CN103044330B - The new green synthesizing process of silaenafil intermediate 4- amino -1- methyl -3- n-propyl pyrazoles -5- formamides - Google Patents
The new green synthesizing process of silaenafil intermediate 4- amino -1- methyl -3- n-propyl pyrazoles -5- formamides Download PDFInfo
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Abstract
The invention discloses a kind of novel environment-friendly process of drug sildenafil citrate key intermediate 4- amino -1- methyl -3- n-propyl pyrazoles -5- formamides that treating male erectile dysfunction.The method security height of technique offer, reaction are easy to control, and environmental pollution is small, and the recovery of solvent not only reduces cost, and reduces discharge, more environmentally protective.
Description
Technical field
More specifically it is to be related to a kind for the treatment of male erection function the present invention relates to a kind of preparation method of pharmaceutical intermediate
The green of the drug sildenafil citrate key intermediate 4- amino -1- methyl -3- n-propyl pyrazoles -5- formamides of obstacle is new
Technique belongs to medicine intermediate synthesis technical field.
Background technology
Sildenafil citrate is developed by Pfizer drugmaker, is to be used to treat angiocardiopathy as one earliest
5- phosphodiesterase inhibitors and enter clinical research.In April, 1991, the clinical research are counted out, but subject reports
One accused causes the side effect erected to cause the attention of researcher.Then researcher with regard to silaenafil to penis sponge
The effect of body smooth muscle expands research, and the listing of Federal Food and drug administration is obtained on March 27th, 1998
License, for treating male erectile dysfunction.Entitled 1- methyl -3- n-propyls -5- [the 2- second of chemistry of sildenafil citrate
Oxygroup -5- (4- methyl piperazine -1- sulfonyls) phenyl] -1,6- dihydro -7H- pyrazolos [4,2-d] pyrimidin-7-ones citrate,
Structural formula is as follows：
The preparation method of silaenafil has many reports.Disclosed in Chinese patent CN91104162.1 one kind with 3- just
Propylpyrazol -5- Ethyl formates are raw material, methylate to obtain 1- methyl -3- propylpyrazol -5- Ethyl formates, then hydrolyze to obtain 1-
Methyl -3- n-propyl pyrazoles -5- formic acid；Then with the mixed acid nitrification that is made of fuming nitric aicd and oleum, 4- nitros-are obtained
1- methyl -3- n-propyl pyrazoles -5- formic acid；After chlorosulfuric acid chloro, 4- nitro -1- methyl -3- is condensed to yield with concentrated ammonia liquor
N-propyl pyrazoles -5- formamides；4- amino -1- methyl -3- n-propyl pyrazoles -5- formamides then are obtained with tin chloride reduction,
4- (2- ethoxybenzenes formamido group) -1- methyl -3- n-propyl pyrazoles -5- formyls are condensed to obtain with 2- ethoxy benzoyl chlorides again
Amine；5- (2- ethoxyl phenenyls) -1- methyl -3- n-propyls -1,6- dihydro -7H- pyrazolos [4,3-d] pyrimidine-is obtained after cyclization
7- ketone；Then chlorosulfonation is carried out in chlorosulfonic acid to obtain 5- (5- chlorosulfonyl -2- ethoxyl phenenyls) -1- methyl -3- is just
Propyl -1,6- dihydro -7H- pyrazolos [4,3-d] pyrimidin-7-ones, then it is condensed to obtain silaenafil with 1- methyl piperazines.Synthetic route
As follows：
As described above, 4- amino -1- methyl -3- n-propyl pyrazoles -5- formamides shown in Formulas I are synthesis silaenafils
Key intermediate.It is known in the art there is several methods that can be used for synthesizing 4- amino -1- methyl -3- n-propyl pyrroles shown in Formulas I
Azoles -5- formamides.It is described in WO2003053974 using 1- methyl -3- n-propyl pyrazoles -5- formic acid as raw material, with 90% nitre
The nitration mixture of acid and the concentrated sulfuric acid is nitrified, and 4- nitro -1- methyl -3- n-propyl pyrazoles -5- formic acid, yield 34% are obtained；So
It is condensed with ammonia by after superchlorination sulfoxide chloro, obtains 4- nitro -1- methyl -3- n-propyl pyrazoles -5- formamides, yield is
94%；It uses hydrogen and Raney's nickel to restore again, obtains 4- amino -1- methyl -3- n-propyl pyrazoles -5- formamides (I), yield is
73%.Synthetic route is as follows：
Japanese plum has had been reported that 1- methyl -3- n-propyls pyrazoles -5- formic acid after oleum and fuming nitric aicd nitrification, obtains
4- nitro -1- methyl -3- n-propyl pyrazoles -5- formic acid, yield 80%；It is obtained using the amination of the chloro and ammonium hydroxide of thionyl chloride
To 4- nitro -1- methyl -3- n-propyl pyrazoles -5- formamides, yield 85%；It restores to obtain 4- amino -1- first with ammonium formate again
Base -3- n-propyl pyrazoles -5- formamides (I), yield 89% (fine chemistry industry, 2001,18 (7), 396~397.).Synthetic route
As follows：
Xu Baofeng etc. reports similar method, and 1- methyl -3- n-propyl pyrazoles -5- formic acid is after mixed acid nitrification, through chlorine
Change sulfoxide chloro, with after ammonia condensation, obtains 4- nitro -1- methyl -3- n-propyl pyrazoles -5- formamides, then with hydrazine hydrate and three
Iron chloride reduction after obtain 4- amino -1- methyl -3- n-propyl pyrazoles -5- formamides (I) (chemical research with application, 2002,14
(5), 605~607.).Synthetic route is as follows：
Use the nitration mixture of the nitric acid of various concentration and the sulfuric acid composition of various concentration as reaction in above method
Solvent carries out nitration reaction, and the nitrification ability of this nitration mixture is strong, can release a large amount of heat during the reaction.And nitration reaction
Very sensitive to temperature, with the rising of temperature, reaction speed is drastically accelerated, and the side reactions such as oxidation are also with appearance, or even can go out
Existing danger out of control.The refrigeration equipment that large capacity is generally required in production just can guarantee that nitration reaction carries out safely, while also want
Independent Workplace is set to prevent influence of the quick-fried spray accident to environment.This not only needs to increase the hardware such as equipment, place,
Also limit its application industrially.Meanwhile a large amount of heat is often released in excessive nitration mixture post-processing, needs a large amount of water
It is neutralized with alkali, this also brings very serious environmental protection pressure to heavy industrialization.
Hazardous chemical thionyl chloride or chlorosulfuric acid are used during chlorination in above method, it is to production process
In equipment, pipeline generate unusual heavy corrosion, be inevitably generated irritating hydrogen chloride gas in use, grasp
Make personnel and needs more protection.Meanwhile the exhaust gas of generation generates greatly pollution to environment.
And in the reduction of nitro, the noble metals such as Raney's nickel, palladium charcoal need to be used as catalyst under high pressure.Meanwhile easily
The use of the catalyst of combustion, the hydrogen of explosive, which is often given in production, brings many unfavorable factors for security.And use dichloro
To change the reducing agents such as tin, sodium borohydride to be restored, reaction terminates to generally require to carry out soda acid destruction, is also easy to produce a large amount of waste residue,
And it isolates and purifies often unsatisfactory.
Invention content
The purpose of the present invention is to provide a kind of greens preparing 4- amino -1- methyl -3- n-propyl pyrazoles -5- formamides
New process, it is intended to overcome the disadvantage in above-mentioned synthetic method.The method security height of technique offer, reaction are easy to control, to ring
Border pollution is small, and the recovery of solvent not only reduces cost, and reduces discharge, more environmentally protective.
Ionic liquid is the complete substance being made of ion being in a liquid state under room temperature or nearly ambient temperature.As a kind of green
Color solvent is low with fusing point, vapour pressure is small, electrochemical window is big, acidity is adjustable and good solubility, viscosity and density etc.
Feature.Ionic liquid due to its advantageous property separation, organic synthesis and catalysis reaction etc. fields be widely used, to environment
Close friend is so that application prospect industrially is good.Ionic liquid can be used as a kind of safe, recyclable solvent recycled
Also original in aromatic nitro prepares aromatic amine.Khan etc. is reported in ionic liquid [bmim] [BF4] or [bmim] [PF6] in,
Aromatic nitro restored as reducing agent using metallic zinc and ammonium formate or ammonium chloride, it can be highly selective, in high yield
To corresponding aromatic amine compound (Tetrahedron Letters, 2003,44,7783~7787.).
The present invention using 1- methyl -3- n-propyl pyrazoles -5- formamides shown in Formula II as raw material, in organic solvent and
It at certain temperature, is reacted with fuming nitric aicd or nitration mixture, obtains 4- nitros -1- methyl -3- n-propyl pyrroles shown in formula III
Azoles -5- formamides；Then in ion liquid solvent and at a certain temperature, 4- nitro -1- methyl -3- n-propyls pyrazoles -
5- formamides (III) carry out reduction reaction with metallic zinc and ammonium salt, obtain 4- amino -1- methyl -3- n-propyl pyrazoles -5- formyls
Amine (I).Synthetic route is as follows：
Specifically, novel environment-friendly process provided by the invention includes the following contents：
1- methyl -3- n-propyls pyrazoles -5- formamides shown in Formula II are dissolved or suspended in suitable organic solvent,
Fuming nitric aicd or nitration mixture is added into the mixture of gained under controlling reaction temperature, the reaction was continued in suitable temperature；Instead
After answering, 4- nitros -1- methyl -3- n-propyl pyrazoles -5- formamides shown in formula III are obtained by conventional post-processing.Its
In, organic solvent be selected from dichloromethane, chloroform, carbon tetrachloride, carbon disulfide, 1,2- dichloroethanes, 1,2- Bromofumes,
One or more of water mixture；Nitration mixture is fuming nitric aicd and oleum, the fuming nitric aicd and concentrated sulfuric acid, concentrated nitric acid and smoke
One kind in sulfuric acid or concentrated nitric acid and the concentrated sulfuric acid；Reaction temperature be -10 DEG C of reflux temperatures to solvent, preferably 10~40 DEG C.
4- nitro -1- methyl -3- n-propyl pyrazoles -5- formamides (III), metallic zinc and ammonium salt are added to ionic liquid
It in solvent, reacts at a suitable temperature, until raw material disappears；After ether extraction is added, ether is evaporated off and obtains product 4- amino -1-
Methyl -3- n-propyl pyrazoles -5- formamides (I).Wherein the ionic liquid is [bmim] [BF4] or [bmim] [PF6]；Ammonium
Salt is one or more of ammonium formate, ammonium chloride or ammonium sulfate mixture；The reaction temperature is -10 DEG C to 50 DEG C, excellent
Select 10~40 DEG C.
Ionic liquid phase after ether extraction, is added suitable dichloromethane, filters, concentrate, be dried to obtain back after filtering
The ionic liquid of receipts, it is reusable, number is reused up to 3 times or more.
The above new process provided by the present invention uses the method that organic solvent is added in nitration reaction step, can
To allow the nitration reaction of pyrazole ring in room temperature or close to progress very gentle at room temperature, reaction is as mild as a dove.It is demonstrated experimentally that
There is not the reaction process of focus type in the nitration reaction carried out using this method, and thermal discharge is small, it is easy to it controls, it can be significantly
Reduce the use of cooling medium.And it is thorough using the nitration reaction that this method carries out, yield reaches 90% or more.
In short, method security provided by the present invention is high, reaction is more easy to control, the reduction carried out in ionic liquid is anti-
Response environment pollution is small, and the recovery of solvent not only reduces cost, and reduces discharge, more environmentally protective.
Specific implementation mode
Following exemplary embodiments are used for illustrating the present invention, the letter that technical staff in the art is the present invention
Single replacement or improvement etc. belong within the technical solution that the present invention is protected.
Embodiment 1：The preparation (III) of 4- nitro -1- methyl -3- n-propyl pyrazoles -5- formamides
1- methyl -3- n-propyl pyrazoles -5- the formamides of 16.7g are added in 50mL dichloromethane, control temperature exists
15 DEG C hereinafter, be added dropwise fuming nitric aicd (12g).It is stirred to react at 20~25 DEG C, TLC tracking, until raw material point disappears.Later will
Reaction solution is poured into ice water, is stirred, and separation, organic phase is washed with water (20mL × 2), dry, filtering, and concentration dichloromethane is extremely
It is dry, 4- nitro -1- methyl -3- n-propyl pyrazoles -5- formamide 19.3g, yield 91% are obtained, HPLC purity is 95.6%.
Embodiment 2：The preparation (III) of 4- nitro -1- methyl -3- n-propyl pyrazoles -5- formamides
1- methyl -3- n-propyl pyrazoles -5- the formamides of 16.7g are added in 50mL dichloromethane, control temperature exists
15 DEG C hereinafter, dropwise addition 25g concentrated nitric acids, after forty minutes, the 5g concentrated sulfuric acids are added dropwise at 15 DEG C or less for control temperature for stirring.At 20~25 DEG C
Under be stirred to react, TLC tracking, until raw material point disappear.Reaction solution is poured into ice water later, is stirred, separation, organic phase water
It washs (20mL × 2), dry, filtering, concentration dichloromethane obtains 4- nitro -1- methyl -3- n-propyl pyrazoles -5- first to doing
Amide 20.1g, yield 95%, HPLC purity are 96.8%.
Embodiment 3：The preparation (I) of 4- amino -1- methyl -3- n-propyl pyrazoles -5- formamides
By 4- nitro -1- methyl -3- n-propyl pyrazoles -5- formamides, [bmim] [BF of 21.2g4] 100mL, zinc granule
After 13g, 10mL water are mixed with 9.5g ammonium formates, quickly stirring at room temperature, TLC tracking reactions, until raw material disappears.Ether is added
It extracts (150mL × 3), merges ether phase, 4- amino -1- methyl -3- n-propyl pyrazoles -5- formamides are obtained after being concentrated to dryness
16.2g, yield 89%, HPLC purity are 95.1%.
Ionic liquid layer is dissolved in 100mL dichloromethane, filters out drier after anhydrous sodium sulfate drying is added, decompression is dense
It is reduced to dry, obtains reusable ionic liquid 92mL.
Embodiment 4：The preparation (I) of 4- amino -1- methyl -3- n-propyl pyrazoles -5- formamides
By the 4- nitro -1- methyl -3- n-propyl pyrazoles -5- formamides of 21.2g, [bmim] [PF of 150mL6], zinc granule
After 13g, 10mL water are mixed with 16g ammonium chlorides, quickly stirring at room temperature, TLC tracking reactions, until raw material disappears.Ether is added
It extracts (150mL × 3), merges ether phase, 4- amino -1- methyl -3- n-propyl pyrazoles -5- formamides are obtained after being concentrated to dryness
16.9g, yield 93%, HPLC purity are 97.2%.
Ionic liquid layer is dissolved in 100mL dichloromethane, filters out drier after anhydrous sodium sulfate drying is added, decompression is dense
It is reduced to dry, obtains reusable ionic liquid 135mL.
Claims (7)
1. the new method of 4- amino -1- methyl -3- n-propyl pyrazoles -5- formamides shown in a kind of formula I, it is characterised in that
The preparation method includes the following steps：
(a) 1- methyl -3- n-propyls pyrazoles -5- formamides shown in Formula II, in organic solvent and at a certain temperature, with
Fuming nitric aicd or nitration mixture reaction, obtain 4- nitros -1- methyl -3- n-propyl pyrazoles -5- formamides shown in formula III；
(b) in ion liquid solvent and at a certain temperature, 4- nitro -1- methyl -3- n-propyl pyrazoles -5- formamides
(III) reduction reaction is carried out with metallic zinc and ammonium salt, obtains 4- amino -1- methyl -3- n-propyl pyrazoles -5- formamides (I).
2. according to the method described in claim 1, it is characterized in that organic solvent described in step (a) be selected from dichloromethane,
One or more of chloroform, carbon tetrachloride, carbon disulfide, 1,2- dichloroethanes, glycol dibromide, water mixture.
3. according to the method described in claim 1, it is characterized in that the nitration mixture described in step (a) is fuming nitric aicd and oleum
One kind in acid, fuming nitric aicd and the concentrated sulfuric acid, concentrated nitric acid and oleum or concentrated nitric acid and the concentrated sulfuric acid.
4. according to the method described in claim 1, it is characterized in that the reaction temperature described in step (a) is 10~40 DEG C.
5. according to the method described in claim 1, it is characterized in that the ionic liquid described in step (b) is [bmim] [BF4] or
[bmim][PF6]。
6. according to the method described in claim 1, it is characterized in that ammonium salt described in step (b) be ammonium formate, ammonium chloride or
One or more of ammonium sulfate mixture.
7. according to the method described in claim 1, it is characterized in that the reaction temperature described in step (b) is 10~40 DEG C.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1106399C (en) * | 1996-06-14 | 2003-04-23 | 辉瑞研究开发公司 | Process for preparing sildenafil |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1106399C (en) * | 1996-06-14 | 2003-04-23 | 辉瑞研究开发公司 | Process for preparing sildenafil |
Non-Patent Citations (2)
| Title |
|---|
| 1-甲基-3-正丙基-4-氨基-5-吡唑羧酰胺的制备;徐宝财等;《精细化工》;20030228;第20卷(第2期);第119-122页 * |
| 水合肼还原法合成4-氨基-1-甲基-3-正丙基吡唑-5-甲酰胺;徐宝峰等;《化学工程师》;20021231;第90卷(第3期);第1–2页 * |
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