CN102260179A - Novel technology for resolving salbutamol sulfate - Google Patents
Novel technology for resolving salbutamol sulfate Download PDFInfo
- Publication number
- CN102260179A CN102260179A CN2010101803786A CN201010180378A CN102260179A CN 102260179 A CN102260179 A CN 102260179A CN 2010101803786 A CN2010101803786 A CN 2010101803786A CN 201010180378 A CN201010180378 A CN 201010180378A CN 102260179 A CN102260179 A CN 102260179A
- Authority
- CN
- China
- Prior art keywords
- salbutamol
- salbutamol sulfate
- sulfate
- resolving
- chiral acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
- BNPSSFBOAGDEEL-UHFFFAOYSA-N albuterol sulfate Chemical compound OS(O)(=O)=O.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 BNPSSFBOAGDEEL-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 238000005516 engineering process Methods 0.000 title abstract description 4
- 229960002052 salbutamol Drugs 0.000 claims abstract description 18
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000002253 acid Substances 0.000 claims abstract description 10
- NDAUXUAQIAJITI-LBPRGKRZSA-N (R)-salbutamol Chemical compound CC(C)(C)NC[C@H](O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-LBPRGKRZSA-N 0.000 claims abstract description 8
- 229950008204 levosalbutamol Drugs 0.000 claims abstract description 8
- 238000005194 fractionation Methods 0.000 claims description 7
- 238000001953 recrystallisation Methods 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 3
- 230000003287 optical effect Effects 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 3
- 230000003113 alkalizing effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000011017 operating method Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- VNVNZKCCDVFGAP-FPDJQMMJSA-N 4-[(1r)-2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;(2r,3r)-2,3-dihydroxybutanedioic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.CC(C)(C)NC[C@H](O)C1=CC=C(O)C(CO)=C1.CC(C)(C)NC[C@H](O)C1=CC=C(O)C(CO)=C1 VNVNZKCCDVFGAP-FPDJQMMJSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229940076884 levalbuterol tartrate Drugs 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- YONLFQNRGZXBBF-KBPBESRZSA-N (2s,3s)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-KBPBESRZSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 201000009267 bronchiectasis Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a technology for resolving salbutamol sulfate, and the technology comprises the following steps: (1) alkalizing salbutamol sulfate; (2) resolving and salifying salbutamol and chiral acid; (3) recrystallizing chiral acid salt of salbutamol; (4) conveying chiral acid salt of salbutamol to levoamlo (R) salbutamol sulfate.
Description
Technical field the present invention relates to prepare the fractionation novel process of left-handed (R) salbutamol sulfate.Synthesis step of the present invention comprises: the alkalization method of (1) salbutamol sulphate; (2) fractionation of salbutamol sulfate and chiral acid, salifying method; (3) recrystallization method of the chirality hydrochlorate of salbutamol; (4) salbutamol chirality hydrochlorate changes into left-handed (R) salbutamol sulfate.
The background technology salbutamol sulfate is a kind of bronchiectasis medicine, and its raceme has gone on the market for many years and has been extensive use of clinical.
The present invention relates to the resolution process of salbutamol sulfate, key step is as follows:
(1) alkalization of salbutamol sulfate; (2) fractionation of salbutamol and chiral acid, salify; (3) recrystallization of the chirality hydrochlorate of salbutamol; (4) salbutamol chirality hydrochlorate changes into left-handed (R) salbutamol sulfate.
Summary of the invention
The present invention proposes to use that corresponding chiral acid and salbutamol split, salify, the method for preparation left-handed (R) salbutamol sulfate behind recrystallization.Fig. 1: the structure of left-handed (R) salbutamol sulfate; Fig. 2: the fractionation preparation method of left-handed (R) salbutamol sulfate.
The present invention finds to use different chiral acids and salbutamol salify, and the otherness of the non-corresponding isomer of formation has obvious difference, and finds the method and the rule of the non-corresponding isomer that is formed with the significance difference opposite sex.Adopting the most frequently used straight chain chiral acid tartrate and the most frequently used phenyl ring is the chiral acid amygdalic acid, with racemization salbutamol salify, can't separate out crystal or separate out crystallization seldom in common solvent.The otherness that shows above-mentioned two kinds of resolving agents and the formed salt of salbutamol two enantiomorphs is little, can not be used for above-mentioned fractionation, and adopt sterically hindered bigger palmistry acid---D-(+)-dibenzoyl tartaric acid, helps the fractionation of this product.
Embodiment
1, alkalization
[proportioning raw materials]
Material name specification dosage mol counts the mol ratio
Salbutamol sulfate A.R. 144.2 grams 0.5 1
Sodium Metal 99.5 A.R. 11.5 grams 0.5 1
Methyl alcohol 1000ml
[operating procedure]
Sodium Metal 99.5 and methyl alcohol reaction are made sodium methoxide solution, standby.Salbutamol sulfate is added in the 500ml alcohol, and cooling is the dropping sodium methoxide solution down, drips and finishes, and stirs 30 minutes, filters, and it is dried that filtrate decompression is concentrated into, and cooling gets product 104.18g.
2, salify splits
[proportioning raw materials]
Material name specification dosage mol counts the mol ratio
Salbutamol self-control 100 grams 0.41 1
D-(+)-dibenzoyl tartaric acid A.R. 66 grams 0.44 1.03
Methyl alcohol 250ml
Ethyl acetate 250ml
[operating procedure]
With above-mentioned mixing of materials, reflux 2 hours, cooling, crystallization is filtered, and gets product 85g.Yield 50%.
The HPLC:S-salbutamol accounts for: 47.6%
3, refining
[proportioning raw materials]
Material name specification dosage mol counts the mol ratio
Levalbuterol tartrate self-control 100 grams
Methyl alcohol 1500ml
Ethyl acetate 1500ml
[operating procedure]
With above-mentioned mixing of materials, reflux 2 hours, cooling, crystallization is filtered, and gets product 52.18g.Yield 52%.
HPLC: through 3 recrystallizations, S-salbutamol proportion is reduced to 1.2% by 47.6%
4, salt-forming reaction
[proportioning raw materials]
Material name specification dosage mol counts the mol ratio
Levalbuterol tartrate self-control 17.33 grams
Sodium Metal 99.5 A.R. 2.07 grams
Methyl alcohol 170+50ml
Sulfuric acid is an amount of
[operating procedure]
Sodium Metal 99.5 and methyl alcohol (50ml) reaction are made sodium methoxide solution, standby.The Levalbuterol tartrate is added in the 170ml methyl alcohol, and cooling drips down sodium methoxide solution, drips and finishes, and stirs 30 minutes, filters, and filtrate is regulated PH to 4-4.5 with sulfuric acid under the frozen water cooling, stirs 1 hour, and filtration gets product 15.67g.Yield 86%.
The HPLC:S-salbutamol accounts for: 0.15%
Claims (1)
1. the preparation method of the single optical isomer of salbutamol sulfate comprises the following step:
(1) alkalization of salbutamol sulphate;
(2) fractionation of salbutamol sulfate and chiral acid, salify;
(3) recrystallization of the chirality hydrochlorate of salbutamol;
(4) salbutamol chirality hydrochlorate changes into left-handed (R) salbutamol sulfate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101803786A CN102260179A (en) | 2010-05-24 | 2010-05-24 | Novel technology for resolving salbutamol sulfate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101803786A CN102260179A (en) | 2010-05-24 | 2010-05-24 | Novel technology for resolving salbutamol sulfate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102260179A true CN102260179A (en) | 2011-11-30 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010101803786A Pending CN102260179A (en) | 2010-05-24 | 2010-05-24 | Novel technology for resolving salbutamol sulfate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102260179A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108069865A (en) * | 2016-11-17 | 2018-05-25 | 上海医药工业研究院 | The method for splitting and intermediate of 2- diethylin propyl alcohol |
| CN115109026A (en) * | 2022-06-28 | 2022-09-27 | 北京云鹏鹏程医药科技有限公司 | Preparation method of levalbuterol intermediate and hydrochloride with high ee value |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1273966A (en) * | 1999-10-19 | 2000-11-22 | 中国科学院成都有机化学研究所 | Process for preparing adrenin beta-excitomotors by combinaion and disconnection method |
| CN1382685A (en) * | 2001-04-26 | 2002-12-04 | 中国科学院成都有机化学研究所 | Process for preparing R-salbutamol tartrate |
| US20040054215A1 (en) * | 2000-12-11 | 2004-03-18 | Hamied Yusuf Khwaja | Process for preparing isomers of salbutamol |
| US20050261368A1 (en) * | 2004-05-20 | 2005-11-24 | Valeriano Merli | Preparation of levalbuterol hydrochloride |
| CN1927813A (en) * | 2005-09-08 | 2007-03-14 | 上海医药工业研究院 | Synthesis method of levorotatory albuterol hydrochloride |
-
2010
- 2010-05-24 CN CN2010101803786A patent/CN102260179A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1273966A (en) * | 1999-10-19 | 2000-11-22 | 中国科学院成都有机化学研究所 | Process for preparing adrenin beta-excitomotors by combinaion and disconnection method |
| US20040054215A1 (en) * | 2000-12-11 | 2004-03-18 | Hamied Yusuf Khwaja | Process for preparing isomers of salbutamol |
| CN1382685A (en) * | 2001-04-26 | 2002-12-04 | 中国科学院成都有机化学研究所 | Process for preparing R-salbutamol tartrate |
| US20050261368A1 (en) * | 2004-05-20 | 2005-11-24 | Valeriano Merli | Preparation of levalbuterol hydrochloride |
| CN1927813A (en) * | 2005-09-08 | 2007-03-14 | 上海医药工业研究院 | Synthesis method of levorotatory albuterol hydrochloride |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108069865A (en) * | 2016-11-17 | 2018-05-25 | 上海医药工业研究院 | The method for splitting and intermediate of 2- diethylin propyl alcohol |
| CN115109026A (en) * | 2022-06-28 | 2022-09-27 | 北京云鹏鹏程医药科技有限公司 | Preparation method of levalbuterol intermediate and hydrochloride with high ee value |
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| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20111130 |