CN105218402B - A kind of aminopropionitrile compound and preparation method thereof - Google Patents
A kind of aminopropionitrile compound and preparation method thereof Download PDFInfo
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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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- -1 aminopropionitrile compound Chemical class 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 9
- LRDFRRGEGBBSRN-UHFFFAOYSA-N isobutyronitrile Chemical compound CC(C)C#N LRDFRRGEGBBSRN-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229940125898 compound 5 Drugs 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- 229940126214 compound 3 Drugs 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 claims description 2
- 238000005882 aldol condensation reaction Methods 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 229940125782 compound 2 Drugs 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 238000005481 NMR spectroscopy Methods 0.000 claims 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims 1
- 150000001540 azides Chemical group 0.000 claims 1
- JAMNHZBIQDNHMM-UHFFFAOYSA-N pivalonitrile Chemical compound CC(C)(C)C#N JAMNHZBIQDNHMM-UHFFFAOYSA-N 0.000 claims 1
- 230000006103 sulfonylation Effects 0.000 claims 1
- 238000005694 sulfonylation reaction Methods 0.000 claims 1
- 201000010099 disease Diseases 0.000 abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
- 230000001272 neurogenic effect Effects 0.000 abstract description 3
- 230000002265 prevention Effects 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 238000010189 synthetic method Methods 0.000 abstract description 2
- JCLSEQJEXYHVTC-UHFFFAOYSA-N 2-amino-2-methylbutanenitrile Chemical compound CCC(C)(N)C#N JCLSEQJEXYHVTC-UHFFFAOYSA-N 0.000 abstract 1
- 239000003874 central nervous system depressant Substances 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 241000700159 Rattus Species 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 238000000605 extraction Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 206010009346 Clonus Diseases 0.000 description 3
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 239000010977 jade Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 1
- 206010028347 Muscle twitching Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical class [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000003974 aralkylamines Chemical class 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 210000001097 facial muscle Anatomy 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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
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)
| 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 |
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Patent Citations (2)
| 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 |
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| Title |
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| RN：1506664-65-8;-;《STN-Registry》;20131230;第1页 * |
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