CN113072508A - Novel method for preparing 7-amino-clonazepam compound - Google Patents
Novel method for preparing 7-amino-clonazepam compound Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 27
- -1 7-amino-clonazepam compound Chemical class 0.000 title claims description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 230000008569 process Effects 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 6
- UEALKTCRMBVTFN-UHFFFAOYSA-N 4-nitroanthranilic acid Chemical compound NC1=CC([N+]([O-])=O)=CC=C1C(O)=O UEALKTCRMBVTFN-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 4
- 238000007273 lactonization reaction Methods 0.000 claims abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 56
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 47
- 239000000543 intermediate Substances 0.000 claims description 46
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 239000007810 chemical reaction solvent Substances 0.000 claims description 22
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 18
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- HEFRPWRJTGLSSV-UHFFFAOYSA-N 7-Aminoclonazepam Chemical class C12=CC(N)=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl HEFRPWRJTGLSSV-UHFFFAOYSA-N 0.000 claims description 15
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 9
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 9
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 9
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- 239000007818 Grignard reagent Substances 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 4
- 150000001266 acyl halides Chemical class 0.000 claims description 4
- 150000004795 grignard reagents Chemical class 0.000 claims description 4
- 238000006722 reduction reaction Methods 0.000 claims description 4
- 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 4
- BQRIIWKHNJGQFH-UHFFFAOYSA-M [Br-].[Mg+]C1=CC=CC=C1Cl Chemical group [Br-].[Mg+]C1=CC=CC=C1Cl BQRIIWKHNJGQFH-UHFFFAOYSA-M 0.000 claims description 3
- 150000008064 anhydrides Chemical class 0.000 claims description 3
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012346 acetyl chloride Substances 0.000 claims description 2
- 150000001262 acyl bromides Chemical class 0.000 claims description 2
- 150000001263 acyl chlorides Chemical class 0.000 claims description 2
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 2
- NDLIRBZKZSDGSO-UHFFFAOYSA-N tosyl azide Chemical compound CC1=CC=C(S(=O)(=O)[N-][N+]#N)C=C1 NDLIRBZKZSDGSO-UHFFFAOYSA-N 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 238000001914 filtration Methods 0.000 abstract description 3
- 229910001385 heavy metal Inorganic materials 0.000 abstract description 3
- 230000009467 reduction Effects 0.000 abstract description 3
- 238000003747 Grignard reaction Methods 0.000 abstract description 2
- 150000001408 amides Chemical class 0.000 abstract description 2
- 238000006482 condensation reaction Methods 0.000 abstract description 2
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 229960001454 nitrazepam Drugs 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 11
- 238000005406 washing Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 3
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 3
- 229960003529 diazepam Drugs 0.000 description 3
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 241001274216 Naso Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical group 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 230000000049 anti-anxiety effect Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 description 1
- 229960003120 clonazepam Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
- C07D243/28—Preparation including building-up the benzodiazepine skeleton from compounds containing no hetero rings
Abstract
The invention discloses a new method for preparing a 7-amino-chloro-nitrazepam compound, which belongs to the technical field of organic synthesis, and the preparation method takes 2-amino-4-nitrobenzoic acid as an initial raw material to obtain a target compound through the processes of acetyl-lactonization, Grignard reaction, amide hydrolysis, intramolecular condensation reaction, reduction and the like; the method disclosed by the invention is safe to operate, avoids the use of heavy metals, is simple and convenient in post-treatment, can obtain a product by directly filtering and recrystallizing, and does not need other purification; only conventional acid and alkali and solvents are used in the whole reaction process, so that the method has the advantages of less environmental pollution, low cost and higher yield.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a novel method for preparing a 7-amino-chloro-nitrazepam compound.
Background
Clonazepam belongs to benzodiazepines drugs, is approved by the U.S. Food and Drug Administration (FDA) to be marketed in 1975, has similar effect to diazepam (diazepam), but has an anticonvulsant effect 5-10 times stronger than that of diazepam, and has obvious and rapid effects in hypnosis, antianxiety, epilepsy and convulsion. And 7-amino clonazepam is indispensable to the research of the metabolite as the metabolite.
At present, few reports on the synthesis method of 7-amino-clonazepam are available. The documents Steiger.N., Sach.G., J.Med.chem.1963,6,3, 261-265 report that the product is directly nitrated and then reduced, but the problems of selectivity are involved and the specific operation is difficult.
In addition, EP2687854a1 discloses the synthesis of intermediate (I) from para-substituted aniline via friedel-crafts acylation, which normally occurs if the para-substituent is substituted with a halogen atom, but which is difficult to synthesize first of all intermediate (I) if the para-substituent is substituted with a nitro group, at temperatures up to 200 ℃, and in the subsequent ring closure of Intermediate (IV) with the concomitant occurrence of a six-membered ring by-product, with low yields.
Although the chinese patent with chinese patent application No. 2021102277606 was a patent application filed by the applicant of the present application, the present application invented a method for synthesizing 7-aminochloronitrazepam, which solves the above problems, but the method requires heavy metals Pd and the like, and the post-treatment is troublesome, and has a large environmental impact, and further improvement is necessary.
Disclosure of Invention
The object of the present invention is to provide a new process for the preparation of 7-aminochloronitrazepam compounds, in order to solve the above problems.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows: a novel process for the preparation of 7-amino clonazepam compounds comprising the steps of:
(1) the 2-amino-4-nitrobenzoic acid is subjected to acetyl-lactonization reaction in the presence of an anhydride reagent to obtain an intermediate (I), the reaction temperature is 0-150 ℃, preferably 120 ℃, and the yield is higher when the reaction is carried out at 120 ℃;
(2) reacting the intermediate (I) obtained in the step (1) with a Grignard reagent in a reaction solvent A to obtain an intermediate (II), wherein the reaction temperature is 0-50 ℃, and preferably 25 ℃;
(3) carrying out hydrolysis reaction on the intermediate (II) obtained in the step (2) under the action of acid to obtain an intermediate (III), wherein the reaction temperature is 0-120 ℃, and preferably 100 ℃;
(4) reacting the intermediate (III) obtained in the step (3) with an acyl halide reagent in a reaction solvent B under the action of alkali to obtain an Intermediate (IV), wherein the reaction temperature is 0-50 ℃, and preferably 25 ℃;
(5) reacting the Intermediate (IV) obtained in the step (4) with an azide compound in a reaction solvent C to obtain an intermediate (V), wherein the reaction temperature is 0-50 ℃, and preferably 25 ℃;
(6) and (3) reacting the intermediate (V) obtained in the step (5) with triphenylphosphine in a reaction solvent D to obtain a target product (VI), wherein the reaction temperature is 0-100 ℃, and preferably 100 ℃.
(7) Carrying out reduction reaction on the intermediate (VI) obtained in the step (6) in a reaction solvent acetic acid by adopting a reducing agent to obtain a target product (VII), wherein the reaction temperature is 0-50 ℃, and preferably 50 ℃;
the invention takes 2-amino-4-nitrobenzoic acid as a starting material to obtain a target compound through the processes of acetyl-lactonization, Grignard reaction, amide hydrolysis, intramolecular condensation reaction, reduction and the like, and the reaction equation is as follows:
as a preferred technical scheme: in the step (1), the reagent is selected from acid anhydride reagent used in the step (1) and is selected from one of acetic anhydride and acetyl chloride;
acetic anhydride is further preferred because it allows the reaction to occur in higher yields without the additional use of other solvents.
As a preferred technical scheme: in the step (2), the Grignard reagent is 2-chlorophenyl magnesium bromide, and the reaction solvent is tetrahydrofuran.
As a preferred technical scheme: in the step (3), the acid or alkali is at least one selected from hydrochloric acid, sulfuric acid, sodium hydroxide and potassium hydroxide,
hydrochloric acid is further preferred, and the hydrochloric acid is convenient to treat and does not cause reagent residue.
As a preferred technical scheme: in the step (3), the reaction solvent A is at least one selected from toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, ethanol, methanol, 1, 4-dioxane, acetic acid, chlorobenzene and water,
ethanol is further preferably used as the solvent, and the yield is higher, green and safe when ethanol is used as the solvent.
As a preferred technical scheme: the acyl halide reagent in the step (4) is selected from acyl chloride or acyl bromide, and bromoacetyl bromide is further preferred, so that the reaction time can be greatly shortened, and the cost and the energy consumption can be reduced.
As a preferred technical scheme: in the step (4), the reaction solvent B is at least one selected from toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, ethanol, methanol, 1, 4-dioxane, acetic acid and chlorobenzene,
dichloromethane is further preferred, and the yield is higher when dichloromethane is used as the solvent.
As a preferred technical scheme: in the step (5), the azide compound is selected from one of p-toluenesulfonyl azide, diphenylphosphoryl azide and sodium azide,
sodium azide is further preferred, so that the reaction time can be shortened and the yield can be improved;
in the step (5), the reaction solvent C is at least one selected from toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, ethanol, methanol, 1, 4-dioxane, N-dimethylformamide, dimethyl sulfoxide, acetic acid and chlorobenzene,
dimethyl sulfoxide is further preferably selected as a reaction solvent, the reaction time is greatly shortened, the yield is improved, the reaction can be carried out only when the melting point of the dimethyl sulfoxide is higher, and the reaction yield is improved.
As a preferred technical scheme: in the step (6), the reaction solvent D is at least one selected from toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, ethanol, methanol, 1, 4-dioxane, acetic acid and chlorobenzene,
toluene is further preferred because the reaction requires temperature, the reaction is difficult at low temperature, and toluene having a higher boiling point is selected as the preferred solvent in combination with the reaction time and yield.
As a preferred technical scheme: in the step (7), the reducing agent is selected from Zn/diluted HCl, Zn/acetic acid, Fe/diluted HCl, Fe/acetic acid, sodium borohydride, sodium cyanoborohydride and SnCl2In the method, Fe/acetic acid is further preferred, and when other reducing agents are selected, excessive reduction byproducts can be generated, the imine in the structure is reduced, and the yield is reduced;
in the step (7), the reaction solvent E is at least one selected from toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, ethanol, methanol, 1, 4-dioxane, acetic acid and chlorobenzene.
Compared with the prior art, the invention has the advantages that: the method disclosed by the invention is safe to operate, avoids the use of heavy metals, is simple and convenient in post-treatment, can obtain a product by directly filtering and recrystallizing, and does not need other purification; only conventional acid and alkali and solvents are used in the whole reaction process, so that the method has the advantages of less environmental pollution, low cost and higher yield.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of 7-amino clonazepam obtained in example 1;
FIG. 2 is a nuclear magnetic carbon spectrum of 7-amino clonazepam obtained in example 1;
FIG. 3 is a high resolution mass spectrum of 7-amino clonazepam obtained in example 1.
Detailed Description
The invention will be further explained with reference to the drawings.
Example 1
A method of synthesizing a 7-amino clonazepam compound, comprising the steps of:
(1) synthesis of intermediate I:
2-amino-4-nitrobenzoic acid (5.46g,30mmol) was weighed and transferred to a 250mL flask, and acetic anhydride was added in 80mL, followed by heating to reflux for 12 h. Cooling to room temperature, filtering, leaching the obtained solid with petroleum ether-ethyl acetate mixed solution to obtain an intermediate I which is 5.75g of light yellow solid and has 93% of yield;
(2) and (3) synthesizing an intermediate II:
weighing an intermediate I (4.12g and 20mmol), dissolving in 80mL, dropwise adding 2-chlorophenyl magnesium bromide (40mmol and 1mol/L tetrahydrofuran solution) in an ice-water bath, removing the ice-water bath after 20 minutes, adding 30mL of saturated ammonium chloride solution after the reaction is finished, quenching the reaction, separating, collecting an organic phase, extracting an aqueous phase (30mL by 2), combining the organic phases, washing the organic phase once with saturated NaCl solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude intermediate II which is yellow oily;
(3) and (3) synthesis of an intermediate III:
dissolving the crude intermediate II in 50mL of ethanol, adding 30mL of 6mol/L hydrochloric acid under stirring to obtain a yellow transparent solution, heating to reflux, cooling to room temperature after TLC detection reaction, adjusting pH to 10, extracting with ethyl acetate (30mL) for three times, combining organic phases, washing the organic phases with 30mL of water and saturated NaCl solution once, drying with anhydrous sodium sulfate, concentrating under reduced pressure, separating the residue by column chromatography, and eluting with petroleum ether-ethyl acetate (6:1) to obtain 4.54g of intermediate III as a yellow solid with the yield of 82%.
(4) And (3) synthesizing an intermediate IV:
weighing intermediate I (5.53g,20mmol) and sodium carbonate (3.18g,30mmol), adding dichloromethane 60mL, dropwise adding S3(4.84g,24mmol) in 10mL dichloromethane solution under ice water bath, removing ice water bath after 10 minutes, after the reaction is finished, adding water 30mL to quench the reaction, separating liquid, collecting organic phase, extracting aqueous phase dichloromethane (30mL x 2), combining organic phases, washing once with saturated NaCl solution, and removing anhydrous NaSO4Drying, concentration under reduced pressure and washing with petroleum ether/ethyl acetate 6:1 gave intermediate II as a white solid 7.47g, 94% yield.
(5) And (3) synthesis of an intermediate V:
intermediate IV (5.96g,15mmol) was weighed, 50mL of dimethyl sulfoxide was added, and NaN was slowly added in portions under stirring3(2.44g,37.5mmol), the system is yellow transparent solution after the addition, 50mL of water is added to quench the reaction after the TLC detection reaction is finished (5-10 min), ethyl acetate (50mL x 3) is used for extracting and combining organic phases, water (50mL x 3) is used for washing the organic phases, saturated NaCl solution is used for washing once, and anhydrous NaSO is used for washing once4Drying, concentrating under reduced pressure, eluting with petroleum ether-ethyl acetate to obtain intermediate V as light yellow solid 5.13g with yield of 95％。
(6) Synthesis of intermediate vi:
intermediate V (3.6g,10mmol) was weighed, 60mL of anhydrous toluene was added, and PPh was added slowly in portions with stirring3(3.15g,12mmol) and a large amount of bubbles emerge at the moment, after the gas is discharged, the tube is sealed and heated to 100 ℃, the reaction is carried out for 5h, the reaction is carried out until the temperature is reduced to room temperature, a solid is separated out, and the intermediate VI is filtered and washed to obtain 2.91g of a light yellow solid with the yield of 92 percent.
(7) And (3) synthesizing a target product VII:
weighing reduced iron powder (10g, excess), adding acetic acid 30mL, heating to 50 ℃, dropwise adding 20mL of acetic acid solution of intermediate VI (2.0g,6.34mmol), detecting reaction completion by TLC about 20 minutes, adding water 20mL to quench reaction, converting system from yellow turbidity to reddish brown, adsorbing iron powder by magneton, pouring reaction solution into a beaker, extracting with DCM (30mL × 5), combining organic phases, and using saturated NaHCO as organic phase3Washing the solution until no bubbles emerge and no NaSO is generated4Drying and concentrating petroleum ether/ethyl acetate under reduced pressure, wherein the petroleum ether/ethyl acetate ratio is 5:1, washing is carried out, and the target product VII is 1.72g of yellow solid and is obtained in 94% yield.
And (3) structural identification of the obtained target product VII:
nuclear magnetic hydrogen spectrum:1HNMR(300MHz,DMSO-d6) δ 10.14(s,1H),7.46(s,4H),6.91(d, J ═ 8.6Hz,1H),6.74(dd, J ═ 8.6,2.6Hz,1H),6.16(d, J ═ 2.5Hz,1H),5.11(s,2H),4.09(s,2H). as shown in fig. 1;
nuclear magnetic carbon spectrum:13CNMR(75MHz,DMSO-d6) δ 169.3,169.2,144.3,139.4,131.9,131.1,130.5,129.6,128.6,128.0,127.1,122.0,118.1,112.0,56.9, as shown in fig. 2;
high resolution mass spectrometry: HRMS (ESI) Calcdr C15H13ClN3O[M+H]+286.0742; 286.0732, as shown in FIG. 3.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. A novel process for the preparation of 7-aminochloronitrazepam compounds characterized by: the method comprises the following steps:
(1) performing acetyl-lactonization reaction on 2-amino-4-nitrobenzoic acid in the presence of an anhydride reagent to obtain an intermediate (I), wherein the reaction temperature is 0-150 ℃, and preferably 120 ℃;
(2) reacting the intermediate (I) obtained in the step (1) with a Grignard reagent in a solvent to obtain an intermediate (II), wherein the reaction temperature is 0-50 ℃, and preferably 25 ℃;
(3) carrying out hydrolysis reaction on the intermediate (II) obtained in the step (2) in a reaction solvent A under the action of acid or alkali to obtain an intermediate (III), wherein the reaction temperature is 0-120 ℃, and preferably 100 ℃;
(4) reacting the intermediate (III) obtained in the step (3) with an acyl halide reagent in a reaction solvent B under the action of alkali to obtain an Intermediate (IV), wherein the reaction temperature is 0-50 ℃, and preferably 25 ℃;
(5) reacting the Intermediate (IV) obtained in the step (4) with an azide compound in a reaction solvent C to obtain an intermediate (V), wherein the reaction temperature is 0-50 ℃, and preferably 25 ℃;
(6) reacting the intermediate (V) obtained in the step (5) with triphenylphosphine in a reaction solvent D to obtain a target product (VI), wherein the reaction temperature is 0-100 ℃, and preferably 100 ℃;
(7) carrying out reduction reaction on the intermediate (VI) obtained in the step (6) in a reaction solvent E by adopting a reducing agent to obtain a target product (VII), wherein the reaction temperature is 0-50 ℃, and preferably 50 ℃;
the structures of the intermediates (I), (II), (III), (IV), (V) (VI) and the target product (VII) are shown as follows:
2. a new process for the preparation of 7-amino clonazepam compounds according to claim 1, characterized in that: the anhydride reagent used in the step (1) is one of acetic anhydride and acetyl chloride; acetic anhydride is preferred.
3. A new process for the preparation of 7-amino clonazepam compounds according to claim 1, characterized in that: in the step (2), the Grignard reagent is 2-chlorophenyl magnesium bromide, and the solvent is tetrahydrofuran.
4. A new process for the preparation of 7-amino clonazepam compounds according to claim 1, characterized in that: in the step (3), the acid or alkali is selected from one of hydrochloric acid, sulfuric acid, sodium hydroxide and potassium hydroxide, and hydrochloric acid is preferred.
5. A new process for the preparation of 7-amino clonazepam compounds according to claim 1, characterized in that: in the step (3), the reaction solvent A is at least one selected from toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, ethanol, methanol, 1, 4-dioxane, acetic acid and chlorobenzene, preferably ethanol.
6. A new process for the preparation of 7-amino clonazepam compounds according to claim 1, characterized in that: in the step (4), the acyl halide reagent is selected from one of acyl chloride or acyl bromide, preferably bromoacetyl bromide.
7. A new process for the preparation of 7-amino clonazepam compounds according to claim 1, characterized in that: in the step (4), the reaction solvent B is at least one selected from toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, ethanol, methanol, 1, 4-dioxane, acetic acid and chlorobenzene, preferably dichloromethane.
8. A new process for the preparation of 7-amino clonazepam compounds according to claim 1, characterized in that: in the step (5), the azide compound is selected from one of p-toluenesulfonyl azide, diphenylphosphoryl azide and sodium azide, preferably sodium azide; the reaction solvent C is at least one selected from toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, ethanol, methanol, 1, 4-dioxane, N-dimethylformamide, dimethyl sulfoxide, acetic acid and chlorobenzene, and preferably is dimethyl sulfoxide.
9. A new process for the preparation of 7-amino clonazepam compounds according to claim 1, characterized in that: in the step (6), the reaction solvent D is at least one selected from toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, ethanol, methanol, 1, 4-dioxane, acetic acid and chlorobenzene, and toluene is preferred.
10. A new process for the preparation of 7-amino clonazepam compounds according to claim 1, characterized in that: in the step (7), the reducing agent is selected from Zn/diluted HCl, Zn/acetic acid, Fe/diluted HCl, Fe/acetic acid, sodium borohydride, sodium cyanoborohydride and SnCl2Preferably Fe/acetic acid, and the reaction solvent E is acetic acid.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113773266A (en) * | 2021-09-28 | 2021-12-10 | 公安部物证鉴定中心 | clonazepam-D2 and preparation method thereof |
| CN114736107A (en) * | 2022-05-10 | 2022-07-12 | 广州医科大学 | Preparation method of alkynylamide mediated ketone compound |
| CN114989102A (en) * | 2021-12-24 | 2022-09-02 | 成都硕德药业有限公司 | Preparation method of oxazepam |
| CN115304554A (en) * | 2022-09-19 | 2022-11-08 | 公安部物证鉴定中心 | Preparation method of 2' -chlorodiazepam-D3 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL47941A0 (en) * | 1974-09-23 | 1975-11-25 | Pfizer | The preparation of 6-chloro-2-chloromethyl-4-phenylquinazoline-3-oxide and intermediates used therefor |
| JPS54157585A (en) * | 1978-05-30 | 1979-12-12 | Yasumitsu Tamura | Manufacture of 1*44benzodiazepin |
| CN107365276A (en) * | 2017-08-08 | 2017-11-21 | 公安部物证鉴定中心 | A kind of diazepam D5 preparation method |
| CN107501196A (en) * | 2017-08-08 | 2017-12-22 | 公安部物证鉴定中心 | Intermediate for preparing diazepam D5 and diazepam D8 and preparation method thereof |
| CN107522667A (en) * | 2017-08-08 | 2017-12-29 | 公安部物证鉴定中心 | Diazepam D8 and preparation method thereof |
-
2021
- 2021-03-25 CN CN202110322430.5A patent/CN113072508A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL47941A0 (en) * | 1974-09-23 | 1975-11-25 | Pfizer | The preparation of 6-chloro-2-chloromethyl-4-phenylquinazoline-3-oxide and intermediates used therefor |
| US3932325A (en) * | 1974-09-23 | 1976-01-13 | Pfizer Inc. | Process for preparing 6-chloro-2-chloromethyl-4-phenylquinazoline-3-oxide and intermediates therefor |
| JPS54157585A (en) * | 1978-05-30 | 1979-12-12 | Yasumitsu Tamura | Manufacture of 1*44benzodiazepin |
| CN107365276A (en) * | 2017-08-08 | 2017-11-21 | 公安部物证鉴定中心 | A kind of diazepam D5 preparation method |
| CN107501196A (en) * | 2017-08-08 | 2017-12-22 | 公安部物证鉴定中心 | Intermediate for preparing diazepam D5 and diazepam D8 and preparation method thereof |
| CN107522667A (en) * | 2017-08-08 | 2017-12-29 | 公安部物证鉴定中心 | Diazepam D8 and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| C P GODDARD，等: "Preparation and purification of 7-iodoclonazepam for use in radioimmunoassay", 《JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS》, vol. 23, no. 4, pages 383 - 391 * |
| HENRI A. VAN KALKEREN等: "Catalytic Staudinger/Aza-Wittig Sequence by in situ Phosphane Oxide Reduction", 《EUR. J. ORG. CHEM.》, pages 7056 - 7066 * |
| YASUMMTISU TAMURA等: "Synthesis and some Chemical Transformations of 2-Azidomethylindoles", 《CHEM. PHARM. BULL.》, vol. 26, pages 2874 - 2879 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113773266A (en) * | 2021-09-28 | 2021-12-10 | 公安部物证鉴定中心 | clonazepam-D2 and preparation method thereof |
| CN114989102A (en) * | 2021-12-24 | 2022-09-02 | 成都硕德药业有限公司 | Preparation method of oxazepam |
| CN114989102B (en) * | 2021-12-24 | 2024-01-09 | 成都硕德药业有限公司 | Preparation method of oxazepam |
| CN114736107A (en) * | 2022-05-10 | 2022-07-12 | 广州医科大学 | Preparation method of alkynylamide mediated ketone compound |
| CN115304554A (en) * | 2022-09-19 | 2022-11-08 | 公安部物证鉴定中心 | Preparation method of 2' -chlorodiazepam-D3 |
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