CN108191741A - A kind of synthetic method for bacterial-infection resisting medicine intermediate - Google Patents
A kind of synthetic method for bacterial-infection resisting medicine intermediate Download PDFInfo
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- CN108191741A CN108191741A CN201810058132.8A CN201810058132A CN108191741A CN 108191741 A CN108191741 A CN 108191741A CN 201810058132 A CN201810058132 A CN 201810058132A CN 108191741 A CN108191741 A CN 108191741A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention belongs to chemical and medicine industry intermediate synthesis technical fields, and in particular to a kind of synthetic method for bacterial-infection resisting medicine intermediate；The present invention uses liquefied ammonia that diester-type secondary amine compound 1 is made for raw material with acrylate, then after piperidones is made in cyclization, the substitution reaction of secondary amine and Iso-Propyl iodide is utilized using the catalysts of science, temperature and time again, target product is synthesized by six-step process altogether, entire route yield is up to 35%.
Description
Technical field
The invention belongs to chemical and medicine industry intermediate synthesis technical fields, and in particular to one kind is in bacterial-infection resisting medicine
The synthetic method of mesosome.
Background technology
Piperidones and its derivative are very important members in piperidine derivative, refer to 4- piperidones under normal circumstances.Piperazine
Not only there are nitrogen-atoms and carbonyl to can be used as active site, while the introducing of carbonyl makes on its ortho position in the molecular structure of pyridine ketone
Two methylene also become active, therefore can cause many organic reactions by parent of piperidones, thus derive many
Practical medicine, pesticide and chemical intermediate.
Structural formula isCompound have bacterial-infection resisting activity,
It is the intermediate for synthesizing bacterial-infection resisting medicine.R in such compound1, R2, R3It is taken for hydrogen atom, hydroxyl, amido, alkyl etc.
Dai Ji；W is the substituent groups such as methylene, oxygen atom, imido grpup, R4, R5Can be hydrogen original for the substituent group being connected on carbon atom
Son or methyl, ethyl, amido, amino, hydroxyl, cyano etc.；A rings are carbocyclic ring or nitrogen heterocyclic ring.Work as R4During for hydrogen, N-
Isopropyl -4- piperidones can be as the intermediate for synthesizing the bacterial-infection resisting medicine.
The synthetic method of piperidones has two kinds of reduction method and cyclization method, and wherein reduction method cost of material is high, and step is few；Cyclization
Method cost of material is low, and synthesis step is more.Cost of material is minimum for dibasic acid esters synthetic method in cyclization method, and reactive chemistry formula is such as
Under：
Wherein, R1 is alkyl or benzyl, and R, R2, R3, R4, R5 is generally hydrogen or alkyl.Since this route starting material is inexpensively easy
, operation is simple, has been promoted at present, for synthesizing a series of compound containing 4- piperidones structures.R1 is
When alkyl or benzyl, the raw materials used primary amine replaced for alkyl or benzyl, when R1 is hydrogen, raw material is ammonia；But R1 is generally second
Base or methyl；R2, R3, R4, R5 are generally hydrogen or alkyl.If this method raw material is symmetry dibasic acid esters, simplest situation is R2,
R3, R4, R5 are hydrogen, then ammonia or primary amine can be used to be obtained with acrylate by addition reaction at this time.Primary amine for example methylamine, propylamine,
Easy to operate, mild condition that benzylamine etc. and acrylate by addition reaction prepare the tertiary amine containing di-ester-base, and yield is higher.
After general normal-temperature reaction a few hours, sterling is can obtain through air-distillation or vacuum distillation.
The master thesis at University Of Tianjin Sun Ju peaks《The study on the synthesis of N- substitution -4- piperidones》In once to the structure of amine
Influence to its addition reaction product and yield with acrylate has carried out systematic research, is shown in Table 1.Study the reality in table 1
It tests as a result, finding the structure of amine all has the type and yield in reaction time, product the influence of regularity.With amine chemical combination
The increase of object carbon atom number, the rate that addition reaction is carried out with methyl acrylate is gradually lowered, with aminated compounds carbon
The growth of chain, the increase of branch, steric hindrance increase, degree of freedom reduce, and molecular motion resistance increases, so as to make addition reaction
Rate reduces, and reaction is more not easy to carry out.
1 primary amine of table and the methyl acrylate addition reaction result table of comparisons
It can be seen that the defects of preparing N- isopropyl -4- piperidones using dibasic acid esters cyclization method is：Isopropylamine is connected to due to nitrogen-atoms
On secondary carbon, steric hindrance is larger, and reactivity is relatively low, is reacted at room temperature 11 days with acrylate, and the yield of dibasic acid esters is only
4%, yield is too low, so that target piperidinone products yield is extremely low.
Invention content
To solve the above problems, the purpose of the present invention is to provide a kind of synthesis for bacterial-infection resisting medicine intermediate
Method uses ammonia and acrylate as raw material first, and 4- piperidones is synthesized by dibasic acid esters synthetic method, then different with iodo again
Target product is obtained by the reaction in propane, and yield is higher.
To achieve the above object, the technical scheme is that：A kind of synthesis for bacterial-infection resisting medicine intermediate
Method, the bacterial-infection resisting medicine intermediate that is used for is N- isopropyl -4- piperidones, and synthetic method includes the following steps：
Step 1：Compound 1 is obtained by the reaction with liquefied ammonia in ethyl acrylate；
Step 2：Compound 1 is reacted with ethyl chloroformate protects amido, obtains compound 2；
Step 3：Compound 2 reacts cyclization by diekmann condensation and obtains compound 3；
Step 4：Compound 4 is obtained by the reaction by beta-ketoester hydrolysis decarboxylation in compound 3；
Step 5：Compound 4 sloughs amino protecting groups by hydrolysis and obtains compound 5；
Step 6：Compound 6 is obtained by the reaction with Iso-Propyl iodide in compound 5；
Wherein：
。
Optimization, the concrete operations of step 1 include：Liquefied ammonia and acrylate are added in closed reactor, -30 DEG C -
20 DEG C of reactions are no more than 1 h, and post-treated purification obtains compound 1；The ratio of the wherein amount of the substance of liquefied ammonia and acrylate is
（2-3）：1.
Optimization, the concrete operations of step 2 include：Compound 1 and water are added in the there-necked flask equipped with thermometer,
Ice salt bath treats that temperature is down to 0 DEG C hereinafter, the wet chemical that addition mass fraction is 5%, under stirring, adds in chloro-carbonic acid second
Ester maintains the temperature at less than 0 DEG C reaction 0.5-1 h, is then warmed to room temperature reaction 1-3h, and post-treated purification obtains compound 2.
Optimization, the concrete operations of step 3 include：The toluene of compound 2, absolute ethyl alcohol and drying is added to
In there-necked flask, lead to nitrogen, under stirring, add in metallic sodium, react at room temperature 24-36 h, instill dilute salt into reaction solution under stiring
Acid to acidity, post-treated purification obtains compound 3.
Optimization, the concrete operations of step 4 include：By compound 3, absolute ethyl alcohol, dilute hydrochloric acid is added to equipped with returned cold
In the there-necked flask of solidifying pipe and thermometer, 4-8h is heated to reflux, post-treated purification obtains compound 4.
Optimization, the concrete operations of step 5 include：Compound 4, water, dilute hydrochloric acid are added to equipped with reflux condensing tube and
In the there-necked flask of thermometer, heating reflux reaction 4-8h, post-treated purification obtains compound 5.
Optimization, the concrete operations of step 6 include：Compound 5, Iso-Propyl iodide, cesium carbonate, DMF are added in into reactor
In, 40-70 DEG C of reaction 4-8h, post-treated purification obtains compound 6.
The chemical equation of each step reaction provided by the invention is：
Step 1：。
Step 2：。
Step 3：。
Step 4：。
Step 5：。
Step 6：。
The target product piperidones of the present invention is N alkyl substituted piperidine ketone, has isopropyl substituents, but isopropyl on N
For amine since nitrogen-atoms is connected on secondary carbon, steric hindrance is larger, and reactivity is relatively low, with acrylate room temperature reaction 11
My god, the yield of dibasic acid esters is only 4%, and yield is too low, so that target piperidinone products yield is extremely low.The present invention using liquefied ammonia with
Diester-type secondary amine compound 1 is made for raw material in acrylate, then after piperidones is made in cyclization, recycles secondary amine and iodo
The substitution reaction of isopropyl alkane, the method for synthesizing target product are avoided using the big isopropylamine of steric hindrance and acrylate
Reaction improves the reaction yield of entire route.
Secondary amine compound and Iso-Propyl iodide react in step 6, the present invention by using science catalysts,
Temperature and time improves one-step reaction yield, and then improves the reaction yield of entire route.
The beneficial effects of the present invention are：The present invention provides a kind of synthesis side for bacterial-infection resisting medicine intermediate
Method uses liquefied ammonia that diester-type secondary amine compound 1 is made for raw material with acrylate, then after piperidones is made in cyclization,
The substitution reaction of secondary amine and Iso-Propyl iodide is utilized using the catalysts of science, temperature and time again, synthesizes target product,
Entire route yield is up to more than 35%.
Specific embodiment
The present invention is illustrated below in conjunction with specific embodiment.
Present embodiment provide technical solution be：A kind of synthetic method for bacterial-infection resisting medicine intermediate, institute
It is N- isopropyl -4- piperidones to state for bacterial-infection resisting medicine intermediate, and synthetic method includes the following steps：
Step 1：Compound 1 is obtained by the reaction with liquefied ammonia in ethyl acrylate；
Step 2：Compound 1 is reacted with ethyl chloroformate protects amido, obtains compound 2；
Step 3：Compound 2 reacts cyclization by diekmann condensation and obtains compound 3；
Step 4：Compound 4 is obtained by the reaction by beta-ketoester hydrolysis decarboxylation in compound 3；
Step 5：Compound 4 sloughs amino protecting groups by hydrolysis and obtains compound 5；
Step 6：Compound 6 is obtained by the reaction with Iso-Propyl iodide in compound 5.
Embodiment 1
The synthetic method of pharmaceutical intermediate N- isopropyls -4- piperidones provided in this embodiment, includes the following steps：
The concrete operations of step 1 include：30.60mmol liquefied ammonia and 10.20mmol acrylate are added in closed reactor,
Reaction solution self-temperature is at -30 DEG C, under liquid nitrogen control so that temperature is no more than 20 DEG C, maintains reaction 45min, and maintenance does not surpass
It crosses at 20 DEG C, water and chloroform is added in into reactor, adjust pH value to primary product and be extracted in organic phase, with anhydrous sulphur
Sour sodium drying, revolving remove solvent, and silica gel column chromatography purifies to obtain compound 1.
The concrete operations of step 2 include：5.86 mmol compounds, 1,1.36 g water is added to 100 equipped with thermometer
In mL there-necked flasks, ice salt bath treats that temperature is down to 0 DEG C, cold 5% aqueous solution containing 8.20 mmol potassium carbonate is added in, violent
Under stirring, 8.20 mmol ethyl chloroformates are added in, 0 DEG C of 0.5 h of reaction is maintained the temperature at, is then warmed to room temperature 1 h of reaction, adds
After entering dilute hydrochloric acid acidification, with dichloromethane extraction three times, merge organic phase, be washed to neutrality, add in anhydrous sodium sulfate drying, mistake
Filter, filtrate are spin-dried for Rotary Evaporators, and gained crude product is detached with silica gel column chromatography, obtains deep yellow color liquid i.e. compound 2, yield
94.6%
The concrete operations of step 3 include：The toluene that 2,1 mL absolutes ethyl alcohol of 8mmol compounds and 20 mL are dried is added in
Into 100 mL there-necked flasks of drying, lead to nitrogen, and access surge flask and bubbler convenient for observation air-flow.Under electromagnetic agitation,
8mmol there is the metallic sodium of metallic luster, be cut into thin strips, is carefully added into there-necked flask.React at room temperature 48 h.Under stiring to anti-
The hydrochloric acid for carefully instilling 20% in liquid is answered with dichloromethane extraction three times, to merge organic phase to acidity, be washed to neutrality, add in nothing
Aqueous sodium persulfate is dried, and filtering, filtrate is spin-dried for Rotary Evaporators, and gained crude product detaches to obtain deep yellow color liquid with silica gel column chromatography
Compound 3, yield 98.7%.
The concrete operations of step 4 include：3,10 mL ethyl alcohol of 1mmol compounds, the hydrochloric acid of 3mL20%, which is added to, to be equipped with back
In the 100 mL there-necked flasks for flowing condenser pipe and thermometer, heating, 83-85 DEG C of when, flows back, and solution colour becomes shallow from colourless after 1 h
Yellow is simultaneously gradually deepened, thin-layered chromatography monitoring reaction process, and the reaction was complete after 6 h, after reaction solution cooling, uses dichloromethane
Extraction three times, merges organic phase, is washed to neutrality, adds in anhydrous sodium sulfate drying, filtering, and filtrate is spin-dried for Rotary Evaporators,
Gained crude product is detached with silica gel column chromatography, obtains colourless liquid i.e. compound 4, yield 98.2%.
The concrete operations of step 5 include：1mmol compounds 4,10mL water, the hydrochloric acid of 3 mL20% are added to equipped with reflux
It in 100 mL there-necked flasks of condenser pipe and thermometer, heats, solution colour becomes light yellow from colourless after 100 DEG C of back flow reaction 4h
And gradually deepen, thin-layered chromatography monitoring reaction process, the reaction was complete after 6 h, after reaction solution cooling, pH value is adjusted to 8, with two
Chloromethanes extracts three times, merges organic phase, is washed to neutrality, adds in anhydrous sodium sulfate drying, filtering, filtrate Rotary Evaporators
It is spin-dried for, gained crude product detaches to obtain colourless liquid i.e. compound 5, yield 90.7% with silica gel column chromatography.
The concrete operations of step 6 include：By 1mmol compounds 5,3mmol Iso-Propyl iodides, 0.1mmol cesium carbonates,
20mLDMF is added in reactor, and 50 DEG C of reaction 6h, after reaction solution is cooled to room temperature, filtering, tune pH value to 8 adds in suitable quantity of water,
After washing away the hydrotrope in three times, anhydrous sodium sulfate drying is filtered, and filtrate is spin-dried for Rotary Evaporators, gained crude product silicagel column
Chromatography detaches to obtain colourless liquid i.e. compound 6.
Wherein step 2 is to five being classical reaction, and reaction single step yield is more than 90%, and even up to more than 98%, most
After obtain 6 gross production rate of compound more than 35%, it is seen that the committed step for influencing gross production rate is step 1 and step 6.
The nuclear magnetic spectrogram analysis in table 1 of compound 6.
The nuclear magnetic resonance spectroscopy parsing of 1 compound 6 of table
Embodiment 2-3 and comparative example 1-2
Embodiment 2-3 and comparative example 1-3, with embodiment 1 difference lies in the ratio of the reaction raw materials by step 1, temperature and
Time is specifically shown in Table 2.
2 step 1 reaction condition of table compares
Note：The ratio between the amount of substance of raw material than referring to ammonia and acrylate.
By upper table it is found that embodiment provided by the invention is by the way that the reaction condition control of step 1 is existed：- 30 DEG C-
20 DEG C of reactions are no more than 1 h, and the ratio of the amount of the substance of liquefied ammonia and acrylate is（2-3）：1, the yield of compound 1 is increased to
More than 47%, greatly improve the yield of single step, and then improve gross production rate, no matter improved in comparative example ammonia addition or
It is the reaction of propagation time, yield can not be correspondingly improved, can generates a considerable amount of amide by-products to reacting unfavorable instead
Object.Therefore embodiment provided by the invention is better than comparative example.
Comparative example 3
Difference lies in include the concrete operations of the step one in embodiment 1 with embodiment 1 for this comparative example：By absolute second
Alcohol is added in dry reaction bulb, is passed through 10mmol ammonias, is added with stirring ethyl acrylate, be kept stirring, successively -20
DEG C reaction 40h, 30 DEG C reaction 10h, be heated to 100 degrees Celsius of 10 h of back flow reaction, through liquid phase detect reaction process, do not find 1
Molecule ammonia and 2 molecule methyl acrylates obtain secondary amine product by addition reaction, the predominantly three molecule acrylic acid of the reaction
The product of ester and ammonia addition is denoted as compound 7, the yield of compound 7 respectively 47%, 52%, more than 80%, compound 7
Structural formula is。
As it can be seen that the route of this comparative example 3 can not obtain compound 1.
Embodiment 4-6 and comparative example 4-5
Embodiment 4-6 and comparative example 4-5, difference lies in catalyst, the temperature and time by step 6, tools with embodiment 1
Body is shown in Table 3.
3 step 6 reaction condition of table compares
By the comparison of upper table it is found that catalysts, temperature and time of the embodiment provided by the invention by using science
One-step reaction yield is improved, and then improves the reaction yield of entire route, better than comparative example.
In conclusion the present invention provides a kind of synthetic method for bacterial-infection resisting medicine intermediate, liquefied ammonia is used
Diester-type secondary amine compound 1 is made for raw material with acrylate, then after piperidones is made in cyclization, then using the anti-of science
Catalyst, temperature and time is answered to synthesize target product, entire route yield is high using the substitution reaction of secondary amine and Iso-Propyl iodide
Reach more than 35%.
Claims (7)
1. a kind of synthetic method for bacterial-infection resisting medicine intermediate, it is characterised in that：It is described to be used for bacterial-infection resisting medicine
Object intermediate is N- isopropyl -4- piperidones, and synthetic method includes the following steps：
Step 1：Compound 1 is obtained by the reaction with liquefied ammonia in ethyl acrylate；
Step 2：Compound 1 is reacted with ethyl chloroformate protects amido, obtains compound 2；
Step 3：Compound 2 reacts cyclization by diekmann condensation and obtains compound 3；
Step 4：Compound 3 passes throughβCompound 4 is obtained by the reaction in -one acid esters hydrolysis decarboxylation；
Step 5：Compound 4 sloughs amino protecting groups by hydrolysis and obtains compound 5；
Step 6：Compound 6 is obtained by the reaction with Iso-Propyl iodide in compound 5；
Wherein：
。
2. a kind of synthetic method for bacterial-infection resisting medicine intermediate according to claim 1, it is characterised in that：Step
Rapid one concrete operations include：Liquefied ammonia and acrylate are added in closed reactor, are no more than 1 in -30 DEG C of -20 DEG C of reactions
H, post-treated purification obtain compound 1；The ratio of the wherein amount of the substance of liquefied ammonia and acrylate is（2-3）：1.
3. a kind of synthetic method for bacterial-infection resisting medicine intermediate according to claim 1, it is characterised in that：Step
Rapid two concrete operations include：Compound 1 and water are added in the there-necked flask equipped with thermometer, ice salt bath treats that temperature is down to 0
DEG C hereinafter, add in mass fraction be 5% wet chemical, under stirring, add in ethyl chloroformate, maintain the temperature at less than 0 DEG C
0.5-1 h are reacted, are then warmed to room temperature reaction 1-3h, post-treated purification obtains compound 2.
4. a kind of synthetic method for bacterial-infection resisting medicine intermediate according to claim 1, it is characterised in that：Step
Rapid three concrete operations include：The toluene of compound 2, absolute ethyl alcohol and drying is added in there-necked flask, leads to nitrogen, stirs
It mixes down, adds in metallic sodium, react at room temperature 24-36 h, instill dilute hydrochloric acid into reaction solution under stiring to acidity, it is post-treated to carry
It is pure to obtain compound 3.
5. a kind of synthetic method for bacterial-infection resisting medicine intermediate according to claim 1, it is characterised in that：Step
Rapid four concrete operations include：By compound 3, absolute ethyl alcohol, dilute hydrochloric acid is added to three equipped with reflux condensing tube and thermometer
In mouth bottle, 4-8h is heated to reflux, post-treated purification obtains compound 4.
6. a kind of synthetic method for bacterial-infection resisting medicine intermediate according to claim 1, it is characterised in that：Step
Rapid five concrete operations include：Compound 4, water, dilute hydrochloric acid are added in the there-necked flask equipped with reflux condensing tube and thermometer,
Heating reflux reaction 4-8h, post-treated purification obtain compound 5.
7. a kind of synthetic method for bacterial-infection resisting medicine intermediate according to claim 1-6 any one,
It is characterized in that：The concrete operations of step 6 include：Compound 5, Iso-Propyl iodide, cesium carbonate, DMF are added in reactor, 40-
70 DEG C of reaction 4-8h, post-treated purification obtain compound 6.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110483375A (en) * | 2019-09-11 | 2019-11-22 | 陈建江 | A kind of synthetic method of intermediate 4- piperidones |
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| CN110483375A (en) * | 2019-09-11 | 2019-11-22 | 陈建江 | A kind of synthetic method of intermediate 4- piperidones |
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