CN104109133A - Method for preparing N-acyl phenothiazine - Google Patents

Method for preparing N-acyl phenothiazine Download PDF

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Publication number
CN104109133A
CN104109133A CN201410299180.8A CN201410299180A CN104109133A CN 104109133 A CN104109133 A CN 104109133A CN 201410299180 A CN201410299180 A CN 201410299180A CN 104109133 A CN104109133 A CN 104109133A
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Prior art keywords
thiodiphenylamine
preparing
acyl group
grinding
phenothiazine
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CN201410299180.8A
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Chinese (zh)
Inventor
尹大伟
刘蓓蓓
刘玉婷
靖春燕
张晓莉
杨阿宁
王金玉
宋思梦
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Shaanxi University of Science and Technology
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Shaanxi University of Science and Technology
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Priority to CN201410299180.8A priority Critical patent/CN104109133A/en
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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
    • C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
    • C07D279/30—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with acyl radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a method for preparing N-acyl phenothiazine. The method comprises the steps of adding A mol of an aromatic acid and B mol of phosphorus oxychloride in a reaction vessel; grinding uniformly; then adding C mol of phenothiazine; grinding continuously until phenothiazine is reacted completely to obtain a product; standing the product; washing the product with water; carrying out suction filtration; drying a filter cake; and carrying out re-crystallization to obtain N-acyl phenothiazine. A ratio of A to B to C is (1-1.2):(1-1.2):1. A synthetic method of solid phase grinding is adopted to grind reactants directly for reaction. The method is mild in conditions, short in reaction time and obvious in reaction phenomena, is in no need of solvent, and has small pollution to an environment. The method is simple and convenient for operations; reactions can be carried out only by grinding; and requirements for equipment are low. The yield of a target product can reach over 92%. The method is a simple and convenient method for preparing N-acyl phenothiazine.

Description

A kind of method of preparing N-acyl group thiodiphenylamine
Technical field
The invention belongs to the field of chemical synthesis, particularly a kind of method of preparing N-acyl group thiodiphenylamine.
Background technology
Phenothiazines is the compounds based on thiodiphenylamine ring, be mainly used in clinically antipsychotic treatment, conventional have chlorpromazine, Fluphenazine and a trifluoperazine (TFP), after absorbing, is mainly combined with plasma proteins in body, and the concentration in brain can reach 10 times of plasma concentration.Since the sixties in 20th century, the effect of this type of medicine in oncotherapy paid attention to gradually and studied, and a large amount of in vitro study evidences show, growth and the propagation of phenothiazines to multiple normal cell and tumour cell is all inhibited.Some researchs are found at no distant date, phenothiazines (with the corresponding plasma concentration 2.36ttmol/L of clinical common dose within the scope of H ' entangle) can reduce significantly leukemia cell's survival ability, to normal lymphocyte without any cytotoxicity.This finds that prompting phenothiazines and derivatives for treatment tumour thereof may have clinical meaning, needs further to be developed.Therefore about the research of phenothiazine derivative receives much concern always.
The method of traditional synthetic phenothiazine derivative is to make solvent with acetonitrile, and formic acid and thiodiphenylamine carry out back flow reaction and obtain.The reaction process time is longer, and in reaction process, uses many organic solvents, and environmental pollution is comparatively serious, and aftertreatment comparatively bothers.
Summary of the invention
The invention provides a kind of method of the N-of preparation acyl group thiodiphenylamine, the method reaction conditions gentleness, the reaction times is short, easy and simple to handle, and target product productive rate is high.
For achieving the above object, the present invention adopts following technical scheme:
Prepare a method for N-acyl group thiodiphenylamine, its concrete steps are:
In reaction vessel, add A mol aromatic acid and B mol phosphorus oxychloride, grind evenly, then add C mol thiodiphenylamine, continue to be ground to thiodiphenylamine and react completely, obtain product, wherein A:B:C=(1～1.2): (1～1.2): 1; After product is left standstill, wash again suction filtration, by recrystallization after filtration cakes torrefaction, obtain N-acyl group thiodiphenylamine.
The structural formula of described aromatic acid is RCOOH, wherein R be phenyl, p-methylphenyl, o-methyl-phenyl-, an aminomethyl phenyl, o-methoxyphenyl, p-methoxyphenyl, m-methoxyphenyl, 2-fluorophenyl, to fluorophenyl, p-aminophenyl, m-aminophenyl base, adjacent aminophenyl, Chloro-O-Phenyl, rubigan, 2,4-dichlorophenyl, m-nitro base, p-nitrophenyl, 3,5-dinitrophenyl, to bromophenyl, o-bromophenyl or 4-pyridyl.
Described reaction vessel is dry mortar.
Described grinding is at room temperature carried out, and grinding the even required time is 0.5～1h.
With TLC monitoring, in the time that disappearing, the raw material point of thiodiphenylamine stops grinding.
It is that volume ratio is the ethyl acetate of 1:3 and the mixing solutions of sherwood oil that described TLC monitors developping agent used.
Described time of repose is 0.5～1h.
Described standingly at room temperature carry out.
Described dry be to be at room temperature dried 22～24h.
Described recrystallization solvent used is water.
Compared with prior art, beneficial effect of the present invention is:
The invention provides a kind of method of the N-of preparation acyl group thiodiphenylamine, taking aromatic acid, thiodiphenylamine as raw material, as catalyzer, adopt solid-phase grinding method to prepare N-acyl group thiodiphenylamine with phosphorus oxychloride.Compared with prior synthesizing method, the method, without solvent, therefore need not be carried out complexity and loaded down with trivial details back flow reaction, and operating process is simple, only former abrasive lapping evenly can need be reacted, low for equipment requirements, reaction conditions gentleness, at room temperature can carry out, the reaction times is short, and environmental pollution is little.The aftertreatment of the method is simultaneously simple, environmental protection, and catalyzer phosphorus oxychloride is cheap to be easy to get; toxicity is little; environmental pollution is little, and the productive rate of the target product making, up to 92%, is a kind of Green Chemistry concept and safe and simple novel method of preparing efficiently N-acyl group thiodiphenylamine of meeting.
Embodiment
The present invention is taking aromatic acid, thiodiphenylamine as raw material, and taking phosphorus oxychloride as catalyzer, reaction generates N-acyl group thiodiphenylamine, and its reaction equation is suc as formula shown in (1).
Wherein R be phenyl, p-methylphenyl, o-methyl-phenyl-, an aminomethyl phenyl, o-methoxyphenyl, p-methoxyphenyl, m-methoxyphenyl, 2-fluorophenyl, to fluorophenyl, p-aminophenyl, m-aminophenyl base, adjacent aminophenyl, Chloro-O-Phenyl, rubigan, 2,4-dichlorophenyl, m-nitro base, p-nitrophenyl, 3,5-dinitrophenyl, to bromophenyl, o-bromophenyl or 4-pyridyl.
The general structure of the prepared N-acyl group of the present invention thiodiphenylamine is suc as formula shown in (2):
R is phenyl, p-methylphenyl, o-methyl-phenyl-, an aminomethyl phenyl, o-methoxyphenyl, p-methoxyphenyl, m-methoxyphenyl, 2-fluorophenyl, to fluorophenyl, p-aminophenyl, m-aminophenyl base, adjacent aminophenyl, Chloro-O-Phenyl, rubigan, 2,4-dichlorophenyl, m-nitro base, p-nitrophenyl, 3,5-dinitrophenyl, to bromophenyl, o-bromophenyl or 4-pyridyl.
Below in conjunction with preferred embodiment of the present invention, the present invention is described in further details.
Embodiment 1
In dry mortar, add 0.0055mol phenylformic acid and 0.0055mol phosphorus oxychloride, under room temperature, grind 0.5h to grinding evenly, add again 0.005mol thiodiphenylamine, continue to grind, with TLC monitoring reaction, until thiodiphenylamine reacts completely, now the raw material point of thiodiphenylamine disappears, and stops grinding, and obtains product, wherein to monitor developping agent used be that volume ratio is the ethyl acetate of 1:3 and the mixing solutions of sherwood oil to TLC, then product left standstill to 1h in room temperature; Wash again suction filtration, by room temperature water recrystallization after dry 24h of filter cake, obtain N-acyl group phenyl thiodiphenylamine.Productive rate is 93.1%.Fusing point 150-154 DEG C.
IR (KBr, cm -1): 3089cm -1, 3056cm -1(unsaturated C-H); 1671cm -1(acid amides); 1596cm -1, 1502cm -1, 1472cm -1(phenyl ring vibration absorption peak); 1256cm -1(C-N-C); 696cm -1, 762cm -1(phenyl ring is monosubstituted).
Embodiment 2
In dry mortar, add 0.0055mol m-methyl benzoic acid and 0.0055mol phosphorus oxychloride, under room temperature, grind 1h to grinding evenly, add again 0.005mol thiodiphenylamine, continue to grind, with TLC monitoring reaction, until thiodiphenylamine reacts completely, now the raw material point of thiodiphenylamine disappears, and stops grinding, and obtains product, wherein to monitor developping agent used be that volume ratio is the ethyl acetate of 1:3 and the mixing solutions of sherwood oil to TLC, then product left standstill to 0.5h in room temperature; Wash again suction filtration, by room temperature water recrystallization after dry 22h of filter cake, obtain aminomethyl phenyl thiodiphenylamine between N-acyl group.Productive rate is 94.4%.Fusing point is 110-112 DEG C.
IR (KBr, cm -1): 3098cm -1, 3054cm -1(unsaturated C-H); 2994cm -1, 2911cm -1(saturated C-H); 1656cm -1(acid amides); 1595cm -1, 1500cm -1, 1471cm -1(phenyl ring vibration absorption peak); 1256cm -1(C-N-C); 715cm -1, 824cm -1(between phenyl ring, position replaces).
Embodiment 3
In dry mortar, add 0.005mol Chlorodracylic acid and 0.0055mol phosphorus oxychloride, under room temperature, grind 0.8h to grinding evenly, add again 0.005mol thiodiphenylamine, continue to grind, with TLC monitoring reaction, until thiodiphenylamine reacts completely, now the raw material point of thiodiphenylamine disappears, and stops grinding, and obtains product, wherein to monitor developping agent used be that volume ratio is the ethyl acetate of 1:3 and the mixing solutions of sherwood oil to TLC, then product left standstill to 0.8h in room temperature; Wash again suction filtration, by room temperature water recrystallization after dry 23h of filter cake, obtain N-acyl group rubigan thiodiphenylamine.Productive rate is 92.6%.Fusing point 134-139 DEG C.
IR (KBr, cm -1): 3089cm -1, 3024cm -1(unsaturated C-H); 1654cm -1(acid amides); 1598cm -1, 1502cm -1, 1459cm -1(phenyl ring vibration absorption peak); 1284cm -1(C-N-C); 754cm -1, 828cm -1(phenyl ring para-orientation).
Embodiment 4
In dry mortar, add 0.0055mol 2,4-dichlorobenzoic acid and 0.005mol phosphorus oxychloride, grind 0.5h to grinding evenly, then add 0.005mol thiodiphenylamine under room temperature, continue to grind, with TLC monitoring reaction, until thiodiphenylamine reacts completely, now the raw material point of thiodiphenylamine disappears, stop grinding, obtain product, wherein to monitor developping agent used be that volume ratio is the ethyl acetate of 1:3 and the mixing solutions of sherwood oil to TLC, then product left standstill to 1h in room temperature; Wash again suction filtration, by room temperature water recrystallization after dry 24h of filter cake, by recrystallization after filtration cakes torrefaction, obtain N-acyl group-2,4 dichloro benzene base thiodiphenylamine.Productive rate is 94.7%.Fusing point 95-96 DEG C.
IR (KBr, cm -1): 3061cm -1(unsaturated C-H); 1674cm -1(acid amides); 1583cm -1, 1556cm -1, 1464cm -1(phenyl ring vibration absorption peak); 1291cm -1(C-N-C); 756cm -1, 828cm -1(phenyl ring three replaces, and has isolated hydrogen).
Embodiment 5
In dry mortar, add 0.006mol3,5-dinitrobenzoic acid and 0.006mol phosphorus oxychloride, grind 0.5h to grinding evenly, then add 0.005mol thiodiphenylamine under room temperature, continue to grind, with TLC monitoring reaction, until thiodiphenylamine reacts completely, now the raw material point of thiodiphenylamine disappears, stop grinding, obtain product, wherein to monitor developping agent used be that volume ratio is the ethyl acetate of 1:3 and the mixing solutions of sherwood oil to TLC, then product left standstill to 1h in room temperature; Wash again suction filtration, by room temperature water recrystallization after dry 24h of filter cake, obtain N-acyl group-3,5-dinitrophenyl thiodiphenylamine.Productive rate is 92.5%.Fusing point is 165-169 DEG C.
IR (KBr, cm -1): 3095cm -1, 3057cm -1(unsaturated C-H); 1624cm -1(acid amides); 1596cm -1, 1554cm -1, 1471cm -1(phenyl ring vibration absorption peak); 1295cm -1(C-N-C); 822cm -1(between phenyl ring, position three replaces).
Embodiment 6
In dry mortar, add 0.0055mol gavaculine and 0.0055mol phosphorus oxychloride, under room temperature, grind 0.5h to grinding evenly, add again 0.005mol thiodiphenylamine, continue to grind, with TLC monitoring reaction, until thiodiphenylamine reacts completely, now the raw material point of thiodiphenylamine disappears, and stops grinding, and obtains product, wherein to monitor developping agent used be that volume ratio is the ethyl acetate of 1:3 and the mixing solutions of sherwood oil to TLC, then product left standstill to 1h in room temperature; Wash again suction filtration, by room temperature water recrystallization after dry 24h of filter cake, obtain N-acyl group m-aminophenyl base thiodiphenylamine.Productive rate is 93.3%.Fusing point is 155-161 DEG C.
IR (KBr, cm -1): 3098cm -1, 3054cm -1(unsaturated C-H); 3340cm -1, 3181cm -1(primary amine); 1687cm -1(acid amides); 1596cm -1, 1509cm -1, 1471cm -1(phenyl ring vibration absorption peak); 1261cm -1(C-N-C); 707cm -1, 822cm -1(between phenyl ring, position replaces).
Embodiment 7～embodiment 21 is identical with the step of embodiment 1, and the aromatic acid adopting is specifically as shown in table 1 with the N-acyl group thiodiphenylamine making.
Table 1

Claims (10)

1. a method of preparing N-acyl group thiodiphenylamine, is characterized in that, its concrete steps are:
In reaction vessel, add A mol aromatic acid and B mol phosphorus oxychloride, grind evenly, then add C mol thiodiphenylamine, continue to be ground to thiodiphenylamine and react completely, obtain product, wherein A:B:C=(1～1.2): (1～1.2): 1; After product is left standstill, wash again suction filtration, by recrystallization after filtration cakes torrefaction, obtain N-acyl group thiodiphenylamine.
2. the method for preparing N-acyl group thiodiphenylamine according to claim 1; it is characterized in that: the structural formula of described aromatic acid is RCOOH; wherein R be phenyl, p-methylphenyl, o-methyl-phenyl-, an aminomethyl phenyl, o-methoxyphenyl, p-methoxyphenyl, m-methoxyphenyl, 2-fluorophenyl, to fluorophenyl, p-aminophenyl, m-aminophenyl base, adjacent aminophenyl, Chloro-O-Phenyl, rubigan, 2; 4-dichlorophenyl, m-nitro base, p-nitrophenyl, 3,5-dinitrophenyl, to bromophenyl, o-bromophenyl or 4-pyridyl.
3. the method for preparing N-acyl group thiodiphenylamine according to claim 1 and 2, is characterized in that: described reaction vessel is dry mortar.
4. the method for preparing N-acyl group thiodiphenylamine according to claim 1 and 2, is characterized in that: described grinding is at room temperature carried out, and grinding the even required time is 0.5～1h.
5. the method for preparing N-acyl group thiodiphenylamine according to claim 1 and 2, is characterized in that: with TLC monitoring, in the time that the raw material point of thiodiphenylamine disappears, stop grinding.
6. the method for preparing N-acyl group thiodiphenylamine according to claim 5, is characterized in that: it is that volume ratio is the ethyl acetate of 1:3 and the mixing solutions of sherwood oil that described TLC monitors developping agent used.
7. the method for preparing N-acyl group thiodiphenylamine according to claim 1 and 2, is characterized in that: described time of repose is 0.5～1h.
8. the method for preparing N-acyl group thiodiphenylamine according to claim 7, is characterized in that: described standingly at room temperature carry out.
9. the method for preparing N-acyl group thiodiphenylamine according to claim 1 and 2, is characterized in that: described dry be to be at room temperature dried 22～24h.
10. the method for preparing N-acyl group thiodiphenylamine according to claim 1 and 2, is characterized in that: described recrystallization solvent used is water.
CN201410299180.8A 2014-06-26 2014-06-26 Method for preparing N-acyl phenothiazine Pending CN104109133A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113149932A (en) * 2020-12-28 2021-07-23 虎丘影像（苏州）有限公司 Preparation method of heat-sensitive dye compound N-acyl phenothiazine
US11084807B2 (en) 2016-08-18 2021-08-10 Vidac Pharama Ltd. Piperazine derivatives, pharmaceutical compositions and methods of use thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09301939A (en) * 1996-05-10 1997-11-25 Kureha Chem Ind Co Ltd Production of fluoroalkanecarboxylic amides

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
JPH09301939A (en) * 1996-05-10 1997-11-25 Kureha Chem Ind Co Ltd Production of fluoroalkanecarboxylic amides

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SULTAN DARVESH ET AL.: "Selective reversible inhibition of human butyrylcholinesterase by aryl amide derivatives of phenothiazine", 《BIOORGANIC & MEDICINAL CHEMISTRY》 *
张应鹏等: "研磨法运用于固相有机合成中的新进展", 《江西化工》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11084807B2 (en) 2016-08-18 2021-08-10 Vidac Pharama Ltd. Piperazine derivatives, pharmaceutical compositions and methods of use thereof
CN113149932A (en) * 2020-12-28 2021-07-23 虎丘影像（苏州）有限公司 Preparation method of heat-sensitive dye compound N-acyl phenothiazine

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Application publication date: 20141022