KR810000556B1 - Process for preparation of nitrosourea compounds - Google Patents

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Description

Preparation of Nitroso Urea Compounds

The present invention relates to the preparation of nitroso urea compounds. More specifically, the present invention is a general formula:

Wherein R ¹ is alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkenyl of 3 to 5 carbon atoms or alkynyl of 3 to 5 carbon atoms , R ² is aldofento pranosyl, aldofento pyranosyl, aldo-hexopyranosyl, 0-aldo-hexopyranosyl- (1 → 4) -aldo-hexopyranosyl, or general formula: -CH ₂ (CHOH) _n CH ₂ OH, where n is 0 or an integer from 1 to 4) (N'-chloroethyl-N'-nitroso carbamoyl) -amino derivatives of monosaccharides are alkali metal nitrites such as sodium nitrite It is well known to the general public to prepare nitro (N'-chloroethyl carbamoyl) amino-monosaccharides. (Japanese Patent Application Nos. 31131/1975, 90266/1974 and 124319/1974, respectively published in No. 108043/1976, 26876/1976 and 52128/1976), and these patent applications also include 1- (2-chloroethyl)- 1-nitroso-3-D-mannopyranosyl urea and 1- (2-chloroethyl) -1-nitroso-3-D-glucopyranosyl urea (the latter compound is hereinafter referred to as "GANU") It has been reported to extend the lifespan of young rats implanted with lymphoid leukemia L-1210 tumor cells in the abdominal cavity. Also, disaccharides such as 1- (2-chloroethyl) -1-nitroso-3-D-lactosyl urea and 1- (2-chloroethyl) -1-nitroso-3-D-maltosyl urea ( N'-chloroethyl-N'-nitroso carbamoyl) amino derivatives are prepared from the corresponding (N'-chloroethyl carbamoyl) amino-2saccharides in the same manner as described above to provide antitumor activity against leukemia cells. It is known to the public.

(Japanese Patent Application No. 64073/1975, published as No. 141815/1976).

The Nitroso urea compound [I] of the present invention has been found to be useful for suppressing the growth of malignant tumor cells of warm-blooded animals by showing the action of anti-tumor or anti-leukemia with low toxicity.

For example, the antitumor effect on leukemia was continued in the abdominal cavity for 5 days (ie, rats injected with leukemia L-1210 tumor cells) inoculated with tumor cells. Dose 1.0 mg / kg 1- (2-chloroethyl) -1-nitroso-3-isobutyl-3-D-galacto pyranosyl ureana daily dose 0.9 mg / kg 1- (2- Chloroethyl) -1-nitroso-3-isobutyl-3- [0-α-D-gluco pyranosyl- (1 → 4) -Dgluco pyranosyl] urea is approximately 30% of the average lifespan of these mice. Indicates an extension.

1- (2-Chloroethyl) -1-nitroso-3-n-butyl-3-D-glucopyranosyl urea, 1- (2-chloroethyl) -1, for Ehrlich's ascites tumor -Nitroso-3-isobutyl-3-D-galacto pyranosyl urea and 1- (2-chloroethyl)-1-nitroso-3-isobutyl-3- [0-α-D-gluco pyranosyl -(1 → 4) -D-Glucopyranosyl] The urea's prophylactic effect is 1- (2-chloroethyl) -1 published in TP Johnson and others 9892 (1966). It is also 8 to 16 times stronger than the effect of nitroso-3-cyclohexyl urea (CCNU: R ¹ = H, R ² = cyclo hexyl).

In addition, the nitroso urea compound [I] of the present invention showed low toxicity and high safety for use as an anti-tumor agent.

For example, the cure rate is the maximum extension in the life of a saeangjwi inoculated with the appropriate dosage (tumor cells with respect to the case of leukemia L-1210 ILS _{30 (30%} minimum daily dose showing the extension of the life of the saeangjwi) 1- (2-chloroethyl) -1-nitroso-3-isobutyl-3- [0-α-D-gluco pyranosyl- (1 → 4)- D-gluco pyranosyl] urea was more than 10 times more effective than CCNU and GANU.

Compound [I] also showed a maximum dose (100% inhibition of growth of pluripotent tumors) to 100% inhibition of the growth of pluripotent tumors of Erich in rats without death of the mice. It is characterized by the high treatment rate estimated by the ratio of ().

For example, 1- (2-chloroethyl) -1-nitroso-3-n-butyl-3-D-galacto pyranosyl urea, 1- (2-chloroethyl) -1-nitroso-3- Isobutyl-3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea and 1- (2-chloroethyl) -1-nitroso-3- (2- The treatment rate (maximum dose, minimum dose) of propenyl) -3-L-arabino pyranosyl urea is three times more than that of GANU and CCNU.

Compound [I] of the present invention also exhibits low bone gain.

In the general formula [I], a group represented by a typical example of R ¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, isopentyl, Linear or branched alkyl, 2-n-propenyl, such as neopentyl, 1-methylbutyl, 1-ethylpropyl, tertiary pentyl, n-hexyl, 2-methylpentyl, isohexyl and 3,3-dimethylbutyl, Straight or branched chain alkenyl, 2-propynyl, 2-butynyl, 3-n-butynyl, such as 2-methyl-2-n-propenyl, 2-n-butenyl and 3-n-butenyl, and Alkynyl, such as 2-methyl-3-butynyl, and hydroxyalkyl, such as 2-hydroxyethyl and 3-hydroxy-n-propyl. On the other hand, groups represented by representative examples of R ² include aldo-pentopranosyl, such as D-ribofuranosyl and D-deoxyribofuranosyl, aldo- such as L-arabino pyranosyl and D-xyl pyranosyl; Aldo-hex pyranosyl, 0- such as pento pyranosyl, D-gluco pyranosyl, D-galacto pyranosyl, D-mannopyranosyl, L-rhamnopyranosyl, D-fucopyranosyl and D-talofyranosyl, 0- α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl (= D-maltosyl) and 0-β-D-galacto pyranosyl- (1 → 4) -D-0-glucophyra 0-Aldo-hex pyranosyl- (1 → 4) -aldo-hex pyranosyl, such as nosyl (= D-lactosyl), 2-hydroxyethyl, 2,3-dihydroxy-n-propyl, 2 General formula such as, 3,4-trihydroxy-n-butyl, 2,3,4,5-tetrahydroxy-n-pentyl and 2,3,4,5,6-pentahydroxy-n-hexyl : Group of CH ₂ (CHOH) nCH ₂ OH.

Among the compounds of the invention, suitable compounds are those in which R ¹ is alkyl of 1 to 5 carbon atoms, alkenyl of 3 to 4 carbon atoms, alkynyl of 3 carbon atoms or alkynyl of 2-hydroxyethyl, and R ² is D -Aldo-pentopranosyl, D- or L-Aldo-pentopyranosyl, D- or L-Aldo-hexopranosyl, 0-α-D-Aldo-hexopyranosyl- (1 → 4) -D- General formula wherein aldo-hex pyranosyl or n is 0 or an integer from 1 to 4, -CH ₂ (CHOH) nCH ₂ OH, the compound of general formula [I].

Other suitable compounds are those in which R ¹ is alkyl of 1 to 5 carbon atoms or alkenyl of 3 to 4 carbon atoms, R ² is D-gluco pyranosyl, D-galacto pyranosyl, D-mannopyranosyl, D-ch Silopyranosyl, L-arabino pyranosyl, 0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl, or a formula wherein m is an integer of 1,2 or 4: -CH ₂ (CHOH ) m-CH ₂ OH is a compound of the general formula [I].

Another suitable compound of the invention is R ¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl, 2-n-propenyl, 2-methyl- 2-n-pyrophenyl, 2-n-butenyl or 3-n-butenyl, R ² is D-gluco pyranosyl, D-galacto pyranosyl, L-arabino pyranosyl, 0-α-D A compound of formula [I], which is -glucopyranosyl- (1 → 4) -D-gluco pyranosyl, 2,3-dihydroxy-n-propyl or 2,3,4-trihydroxy-n-butyl to be.

The most suitable compounds of the present invention are also R ¹ is n-butyl, isobutyl or 2-methyl-2-n-propenyl, R ² is D-galacto pyranosyl, L-arabino pyranosyl or 0-α. It is a compound of the general formula [I] which is -D-glucoy pyranosyl- (1 → 4) -D-glucoy pyranosyl.

According to the present invention, the nitroso urea compound [I] is represented by the general formula R ¹ and R ² as defined above:

It is prepared by nitrosation of a compound with

Starting compound [II] is easily obtained.

(여기서, R¹과 R²는 위에서 정의한 바와 동일하다)의 2차 아민을 이루고, 그 다음 이 2차 아민을 2-클로로에틸 이소시안산 염으로 적당한 용매(예를 들면,테트라히드로푸란,메탄올,에탄올)에서 0°내지 30℃로 축합하여 제조할 수 있다.For example, a primary amine of the general formula: R ¹ -NH ₂ , where R ¹ is the same as defined above, may be substituted with the general formula: R ² -X, where R ² is as defined above and X is hydroxyl Or halogen) and condensed in an inert solvent (eg, methanol, ethanol) at about 20 ° to 80 ° C.

(Wherein R ¹ and R ² are the same as defined above), and the secondary amine is then substituted with a 2-chloroethyl isocyanate salt with a suitable solvent (e.g., tetrahydrofuran, methanol , Ethanol) can be prepared by condensation at 0 ° to 30 ° C.

Nitriding of the present invention is achieved by contacting compound [II] with nitrous acid, nitrogen trioxide or nitrogen tetraoxide in a suitable solvent. The reaction is suitably carried out at temperatures between -20 ° and 20 ° C, in particular between about 0 ° and about 5 ° C.

Water, lower alkanols (e.g., methanol, ethanol), tetrahydrofuran, methylene chloride, ethyl acetate, acetic acid, formic acid and the like are suitable as inert solvents.

Free nitrite is used as alkali metal salt of nitrite (e.g. sodium nitrite, potassium nitrite) or lower alkyl esters thereof (e.g. butyl nitrite, amyl nitrite) to mine or organic acid (e.g. hydrochloric acid, sulfuric acid, formic acid, It is suitable to use the above-mentioned free nitrous acid for the preparation by reacting with isotropic acetic acid) and nitriding it.

On the other hand, when nitrogen trioxide or nitrogen tetraoxide is used in the present invention, the starting compound [II] is dissolved in a suitable inert solvent, and then gaseous nitrogen trioxide or tetraoxide is added thereto with or without an acid acceptor. It is suitable to introduce and carry out nitriding reaction. Sodium bicarbonate, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate and the like are suitable as acid acceptors.

When the nitriding reaction is completed, the compound [I] of the present invention is easily recovered from the reaction mixture and can be further purified by silica gel chromatography if necessary.

The Nitroso urea compound [I] thus obtained is a variety of tumor cells such as Erich's carcinoma, sarcoma 180, leukemia L-1210, Lewis's carcinoma, Yoshida's sarcoma, rat ascites liver cancer, etc. Show potent anti-tumor activity against.

This is useful for prolonging the survival of warm-blooded animals and / or minimizing the growth of the aforementioned cancers in these animals.

It is also used to treat malignant lymphomas, leukemias, gastric tumors, liver cancers and other malignancies.

Nitroso urea compound [I] can be used for preparation in the form of a pharmaceutical suitable for oral or parenteral administration. Compound [I] can also be used in combination or mixed with pharmaceutical excipients. The excipient selected should be one that does not react with compound [I].

Suitable excipients include, for example, colloids, lactose, glucose, sodium chloride, starch, magnesium stearate, talc powder, vegetable oils, and the like, and generally known pharmaceutical excipients and the like can be used.

Pharmaceutical preparation may be in the form of tablets, pills or capsche rates or liquid dosages such as solutions, suspensions or emulsions coated with a solid dose body such as a tablet.

Compound [I] can also be used in the form of injections or suppositories when administered parenterally.

Pharmaceutical formulations may be sterilized or may contain adjuvants such as preservatives and stabilizers.

The dosage of the compound [I] for preparation depends on the route of administration, namely the age, weight and condition of the patient and the particular disease to be treated. In general, an amount of 0.1 to 30 mg / kg, in particular 0.2 to 10 mg / kg, per day can be used for pharmaceutical purposes.

Substantial embodiments of the present invention will be apparently described as the following examples.

As used herein, the terms "lower alkanol" and "lower alkyl" refer to alkanol or alkyl of 1 to 6 carbon atoms.

Example 1

(1) A mixture of 3.6 g of D-glucose and 10% methylamine-methanol solution is heated to 60 ° C. for 20 minutes in a sealed tube.

The reaction mixture is concentrated to dryness under reduced pressure to obtain 3.8 g of 1-methylamino-1-deoxy-D-glucose as a crude product.

3.8 g of this crude product are dissolved in 40 ml of methanol, and a solution of 2.5 g of 2-chloroethyl isocyanate added to 10 ml of tetrahydrofuran is added dropwise at 0 ° to 5 ° C.

The solution is stirred at the same temperature for 1.5 hours.

The reaction solution is then concentrated under reduced pressure, and a mixture of ethyl acetate and ether is added to the residue.

Thus, 4.5 g of 1- (2-chloroethyl) -3-methyl-3-D-gluco pyranosyl urea is obtained as colorless caramel.

(2) 1.2 g of 1- (2-chloroethyl) -3-methyl-3-D-glucopyranosyl urea was dissolved in 10 ml of formic acid, and 0.56 g of sodium nitrite was dissolved at 0 ° to 5 ° C. Add with stirring.

The mixture is stirred for another 1.5 hours at the same temperature to react and then the mixture is lyophilized.

The residue thus obtained was purified by silica gel chromatography (solvent: chloroform-ethyl acetate-methanol (2: 1: 1)) and 0.6 g of 1- (2-chloroethyl) -1-nitroso-3-methyl- 3-D-Gluco pyranosyl urea is obtained as a pale yellow powder.

Example 2

80 g of tetrahydrofuran and 80 ml of 3.0 g of 1- (2-chloroethyl) -3-methyl-3-D-glucopyranosyl urea prepared in the same manner as described in Example 1- (1) Is dissolved in a mixture of methylene chloride, and 15 g of anhydrous sodium carbonate is added thereto.

5 g of nitrogen tetraoxide gas is introduced into the mixture under ice cooling for 10 minutes.

The mixture is further stirred at the same temperature for 10 minutes to react, and then 10 ml of methanol and 3 ml of water are added to the mixture, the mixture is stirred for 10 minutes, and the mixture is dried, filtered and evaporated to remove the solvent.

The resulting residue was then purified by silica gel chromatography (solvent: ethyl acetate-chloroform-methanol (5: 2: 1) and 2.4 g of 1- (2-chloroethyl) -1-nitroso-3-methyl-3- D-gluco pyranosyl urea is obtained as a pale yellow powder Melting point: 69 ° C (decomposition)

Example 3

(1) 3.6 g of D-glucose, 1.1 g of ethylamine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 1- (1) to 5.5 g of 1- (2 -Chloroethyl) -3-ethyl-3-D-gluco pyranosyl urea is obtained as colorless caramel.

(2) 6.0 g of 1- (2-chloroethyl) -3-ethyl-3-D-gluco pyranosyl urea is dissolved in 15 ml of formic acid, and 4.0 g of sodium nitrite is dissolved therein at 0 ° to 5 ° C. Add slowly with stirring for 1 hour.

The mixture is stirred for another 20 minutes at the same temperature, and then 100 ml of ether-hexane (1: 1) is added to the reaction mixture, and the oil produced therefrom is collected.

The oil is washed with ether, and then 100 ml of methylene chloride-methanol (5: 1) is added to the oil, and the insolubles are filtered off.

The filtrate was evaporated to remove the solvent, and the residue was purified by silica gel chromatography (solvent: chloroform-ethyl acetate-methanol (2: 1: 1) to give 2.0 g of 1- (2-chloroethyl) -nitroso- 3-ethyl-3-D-glucopyranosyl urea is obtained as pale yellow caramel.

Example 4

3.1 g of 1- (2-chloroethyl) -3-ethyl-3-D-gluco pyranosyl urea is dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of anhydrous sodium carbonate is added thereto. Add.

5 g of nitrogen tetraoxide gas is introduced into the mixture under ice cooling for 10 minutes.

This mixture is treated in the same manner as described in Example 2 to give 2.6 g of 1- (2-chloroethyl) -1-nitroso-3-ethyl-3-D-gluco pyranosyl urea as pale yellow caramel.

Example 5

(1) A mixture of 3.6 g of D-glucose, 1.3 g of n-propylamine and 15 ml of methanol is heated at 60 ° C. for 30 minutes.

The reaction mixture is concentrated to dryness under reduced pressure and the residue is washed with ether to give 4.4 g of 1-n-propylamino-1-deoxy-D-glucose as crude product.

4.4 g of this crude product are dissolved in 50 ml of methanol, and a solution of 2.5 g of 2-chloroethyl isocyanate added to 10 ml of tetrahydrofuran is added dropwise at 0 ° to 5 ° C.

The reaction solution is concentrated under reduced pressure while stirring the solution at room temperature for 1 hour.

The residue thus obtained is dissolved in 20 ml of formic acid and allowed to stand at room temperature for 20 minutes.

To this solution was added 200 ml of an ether-N-hexane mixture (1: 1) and the resulting oily product was washed repeatedly with ether to give 5.0 g of 1- (2-chloroethyl) -3-n-propyl-3- D-gluco pyranosyl urea is obtained as brown caramel and, if necessary, purified by silica gel chromatography (solvent: chloroform-ethyl acetate-methanol (1: 1: 1)) to obtain colorless caramel.

(2) 4.5 g of 1- (2-chloroethyl) -3-n-propyl-3-D-glucopyranosyl urea is dissolved in 20 ml of formic acid, and 2.8 g of sodium nitrite is 0 ° to 5 Add slowly with stirring for 1 hour at < RTI ID = 0.0 >

The mixture was stirred for an additional hour at the same temperature, and then 20 ml of methanol was added to the reaction mixture. The mixture is neutralized with potassium carbonate under ice cooling, and then 150 ml of ethyl acetate is added to the mixture, and the insolubles are filtered off.

The filtrate is washed with aqueous sodium bicarbonate solution, dried and evaporated to remove the solvent.

The residue thus obtained was purified by silica gel chromatography (solvent: methanol-chloroform (1: 5)) to obtain 1.5 g of 1- (2-chloroethyl) -1-nitroso-3-n-propyl-3-D. Glucopyranosyl urea is obtained as a pale yellow caramel.

Example 6

3.3 g of 1- (2-chloroethyl) -3-n-propyl-3-D-gluco pyranosyl urea is dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of anhydrous is added thereto. Sodium carbonate is added.

5 g of nitrogen tetraoxide gas is introduced into the mixture under ice cooling for 10 minutes.

This mixture was treated in the same manner as described in Example 2 to give 2.6 g of 1- (2-chloroethyl) -1-nitroso-3-n-propyl-3-D-gluco pyranosyl urea as a yellow caramel. Get

Example 7

(1) 3.6 g of D-glucose, 2.0 g of isopropylamine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 5- (1) to 4.8 g of 1- ( 2-Chloroethyl) -3-isopropyl-3-D-gluco pyranosyl urea is obtained as colorless caramel.

(2) 6.0 g of 1- (2-chloroethyl) -3-isopropyl-3-D-gluco pyranosyl urea are dissolved in 50 ml of 10% hydrochloric acid, and 6 g of sodium nitrite is 0 ° to 5 Add slowly with stirring at ° C.

The mixture is stirred for 10 minutes at the same temperature.

The reaction mixture is extracted with ethyl acetate.

The extract is washed with aqueous sodium bicarbonate solution and evaporated to dryness to remove solvent.

The residue thus obtained was purified by silica gel chromatography (solvent: chloroform-methanol (5: 1)) to give 2.0 g of 1- (2-chloroethyl) -1-nitroso-3-isopropyl-3-D- Gluco pyranosyl urea is obtained as pale yellow caramel.

Example 8

(1) 3.6 g of D-glucose, 1.7 g of n-butylamine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 5- (1).

5.0 g of 1- (2-chloroethyl) -3-n-butyl-3-D-gluco pyranosyl urea is obtained as colorless caramel.

(2) 2.2 g of 1- (2-chloroethyl) -3-n-butyl-3-D-gluco pyranosyl urea is dissolved in 10 ml of formic acid, and 1 g of sodium nitrite is 0 ° to 5 ° C. Add slowly for 40 minutes with stirring at.

The mixture is stirred for another 1.5 hours at the same temperature, and then the mixture is treated in the same manner as described in Example 5- (2).

Thus 1.0 g of 1- (2-chloroethyl) -1-nitroso-3-n-butyl-3-D-gluco pyranosyl urea is obtained as pale yellow caramel.

Example 9

3.4 g of 1- (2-chloroethyl) -3-n-butyl-3-D-gluco pyranosyl urea is dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of Anhydrous sodium carbonate is added.

5 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes under ice-cooling.

The mixture was treated in the same manner as described in Example 2 to give 2.9 g of 1- (2-chloroethyl) -1-nitroso-3-n-butyl-3-D-gluco pyranosyl urea as a yellow caramel. Get

Example 10

(1) 3.6 g of D-glucose, 2.5 g of isobutylamine and 2-chloroethyl isocyanate were treated in the same manner as described in Example 5- (1) to 5.0 g of 1- (2-chloro Ethyl) -3-isobutyl-3-D-gluco pyranosyl urea is obtained as colorless caramel.

(2) 3.4 g of 1- (2-chloroethyl) -3-isobutyl-3-D-glucopyranosyl urea is dissolved in a mixture of 70 ml of tetrahydrofuran and 70 ml of methylene chloride, and 15 g of Anhydrous sodium carbonate was added.

5 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes while stirring under ice cooling.

This mixture is treated in the same manner as described in Example 2 to give 2.8 g of 1- (2-chloroethyl) -1-nitroso-3-isobutyl-3-D-gluco pyranosyl urea as a yellow caramel. .

Example 11

(1) 3.6 g of D-glucose, 2.1 g of n-pentylamine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 5- (1) to 6.5 g of 1-. (2-Chloroethyl) -3-n-pentyl-3-D-gluco pyranosyl urea is obtained as dark blue caramel.

(2) 3.5 g of 1- (2-chloroethyl) -3-n-pentyl-3-D-gluco pyranosyl urea is dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride and 15 g of anhydrous sodium carbonate are added.

5 g of nitrogen tetraoxide gas is introduced into the mixture under ice cooling for 10 minutes.

This mixture was treated in the same manner as described in Example 2 to give 3.1 g of 1- (2-chloroethyl) -1-nitroso-3-n-pentyl-3-D-gluco pyranosyl urea as a yellow caramel. Get

Example 12

(1) 3.6 g of D-glucose, 2.5 g of n-hexylamine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 5- (1) to 6.8 g of 1-. (2-Chloroethyl) -3-n-hexyl-3-D-gluco pyranosyl urea is obtained as a brownish caramel.

(2) 4.3 g of 1- (2-chloroethyl) -3-n-hexyl-3-D-gluco pyranosyl urea are dissolved in 15 ml of formic acid, and 2.4 g of sodium nitrite is 0 ° to 5 Add slowly for 1 hour with stirring at ° C.

The mixture is further stirred at the same temperature for 1.5 hours to react and then the mixture is treated in the same manner as described in Example 5- (2).

Thus, 1.8 g of 1- (2-chloroethyl) -1-nitroso-3-n-hexyl-3-D-gluco pyranosyl urea is obtained as a yellow oil phase.

Example 13

3.7 g of 1- (2-chloroethyl) -3-n-hexyl-3-D-gluco pyranosyl urea is dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of anhydrous is added thereto. Sodium carbonate is added.

5 g of nitrogen tetraoxide gas is introduced into the mixture under ice cooling for 10 minutes.

The mixture was treated in the same manner as described in Example 2 to give 3.1 g of 1- (2-chloroethyl) -1-nitroso-3-n-hexyl-3-D-gluco pyranosyl urea as a yellow oil phase. Get

Example 14

(1) 4.5 g of 1- was treated with 3.6 g of D-galactose, 1.5 g of n-propylamine and 2.5 g of 2-chloroethyl isocyanate in the same manner as described in Example 5- (1). (2-Chloroethyl) -3-n-propyl-3-D-galacto pyranosyl urea is obtained as colorless caramel.

(2) 6.0 g of 1- (2-chloroethyl) -3-n-propyl-3-D-galacto pyranosyl urea is dissolved in 15 ml of formic acid, and 4.2 g of sodium nitrite is 0 ° to Add slowly for 1 hour with stirring at 5 ° C.

The mixture was further stirred for 1 hour at the same temperature, followed by reaction in the same manner as described in Example 5- (2) to 1.8 g of 1- (2-chloroethyl) -1-nitroso 3-n-propyl-3-D-galacto pyranosyl urea is obtained as pale yellow caramel.

Example 15

3.3 g of 1- (2-chloroethyl) -3-n-propyl-3-D-galacto pyranosyl urea is dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of Anhydrous sodium carbonate is added.

5 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes under ice cooling.

This mixture was treated in the same manner as described in Example 2 to give 2.8 g of 1- (2-chloroethyl) -1-nitroso-3-n-propyl-3-D-galacto pyranosyl urea as pale yellow caramel Get as.

Example 16

(1) 3.6 g of D-galactose, 2.4 g of isopropylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 5- (1).

Thus 5.0 g of 1- (2-chloroethyl) -3-isopropyl-3-D-galacto pyranosyl urea are obtained as colorless caramel.

(2) 6.0 g of 1- (2-chloroethyl) -3-isopropyl-3-D-galacto pyranosyl urea is dissolved in 20 ml of formic acid, and 4.2 g of sodium nitrite is 0 ° to 5 Add slowly for 1 hour with stirring at ° C.

The mixture was further stirred for 1 hour at the same temperature, followed by reaction in the same manner as described in Example 5- (2) to 1.8 g of 1- (2-chloroethyl) -1-nitroso 3-Isopropyl-3-D-galacto pyranosyl urea is obtained as pale yellow caramel.

Example 17

(1) 5.2 g of 1- was treated with 3.6 g of D-galactose, 1.8 g of n-butylamine and 2.5 g of 2-chloroethyl isocyanate in the same manner as described in Example 5- (1). (2-Chloroethyl) -3-n-butyl-3-D-galacto pyranosyl urea is obtained as colorless caramel.

(2) 4.8 g of 1- (2-chloroethyl) -3-n-butyl-3-D-galacto pyranosyl urea was dissolved in 15 ml of formic acid, and 2.4 g of sodium nitrite was 0 ° to 0. Add slowly for 1 hour with stirring at 5 ° C. The mixture was stirred for another 1.5 hours at the same temperature, and then the mixture was treated in the same manner as described in Example 5- (2) to 1.8 g of 1- (2-chloroethyl) -1-nitroso- 3-n-butyl-3-D-galacto pyranosyl urea is obtained as a yellow powder.

Example 18

3.4 g of 1- (2-chloroethyl) -3-n-butyl-3-D-galacto pyranosyl urea dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride and 15 g of anhydrous thereto Sodium carbonate is added.

5 g of nitrogen tetraoxide gas is introduced into the mixture under ice cooling for 10 minutes.

This mixture was treated in the same manner as described in Example 2 to give 2.8 g of 1- (2-chloroethyl) -1-nitroso-3-n-butyl-3-D-galacto pyranosyl urea as a yellow powder. Get as.

Melting Point 44 ~ 46.5 ℃ (Decomposition)

Example 19

(1) A mixture of 3.6 g of D-galactose 20 g of isobutylamine and 2.5 g of 2-chloroethyl isocyanate was treated in the same manner as described in Example 5- (1) to give 5.5 g of 1- ( 2-Chloroethyl) -3-isobutyl-3-D-galacto pyranosyl urea is obtained as colorless caramel.

(2) Dissolve 7.0 g of 1- (2-chloroethyl) -3-isobutyl-3-D-galacto pyranosyl urea in 15 ml of formic acid and dissolve 5.0 g of sodium nitrite 0 ° to 5 Add slowly for 1 hour with stirring at ° C.

The mixture is further stirred at the same temperature for 1 hour for reaction, and then the mixture is treated in the same manner as described in Example 5- (2).

Thus 2.0 g of 1- (2-chloroethyl) -1-nitroso-3-isobutyl-3-D-galacto pyranosyl urea is obtained as a pale yellow powder.

Example 20

3.4 g of 1- (2-chloroethyl) -3-isobutyl-3-D-galacto pyranosyl urea was dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of anhydrous was added thereto. Sodium carbonate is added.

5 g of nitrogen tetraoxide gas are introduced into the mixture for 10 minutes under ice cooling.

This mixture was treated in the same manner as described in Example 2 to give 3.0 g of 1- (2-chloroethyl) -1-nitroso-3-isobutyl-3-D-galacto pyranosyl urea as a yellow powder. Get

Example 21

(1) 4.5 g of 1- was treated with 3.6 g of D-galactose, 5 g of secondary butylamine, and 3.0 g of 2-chloroethyl isocyanate in the same manner as described in Example 5- (1). (2-Chloroethyl) -3-second butyl-3-D-galacto pyranosyl urea is obtained as light brown caramel.

(2) 7.0 g of 1- (2-chloroethyl) -3-secondary butyl-3-D-galacto pyranosyl urea is dissolved in 20 ml of formic acid, and 5.0 g of sodium nitrite is 0 ° to Add slowly for 1 hour with stirring at 5 ° C.

The mixture was further stirred for 1 hour at the same temperature, followed by reaction in the same manner as described in Example 5- (2) to 1.7 g of 1- (2-chloroethyl) -1-nitro Bovine-3-secondary butyl-3-D-galacto pyranosyl urea is obtained as pale yellow caramel.

Example 22

(1) 5.5 g of 1- was treated with 3.6 g of D-galactose, 2.3 g of n-pentylamine and 2.5 g of 2-chloroethyl isocyanate in the same manner as described in Example 5- (1). (2-Chloroethyl) -3-n-pentyl-3-D-galacto pyranosyl urea is obtained as colorless caramel.

(2) 3.5 g of 1- (2-chloroethyl) -3-n-pentyl-3-D-galacto pyranosyl urea is dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, which is To 15 g of anhydrous sodium carbonate are added.

5 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes under ice cooling.

This mixture was treated in the same manner as described in Example 2 to give 2.7 g of 1- (2-chloroethyl) -1-nitroso-3-n-pentyl-3-D-galacto pyranosyl urea as a yellow caramel. Get as.

Example 23

(1) 3.6 g of D-galactose, 2.3 g of isopentylamine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 5- (1) to give 5.5 g of 1- ( 2-Chloroethyl) -3-isopentyl-3-D-galacto pyranosyl urea is obtained as colorless caramel.

(2) 3.5 g of 1- (2-chloroethyl) -3-isopentyl-3-D-galacto pyranosyl urea is dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of anhydrous sodium carbonate are added.

5 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes under ice cooling.

The mixture was treated in the same manner as described in Example 2 to give 2.6 g of 1- (2-chloroethyl) -1-nitroso-3-isopentyl-3-D-galacto pyranosyl urea as a yellow caramel. Get

Example 24

(1) 3.6 g of D-galactose, 3.5 g of neopentylamine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 5- (1) to obtain 5.0 g of 1- ( 2-Chloroethyl) -3-neopentyl-3-D-galacto pyranosyl urea is obtained as colorless caramel.

(2) 3.6 g of 1- (2-chloroethyl) -3-neopentyl-3-D-galacto pyranosyl urea is dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of anhydrous sodium carbonate are added.

5 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes under ice cooling.

This mixture was treated in the same manner as described in Example 2 to give 2.9 g of 1- (2-chloroethyl) -1-nitroso-3-neopentyl-3-D-galacto pyranosyl urea as a yellow caramel. Get

Example 25

(1) 3.6 g of D-galactose, 1.5 g of 2-propenylamine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 5- (1) to give 4.3 g of 1 -(2-Chloroethyl) -3- (2-propenyl) -3-D-galacto pyranosyl urea is obtained as colorless caramel.

(2) 3.2 g of 1- (2-chloroethyl) -3- (2-propenyl) -3-D-galacto pyranosyl urea was dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride 15 g of anhydrous sodium carbonate is added thereto.

5 g of nitrogen tetraoxide gas is introduced into the mixture while stirring under ice cooling for 10 minutes.

This mixture was treated in the same manner as described in Example 2 to give 2.5 g of 1- (2-chloroethyl) -1-nitroso-3- (2-propenyl) -3-D-galacto pyranosyl urea Is obtained as a yellow caramel.

Example 26

(1) 3.6 g of D-galactose, 1.4 g of 2-propenylamine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 5- (1) to give 4.3 g of 1 -(2-Chloroethyl) -3- (2-propenyl) -3-D-galacto pyranosyl urea is obtained as colorless caramel.

(2) 3.2 g of 1- (2-chloroethyl) -3- (2-propynyl) -3-D-galacto pyranosyl urea were dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride 15 g of anhydrous sodium carbonate is added thereto.

5 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes with stirring under ice cooling.

This mixture was treated in the same manner as described in Example 2 to give 2.5 g of 1- (2-chloroethyl) -1-nitroso-3- (2-propenyl) -3-D-galacto pyranosyl urea Is obtained as a pale yellow powder.

Example 27

(1) 3.0 g of D-ribose, 1.0 g of methylamine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 1- (1) to obtain 4.0 g of 1- ( 2-Chloroethyl) -3-methyl-3-D-ribofuranosyl urea is obtained as colorless caramel.

(2) 2 g of 1- (2-chloroethyl) -3-methyl-3-D-ribofuranosyl urea are dissolved in 10 ml of formic acid, and 1.1 g of sodium nitrite is stirred therein at 0 ° to 5 ° C. Apply slowly for 1 hour.

The mixture was allowed to react with stirring for another hour at the same temperature, and then the mixture was treated in the same manner as described in Example 1- (2) to 1.4 g of 1- (2-chloroethyl) -1-nitro So-3-methyl-3-D-ribofuranosyl urea is obtained as a yellow powder.

Example 28

27 g of 1- (2-chloroethyl) -3-methyl-3-D-ribofuranosyl urea was dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of anhydrous sodium carbonate was added thereto. do.

5 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes under ice cooling.

This mixture is treated in the same manner as described in Example 2 to give 2.1 g of 1- (2-chloroethyl) -1-nitroso-3-methyl-3-D-ribofuranosyl urea as a yellow powder.

Example 29

(1) 5.0 g of 1- was treated with 3.0 g of D-ribose, 1.9 g of n-butylamine and 2.5 g of 2-chloroethyl isocyanate in the same manner as described in Example 5- (1). (2-Chloroethyl) -3-n-butyl-2-D-ribofuranosyl urea is obtained as colorless caramel.

(2) 3.1 g of 1- (2-chloroethyl) -3-n-butyl-3-D-ribofuranosyl urea is dissolved in 10 ml of formic acid, and 1.5 g of sodium nitrite is 0 ° to 5 Add slowly for 1 hour with stirring at ° C.

The mixture was further stirred for 1 hour at the same temperature, followed by reaction in the same manner as described in Example 5- (2) to 1.4 g of 1- (2-chloroethyl) -1-nitro So-3-n-butyl-3-D-ribofuranosyl urea is obtained as a yellow caramel.

Example 30

(1) 5.3 g of D-mannose, 1.8 g of n-butylamine, and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 5- (1) to give 5.3 g of 1 -(2-Chloroethyl) -3-n-butyl-3-D-manno pyranosyl urea is obtained as colorless caramel.

(2) 3.4 g of 1- (2-chloroethyl) -3-n-butyl-3-D-manno pyranosyl urea is dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride and 15 g of anhydrous sodium carbonate are added.

5 g of nitrogen tetraoxide gas is introduced into the mixture under ice cooling for 10 minutes.

This mixture was treated in the same manner as described in Example 2 to give 2.9 g of 1- (2-chloroethyl) -1-nitroso-3-n-butyl-3-D-manno pyranosyl urea as a yellow caramel. Get

Example 31

5.4 g of 1- (2-chloroethyl) -3-n-butyl-3-D-manno pyranosyl urea was dissolved in 20 ml of formic acid, and 3.5 g of sodium nitrite was added thereto for 2 hours while stirring under ice cooling. Apply slowly.

40 ml of methanol and 30 g of anhydrous potassium carbonate are added to the mixture.

The mixture was then allowed to react for 10 more minutes under ice-cooling reaction and then the mixture was treated in the same manner as described in Example 5- (2) to give 1.6 g of 1- (2-chloroethyl) -1 Nitroso-3-n-butyl-3-D-manno pyranosyl urea is obtained as a yellow caramel.

Example 32

(1) 3.0 g of D-xylose, 1.5 g of n-propylamine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 5- (1) to obtain 4.0 g of 1 -(2-Chloroethyl) -3-n-propyl-3-D-xyl pyranosyl urea is obtained as colorless caramel.

(2) 9.0 g of 1- (2-chloroethyl) -3-n-propyl-3-D-xyl pyranosyl urea is dissolved in 25 ml of formic acid, and 6.0 g of sodium nitrite is 0 ° to Add slowly with stirring at 5 ° C. for 1 hour.

The mixture was allowed to react by stirring for 30 minutes at the same temperature, and then the mixture was treated in the same manner as described in Example 5- (2) to give 3.7 g of 1- (2-chloroethyl) -1-nitroso 3-n-propyl-3-D-xyl pyranosyl urea is obtained as pale yellow caramel.

Example 33

3.0 g of 1- (2-chloroethyl) -3-n-propyl-3-D-xylo pyranosyl urea is dissolved in a mixture of 80 ml of tetrahydrofuran and 50 ml of methylene chloride, and 15 g of Anhydrous sodium carbonate is added.

5 g of nitrogen tetraoxide gas is introduced into the mixture under ice cooling for 10 minutes.

This mixture was treated in the same manner as described in Example 2 to give 2.6 g of 1- (2-chloroethyl) -1-nitroso-3-n-propyl-3-D-xylo pyranosyl urea as a yellow caramel Get as.

Example 34

(1) 3.0 g of D-xylose, 2.5 ml of isopropylamine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 5- (1) to obtain 4.0 g of 1-. (2-Chloroethyl) -3-isopropyl-3-D-xylo pyranosyl urea is obtained as colorless caramel.

(2) 3.0 g of 1- (2-chloroethyl) -3-isopropyl-3-D-xyl pyranosyl urea was dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, 15 g of anhydrous sodium carbonate are added.

5 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes under ice cooling.

This mixture is treated in the same manner as described in Example 2 to give 2.5 g of 1- (2-chloroethyl) -1-nitroso-3-D-xylo pyranosyl urea as a yellow powder.

Example 35

(1) 3.0 g of L-arabinose, 1.5 g of n-propylamine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 5- (1) to give 4.1 g of 1 -(2-Chloroethyl) -3-n-propyl-3-L-arabino pyranosyl urea is obtained as colorless caramel.

(2) 9.0 g of 1- (2-chloroethyl) -3-n-propyl-3-L-arabian pyranosyl urea is dissolved in 25 ml of formic acid, and 6.0 g of sodium nitrite is 0 ° to 5 Add slowly for 1 hour with stirring at ° C. The mixture was allowed to react by stirring for 30 minutes at the same temperature, and then the mixture was treated in the same manner as described in Example 5- (2) to give 3.5 g of 1- (2-chloroethyl) -1-nitroso 3-n-propyl-3-L-arabino pyranosyl urea is obtained as pale yellow caramel.

Example 36

3.0 g of 1- (2-chloroethyl) -3-n-propyl-3-L-arabino pyranosyl urea is dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of Sodium carbonate is added.

5 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes under ice cooling.

This mixture was treated in the same manner as described in Example 2 to give 2.5 g of 1- (2-chloroethyl) -1-nicroso-3-n-propyl-3-L-aribino pyranosyl urea as a yellow caramel Get as.

Example 37

(1) 3.0 g of L-arabinose, 2.5 g of isopropylamine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 5- (1). Thus 4.2 g of 1- (2-chloroethyl) -3-isopropyl-3-L-arabino pyranosyl urea are obtained as colorless caramel.

(2) 3.0 g of 1- (2-chloroethyl) -3-isopropyl-3-L-arabino pyranosyl urea is dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of anhydrous sodium carbonate are added.

5 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes under ice cooling.

The mixture was treated in the same manner as described in Example 2 to give 2.4 g of 1- (2-chloroethyl) -1-nitroso-3-isopropyl-3-L-arabino pyranosyl urea as a yellow caramel. Get

Example 38

(1) 3.0 g of L-arabinose, 1.8 g of isobutylamine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 5- (1) to give 4.3 g of 1-. (2-Chloroethyl) -3-isobutyl-3-L-arabinopy ranosyl urea is obtained as colorless caramel.

(2) 3.1 g of 1- (2-chloroethyl) -3-isobutyl-3-L-arabino pyranosyl urea is dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of anhydrous sodium carbonate are added.

5 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes under ice cooling.

The mixture was treated in the same manner as described in Example 2 to give 2.3 g of 1- (2-chloroethyl) -1-nitroso-3-isobutyl-3-L-arabino pranosyl urea as pale yellow caramel. Get

Example 39

(1) 4.5 g of L-arabinose, 2.5 g of 2-propenylamine and 3.5 g of chloroethyl isocyanate were treated in the same manner as described in Example 5- (1) to 5.5 g of 1- (2-Chloroethyl) -3- (2-propenyl) -3-L-arabino pyranosyl urea is obtained as a colorless powder.

(2) 3.2 g of 1- (2-chloroethyl) -3- (2-propenyl) -3-L-arabino pyranosyl urea was dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride 15 g of anhydrous sodium carbonate is added thereto.

5 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes with stirring under ice cooling.

This mixture was treated in the same manner as described in Example 2 to give 2.3 g of 1- (2-chloroethyl) -1-nitroso-3- (2-propenyl) -3-L-arabino pyranosyl urea Is obtained as a yellow caramel.

Example 40

(1) 3.3 g of L-rhamnose, 1.8 g of n-butylamine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 5- (1) to give 4.2 g of 1 -(2-Chloroethyl) -3-n-butyl-3-L-rhamno pyranosyl urea is obtained as colorless caramel.

(2) 3.2 g of 1- (2-chloroethyl) -3-n-butyl-3-L-rhamno pyranosyl urea are dissolved in 10 ml of formic acid, and 1.5 g of sodium nitrite is 0 ° to 5 Add slowly for 1 hour with stirring at ° C.

The mixture was allowed to react by stirring for 1 hour at the same temperature, and then the mixture was treated in the same manner as described in Example 5- (2) to 0.8 g of 1- (2-chloroethyl) -1-nitroso 3-n-butyl-3-L-rhamnopyranosyl urea is obtained as a yellow caramel.

Example 41

3.2 g of 1- (2-chloroethyl) -3-n-butyl-3-L-rhamno pyranosyl urea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of ethylene chloride, and 15 g of sodium carbonate is added thereto. Add.

5 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes under ice-cooling.

This mixture was treated in the same manner as described in Example 2 to give 3.5 g of 1- (2-chloroethyl) -1-nitroso-3-n-butyl-3-L-rhamno pyranosyl urea as a yellow caramel. Get

[42]

(1) A mixture of 7.2 g of D-maltose monohydrate, 0.9 g of methylamine, and 20 ml of methanol is heated to 60 ° C. in a sealed tube for 1 hour.

The reaction mixture was concentrated to dryness under reduced pressure and the residue was washed with ether to give 7.1 g of [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] -methylamine 9 , 1-methylamino-1-deoxy-D-maltose) was obtained as a preparation product, and 2.5 g of 2-g of 7.1 g of this crude product was dissolved in 50 ml of methanol and placed in 10 ml of tetrahydrofuran. A solution of chloroethyl isocyanate is added at 0 ° -5 ° C.

The solution was stirred at room temperature for 1.5 hours, the reaction solution was concentrated under reduced pressure, and a mixture of ethyl acetate and ether was added to the residue, and 7.4 g of 1- (2-chloroethyl) -3-methyl-3- [ 0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea (ie 1- (2-chloroethyl) -3-methyl-3-D-maltosyl urea) colorless amorphous Obtained as a powder.

(2) 10 ml of formic acid containing 3.0 g of 1- (2-chloroethyl) -3-methyl-3- [1-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea Dissolved in, and slowly added 1.0 g of sodium nitrite at 0 ° to 5 ° C for 40 minutes with stirring.

The mixture was further stirred for 1.5 hours at the same temperature, and then the mixture was treated in the same manner as described in Example 1- (2) (solvent used for chromatography: chloroform-acetic acid ethyl-methanol (1 : 1: 1)).

Thus 1.0 g 1- (2-chloroethyl) -1-nitroso-3-methyl-3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea (Ie 1- (2-chloromethyl) -1-nitroso-3-methyl-D-maltosyl urea) is obtained as a pale yellow powder. Melting Point 66-70 ℃ (Decomposition)

Example 43

4.6 g of 1- (2-chloroethyl) -3-methyl-3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea with 170 ml of tetrahydrofuran It is dissolved in a mixture of 30 ml of acetic acid and 20 g of anhydrous sodium acetate is added thereto.

8 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes with stirring under ice cooling.

The mixture is further stirred at the same temperature for 20 minutes to react, and then 200 ml of n-hexane is added to the mixture, and the mixture is filtered.

200 ml of methanol-ether (1:20) was added to the residue obtained by evaporating the filtrate to remove the solvent, and the resulting oily product was subjected to silica gel chromatography (solvent: ethyl acetate-chloroform-methanol (2: 1: 1). Purified))) to 3.35 g of 1- (2-chloroethyl) -1-nitoroso-3-methyl-3- [0-α-D-glucopyranosyl- (1 → 4) -D-glucopyra Nosyl] Urea (ie 1- (2-chloroethyl) -1-nitroso-3-methyl-3-D-maltosyl urea) is obtained as a pale yellow powder. Melting Point 66-70 ℃ (Decomposition)

Example 44

(1) 8.5 g of D-maltose monohydrate, 1.5 g of n-propylamine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 42- (1) to 8.5 g. 1- (2-Chloroethyl) -3-n-propyl-3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea (ie, 1- (2- Chloroethyl) -3-n-propyl-3-D-maltosyl urea) is obtained as a colorless amorphous powder.

(2) 20 ml of 5.0 g of 1- (2-chloroethyl) -3-n-propyl-3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea Is dissolved in formic acid, and 1.5 g of sodium nitrite is slowly added thereto for 1 hour while stirring at 0 ° to 5 ° C.

The mixture was allowed to react by stirring for another 1.5 hours at the same temperature, and then the mixture was treated in the same manner as described in Example 1- (2) (solvent used for chromatography: chloroform-ethyl acetate-methanol (1 : 2: 1)).

0.8 g of 1- (2-chloroethyl-1-nitroso-3-n-propyl-3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] in this manner Urea (ie 1- (2-chloroethyl) -1-nitroso-3-n-propyl-3-D-maltosyl urea) is obtained as a pale yellow powder Melting point 59-62 ° C. (decomposition)

Example 45

4.8 g of 1- (2-chloroethyl) -3-n-propyl-3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea was added to 170 ml of tetrahydro. It is dissolved in a mixture of furan and 30 ml of acetic acid, and 20 g of sodium acetate anhydride is added thereto.

8 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes with stirring under ice cooling.

This mixture was treated in the same manner as described in Example 43 to give 3.6 g of 1- (2-chloroethyl) -1-nitroso-3-n-propyl-3- [0-α-D-gluco pyranosyl -(1 → 4) -D-Glucopyranosyl] Urea (ie 1- (2-chloroethyl-1-nitroso-3-n-propyl-3-D-maltosyl urea) is obtained as a pale yellow powder.

Example 46

(1) 7.2 g of D-maltose monohydrate, 200 g of isopropyl amine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 42- (1) to give 7.2 g of 1 -(2-Chloroethyl) -3-isopropyl-3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea (ie 1- (2-chloroethyl) 3-isopropyl-3-D-maltosyl urea) is obtained as a colorless amorphous powder.

(2) 170 ml of 4.8 g of 1- (2-chloroethyl) -3-isopropyl-3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea It is dissolved in a mixture of tetrahydrofuran and 30 ml of acetic acid, and 20 g of anhydrous sodium acetate is added thereto.

8 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes with stirring under ice cooling.

This mixture was treated in the same manner as described in Example 43, whereby 3.6 g of 1- (2-chloroethyl) -1-nitroso-3-isopropyl-3- [0-α-D-glucopyranosyl- (1 → 4) -D-Glucopyranosyl] Urea (ie 1- (2-chloroethyl) -1-nitroso-3-isopropyl-3-D-maltosyl urea) is obtained as a pale yellow powder.

Example 47

(1) 8.0 g of 7.2 g of D-maltose monohydrate, 2.2 g of n-butylamine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 42- (1). 1- (2-Chloroethyl) -3-n-butyl-3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea (ie, 1- (2- Chloroethyl) -3-n-butyl-3-D-maltosyl urea) is obtained as a colorless powder. Melting Point 91-95 ° C (Decomposition)

(2) 10 ml of 4.5 g of 1- (2-chloroethyl) -3-n-butyl-3- [0-α-D-glucopyranosyl- (1 → 4) -D-glucopyranosyl] urea Is dissolved in formic acid, and 1.5 g of sodium nitrite is slowly added thereto for 50 minutes with stirring at 0 ° to 5 ° C.

The mixture was further stirred for 1.5 hours at the same temperature, and then the mixture was treated in the same manner as described in Example 1- (2) to give 1.4 g of 1- (2-chloroethyl) -1-nitro. Bovine-3-n-butyl-3- [0-α-D-glucopyranosyl- (1 → 4) -D-glucopyranosyl] urea (ie 1- (2-chloroethyl) -1-nitroso 3-n-butyl-3-D-maltosyl urea) is obtained as a yellow powder. Melting Point 76-80 ℃ (Decomposition)

Example 48

4.9 g of 1- (2-chloroethyl) -3-n-butyl-3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea is charged with 150 ml of tetrahydro. It is dissolved in a mixture of furan and 30 ml of acetic acid and 20 g of anhydrous sodium acetate is added thereto.

8 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes with stirring under ice cooling.

This mixture was treated in the same manner as described in Example 43, whereby 3.8 g of 1- (2-chloroethyl) -1-nitroso-3-n-butyl-3- [0-α-D-glucopyranosyl -(1 → 4) -D-Glucopyranosyl] Urea (ie 1- (2-chloroethyl) -1-nitroso-3-n-butyl-3-D-maltosyl urea) is obtained as a pale yellow powder .

Example 49

(1) 8.0 g of 7.2 g of D-maltose monohydrate, 2.9 g of isobutylamine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 42- (1). 1- (2-chloroethyl) -3-isobutyl-3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea (ie 1- (2-chloroethyl ) -3-isobutyl-D-maltosyl urea) is obtained as a colorless powder. Melting Point 86-90 ℃ (Decomposition)

(2) 150 ml of 4.9 g of 1- (2-chloroethyl) -3-isobutyl-3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea It is dissolved in a mixture of tetrahydrofuran and 20 ml of acetic acid, and 20 g of sodium acetate anhydride is added thereto.

8 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes with stirring under ice cooling.

The mixture was treated in the same manner as described in Example 43 to give 2.5 g of 1- (2-chloroethyl) -1-nitroso-3-isobutyl-3- [0-α-D-glucopyranosyl- (1 → 4) -D-Glucopyranosyl] Urea (ie 1- (2-chloroethyl) -1-nitroso-3-isobutyl-3-D-maltosyl urea) is obtained as a yellow powder.

Example 50

(1) 8.1 g of D-maltose monohydrate, 2.5 g of n-pentylamine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 42- (1) to 8.1 g. 1- (2-Chloroethyl) -3-n-pentyl-3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea (ie, 1- (2- Chloroethyl) -3-n-pentyl-3-D-maltosyl urea) is obtained as a colorless powder.

(2) 20 ml of 5.2 g of 1- (2-chloroethyl) -3-n-pentyl-3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea Is dissolved in formic acid, and 2 g of sodium nitrite is slowly added thereto for 1 hour with stirring at 0 ° to 5 ° C.

The mixture was further stirred for 1.5 hours at the same temperature, and then the mixture was treated in the same manner as described in Example 1- (2) to give 1.0 g of 1- (2-chloroethyl) -1-nitroso -3-n-pentyl-3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea (ie 1- (2-chloroethyl) -1-nitroso- 3-n-pentyl-3-D-maltosyl urea) is obtained as a pale yellow powder. Melting Point 71-75 ° C (Decomposition)

Example 51

150 ml of tetrahydro of 5.1 g of 1- (2-chloroethyl) -3-n-pentyl-3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea It is dissolved in a mixture of furan and 20 ml of acetic acid, and 20 g of anhydrous sodium acetate is added thereto.

8 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes with ice cooling and stirring.

This mixture was treated in the same manner as described in Example 43, whereby 3.8 g of 1- (2-chloroethyl) -1-nitroso-3-n-pentyl-3- [0-α-D-glucopyranosyl -(1 → 4) -D-Glucopyranosyl] Urea (ie 1- (2-chloroethyl) -1-nitroso-3-n-pentyl-3-D-maltosyl urea) is obtained as a pale yellow powder .

Example 52

(1) 8.3 g of D-malose monohydrate, 3.0 g of n-hexylamine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 42- (1) to 8.3 g. 1- (2-Chloroethyl) -3-n-hexyl-3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea (ie, 1- (2- Chloroethyl) -3-n-hexyl-3-D-maltosyl urea) is obtained as a colorless powder.

(2) 150 ml of 5.2 g of 1- (2-chloroethyl) -3-n-hexyl-3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea Is dissolved in a mixture of tetrahydrofuran and 30 ml of acetic acid, and 20 g of anhydrous sodium acetate is added thereto.

8 g of nitrogen tetraoxide gas are introduced into the mixture for 10 minutes with stirring under ice cooling.

This mixture was treated in the same manner as described in Example 43 to give 4.2 g of 1- (2-chloroethyl) -1-nitroso-3-n-hexyl-3- [0-α-D-glucopyranosyl -(1 → 4) -D-Glucopyranosyl] Urea (ie 1- (2-chloroethyl) -1-nitroso-3-n-hexyl-3-D-maltosyl urea) is obtained as a pale yellow powder .

Example 53

(1) 7.2 g of D-maltose monohydrate, 1.5 g of n-propenylamine, and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 42- (1). 8.0 g of 1- (2-chloroethyl) -3- (2-propenyl) -3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea (ie 1- (2-chloroethyl) -3- (2-propenyl) -3-D-maltosyl urea) is obtained as a colorless powder.

(2) 4.8 g of 1- (2-chloroethyl) -3- (2-propenyl) -3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea Was dissolved in a mixture of 150 ml of tetrahydrofuran and 20 ml of acetic acid, and 20 g of sodium acetate anhydride was added thereto.

8 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes with stirring under ice cooling.

This mixture was treated in the same manner as described in Example 43 to give 3.2 g of 1- (2-chloroethyl) -1-nitroso-3- (2-propenyl) -3- [0-α-D- Gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea (ie 1- (2-chloroethyl) -1-nitroso-3- (2-propenyl) -3-D-maltosyl urea Is obtained as a pale yellow powder.

Example 54

(1) 7.2 g of D-maltose monohydrate, 2.8 g of 2-methyl-2-propenylamine and 2.5 g of 2-chloroethyl isocyanate as in Example 42- (1) 7.8 g of 1- (2-chloroethyl) -3- (2-methyl-2-propenyl) -3- [0-α-D-gluco pyranosyl- (1 → 4) -D-glucose Pyranosyl] urea (ie 1- (2-chloroethyl) -3- (2-methyl-2-propenyl) -3-D-maltosyl urea) is obtained as a colorless powder.

(2) 4.9 g of 1- (2-chloroethyl) -3- (2-methyl-2-propenyl) -3- [0-α-D-glucoy pyranosyl- (1 → 4) -D-glucose Pyranosyl] Urea is dissolved in a mixture of 150 ml of tetrahydrofuran and 20 ml of acetic acid, and 20 g of sodium acetate anhydride is added thereto. 8 g of nitrogen tetraoxide gas were treated in the same manner as described in Example 43 to give 3.6 g of 1- (2-chloroethyl) -1-nitroso-3- (2-methyl-2-propenyl ) -3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea (ie 1- (2-chloroethyl) -nitroso-3- (2-methyl- 2-propenyl) -3-D-maltosyl urea) is obtained as a pale yellow powder.

Example 55

(1) 7.2 g of D-maltose monohydrate, 2.1 g of 2-butenyl amine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 42- (1) to give 8.2 g of 1- (2-chloroethyl) -3- (2-butynyl) -3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea (ie 1 -(2-chloroethyl) -3- (2-butenyl) -3-D-maltosyl urea) is obtained as a colorless powder.

(2) 4.9 g of 1- (2-chloroethyl) -3- (2-butenyl) -3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea Was dissolved in a mixture of 150 ml of tetrahydrofuran and 20 ml of acetic acid, and 20 g of sodium acetate anhydride was added thereto.

8 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes by stirring under ice cooling.

This mixture was treated in the same manner as described in Example 43, whereby 3.8 g of 1- (2-chloroethyl) -1-nitroso-3- (2-butenyl) -3- [0-α-D- Gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea (ie 1- (2-chloroethyl) -1-nitroso-3- (2-butenyl) -3-D-maltosyl urea ) Is obtained as a pale yellow powder.

Example 56

(1) 8.0 g of 7.2 g of D-maltose monohydrate, 2.0 g of 3-butenyl amine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 42- (1). g of 1- (2-chloroethyl) -3- (3-butenyl) -3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea (ie 1 -(2-chloroethyl) -3- (3-butenyl) -3-D-maltosyl urea) is obtained as a colorless powder.

(2) 4.9 g of 1- (2-chloroethyl) -3- (3-butenyl) -3- [0-α-D-gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea Was dissolved in a mixture of 150 ml of tetrahydrofuran and 20 ml of acetic acid, and 20 g of sodium acetate anhydride was added thereto.

8 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes by stirring under ice cooling.

This mixture was treated in the same manner as described in Example 43, whereby 3.9 g of 1- (2-chloroethyl) -1-nitroso-3- (3-butenyl) -3- [0-α-D- Gluco pyranosyl- (1 → 4) -D-gluco pyranosyl] urea (ie 1- (2-chloroethyl) -1-nitroso-3- (3-butenyl) -3-D-maltosyl urea ) Is obtained as a pale yellow powder.

Example 57

(1) 7.2 g of D-lactose monohydrate, 1.9 g of 3-butyl amine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 42- (1) to obtain 8.5 g of 1- (2-chloroethyl) -3-n-butyl-3- [0-β-D-galacto pyranosyl- (1 → 4) -D-gluco pyranosyl] urea (ie 1- (2- Chloroethyl) -3-n-butyl-3-D-maltosyl urea) is obtained as a colorless powder.

(2) 5.1 g of 1- (2-chloroethyl) -3-n-butyl-3- [0-β-D-galacto pyranosyl- (1 → 4) -D-gluco pyranosyl] urea Dissolve in ml of formic acid and slowly add to it 20 g of sodium nitrite for 1 hour with stirring at 0 ° to 5 ° C.

The mixture was further stirred for 1 hour at the same temperature, and then the mixture was treated in the same manner as described in Example 1- (2) to 0.8 g of 1- (2-chloroethyl) -1-nitro Bovine-3-n-butyl-3- [0-β-D-galacto pyranosyl- (1 → 4) -D-gluco pyranosyl] urea (ie 1- (2-chloroethyl) -1-nitro Bovine-3-n-butyl-3-D-lactosyl-urea) is obtained as a pale yellow powder.

Example 58

4.9 g of 1- (2-chloroethyl) -3-n-butyl-3- [0-β-D-galacto pyranosyl- (1 → 4) -D-gluco pyranosyl] urea with 150 ml of tetra It is dissolved in a mixture of hydrofuran and 20 ml of acetic acid, and 20 g of sodium acetate anhydride is added thereto.

8 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes with stirring under ice cooling.

This mixture was treated in the same manner as described in Example 43, whereby 3.8 g of 1- (2-chloroethyl) -1-nitroso-3-n-butyl-3- [0-β-D-galactopyra Nosyl- (1 → 4) -D-gluco pyranosyl] urea (ie 1- (2-chloroethyl) -1-nitroso-3-n-butyl-3-D-lactosyl urea) as pale yellow powder Get

Example 59

(1) 7.2 g of D-lactose monohydrate, 2.5 g of isobutylamine and 2.5 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 42- (1) to 8.2 g of 1 -(2-Chloroethyl) -3-isobutyl-3- [0-β-D-galacto pyranosyl- (1 → 4) -D-gluco pyranosyl] urea (ie 1- (2-chloroethyl ) -3-isobutyl-3-D-lactosyl urea) is obtained as a colorless powder.

(2) 150 mL of 4.9 g of 1- (2-chloroethyl) -3-isobutyl-3- [0-β-D-galacto pyranosyl- (1 → 4) -D-gluco pyranosyl] urea Is dissolved in a mixture of tetrahydrofuran and 20 ml of acetic acid, and 20 g of sodium acetate anhydride is added thereto.

8 g of nitrogen tetraoxide gas is introduced into the mixture for 10 minutes with stirring under ice cooling.

This mixture was treated in the same manner as described in Example 43 to give 4.0 g of 1- (2-chloroethyl) -1-nitroso-3-isobutyl-3- [0-β-D-galacto pyranosyl -(1-4) -D-glucopyranosyl] Urea (ie 1- (2-chloroethyl) -1-nitroso-3-isobutyl-3-D-lactosyl urea) is obtained as a pale yellow powder.

Example 60

(1) 1.5 g of N-methyl-ethanol amine is dissolved in 30 ml of tetrahydrofuran, and 2.1 g of 2-chloroethyl isocyanate is added dropwise thereto at 0 ° to 5 ° C. The solution was stirred at room temperature for 1.5 hours, and then the reaction solution was concentrated under reduced pressure to give 3.5 g of 1- (2-chloroethyl) -3-methyl-3- (2-hydroxyethyl) urea as a colorless oil. Get

(2) 0.9 g of 1- (2-chloroethyl) -3-methyl-3- (2-hydroxyethyl) urea is dissolved in 10 ml of acetic acid and 0.9 g of sodium nitrite is added thereto while stirring. The mixture is stirred at room temperature for 1 hour.

Then, 0.5 g of sodium nitrite was further added to the mixture, the mixture was further stirred at the same temperature for 4 hours, and then reacted to freeze-dry the mixture, and the residue was purified by silica gel chromatography (solvent: chloroform-methanol). = 10: 1) to obtain 0.7 g of 1- (2-chloroethyl) -1-nitroso-3-methyl-3- (2-hydroxyethyl) urea as a pale yellow oily phase.

Example 61

(1) 2.1 g of diethanol amine is dissolved in 30 ml of tetrahydrofuran, and 2.1 g of 2-chloroethyl isocyanate is added dropwise thereto at 0 ° to 5 ° C.

The solution is stirred at room temperature for 2 hours, then the reaction solution is concentrated under reduced pressure to give 4.2 g of 1- (2-chloroethyl) -3,3-bis (2-hydroxyethyl) urea as a colorless oil. .

(2) 4.0 g of 1- (2-chloroethyl) -3,3-bis (2-hydroxyethyl) urea is dissolved in 30 ml of acetic acid, and 2.5 g of sodium nitrite is added thereto while stirring. The mixture is stirred at room temperature for 4 hours and then reacted to treat this mixture in the same manner as described in Example 60- (2) (solvent used for chromatography: chloroform-methanol (10: 1)).

Thus, 3.0 g of 1- (2-chloroethyl) -1-nitroso-3,3-bis (2-hydroxyethyl) urea is obtained as a yellow oil.

Example 62

(1) A mixture of 3.3 g of 3-chloro-1,2-dihydroxy-n-propane and 20 ml of 30% methylamine-methanol solution is left at room temperature for 3 days.

The reaction mixture is concentrated to dryness under reduced pressure to obtain 4.2 g of N-methyl-2,3-dihydroxy-n-propylamine hydrochloride as a crude product.

4.2 g of this crude product and 3 g of triethylamine are dissolved in 30 ml of methanol.

3.2 g of 2-chloroethyl isocyanate is added dropwise to this solution at 0 ° to 5 ° C.

The solution is stirred at room temperature for 2 hours.

Then, the residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel chromatography (solvent: chloroform-ethyl acetate-methanol (3: 1: 1)) to obtain 3.5 g of 1- (2-chloroethyl) -3. -Methyl-3- (2,3-dihydroxy-n-propyl) urea is obtained as a colorless oil phase.

(2) 2.1 g of 1- (2-chloroethyl) -3-methyl-3- (2,3-dihydroxy-n-propyl) urea are dissolved in 10 ml of acetic acid and 1.4 g of sodium nitrite Is added while stirring.

The mixture was stirred at room temperature for 2 hours, and then 2 ml of concentrated hydrochloric acid and 1 g of sodium nitrite were added to the mixture, and the mixture was further stirred at the same temperature for 2 hours, and then reacted to give the mixture by Example 60 The treatment was carried out in the same manner as described in-(2) (solvent used for chromatography: chloroform-ethyl acetate-methanol (3: 1: 1)).

Thus, 1.5 g of 1- (2-chloroethyl) -1-nitroso-3-methyl-3- (2,3-dihydroxy-n-propyl) urea is obtained as a pale yellow oily phase.

Example 63

(1) 6.1 g of 1-n-butyl amino-1-deoxy-2,4-0-ethylritene-D-erythritol [Method of Geederer (I. Zedermann and E. Dimant 2 agent ( I. Ziderman and E. Dimant, J.) organic chemistry, 31,223 (1966)), dissolved in 20 ml of 10% aqueous hydrochloric acid. The solution is heated at 80 ° C. for 1 hour.

The reaction mixture was concentrated to dryness under reduced pressure to obtain 6.4 g of 1-n-butylamino-1-deoxy-D-erythrite as a crude product.

6.4 g of this crude product and 3 g of triethylamine are dissolved in 40 ml of methanol.

3.2 g of 2-chloroethyl isocyanate is added dropwise to this solution at 0 ° to 5 ° C.

The reaction mixture was treated in the same manner as described in Example 62- (1) to give 5.0 g of 1- (2-chloroethyl-3-n-butyl-3- (1-deoxy-D-erythritolyl ) Urea is obtained as colorless oil.

(2) 3.1 g of 1- (2-chloroethyl) -3-n-butyl-3- (1-deoxy-D-erythritolyl) urea is dissolved in 10 ml of formic acid, and 1.4 g of nitrous acid is added thereto. Sodium is added. The mixture was stirred and reacted for 3 hours at 0 ° to 5 ° C. and then the mixture was treated in the same manner as described in Example 62- (2) to give 2.0 g of 1- (2-chloroethyl) -1 Nitroso-3-n-butyl-3- (1-deoxy-D-erythritolyl) urea is obtained as a yellow oil phase.

Example 64

(1) A mixture of 3.3 g of 3-chloro-1,2-dihydroxy-n-propane and 8 g of n-propylamine is left at room temperature for 5 days.

The reaction mixture is concentrated to dryness under reduced pressure to obtain 5.0 g of N-n-propyl-2,3-dihydroxy-D-propylamine hydrochloride as a crude product.

5.0 g of this crude product and 3 g of triethylamine are dissolved in 40 ml of methanol.

3.2 g of 2-chloroethyl isocyanate was added to the dissolved solution at 0 DEG C. to 5 DEG C. Then, the reaction mixture was treated in the same manner as described in Example 62- (1) to give 3.0 g of 1- ( 2-Chloroethyl) -3-n-propyl-3- (2,3-dihydroxy-n-propyl) urea is obtained as a colorless oil phase.

(2) 3 g of 1- (2-chloroethyl) -3-n-propyl-3- (2,3-dihydroxy-n-propyl) urea are dissolved in 10 ml of acetic acid and 1.5 g of Sodium nitrite is added with stirring.

The mixture was stirred at the same temperature for 4 hours and then reacted to treat the mixture in the same manner as described in Example 62- (2) to 1.7 g of 1- (2-chloroethyl) -1-nitroso- 3-n-propyl-3- (2,3-dihydroxy-n-propyl) urea is obtained as a yellow oil phase.

Example 65

(1) A solution of 1.6 g of 2-chloroethyl isocyanate in 5 ml of tetrahydrofuran was added to 50 ml of methanol solution containing 2.9 g of N-methyl glucosamine under ice-cooling, and the mixture was cooled at room temperature. After stirring for 1 hour and reacting, the mixture is concentrated under reduced pressure.

The obtained residue is recrystallized from a mixture of ethanol and ethyl acetate to obtain 3.5 g of 1- (2-chloroethyl) -3-methyl-3- (1-deoxy-D-glucinotolyl) urea as colorless crystals.

(2) 1.9 g of 1- (2-chloroethyl) -3-methyl-3- (1-deoxy-D-glucintolyl) urea are dissolved in 10 ml of formic acid, and 0.9 g of sodium nitrite is added thereto. Is added slowly for 1 hour with stirring at 0 ° -5 ° C.

The mixture is further stirred at the same temperature for 30 minutes and then reacted to freeze-dry the mixture.

The residue thus obtained was purified by silica gel chromatography (solvent: chloroform-ethyl acetate-methanol (2: 1: 1)) to 0.7 g of 1- (2-chloroethyl) -1-nitroso-3-methyl- 3- (1-deoxy-D-glucintolyl) urea is obtained as pale yellow caramel.

Example 66

(1) of 2.4 g prepared by hydrocracking of 1-n-butylamino-1-deoxy-D-glucose (see F. Kagan and others, US Chem., 793541 (1957)) Nn-butylglucoamine and 1.1 g of 2-chloroethyl isocyanate were treated in the same manner as described in Example 65- (1) to 3.5 g of 1- (2-chloroethyl) -3-n- Butyl-3- (1-deoxy-D-glucintolyl) urea is obtained as colorless caramel.

(2) 4 g of 1- (2-chloroethyl) -3-n-butyl-3- (1-deoxy-D-glucintolyl) urea are dissolved in 15 ml of formic acid, and 2.5 g of nitrous acid is added thereto. Sodium is added slowly under ice cooling for 1 hour.

The mixture is stirred for 30 minutes and then reacted to treat this mixture in the same manner as described in Example 65- (2) (solvent used for chromatography: chloroform-methanol (5: 1)).

This gives 1.8 g of 1- (2-chloroethyl) -1-nitroso-3-n-butyl-3- (1-deoxy-D-glucinotolyl) urea as a pale yellow powder.

Claims (1)

A method for producing a nitrosourea compound represented by the following general formula (I), wherein the compound represented by the following general formula (II) is subjected to nitrosation reaction by contacting with nitrous acid, nitrogen trioxide or nitrogen tetraoxide.

Wherein R ¹ is a group selected from the group consisting of alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkenyl of 3 to 5 carbon atoms and alkynyl of 3 to 5 carbon atoms, R ² is a group selected from the group consisting of aldo-pentopuranosyl, aldo-pentopyranosyl, aldo-hexopyranosyl, 0-aldo-hexopyranosyl- (1 → 4) -aldo-hexopyranosyl and general Formula: -CH ₂ (CHOH) n-CH ₂ OH, wherein n is 0 or an integer from 1 to 4.