KR790000979B1 - Preparation of n-2-(6-hydroxybenzothiazolyl)-n'-phenyl (or substituted-phenyl)ureas - Google Patents

Abstract

Title compd. [I; R = H, (C1-C3) alkyl, (C1-C3) alkoxy or halogen was prepd. by hydrolyzation of 6-carbamoyl compound [IV of formula III. 2-Amino- 6-hydroxy benzothiazol reacted with phenyl isocyanate of formula II to give IV, and IV hydrolyzed with alkali metal hydroxides or carbonates, ammonium hydroxides in an inert solvent at a temp. not higher than 100≰C to give I, which is used as an immune regulant.

Description

Process for preparing N-2- (6-hydroxybenzothiazolyl) -N'-phenyl (or substituted phenyl) urea

The present invention relates to a process for the preparation of N-2- (6-hydroxybenzothiazolyl-N'-phenyl (or substituted phenyl) ureas useful as immune regulants.

The present invention relates to a method for preparing a compound of formula (I)

R is hydrogen or alkyl having 1-3 carbon atoms, alkoxy or halogen having 1-3 carbon atoms.

Reacting the benzothiazole of formula (V) with the substituted phenyl compound of formula (VI),

Where R is as described above

R ¹ and R ² are -N = C = O or NH ₂

When R ¹ is -NCO R ² is -NH ₂

When R ¹ is -NH _2, R ² is -NCO.

It is the selected protection.

Specifically, the compound of formula (I) is a 6-carbamoyloxy compound of formula (III) obtained by reacting a 2-amino-6-hydroxy benzothiazol compound with 1-2 moles of phenyl isocyanate. It is prepared by hydrolyzing an alkali metal hydroxide or carbonate, ammonium hydroxide, and (C ₁ -C ₂ ) alkyl-substituted ammonium hydroxide in an inert solvent at a temperature of 100 ° C. or lower.

R is hydrogen, alkyl having 1-3 carbon atoms, alkoxy having 1-3 carbon atoms, and halogen.

Alternatively, 2-amino-6-hydroxybenzothiazol and phenyl chloro formate are reacted to obtain 2-phenylcarbamate, which is reacted with excess trimethylsilylchloride to give 6-trimethylsilyloxy-2-benzothia. The compound of structural formula (I) can be prepared by synthesizing the zyl isocyanate and then treating with aniline of structural formula (IV).

Where R is as described above.

2-substituted benzimidazoles, benzochiazoles, and benzoxazoles have recently had several uses, mainly in the agricultural sector. For example, 2-trihulo methylbenzimidazoles are reported in British Patent No. 1,097,561 as extremely potent herbicides. The compounds contained therein are also reported to have mollusc killing, insecticidal and bactericidal activity. Other 2-substituted benzimidazoles have been found to have potent antisporicidal action. In particular 2- (4-thiazolyl) benzimidazole (thiabendazole) is currently commercially available as an antiparasitic agent. Some 2-hydroxybenzimidazoles also exhibit potent anti-viral properties. (See US Pat. No. 3,331,739). The use of benzoxazoles and benzothiazols in this field has not been as thoroughly researched and developed as the benzimidazoles, although considerable interest has been paid to the action of these compounds, in particular to the action of antispores.

Urea derivatives of this class are sometimes described in the literature.

N- (2-benzothiazolyl) -N'-phenylurea is described in Chem. Abs., 29, 2,660; 55 8, 389; 57 801, the corresponding 4-methyl compound is described in Chem. Abs 25, 104; 50, 1,776-1,777 and the corresponding 5-methoxy derivatives are described in Chem. Abs. 52, 20,673. N- (2-benzimidazolyl) -N'-phenylurea is described in Beilstein 24 (II), 62 and Chem. Abs. 15, 3,077. U.S. Patent No. 3,299,085 discloses N- (2-benzothiazolyl) or N- (2-benzoxazolyl) -N'-C ₁ -C ₅ -aliphatic ureas as intermediates for the preparation of some herbicides. U. S. Patent No. 3,162, 644 describes a 2-benzoxazolyl urea useful as a plant growth regulator and useful as a crude relaxant. US Patent No. 3,399,212; 3,336,191; And 3,401,171 describe benzimidazolyl ureas as an antiparasitic agent, and finally, South African Patent 68 / 4,748 (Derwent pharmdoc basic No. 36,565) describes benzimidazolyl ureas as disinfectant in cleaning agent compositions.

(IMURAN)

이다.In recent years, immunosuppressants have become prominent because they are used for organ transplantation, such as heart transplantation and especially kidney transplantation. Removing foreign antibodies (in this case, transplanted organs) is part of the defense mechanism. Therefore, in all organ transplant operations, it is necessary to administer a large amount of immunosuppressive before surgery and continue afterwards to prevent the host from rejecting the donor organ. An immunosuppressive drug is azachioprine, or immuran

(IMURAN)

to be.

(U.S. Patent No. 3,056,785)

Belgian Patent No. 744,970, issued July 27, 1970 (see British Patent No. 1,296,561, published November 15, 1972) contains N-2- (6-methoxybenzothiazolyl) -N'-phenylurea. A number of 6-substituted-benzothiazolylphenylureas have been described, including. These compounds are said to be useful as immunosuppressants and immunosuppressants.

The immune response is a biochemical response that drives two series of responses to cell transformation and foreign bodies (antigens). The cells involved in the reaction come from the hepatocytes produced in the bone marrow and settle in the peripheral lymphoid organs. Here, antigenic stimulation, followed by antibody response, takes place in the form of serum cells and specific immune lymphocytes that produce antibodies.

Antibodies are released into the circulatory system and work away from the producing cell. (Humoral immunity) Certain immune lymphocytes also enter the circulatory system and act at the site of injury. (Cellular immunity) The reaction of antibodies and antigens results in histamine release from basophil leukocytes; Histamine, in turn, alters the permeability of blood vessels, increasing the rate of entry of antibodies and specific immune lymphocytes into the injury site. Thus, the immune response consists of a series of biochemical reactions of cells in different parts of the body. In the case of the compounds discussed here, a number of biochemicals, i.e., can alter or inhibit the immune response at the site of reaction of cells.

Antihistamines only affect the secondary response in the immune response and have no direct effect on antibody-forming cells or specific immune lymphocytes. Many drugs that have recently been used as immunosuppressants act much later in the series of reactions called immune responses. Anti-inflammatory steroids such as cortisone not only inhibit the production of antibodies and specific immune lymphocytes, but also deplete normal lymphoid tissues and involve many side effects. Several anti-neoplastic drugs, such as azapofrin, cyclophosphamide, and methotrexate, are also used as anti-inflammatory agents, but they deplete normal lymphoid tissue and fundamentally lower the cells produced in other bone marrow. The general cytotoxicity of the latter drugs can be anticipated because they were chosen in consideration of their toxicity to a range of cells. In the above formula (I), alkyl having 1-3 carbon atoms includes methyl, ethyl, n-propyl, and isopropyl. Therefore, alkoxy having 1-3 carbon atoms includes methoxy, ethoxy, n-propoxy and isopropoxy.

"Halogen" includes fluorine, chlorine, bromine and iodine.

The compound of structural formula (I) has the following;

N-2- (6-hydroxybenzothiazolyl) -N '-(3-methoxyphenyl) urea

N-2- (6-hydroxybenzothiazolyl) -N '-(2-ethylphenyl) urea

N-2- (6-hydroxybenzothiazolyl) -N '-(4-n-propoxyphenyl) urea

N-2- (6-hydroxybenzothiazolyl) -N '-(2-chlorophenyl) urea

N-2- (6-hydroxybenzothiazolyl) -N '-(4-bromophenyl) urea

N-2- (6-hydroxybenzothiazolyl) -N '-(3-fluorofluoro) urea

N-2- (6-hydroxybenzothiazolyl) -N '-(4-iodophenyl) urea

N-2- (6-hydroxybenzothiazolyl) -N '-(2-ethoxyphenyl) urea

N-2- (6-hydroxybenzothiazolyl) -N '-(4-isopropoxyphenyl) urea

N-2- (6-hydroxybenzothiazolyl) -N '-(4-isopropylphenyl) urea

N-2- (6-hydroxybenzothiazolyl) -N '-(3-tolyl) urea

N-2- (6-hydroxybenzothiazolyl) -N '-(4-tolyl) urea and the like.

Compounds represented by Structural Formula (I) may be prepared by the following two synthetic methods with high melting point and white crystals. In both methods, the starting material is 2-amino-6-hydroxybenzothiazol as J. Org. Chem. 35, 4103 (1970), by condensing quinones and thioureas or by J. Hetero. Chem. 10, 769 (1975) can be prepared by demethylation of 2-amino-6-methoxy-benzothiazol.

In the first method, the 2-amino group of benzothiazol is carbamate with phenyl chloroformate, for example P-nitrophenylchloroformate, and this is followed by Angew. Chem. internat. Edit. 7, trimethylsilyl chloride according to 941 (1968). In this reaction, the trimethylsilyl group has two functions. The first converts the P-nitrophenyl carbamate group to an isocyanate group, and the second protects the free hydroxyl group of benzothiazol, preventing the free hydroxyl group and the isocyanate formed in the thiazole group from reacting. The 6-hydroxybenzothiazolyl-2-isocyanate thus produced is rapidly reacted with aniline or a suitably substituted aniline to prepare urea. When water is added to the reaction mixture, the trimethylsilyl group is hydrolyzed to obtain the compound of the present invention of formula (I). This synthesis reaction is well illustrated by the following scheme.

Phenyl chloroformmate used in Reaction Sequence I used P-nitro derivatives as an example, but other phenyl chloroformates can also be reacted with aminohydroxybenzothiazol. Examples are unsubstituted phenylchloroformate or tolylchloroformate. However, these other chloroformates require higher reaction temperatures and / or longer reaction times to decompose trimethylsilyl compounds to produce benzothiazolyl isocyanates. In addition, the silylation in reaction sequence I used trimethylsilyl chloride. But Greber and Kricheldorf cloc. As pointed out by cit.), either mono or bis (trimethylsilyl) acetamide can be used to prepare disilylated derivatives.

A second synthetic method for preparing the compound of formula (I) is obtained by reacting 1-2 mole (up to 100% excess) of phenyl isocyanate (RC ₆ H ₄ -NCO) with 2-amino-6-hydroxybenzothiazol. A reaction mixture containing a carbamoyloxy derivative (formula III) and some compounds of formula (1) is prepared.

The N-2- (6-phenylcarbamoyloxybenzothiazolyl) -N'-phenylurea (3) thus produced was 6-phenylcarbamoyl of benzothiazolyl urea in an inert solvent at a temperature of about 100 ° C. or less. The base is treated with oxy groups until the oxy groups are hydrolyzed to form compounds of formula (I).

The 6-phenylcarbamoyl compound produced in the isocyanate reaction is hydrolyzed in the original reaction mixture or in the initial separation step using the base soluble due to the phenolic properties of the 6-hydroxy group to become 6-hydroxy derivatives. The base-insoluble compound is separated off and then hydrolyzed. Of course-it is good to carry out the hydrolysis in the unreacted reaction mixture. The 6-hydroxyurea (I) already present or the 6-hydroxyurea produced by hydrolysis are not adversely affected under certain hydrolysis reaction conditions.

1 mole of phenyl isocyanate in the reaction of phenyl isocyanate (RC ₆ H ₄ -NCO) with 2-amino-6-hydroxybenzothiazol because the 2-amino group of benzothiazolyl reacts much faster than the 6-hydroxy group The reaction product is dominated by N-2- (6-hydroxybenzothiazolyl) -N'-phenylurea. However, the reaction between the hydroxy group and the phenyl isocyanate proceeds at an appropriate ratio. Therefore, if only 1 mole of isocyanate is used, the main reaction product is urea of formula (I), 2-amino-6-carbamoyloxybenzothiazol, N-2- (6-carbamoyloxybenzothiazolyl, as described above). ) -N'-phenylurea and unreacted starting material 2-amino-6-hydroxybenzothiazol. A sufficient amount, preferably 25-100% excess of phenyl isocyanate or substituted phenyl isocyanate, should be used to reinforce the 2-amino group of benzothiazol to the corresponding urea. Of course, it is not necessary to use an excess amount of 100% or more (two times molar relative to aminobenzothiazol). This is because in the presence of 2 moles of phenyl isocyanate to be substituted, all of the benzothiazol will be converted to 6-carbamoyloxyurea of formula (III).

If more than one mole of isocyanate and less than two moles of isocyanate are used per mole of benzothiazol, the reaction mixture will contain both 6-hydroxy and 6-carbamoyloxy derivatives. In any case, in order to obtain a large amount of 6-hydroxy compound, the 6-carbamoyloxy derivative produced in the isocyanate reaction has to be hydrolyzed with a base in an inert solvent up to about 100 ° C. Useful inert solvents include water and lower alkanols such as methanol and ethanol. Suitable bases include sodium hydroxide, hydroxides of alkali metals such as potassium hydroxide, sodium carbonates, carbonates of alkali metals such as potassium carbonate and substituted hydroxides such as ammonium hydroxide, triethyl ammonium hydroxide or trimethylammonium hydroxide Ammoniums are present. The reaction is generally carried out at reflux temperature of the solvent. For example, from 65 ° C. of methanol to 100 ° C. of water. As experts know, the higher the reflux temperature, the shorter the time required for hydrolysis. Similarly, solubility of bases in inert solvents is also important. Alkali metal hydroxides dissolve better than carbonates. Therefore, the use of hydroxide has a shorter reaction time than the use of carbonate. Generally, complete hydrolysis of the 6-phenylcarbamoyloxy compound takes 1-18 hours depending on the solvent, base and temperature, and also the nature of 6-phenyl (or substituted-phenyl) carbamoyl oxy.

The properties of isocyanates (RC ₆ H ₄ -NCO) not only affect the rate of hydrolysis of 6-phenyl (or substituted-phenyl) carbamoyloxy groups, but also the specific isocyanates and 2-amino-6-hydroxybenzothiazol. Affects the rate of urea formation relative to the rate of the various reaction products, in particular to the rate of 6-hydroxy others.

N-2- (6-hydroxybenzothiazolyl) -N'-phenylurea and other substituted phenylureas represented by structural formula (I) are useful antiviral agents and immunosuppressants.

An obvious way to prepare the compound of formula (I) would have been to demethylate the corresponding 6-methoxy ether with 48% HBr. This method proved to be ineffective and was found to be particularly unsuitable for the preparation of compounds of formula (I) wherein R is methoxy. This is because demethylation results in the formation of hydroxyl groups in both rings. However, the compound of formula (I) can be enzymatically demethylated. Because 6-methoxy compounds were found to be metabolites when administered to rats.

These compounds are useful for altering the immune response of mammals. Thus, these compounds can be classified as “immune inhibitors”, which are drugs that can reduce antibody formation against diproteins. This action is also characterized by an allergic reaction, which is part of the body's defense against foreign antigens. (This action is quite different from antihistamine action, which affects only the effects of histamine released by the antigen-antibody reaction.) Even in mammals, it should be noted that the action on this protein (antigen) is of the same form.

The ability of the compound of the above formula to change the immune mechanism in the host animal is measured by the following test. Intraperitoneal injection of the standard suspension of antigen, in this case, positive blood cells, is made of 5 groups of 20 g Swiss mice. The active ingredient is administered intraperitoneally to this antigen several hours before and after. On day 8 after antigen injection, mice were bled to collect serum from each group. Antibodies are measured by hemagglutination in this serum and the treatment and control groups are compared. Table I below shows the activity at the dose required to inhibit hemagglutinin titer in the treated compound of the test compound compared to the control.

In Table 1, the first column is the compound name, the second column is the route of administration, the third column is the dose, and the fourth column is the level of inhibition. In general, a potent immunosuppressive action showed inhibition of hemagglutination by four or more times.

TABLE 1

Other compounds were tested for immunosuppression in a similar assay as described above by individual serum assay methods. In the latter method, 5 x 10 ⁷ positive red blood cells are injected intraperitoneally into a group of 20 g Swiss mice. In each group of 10 rats, the test drug was administered at different doses for 3 days before administration of the antigen, red blood cells. Ten controls received only excipients and amounts of red blood cells. Seven days after administration of the antigenic amount of red blood cells, each rat is bleeded to measure the amount of antibody in the serum. In a similar experiment, oral predetermined doses of the test compound are administered orally for 10 days starting from 3 days prior to administration of 5 × 10 ⁷ red blood cells. The results are shown in Table 2. In the table, the first column is the compound name, the second column is the mg / kg body weight in the abdominal and oral doses, and the third column is the hemagglutinin ± logarithm of the base 2 standard error.

TABLE 2

* "<" Refers to one or more sera in the group where no hemagglutinin was detected in the dilution test.

** P <0.01-trust level.

The compounds are useful for preventing the host from rejecting the donor organ in organ transplant surgery. In addition to the use for such organ transplantation, immunosuppressants are useful for a number of diseases, mainly "self-immune" diseases, of unknown etiology. These diseases include autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, lupus erythematosus, lupus hepatitis, lupus nephritis, glomerulonephritis, kidney symptoms, goodpasture symptom, wegener's granulomatosis, scleroderma, cystic disease, psoriasis , Uveitis, rheumatoid arthritis, ulcerative colitis, thyroiditis, orchitis. Immune inhibitors are useful for the treatment of such diseases due to somewhat autoimmune mechanisms.

Routes of administration include oral, intraperitoneal, topical and subcutaneous administration. For oral administration, this immunosuppressant is dissolved or suspended in polyethylene glycol and mixed with corn oil at a rate of 1-200 mg / ml. Particularly useful as oral medulls are mixtures of 50% polyethylene 200, 40% corn oil and 10% polyoxyethylene sorbitol monostearate. Aqueous media with surfactant added are useful. For topical administration, the compound is administered with ethanol or the above polyethylene glycol-corn oil-surfactant and the like and subcutaneous injection should be used as an isotonic solution. The immunosuppressant is preferably in the ratio of 1-200 mg / ml relative to the carrier.

Unlike most conventional immunosuppressive mechanisms for mammalian hosts, heterocyclic ureas are useful for converting immune responses. These compounds act differently than antihistamines antagonize histamine action directly. On the other hand, they do not degrade the bone marrow, as are the anti-neoplastic agents commonly used in tissue transplantation. This heterocyclic urea compound is very similar to the corticoids in regard to the immune response, but there is essentially no such action in that the corticoids deplete lymphoid tissue.

Therefore, it is clear that this compound does not deplete normal lymphoid tissue and does not deteriorate bone marrow function, thus acting as a mechanism to avoid defects in widely used immunosuppressive or corticosteroid-based drugs and anti-neoplastic agents. Do.

The formulations and uses are described in the following examples. (PKa) values are all measured at 66% dimethylformamide / water).

Example 1

N-2- (6-hydroxybenzothiazolyl) -N'-phenylurea

J. Org. A slurry containing 16.7 g of 2-amino-6-hydroxybenzothiazole hydrochloride prepared according to the method of Chem 35,4103 (1970) was prepared in 300 ml of acetone and 11 g of potassium bicarbonate. It is stirred under anhydrous conditions while dropwise adding 22.4 g of P-nitrophenyl chloroformate in 300 ml of acetone to the is slurry. The reaction mixture is stirred for about 18 hours and then poured into 3 liters of water.

수화물로서 결정화된다.The reaction mixture is filtered to wash the 2-amino-6-hydroxy benzothiazolyl-P-nitrophenyl carbamate produced in the reaction with ether. This compound

It crystallizes as a hydrate.

H₂OElemental Analysis: C ₁₄ H ₁₉ N ₃ O ₄ S:

H ₂ O

Calc .: C 51.85; H 2.88; N 13.33

Found: C 51.74; H 3.40; N 12.74

A slurry containing 600 mg of the above carbamate was prepared in 25 ml of acetone and about 0.5 ml of acetone was added dropwise.

0.3 ml of trimethylsilyl chloride is added dropwise to the reaction mixture with a syringe and stirred at the surrounded temperature. The mixture was refluxed for 18 hours to yield a yellow solution. The reaction mixture is cooled, poured into water with stirring and filtered. The filtrate is washed with ether and dried. This filtrate contains N-2- (6-hydroxybenzothiazolyl) -N'-phenylurea having a melting point of 250 ° C. or higher and a yield of 60%.

Mass spectrometry: 285, 212, 192, 162: PKa = 10.9

Elemental Analysis: C ₁₄ H ₁₁ N ₃ O ₂ S

Calc .: C 58.93; H 3.89; N 14.73

Found: C 58.34; H 3.76; N 13.76

The following examples are prepared in the same manner as above.

N-2- (6-hydroxybenzothiazoline) -N '-(4-methoxyphenyl) urea;

PKa = 11.1; Mass spectrometry 315, 192, 166;

Melting Point: 250 ℃ or higher

H₂OElemental analysis: C ₁₅ H ₁₃ N ₃ O ₂ S

H ₂ O

Calc .: C 57.88; H 4.82; N 13.50

Found: C 57.42; H 4.27; N 13.18

N-2- (6-hydroxybenzothiazolyl) -N '-(2-fluorofluoro) urea;

Melting point of 250 ° C. or higher, 1 point in thin layer chromatography,

PKa = 10.3; Mass spectrometry 303, 192, 166

Elemental analysis: C ₁₄ H ₁₀ FN ₃ O ₂ S

Calc .: C 55.44; H 3.32; N 13.85

Found: C 55.28; H 3.47; N 13.31

N-2- (6-hydroxybenzothiazolyl) -N '-(2-tolyl) urea;

Melting | fusing point: 250 degreeC or more, 1 point in thin layer chromatography; PKa = 10.6

Elemental analysis: C ₁₅ H ₁₃ N ₃ O ₃ S

Calc .: C 57.13; H 4.16; N 13.33

Found: C 56.90; H 4.40; N 13.37

Example 2

N-2- (6-hydroxybenzothiazolyl) -N'-phenylurea (other method)

A slurry of 152 g of 2-amino-6-hydroxybenzothiazolyl is prepared in 3 liters of acetone. 109 g of phenyl isocyanate and 150 ml of acetone are added dropwise thereto, and after completion of the dropwise addition, the reaction mixture is heated at reflux overnight. The reaction mixture is cooled to about 50 DEG C, decolorized with activated charcoal, filtered and 109 g of phenyl isocyanate in acetone is further added to the filtrate. After refluxing again for 2 hours, white N-2- (6-phenylcarbamoyloxybenzothiazolyl) -N'-phenylurea precipitates. The precipitate is filtered off and washed with acetone.

Yield: 73%, melting point 250 ℃ or more

Elemental analysis: C ₂₁ H ₁₅ N ₄ O ₃ S

Calc .: C 62.52; H 3.75; N 13.89; S 7.95

Found: C 62.30; H 3.97; N 13.69; S 7.76

4 g of the above-mentioned N-2- (6-carbamoyloxybenzothiazolyl) -N'-phenylurea is dissolved in 150 ml of anhydrous methanol, and a 10% slurry of 0.5 g of sodium methylate in methanol is added while stirring.

The reaction mixture is stirred overnight at room temperature. Thin layer chromatography shows that the carbamoyloxy group is released at about 50% by hydrolysis. Again, the reaction mixture is slowly heated to continuously observe the reaction by thin layer chromatography.

After 2 hours of heating to about 45 ° C., the hydrolysis is substantially 100% complete. The mixture is cooled and carefully adjusted to pH 4 with 10% hydrochloric acid. N-2- (6-hydroxybenzothiazolyl) -N'-phenylurea is isolated and filtered and washed with methanol, ether. The NMR spectrum shows that there is no longer any phenyl-carbamoyloxy group.

In addition, the ultraviolet absorption spectrum shows the above facts. This gave N-2- (6-hydroxybenzothiazolyl) -N'-phenylurea, melting point of 250 ° C. or higher, mass spectrometry 285, 212, 192, 162;

PKa = 10.9 (66% DMF).

Elemental Analysis: C ₁₄ H ₁₁ N ₃ O ₂ S

Calc .: C 58.93; H 3.89; N 14.73

Found: C 58.34; H 3.79; N 13.76

Example 3

If a mixture of N-2- (6-phenylcarbamoyloxybenzothiazolyl) -N'-phenylurea 100 mg, sodium methylate 100 mg, and 25 ml of methanol was refluxed for 30 minutes, thin layer chromatography showed no starting material and the product was completely free. It is confirmed that it is a 6-hydroxy compound. The reaction mixture was refluxed for 18 hours to yield N-2- (6-hydroxybenzothiazolyl) -N'-phenyl urea without degradation.

Example 4

20 mg of potassium hydroxide was used in place of the sodium methylate of Example 3, to obtain the same procedure as in Example 3. After 6 hours, thin layer chromatography does not completely hydrolyze the 6-phenyl-carbamoyloxy group.

12 hours of further reflux confirms the completion of the hydrolysis and confirms that the starting material has been completely converted to the 6-hydroxy compound.

Example 5

Example 2 was carried out using 35 mg of potassium carbonate.

The hydrolysis takes 18 hours to complete.

Example 6

25 ml of water instead of methanol is used as in Example 4. The reaction mixture is slowly heated to dissolve the solid starting material at about 80 ° C. Reflux for 1 hour completes the hydrolysis of the 6-phenylcarbamoyloxy group.

Example 7

As Example 3, using 0.35 ml of triethylamine instead of sodium methylate. After 6 hours, the hydrolysis was completed.

Claims (1)

The benzothiazole of formula (5) is reacted with the substituted phenyl compound of formula (6) and the resulting compound is hydrolyzed to yield N-2- (6-hydroxybenzothiazolyl) -N'- of formula (I). Process for preparing phenyl (or substituted phenyl) ureas.

Where R is hydrogen or alkyl of 1-3 carbon atoms, alkoxy of 1-3 carbon atoms or halogen R ¹ and R ² are -N = C = O or NH ₂ When R ¹ is -NCO R ² is -NH ₂ When R ¹ is -NH _2, R ² is -NCO.

It is the selected protection stage.