CN108794351A - A kind of preparation method of Mo Fanselin key intermediate - Google Patents
A kind of preparation method of Mo Fanselin key intermediate Download PDFInfo
- Publication number
- CN108794351A CN108794351A CN201810832235.5A CN201810832235A CN108794351A CN 108794351 A CN108794351 A CN 108794351A CN 201810832235 A CN201810832235 A CN 201810832235A CN 108794351 A CN108794351 A CN 108794351A
- Authority
- CN
- China
- Prior art keywords
- reaction
- isobutoxy
- method described
- benzonitriles
- fanselin
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C263/00—Preparation of derivatives of isocyanic acid
- C07C263/10—Preparation of derivatives of isocyanic acid by reaction of amines with carbonyl halides, e.g. with phosgene
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses the preparation methods of a kind of Mo Fanselin key intermediate.Synthetic route includes
Description
Technical field
The present invention relates to the synthesis fields of pharmaceutical molecules, the more particularly to synthesis technology of pharmaceutical molecules, and in particular to a kind of
Prepare body method among a Mo Fanselin.
Background technology
Whole world parkinsonian about 7 million to one 10,000,000 at present, China just have 2,600,000, rank first in the world, often
Year can also increase by 100,000 neopathy patients.50% or more parkinsonian once had mental symptom (PDP).These spirit
Symptom is mainly shown as illusion and vain hope, and the treatment and tourniquet to parkinsonian carry out bigger challenge.Parkinson's disease essence
Refreshing disease is the main cause that Parkinsonian enters old nurse apartment.Parkinson's disease psychosis is now in addition to low at present
Without approval other drugs except dose clozapine (clozapine, Clozaril), and Clozapine has serious security risk,
It can lead to dangerous quantity of leucocyte decline and drowsiness side effect.
The tartaric acid Mo Fanselin (Pimavanserin, Nuolazid) of company of Acadia research and development is for treating pa gold
Sen Shi disease mental symptoms are non-dopamine neurotransmitter similar to object, can be more without influencing with selective exclusion five hydroxytryptamine 2A receptors
The effect of bar amine.
So far, less about the synthesis patent of Mo Fanselin synthesis, CN105111135A reports following route：
The route tries although avoiding using severe toxicity is dangerous using carbonyl dimidazoles as active urea intermediate source is obtained
Agent, but route steps are long, intermediate is not purified, and the purifying of finished product is relatively difficult.
CN105418460A discloses following preparation methods：
Though this method has used chloro-formate instead of the phosgene of severe toxicity, chloro-formate toxicity is still huge, environment
It is seriously polluted, and reaction step is more, yield is low.
CN201610302251 discloses following preparation methods：
Though this method needs high temperature, operation dangerous using potassium borohydride/chlorination copper reduction cyano.It uses simultaneously
Carbonyl dimidazoles need strong acid at salt as active urea intermediate source, intermediate is obtained, and operation is complicated, corrodes to equipment
Greatly.
US7790899B2 reports following synthetic route：
The shortcomings that route：(1) it participates in reaction using hydrogen to need to carry out under high pressure, security risk is high；Reaction needs
Palladium catalyst charcoal, it is expensive.(2) virose phosgene is arrived involved in reaction, it is larger to the health effect of operator, it is unfavorable for
Environmental protection, security risk is high, is unfavorable for industrialized production.
Another synthetic route, as follows described in US7601740B2：
The DPPA that the route uses is expensive, and azido compound intermediate, the nitrine of generation will be passed through in reaction process
There are the security risks such as explosion, severe toxicity in compound.
How to develop that a kind of reaction condition is mild, the preparation method of the few Mo Fanselin of reaction step and its tartrate
It is a challenging job.
Invention content
It is an object of the invention to overcome the deficiencies of the prior art and provide a kind of reaction condition is mild, high income not
The preparation method of Fan Selin intermediates.
The technical solution used in the present invention is：
A method of a Mo Fanselin intermediates being prepared, synthetic route includes：
Include the following steps：
1) using 4- hydroxy-phenylformonitriles as raw material, 4- isobutoxy benzonitriles are obtained by etherification reaction；
2) 4- isobutoxy benzonitriles are restored using reducing agent to obtain 4- isobutoxy benzylamines；
3) 4- isobutoxies benzylamine and triphosgene acylation reaction are obtained into isocyanic acid 4- butoxy benzyl esters.
As being further improved for the above method, carries out etherification reaction using 4- hydroxy-phenylformonitriles and alkyl halide reagent and be made
4- isobutoxy benzonitriles, halogenated alkane reagent in chloro-iso-butane, isobutane bromide, iodo isobutane at least one
Kind.
As being further improved for the above method, the acid binding agent that etherification reaction uses is potassium carbonate, sodium carbonate, hydroxide
In sodium, potassium hydroxide, saleratus, sodium bicarbonate, diisopropylethylamine, triethylamine, pyridine, ethylenediamine, triethylene diamine
Any or its arbitrary combination.
As being further improved for the above method, the solvent that etherification reaction uses is acetone, tetrahydrofuran, acetonitrile, Isosorbide-5-Nitrae-
Any one of dioxane, isopropanol, dimethylformamide, dimethylacetylamide or its arbitrary combination.
As being further improved for the above method, the temperature of etherification reaction is 10~110 DEG C, preferably 50~100 DEG C.
As being further improved for the above method, 4- isobutoxy benzonitriles are restored to obtain the use of 4- isobutoxy benzylamines
Reducing agent be selected from borine, boron hydrogen salt.
As being further improved for the above method, boron hydrogen salt is selected from lithium aluminium hydride, sodium borohydride, potassium borohydride.
As being further improved for the above method, 4- isobutoxy benzonitriles are reduced to the reaction of 4- isobutoxy benzylamines
Temperature is -15~70 DEG C, preferably -15~50 DEG C.
As being further improved for the above method, 4- isobutoxy benzonitriles are restored to obtain the use of 4- isobutoxy benzylamines
Solvent be selected from tetrahydrofuran, 1,4- dioxane, toluene, methanol, ethyl alcohol, isopropanol.
As being further improved for the above method, 4- isobutoxy benzonitriles are restored to obtain the use of 4- isobutoxy benzylamines
Catalyst be selected from iodine, calcium chloride, nickel chloride, zirconium chloride, copper chloride, inidum chloride.
As being further improved for the above method, the solvent of acylation reaction is non-protonated organic solvent.
The beneficial effects of the invention are as follows：
The present invention Mo Fanselin preparation methods, by change synthetic route, using borine, boron hydrogen salt as restore
Agent, villaumite restore cyano as catalyst, collective effect, and good reaction selectivity avoids the use of hazardous agents Raney's nickel, drops
The low production safety risk of Mo Fanselin.
The materials safety that the method for the present invention uses, it is of low cost, effectively reduce production cost.
The reaction condition of the method for the present invention is mild, can use big to avoid toxicity and not easy-operating phosgene, industrially
It is easily achieved.
It is easy that the intermediate and product of the method for the present invention isolate and purify, in this embodiment it is not even necessary to pass through separation of intermediates, you can straight
Tapping into row, reaction prepares a Mo Fanselin or Mo Fanselin tartrates, easy to operate, favorable reproducibility, Mo Fanse in next step
The product quality and yield of woods are than prior art higher.
Description of the drawings
Fig. 1 is the Mo Fanselin HPLC collection of illustrative plates of the present invention；
Fig. 2 is the HPLC collection of illustrative plates of the Mo Fanselin tartrates of the present invention；
Fig. 3 is the XRD spectrum of the HPLC crystal forms I of the Mo Fanselin tartrates of the present invention.
Specific implementation mode
A method of a Mo Fanselin intermediates being prepared, synthetic route includes：
Include the following steps：
1) using 4- hydroxy-phenylformonitriles as raw material, 4- isobutoxy benzonitriles are obtained by etherification reaction；
2) 4- isobutoxy benzonitriles are restored using reducing agent to obtain 4- isobutoxy benzylamines；
3) 4- isobutoxies benzylamine and triphosgene acylation reaction are obtained into isocyanic acid 4- butoxy benzyl esters.
As being further improved for the above method, it is different that halogenated alkane reagent is selected from chloro-iso-butane, isobutane bromide, iodo
At least one of butane.The best halogenated alkane reagent under different condition can be determined by monitoring response situation.
As being further improved for the above method, the acid binding agent that etherification reaction uses is potassium carbonate, sodium carbonate, hydroxide
In sodium, potassium hydroxide, saleratus, sodium bicarbonate, diisopropylethylamine, triethylamine, pyridine, ethylenediamine, triethylene diamine
Any or its arbitrary combination.Acid binding agent can preferably initiation reaction, and consume generated in reaction process acid reaction, promote
The progress of reaction.
As being further improved for the above method, the solvent that etherification reaction uses is acetone, tetrahydrofuran, acetonitrile, Isosorbide-5-Nitrae-
Any one of dioxane, isopropanol, dimethylformamide, dimethylacetylamide or its arbitrary combination.These solvents can be with
Reaction is advantageously promoted, the generation of by-product is reduced.
Reaction temperature is low, and reaction is slow, reacts being not thorough for progress；Reaction temperature is high, and side reaction is got higher, and influences product yield
And purity.As being further improved for the above method, the temperature of etherification reaction is 10~110 DEG C, preferably 50~100 DEG C.
Those skilled in the art can determine the optimal reactive temperature under each reaction condition further by monitoring reaction course.
As being further improved for the above method, 4- isobutoxy benzonitriles are restored to obtain the use of 4- isobutoxy benzylamines
Reducing agent be selected from borine, boron hydrogen salt.
As being further improved for the above method, boron hydrogen salt is selected from lithium aluminium hydride, sodium borohydride, potassium borohydride.
As being further improved for the above method, 4- isobutoxy benzonitriles are restored to obtain the use of 4- isobutoxy benzylamines
Catalyst be selected from iodine, calcium chloride, nickel chloride, zirconium chloride, copper chloride, inidum chloride.
As being further improved for the above method, 4- isobutoxy benzonitriles are restored to obtain the use of 4- isobutoxy benzylamines
Solvent be selected from tetrahydrofuran, 1,4- dioxane, toluene, methanol, ethyl alcohol, isopropanol.
Borine, boron hydrogen salt specific type can be adjusted according to catalyst, the type of solvent, the concrete condition of reaction
It is whole, to obtain best reaction effect.
Reaction temperature is low, and reaction is slow, reacts being not thorough for progress；Reaction temperature is high, and side reaction is got higher, and influences product yield
And purity.And reaction temperature is excessively high, and reaction is violent, is easy slug, is unfavorable for production operation.As the above method into one
Step is improved, and the reaction temperature that 4- isobutoxy benzonitriles are reduced to 4- isobutoxy benzylamines is -15~70 DEG C.Preferably -15
~50 DEG C.Those skilled in the art can determine the optimal reactive temperature under each reaction condition further by monitoring reaction course.
To avoid triphosgene from solvent reaction, generating unnecessary by-product during the reaction, yield etc. is influenced.As
The above method is further improved, and the solvent of acylation reaction is non-protonated organic solvent.Non-protonated organic solvent include but
It is not limited to toluene, dichloromethane, chloroform, tetrahydrofuran, 2- methyltetrahydrofurans, acetone etc..It can be reacted by monitoring
Production, reaction speed of byproduct in process object etc. are comprehensive to determine best solvent.
Reaction temperature is low, and reaction is slow, reacts being not thorough for progress；Reaction temperature is high, and side reaction is got higher, and influences product yield
And purity.As being further improved for the above method, the temperature of acylation reaction is -15~100 DEG C, preferably -15~70 DEG C.
Best reaction temperature can be determined by the way that the production of by-product, reaction speed etc. in monitoring reaction course are comprehensive.
With reference to embodiment, the technical solution that further illustrates the present invention.
The part material used in following embodiment can be prepared or be commercially available by existing method, or pressed
Following method synthesizes to obtain.
Embodiment 1
By 1 prepare compound 3 of compound
1) addition parahydroxyben-zaldehyde (14.6g, 122.8mmo1) in 250mL there-necked flasks, Anhydrous potassium carbonate (25.4g,
184.2mmoL), potassium iodide (1.4g, 12.3mmoL) and 75mL DMF, are heated to 85 DEG C；
2) it is slowly added to chloro-iso-butane (34.1g, 368.4mmo1) into reaction system, finishes, system is in 85 DEG C of conditions
Lower reaction 6h；
3) stop reaction, system is cooled to room temperature, filtering, filter cake 90mL ethyl acetate rinses 2 times；
4) filtrate is poured into 250mL water, separates organic phase, water phase is used the extraction of 90mL ethyl acetate three times, merged respectively
Organic phase is washed once with 150mL saturated common salts, and anhydrous sodium sulfate drying, filtering, filtrate is spin-dried for obtaining 19.4g compounds, yellowish
Color liquid, yield 90%.
MS(m/z)：[M+H]+=176.2；3 nuclear magnetic data of compound is as follows：'H NMR(400MHz,CDCl3)(ppm):
7.85(d,2H),7.08(d,2H),3.86(d,2H),1.93-1.85(m,1H),0.96(d,6H)。
By 3 prepare compound 4 of compound
5) addition 4- isobutoxies benzonitrile (10g, 57.07mmo1) in 250mL there-necked flasks, six water nickel chlorides (13.6g,
57.07mmoL), absolute methanol 150mL, nitrogen replace three times, 0~10 DEG C are cooled under nitrogen protection, hydroboration is added portionwise
Sodium (6.5g, 171.2mmo1)；
6) charging finishes, and is to slowly warm up to 20~30 DEG C, insulation reaction 6h；
7) reaction solution is filtered by diatomite, most methanol is evaporated off in filtrate concentration；
8) ethyl acetate 60mL is added, after 10% hydrochloric acid adjusting pH=1~2 are slowly added dropwise, with 15% sodium hydroxide solution
Liquid separation behind adjusting pH=11~12, water phase are extracted with ethyl acetate 60mL, merge organic phase；
9) organic phase with 60mL water washings, wash once by primary, 60mL saturated common salts, and anhydrous sodium sulfate drying has been dried
Finish, filtering, filtrate is spin-dried for obtaining 8.6g compounds, weak yellow liquid, yield 79%.
MS(m/z)：[M+H]+=176.2；4 nuclear magnetic data of compound is as follows：'H NMR(400MHz,CDCl3)(ppm):
7.85(d,2H),7.08(d,2H),4.19(s,2H),3.86(d,2H),1.93-1.85(m,1H),0.96(d,6H)。
By 4 prepare compound Mo Fanselin of compound
10) triphosgene (7.1g, 24mmoL), tetrahydrofuran 86mL are added in 250mL there-necked flasks, nitrogen is replaced three times, nitrogen
- 10~10 DEG C are cooled under gas shielded；Temperature is controlled at -10~10 DEG C, 4- isobutoxies benzylamine/tetrahydrofuran solution is added dropwise
(4- isobutoxy benzylamine 8.6g, 48.0mmoL+ triethylamine 9.7g, 96.0mmoL+ tetrahydrofuran 43mL)；It is added dropwise, -10
~10 DEG C, 4~5h is kept the temperature, keeps the temperature 4~5h, 65~70 DEG C of 4~5h of reflux at room temperature, is concentrated in vacuo solvent to without apparent drop,
Obtain isocyanic acid 4- butoxy benzyl ester crude products；
11) above-mentioned isocyanic acid 4- butoxy benzyl ester crude product is dissolved with tetrahydrofuran 86mL in 250mL there-necked flasks, system
- 10~10 DEG C are cooled to, after stirring 0.5h, the tetrahydrofuran solution (43mL) of compound 8 (9.6g, 43.2mmoL) is added dropwise；Drop
It adds complete, after room temperature 12h, water quenching is slowly added dropwise and goes out reaction, after 40~50 DEG C are concentrated into without apparent fraction, acetic acid second is added
Ester extracting and washing is concentrated into a large amount of solids and dropwise addition normal heptane crystallization is precipitated, obtains a Mo Fanselin crude products, crude product passes through second after dry
Alcohol/water recrystallization, filtration drying obtain white powder Mo Fanselin 17.0g.
Two step yields 83%, HPLC purity 99.9%, [HPLC normalization methods：Chromatographic column Shimadzu C18 columns (250*4.6mm, 6
μm)；0.1% phosphate aqueous solution of mobility (triethylamine is added to adjust pH=6.5)-acetonitrile (50:50), Detection wavelength 215nm；Column temperature
25℃；Flow velocity 1mL/min], HPLC figures are as shown in Figure 1.
Mo Fanselin MS (m/z)：[M+H] +=428.6；Nuclear magnetic data is as follows:'H NMR(400MHz,CDCl3)
(ppm):7.35-7.24(m,2H),7.13-7.01(m,4H),6.85(d,2H),5.94(s,1H),4.77(s,1H),4.25
(s,2H),3.71(d,2H),3.17-3.05(m,2H),2.41-2.34(m,4H),2.7(s,3H),1.86-1.54(m,4H),
0.95(d,6H)。
Embodiment 2：
By 1 prepare compound 3 of compound
1) addition parahydroxyben-zaldehyde (14.6g, 122.8mmo1) in 250mL there-necked flasks, Anhydrous potassium carbonate (25.4g,
184.2mmoL), potassium iodide (1.4g, 12.3mmoL) and 75mL DMF, are heated to 90 DEG C；
2) it is slowly added to isobutane bromide (50.5g, 368.4mmo1) into reaction system, finishes, system is in 90 DEG C of conditions
Lower reaction 5h；
3) stop reaction, system is cooled to room temperature, filtering, filter cake 90mL ethyl acetate rinses 2 times；
4) filtrate is poured into 250mL water, separates organic phase, water phase is used the extraction of 90mL ethyl acetate three times, merged respectively
Organic phase is washed once with 150mL saturated common salts, and anhydrous sodium sulfate drying, filtering, filtrate is spin-dried for obtaining 19.8g compounds, yellowish
Color liquid, yield 92%.
By 3 prepare compound 4 of compound
5) addition 4- isobutoxies benzonitrile (10g, 57.07mmo1) in 250mL there-necked flasks, inidum chloride (12.6g,
57.07mmoL), absolute methanol 150mL, nitrogen replace three times, 0~10 DEG C are cooled under nitrogen protection, hydroboration is added portionwise
Sodium (6.5g, 171.2mmo1)；
6) charging finishes, and is to slowly warm up to 30~35 DEG C, insulation reaction 6h；
7) reaction solution is filtered by diatomite, most methanol is evaporated off in filtrate concentration；
8) ethyl acetate 60mL is added, after 10% hydrochloric acid adjusting pH=1~2 are slowly added dropwise, with 15% sodium hydroxide solution
Liquid separation behind adjusting pH=11~12, water phase are extracted with ethyl acetate 60mL, merge organic phase；
9) organic phase with 60mL water washings, wash once by primary, 60mL saturated common salts, and anhydrous sodium sulfate drying has been dried
Finish, filtering, filtrate is spin-dried for obtaining 7.3g compounds, weak yellow liquid, yield 72%.
By 4 prepare compound Mo Fanselin of compound
10) triphosgene (7.1g, 24mmoL), toluene 86mL are added in 250mL there-necked flasks, nitrogen is replaced three times, and nitrogen is protected
- 10~10 DEG C are cooled under shield；Temperature is controlled at -10~10 DEG C, 4- isobutoxies benzylamine/toluene solution (4- isobutyl oxygen is added dropwise
Base benzylamine 8.6g, 48.0mmoL+ triethylamine 9.7g, 96.0mmoL+ toluene 43mL)；It is added dropwise, at -10~10 DEG C, heat preservation 4
~5h, keeps the temperature 4~5h at room temperature, and 60~70 DEG C of 1~2h of heat preservation are concentrated in vacuo solvent to without apparent drop, obtain isocyanic acid 4- fourths
Oxy-benzyl ester crude product；
11) above-mentioned isocyanic acid 4- butoxy benzyl ester crude product is dissolved with toluene 86mL in 250mL there-necked flasks, system cooling
To -10~10 DEG C, after stirring 0.5h, the toluene solution (43mL) of compound 8 (9.6g, 43.2mmoL) is added dropwise, is added dropwise.?
After room temperature 12h, water quenching is slowly added dropwise and goes out reaction, stand liquid separation, after toluene two extracts, organic phase is washed with water, and is concentrated into after dry
A large amount of solids, which are precipitated, is added dropwise normal heptane crystallization, obtains a Mo Fanselin crude products, crude product is recrystallized by ethanol/water, and filtration drying obtains
To white powder Mo Fanselin 16.6g, two step yields 81%, HPLC purity 99.8%.
Embodiment 3：
By 1 prepare compound 3 of compound
1) addition parahydroxyben-zaldehyde (14.6g, 122.8mmo1) in 250mL there-necked flasks, Anhydrous potassium carbonate (25.4g,
184.2mmoL), potassium iodide (1.4g, 12.3mmoL) and 75mL DMF, are heated to 100 DEG C；
2) it is slowly added to iodo isobutane (67.8g, 368.4mmo1) into reaction system, finishes, system is in 100 DEG C of items
5h is reacted under part；
3) stop reaction, system is cooled to room temperature, filtering, filter cake 90mL ethyl acetate rinses 2 times；
4) filtrate is poured into 250mL water, separates organic phase, water phase is used the extraction of 90mL ethyl acetate three times, merged respectively
Organic phase is washed once with 150mL saturated common salts, and anhydrous sodium sulfate drying, filtering, filtrate is spin-dried for obtaining 19.6g compounds, yellowish
Color liquid, yield 91%.
By 3 prepare compound 4 of compound
5) addition 4- isobutoxies benzonitrile (10g, 57.07mmo1) in 250mL there-necked flasks, copper chloride (9.7g,
57.07mmoL), absolute methanol 150mL, nitrogen replace three times, 0~10 DEG C are cooled under nitrogen protection, hydroboration is added portionwise
Sodium (6.5g, 171.2mmo1)；
6) charging finishes, and is to slowly warm up to 40~50 DEG C, insulation reaction 6h；
7) reaction solution is filtered by diatomite, most methanol is evaporated off in filtrate concentration；
8) ethyl acetate 60mL is added, after 10% hydrochloric acid adjusting pH=1~2 are slowly added dropwise, with 15% sodium hydroxide solution
Liquid separation after adjusting pH=11-12, water phase are extracted with ethyl acetate 60mL, merge organic phase；
9) organic phase with 60mL water washings, wash once by primary, 60mL saturated common salts, and anhydrous sodium sulfate drying has been dried
Finish, filtering, filtrate is spin-dried for obtaining 7.0g compounds, weak yellow liquid, yield 69%.
By 4 prepare compound Mo Fanselin of compound
10) triphosgene (7.1g, 24mmoL), dichloromethane 86mL are added in 250mL there-necked flasks, nitrogen is replaced three times, nitrogen
- 10~10 DEG C are cooled under gas shielded；Temperature is controlled at -10~10 DEG C, 4- isobutoxies benzylamine/dichloromethane solution is added dropwise
(4- isobutoxy benzylamine 8.6g, 48.0mmoL+ triethylamine 9.7g, 96.0mmoL+ dichloromethane 43mL)；It is added dropwise, -10
~10 DEG C, 4~5h is kept the temperature, keeps the temperature 4~5h at room temperature, 35-40 DEG C of 4~5h of reflux is concentrated in vacuo solvent to without apparent drop, obtains
Isocyanic acid 4- butoxy benzyl ester crude products.
11) above-mentioned isocyanic acid 4- butoxy benzyl ester crude product is dissolved with toluene 86mL in 250mL there-necked flasks, system cooling
To -10~10 DEG C, after stirring 0.5h, the dichloromethane solution (43mL) of compound 8 (9.6g, 43.2mmoL) is added dropwise, drips
Finish.After room temperature 12h, water quenching is slowly added dropwise and goes out reaction, stand liquid separation, after dichloromethane two extracts, organic phase is washed with water, dry
After be concentrated into a large amount of solids and be precipitated normal heptane crystallizations are added dropwise, obtain a Mo Fanselin crude products, crude product is recrystallized by ethanol/water, mistake
It is filtered dry dry, obtains white powder Mo Fanselin 16.0g, two step yields 78%, HPLC purity 99.8%.
Since isocyanic acid 4- butoxy benzyl esters itself are not sufficiently stable, it is difficult to measure its purity data, therefore pass through a not model
The preparation of color woods is illustrated.Embodiment the result shows that, the method for the present invention can easily obtain the Mo Fanse of high-purity
Woods, while its yield is also significantly greater than the prior art.
Route described in document and patent is repeated, its yield and purity data is obtained, is compared with data of the present invention：
Comparative example 1：Method disclosed in US7790899B2 prepares tartaric acid Mo Fanselin
Comparative example 2：Method disclosed in CN105418460A prepares a Mo Fanselin
The comparable situation of different Mo Fanselin preparation methods is as shown in table 1：
The case where table 1, different Mo Fanselin preparation methods comparison sheet
From the data in the table：
By changing synthesis technology the amount of impurity in product is greatly reduced, with comparative example 1 and right in the method for the present invention
Ratio 2 is compared, and the amount of impurity is reduced to 0.1~0.2% by 1.6% and 1.0 respectively, and the amount of impurity substantially reduces, the matter of product
It measures more controllable, greatly reduces the purifying difficulty of product.
Compared with comparative example 1, embodiment 1,2 and 3 differences reside in reduced reaction step, and avoid Raney's nickel, phosgene
Use, intermediate be not necessarily at after salt dissociate participate in reaction.Simplifying step reduces Material Cost, and generation is safer, and yield
It is significantly increased.
Compared with comparative example 2：Embodiment 1,2 and 3 differences are to use NaBH4/ chloride system restores, and intermediate is not necessarily to
Reaction is participated at dissociating after salt, Mo Fanselin is purified without column chromatography.Material Cost is reduced, operation is simplified, carries simultaneously
The high yield of product.
The discovery of comparative example 1,2 and 3, NaBH4The reduction system reducing effect of/six water nickel chlorides is best, to promote
Yield is obviously improved.Supposition is that sodium borohydride and chlorination nickel reactant generate boron nickel compound and hydrogen, the catalysis of boron nickel compound
It is active high, to which efficient catalytic reduction cyano is amino.
In conclusion the synthesis work of tartaric acid Mo Fanselin can be simplified by implementing reaction using the technological parameter of the present invention
Skill, reaction condition is mild, and operating procedure is simple, and product quality and yield significantly improve, and reduces tartaric acid Mo Fanselin's
Synthesis cost.
Mo Fanselin tartrates are prepared by Mo Fanselin
90mL isopropanols, 6g Mo Fanselin, 1.08gL- tartaric acid, dichloromethane 6mL, nitrogen is added in 250mL there-necked flasks
It replaces, 70 ± 5 DEG C is warming up under nitrogen protection, keep the temperature 5h, slow cooling filters, filter cake is pre- with 9mL to 0-5 DEG C after keeping the temperature 2h
Cold isopropanol elution, wet product are dried in vacuo at 60 DEG C, obtain white powder Mo Fanselin tartrate 6.5g, yield
93%, (there is an isopropanol for Mo Fanselin tartrates in purity 99.9% (HPLC collection of illustrative plates is as shown in Figure 2), isopropanol 2.0%
Solvate).It is confirmed as crystal form I by XRD (Fig. 3), dsc measurement shows that fusing point is about 128 DEG C, and melting enthalpy is about
75.02J/g。
The X-ray powder diffraction characteristic peak data of obtained solid is as shown in table 2：
Table 2, obtained Mo Fanselin tartrate X-ray powder diffraction characteristic peak data
Prepare unformed Mo Fanselin tartrate
10 grams of samples are taken to be added 40mL purified waters, stirring and dissolving 0.5h under room temperature.Lysate is passed through into 0.22 μm of filter membrane mistake
After filter by filtrate at -15--10 DEG C pre-freeze 12h.Lyophilized plate is transferred to small freeze dryer and carries out freeze-drying operation.Parameter is lyophilized：It is cold
- 78~-80 DEG C of hydrazine temperature, vacuum degree < 100Pa, 36~48h of freeze-drying time.Unformed Mo Fanselin 9.8g is finally obtained,
Yield 98%.Confirm that products therefrom is unformed state by differential scanning calorimetry and x-ray powder diffraction detection.
The basic principles and main features and advantages of the present invention of the present invention have been shown and described above.The skill of the industry
Art personnel it should be appreciated that the present invention is not limited to the above embodiments, the above embodiments and description only describe
The principle of the present invention, without departing from the spirit and scope of the present invention, various changes and improvements may be made to the invention, these
Changes and improvements all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and
Its equivalent thereof.
Claims (10)
1. a kind of preparing a method for Mo Fanselin intermediates, synthetic route includes：
Include the following steps：
1) using 4- hydroxy-phenylformonitriles and halogenated iso-butane as raw material, 4- isobutoxy benzonitriles are obtained by etherification reaction；
2) 4- isobutoxy benzonitriles are restored using reducing agent to obtain 4- isobutoxy benzylamines；
3) 4- isobutoxies benzylamine and triphosgene acylation reaction are obtained into isocyanic acid 4- butoxy benzyl esters.
2. according to the method described in claim 1, it is characterized in that：Halogenated iso-butane be selected from chloro-iso-butane, isobutane bromide,
At least one of iodo isobutane.
3. according to the method described in claim 1, it is characterized in that：The acid binding agent that etherification reaction uses be potassium carbonate, sodium carbonate,
Sodium hydroxide, potassium hydroxide, saleratus, sodium bicarbonate, diisopropylethylamine, triethylamine, pyridine, ethylenediamine, triethylene two
Any one of amine or its arbitrary combination.
4. according to the method described in claim 1, it is characterized in that：The solvent that etherification reaction uses is acetone, tetrahydrofuran, second
Any one of nitrile, 1,4- dioxane, isopropanol, dimethylformamide, dimethylacetylamide or its arbitrary combination.
5. making the method described in one according to Claims 1 to 4, it is characterised in that：The temperature of etherification reaction is 10~110 DEG C.
6. according to the method described in claim 1, it is characterized in that：It restores 4- isobutoxy benzonitriles to obtain 4- isobutoxies
The reducing agent that benzylamine uses is selected from borine, boron hydrogen salt.
7. according to the method described in claim 1, it is characterized in that：4- isobutoxy benzonitriles are reduced to 4- isobutoxy benzyls
The reaction temperature of amine is -15~70 DEG C.
8. according to the method described in claim 1, it is characterized in that：It restores 4- isobutoxy benzonitriles to obtain 4- isobutoxies
The solvent that benzylamine uses is selected from tetrahydrofuran, 1,4- dioxane, toluene, methanol, ethyl alcohol, isopropanol.
9. according to the method described in claim 1, it is characterized in that：It restores 4- isobutoxy benzonitriles to obtain 4- isobutoxies
The catalyst that benzylamine uses is selected from iodine, calcium chloride, nickel chloride, zirconium chloride, copper chloride, inidum chloride.
10. according to Claims 1 to 4,6~9 any one of them methods, it is characterised in that：The solvent of acylation reaction is non-matter
Sonization organic solvent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810832235.5A CN108794351B (en) | 2018-07-26 | 2018-07-26 | Preparation method of pimavanserin key intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810832235.5A CN108794351B (en) | 2018-07-26 | 2018-07-26 | Preparation method of pimavanserin key intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108794351A true CN108794351A (en) | 2018-11-13 |
| CN108794351B CN108794351B (en) | 2021-02-09 |
Family
ID=64078222
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810832235.5A Active CN108794351B (en) | 2018-07-26 | 2018-07-26 | Preparation method of pimavanserin key intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108794351B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110066221A (en) * | 2019-05-16 | 2019-07-30 | 海门瑞一医药科技有限公司 | A kind of preparation method of cyclopropyl-methylamine |
| WO2020020064A1 (en) * | 2018-07-26 | 2020-01-30 | 丽珠集团新北江制药股份有限公司 | Method for safely preparing pimavanserin and tartrate salt thereof using triphosgene |
| CN111377928A (en) * | 2018-12-28 | 2020-07-07 | 南京艾德凯腾生物医药有限责任公司 | Method for preparing acarabretinib |
| CN112119058A (en) * | 2018-04-26 | 2020-12-22 | 欧伦股份公司 | Process for the preparation of pimavanserin base |
| CN114874103A (en) * | 2022-05-11 | 2022-08-09 | 合肥立方制药股份有限公司 | Continuous synthesis method of pimavanserin intermediate 4-isobutoxy benzylamine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105820110A (en) * | 2016-05-09 | 2016-08-03 | 杭州科巢生物科技有限公司 | Novel synthesis method for pimavanserin |
| CN105906531A (en) * | 2015-12-23 | 2016-08-31 | 嘉实（湖南）医药科技有限公司 | Preparation method of pimavanserin intermediate |
-
2018
- 2018-07-26 CN CN201810832235.5A patent/CN108794351B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105906531A (en) * | 2015-12-23 | 2016-08-31 | 嘉实（湖南）医药科技有限公司 | Preparation method of pimavanserin intermediate |
| CN105820110A (en) * | 2016-05-09 | 2016-08-03 | 杭州科巢生物科技有限公司 | Novel synthesis method for pimavanserin |
Non-Patent Citations (2)
| Title |
|---|
| VALDEMAR L. ANDERSEN, ET AL: "11C-labeling and preliminary evaluation of pimavanserin as a 5-HT2A receptor PET-radioligand", 《BIOORGANIC MEDICINAL CHEMISTRY LETTERS》 * |
| 谢如刚主编: "《现代有机合成化学》", 31 January 2007, 华东理工大学出版社 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112119058A (en) * | 2018-04-26 | 2020-12-22 | 欧伦股份公司 | Process for the preparation of pimavanserin base |
| WO2020020064A1 (en) * | 2018-07-26 | 2020-01-30 | 丽珠集团新北江制药股份有限公司 | Method for safely preparing pimavanserin and tartrate salt thereof using triphosgene |
| CN111377928A (en) * | 2018-12-28 | 2020-07-07 | 南京艾德凯腾生物医药有限责任公司 | Method for preparing acarabretinib |
| CN110066221A (en) * | 2019-05-16 | 2019-07-30 | 海门瑞一医药科技有限公司 | A kind of preparation method of cyclopropyl-methylamine |
| CN110066221B (en) * | 2019-05-16 | 2022-03-08 | 海门瑞一医药科技有限公司 | Preparation method of cyclopropylmethylamine |
| CN114874103A (en) * | 2022-05-11 | 2022-08-09 | 合肥立方制药股份有限公司 | Continuous synthesis method of pimavanserin intermediate 4-isobutoxy benzylamine |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108794351B (en) | 2021-02-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108947891A (en) | The method for safely preparing a Mo Fanselin and its tartrate using triphosgene | |
| CN108794351A (en) | A kind of preparation method of Mo Fanselin key intermediate | |
| CN110590746B (en) | Preparation method of low-impurity Vonoprazan fumarate | |
| CN104926790A (en) | High-purity Vonoprazan Fumarate compound, intermediate and impurity thereof and preparation methods of high-purity Vonoprazan Fumarate compound, intermediate and impurity | |
| CN109020881A (en) | A kind of Ah pa replaces the preparation method of Buddhist nun | |
| CN106316889A (en) | Preparation method of Edoxaban intermediate | |
| CN109293592A (en) | A method of preparing Gadobutrol | |
| CN108699068A (en) | A kind of pyran derivate preparation method of trifluoromethyl substitution | |
| CN105330582B (en) | (R) preparation method of-Esomeprazole | |
| CN108976164A (en) | The preparation method of chiral piperidine amine compounds and the recovery method of chiral resolving agent | |
| CN108794416A (en) | A kind of cycleanine production purification process | |
| CN110240586A (en) | The preparation method of 2,3- dihydro -1H- benzo [f] chroman -2- amine derivative | |
| CN102367236A (en) | Synthesizing technology of donepezil hydrochloride | |
| CN107056720A (en) | A kind of preparation and purification method of Valsartan | |
| CN108586355A (en) | A kind of process for purification of olaparib | |
| CN108084104A (en) | 1,2,3- phentriazine -4（3H）The synthetic method of -one compound | |
| CN106543076A (en) | The method for preparing Acrivastine | |
| CN106608853B (en) | The preparation method of dipeptidy peptidase in inhibitors | |
| CN105461640A (en) | Preparation method of tyrosine kinase inhibitor | |
| CN108794448A (en) | The preparation method of one koji Ge Lieting and its salt | |
| CN101735220A (en) | Crystal form of 6, 7-dihydro-6-mercapto-5H-pyrazolo[1,2-alpha][1,2,4] triazoliumchloride and preparation method thereof | |
| CN111100042B (en) | Preparation method of 2-methoxy-5-sulfonamide benzoic acid | |
| CN106432059A (en) | Preparation method of 3-hydroxypiperidine, preparation method of derivative of 3-hydroxypiperidine, and intermediate of 3-hydroxypiperidine | |
| CN109651234A (en) | A kind of synthetic method of Doneppezil Hydrochloride | |
| CN107868055B (en) | Preparation method of macitentan |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |