing for 4.5min;
sample introduction disc temperature: 5 ℃;
detection wavelength: 200nm and 240nm;
comprises the following steps
(1) Taking the structural formula asDissolving with acetonitrile to prepare a sample solution containing intermediate 2mg per 1mL of acetonitrile;
(2) Dissolving urea with acetonitrile to prepare a limit solution containing 0.005mg of urea per 1mL of acetonitrile;
(3) Dissolving acetic acid in acetonitrile to prepare a limit solution containing 0.005mg of acetic acid per 1mL of acetonitrile;
(4) And (3) injecting 1 mu L of the solution obtained in the steps (1), (2) and (3) into a liquid chromatograph, recording the chromatograms, and detecting the purity of the intermediate, the impurity content and the residual solvent.
2. The method for detecting purity of the intermediate of pa Luo Weide by HPLC-UV according to claim 1, wherein the detection wavelength is 200nm for quantifying unknown impurities, urea, caronic acid, toluene, acetic acid, and the detection wavelength is 240nm for quantifying acetic anhydride, caronic anhydride.
3. The method for HPLC-UV detection of the purity of a pampers Luo Weide intermediate according to claim 1, wherein the liquid chromatograph is a Thermo Ultimate 3000/VC, DAD detector.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06178685A (en) * | 1992-12-15 | 1994-06-28 | Tokuyama Soda Co Ltd | Benzylamine transaminase |
| WO2012049688A1 (en) * | 2010-10-12 | 2012-04-19 | Arch Pharmalabs Limited | An improved process for the preparation of racemic 6, 6- dimethyl-3-azabicyclo-[3.1.0]-hexane and its salts, a key raw material for hcv inhibitor. |
| CN114085180A (en) * | 2022-01-18 | 2022-02-25 | 凯莱英医药集团（天津）股份有限公司 | Preparation method of azacyclo derivative intermediate and preparation method of chiral proline derivative intermediate |
| CN114105859A (en) * | 2022-01-27 | 2022-03-01 | 南京桦冠生物技术有限公司 | Synthetic method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2008008350A (en) * | 2005-12-22 | 2008-09-03 | Schering Corp | Process for the preparation of 6, 6-dimethyl-3-azabicyclo-[3.1.0] -hexane compounds and enantiomeric salts thereof. |
| EP2225203A1 (en) * | 2007-11-28 | 2010-09-08 | Schering Corporation | Dehydrohalogenation process for the preparation of intermediates useful in providing 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane compounds |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06178685A (en) * | 1992-12-15 | 1994-06-28 | Tokuyama Soda Co Ltd | Benzylamine transaminase |
| WO2012049688A1 (en) * | 2010-10-12 | 2012-04-19 | Arch Pharmalabs Limited | An improved process for the preparation of racemic 6, 6- dimethyl-3-azabicyclo-[3.1.0]-hexane and its salts, a key raw material for hcv inhibitor. |
| CN114085180A (en) * | 2022-01-18 | 2022-02-25 | 凯莱英医药集团（天津）股份有限公司 | Preparation method of azacyclo derivative intermediate and preparation method of chiral proline derivative intermediate |
| CN114105859A (en) * | 2022-01-27 | 2022-03-01 | 南京桦冠生物技术有限公司 | Synthetic method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane |
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