CN113072509A - Method for synthesizing 7-amino clonazepam compound - Google Patents
Method for synthesizing 7-amino clonazepam compound Download PDFInfo
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- 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
- C07D243/26—Preparation from compounds already containing the benzodiazepine skeleton
Abstract
The invention discloses a method for synthesizing a 7-amino-chloro-nitrazepam compound, which belongs to the technical field of organic synthesis, and the preparation method comprises the steps of starting from 2-cyano-4-nitroaniline serving as a starting raw material, and carrying out processes of oxidative coupling, amidation, affinity substitution reaction, intramolecular Wittig reaction, reduction reaction and the like to obtain a target compound; the invention provides a brand new synthetic route for 7-amino-chloro-nitrazepam, the method has the advantages of short synthetic step, safe operation and simple and convenient post-treatment, only uses conventional acid-base and solvent in the whole reaction process, has low cost, and improves the yield by more than 20%.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing 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.
Therefore, in view of the important significance of the research of 7-amino-clonazepam in the aspect of medicine, the design and development of a new synthetic route with higher yield and lower cost have important practical significance.
Disclosure of Invention
The invention aims to provide a method for synthesizing a 7-amino-clonazepam compound so as to solve the problems.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows: a method of synthesizing a 7-amino clonazepam compound, comprising the steps of:
(1) carrying out oxidative coupling reaction on 2-cyano-4-nitroaniline and 2-chlorobenzeneboronic acid in a reaction solvent A under the condition of adding a metal reagent and an additive to obtain an intermediate (I), wherein the reaction temperature is 0-100 ℃, preferably 100 ℃, and the yield is higher while ensuring the reaction to occur at 100 ℃;
(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 temperature is simple to operate and ensures the yield;
(3) reacting the intermediate (II) obtained in the step (2) with an azide compound in a reaction solvent C to obtain an intermediate (III), wherein the reaction temperature is 0-50 ℃, and preferably 25 ℃;
(4) reacting the intermediate (III) obtained in the step (3) with triphenylphosphine in a reaction solvent D to obtain an Intermediate (IV), wherein the reaction temperature is 0-100 ℃, and preferably 100 ℃;
(5) carrying out reduction reaction on the Intermediate (IV) obtained in the step (4) in a reaction solvent E by adopting a reducing agent to obtain a target product (V), wherein the reaction temperature is 0-50 ℃, preferably 50 ℃, and the reaction is cleaner at the reaction temperature to obtain a product with higher yield;
wherein the structures of the intermediates (I), (II), (III), (IV) and the target product (V) are shown as follows:
the invention takes 2-cyano-4-nitroaniline as a starting material to obtain a target compound through processes of oxidative coupling, amidation, affinity substitution reaction, intramolecular Wittig reaction, reduction reaction and the like, wherein the reaction equation is as follows:
as a preferred technical scheme: in step (1), the metal reagent is selected from Cu (OAc)2、Cu(OTf)2、PdCl2、Pd(OAc)2And Pd (TFA)2At least one of them, intoOne step preferably is Pd (TFA)2Because Pd (TFA) is selected2The yield can be higher while the reaction is taking place.
As a preferred technical scheme: in the step (1), the additive is selected from one of p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid and benzoic acid, further preferably methanesulfonic acid, and the reason for selecting methanesulfonic acid is as follows: on one hand, the reaction system is homogeneous, and on the other hand, the yield is improved more obviously.
As a preferred technical scheme: in the step (1), the reaction solvent A is selected from one of toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, ethanol, methanol, 1, 4-dioxane, acetic acid and chlorobenzene, tetrahydrofuran is further preferred, and the yield is higher by selecting tetrahydrofuran as a solvent.
As a preferred technical scheme: the alkali in the step (2) is at least one selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydroxide and cesium carbonate, and sodium carbonate is further preferable because the alkali is too strong to cause reaction by-products to be abundant and the system is disordered, and the weak alkali is difficult to perform the reaction.
As a preferred technical scheme: the acyl halide reagent in the step (2) is selected from acyl chloride or acyl bromide, bromoacetyl bromide is further preferred, 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 (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 dichloromethane is further preferable, and the yield is higher when dichloromethane is used as the solvent.
As a preferred technical scheme: in the step (3), the azide compound is selected from one of p-toluenesulfonyl azide, diphenylphosphoryl azide and sodium azide, and sodium azide is further preferred, so that the reaction time can be shortened and the yield can be improved;
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 preferred, and the dimethyl sulfoxide is selected as the reaction solvent, so that the reaction time is greatly shortened, the yield is improved, and the reaction can be carried out only when the melting point of the dimethyl sulfoxide is higher than the melting point of the dimethyl sulfoxide, and the reaction yield is improved.
As a preferred technical scheme: in the step (4), 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 further preferably used because the reaction requires a low temperature, the reaction is difficult to proceed, and toluene with a higher boiling point is selected as a preferred solvent in combination with the reaction time and yield.
As a preferred technical scheme: the reducing agent is selected from Zn/diluted HCl, Zn/acetic acid, Fe/diluted HCl, Fe/acetic acid, sodium borohydride, sodium cyanoborohydride, 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;
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 invention provides a brand new synthetic route for 7-amino-chloro-nitrazepam, the method has the advantages of short synthetic step, safe operation and simple and convenient post-treatment, only uses conventional acid-base and solvent in the whole reaction process, has low cost, and improves the yield by more than 20%.
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:
weighing Pd (TFA)2(276mg,1.5mmol), L (276mg,1.5mmol) in a sealed tube, N2Adding 50mL of 2-methyltetrahydrofuran under protection, stirring for 30 min, adding S1(1.63g,10mmol), S2(3.12g,20mmol) and water (25mL), injecting MsOH (9.6g,10mL) under ice-water bath, and blowing N after adding2The tube is sealed and heated to 100 ℃ for reaction for 36 h. Cooling to room temperature, adding 50mL of water, extracting the combined organic phases with ethyl acetate (50 mL. times.3), and saturating the combined organic phases with NaHCO3Washing the organic phase with a solution, washing once with a saturated NaCl solution, anhydrous NaSO4Drying, concentrating under reduced pressure, and eluting by column chromatography petroleum ether/ethyl acetate (8: 1-5: 1) to obtain a synthetic intermediate I which is 1.7g of light yellow solid with a yield of 95%;
(2) and (3) synthesizing an intermediate II:
weighing intermediate I (4.153g,15mmol) and sodium carbonate (3.18g,30mmol), adding 50mL of dichloromethane, dropwise adding 10mL of dichloromethane solution of S3(3.63g,18mmol) in ice water bath, removing ice water bath after 10 minutes of addition, after the reaction is finished, adding 30mL of water to quench the reaction, separating liquid, collecting organic phase, extracting aqueous phase dichloromethane (30mL x 2), combining the organic phases, washing once with saturated NaCl solution, and washing with anhydrous NaSO4Drying, concentrating under reduced pressure, and washing with petroleum ether/ethyl acetate 6:1 to obtain intermediate II as white solid 5.57g with 93% yield;
(3) synthesis of intermediate ii:
intermediate II (5.57g,14mmol) was weighed, 50mL of dimethyl sulfoxide was added, and NaN was slowly added in portions with stirring3(2.28g,35mmol), 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, and eluting with column chromatography petroleum ether/ethyl acetate 3:1 to obtain intermediate (III) as light yellow solid 3.65g with 96% yield;
(4) and (3) synthesizing an intermediate IV:
intermediate III (3.6g,10mmol) was weighed, 60mL of anhydrous toluene was added, and PPh was added slowly in portions with stirring3(3.15g,12mmol) when a large amount of bubbles emerge, after the gas is discharged, the tube is sealed and heated to 100 ℃, the reaction is carried out for 5h, the reaction is cooled to room temperature, a solid is separated out, and the intermediate IV is filtered and washed to obtain 2.79g of a light yellow solid with the yield of 93 percent.
(5) Synthesizing a target product V:
weighing reduced iron powder (10g, excess), adding 60mL of acetic acid, heating to 50 ℃, dropwise adding 20mL of acetic acid solution of intermediate IV (1.2g,3.8mmol), detecting the reaction by TLC about 20 minutes, adding 50mL of water to quench the reaction, converting the system from yellow turbidity to reddish brown, adsorbing the iron powder by a magneton, pouring the reaction solution into a beaker, extracting DCM (50mL 5), combining organic phases, and using saturated NaHCO for an organic phase3Washing the solution until no bubbles emerge and no NaSO is generated4Drying and decompressingThe concentrate petroleum ether/ethyl acetate 5:1 washes to give the title product V as a yellow solid 1.02g, 94% yield.
And (3) structural identification of the obtained target product V:
nuclear magnetic hydrogen spectrum:1H NMR(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:13C NMR(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) Calcd15H13ClN3O[M+H]+286.0742; 286.0732, as shown in FIG. 3.
Example 2
(1) Synthesis of intermediate I:
weighing Pd (TFA)2(276mg,1.5mmol), L (276mg,1.5mmol) in a sealed tube, 50mL tetrahydrofuran, stirring for 30 minutes, adding S1(1.63g,10mmol), S2(3.12g,20mmol), and water (25mL), injecting MsOH (9.6g,10mL) under an ice-water bath, heating to 100 ℃ after addition, and reacting for 48 hours. Cooling to room temperature, adding 50mL of water, extracting the combined organic phases with ethyl acetate (50 mL. times.3), and saturating the combined organic phases with NaHCO3Washing the organic phase with a solution, washing once with a saturated NaCl solution, anhydrous NaSO4Drying, concentrating under reduced pressure, and eluting by column chromatography petroleum ether/ethyl acetate (8: 1-5: 1) to obtain a synthetic intermediate I which is 0.9g of light yellow solid with a yield of 50.3%;
the method for synthesizing the intermediates II, III and IV is the same as that of the example 1;
synthesizing a target product V:
adding 20mL of ethanol and 20mL of HCl (2mol/L) into 10mL of dichloromethane solution of the intermediate IV (316mg,1mmol), weighing zinc powder (1g, excess) at room temperature, slowly adding the zinc powder, detecting by TLC for 12h after the reaction is finished, adding 50mL of water to quench the reaction, pouring the reaction solution into a beaker, extracting DCM (50mL 5), combining organic phases, and using saturated NaHCO for the organic phase3Washing the solution until no bubbles emerge and no NaSO is generated4Drying, and concentrating under reduced pressure to give petroleum ether/ethyl acetate (5: 1), and washing to give the desired product V as a yellow solid (205.3 mg) with a yield of 72%.
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 method for synthesizing a 7-amino-clonazepam compound is characterized in that: the method comprises the following steps:
(1) carrying out oxidative coupling reaction on 2-cyano-4-nitroaniline and 2-chlorobenzeneboronic acid in a reaction solvent A under the condition of adding a metal reagent and an additive to obtain an intermediate (I), wherein the reaction temperature is 0-100 ℃, and preferably 100 ℃;
(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 ℃, and preferably 25 ℃;
(3) reacting the intermediate (II) obtained in the step (2) with an azide compound in a reaction solvent C to obtain an intermediate (III), wherein the reaction temperature is 0-50 ℃, and preferably 25 ℃;
(4) reacting the intermediate (III) obtained in the step (3) with triphenylphosphine in a reaction solvent D to obtain an Intermediate (IV), wherein the reaction temperature is 0-100 ℃, and preferably 100 ℃;
(5) carrying out reduction reaction on the Intermediate (IV) obtained in the step (4) in a reaction solvent E by adopting a reducing agent to obtain a target product (V), wherein the reaction temperature is 0-50 ℃, and preferably 50 ℃;
wherein the structures of the intermediates (I), (II), (III), (IV) and the target product (V) are shown as follows:
2. a method of synthesizing a 7-amino clonazepam compound according to claim 1, wherein: in step (1), the metal reagent is selected from Cu (OAc)2、Cu(OTf)2、PdCl2、Pd(OAc)2And Pd (TFA)2At least one of them, preferably Pd (TFA)2。
3. A method of synthesizing a 7-amino clonazepam compound according to claim 1, wherein: in the step (1), the additive is selected from one of p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid and benzoic acid, and preferably methanesulfonic acid.
4. A method of synthesizing a 7-amino clonazepam compound according to claim 1, wherein: in the step (1), the reaction solvent A is selected from one of toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, ethanol, methanol, 1, 4-dioxane, acetic acid and chlorobenzene, and tetrahydrofuran is preferred.
5. A method of synthesizing a 7-amino clonazepam compound according to claim 1, wherein: in the step (2), the alkali is at least one selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydroxide and cesium carbonate, and is preferably sodium carbonate.
6. A method of synthesizing a 7-amino clonazepam compound according to claim 1, wherein: in the step (2), the acyl halide reagent is selected from one of acyl chloride or acyl bromide, preferably bromoacetyl bromide.
7. A method of synthesizing a 7-amino clonazepam compound according to claim 1, wherein: 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, preferably dichloromethane.
8. A method of synthesizing a 7-amino clonazepam compound according to claim 1, wherein: in the step (3), the azide compound is selected from one of p-toluenesulfonyl azide, diphenylphosphoryl azide and sodium azide, preferably sodium azide; the reaction solvent C is selected from toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, ethanol, methanol, 1, 4-dioxane, methanol, ethanol,N,N-at least one of dimethylformamide, dimethylsulfoxide, acetic acid, chlorobenzene, preferably dimethylsulfoxide.
9. A method of synthesizing a 7-amino clonazepam compound according to claim 1, wherein: in the step (4), 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 method of synthesizing a 7-amino clonazepam compound according to claim 1, wherein: the reducing agent is selected from Zn/diluted HCl, Zn/acetic acid, Fe/diluted HCl, Fe/acetic acid, sodium borohydride, sodium cyanoborohydride, SnCl2Preferably Fe/acetic acid; 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.
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| CN114702452A (en) * | 2022-03-29 | 2022-07-05 | 国药集团国瑞药业有限公司 | Preparation method of clonazepam, intermediate and application thereof |
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