CN113149915B - Method for synthesizing clonazepam compound - Google Patents
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- -1 clonazepam compound Chemical class 0.000 title claims abstract description 14
- 229960003120 clonazepam Drugs 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 title claims abstract description 11
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000000543 intermediate Substances 0.000 claims description 14
- 239000007810 chemical reaction solvent Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 150000001266 acyl halides Chemical class 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical group BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 claims description 2
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 claims description 2
- 101150003085 Pdcl gene Proteins 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 239000002904 solvent Substances 0.000 abstract description 4
- 230000009435 amidation Effects 0.000 abstract description 2
- 238000007112 amidation reaction Methods 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 238000001914 filtration Methods 0.000 abstract description 2
- 238000002386 leaching Methods 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 238000006482 condensation reaction Methods 0.000 abstract 1
- 238000005691 oxidative coupling reaction Methods 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 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 5
- 238000005406 washing Methods 0.000 description 5
- 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
- 239000003208 petroleum Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 3
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 3
- 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 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 229960003529 diazepam Drugs 0.000 description 2
- 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 2
- 238000001035 drying Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 150000001262 acyl bromides Chemical class 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000001037 epileptic effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 1
- WVKIFIROCHIWAY-UHFFFAOYSA-N hydron;2-(methylamino)acetic acid;chloride Chemical compound Cl.CNCC(O)=O WVKIFIROCHIWAY-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
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
- C07D243/28—Preparation including building-up the benzodiazepine skeleton from compounds containing no hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing a clonazepam compound, which belongs to the technical field of organic chemical synthesis, and the preparation method comprises the steps of taking 2-amino-4-nitrophenyl potassium trifluoroborate as a starting material to obtain a target compound through the processes of oxidative coupling, amidation, affinity substitution reaction, intramolecular condensation reaction and the like; the method has the advantages of short synthesis steps, safe operation, simple and convenient post-treatment, and can obtain the product by direct filtration and leaching without other purification; only conventional acid-base and solvent are used in the whole reaction process, so that the cost is low, and the yield is improved by more than 30%.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a synthesis method of a clonazepam compound.
Background
The clonazepam belongs to benzodiazepine medicines, is approved to be marketed by the U.S. Food and Drug Administration (FDA) in 1975, has similar action to diazepam (tranquilization), but has 5-10 times stronger anticonvulsant action than diazepam, and has obvious and rapid action in hypnotizing, anxiolytic, epileptic and convulsion aspects. The synthesis reports of clonazepam are seen in earlier literature and patents, and the reports have larger limitations in specific operation and application, and have complicated steps, complex operation, lower yield and higher cost. Therefore, the design and development of a new synthesis route have important significance. In view of the important significance of the research on medicines, the design and development of a new synthetic route have important practical significance.
Disclosure of Invention
The invention aims to provide a novel synthesis method of a clonazepam compound so as to solve the problems.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: a method of synthesizing a clonazepam compound comprising the steps of:
(1) Under the condition of adding a metal reagent and alkali, carrying out Suzuki coupling reaction on 2-amino-4-nitrophenyl potassium trifluoroborate and 2-chlorobenzoyl chloride in a reaction solvent A to obtain an intermediate (I), wherein the reaction temperature is 0-100 ℃, preferably 90 ℃, and the yield is higher while the reaction is ensured to occur when 90 ℃ is selected;
(2) Reacting the intermediate (I) obtained in the step (1) with an acyl halide reagent in a reaction solvent B under the action of alkali to obtain an intermediate (II), wherein the reaction temperature is 0-50 ℃, preferably 25 ℃, and the operation at the temperature is simple while the yield is ensured;
(3) The intermediate (II) obtained in the step (2) adopts ammonia gas to carry out reduction reaction in a reaction solvent E to obtain a target product (V), the reaction temperature is 0-100 ℃, preferably 80 ℃, the reaction is clean at the reaction temperature, and the product with higher yield is obtained while the reaction time is shortened;
wherein the structures of the intermediates (I), (II) and the target product (III) are as follows:
the invention takes 2-amino-4-nitrophenyl potassium trifluoroborate as a starting material to obtain a target compound through Suzuki coupling, amidation, ammonolysis, intramolecular condensation cyclization reaction and other processes, wherein the reaction equation is as follows:
as a preferable technical scheme: in step (1), the metal reagent is selected from Cu (OAc) 2 、Cu(OTf) 2 、PdCl 2 At least one of Pd (OAc) 2, pd (PPh 3) 4 and Pd (TFA) 2, and more preferably Pd (PPh 3) 4 Because Pd (PPh 3) is selected 4 The yield is higher while the reaction is taking place.
As a preferable technical scheme: in the step (1), the base used is selected from one of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, and potassium carbonate is further preferred, because the yield is improved more remarkably by selecting potassium carbonate.
As a preferable technical scheme: in the step (1), the reaction solvent A is at least one selected from toluene, mesitylene, methylene chloride, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, ethanol, methanol, 1, 4-dioxane, acetic acid, chlorobenzene and water, and a toluene and water mixed solvent is further preferable because the yield is higher when toluene and water are mixed as the solvent.
As a preferable technical scheme: the acyl halide reagent in the step (2) is selected from one of 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 preferable technical scheme: in the step (2), 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, and further preferably dichloromethane, wherein the yield is higher when the dichloromethane is used as a solvent.
As a preferable technical scheme: in the step (3), the ammonia water is at least one selected from ammonium chloride, ammonia water, ammonia gas, urotropine and the like, and ammonia gas is further preferred;
as a preferable technical scheme: in the step (3), 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 further preferably methanol, and methanol is selected as the reaction solvent, so that the reaction time is greatly shortened, byproducts are fewer and the yield is improved.
Compared with the prior art, the invention has the advantages that: the invention provides a brand new feasible synthesis route for the clonazepam, and the method has the advantages of short synthesis steps, safe operation, simple and convenient post-treatment, and can obtain the product by direct filtration and leaching without other purification; only conventional acid-base and solvent are used in the whole reaction process, so that the cost is low, and the yield is improved by more than 30%.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of clonazepam obtained in example 1;
FIG. 2 is a nuclear magnetic carbon spectrum of clonazepam obtained in example 1.
The specific operation scheme is as follows.
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Example 1
A method of synthesizing a clonazepam compound comprising the steps of:
(1) Synthesis of intermediate I:
weighing Pd (PPh) 3 ) 4 (208 mg,0.18 mmol) and S1 (2.86 g,10 mmol) were placed in a flask, 50mL of toluene was added, S2 (3.50 g,20 mmol) and water (5 mL) were added with stirring, and then heated to 90℃for reaction for 12h. Cooling to room temperature, adding 50mL of water, extracting and combining organic phases by ethyl acetate (50 mL of 3), washing by saturated sodium chloride solution once, drying by anhydrous sodium sulfate, concentrating under reduced pressure, eluting by column chromatography petroleum ether/ethyl acetate=8:1-5:1, wherein the obtained synthetic intermediate I is 2.60g of light yellow solid, and the yield is 94%;
reaction condition screening and results:
(2) Synthesis of intermediate II:
weighing intermediate I (5.54 g,20 mmol), adding 50mL of dichloromethane, dropwise adding 10mL of dichloromethane solution of S3 (3.63 g,18 mmol) in an ice water bath, removing the ice water bath after the addition is completed for 10 minutes, adding 30mL of water to quench the reaction, separating liquid, collecting an organic phase, extracting aqueous dichloromethane (30 mL of 2), merging the organic phases, washing the organic phase once with saturated NaCl solution, drying the aqueous solution with anhydrous sodium sulfate, concentrating the aqueous solution under reduced pressure, and washing the petroleum ether/ethyl acetate=6:1 to obtain intermediate II which is 7.43g of white solid with the yield of 93%;
(3) Synthesis of target product III:
intermediate II (5.57 g,14 mmol) was weighed, a freshly prepared saturated solution of ammonia in methanol was added Bi Tiji as a yellow transparent solution, bi Fengguan was added to heat to 80 ℃, after TLC detection reaction was completed, the mixture was concentrated under reduced pressure, and petroleum ether/ethyl acetate=3:1 was eluted to obtain the target product III as a pale yellow solid 4.2g, with a yield of 95%.
Structural identification of the obtained target product III:
nuclear magnetic hydrogen spectrum: 1 HNMR(300MHz,DMSO-d 6 ) δ11.32 (s, 1H), 8.37 (dd, j=9.0, 2.6hz, 1H), 7.74 (d, j=2.6 hz, 1H), 7.69-7.61 (m, 1H), 7.51 (m, j=9.4, 6.6,3.3hz, 3H), 7.43 (d, j=9.0 hz, 1H), 4.31 (s, 2H), as shown in fig. 1;
nuclear magnetic hydrogen spectrum: 13 C NMR(75MHz,DMSO-d 6 ) Delta 169.4,168.0,144.4,141.6,138.0,131.8,131.6,131.5,129.9,127.6,127.0,126.5,125.0,122.2,57.1 (2C), as shown in fig. 2.
Comparative example 1:
intermediate I (553 mg,2 mmol) was weighed, methyl glycine hydrochloride (502 mg,4 mmol), 10mL of pyridine was added, the temperature was raised to reflux, after the reaction was completed, 10mL of water was added, dichloromethane was used for extraction, 20mL of 1M diluted hydrochloric acid was used for washing the organic phases, the organic phases were combined, the saturated NaCl solution was washed once, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and petroleum ether/ethyl acetate=6:1 was used for washing intermediate ii as a pale yellow solid 328mg, the yield was 52%.
Claims (1)
1. A method for synthesizing a clonazepam compound, characterized by: the method comprises the following steps:
(1) Under the condition of adding metal reagent and alkali, carrying out Suzuki coupling reaction on 2-amino-4-nitrophenyl potassium trifluoroborate and 2-chlorobenzoyl chloride in a reaction solvent A to obtain an intermediate (I), wherein the reaction temperature is 90 ℃, and the metal reagent is PdCl 2 (PPh 3 ) 4 The alkali is potassium carbonate, the reaction solvent A is a mixed solvent of toluene and water, and the volume ratio of the toluene to the water is 10:1;
(2) Reacting the intermediate (I) obtained in the step (1) with an acyl halide reagent in a reaction solvent B under the action of alkali to obtain an intermediate (II), wherein the reaction temperature is 0-25 ℃; the alkali is sodium carbonate, the acyl halide reagent is bromoacetyl bromide, the reaction solvent B is methylene dichloride,
(3) Reacting the intermediate (II) obtained in the step (2) with an amine compound in a reaction solvent C to obtain a target product (III), wherein the reaction temperature is 80 ℃, the amine compound is ammonia, and the reaction solvent C is methanol;
the structures of the intermediates (I), (II) and the target product (III) are shown as follows:
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1392681A (en) * | 1972-08-21 | 1975-04-30 | Hoffmann La Roche | Process for the mahufacture of benzodiazepine derivatives |
| US3996209A (en) * | 1973-05-14 | 1976-12-07 | Hoffmann-La Roche Inc. | Process for preparing benzodiazepines |
| CN107365276A (en) * | 2017-08-08 | 2017-11-21 | 公安部物证鉴定中心 | A kind of diazepam D5 preparation method |
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