CN108558703A - A kind of synthetic method of medicine intermediate chlorine ketone - Google Patents
A kind of synthetic method of medicine intermediate chlorine ketone Download PDFInfo
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- CN108558703A CN108558703A CN201810539253.4A CN201810539253A CN108558703A CN 108558703 A CN108558703 A CN 108558703A CN 201810539253 A CN201810539253 A CN 201810539253A CN 108558703 A CN108558703 A CN 108558703A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/002—Mixed oxides other than spinels, e.g. perovskite
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/16—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of arsenic, antimony, bismuth, vanadium, niobium, tantalum, polonium, chromium, molybdenum, tungsten, manganese, technetium or rhenium
- B01J23/20—Vanadium, niobium or tantalum
- B01J23/22—Vanadium
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Abstract
The invention discloses a kind of synthetic method of medicine intermediate chlorine ketone, N BOC L phenylalanines, triethylamine, ethyl chloroformate, diazomethane, Bi（NO3）3·5H2O、NaVO3, polyvinylpyrrolidone and terephthalic acid (TPA) be primary raw material, it is raw materials used according to the following ratio：N BOC L phenylalanines, ethyl chloroformate mass ratio are 5：4；Bi（NO3）3·5H2O、NaVO3Quality is 3：1；Vinylpyrrolidone, terephthalic acid (TPA) mass ratio are 4：5；The synthesis technology of the present invention is passed directly into hydrogen chloride gas using one kettle way after diazotising and prepares chlorine ketone, reduce the risk of diazomethane leakage when diazo-ketones takes out, industrial operation difficulty is also reduced simultaneously, and the selectivity that addition Bi V O catalyst improves its reaction makes actual industrial products yield greatly improve.
Description
Technical field
The present invention relates to a kind of synthetic methods of medicine intermediate chlorine ketone, belong to chemical industry synthesis field.
Background technology
AIDS, that is, Immune Deficiency Syndrome（Acquired Immune Deficiency Syndrome,
AIDS）It is that human injection has infected " human immunodeficiency virus "（HIV-human immunodeficiency）Caused biography
It catches an illness.As the mankind are increasingly deep to the research of viruses molecule, the up to the present research of antiradiation drug and Jian send out primarily directed to
Three reverse transcriptase that HIV-1 genes play a crucial role in a replication process, integrase and protease key enzymes.It is answered by clinic
Also gradually expose that its bioavilability is low, side effect is big and the problems such as drug resistance easily occurs with, protease inhibitors.Chlorine ketone
Important intermediate of protease inhibitor, research always efficient chlorine ketone synthetic method very it is necessary to.
Invention content
The purpose of the present invention is to provide the synthetic method of medicine intermediate chlorine ketone, this method can be catalyzed with optimal conditions
The reaction of N-BOC-L- phenylalanines and ethyl chloroformate has higher product yield.
A kind of synthetic method of medicine intermediate chlorine ketone, this approach includes the following steps：
Step 1, into the 500m1 four-hole boiling flasks equipped with blender, constant pressure funnel be added 0.2g Bi-V-O catalyst and
120m1THF keeps room temperature；
Step 2 puts into lOg N-BOC-L- phenylalanines to above-mentioned flask, cools down after stirring dissolved clarification, controls 5 DEG C of temperature, successively
7.75g triethylamines and 8.13g ethyl chloroformates are instilled, -20 DEG C are cooled to after keeping the temperature 0.5h；
Step 3, diazomethane/diethyl ether solution that 89.2m1 concentration 0.8mol/L is slowly dropped into above-mentioned mixed liquor, are added dropwise
Insulated and stirred 1h afterwards is passed through hydrogen chloride gas to after the reaction was complete, and sodium bicarbonate aqueous solution is added and is washed till PH=6, acetic acid second is added
Ester extracts, and removes ethyl acetate under reduced pressure, is filtered after recrystallizing methanol is added, and vacuum drying obtains the inhibition of white powder protease
Agent intermediate chlorine ketone.
The powdered Bi-V-O method for preparing catalyst is as follows：
Step 1, by 60mgBi（NO3）3·5H2O、20mgNaVO3, 40mg polyvinylpyrrolidones, 50mg terephthalic acid (TPA)s be put into
In the N of 80ml water and 60ml, N dimethyl formamide mixed solution, magnetic agitation 20min is uniformly mixed；
Above-mentioned solution is transferred in the dynamic response kettle equipped with polytetrafluoroethyllining lining by step 2, and dynamic response kettle is sealed
It is good, 6h is reacted at a temperature of 150 DEG C, obtains Bi-V-O composite materials, waits for that reaction being cooled to room temperature, by product deionized water with
N, N dimethyl formamide cross washing 3 times, in 7400r/min centrifugations, 60 DEG C of baking ovens it is dry for 24 hours, obtain yellowish powder
Shape Bi-V-O catalyst.
Advantageous effect：The present invention provides a kind of synthetic method of medicine intermediate chlorine ketone, using diazonium first institute's route into
The chloromethylation of row phenylalanine, use first chloro-formate carboxyl is activated to obtain it is anti-with diazomethane after activation acid anhydrides
Diazo-ketones should be obtained, hydrogen chloride gas is finally passed through and obtains chlorine ketone, hydrogen chloride is passed directly into after diazotising using one kettle way
Gas prepares chlorine ketone, reduces the risk of diazomethane leakage when diazo-ketones takes out, while also reducing industrial operation difficulty,
In order to reduce the generation of side reaction, select chloro-formate as raw material as dehydrating agent, but excessive chloro-formate and certainty
It can lead to the generation of other side reactions, therefore from cost consideration, the selectivity that addition Bi-V-O catalyst improves its reaction is also
Necessary, gained yield is calculated with the high-content product quality obtained after refined, and actual industrial production yield greatly improves.
Specific implementation mode
Embodiment 1
A kind of synthetic method of medicine intermediate chlorine ketone, this approach includes the following steps：
Step 1, into the 500m1 four-hole boiling flasks equipped with blender, constant pressure funnel be added 0.2g Bi-V-O catalyst and
120m1THF keeps room temperature；
Step 2 puts into lOg N-BOC-L- phenylalanines to above-mentioned flask, cools down after stirring dissolved clarification, controls 5 DEG C of temperature, successively
7.75g triethylamines and 8.13g ethyl chloroformates are instilled, -20 DEG C are cooled to after keeping the temperature 0.5h；
Step 3, diazomethane/diethyl ether solution that 89.2m1 concentration 0.8mol/L is slowly dropped into above-mentioned mixed liquor, are added dropwise
Insulated and stirred 1h afterwards is passed through hydrogen chloride gas to after the reaction was complete, and sodium bicarbonate aqueous solution is added and is washed till PH=6, acetic acid second is added
Ester extracts, and removes ethyl acetate under reduced pressure, is filtered after recrystallizing methanol is added, and vacuum drying obtains the inhibition of white powder protease
Agent intermediate chlorine ketone.
The powdered Bi-V-O method for preparing catalyst is as follows：
Step 1, by 60mgBi（NO3）3·5H2O、20mgNaVO3, 40mg polyvinylpyrrolidones, 50mg terephthalic acid (TPA)s be put into
In the N of 80ml water and 60ml, N dimethyl formamide mixed solution, magnetic agitation 20min is uniformly mixed；
Above-mentioned solution is transferred in the dynamic response kettle equipped with polytetrafluoroethyllining lining by step 2, and dynamic response kettle is sealed
It is good, 6h is reacted at a temperature of 150 DEG C, obtains Bi-V-O composite materials, waits for that reaction being cooled to room temperature, by product deionized water with
N, N dimethyl formamide cross washing 3 times, in 7400r/min centrifugations, 60 DEG C of baking ovens it is dry for 24 hours, obtain yellowish powder
Shape Bi-V-O catalyst.
Embodiment 2
Step 2 puts into 8.0g N-BOC-L- phenylalanines to above-mentioned flask, cools down after stirring dissolved clarification, controls 5 DEG C of temperature, successively
7.75g triethylamines and 8.13g ethyl chloroformates are instilled, -20 DEG C are cooled to after keeping the temperature 0.5h；Remaining step is the same as embodiment 1.
Embodiment 3
Step 2 puts into 6.0g N-BOC-L- phenylalanines to above-mentioned flask, cools down after stirring dissolved clarification, controls 5 DEG C of temperature, successively
7.75g triethylamines and 8.13g ethyl chloroformates are instilled, -20 DEG C are cooled to after keeping the temperature 0.5h；Remaining step is the same as embodiment 1.
Embodiment 4
Step 2 puts into 4.0g N-BOC-L- phenylalanines to above-mentioned flask, cools down after stirring dissolved clarification, controls 5 DEG C of temperature, successively
7.75g triethylamines and 8.13g ethyl chloroformates are instilled, -20 DEG C are cooled to after keeping the temperature 0.5h；Remaining step is the same as embodiment 1.
Embodiment 5
Step 2 puts into 2.0g N-BOC-L- phenylalanines to above-mentioned flask, cools down after stirring dissolved clarification, controls 5 DEG C of temperature, successively
7.75g triethylamines and 8.13g ethyl chloroformates are instilled, -20 DEG C are cooled to after keeping the temperature 0.5h；Remaining step is the same as embodiment 1.
Embodiment 6
Step 2 puts into lOg N-BOC-L- phenylalanines to above-mentioned flask, cools down after stirring dissolved clarification, controls 5 DEG C of temperature, successively
7.75g triethylamines and 4.13g ethyl chloroformates are instilled, -20 DEG C are cooled to after keeping the temperature 0.5h；Remaining step is the same as embodiment 1.
Embodiment 7
Step 2 puts into lOg N-BOC-L- phenylalanines to above-mentioned flask, cools down after stirring dissolved clarification, controls 5 DEG C of temperature, successively
7.75g triethylamines and 2.13g ethyl chloroformates are instilled, -20 DEG C are cooled to after keeping the temperature 0.5h；Remaining step is the same as embodiment 1.
Embodiment 8
Step 2 puts into lOg N-BOC-L- phenylalanines to above-mentioned flask, cools down after stirring dissolved clarification, controls 5 DEG C of temperature, successively
7.75g triethylamines and 12.20g ethyl chloroformates are instilled, -20 DEG C are cooled to after keeping the temperature 0.5h；Remaining step is the same as embodiment 1.
Embodiment 9
Step 2 puts into lOg N-BOC-L- phenylalanines to above-mentioned flask, cools down after stirring dissolved clarification, controls 5 DEG C of temperature, successively
7.75g triethylamines and 16.20g ethyl chloroformates are instilled, -20 DEG C are cooled to after keeping the temperature 0.5h；Remaining step is the same as embodiment 1.
Embodiment 10
Step 2 puts into lOg N-BOC-L- phenylalanines to above-mentioned flask, cools down after stirring dissolved clarification, controls 5 DEG C of temperature, successively
7.75g triethylamines and 20.20g ethyl chloroformates are instilled, -20 DEG C are cooled to after keeping the temperature 0.5h；Remaining step is the same as embodiment 1.
Reference examples 1
It is with 1 difference of embodiment：In the synthesis step 2 of intermediate, replace triethylamine, remaining step and reality with equivalent pyridine
It is identical to apply example 1.
Reference examples 2
It is with 1 difference of embodiment：In the synthesis step 2 of intermediate, with equivalent lithium diisopropyl amido substituted ethylene diamine,
Remaining step is identical with embodiment 1.
Reference examples 3
It is with 1 difference of embodiment：In the synthesis step 2 of intermediate, replace ethyl chloroformate, remaining step with thionyl chloride
It is identical with embodiment 1.
Reference examples 4
It is with 1 difference of embodiment：In the synthesis step 2 of intermediate, replace ethyl chloroformate, remaining step and reality with chlorine
It is identical to apply example 1.
Reference examples 5
It is with 1 difference of embodiment：In the synthesis step 3 of intermediate, it is slowly dropped into the diazonium of 45.0m1 concentration 0.8mol/L
Methane/diethyl ether solution, remaining step are identical with embodiment 1.
Reference examples 6
It is with 1 difference of embodiment：In the synthesis step 3 of intermediate, it is slowly dropped into the diazonium of 89.2 m1 concentration 1.6mol/L
Methane/diethyl ether solution, remaining step are identical with embodiment 1.
Reference examples 7
It is with 1 difference of embodiment：In the synthesis step 3 of intermediate, with dilute hydrochloric acid tune PH=2；Remaining step and embodiment 1
It is identical.
Reference examples 8
It is with 1 difference of embodiment：In the synthesis step 3 of intermediate, with ammonium hydroxide tune PH=11；Remaining step and embodiment 1 are complete
It is exactly the same.
Reference examples 9
It is with 1 difference of embodiment：In the synthesis step 1 of catalyst, Bi is not added（NO3）3·5H2O, remaining step with
Embodiment 1 is identical.
Reference examples 10
It is with 1 difference of embodiment：In the synthesis step 1 of catalyst, NaVO is not added3, remaining step and embodiment 1 are complete
It is exactly the same.
It is as shown in the table for reaction result under embodiment and reference examples different condition
| Protease inhibitor intermediate chlorine ketone yield/% | |
| Embodiment 1 | 99.6 |
| Embodiment 2 | 98.4 |
| Embodiment 3 | 64.0 |
| Embodiment 4 | 85.5 |
| Embodiment 5 | 78.4 |
| Embodiment 6 | 88.4 |
| Embodiment 7 | 66.0 |
| Embodiment 8 | 62.2 |
| Embodiment 9 | 83.5 |
| Embodiment 10 | 71.3 |
| Reference examples 1 | 49.0 |
| Reference examples 2 | 53.0 |
| Reference examples 3 | 38.1 |
| Reference examples 4 | 42.3 |
| Reference examples 5 | 43.9 |
| Reference examples 6 | 47.1 |
| Reference examples 7 | 33.2 |
| Reference examples 8 | 41.3 |
| Reference examples 9 | 54.7 |
| Reference examples 10 | 47.1 |
The experimental results showed that catalyst has good catalysis to the synthetic reaction of N-BOC-L- phenylalanines and ethyl chloroformate
Effect, in one timing of reaction condition, intermediate yield is higher, and catalytic performance is better, otherwise poorer；N-BOC-L- phenylalanines,
Ethyl chloroformate mass ratio is 5：When 4, other dispensings are fixed, and synthetic effect is best, with embodiment 1 the difference lies in that embodiment 3
The dosage and proportioning for changing primary raw material N-BOC-L- phenylalanines, ethyl chloroformate respectively to embodiment 10, to synthetic product
Yield have different influences；Reference examples 1 to the lithium diisopropyl amido of reference examples 2 and pyridine replaces three second of organic base respectively
Amine, other steps are identical, and product yield is caused to be substantially reduced, and it is very big to illustrate that triethylamine influences the product of reaction；Control
Example 3 to reference examples 4 replace ethyl chloroformate respectively with thionyl chloride and chlorine, change anhydride reaction raw material effect still not
It is good, illustrate that ethyl chloroformate is conducive to the progress of reaction；Reference examples 5 reduce the dosage of diazomethane to reference examples 6, and middle desalination is anti-
Should be incomplete, diazo-ketones production quantity is less to reacting still unfavorable；Reference examples 7 change the pH value of solution to reference examples 8, and catalysis is anti-
It is very big to illustrate that PH influences reaction for the variation with obvious effects answered；Reference examples 9 to reference examples 10 do not add Bi（NO3）3·5H2O、
NaVO3, the activated centre of catalyst changes, and the conversion ratio and selectivity of reaction are very low, and reaction effect is obviously deteriorated, product
Yield is not still high；Therefore had to the synthetic reaction of protease inhibitor intermediate chlorine ketone using the catalyst of the present invention excellent
Catalytic effect.
Claims (2)
1. a kind of synthetic method of medicine intermediate chlorine ketone, it is characterised in that this approach includes the following steps：
Step 1, into the 500m1 four-hole boiling flasks equipped with blender, constant pressure funnel be added 0.2g Bi-V-O catalyst and
120m1THF keeps room temperature；
Step 2 puts into lOg N-BOC-L- phenylalanines to above-mentioned flask, cools down after stirring dissolved clarification, controls 5 DEG C of temperature, successively
7.75g triethylamines and 8.13g ethyl chloroformates are instilled, -20 DEG C are cooled to after keeping the temperature 0.5h；
Step 3, diazomethane/diethyl ether solution that 89.2m1 concentration 0.8mol/L is slowly dropped into above-mentioned mixed liquor, are added dropwise
Insulated and stirred 1h afterwards is passed through hydrogen chloride gas to after the reaction was complete, and sodium bicarbonate aqueous solution is added and is washed till PH=6, acetic acid second is added
Ester extracts, and removes ethyl acetate under reduced pressure, is filtered after recrystallizing methanol is added, and vacuum drying obtains the inhibition of white powder protease
Agent intermediate chlorine ketone.
2. a kind of synthetic method of medicine intermediate chlorine ketone according to claim 1, which is characterized in that
The powdered Bi-V-O method for preparing catalyst is as follows：
Step 1, by 60mgBi（NO3）3·5H2O、20mgNaVO3, 40mg polyvinylpyrrolidones, 50mg terephthalic acid (TPA)s be put into
In the N of 80ml water and 60ml, N dimethyl formamide mixed solution, magnetic agitation 20min is uniformly mixed；
Above-mentioned solution is transferred in the dynamic response kettle equipped with polytetrafluoroethyllining lining by step 2, and dynamic response kettle is sealed
It is good, 6h is reacted at a temperature of 150 DEG C, obtains Bi-V-O composite materials, waits for that reaction being cooled to room temperature, by product deionized water with
N, N dimethyl formamide cross washing 3 times, in 7400r/min centrifugations, 60 DEG C of baking ovens it is dry for 24 hours, obtain yellowish powder
Shape Bi-V-O catalyst.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101791548A (en) * | 2010-04-22 | 2010-08-04 | 华中科技大学 | Visible light catalyst BiVO4 and preparation method thereof |
| CN104387299A (en) * | 2014-10-23 | 2015-03-04 | 凯莱英医药集团（天津）股份有限公司 | Method for preparing 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-benzene butyl]-N-isobutyl benzsulfamide |
-
2018
- 2018-05-30 CN CN201810539253.4A patent/CN108558703A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101791548A (en) * | 2010-04-22 | 2010-08-04 | 华中科技大学 | Visible light catalyst BiVO4 and preparation method thereof |
| CN104387299A (en) * | 2014-10-23 | 2015-03-04 | 凯莱英医药集团（天津）股份有限公司 | Method for preparing 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-benzene butyl]-N-isobutyl benzsulfamide |
Non-Patent Citations (1)
| Title |
|---|
| VAGNER D. PINHO ET AL.: "Continuous Flow Synthesis of α‑Halo Ketones: Essential Building Blocks of Antiretroviral Agents", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
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