DE1645921B2 - 2-OXO-1,3,2-OXAZAPHOSPHORINANES, THE PROCESS FOR THEIR MANUFACTURING AND THE PHARMACEUTICAL PREPARATIONS CONTAINING THEM - Google Patents

Description

where R _{1 is} the 2-chloroethyl or 3-chloropropyl radical, R ₂ and R ₃ together represent the 1,2-ethylene radical or R _{2 is} the 2-chloroethyl radical and R _{3 is} hydrogen, the methyl group, the 2-chloroethyl or the 2 -Hydroxyethyl radical and Z ₁ and Z ₂ , which can be identical or different, are hydrogen or alkyl radicals having 1-4 carbon atoms.

2. 2- [N, N-bis (2-chloroethyl) amino] -3- (2-chloroethyl) -2-oxo-1,3,2-oxazaphosphorinane.

3.2- (2-chloroethylamino) -3- (2-chloroethyl) -2-oxo-1,3,2-oxazaphosphorinane.

4. Process for the preparation of the compounds according to claim 1, characterized in that one in a manner known per se

A) a phosphoric acid amide dihalide of the formula

C) a 2-oxo-1,3,2-oxazaphosphorinane of the formula

R4

NC Z ₁ Z ₂

CZ ₁ item ₂

N-P = O

R ₃ O-CZ ₁ Z ₂

wherein R _{4 is} the 2-hydroxyethyl or 3-hydroxypropyl radical, is reacted with a chlorinating agent.

5. Pharmaceutical preparations consisting of a compound according to claim 1 and customary pharmaceutical carriers and / or diluents.

20th

N-P = O

Rv
₃

wherein X are halogen atoms with a compound of the formula

The invention relates to 2-rinane of the formula

Ri

NC Z ₁ Z ₂

^ NP = OCZ ₁ Z ₂

O —CZ ₁ Z ₂

wherein R _{1 is} the 2-chloroethyl or 3-chloropropyl radical, R ₂ and R ₃ together represent the 1,2-ethylene radical or R _{2 is} the 2-chloroethyl radical and R _{3 is} hydrogen, the methyl group, the 2-chloroethyl or the j5 2-hydroxyethyl radical and Z ₁ and Z ₂ , which can be identical or different, with hydrogen or alkyl groups. Are 1-4 carbon atoms.

Because of their particularly good properties, the compounds of the formula

R ₁ -NH-

OH

B) a compound of the formula

NH

with a 2-halo-2-oxo-1,3,2-oxazaphosphorinane of the formula

NC Z ₁ Z ₂
XP = O CZ ₁ Z ₂

O —CZ ₁ Z ₂

wherein X is a halogen atom, in the presence of an acid-binding agent or

_{/ N} -CH,

Cl-CH ₂ CH ₂ -NP = O CH ₂

R ₃ O -CH ₂

preferred.

Among these compounds, the compounds of the formulas have the best properties

CH ₂ CH ₂ Cl

55

Cl-CH ₂ CH ₂ N-CH ₂

NP = O CH ₂

Cl-CH ₂ CH ₂

O-CH ₂ CH ₂ CH ₂ Cl

b5

Cl-CH ₂ CH ₂ -NP = O CH ₂

H 0-CH ₂

Let the new 2-oxo-l, 3,2-oxazaphosphorinane

produce themselves in a manner known per se by the fact that
A) a phosphoric acid amide dihalide of the formula

N-P = O

R ₃ X

wherein X are halogen atoms, generally chlorine atoms, with a compound of the formula

R ₁ -NH-

or
B) a compound of the formula

OH

NH

with a 2-halogeno-2-oxo-1,3,2-oxazaphosphorinane of the formula

NC Z ₁ Z ₂

XP = OCZ ₁ Z ₂

O —CZ ₁ Z ₂

wherein X is a halogen atom, generally a chlorine atom, in the presence of an acid-binding agent or
C) a 2-oxo-l, 3,2-oxazaphosphorinane of the formula In general, reactions A, B and C are carried out in an inert solvent such as. B. a low molecular weight haloalkyl such as chloroform or methylene chloride, or in an aromatic hydrocarbon such as benzene or toluene, or in an ether such as diethyl ether or dioxane. The acid-binding agent is expediently present in process variant A in an amount corresponding to at least 2 molar equivalents and in process variant B in an amount corresponding to at least 1 molar equivalent, since the total amount of the acid HX formed during the reaction is preferably captured. As acid-binding agents, numerous basic compounds are known to the person skilled in the art, such as, for. B. alkali carbonates and bicarbonates and especially tertiary amines such as triethylamine or pyridine. The reaction can be carried out at room temperature or at an elevated temperature, such as up to the boiling point of the solvent at an elevated temperature. Halogenating agents for exchanging aliphatically bound hydroxyl groups for halogen atoms are also known to the person skilled in the art. Examples are the phosphorus trihalides such as phosphorus trichloride, phosphorus tribromide, the phosphoric acid halides such as phosphorus pentachloride, phosphorus oxychloride and phosphorus oxybromide, the sulphurous and sulfuric acid halides such as sulfuryl chloride and thionyl chloride or phosgene. Because of its easy handling, thionyl chloride is preferably used to replace hydroxyl groups with chlorine atoms. Reaction-sensitive groups may need to be protected by introducing known protective groups beforehand and subsequently splitting them off. On the other hand, it may also be desirable to _{exchange hydroxyl groups in the formula given, in which both R 3} and R ₄ contain hydroxyl groups, for halogen atoms at the same time.

In process A) it is also possible to use an ethyleneimino alcohol of the formula

NC Z ₁ Z ₂

NP = OCZ ₁ Z ₂

R ₃ O-CZ ₁ Z ₂

wherein R _{4 is} the 2-hydroxyethyl or 3-hydroxypropyl radical, is reacted with a halogenating agent. The synthesis according to A takes place, for. B. according to German patents 10 57119 and 10 54997, in which the reaction of phosphamide dichlorides of the formula given in an inert solvent in the presence of two molar equivalents of triethylamine is described as an acid scavenger. The synthesis according to B is as in J. org. Chem. 26 (1961) p. 4743. Method C is carried out according to the usual methods for replacing aliphatic hydroxyl groups with halogen atoms. The starting materials used are known or can be prepared according to procedures known from the literature.

CH ₂

N-

CH ₂

No. ₁
-C-

4-OH

HCl

Cl-CH ₂ CH ₂ -NH-

can be assumed. In this case the starting product is made in situ by splitting the ethyleneimine ring formed by the hydrogen chloride formed during the reaction, which is then prepared according to synthesis A continues to react.

The 2-OxO-I ₁ S ^ -OXaZaPhOSPhO-rinanes according to the invention are valuable as cytostatically active compounds in human and veterinary medicine.

The compound of Example 1 is characterized by

a very good chemotherapeutic efficacy on the chemotherapy-resistant mouse tumor sarcoma 37 and Ehrlich's carcinoma, on which the known comparison substance 2- [N, N-bis- (2-chloroethyl) -amino] -2-oxo-1,3,2-oxazaphosphorinane U.N-

is effective or only works in a sub-toxic dose. The compound of Example 4 is distinguished from the comparison substance in that the accumulation of the toxic active components is lower in the lethality test. The d .'.- r DL ₅₀ (4) value for substance A is 140 mg / kg and thus lower than the DL ₅₀ (I) value, while the DL ₅₀ (4) for the compound of Example 4 Value of 190 mg / kg is clearly higher than the DL ₅₀ (I) value. The lower toxic accumulation is important for the longer application.

In addition, the compound of Example 4 is distinguished by good solubility in water and also represents a new type of cytostatic action in which the two 2-chloroethyl groups no longer on the same nitrogen atom as with the nitrogen mustard compounds, but on two different ones acid amide-linked nitrogen atoms.

Finally, the compounds according to the invention stand out well compared to those in practice introduced, cytostatically active 2- [N, N-bis (2 - chloroethyl) - amino] - 2 - oxo -1,3,2 - oxazaphosphorinane characterized by greater stability in aqueous solution.

The following examples explain the process according to the invention:

example 1

2- [N, N-bis (2-chloroethyl) amino] -3- (2-chloroethyl) -

2-oxo-1,3,2-oxazaphosphorinane

259 g (1 mol) of N, N-bis (2-chloroethyl) phosphoric acid amide dichloride, 209 g (1.2 mol) of N- (2-chloroethyl) -N- (3-hydroxypropyl) amine hydrochloride (crude), 1000 ml of methylene chloride, 344 g (3.4 mol) of triethylamine.

The N, N-bis (2-chloroethyl) -phosphoric acid amide dichloride is dissolved in the methylene dichloride, the N- (2-chloroethyl) -N- (3-hydroxypropyl) amine hydrochloride is suspended in this solution and the triethylamine is suspended with stirring dripped in. The solution comes to a boil. The mixture is then heated to boiling for a further 6 hours, ^{cooled to about 0 °} C. overnight and the triethylamine hydrochloride which has precipitated is filtered off with suction. The methylene chloride solution is concentrated, the residue (~ 370g) is suspended in about 3.21 ether and briefly heated to the boil. The ethereal solution is decanted from the insoluble fraction (~ 90 g), adjusted to pH 6.5-7 with ethereal hydrochloric acid, filtered clear with charcoal and then concentrated. Do not exceed 40 ° C. The residue is dissolved in 0.5 times the amount of ether (240 g in 120 ml), cooled to -5 ° C and inoculated. After 24 hours, 143 g have crystallized out. After suction, the mother liquor is diluted to five times its volume with ether, filtered through charcoal, concentrated again and again dissolved in half the volume of ether. Crystallize by again cooling down to -5 ⁰ C and seeding a further 18 g of.

Yield: 161 g = 50% of theory.

Mp .: 50-51 ⁰ C.

Example 2

2- [N, N-bis (2-chloroethyl) amino] -3- (2-chloroethyl) -2-oxo-1,3,2-oxazaphosphorinane

64.7 g (0.25 mol) of N, N-bis (2-chloroethyl) phosphoric acid amide dichloride, 130 ml dioxane, 25.2 g (0.25 mol)

50

55

60

65 ethyleneiminopropanol, 25.2 g (0.25 mol) of triethylamine, 50 ml of dioxane. The solution of ethyleneimino-propanol and triethylamine in 50 ml of dioxane is added dropwise with stirring to the solution of N, N-bis (2-chloroethyl) phosphoric acid amide dichloride in 130 ml of dioxane. The temperature must be kept ^{at 50 ° C. by cooling.} After the end of the dropping in, the mixture is stirred for a further 3 hours at 50 ° C., cooled and the precipitated triethylamine hydrochloride is filtered off with suction. The mother liquor is concentrated in vacuo and the residue is dissolved in 500 ml of ether. This solution is washed 3 times with water, then with dilute soda solution and again with water. Then dried over sodium sulfate and concentrated to about 130 g. This solution is cooled to -5 ° C. and seeded, 28 g crystallize out in the process. The mother liquor is diluted to five times its volume with ether, filtered through charcoal and concentrated. The residue is then dissolved in half the volume of ether and cooled again to -5 ° C. After inoculation, a further 10 g crystallize out.

Yield: 38 g = 47% of theory.

Mp .: 50-51 ⁰ C.

Example 3

2- [N, N-bis (2-chloroethyl) amino] -3- (2-chloroethyl) -2-oxo-1,3,2-oxazaphosphorinane

42.6 g (0.30 mol) of N, N-bis (2-chloroethyl) amine, 150 ml of methylene dichloride, 32.7 g (0.15 mol) of 2-chloro-3- (2-chloroethyl) -2H-tetrahydro -l, 3,2-oxazaphosphorine-2-oxide, 65 ml of methylene dichloride.

42.6 g of N, N-bis- (2-chloroeth3'l) -amine in 150 m! Dissolved methylene dichloride and, with stirring, with a solution of 32.7 g of 2-chloro-3- (2-chloroethyl) -2-oxo-1,3,2-oxazaphosphorinane added in 65 ml of methylene chloride. The mixture is boiled for 1 hour heated and then concentrated in vacuo. The residue is with 350 ml of abs. Ether shifted and the precipitated N, N-bis (2-chloroethyl) amine HCl sucked off. The ethereal solution is washed with dilute hydrochloric acid and sodium bicarbonate solution. After drying over sodium sulfate, the ether is distilled off and the oily residue is good dried, abs in 10 times the volume. Dissolved ether, filtered through charcoal and concentrated again. The residue is in 40 ml abs. Ether dissolved and for crystallization after cooling to -5 ° C with a Inoculated with crystal. After 24 hours, it is suctioned off and dried in vacuo.

Yield: 24.3 g = 50.1% of theory.

M.p .: 51-52 ° C.

Example 4

2- (2-chloroethylamino) -3- (2-chloroethyl) -2-oxo-1,3,2-oxazaphosphorinane

In a solution of 218 g (1 mol) of 2-chloro-3- (2-chloroethyl) -2-oxo-1,3,2-oxazaphosphorinane 127.6 g (1.1 mol) of N- (2-chloroethyl) amine hydrochloride are suspended in 600 ml of methylene chloride and 212 g of triethylamine were added dropwise with stirring. The mixture comes to a boil. After finished The dropwise addition is heated to boiling for a further 2 hours and, after cooling, the precipitated triethylamine hydrochloride sucked off. The filtrate is diluted with approx. 60 ml of diluted HCl (pH 3), twice with water, diluted soda solution and poured water twice

telt. After drying over Na ₂ SO ₄ , the methylene chloride is distilled off at normal pressure. The oily residue is dried in vacuo and then with 500 ml of abs in a perforator. Ether extracted. The oily extract crystallizes in the refrigerator after inoculation. After a few hours, it is filtered off with suction, washed with a little cold ether and dried in vacuo at room temperature.

Yield: 185 g = 71% of theory.

Fp .: 39-4 Γ C.

Example 5

2- (methyl-2-chloroethyl-amino) -3- (2-chloroethyl) -2-oxo-1,3,2-oxazaphosphorinane

90.8 g of triethylamine were added to a suspension of 52.2 g of 2-chloroethyl-3-hydroxypropylamine hydrochloride in 210 ml of methylene chloride and, with stirring, a solution of 52.5 g of N-methyl-N - (2-chloroethyl) - phosphoric acid amide dichloride added dropwise to 52.5 ml of methylene chloride. The mixture comes to a boil. After the end of the dropping in, the mixture was heated to boiling for a further 5 hours and, after cooling, the precipitated triethylamine-HCl was filtered off with suction. The filtrate was washed successively with dilute hydrochloric acid, water, 2N soda solution and twice more with water. After drying over Na ₂ SO ₄ , the mixture was concentrated in vacuo and the oily residue was dissolved in 12 times the amount of ether, filtered through charcoal and concentrated again. The colorless oil was dried in vacuo.

Yield: 52 g = 75.5% of theory.

Example 6

2-Ethylenimino-3- (2-chloroethyl) -2-oxo-1,3,2-oxazaphosphorinane

A solution of 4.73 g of ethyleneimine and 11.1 g Triethylamine in 30 ml of ether is stirred into a solution of 21.8 g of 2-chloro-3- (2-chloroethyl) -2-oxo-1,3,2-oxazaphosphorinane in 132 mi abs. Ether dripped in. The mixture heats up and triethylamine HCl was cancelled. After the dropwise addition, the mixture is stirred for a further 2 hours at room temperature. then the precipitated triethylamine-HCl is suctioned off, the filtrate is filtered through charcoal and the solvent is removed distilled off. The remaining oil is well dried in vacuo and then in 10 times the volume Section. Ether dissolved. The solution is filtered once more through charcoal and concentrated again. The oily residue is dried thoroughly in vacuo.

Yield: 15 g = 67% of theory.

Example 7

2- [N, N-bis (2-chloroethyl) amino] -3- (3-chloropropyl) -2-oxo-1,3,2-oxazaphosphorinane

31.9 g (V ₁₀ mol) 2- [N, N-bis- (2-chloroethyl) -amino] -3- (3-hydroxypropyl) -2-oxo-1,3,2-oxazaphosphorinane are dissolved in 80 ml Dissolved chloroform and mixed with a solution of 14 ml (V ₁₀ mol) SOCl ₂ in 20 ml chloroform with stirring. A weak exothermic reaction occurs. After the end of the dropping in, the mixture is heated to an internal temperature of 38-40 ° C. while passing nitrogen through. After 3 hours, the evolution of HCl and SO _{2 has} ended. After cooling, the solution is shaken with 0.1 N hydrochloric acid until the acidic reaction persists. It is then neutralized with dilute sodium bicarbonate solution and the chloroform solution is dried with sodium sulfate. After the sodium sulfate has been filtered off with suction, the chloroform is distilled off in vacuo and the oily residue is dried thoroughly. Yield: 16 g = 47.4% of theory.

Example 8

'"2- [N, N-bis- (2-chloroethyl) -amino] -3- (3-chloropropyl) -2-oxo-1, j, 2-oxazaphosphorinane

25.9 g of N, N-bis (2-chloroethyl) phosphoric acid amide dichloride (0.1 mol), 18.8 g of N- (3-chloropropyl) -N- (3-hydroxypropyl) amine hydrochloride (0.1 mol), 30.3 g of triethylamine (0.3 mol), 100 ml of dioxane.

The starting materials are heated to 50 ° C. for 3 hours while stirring. After cooling down, this will be Triethylamine hydrochloride which has precipitated is filtered off with suction and the solution is concentrated in vacuo. The oily residue is dissolved in 250 ml of ether and shaken with 0.1 N hydrochloric acid until the acidic reaction persists. It is then neutralized with dilute sodium bicarbonate solution and dried over sodium sulfate. Of the Ether is then carefully distilled off and the oily residue is dried thoroughly. Yield: 25 g = 74% of theory.

Example 9

2- [N, N-bis (2-chloroethyl) amino] -3- (2-hydroxyethyl) -2-oxo-1,3,2-oxazaphosphorinane

To a solution 8.0 g of N- (2-chloroethyl) -N- (2-hydroxyethyl) amine hydrochloride ( ¹ Z ₂₀ mol)

and 10.1 g of triethylamine ('/ ίο mol) in 50 ml of chloroform is a solution of 10.9 g of 2-chloro-3- (2-chloroethyl) -2-oxo-1,3 within 45 minutes at 28 ° C , 2-oxazaphosphorinane in 50 ml of chloroform was added dropwise. The mixture is stirred at room temperature for 2 hours and then at 40 ° C. for 2 hours. After standing overnight, the precipitated triethylamine hydrochloride is filtered off with suction and the solution is concentrated in vacuo. The oily residue is in the Soxhlet for several hours with abs. Ether extracted and the ether extract concentrated in vacuo. The resulting oil is extracted again in the liquid extractor and concentrated again. The oil is mixed with a little Al ₂ O ₃ and sucked through a G4 frit. The result is a pale yellow, medium-viscosity, water-soluble oil which is dried for several hours in a high vacuum. Yield: 6.5 g = 42.5% of theory.

Example 10

2- (methyl-2-chloroethyl-amino) -3- (3-chloropropyl) -2-oxo-1,3,2-oxazaphosphorinane

In a solution of 23.5 g of 2- (methyl-2-chloroethylamino) -3 - (3-hydroxypropyl) -2-oxo-1,3,2-oxazaphosphorinane and 14 g of pyridine in 100 ml of chloroform is stirred and passed through A solution of 13 ml of thionyl chloride in 50 ml of chloroform was added dropwise by nitrogen. After the end of the dropping in, ^{the mixture is heated to 50 °} C. for 3 hours and, after cooling, 100 ml of water are added. After the chloroform layer has been separated off and dried over sodium sulfate, the mixture is concentrated in vacuo at about 30 ° C. The oily residue is abs in 250 ml. Dissolved ether, filtered through charcoal and concentrated. The residue

is dried in a high vacuum.
Yield: 15 g = 60% of theory.
n'i: 1.4989.

Example 11

2- (methyl-2-chloroethyl-amino) -3- (2-chloroethyl) -2-oxo-1, 3,2-oxazaphosphorinane

In a solution of 45.2 g of 2- (methyl-2-hydroxyethyl) - amino - 3 - (2 - chloroethy 1) - 2 - oxo - 1,3,2 - oxazaphosphorinane and 27.9 g of pyridine in 150 ml of chloroform a solution of 41.9 g of thionyl chloride in 50 ml of chloroform is added dropwise while stirring and passing nitrogen through. By cooling with ice water, the temperature to 20-25 ° C is maintained, later 3 hours, heated to 40 ⁰ C. After cooling, 200 ml of water are added, the mixture is shaken vigorously, the chloroform phase is separated off, neutralized with a sodium bicarbonate solution and, after being separated off again, dried over magnesium sulfate. The chloroform is then distilled off in vacuo and the remaining oil is dried in a high vacuum.

Yield: 32 g = 66.1% of theory.

nf: 1.5042.

Example 12

2- [N, N-bis (2-chloroethyl) -amino] -3- (2-chloroethyl) -6-methyl-2-oxo-1,3,2-oxazaphosphorinane

In a solution of 22.5 g of N, N-bis (2-chloroethyl) amidophosphoric acid dichloride 18 g of N- (2-chloroethyl) -N- (3-hydroxybutyl) amine HCl are found in 75 ml of methylene chloride suspended and with stirring a solution of 27.3 g of triethylamine in 25 ml of methylene chloride dripped in. After the end of the dropping in, the mixture is heated to boiling after 3 hours and after that The precipitated triethylamine-HCl is filtered off with suction. The mother liquor is concentrated in vacuo at about 30 ° C, the oily residue in 300 ml of abs. ether dissolved, filtered through charcoal and again concentrated in vacuo.

Yield: 23 g = 78.3% of theory.

nV: 1.5059.

Example 13

2- (2-chloroethylamino) -3- (2-chloroethyl) -6-methyl-2-oxo-1,3,2-oxazaphosphorinane

In a solution of 46 g of 2-chloro-3- (2-chloroethyl) -6-methyl-2-oxo-1,3,2-oxazaphosphorinane 25.3 g / i-chloroethylamine-HCl are added to 100 ml of methylene chloride suspended and a solution of 42.1 g of triethylamine in 50 ml of methylene chloride was added dropwise with stirring. It is then heated to boiling for 2 hours and, after cooling, the precipitated Sucked off triethylamine-HCl. The mother liquor is concentrated in vacuo at about 30 ° C. and the oily one Residue in 500 ml of abs. Dissolved ether, filtered through charcoal and concentrated again in vacuo.

Yield: 49.8 g = 91.4% of theory.

nV: 1.5002.

Example 14

2- [N- (2-chloroethyl) -amino] -3- (2-chloroethyl) -4-methy 1-2-oxo-1,3,2-oxazaphosphorinane

32 g of 2-chloro-3- (2-chloroethyl) -4-methyl-2-oxo-1,3,2-oxazaphosphorinane and 17.7 g of N- (2-chloroethyl) amine HCl are placed in 75 ml of methylene chloride and 29.4 g of triethylamine in 25 ml of methylene chloride were added dropwise with stirring. Then 2 hours heated to boiling, cooled, the triethylamine-HCl suction filtered and the mother liquor diluted with 15 ml HCl, then with 10 ml of water and finally with 10 ml of sodium bicarbonate solution and Shaken twice with 10 ml of water. The methylene chloride phase is dried over sodium sulfate concentrated in vacuo. The oily residue is abs in 4 times the amount. Ether dissolved and filtered through charcoal, then concentrated in vacuo.

Yield: 32.3 g = 85% of theory.

nS ¹ : 1.5067.

Example 15

2- [N, N-bis (2-chloroethyl) amino] -3- (2-chloroethyl) -4-methyl-2-oxo-1,3,2-oxazaphosphorinane

21.4 g of N.N-Bis - ^ - chloroethyl / phosphoric acid amide dichloride and 17 g of N- (2-chloroethyl) -N- [4-hydroxybutyl- (2)] - amine hydrochloride are in 75 ml of methylene chloride submitted and added dropwise with stirring 25.8 g of triethylamine in 25 ml of methylene chloride.

The mixture is then heated to boiling for 2 hours, cooled, the triethylamine HCl is suctioned off and the Mother liquor concentrated in vacuo. The residue is abs in 20 times the amount. Ether dissolved, with HCl ether adjusted to neutral, filtered through charcoal and concentrated in vacuo.

Yield: 22.2 g = 80% of theory.
n'i: 1.5128.

Example 16

^J5 2- (2-chloroethylamino) -3- (2-chloroethyl) -5,5-diethyl-2-oxo-1,3,2-oxazaphosphorinane

20.2 g of 2,2-dimethyl-N- (2-chloroethyl-aminopropanol- (1,3) -hydrochloride (V ₁₀ mol) are suspended in 160 ml of absolute chloroform, 31 g of triethylamine (V ₁₀ mol) was added portionwise The resulting clear solution is g in the course of 1 hour with mechanical stirring at an internal temperature of 20-25 ° C in a solution of 19.6 N -. ^ - ChloräthyO-phosphoric acid amide dichloride (Vio mol) in 120 ml of absolute chloroform are added dropwise, the mixture is stirred for a further 2 hours at 40 ° C., the solvent is evaporated in a water jet vacuum and the semi-solid residue is mixed with 100 ml of ether, the oily portion dissolves in the process, the crystalline portion consists of triethylamine hydrochloride is concentrated and the oil is purified by extraction with ether / petroleum ether (3: 1) in a perforator.The clear, colorless oil is soluble in alcohol, chloroform, dioxane and acetone.

Yield: 12.9 g d. see 44.6% of theory.

n'a ': 1.5012.

The oil can be kept solid if it is in

CHCl ₃ dissolved, with -yg- HCl, 5% NaHCO ₃ solution

and water, _{dried over CaCl 2} and concentrated again. The residue is dissolved in a little chloroform and placed on a column charged with 110 g of silica gel. It is eluted with 500 ml of chloroform. The remaining oil is dissolved in a little ether and crystallized in the refrigerator by rubbing with a glass rod.
M.p .: 71-72 ° C.

Example 17

2- [N, N-bis (2-chloroethyl) amino] -3- (2-chloroethyl) -5,5-dimethyl-2-oxo-1,3,2-oxazaphosphorinane

A suspension of 20.2 g of N- (2-chloroethyl) -2,2-dimethyl- is added with stirring and cooling

aminopropanol (l, 3) hydrochloride (7io mol) in 150 ml of abs. Chloroform in portions with 31 g of triethylamine ( ³ / io mol). The resulting clear solution is left in a dropping funnel over a period of 50 minutes at 25 ⁰¹ C in a solution of 25.9 g of N, N-bis (2-chloroethyl) phosphoric acid amide dichloride (7ioMol) in 130 ml of abs. Flow in CHCl ₃ . After stirring for 2 hours at 40 ° C., 150 ml of ether are added to completely separate out triethylamine hydrochloride and the mixture is left to stand in the refrigerator for 20 hours. The hydrochloride is separated off, the filtrate is concentrated in a water jet vacuum and the oily residue is extracted in a perforator with ether / petroleum ether (1: 2). Then the oil is dissolved in CH ₂ Cl ₂ , one after the other

with 35 HCl, 5% NaHCO ₃ solution and water

washed and dried over Na ₂ SO ₄ . dried. The solvent is removed in a water jet vacuum and dried in a high vacuum.

The result is a clear, colorless oil that dissolves in alcohol, Chloroform, acetone and dioxane is soluble.

Yield: 23 g (66.4% of theory).

ni °: 1.5067.

Example 18

2- (2-chloroethylamino) -3- (2-chloroethyl) -6-ethyl-2-oxo-1,3,2-oxazaphosphorinane

In a solution of 10.5 g of 2-chloro-3- (2-chloroethyl) -6-ethyl-2 H-tetrahydro-1,3,2-oxazaphosphorine-2-oxide in 50 ml of methylene chloride, 5.5 g of 2 -Chloräthylamin-HCl suspended and added dropwise with stirring a solution of 8.6 g of triethylamine in 30 ml of methylene chloride. The mixture is then heated to boiling for 3 hours and, after cooling, the precipitated triethylamine-HCl is filtered off with suction. The mother liquor is washed with water, dilute HCl and dilute Na ₂ CO ₃ solution, then dried and concentrated in vacuo. The oily residue is dissolved in ten times the amount of abs. Ether, filtered through charcoal and concentrated again in vacuo. The residue is taken up in a little ether and allowed to crystallize _{in an acetone-CO 2 mixture with cooling.}

Yield: 11.2 g = 91% of theory.

M.p .: 64-66 ° C.

Example 19

2- (2-chloroethylamino) -3- (2-chloroethyl) -6-propyl-2-oxo-1,3,2-oxazaphosphorinane

ίο In a solution of 9.4 g of 2-chloro-3- (2-chloroethyl) -6-propyl-2-oxo-1,3,2-oxazaphosphorinane in 50 ml of methylene chloride were 4.2 g of 2-chloroethylamine-HCl suspended and with stirring a solution of. 7.3 g of triethylamine in 20 ml of methylene chloride were added dropwise. The mixture was then heated to boiling for 2 hours and, after cooling, the reaction mixture washed with water, dilute hydrochloric acid, water, dilute soda solution and again with water. After drying with sodium sulfate, the mixture was concentrated in vacuo. The oily residue was in Dissolved a little ether and crystallized with a dry ice-acetone mixture while cooling. It was filtered off with suction and dried in vacuo at room temperature. White crystals.

Yield: 6.7 g = 61.4% of theory.
M.p .: 40- ^ 1 ° C.

Example 20

2- [bis- (2-chloroethyl) -amino] -3- (2-chloroethyl) -6-propyl-2-oxo-1,3,2-oxazaphosphorinane

25.9 g of N, N-bis (2-chloroethyl) amido-phosphoric acid dichloride and 32.4 g of N- (2-chloroethyl) -N- (3-hydroxyhexyl) -amine-HCl were in 120 ml of methylene chloride submitted and a solution of 35.3 g of triethylamine in 30 ml of methylene chloride with stirring dripped in. The mixture was then heated to boiling for 3 hours, and after cooling was the Reaction mixture with water, dilute hydrochloric acid, water, dilute soda solution and again with Water washed. The methylene chloride phase was dried over sodium sulfate and in vacuo constricted. The oily residue was purified by column chromatography on silica gel with benzene as the eluent purified to acetone = 1: 1.

Yield: 26 g = 71% of theory.

Light oil: η ξ, ': 1.5060.

Claims (1)

Patent claims:
1. 2-Oxo-1,3,2-oxazaphosphorinanes of the formula N-P = O NC Z ₁ Z ₂ CZ ₁ item ₂ R ₃ 0-CZ _{1 line 2}