CN105218402B - A kind of aminopropionitrile compound and preparation method thereof - Google Patents

A kind of aminopropionitrile compound and preparation method thereof Download PDF

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CN105218402B
CN105218402B CN201510718891.9A CN201510718891A CN105218402B CN 105218402 B CN105218402 B CN 105218402B CN 201510718891 A CN201510718891 A CN 201510718891A CN 105218402 B CN105218402 B CN 105218402B
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aminopropionitrile
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CN105218402A (en
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姚庆佳
李长永
敖军礼
俞悦
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Sphinx drug development (Tianjin) Limited by Share Ltd
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Tianjin Sphinx Medicine R&d Co Ltd
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Abstract

The present invention relates to a kind of aminopropionitrile compound and preparation method thereof, the compound is (4 fluorophenyl) 2 of 3 amino 3,2 dimethyl propionitrile, using isobutyronitrile as original raw material, reacted and synthesized by 4 steps, the compound is to prepare the very important part of central nervous system depressant, is with a wide range of applications in prevention and treatment neurogenic disease;Its preparation method raw material is cheap and easily-available, and synthetic method is simple, is a kind of completely new approach of synthesizing amino propionitrile compound, the need for being adapted to scale industrial production.

Description

A kind of aminopropionitrile compound and preparation method thereof
Technical field
The present invention relates to production of chemicals field, especially a kind of aminopropionitrile compound and preparation method thereof.
Background technology
Aminopropionitrile compound is the very important part of inhibitor for preparing central nervous system CNS (Preparation of aralkyl amines as cannabinoid-1 receptor modulators。PCT Int.Appl.PCT Int.Appl. (2005), WO 2005044785 A1), it is one and prevents and treats neurogenic disease very Useful compound.Aminopropionitrile compound is widely present in the drug molecule with bioactivity, in prevention and treatment god Through having application value in terms of property disease.Parent is made of the compound can further carry out synthesizing increasingly complex derivative, be Broadly study such compound property and condition is provided.
The content of the invention
The technical problems to be solved by the invention are to provide a kind of aminopropionitrile compound.
Another technical problem to be solved by this invention is the preparation method for providing above-mentioned aminopropionitrile compound.
In order to solve the above technical problems, the technical scheme is that:
A kind of aminopropionitrile compound, 3- amino -3- (4- fluorophenyls) -2,2- dimethyl propionitrile, its structural formula is (I) institute Show,
It is preferred that, above-mentioned aminopropionitrile compound, the nuclear-magnetism of 3- amino -3- (4- fluorophenyls) -2,2- dimethyl propionitrile is total to The hydrogen modal data that shakes is:1.187(s,3H),1.411(s,3H),3.882(s,1H),7.074-7.031(t,2H),7.414- 7.379(m,2H)。
The preparation method of above-mentioned aminopropionitrile compound, using isobutyronitrile as original raw material, passes through 4 steps reaction synthesis targeted Compound, is comprised the following steps that:
(1) 4-Fluorobenzaldehyde of compound 1 carries out aldol condensation in the presence of n-BuLi with the isobutyronitrile of compound 2 and obtained Compound 3;
(2) hydroxyl of compound 3 carries out semi-annular jade pendant acylation under sodium hydride effect and obtains compound 4;
(3) the semi-annular jade pendant acyl cyano group of compound 4 obtains compound 5 by azide substitution;
(4) nitrine of compound 5 is reduced into cyano group under triphenylphosphine effect and obtains target compound 6;Wherein,
Intermediate compound 3 in the preparation method of above-mentioned aminopropionitrile compound, its structural formula is that (II) is shown,
Intermediate compound 4 in the preparation method of above-mentioned aminopropionitrile compound, its structural formula is that (III) is shown,
Intermediate compound 5 in the preparation method of above-mentioned aminopropionitrile compound, its structural formula is that (IV) is shown,
The specific reaction equation of the preparation method of above-mentioned aminopropionitrile compound is as follows:
The beneficial effects of the invention are as follows:
Above-mentioned aminopropionitrile compound 3- amino -3- (4- fluorophenyls) -2,2- dimethyl propionitrile is to prepare central nervous system The system very important part of inhibitor, is with a wide range of applications in prevention and treatment neurogenic disease;It is prepared Method raw material is cheap and easily-available, and synthetic method is simple, is a kind of completely new approach of synthesizing amino propionitrile compound, is adapted to scale chemical industry The need for industry is produced.
Brief description of the drawings
Fig. 1 is the HNMR spectrograms of 3- amino -3- (4- fluorophenyls) -2,2- dimethyl propionitrile.
Embodiment
In order that those skilled in the art is better understood from technical scheme, with reference to embodiment Technical scheme of the present invention is described in further detail.
Embodiment 1
The preparation method of 3- amino -3- (4- fluorophenyls) -2,2- dimethyl propionitrile, is comprised the following steps that:
(1) 70g isobutyronitriles are dissolved in 700ml tetrahydrofurans (THF), system argon gas is replaced three times, be added dropwise at -40 DEG C (25min is added dropwise) in 250ml n-BuLis, and drop to finish and react 1h at -40 DEG C of temperature control;It is added dropwise at 4-Fluorobenzaldehyde, -78 DEG C of temperature control and reacts 1.5h;It has been reacted that, system is poured into 2.5L saturated ammonium chlorides, EA (ethyl acetate) extractions (2*1.5L) organic phase is dried To compound 3;TLC information:Raw material Rf=0.60, product Rf=0.10.Solvent:PE:EA=5:1, measure product 106g, nothing Color oil, yield 97.2%.
(2) 106g compounds 3 are dissolved in 1300mlTHF, sodium hydride 33g is added in batches, 0 DEG C of temperature control is finished at 0 DEG C 1h is reacted, paratoluensulfonyl chloride (TsCl) (1h is added dropwise) is added dropwise, drop, which finishes, is warmed to room temperature reaction 1h;It has been reacted that, system is poured into 3L and satisfied In ammonium chloride, EA extractions (1*2L), drying is spin-dried for;Residue is washed with PE (petroleum ether), and filtering, filtration cakes torrefaction is changed Compound 4.TLC information:Raw material Rf=0.40, product, Rf=0.50. solvents:PE:EA=3:1, product 75g is measured, white is solid Body, yield 39.4%.
(3) 70g compounds 4 are dissolved in 700ml (DMF) DMF, added at 20g Sodium azides, 80 DEG C React 17h;Reaction is finished, and system adds 1.5L water, and EA (3*800mL) is extracted three times, merges organic phase, organic phase water (2* 600mL) wash twice, camera is mutually dried and is spin-dried for, and obtains compound 5.TLC information:Raw material Rf=0.40, product Rf=0.70, Solvent:PE:EA=5:1;Measure 42 grams of product, brown oil.
(4) 21.5g compounds 5 are dissolved in (tetrahydrofuran) the THF/ aqueous solution (2:1) in mixed solvent 300ml, 51g is added Triphenylphosphine, reacts 1h at 80 DEG C;It has been reacted that, system is spin-dried for, added 1L1N hydrochloric acid, EA extraction (500ml*2) aqueous phase 2N hydrogen Sodium oxide molybdena adjusts pH=8-9, and EA extractions (500ml*3), organic phase is dried and is spin-dried for obtaining target compound 6;TLC information:Raw material Rf =1.00, product Rf=0.45.Solvent:(dichloromethane) DCM:(methanol) MeOH=20:1, measure product 4.8g, yellow Oil, two step yields 24.9%.As shown in figure 1, HNMR (CDCl3) spectrums of 3- amino -3- (4- fluorophenyls) -2,2- dimethyl propionitrile Scheme, its hydrogen modal data is:1.187(s,3H),1.411(s,3H),3.882(s,1H),7.074-7.031(t,2H),7.414- 7.379(m,2H)。
Above-mentioned specific reaction equation is as follows:
Application test example
30 wistar rats are randomly divided into two groups of A, B, wherein, B group rats press 200mg/ (kgd) gavage before modeling The gained compound 6 (3- amino -3- (4- fluorophenyls) -2,2- dimethyl propionitrile) of embodiment 1 is given, successive administration 7 days is sooner or later each Once, after last dose 1h, while to two groups of rats by intraperitoneal injection PTZ (pentylenetetrazol) solution (70mg/kg) of A, B, observing rat Behaviouristics changes 30 minutes, and is showed according to epilepsy outbreak pulvis Racine standard recording each group rat acutes epilepsy outbreak, 0 Level:Without breaking-out reaction, 1 grade:Rhythmicity bicker, ear or facial muscles twitch clonic spasm, 2 grades:Nod and with more serious face Muscle twitches clonic spasm, 3 grades:The double forelimbs of appearance, which are lifted, makees clonic spasm motion, 4 grades:Hindlimb tonic is stretched, 5 grades:Final body it is askew to Side and occur rolling, fall.
As a result show, all broken out in 60 seconds after A group rats by intraperitoneal injection PTZ, and there are 8 rats to be eventually developed to 5 grades Breaking-out, and the duration of seizure of B group rats is all breaking-outs in 103 seconds, whole rats show as 2-3 grades of breaking-outs.
The above-mentioned detailed description carried out with reference to embodiment to a kind of aminopropionitrile compound and preparation method thereof, It is illustrative rather than limited, several embodiments can be included according to limited scope, therefore do not departing from this hair Changing and modifications under bright general plotting, should belong within protection scope of the present invention.

Claims (3)

1. a kind of aminopropionitrile compound, it is characterised in that:For 3- amino -3- (4- fluorophenyls) -2,2- dimethyl propylenes Nitrile, its structural formula is that (I) is shown,
2. aminopropionitrile compound according to claim 1, it is characterised in that:3- amino -3- (4- fluorophenyls) - The hydrogen nuclear magnetic resonance modal data of 2,2- dimethyl propionitrile is:1.187 (s, 3H), 1.411 (s, 3H), 3.882 (s, 1H), 7.074-7.031 (t, 2H), 7.414-7.379 (m, 2H).
3. the preparation method of the aminopropionitrile compound described in claim 1, it is characterised in that:Using isobutyronitrile as original raw material, Synthesising target compound is reacted by 4 steps, is comprised the following steps that:
(1) 4-Fluorobenzaldehyde of compound 1 carries out aldol condensation with the isobutyronitrile of compound 2 in the presence of n-BuLi and obtains chemical combination Thing 3;
(2) hydroxyl of compound 3 carries out sulfonylation under sodium hydride effect and obtains compound 4;
(3) the sulphonyl cyano group of compound 4 obtains compound 5 by azide substitution;
(4) nitrine of compound 5 is reduced into cyano group under triphenylphosphine effect and obtains target compound 6;Wherein,
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1871208A (en) * 2003-10-30 2006-11-29 默克公司 Aralkyl amines as cannabinoid receptor modulators
CN104672105A (en) * 2015-02-18 2015-06-03 杭州千泰生物科技有限公司 Method for preparing L-3-(3,4-dimethoxyphenyl)-2-amino-2-methyl propionitrile hydrochloride

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1871208A (en) * 2003-10-30 2006-11-29 默克公司 Aralkyl amines as cannabinoid receptor modulators
CN104672105A (en) * 2015-02-18 2015-06-03 杭州千泰生物科技有限公司 Method for preparing L-3-(3,4-dimethoxyphenyl)-2-amino-2-methyl propionitrile hydrochloride

Non-Patent Citations (1)

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Title
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