US2784186A - Halo derivatives of benzoyl leuco - Google Patents

Halo derivatives of benzoyl leuco Download PDF

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US2784186A
US2784186A US2784186DA US2784186A US 2784186 A US2784186 A US 2784186A US 2784186D A US2784186D A US 2784186DA US 2784186 A US2784186 A US 2784186A
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phenothiazine
chloride
bis
benzoyl
dimethylamino
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • 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
    • 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
    • C07D279/24—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom

Definitions

  • the known unhalogenated leuco compound IO-benzoyl- 3,7-bis(dimethylamino)phenothiazine also known as benzoyl leucomethylene blue
  • IO-benzoyl- 3,7-bis(dimethylamino)phenothiazine also known as benzoyl leucomethylene blue
  • a base web of paper having a coating made of wax and oil, the oi1 having dissolved therein a fast-reacting col-orless color reactant-namely, crystal violet lactonewhich is more specifically described as 3,3-bis(p-dimethylaminophenyl)-6-dimethylamino phthalide, which turns to a dark blue color upon coming into contact with attapulgite or halloysite, and the slower-reacting compound 10-;benzoyl-3,7-bis(dimethylamino)phenothiazine, which was mentioned before.
  • a fast-reacting col-orless color reactant namely, crystal violet lactone which is more specifically described as 3,3-bis(p-dimethylaminophenyl)-6-dimethylamino phthalide, which turns to a dark blue color upon coming into contact with attapulgite or halloysite, and the slower-reacting compound 10-;benzoyl-3,7-bis(dimethylamino)
  • crystal violet lactone color fades after prolonged exposure to light, and, as it gradually fades away, the slower-reacting l-benzoyl-3,7-bis(dimethylarnino)phenothiazine gradually develops color, so that the printing or writing is not lost.
  • Another such manifold sheet is one in which the transfer coating is composed of oilcontaining, pressure-rupturable microscopic capsules of gelled hydrophiliccolloid material, and in which the encapsulated oil carries the color reactants of the first mentioned patent, and it is disclosed in United 2,784,186 Patented Mar. 5, 195 7 2 States Patent No. 2,712,507, which issued, on the application of Barrett K. Green, on July 5, 1955. 7
  • halogenated derivatives may be made by reacting the Zinc chloride double salt of leucomethylene blue, having the structure To 73 grams (0.146 mole) of the zinc chloride double salt of leucomethylene blue is added 122 grams 1.55 moles) of pyridine in a round-bottom, three-necked flash fitted with a stirrer, a thermometer, and a dropping funnel. After this has been heated to degrees centigrade, and while it is being stirred, 50 grams (0.284 mole) of o chlorobenzoyl chloride is added, drop by drop, after which the dropping funnel is replaced by a reflux condenser, and the mixture is gently refluxed for one and one half hours.
  • the reaction mixture then is poured into water, whereupon a semi-solid material precipitates out.
  • the water is decanted off, and thesolid residue is mixed with 48 grams of sodium hydroxide dissolved in one liter of water. This mixture is stirred and warmed for one half hour.
  • the washed residue is extracted with two liters of hot benzene.
  • the resulting dark benzene solution then is treated with fullers earth and filteredl
  • the filtrate is concentrated to 600 milliliters, cooled to room temperature, and the reaction cipitated out with petroleum ether.
  • the final product is a white crystalline material;
  • the m-chloro and the p-chloro derivatives may be manufactured by the same process, using, in place of the o-chlorobenzoyl chloride, the m-chlorobenzoyl chloride and the p-chlorobenzoyl chloride, respectively, in the same molecular. proportions.
  • I f The various dichloro, trichloro, tetrachloro,and pentaproduct is prechloro derivativesmay bemadeinthesame manner by I:
  • hemqduct obta n d is 1. -(2.3-dich1Qr beuzoyl)- (dimethylamino)phenothiazine; similarly, using the 2,4- dichlorobenzoy-l chloride the product obtained is Iii-(2,4- dichlorobenzoyl)-3,7 bis(dimethylamino)phenothiazine; using the 2,5 -dichlorobenzoyl chloride the product obtained is lO-(2,5 dichlorobenzoyl)-3,7 bis(dimethylamino) phenothiazine; using the 2,6-dichlorobenzoyl chloride the product obtained is -(2,6-dichlorobenzoyl)- 3,7, bis(dimethylamino)-phenothiazine; using the 3,4-dichlorobenzoyl chloride the product is l0-(3,4-dichlorobenzoyl) 3,7-bis(d
  • Brominated benzoyl chlorides may be used in place of the chlorinated benzoyl chlorides to make the bromo derivatives.
  • the zinc chloride double salt of leucomethylene blue would be reacted with o-bromobenzoyl chloride in the same molecular proportions as set forth in connection with the making of the chloro derivatives.
  • a cheaper product may be made by ha-logenating benzoyl chloride by passing the selected halogen gas through the benzoyl chloride in the presence of a catalyst. This will result in a mixture of halogenated benzoyl chlorides as a consequence of the random attachment of the halogen atoms on the benzene ring.
  • the degree of halogenation may be determined by weighing the benzoyl chloride before and after passing the halogen gas through it.
  • the degree of halogenation estimated by this method is a practical one and not an absolute one; that isto say, if enough halogen gas is combined with the benzoyl chloride, so that in theory each benzoyl chloride molecule could have two halogen atoms thereon, the chances are that in the mixture most of the benzoyl chloride molecules would have two chlorine atoms thereon, and the reaction product would essentially be a mixture of dichlorobenzoyl chloride, the exact positions of the chlorine atoms on the benzene ring not being known.
  • the system is weighed and heated to -45 degrees centigrade. Chlorine is passed in at this temperature range for three hours until approximately 210 grams of chlorine has been adsorbed. The resulting oil is blown with dry air for one half hour to remove any remaining hydrogen chloride and unreacted chlorine. The final net weight gain in the system is 207 grams, which is the theoretical gain.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Description

United States Patent HALO DERIVATIVES OF BENZOYL LEUCO METHYLENE BLUE Clyde 8. Adams, Yellow Springs, Marjorie J. Cormack,
Dayton, and Mary Lou Frazier, Springfield, Ohio, assignors to The National Cash Register Company, Dayton, Ohio, a corporation of Maryland No Drawing. Application October 27, 1955, Serial No. 543,266
8 Claims. (Cl. 260-243) where R is taken from the group consisting of chlorine and bromine, and where N is a number from 1 to 5.
This is a continuation-in-part of our application Serial No. 518,334, filed June 27, 1955, now abandoned.
The known unhalogenated leuco compound IO-benzoyl- 3,7-bis(dimethylamino)phenothiazine, also known as benzoyl leucomethylene blue, normally is substantially colorless and has been used as a color reactant which turns to a blue-green color on prolonged contact with acid clay-like materials such as attapulgite and halloysite. It is used in conjunction with other, faster-reacting, colorless color-reactants, also turned to the colored form on contact .with such acid clay-like materials.
One of the present primary uses of these color-reactant materials in their incorporation in transfer coatings on the rear surfaces of manifold record sheets. When these manifold sheets are placed over paper sensitized with attapulgite or halloysite, and an impression, by printing or writing, is made, transferring the color reactants to the sensitized surfaces of the under sheets, impressions in color are made thereon. One type of manifold sheet having a transfer coating of the type described is disclosed in United States Patent No. 2,646,367, which issued, on the application of Chester Davis and Ned A. Thatcher, on July 21, 1953. In that patent there is disclosed a base web of paper having a coating made of wax and oil, the oi1 having dissolved therein a fast-reacting col-orless color reactant-namely, crystal violet lactonewhich is more specifically described as 3,3-bis(p-dimethylaminophenyl)-6-dimethylamino phthalide, which turns to a dark blue color upon coming into contact with attapulgite or halloysite, and the slower-reacting compound 10-;benzoyl-3,7-bis(dimethylamino)phenothiazine, which was mentioned before. The crystal violet lactone color fades after prolonged exposure to light, and, as it gradually fades away, the slower-reacting l-benzoyl-3,7-bis(dimethylarnino)phenothiazine gradually develops color, so that the printing or writing is not lost. Another such manifold sheet is one in which the transfer coating is composed of oilcontaining, pressure-rupturable microscopic capsules of gelled hydrophiliccolloid material, and in which the encapsulated oil carries the color reactants of the first mentioned patent, and it is disclosed in United 2,784,186 Patented Mar. 5, 195 7 2 States Patent No. 2,712,507, which issued, on the application of Barrett K. Green, on July 5, 1955. 7
One drawback to the use of l0-benzoyl-3,7-bis(dimethylamino)phenothiazine is that it gradually decomposes to the colored form on exposure to light. Thus, if the side of a transfer sheet which is coated with the transferable material is exposed to light, it gradually assumes an undesirable blue-green color. The halogenation of the lO- benzoyl-3,7-bis(dimethylamino)phenothiazine, with either chlorine or bromine, almost completely prevents this.
Therefore, it is the object of this invention to provide essentially light-stable halogenated derivatives of lO-benzoyl-3,7-bis(dimethylamino)phenothiazine.
These halogenated derivatives may be made by reacting the Zinc chloride double salt of leucomethylene blue, having the structure To 73 grams (0.146 mole) of the zinc chloride double salt of leucomethylene blue is added 122 grams 1.55 moles) of pyridine in a round-bottom, three-necked flash fitted with a stirrer, a thermometer, and a dropping funnel. After this has been heated to degrees centigrade, and while it is being stirred, 50 grams (0.284 mole) of o chlorobenzoyl chloride is added, drop by drop, after which the dropping funnel is replaced by a reflux condenser, and the mixture is gently refluxed for one and one half hours.
The reaction mixture then is poured into water, whereupon a semi-solid material precipitates out. The water is decanted off, and thesolid residue is mixed with 48 grams of sodium hydroxide dissolved in one liter of water. This mixture is stirred and warmed for one half hour. The alkaline fluid is decanted oif, and the.rem=ain-- ing solid residue is Washed with water. The washed residue is extracted with two liters of hot benzene. The resulting dark benzene solution then is treated with fullers earth and filteredl The filtrate is concentrated to 600 milliliters, cooled to room temperature, and the reaction cipitated out with petroleum ether. The final product is a white crystalline material; The m-chloro and the p-chloro derivatives may be manufactured by the same process, using, in place of the o-chlorobenzoyl chloride, the m-chlorobenzoyl chloride and the p-chlorobenzoyl chloride, respectively, in the same molecular. proportions. I f The various dichloro, trichloro, tetrachloro,and pentaproduct is prechloro derivativesmay bemadeinthesame manner by I:
using the proper chlorinated benzoyl chloride/f By using -2j3-dichlorob'enzoyl chloride and. reactingit i j with the Zincchloride'double salfo'f leucomethylene blue greener;
hemqduct obta n d is 1. -(2.3-dich1Qr beuzoyl)- (dimethylamino)phenothiazine; similarly, using the 2,4- dichlorobenzoy-l chloride the product obtained is Iii-(2,4- dichlorobenzoyl)-3,7 bis(dimethylamino)phenothiazine; using the 2,5 -dichlorobenzoyl chloride the product obtained is lO-(2,5 dichlorobenzoyl)-3,7 bis(dimethylamino) phenothiazine; using the 2,6-dichlorobenzoyl chloride the product obtained is -(2,6-dichlorobenzoyl)- 3,7, bis(dimethylamino)-phenothiazine; using the 3,4-dichlorobenzoyl chloride the product is l0-(3,4-dichlorobenzoyl) 3,7-bis(dimethylamino) phenothiazine; and using the 3,5-dichlorobenzoyl chloride the product obtained is l0-(3,5-dichlorobenzoyl)-3,7-bis(dimethylamino)phenothiazine. The ingredients are used in the same molecular proportions as first given in connection with the making of l0-(o chlorobenzoyl)-3,7-bis(dimethylamino) phenothiazine.
By using the selected tetrachloro benzoyl chloride, the corresponding IO-(tetrachlorobenzoyl) -3,7-bis (dimethylamino)phenothiazine is produced; and by using pentachlorobenzoyl chloride, IO-(pentachlorobenzoyl)-3,7-bis (dimethylamino)phenothiazine is produced.
Brominated benzoyl chlorides may be used in place of the chlorinated benzoyl chlorides to make the bromo derivatives. Thus, if it is desired to make IO-(o-bromobenzoyl)3,7-bis(dimethylamino)phenothiazine, the zinc chloride double salt of leucomethylene blue would be reacted with o-bromobenzoyl chloride in the same molecular proportions as set forth in connection with the making of the chloro derivatives.
In the foregoing examples, selected known halogenated benzoyl chlorides have been used to react with the zinc chloride double salt of leucomethylene blue.
A cheaper product may be made by ha-logenating benzoyl chloride by passing the selected halogen gas through the benzoyl chloride in the presence of a catalyst. This will result in a mixture of halogenated benzoyl chlorides as a consequence of the random attachment of the halogen atoms on the benzene ring. The degree of halogenation may be determined by weighing the benzoyl chloride before and after passing the halogen gas through it. Generally speaking, the degree of halogenation estimated by this method is a practical one and not an absolute one; that isto say, if enough halogen gas is combined with the benzoyl chloride, so that in theory each benzoyl chloride molecule could have two halogen atoms thereon, the chances are that in the mixture most of the benzoyl chloride molecules would have two chlorine atoms thereon, and the reaction product would essentially be a mixture of dichlorobenzoyl chloride, the exact positions of the chlorine atoms on the benzene ring not being known.
An example will now be given of the process for making a mixture of dichlorobenzoyl chlorides:
A blackened three-necked one-1iter flask, equipped with a below-the-liquid-surface glass inlet tube, stirrer, thermometer, and outlet to a hydrogen chloride adsorber, is charged with 420 grams (3 moles) of technical benzoyl chloride, 3 grams of iodine, and 2 grams of iron.
The system is weighed and heated to -45 degrees centigrade. Chlorine is passed in at this temperature range for three hours until approximately 210 grams of chlorine has been adsorbed. The resulting oil is blown with dry air for one half hour to remove any remaining hydrogen chloride and unreacted chlorine. The final net weight gain in the system is 207 grams, which is the theoretical gain.
In making mixed trichlorobenzoyl chlorides, the same apparatus and charge are used except that the chlorination is continued. for four hours at the same temperature range. After blowing with dry air, a net weight gain of 28f7 gramswas noted, which is 95 percentof the theoretie calgain, which is 3 10 grams.
These mixtures of halogenated benzoyl chloride are. then condensed with the zinc chloride salt of methylene blue as previously described, providing a mixture that has characteristics equivalent to the more specific compounds.
What is claimed is:
l. The compound 10-(halobenzoyl)-3,7bis(dimethylamino) phenothiazine, having the structure where N is a number from 1 to 5.
3. The compound IO-(bromobenzoyl)-3,7-bis(dimethyl amino) phenothiazine, having the structure where N is a number from 1 to 5. V
4. The compound 10- (m-chlorohenzoyl)-3,7-bis(dimethylamino) phenothiazine having the structure S (cHmN 5 wens), 8 2i 9 g 1 l 5. The compound 10- (2,4-dichlorobenzoyl)-3,7-bis- (dimethylamino) phenothiazine having the structure S (errant 5 1 more):
5 6. The compound 10 (3,4-dichlorobenzoyl)-3,7-bis- 8. The compound IO-(m-bromobenzoyl)-3,7-bis-(di- (dimethylamino) phenothiazine, having the structure methylamino) phenothiazine, having the structure s (mm 7 6 mom): (Q a):N N(C a)| 5 8 9 I 10 N N B=0 =o References Cited in the file of this patent mZeF1$ fim3131;; 5222?2?23Z'* FREIGN PATENTS P g 113,721 Germany Sept. 28, 1900 (QH3),N 6 5 NwHa)a 51 ,300 Belgium July 15, 1952 7 725,275 Great Britain Mar. 2, 1955 8 9 1o N S=o

Claims (1)

1. THE COMPOUND 10-(HALOBENZOYL)-3,7-BIS(DIMETHYLAMINO) PHENOTHIAZINE, HAVING THE STRUCTURE
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2909520A (en) * 1959-10-20 Process for making acylated
US2915415A (en) * 1957-06-19 1959-12-01 Caribonum Ltd Leucauramine derivate of benzoyl leuco methylene blue and transfer sheet coated therewith
US5424183A (en) * 1993-03-15 1995-06-13 Minnesota Mining And Manufacturing Company Ballasted leuco dyes and photothermographic element containing same
US5432041A (en) * 1993-03-18 1995-07-11 Minnesota Mining And Manufacturing Company Yellow and magenta chromogenic leuco dyes for photothermographic elements
US5583255A (en) * 1993-12-03 1996-12-10 Imation Corp. Yellow and magenta chromogenic leuco dyes for photothermographic elements
US6117624A (en) * 1993-06-04 2000-09-12 Eastman Kodak Company Infrared sensitized, photothermographic article

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE512300A (en) * 1951-06-23
DE113721C (en) * 1899-06-01 1900-09-28 Process for the preparation of acidyl derivatives of leukothionine dyes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE113721C (en) * 1899-06-01 1900-09-28 Process for the preparation of acidyl derivatives of leukothionine dyes
BE512300A (en) * 1951-06-23

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2909520A (en) * 1959-10-20 Process for making acylated
US2915415A (en) * 1957-06-19 1959-12-01 Caribonum Ltd Leucauramine derivate of benzoyl leuco methylene blue and transfer sheet coated therewith
US5424183A (en) * 1993-03-15 1995-06-13 Minnesota Mining And Manufacturing Company Ballasted leuco dyes and photothermographic element containing same
US5432041A (en) * 1993-03-18 1995-07-11 Minnesota Mining And Manufacturing Company Yellow and magenta chromogenic leuco dyes for photothermographic elements
US6117624A (en) * 1993-06-04 2000-09-12 Eastman Kodak Company Infrared sensitized, photothermographic article
US5583255A (en) * 1993-12-03 1996-12-10 Imation Corp. Yellow and magenta chromogenic leuco dyes for photothermographic elements

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