CN109485593A - A kind of synthesis technology of La Luotasai chiral side chain - Google Patents
A kind of synthesis technology of La Luotasai chiral side chain Download PDFInfo
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- CN109485593A CN109485593A CN201811518031.0A CN201811518031A CN109485593A CN 109485593 A CN109485593 A CN 109485593A CN 201811518031 A CN201811518031 A CN 201811518031A CN 109485593 A CN109485593 A CN 109485593A
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- luotasai
- side chain
- chiral side
- synthesis technology
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
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- 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
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- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A kind of synthesis technology of La Luotasai chiral side chain, with (3R, 4S) -3- hydroxy-4-phenyl -2- aza cyclo-butanone is starting material, using one kettle way, it is first directly obtained into La Luotasai chiral side chain with vinyl ethyl ether condensation, again with the condensation of BOC- acid anhydrides, its feature is that step is short, reduces material loss, is directly recrystallized with suitable solvent；In addition, post-processing is extremely simple, and n-hexane polarity is small, and only this product can dissolve wherein in La Luotasai chiral side chain synthesis process, impurity just can be removed disposably by simply filtering, and the purity of product reaches 99.5%.
Description
Technical field
The present invention relates to drug technical field of organic synthesis, refer in particular to a kind of synthesis work of La Luotasai chiral side chain
Skill.
Background technique
La Luotasai (Lay Long Taisu) is bearing taxanes of new generation, and molecular structure is only micro- with Docetaxel
Small change, II phase clinical effectiveness show that drug effect and toxicity are suitable with Docetaxel, but it to the patient of taxol resistance still
Effectively.The product are mainly used for a line and second line treatment and taxanes drug resistance for oophoroma and breast cancer and non-small cell lung cancer
Property patient, further include head and neck cancer, the cancer of the esophagus, seminoma, the treatment of recurrence Fei Hejin lymphomas etc..
Chiral side chain is the critical materials for preparing La Luotasai, and current main chiral side chain is (3R, 4S)-tert-
Butyl 3-(1-ethoxyethoxy)-2-oxo-4-phenylazetidine-1-
Carboxylate, manufacture difficulty is larger, higher cost, few so as to cause market supply, expensive.
Summary of the invention
The present invention provides a kind of synthesis technology of La Luotasai chiral side chain, and main purpose, which is to overcome, to be currently used for making
The critical materials chiral side chain manufacture difficulty of standby La Luotasai is larger, higher cost defect.
In order to solve the above technical problems, the present invention adopts the following technical scheme:
A kind of synthesis technology of La Luotasai chiral side chain, comprising the following steps:
1) (3R, 4S) -3- hydroxy-4-phenyl -2- aza cyclo-butanone 50g, tetrahydrofuran 1200ml, vinyl second are weighed according to the ratio
Ether 50ml, 6~8g of methane sulfonic acid, 180~260ml of triethylamine, 180~260g of BOC- acid anhydrides, 4-dimethylaminopyridine 10~
16g, water 6000ml, saturated salt solution 1000ml, n-hexane 1500ml；
2) reaction flask is taken, (3R, 4S) -3- hydroxy-4-phenyl -2- aza cyclo-butanone 50g and tetrahydrofuran are charged with
1200ml is cooled to 0 DEG C after stirring and dissolving；Be added again into the reaction flask later vinyl ethyl ether 50ml and methane sulfonic acid 6~
8g, by TLC detection after completion of the reaction, then into the reaction flask be added 180~260ml of triethylamine, BOC- acid anhydrides 180~
260g, 10~16g of 4-dimethylaminopyridine, are placed in and react 2h at room temperature, obtain reactant；
3) it takes reactant made from step 2 to mix with water 6000ml, is extracted with dichloromethane, merge organic phase, then eaten with saturation
Salt water 1000ml washing, finally with the dry 2h of anhydrous sodium sulfate, filtering obtains filtrate, then the filtrate is placed in 40 DEG C of water-bath decompressions
It is concentrated to dryness, obtains solid；
4) n-hexane 1500ml is added made from the step 3 in solid, in stirred at reflux until substantially without solid after 20g is added
Active carbon stirs 30min, heat filter, then filtrate is placed in -20 DEG C of refrigerator-freezers and stays overnight crystallization, filters again later, and filter cake is placed in
50 DEG C of vacuum drying, obtain off-white powder compound 48g；
The reaction equation reacted in the reaction flask is as follows:
。
Further, the reaction flask is 2L there-necked flask.
Further, the methane sulfonic acid of addition is 6g.
Further, the triethylamine of addition is 200ml.
Further, the BOC- acid anhydrides of addition is 200g.
Further, the 4-dimethylaminopyridine of addition is 12g.
Compared to the prior art, the beneficial effect that the present invention generates is:
The present invention with (3R, 4S) -3- hydroxy-4-phenyl -2- aza cyclo-butanone for starting material, using one kettle way, by its first with
Vinyl ethyl ether condensation directly obtains La Luotasai chiral side chain with the condensation of BOC- acid anhydrides again, and feature is that step is short, reduces
Material loss is directly recrystallized with suitable solvent；In addition, post-processing pole in La Luotasai chiral side chain synthesis process
To be simple, n-hexane polarity is small, and only this product can dissolve wherein, and impurity just can be removed disposably by simply filtering, and produces
The purity of product reaches 99.5%.
Specific embodiment
Illustrate a specific embodiment of the invention below.
A kind of synthesis technology of La Luotasai chiral side chain, comprising the following steps:
1) (3R, 4S) -3- hydroxy-4-phenyl -2- aza cyclo-butanone (II) 50g, tetrahydrofuran 1200ml, ethylene are weighed according to the ratio
Base ether 50ml, methane sulfonic acid 6g, triethylamine 200ml, BOC- acid anhydrides 200g, 4-dimethylaminopyridine 12g, water 6000ml, satisfy
With saline solution 1000ml, n-hexane 1500ml；
2) reaction flask is taken, (3R, 4S) -3- hydroxy-4-phenyl -2- aza cyclo-butanone 50g and tetrahydrofuran are charged with
1200ml is cooled to 0 DEG C after stirring and dissolving；Vinyl ethyl ether 50ml and methane sulfonic acid 6g is added into the reaction flask again later,
After completion of the reaction by TLC detection, then triethylamine 200ml, BOC- acid anhydrides 200g, 4- dimethylamino pyrrole are added into the reaction flask
Pyridine 12g is placed in and reacts 2h at room temperature, obtains reactant；The reaction flask can be 2L there-necked flask；
3) it takes reactant made from step 2 to mix with water 6000ml, is extracted with dichloromethane, merge organic phase, then eaten with saturation
Salt water 1000ml washing, finally with the dry 2h of anhydrous sodium sulfate, filtering obtains filtrate, then the filtrate is placed in 40 DEG C of water-bath decompressions
It is concentrated to dryness, obtains solid；
4) n-hexane 1500ml is added made from the step 3 in solid, in stirred at reflux until substantially without solid after 20g is added
Active carbon stirs 30min, heat filter, then filtrate is placed in -20 DEG C of refrigerator-freezers and stays overnight crystallization, filters again later, and filter cake is placed in
50 DEG C of vacuum drying, obtain off-white powder compound (I) 48g；
The reaction equation reacted in the reaction flask is as follows:
。
The present invention with (3R, 4S) -3- hydroxy-4-phenyl -2- aza cyclo-butanone be starting material, using one kettle way, by it
La Luotasai chiral side chain is first directly obtained with vinyl ethyl ether condensation, again with the condensation of BOC- acid anhydrides, feature is that step is short, drop
Low material loss is directly recrystallized with suitable solvent；In addition, in La Luotasai chiral side chain synthesis process, it is rear to locate
Manage extremely simple, n-hexane polarity is small, and only this product can dissolve wherein, and impurity just can be removed disposably by simply filtering
It goes, the purity of product reaches 99.5%.
The above is only a specific embodiment of the present invention, but the design concept of the present invention is not limited to this, all to utilize this
Design makes a non-material change to the present invention, and should all belong to behavior that violates the scope of protection of the present invention.
Claims (6)
1. a kind of synthesis technology of La Luotasai chiral side chain, which comprises the following steps:
1) (3R, 4S) -3- hydroxy-4-phenyl -2- aza cyclo-butanone 50g, tetrahydrofuran 1200ml, vinyl second are weighed according to the ratio
Ether 50ml, 6~8g of methane sulfonic acid, 180~260ml of triethylamine, 180~260g of BOC- acid anhydrides, 4-dimethylaminopyridine 10~
16g, water 6000ml, saturated salt solution 1000ml, n-hexane 1500ml；
2) reaction flask is taken, (3R, 4S) -3- hydroxy-4-phenyl -2- aza cyclo-butanone 50g and tetrahydrofuran are charged with
1200ml is cooled to 0 DEG C after stirring and dissolving；Be added again into the reaction flask later vinyl ethyl ether 50ml and methane sulfonic acid 6~
8g, by TLC detection after completion of the reaction, then into the reaction flask be added 180~260ml of triethylamine, BOC- acid anhydrides 180~
260g, 10~16g of 4-dimethylaminopyridine, are placed in and react 2h at room temperature, obtain reactant；
3) it takes reactant made from step 2 to mix with water 6000ml, is extracted with dichloromethane, merge organic phase, then eaten with saturation
Salt water 1000ml washing, finally with the dry 2h of anhydrous sodium sulfate, filtering obtains filtrate, then the filtrate is placed in 40 DEG C of water-bath decompressions
It is concentrated to dryness, obtains solid；
4) n-hexane 1500ml is added made from the step 3 in solid, in stirred at reflux until substantially without solid after 20g is added
Active carbon stirs 30min, heat filter, then filtrate is placed in -20 DEG C of refrigerator-freezers and stays overnight crystallization, filters again later, and filter cake is placed in
50 DEG C of vacuum drying, obtain off-white powder compound 48g；
The reaction equation reacted in the reaction flask is as follows:
。
2. a kind of synthesis technology of La Luotasai chiral side chain as described in claim 1, it is characterised in that: the reaction flask is 2L
There-necked flask.
3. a kind of synthesis technology of La Luotasai chiral side chain as described in claim 1, it is characterised in that: the methane sulfonic acid of addition
For 6g.
4. a kind of synthesis technology of La Luotasai chiral side chain as described in claim 1, it is characterised in that: the triethylamine of addition is
200ml。
5. a kind of synthesis technology of La Luotasai chiral side chain as described in claim 1, it is characterised in that: the BOC- acid anhydrides of addition
For 200g.
6. a kind of synthesis technology of La Luotasai chiral side chain as described in claim 1, it is characterised in that: the 4- diformazan ammonia of addition
Yl pyridines are 12g.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811518031.0A CN109485593A (en) | 2018-12-12 | 2018-12-12 | A kind of synthesis technology of La Luotasai chiral side chain |
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| CN201811518031.0A CN109485593A (en) | 2018-12-12 | 2018-12-12 | A kind of synthesis technology of La Luotasai chiral side chain |
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| CN109485593A true CN109485593A (en) | 2019-03-19 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115436525A (en) * | 2022-09-26 | 2022-12-06 | 山西振东制药股份有限公司 | LLTS-M3 and detection method and application of related substances thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1123547A (en) * | 1993-03-26 | 1996-05-29 | 纽约州州立大学研究基金会 | Anti-tumor compounds, pharmaceutical compositions, methods for preparation thereof and for treatment |
| CN1482251A (en) * | 2003-08-14 | 2004-03-17 | 阎家麒 | Biocatalyzing chiral taxil side-chain and taxol semisynthesis |
| CN102241648A (en) * | 2011-01-31 | 2011-11-16 | 复旦大学 | Multimedicine-resistance medicine-resistance taxane derivatives and preparation method and use thereof |
-
2018
- 2018-12-12 CN CN201811518031.0A patent/CN109485593A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1123547A (en) * | 1993-03-26 | 1996-05-29 | 纽约州州立大学研究基金会 | Anti-tumor compounds, pharmaceutical compositions, methods for preparation thereof and for treatment |
| CN1482251A (en) * | 2003-08-14 | 2004-03-17 | 阎家麒 | Biocatalyzing chiral taxil side-chain and taxol semisynthesis |
| CN102241648A (en) * | 2011-01-31 | 2011-11-16 | 复旦大学 | Multimedicine-resistance medicine-resistance taxane derivatives and preparation method and use thereof |
Non-Patent Citations (2)
| Title |
|---|
| LUCATELLI, CHRISTOPHE 等: "Synthesis of C-3" Methyl Taxotere (Docetaxel)", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| OJIMA, IWAO 等: "SYNTHESES OF NEW FLUORINE-CONTAINING TAXOIDS BY MEANS OF ~-LACTAM SYNTHON METHOD", 《TERRAHEDRON》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115436525A (en) * | 2022-09-26 | 2022-12-06 | 山西振东制药股份有限公司 | LLTS-M3 and detection method and application of related substances thereof |
| CN115436525B (en) * | 2022-09-26 | 2024-04-12 | 山西振东制药股份有限公司 | LLTS-M3 and detection method and application of related substances thereof |
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