DE1644647A1 - Process for the production of xanthene derivatives - Google Patents

Description

PATENT ADVOCATE

DIPL-ING. ADOLF SPREER

3 HANOVER

ABBESTRASSE 20 TELEPHONE 83 45 30 PATENT ADVOCATE

DiPL.-PHYS. DR. W. JUNIUS

16U647

Vi. July 1965

Heine file: 9B66 Dr. J./Hl.

3P0FÄ odr-uzeni podniicu pro zdravotnickou vyrobu F r a h a 3 I-Iusineoka 11a

Process for the preparation of Xanthendei'ivataa

The invention "relates to a process for the production of Xanthene derivatives of the general Je onael X

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Ln i. oils GrupOü -C. odor- ,, U-.,) (---,) and Ί5 the oxygen-; u 'we ¹ (LL ^ iru £ .Eiu - -' (a - ^) v,) u & aeutüt, v / ccei the: . .'Juosti- ; itiui ι ·. ·; .-. ύ _ο ,: ^ iolJ :. O'i. i. ¹ Ytirtün Ls ten, fur ^ v l.! C.7 "lr ds te

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16U647

The named derivatives, which have the character of dyes, are used in microbiological practice as hardening substances for the detection of various biologically important substances, such as antigens and the like.

In the known processes for the preparation of compounds of the general formula I, if A is the OH group, 4-nitrophthalic acid is used, which can be converted into a mixture of 4- '- and 5 ¹ - by condensation with resorcinol. Nitrofluores ^ Ln transferred. The mixture of the two isomers can be separated using the corresponding diacetyl derivative. ! laughing alkaline saponification reduced to the Nitrofluoreszein obtained by hydrogenation in alcohol under / SE OF Faney nickel as a catalyst, "The obtained 4 '- and 5 ¹ -Aminofluoreszein is then acidic aqueous-by reaction with thiophosgene in one or acetonic medium in 4' - or 5 '-fluorescein isothiocyanate transferred (J.Exp.Med. 91, 1, 1950).

The preparation of compounds of the general formula I,

Θ /

ν; or in λ the group -IT (R-KR ₉ ) and B the group = I7 (R -) (R ₂ ) means, is analcgic, instead of resorcinol is used for

Condensation ^ with the 4-Hitrophtal3äure n-Dialkylami nO- phenol and. ^ en according to the reaction ruit Thi:.: - hoaxer.

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a 4 'or 5' aminorhodamine derivative (Am.J.Pathol. 34, 1087, 1958; British patent 846,674).

The disadvantage of the manufacturing process mentioned lies in working with thiophosgene, which is used as a health <~ dangerous connection is known and which is difficult and is available in low yield.

It has been found that maij xanthene derivatives of the general formula I can be obtained more advantageously and more easily, according to the present invention, which is characterized in
that one ^ a compound of the general formula II

ir

wherein A and .α are the same as in formula I, through Reaction lait carbon disulfide in an "alkaline"

reacting aqueous LcslliiT in the corresponding 009838/0493

Overfilled dithic carbamate, which reacts with a soluble ^ς α1ζ of a heavy metal, such as iron, mercury, copper or lead, to give the compound of the general formula I.

A centered aqueous ammonia solution is preferably used as an alkaline reacting aqueous solution. The reaction of the compound of general formula II with carbon disulfide can be carried out at temperatures of from ⁰ ° C to f 'O ^c C, preferably perform C-5 at a temperature of ⁰ C to 2O ^0th As a soluble heavy metal salt, iron trichloride is best.

The flagging according to the invention, which is based on known Reaction of the amines with Sch'.vefelkcarbonstoff and conversion " of the resulting dithiocarbamate is based in isothiocyanate with the help of Schwendetail salts, which enables bypassing the unpleasant! manipulation with the dangerous thiophosgene, whereby the quality of the obtained products is preserved.

In general-one proceeds in such a way that one leads to a solution or suspension of 1 liter of the starting compound of the general formula II in an alkaline oil, which • e.g. 1 to 1 * 5 -oil contains ammonia at one temperature

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from O ⁰ O to 30 ⁰ O carbon disulfide in an amount of 1 - 15 mol is added dropwise. They are acidified for 2 - 1 hour

Reaction mixture. The yield is quantitative diesemPalle If you als'Ausgangsverbindung the general formula II rhodanine my μ ver / ends, it is the reaction _naoh?; tion with the heavy metal salt necessary to alkalize the reaction mixture again with sodium bicarbonate, to mask the metal, if necessary to extract the product with a suitable organic, water-immiscible solvent, for example chloroform. The obtained crude isothiocyanates contain about 1 - 3 $> of water-insoluble metal salts, which can easily be removed in a known manner, e.g. by acidifying an icetone solution with a calculated amount of hydrochloric acid (if an iron salt is present) «

■ Examples

14 ^ 4 '-Aminofluoreszein are added with stirring naoh and gradually in yi'j ml' jnz. v / üoriger Airimoniaklösuni; pledged, _ The Le

bU'l, ij, ß'l BAD OBfÖlNAL

■ ■■ - £ - ■

of the 4 ¹ -Aminofluoreszeinammoniumaalzes is ^{saturated at 5 0} C with ammonia gas. Thereafter are added dropwise to this solution with vigorous stirring over 2 hours 28 ml of freshly distilled carbon disulfide in such a way that the temperature does not exceed 1O ⁰ C. The induction mixture is stirred for four hours at room temperature and a solution of 100 g of iron trichloride (PeCl ^ _# 6 H 0) in 400 ml of water is slowly added. The resulting B_-egg is stirred for 1/2 hour and then acidified with 15% hydrochloric acid to pH 2 at a temperature not exceeding ^{10 ° C.} After complete excretion, the 4 ^f -fluorescein isothiocyanate formed is suctioned off, washed with water and dried either in the open air or, better, in a vacuum. The yield is quantitative. This product, which contains about 1 - y / a iron ( _{calculated as Pe 2} O ^), leaves me z..3 » _; Clean in the container so that 5 g are dissolved in 35 ml of acetone, the solution is filtered, ^{cooled to 0} ° C. and acidified with 7 ml of 1 IT HCl. After thorough stirring, this solution is poured into 250 ml of soda water a. Dss precipitated isothiocyanate 3 _e is from UGT, v / äscLt nit water and dried freely in air .. the 3i33n2enc.lt decreases below ~, 1 "'j' the 4 '-Pluoreszeinisfitiiiozyanat provides an orange substance-ar d, whose slogans ir U ^- VL ic lit a bt-.r! -: e böller "re Pluorsssenz zei ^ cj ... ·" D-.η! .laximurr. äer;. "Cn-j-ru £ ^ i. infrared ÜpeL'tru '..

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lio.; t Ir.? ΚΌ G-.

0.0 9 8 3 8 / ΰ 4 9 3.;.

BATH

2. A suspension of 1.8 g of 4 '-amino-rhodamine B in 6 ml of conc. aqueous ammonia solution is saturated with ammonia gas ^{at 0 0 O.} Thereafter, stirring vigorously within. 2 hours 3.8 ml of freshly distilled carbon disulfide was added dropwise, v / obei held the temperature at 10 ⁰ C. The reaction mixture is stirred for a further 8 hours at room temperature, a solution of 12.5 g of FeCl - Acidified 2. The resulting solution, which contains 4'-rhodanine, B-isothiocyanate and bisentyl chloride, is made alkaline with lithium bicarbonate and extracted with 100 ml of chloroform concentrated to 10 ml and the isothlosyanate is precipitated with petroleum ether.

One can at; ch procedure so that one au of the solution of 4 ¹ -Kbo- olamine B-Isothiosyanats and Eiseiitrichlorids according Filtr ^ rs ;: a solution of tartaric acid is added in excess, and this mixture with an Sodalcsung on ρΐΐ S - alkalized 9 . The excreted product is suctioned off and washed with water. The obtained 4 '-Rliciamine B-isothiocyanate is a red-brown powder-like substance, its solutions

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starl'i fluoresce orange-red. The Ilaximum, the ITCS-G group in the infrared spectrum is "at 2100 cm".

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Claims (4)

P at e nt a η s ό r u c h e Process for the preparation of xanthene derivatives of the general formula I. HOS where A is the group.-OH or -E (H ₁ ) (Rp) vrA Έ d..s? ^a uerstoff-- atom or the group «■■ ET (Rj) (Rg), wherein the substituents R and Rp is equal to: or different, Allcylreste nit 1-7"'ohlenstoffatonien steken,
marked thereby, "" ■ "". '"
dais Lian a connection. the general formula II - ίο -. wherein A and B are the same as in formula I, through Realrfcion with carbon disulfide in an alkaline reacting aqueous solution into the corresponding dithiocarbamate touched, which by reaction with a soluble salt of a heavy metal, such as iron, mercury, Copper or lead, the compound of general formula I provides. 2. The method according to claim I,
characterized, that one as an alkaline reacting aqueous solution a concentrated aqueous ammonia solution is used. 3 »Method according to claims 1 and 2,
characterized, that the reaction of the compound of the general Forfe mel ⁰ C to 5O ⁰ O, preferred rates carried out at a temperature of 5 ° C to 2O ⁰ C II with carbon disulfide at a temperature of O. 4. The method according to claim 1, 2 and 3, characterized in that
that nan as a heavy metal salt · the sis trichloride used" 009838/0493