CN106632156B - A method of preparing slimming medicine orlistat - Google Patents
A method of preparing slimming medicine orlistat Download PDFInfo
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- CN106632156B CN106632156B CN201611183604.XA CN201611183604A CN106632156B CN 106632156 B CN106632156 B CN 106632156B CN 201611183604 A CN201611183604 A CN 201611183604A CN 106632156 B CN106632156 B CN 106632156B
- Authority
- CN
- China
- Prior art keywords
- orlistat
- lipstatin
- hydrazine hydrate
- pentacarbonyl
- iron
- 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.)
- Expired - Fee Related
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- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 title claims abstract description 55
- 229960001243 orlistat Drugs 0.000 title claims abstract description 55
- 238000000034 method Methods 0.000 title claims abstract description 29
- 239000003814 drug Substances 0.000 title abstract description 6
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 18
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 18
- SIKWOTFNWURSAY-UHFFFAOYSA-N Lipstatin Natural products CCCCCCC1C(CC(CC=CCC=CCCCCC)C(=O)OC(CC(C)C)NC=O)OC1=O SIKWOTFNWURSAY-UHFFFAOYSA-N 0.000 claims abstract description 17
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 17
- OQMAKWGYQLJJIA-CUOOPAIESA-N lipstatin Chemical compound CCCCCC[C@H]1[C@H](C[C@H](C\C=C/C\C=C/CCCCC)OC(=O)[C@H](CC(C)C)NC=O)OC1=O OQMAKWGYQLJJIA-CUOOPAIESA-N 0.000 claims abstract description 17
- 229910052742 iron Inorganic materials 0.000 claims abstract description 15
- 238000006722 reduction reaction Methods 0.000 claims abstract description 9
- 238000012805 post-processing Methods 0.000 claims abstract description 5
- 239000007858 starting material Substances 0.000 claims abstract description 4
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 239000000706 filtrate Substances 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- 239000003208 petroleum Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 239000007789 gas Substances 0.000 claims description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- 230000001681 protective effect Effects 0.000 claims description 3
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 239000001307 helium Substances 0.000 claims description 2
- 229910052734 helium Inorganic materials 0.000 claims description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims 1
- 238000001291 vacuum drying Methods 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 18
- 239000006227 byproduct Substances 0.000 abstract description 3
- 239000003638 chemical reducing agent Substances 0.000 abstract description 3
- 239000001257 hydrogen Substances 0.000 abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 230000006837 decompression Effects 0.000 description 7
- 238000006073 displacement reaction Methods 0.000 description 7
- 239000012046 mixed solvent Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000000855 fermentation Methods 0.000 description 3
- 230000004151 fermentation Effects 0.000 description 3
- LRXRIVSWHMVULO-HKBOAZHASA-N (3s,4s,6r)-3-hexyl-4-hydroxy-6-undecyloxan-2-one Chemical compound CCCCCCCCCCC[C@@H]1C[C@H](O)[C@H](CCCCCC)C(=O)O1 LRXRIVSWHMVULO-HKBOAZHASA-N 0.000 description 2
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- HFBHOAHFRNLZGN-LURJTMIESA-N (2s)-2-formamido-4-methylpentanoic acid Chemical compound CC(C)C[C@@H](C(O)=O)NC=O HFBHOAHFRNLZGN-LURJTMIESA-N 0.000 description 1
- 102100031416 Gastric triacylglycerol lipase Human genes 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 108050006759 Pancreatic lipases Proteins 0.000 description 1
- 102000019280 Pancreatic lipases Human genes 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 108010091264 gastric triacylglycerol lipase Proteins 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- -1 hydrogen furans Chemical class 0.000 description 1
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 description 1
- 229940040461 lipase Drugs 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 230000004130 lipolysis Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229940116369 pancreatic lipase Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D305/10—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having one or more double bonds between ring members or between ring members and non-ring members
- C07D305/12—Beta-lactones
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of method for preparing slimming medicine orlistat, this method is using lipstatin as starting material, under the catalysis of pentacarbonyl-iron, reduction reaction occurs with hydrazine hydrate and obtains orlistat.The method provided by the invention for preparing orlistat, reaction condition is mild, and easy to operate, reaction yield effectively improves；Using hydrazine hydrate as reducing agent and hydrogen source, byproduct of reaction is few, and post-processing is simple.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular, to a method of prepare slimming medicine orlistat.
Background technique
Orlistat (Orlistat), entitled (S) -2- formamido -4- methvl-pentanoic acid ester (the S) -1- of chemistry [[(2S,
3S) -3- hexyl -4- oxygen -2- oxetanyl]-methyl]-dodecyl ester.Orlistat is the novel of Roche Holding Ag's exploitation
Slimming medicine is combined by the active ser position of stomach and enteral gastric lipase and pancreatic lipase and forms covalent bond,
So that lipase is lost activity, lipolysis, absorption and utilization in 15 is prevented, to achieve the purpose that weight-reducing.With other weight-reducing
Medicine is compared, it is advantageous that orlistat does not act on and nervous system, does not enter blood, not appetite-suppressing.
Currently, the preparation of orlistat is broadly divided into two kinds, one obtains orlistat intermediate (Ni Bo for microbial fermentation
Take charge of statin), it is then hydrogenated to obtain orlistat；Two be chemical complete synthesizing process, since orlistat molecule is complicated and has hand
Property center, reaction step is more, and yield is low, is unfavorable for industrialized production.Therefore, it is still produced at present using the first as orlistat
Major way, main research and development focus on microbial fermentation, including screening, the optimization of fermentation condition and subsequent products in army
Purifying etc., but crucial subsequent hydrogenation reaction in this method, since using conventional Pd/C catalytic hydrogenation, by-product is more, instead
Answer yield only 50~60% or so.
The problem of in view of above-mentioned existing method, this field still need to the method for preferably preparing orlistat, special
It is not that mild condition, method be simple and the method for preparing orlistat intermediate of high income.
Summary of the invention
It is an object of the invention to overcome existing hydrogenation reaction condition harshness during preparing orlistat, yield is low
Defect, provides that a kind of mild condition, step be simple and the method for preparing orlistat of high income.
To achieve the goals above, the present invention provides a kind of method for preparing orlistat, and this method is with lipstatin
Reduction reaction occurs with hydrazine hydrate and obtains orlistat under the catalysis of pentacarbonyl-iron for starting material.
Inventor has found under study for action, can when using pentacarbonyl-iron as catalyst and hydrazine hydrate for reducing agent
Smoothly two carbon-carbon double bonds in lipstatin are restored, and do not destroy other groups, reaction yield effectively improves.
In the present invention, in order to enable reduction reaction is more abundant, it is preferable that the detailed process of this method includes：Room temperature
Lipstatin and pentacarbonyl-iron are added in tetrahydrofuran, are then heated to 40~50 DEG C, keeps temperature, instills hydration
Hydrazine, drop finish, continue to be stirred to react 5~8 hours, and post-processing obtains orlistat.
In the present invention, the post-processing after reduction reaction is there is no special, for example, after reaction, being cooled to room temperature, mistake
Filter, filtrate decompression are concentrated to get orlistat.
Preferably, lipstatin and the dosage molar ratio of pentacarbonyl-iron, hydrazine hydrate are 1：0.02~0.05：2~4.
It is further preferred that lipstatin and the dosage molar ratio of pentacarbonyl-iron, hydrazine hydrate are 1：0.03：3.
In the present invention, in order to reduce influence of the air to catalyst and reduction reaction, the reduction reaction is all being protected
It is carried out in the presence of shield gas, the protective gas can be nitrogen, helium or argon gas.
In the present invention, this method can also include the steps that the orlistat that will be obtained refines, specifically, will
To orlistat be dissolved in methylene chloride/petroleum ether mixed solvent (volume ratio 1:20) 60~80 DEG C of stirrings 10, are then heated to
~20min, is filtered while hot, filtrate natural cooling, is filtered, and the orlistat refined is dried in vacuo.Ao Lisi after purification
He reaches 99.5% or more at HPLC purity.
In the present invention, tracking can be monitored to reaction by the method for this field routine during reduction reaction,
Such as TLC, LCMS, GCMS etc., end of reaction refer to TLC monitor not excess raw material disappeared or LCMS, GCMS in it is not excessive
Starting material left is less than 2%.
The specific route that the present invention prepares the method for orlistat is as follows：
Compared with prior art, using the method provided by the invention for preparing orlistat, reaction condition is mild, operation letter
Single, reaction yield effectively improves；Using hydrazine hydrate as reducing agent and hydrogen source, byproduct of reaction is few, and post-processing is simple.
Other features and advantages of the present invention will the following detailed description will be given in the detailed implementation section.
Specific embodiment
Present invention will be further explained below with reference to specific examples.But these embodiments be only limitted to illustrate the present invention without
It is to be further limited to protection scope of the present invention.
Embodiment 1
The preparation of orlistat
Firstly, three times by reaction flask displacement nitrogen, then room temperature is by lipstatin 10g and pentacarbonyl-iron 0.11g
It is added in tetrahydrofuran, is then heated to 50 DEG C, keep temperature, instill hydrazine hydrate 3.1g, drop finishes, and continues to be stirred to react 5 small
When, it is cooled to room temperature, filters, filtrate decompression is concentrated to get orlistat.Obtained orlistat is dissolved in methylene chloride/petroleum
Ether mixed solvent (volume ratio 1:20) 65 DEG C of 10~20min of stirring, are then heated to, are filtered while hot, filtrate natural cooling, are taken out
Filter is dried in vacuo the orlistat 9.1g refined, yield 90.2%, HPLC purity 99.76%.
Embodiment 2
The preparation of orlistat
Firstly, three times by reaction flask displacement nitrogen, then room temperature adds lipstatin 10g and pentacarbonyl-iron 0.1g
Entering into tetrahydrofuran, be then heated to 45 DEG C, keep temperature, instills hydrazine hydrate 3.1g, drop finishes, continues to be stirred to react 6 hours,
It is cooled to room temperature, filters, filtrate decompression is concentrated to get orlistat.Obtained orlistat is dissolved in methylene chloride/petroleum ether
Mixed solvent (volume ratio 1:20) 70 DEG C of 10~20min of stirring, are then heated to, are filtered while hot, filtrate natural cooling, are filtered,
It is dried in vacuo the orlistat 8.9g refined, yield 88.2%, HPLC purity 99.63%.
Embodiment 3
The preparation of orlistat
Firstly, three times by reaction flask displacement nitrogen, then room temperature adds lipstatin 10g and pentacarbonyl-iron 0.2g
Entering into tetrahydrofuran, be then heated to 40 DEG C, keep temperature, instills hydrazine hydrate 4.1g, drop finishes, continues to be stirred to react 6 hours,
It is cooled to room temperature, filters, filtrate decompression is concentrated to get orlistat.Obtained orlistat is dissolved in methylene chloride/petroleum ether
Mixed solvent (volume ratio 1:20) 80 DEG C of 10~20min of stirring, are then heated to, are filtered while hot, filtrate natural cooling, are filtered,
It is dried in vacuo the orlistat 8.9g refined, yield 88.7%, HPLC purity 99.59%.
Embodiment 4
The preparation of orlistat
Firstly, three times by reaction flask displacement nitrogen, then room temperature is by lipstatin 10g and pentacarbonyl-iron 0.11g
It is added in tetrahydrofuran, is then heated to reflux, keep temperature, instill hydrazine hydrate 3.1g, drop finishes, and continues to be stirred to react 5 small
When, it is cooled to room temperature, filters, filtrate decompression is concentrated to get orlistat.Obtained orlistat is dissolved in methylene chloride/petroleum
Ether mixed solvent (volume ratio 1:20) 65 DEG C of 10~20min of stirring, are then heated to, are filtered while hot, filtrate natural cooling, are taken out
Filter is dried in vacuo the orlistat 7.9g refined, yield 78.6%, HPLC purity 99.44%.
Embodiment 5
The preparation of orlistat
Firstly, three times by reaction flask displacement nitrogen, then room temperature adds lipstatin 10g and pentacarbonyl-iron 0.5g
Entering into tetrahydrofuran, be then heated to 50 DEG C, keep temperature, instills hydrazine hydrate 3.1g, drop finishes, continues to be stirred to react 5 hours,
It is cooled to room temperature, filters, filtrate decompression is concentrated to get orlistat.Obtained orlistat is dissolved in methylene chloride/petroleum ether
Mixed solvent (volume ratio 1:20) 65 DEG C of 10~20min of stirring, are then heated to, are filtered while hot, filtrate natural cooling, are filtered,
It is dried in vacuo the orlistat 9.0g refined, yield 89.8%, HPLC purity 99.20%.
Comparative example 1
Three times by reaction flask displacement nitrogen, then lipstatin 10g is added in tetrahydrofuran by room temperature, then plus
Heat keeps temperature to 50 DEG C, instills hydrazine hydrate 3.1g, and drop finishes, continues to be stirred to react 5 hours, be cooled to room temperature, and filters, filtrate
Being concentrated under reduced pressure to give orlistat crude product 5.3g, HPLC purity is 51.2%, yield 26.7%.
Comparative example 2
Three times by reaction flask displacement nitrogen, then lipstatin 10g and iron chloride 0.1g are added to four by room temperature
In hydrogen furans, 50 DEG C are then heated to, keeps temperature, instills hydrazine hydrate 3.1g, drop finishes, continues to be stirred to react 7 hours, be cooled to
Room temperature, filtering, it is 44.8% that filtrate decompression, which is concentrated to get orlistat crude product 6.8g, HPLC purity, yield 30.1%.
The preferred embodiment of the present invention has been described above in detail, still, during present invention is not limited to the embodiments described above
Detail within the scope of the technical concept of the present invention can be with various simple variants of the technical solution of the present invention are made, this
A little simple variants all belong to the scope of protection of the present invention.
It is further to note that specific technical features described in the above specific embodiments, in not lance
In the case where shield, can be combined in any appropriate way, in order to avoid unnecessary repetition, the present invention to it is various can
No further explanation will be given for the combination of energy.In addition, any group can also be carried out between a variety of different embodiments of the invention
It closes, as long as it does not violate the idea of the present invention, it should also be regarded as the disclosure of the present invention.
Claims (3)
1. a kind of method for preparing orlistat, which is characterized in that this method is using lipstatin as starting material, in pentacarbonyl
Under the catalysis for closing iron, reduction reaction occurs with hydrazine hydrate and obtains orlistat, the reduction reaction in the presence of protective gas into
Row, the protective gas are nitrogen, helium or argon gas；
The detailed process of this method includes：Lipstatin and pentacarbonyl-iron are added in tetrahydrofuran by room temperature, then plus
Heat keeps temperature to 40 ~ 50 DEG C, instills hydrazine hydrate, and drop finishes, continues to be stirred to react 5 ~ 8 hours, and post-processing obtains orlistat；
Lipstatin and the dosage molar ratio of pentacarbonyl-iron, hydrazine hydrate are 1：0.02~0.05：2~4.
2. the method according to claim 1 for preparing orlistat, which is characterized in that lipstatin and pentacarbonyl close
Iron, hydrazine hydrate dosage molar ratio be 1：0.03：3.
3. the method according to claim 1 for preparing orlistat, which is characterized in that this method further includes the Austria that will be obtained
Obtained orlistat is specifically dissolved in methylene chloride/petroleum ether volume ratio 1 by the step of Li Sita is refined:20 it is mixed
Bonding solvent is then heated to 60 ~ 80 DEG C of 10 ~ 20min of stirring, filters while hot, filtrate natural cooling, filters, and vacuum drying obtains
The orlistat of purification.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611183604.XA CN106632156B (en) | 2016-12-20 | 2016-12-20 | A method of preparing slimming medicine orlistat |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611183604.XA CN106632156B (en) | 2016-12-20 | 2016-12-20 | A method of preparing slimming medicine orlistat |
Publications (2)
| Publication Number | Publication Date |
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| CN106632156A CN106632156A (en) | 2017-05-10 |
| CN106632156B true CN106632156B (en) | 2018-11-20 |
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Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002523525A (en) * | 1998-08-18 | 2002-07-30 | バイオマット サイエンス，インク． | Adhesive composition for human hard tissue |
| CN101775416A (en) * | 2010-02-04 | 2010-07-14 | 傅军 | Novel method for preparing orlistat |
| CN101948450B (en) * | 2010-10-13 | 2013-04-24 | 鲁南制药集团股份有限公司 | Method for preparing orlistat |
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Effective date of registration: 20181015 Address after: 261500 Gaomi City people's Hospital, 77 Fu Street West, Gaomi City Town, Weifang, Shandong Applicant after: Xu Min Applicant after: Zhong Xia Address before: 266520 1 residential 1708, Changjiang East Road, Huangdao District, Qingdao, Shandong, 1708 Applicant before: Chen Da bio tech ltd, Qingdao |
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