CN113563280B - Synthesis method of 2-cyano phenothiazine - Google Patents

Synthesis method of 2-cyano phenothiazine Download PDF

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CN113563280B
CN113563280B CN202110869328.7A CN202110869328A CN113563280B CN 113563280 B CN113563280 B CN 113563280B CN 202110869328 A CN202110869328 A CN 202110869328A CN 113563280 B CN113563280 B CN 113563280B
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nickel
ligand
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mercaptobenzonitrile
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CN113563280A (en
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罗治斌
孙华
张恒铭
高苏皖
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Zhenjiang Cabo Medical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/18—[b, e]-condensed with two six-membered rings
    • C07D279/20—[b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom

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Abstract

The invention discloses a synthesis method of 2-cyano phenothiazine, which comprises the following steps: step 1, taking 4-halogen-3-nitrobenzonitrile as a raw material, and reacting in the presence of sulfide to obtain 3-amino-4-mercaptobenzonitrile; and 2, reacting 3-amino-4-mercapto-benzonitrile with a compound C in the presence of nickel salt, ligand and alkali to generate 2-cyano-phenothiazine, and synthesizing the 2-cyano-phenothiazine by taking cheap and easily available 4-halogen-3-nitronitrile as a raw material through fewer two steps. The reagent used in the reaction process is cheap and easy to obtain, and the method has the advantages of short steps, simple and convenient operation, high yield, safe operation and no pollution, and is suitable for industrial production.

Description

Synthesis method of 2-cyano phenothiazine
Technical Field
The invention relates to the technical field of organic synthesis and fine chemicals, in particular to a synthesis method of 2-cyano phenothiazine.
Background
2-cyanophenothiazine (CAS No. 38642-74-9) is an important organic synthesis intermediate, and the medicine prepared from the intermediate has multiple medicine functions, particularly has important functions in terms of blood pressure reduction, neuroleptic, pain relief and anticancer, and the demand of the international market for the intermediate is larger at present. The structural formula of the 2-cyano-phenothiazine is as follows
The synthesis of the compound is generally carried out by taking 2-chlorophenothiazine and cuprous cyanide as raw materials, and reacting in high-boiling point organic solvent such as quinoline or N-methyl pyrrolidone, etc. under catalysis of iodine or sodium iodide and potassium iodide.
Although the above-described methods are relatively mature, there are high demands on the raw materials and the environment. In the high-temperature reaction process, the 2-cyano phenothiazine product is hydrolyzed into an amide body by a trace amount of water existing in raw materials or environment, and the impurity is difficult to remove from the product by adopting a solvent recrystallization method, and the repeated recrystallization can reduce the content of the amide body, but greatly influences the product yield. Therefore, the industrial synthetic route for 2-chlorophenothiazine has yet to be optimized, and in particular, a new synthetic route using new raw materials has yet to be developed.
Disclosure of Invention
The invention aims to provide a synthesis method of 2-cyano phenothiazine aiming at the defects of the prior art.
The technical scheme for solving the problems is as follows: a synthetic method of 2-cyano phenothiazine comprises the following steps:
step 1, taking 4-halogen-3-nitrobenzonitrile as a raw material, and reacting in the presence of sulfide to obtain 3-amino-4-mercaptobenzonitrile;
step 2, 3-amino-4-mercaptobenzonitrile reacts with compound C in the presence of nickel salt, ligand and base to form 2-cyanophenothiazine. The reaction synthesis route is as follows:
；
x in structural formula of 4-halogen-3-nitronitrile 1 X in the structural formula of the compound C 2 ，X 3 And one of F, cl, br and I.
Further, in step 1, the sulfide is selected from Na 2 S，NaHS，K 2 S，KHS，(NH 4 ) 2 S，NH 4 HS，Na 2 SO 3 One of them, the reaction temperature is 20-100 ℃.
Further, the mass ratio of sulfide to 4-halogen-3-nitronitrile is 3-4: 1.
further, in the step 2, the nickel salt is selected from one of nickel chloride, nickel bromide, nickel acetate, nickel sulfate, nickel perchlorate and nickel triflate, and the reaction temperature is 80-100 ℃.
Further, the mass ratio of the nickel salt to the 3-amino-4-mercaptobenzonitrile is 2-5: 100.
further, in step 2, the ligand is selected from the group consisting of compounds of the following structures:
in the ligand structure, R 1 R2, R3, R4, R5, R6 and R7 are selected from any one of hydrogen atoms, straight-chain or branched alkyl groups and aryl groups.
Further, the mass ratio of the ligand to the 3-amino-4-mercaptobenzonitrile is 1-2: 20.
further, the synthesis of the ligand involves a two-step reaction: firstly, condensing a bromopyridine aldehyde ketone derivative with formaldehyde and an amine compound under an acidic condition to generate bromo-2-azaindolizine; and secondly, coupling bromo-2-azaindolizine with imidazole derivatives to obtain the ligand. The reaction synthesis route is as follows:
。
the invention has the beneficial effects that:
the invention provides a synthesis method of 2-cyano phenothiazine, which takes cheap and easily available 4-halogen-3-nitronitrile as a raw material, and realizes the synthesis of 2-cyano phenothiazine through fewer two steps. The reagent used in the reaction process is cheap and easy to obtain, and the method has the advantages of short steps, simple and convenient operation, high yield, safe operation and no pollution, and is suitable for industrial production.
Detailed Description
The technical scheme provided by the invention is explained in detail below with reference to specific embodiments.
A synthetic method of 2-cyano phenothiazine comprises the following steps:
step 1, taking 4-halogen-3-nitrobenzonitrile as a raw material, and reacting in the presence of sulfide to obtain 3-amino-4-mercaptobenzonitrile;
step 2, 3-amino-4-mercaptobenzonitrile reacts with compound C in the presence of nickel salt, ligand and base to form 2-cyanophenothiazine. The reaction synthesis route is as follows:
the structural formula of the 4-halogen-3-nitronitrile is shown as the following, X 1 One of F, cl, br and I;
the structural formula of the 3-amino-4-mercaptobenzonitrile is shown as follows,
the structural formula of the compound c is shown as follows, X 2 ，X 3 One of F, cl, br and I;
in step 1, the sulfide is selected from Na 2 S，NaHS，K 2 S，KHS，(NH 4 ) 2 S，NH 4 HS，Na 2 SO 3 The mass ratio of sulfide to 4-halogen-3-nitronitrile is 3-4: 1, the reaction temperature is 20-100 ℃;
in the step 2, the nickel salt is selected from one of nickel chloride, nickel bromide, nickel acetate, nickel sulfate, nickel perchlorate and nickel triflate, and the mass ratio of the nickel salt to 3-amino-4-mercaptobenzonitrile is 2-5: 100, wherein the reaction temperature is 80-100 ℃;
in step 2, the base is selected from DBU, KOBU t (Potassium tert-butoxide), sodium methoxide, naH, cs 2 CO 3 、K 3 PO 4 The mass ratio of the alkali to the 3-amino-4-mercaptobenzonitrile is 2-4: 1, a step of;
in step 2, the ligand is selected from the group consisting of compounds of the following structures:
in the ligand structure, R 1 ，R 2 ，R 3 ，R 4 ，R 5 ，R 6 ，R 7 Any one selected from a hydrogen atom, a linear or branched alkyl group and an aryl group; the mass ratio of the ligand to the 3-amino-4-mercaptobenzonitrile is 1-2: 20.
the synthesis of the ligand involves a two-step reaction: firstly, condensing a bromopyridine aldehyde ketone derivative with formaldehyde and an amine compound under an acidic condition to generate bromo-2-azaindolizine; and secondly, coupling bromo-2-azaindolizine with imidazole derivatives to obtain the ligand. The reaction synthesis route is as follows:
preparing a ligand: in the first step, aniline (0.4 mL, 4.3 mmol), 35% aqueous formaldehyde (0.49 mL, 6.5 mmol), 2.94M HCl in ethanol (1.5 mL, 4.3 mmol), 6-bromopyridine-2-carbaldehyde (4.3 mmol), and ethanol (7.2 mL) were added to the reaction vessel, and the reaction was stirred at room temperature for 15 minutes. Then the solvent is distilled off under reduced pressure, the obtained crude product is dissolved in hot acetonitrile, filtered while the crude product is hot, and recrystallized by acetonitrile/tetrahydrofuran to obtain the corresponding bromo-2-azaindolizine M1 which is orange solid;
second, bromo-2-azaindolizine M1 (2 mmol) and imidazole (2.4 mmol) were dissolved in acetonitrile (10 mL), palladium acetate (0.1 mmol) and potassium phosphate (2.4 mmol) were added, the temperature was raised to 80 degrees to react for 8 hours, filtration was performed while hot, and the obtained crude product was recrystallized from acetonitrile/tetrahydrofuran to obtain the corresponding ligand L1.
The reaction synthesis route is as follows:
example 1
4-chloro-3-nitronitrile (18.3 g,100 mmol) was dissolved in water (100 mL), naHS (6.2 g,110 mmol) was added with stirring, the temperature was raised to 85℃and after reaction 3 h, the reaction mixture was cooled to room temperature and Na was added with stirring 2 SO 3 (27.7 g,220 mmol) then the pH of the reaction was adjusted to 6 by slow addition of 30% hydrochloric acid, the whole process was carried out for about 2 hours, finally extracted with 1, 2-dichloroethane (200 mL) and the organic mixture was separated over MgSO 4 Drying, filtering and concentrating to obtain a crude product, adding the crude product into 100mL toluene, heating and refluxing for 30 minutesThen cooling to 5 ℃ and separating out solid, filtering the obtained solid under vacuum, washing with cold toluene and drying to obtain pure 3-amino-4-mercaptobenzonitrile with the yield of 81%.
Nickel bromide (0.4 g,2 mmol) and ligand L1 (1.5 g,5 mmol) were dissolved in DMF (200 mL), potassium tert-butoxide (24.6 g,220 mmol) was added, after stirring at room temperature for 60 minutes, 3-amino-4-mercaptobenzonitrile (15 g,100 mmol) and o-dichlorobenzene (16.2 g,110 mmol) were added, the temperature was raised to 100deg.C for 10 hours, then 100mL water quench reaction was added and extraction separation was performed with dichloromethane (300 mL). The organic mixture was dried over MgSO 4 The mixture was dried, filtered and concentrated to give a crude product, which was added to 100mL toluene, refluxed for 30 minutes at a temperature of about 5 ℃ and then cooled to precipitate a yellow solid. The yellow solid obtained was filtered under vacuum, washed with cold diethyl ether and dried to give pure 2-cyanophenothiazine in 88% yield.
Example 2
4-fluoro-3-nitronitrile (16.6 g,100 mmol) was dissolved in water (100 mL) and K was added with stirring 2 S (12.1 g,110 mmol), after warming to 80℃and reacting 3 h, the reaction mixture was cooled to room temperature and Na was added with stirring 2 SO 3 (27.7 g,220 mmol) then the pH of the reaction was adjusted to 6 by slow addition of 30% hydrochloric acid, the whole process was carried out for about 2 hours, finally extracted with 1, 2-dichloroethane (200 mL) and the organic mixture was separated over MgSO 4 Drying, filtering and concentrating to obtain a crude product, adding the crude product into 100mL toluene, heating and refluxing for 30 minutes, then cooling to 5 ℃ to precipitate solid, filtering the obtained solid under vacuum, washing with cold toluene, and drying to obtain pure 3-amino-4-mercaptobenzonitrile, wherein the yield is 78%.
Nickel chloride (0.26 g,2 mmol) and ligand L1 (1.9 g,5 mmol) were dissolved in DMF (200 mL), cesium carbonate (72 g,220 mmol) was added, and after stirring at room temperature for 60 minutes, 3-amino-4-mercaptobenzonitrile (15 g,100 mmol) and o-dibromobenzene (26 g,110 mmol) were added, the temperature was raised to 80℃for 10 hours, then 100mL water quench reaction was added, and extraction separation was performed with methylene chloride (300 mL). The organic mixture was dried over MgSO 4 The mixture was dried, filtered and concentrated to give a crude product, which was added to 100mL toluene, refluxed for 30 minutes at a temperature of about 5 ℃ and then cooled to precipitate a yellow solid. The yellow solid obtained was filtered under vacuum, washed with cold diethyl ether and dried to give pure 2-cyanophenothiazine in 90% yield.
Example 3
4-bromo-3-nitronitrile (22.7 g,100 mmol) was dissolved in water (100 mL) and Na was added with stirring 2 S (8.6 g,110 mmol), after warming to 60℃and reacting 2. 2 h, the reaction mixture was cooled to room temperature and Na was added with stirring 2 SO 3 (27.7 g,220 mmol) then the pH of the reaction was adjusted to 6 by slow addition of 30% hydrochloric acid, the whole process was carried out for about 2 hours, finally extracted with 1, 2-dichloroethane (200 mL) and the organic mixture was separated over MgSO 4 Drying, filtering and concentrating to obtain a crude product, adding the crude product into 100mL toluene, heating and refluxing for 30 minutes, then cooling to 5 ℃ to precipitate solid, filtering the obtained solid under vacuum, washing with cold toluene, and drying to obtain pure 3-amino-4-mercaptobenzonitrile, wherein the yield is 83%.
Nickel sulfate (0.3 g,2 mmol) and ligand L1 (1.9 g,5 mmol) were dissolved in DMF (200 mL) solution, DBU (33.4 g,220 mmol) was added, after stirring at room temperature for 60 minutes, 3-amino-4-mercaptobenzonitrile (15 g,100 mmol) and o-diiodobenzene (36.3 g,110 mmol) were added, the temperature was raised to 80℃for 6 hours, then 100mL water quench reaction was added and extraction separation was performed with dichloromethane (300 mL). The organic mixture was dried over MgSO 4 The mixture was dried, filtered and concentrated to give a crude product, which was added to 100mL toluene, refluxed for 30 minutes at a temperature of about 5 ℃ and then cooled to precipitate a yellow solid. The yellow solid obtained was filtered under vacuum, washed with cold diethyl ether and dried to give pure 2-cyanophenothiazine in 87% yield.
Example 4
4-iodo-3-nitronitrile (27.4 g,100 mmol) was dissolved in water (100 mL), stirred, and added (NH) 4 ) 2 S (7.5 g,110 mmol), after warming to 40℃and reacting 2. 2 h, the reaction mixture was cooled to room temperature and Na was added with stirring 2 SO 3 （277g,220 mmol), then 30% hydrochloric acid was slowly added to adjust the pH of the reaction system to 6, the whole process was carried out for about 2 hours, finally 1, 2-dichloroethane (200 mL) was used for extraction separation, and the organic mixture was subjected to MgSO 4 Drying, filtering and concentrating to obtain a crude product, adding the crude product into 100mL toluene, heating and refluxing for 30 minutes, then cooling to 5 ℃ to precipitate solid, filtering the obtained solid under vacuum, washing with cold toluene, and drying to obtain pure 3-amino-4-mercaptobenzonitrile, wherein the yield is 84%.
Nickel acetate (0.36 g,2 mmol) and ligand L1 (1.7 g,5 mmol) were dissolved in DMF (200 mL) solution and K was added 3 PO 4 (46.6 g,220 mmol) and 3-amino-4-mercaptobenzonitrile (15 g,100 mmol) and 2-bromochlorobenzene (21 g,110 mmol) were added and reacted at 90℃for 8 hours after stirring at room temperature, then 100mL water was added to quench the reaction, and extraction separation was performed with methylene chloride (300 mL). The organic mixture was dried over MgSO 4 The mixture was dried, filtered and concentrated to give a crude product, which was added to 100mL toluene, refluxed for 30 minutes at a temperature of about 5 ℃ and then cooled to precipitate a yellow solid. The yellow solid obtained was filtered under vacuum, washed with cold diethyl ether and dried to give pure 2-cyanophenothiazine in 86% yield.
The present invention is not limited to the above-mentioned embodiments, and any equivalent embodiments which can be changed or modified by the technical content disclosed above can be applied to other fields, but any simple modification, equivalent changes and modification made to the above-mentioned embodiments according to the technical substance of the present invention without departing from the technical content of the present invention still belong to the protection scope of the technical solution of the present invention.

Claims (7)

1. A method for synthesizing 2-cyano phenothiazine is characterized in that: the method comprises the following steps:
step 1, taking 4-halogen-3-nitrobenzonitrile as a raw material, and reacting in the presence of sulfide to obtain 3-amino-4-mercaptobenzonitrile;
step 2, 3-amino-4-mercaptobenzonitrile reacts with a compound C in the presence of nickel salt, ligand and alkali to generate 2-cyano phenothiazine; the reaction synthesis route is as follows:
；
x in structural formula of 4-halogen-3-nitronitrile 1 X in the structural formula of the compound C 2 ，X 3 One of F, cl, br and I;
in step 2, the ligand is selected from the group consisting of compounds of the following structures:
。
2. a method for synthesizing 2-cyanophenothiazine according to claim 1, wherein: in step 1, the sulfide is selected from Na 2 S，NaHS，K 2 S，KHS，(NH 4 ) 2 S，NH 4 HS，Na 2 SO 3 One of them, the reaction temperature is 20-100 ℃.
3. A method for synthesizing 2-cyanophenothiazine according to claim 1 or 2, characterized in that: the mass ratio of sulfide to 4-halogen-3-nitronitrile is 3-4: 1.
4. a method for synthesizing 2-cyanophenothiazine according to claim 1, wherein: in the step 2, the nickel salt is selected from one of nickel chloride, nickel bromide, nickel acetate, nickel sulfate, nickel perchlorate and nickel triflate, and the reaction temperature is 80-100 ℃.
5. A method of synthesizing 2-cyanophenothiazine according to claim 1 or 4, wherein: the mass ratio of the nickel salt to the 3-amino-4-mercaptobenzonitrile is 2-5: 100.
6. a method for synthesizing 2-cyanophenothiazine according to claim 1, wherein: the mass ratio of the ligand to the 3-amino-4-mercaptobenzonitrile is 1-2: 20.
7. a method for synthesizing 2-cyanophenothiazine according to claim 1, wherein: the synthesis of the ligand involves a two-step reaction: firstly, condensing a bromopyridine aldehyde ketone derivative with formaldehyde and an amine compound under an acidic condition to generate bromo-2-azaindolizine; coupling bromo-2-azaindolizine with imidazole derivative to obtain ligand; the reaction synthesis route is as follows:
。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1583732A (en) * 2004-06-10 2005-02-23 山西大学 Preparation of 2-cyanophenthiazine
CN102532057A (en) * 2011-11-17 2012-07-04 成都理工大学 Copper catalytic synthesis phenothiazine compound
CN111039898A (en) * 2019-12-26 2020-04-21 暨明医药科技（苏州）有限公司 Preparation method of metopimazine intermediate

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1583732A (en) * 2004-06-10 2005-02-23 山西大学 Preparation of 2-cyanophenthiazine
CN102532057A (en) * 2011-11-17 2012-07-04 成都理工大学 Copper catalytic synthesis phenothiazine compound
CN111039898A (en) * 2019-12-26 2020-04-21 暨明医药科技（苏州）有限公司 Preparation method of metopimazine intermediate

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