DE1645921C3 - 2-Oxo-13,2-osazaphosphorinane, process for their preparation and 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- [NJSf-BisK2-chloroethyl) -ammo] -3- (2-chloroethyl) -2-oxo-1,3,2-oxazaphosphorinane.

3.2- (2 - (^ orätnylamino) -3- (2-chloroethyr) -2-oxo-1,3,2-oxazaphosphorinane.

4. Process for making the compounds according to claim 1, characterized in that in a known manner

A) a phosphoric acid amide dihalide of the formula

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

R ₄ R, 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 chlorinating agent

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

N-P = O

R ₃ X

wherein X are halogen atoms with a compound of the formula

30th

35

R ₁ -NH-

OH

or B) a compound of the formula

NH

The invention relates to 2-rinane of the formula

R ₂ NC Z ₁ Z ₂

NP = OCZ ₁ Z ₂

R ₃ Ο - CZ ₁ Z ₂

where R _{1 is} the 2-chloroethyl or 3-chloropropyl radical, R2 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 2-hydroxyethyl radical and Z ₁ and Z ₂ , which can be the same or different, are hydrogen or alkyl groups having 1-4 carbon atoms.

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

40

45

50

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

1·

N = CZ ₁ Z ₂ XP = O CZ ₁ Z ₂

OC Z ₁ Z ₂

wherein X is a halogen atom, in the presence of one acid-binding agents or

Q-CH ₂ CH ₂ -NP = O CH ₂

R ₃ O-CH ₂

preferred

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

CH ₂ CH ₂ Cl Cl-CH ₂ CH ₂ N-CH ₂

NP = O CH ₂

Cl-CH ₂ CH ₂ CH ₂ Q-

60

65 CH ₂ CH ₂ Cl

N-CH ₂

/ ^S N

Cl-CH ₂ CH ₂ -NP = O CH ₂

HIGH - HIGH ₂

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

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

R ₁ X

N-P = O

R ₃ X

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

R ₁ -NH-

C-

-OH

or B) a compound of the formula

NH

R ₃

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

NC ₁ XP = OCZ ₁ Z ₂

O — CZ _{1 line 2}

wherein X is a halogen atom, generally a chlorine atom, in the presence of an acid-binding agent or C) a 2-Oxc-1,3,2-oxazaphosphorinane of the formula In general, the reactions A, B and C in an inert solvent such as ζ, Β, 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 carried out at least 2 molar equivalents and in the process Variant B in an amount corresponding to at least 1 molar equivalent present, as the total amount of acid formed during the reaction is preferred HX is intercepted. The person skilled in the art is familiar with numerous basic compounds as acid-binding agents knows how B. Alkali carbonates and bicarbonates and especially tertiary amines such as triethylamine or pyridine. The reaction can take place at room temperature or elevated temperature such as carried out up to the boiling point of the solvent elevated temperature will. 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 sulfur and Sulfuric acid halides such as sulfuryl chloride and thionyl chloride or phosgene. Because of its light weight Manageability becomes for the replacement of hydroxy groups against chlorine atoms are preferred by thionyl chloride used Reaction-sensitive groups are, where appropriate, by introducing beforehand to protect known protective groups and subsequent cleavage of the same. On the other hand, it can

j5 it may also be desirable to exchange hydroxyl groups in the given formula, in which both R ₃ and R ₄ contain hydroxyl groups, for halogen atoms at the same time. In method A) can also be from a

Ethylenimino alcohol of the Formsi

R ₂ 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 example, according to German patents 1057119 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,

CH ₂

N-

OH

HCl

No. ₁

CI-CH ₂ CH ₂ -NH-

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

Μ The 2-oxo-1,3,2-oxazaphospho-

rinane are used in human and veterinary medicine valuable as cytostatic compounds.

The compound of Example 1 is characterized by

show a very good chemotherapeutic effectiveness

(, 5 the chemotherapy-resistant mouse tumors sarcoma 37 and Ehrlich's carcinoma, on which the known comparative _{substance 2- [N 1} N-bis- (2-chloro * ethyl) -amino] -2-oxo-1,3,2-oxazaphosphorinane U.N-

is effective or only works in a subtoxic dose. The compound of Example 4 is distinguished from the comparison substance in that the accumulation of the toxic active component in the lethal test is lower. The DL ₅₀ (4) value for substance A is 140 mg / kg and thus lower than the DL ₅₀ (l) value, while for the compound of Example 4 the DL ₅₀ (4) value is 190 mg / kg clearly higher than the DL ₅₀ (I) value, the lower toxic accumulation is of ι ο importance in 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 are 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 what is used 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 ^J0

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. ^J5

The NN-bis - ^ - chloräthyO-phosphoric acid amide dichloride is dissolved in methylene dichloride, the N- (2-chloroethyI) -N- (3-hydroxypropyl) amine hydrochloride is suspended in this solution and the triethylamine is added dropwise with stirring. 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 (~ 370 g) is inoculated in about 3.21 ether and briefly heated to the boil. The ethereal solution is decanted from the insoluble part (~ 90g), adjusted to pH 6.5-7 with ethereal hydrochloric acid, filtered clear with charcoal and then concentrated. 40 ⁰ C must not be exceeded. 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. Another 18 gauss crystallize by cooling again to -5 ° C and inoculating.

Yield: 16Ig = 50% of theory.

Fp .: 50-51 ⁶ C.

Example 2

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

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

60 AthylenimfoopropanQl, 25.2g (0.25 mol) of triethylamine, 50 ml of Diajmn, the solution of ethy lenimino-propanol and triethylamine in 50 ml of dioxane is stirred into the solution of N, N-bis (2-chloroethy |) phosphoric acid amide dichloride added dropwise to 130 ml of dioxane. The temperature must be kept at 50 ° C. by cooling. After the end of the dropwise addition, the mixture is stirred for 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 mixed 3 times with water, then with dilute soda solution and again washed with water. Then dried over sodium sulfate and concentrated to approx. 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 the inoculation, a further 10 g crystallize out.

Yield: 38 g = 47% of the Theone.

M.p .: 50-51 ° 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) -2 H-tetrahydro-1,3,2-oxazaphosphorine-2-oxide, 65 ml of methylene dichloride.

42.6 g of N, N-bis (2-chloroethyl) amine is dissolved in 150 ml Dissolved methylene dichloride and, while stirring, with a solution of 32.7 g of 2-chloro-3- {2-chloroethyI) -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 mixed with 350 ml of abs. Ether shifted and the precipitated N, N-bis- {2-chloroethyI) -amm-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-oxc-1,3,2-oxazaphosphorinane

In a solution of 218 g (1 mol) of 2-chloro-3- (2-chloroethyl) -2-oxo-1,3,2-oxazaphosphorinane In 600 ml of methylene chloride, 127.6 g (1.1 mol) of N- (2-ChloräthylHniin-hydrQ € hlQric!) are suspended and 212 g of triethylamine were added dropwise with stirring. The mixture comes to the boiling point. 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 mixed with approx. 60 ml of dilute HCl (pH 3), twice with water, diluted soda solution and twice water poured out

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 ^ 41 ⁰ C.

Example 5

2- (methyl-2-chloroethyl-amino) -3- (2-chloroethyl> 2-oxo-1,3.2-oxazaphosphorinane

To a suspension of 52.2 g of 2-chloroethyl-3-hydroxypropylamine hydrochloride in 210 ml of methylene chloride were added 90.8 g of trihydric acid 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-HCI was filtered off with suction. The filtrate was sequentially washed with dilute hydrochloric acid. Water, 2 N soda solution and washed twice 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 ethylene imine 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 ml abs. Ether dripped in. The mixture heats up and triethylamine HCI was cancelled. After the dropwise addition, the mixture is stirred for a further 2 hours at room temperature. then the precipitated triethylamine-HCI is suctioned off, the filtrate is filtered through charcoal and the solvent is removed distilled off. The remaining oil is good in a vacuum. dried and then in 10 times the volume Section. Ether dissolved. The solution is again ß'iriert over charcoal and concentrated again. The oily residue is dried thoroughly in vacuo.

Yield: 15 g = 67% of theory.

Example 7

2-oxo-1,3.2-oxazaphosphorinane

31.9 g ( 'I ₀ MoI) 2- [N, N-bis (2-chloräthyI> amino] -3- (3-hydroxypropyl) - 2-oxo-l.3,2-oxazaphosphorinane are dissolved in 80 ml Dissolved chloroform and mixed with a solution of 14 ml i ² 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 nitrogen is passed 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-1,3,2-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, the external TnäinyiämmiiyurüCiiiüTiu is suctioned off 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

2> 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-oxazaphosphonane

To a solution 8.0 g of N- (2-chloroethyl) -N- (2-hydroxyethyl) amine hydrochloride (V _2U mol)

ι, and 10.1 g of triethylamine C ₁₀ MoI) in 50 ml of chloroform is within 45 minutes at 28 'C, a solution of 10.9 g of 2-chloro-3- (2-chloroethyl) -2-oxo-1,3 , 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 in vacuo

4-, narrowed. 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-ainino) -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, while stirring and passing nitrogen through a solution of 13 ml of thionyl chloride in 50 ml of chloroform was added dropwise. 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, it is concentrated in vacuo at approx. 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 ?: 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 - chloroethyl) - 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 is added while stirring and bubbling through nitrogen Chloroform, added dropwise. The temperature is kept at 20-25 ° C by cooling with ice water, later it is heated to 40 ° C. for 3 hours. After cooling, 200 ml of water are added, vigorously shaken, the chloroform phase separated, neutralized with a sodium bicarbonate solution and after being separated off again, dried over magnesium sulfate. Then the chloroform is in vacuo distilled off and the remaining oil dried in a high vacuum.

Yield: 32 g = 66.1% of theory.

n ?: 1.5042.

Example 12

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

Ii a solution of 22.5 g of N, N-bis (2-chloroethyl) amido phosphoric acid dichloride 18 g of N- (2-chloroethyl) -N- {3-hydroxybutyl) -amine-HCl are added to 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-HCI 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.

n ?: 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 in 100 ml of methylene chloride, 25.3 g / I-chloroethylamine-HCl 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 Triethylamine HCI sucked off. The mother liquor is concentrated in vacuo at about 30 ° C. and the oily Residue in 500 ml of abs. Aether dissolved over coal filtered and concentrated again in vacuo

Yield: 49.8 g = 91.4% of theory.

nS: 1.5002.

Example 14

2- [N- {2-chloroethyl) amino] -3 - (. 2-chloroethyl) -4-methyl-2-oxo-1,3,2-oxazapnosphorine

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 dissolved in 75 ml of methylene chloride submitted and added dropwise with stirring 29.4 f, triethylamine in 25 ml of methylene chloride. Then it is heated to boiling for 2 hours, cooled, the triethylamine HCl is suctioned off and the mother liquor is shaken with 15 ml of dilute HCl, then with 10 ml of water and finally with 10 ml of sodium bicarbonate solution and twice with 10 ml of water. After drying over Ναι ο trium sulfate, the methylene chloride phase is concentrated in vacuo. The oily residue is abs in 4 times the amount. Dissolved ether and filtered through charcoal, then concentrated in vacuo. Yield: 32.3 g = 85% of theory.
«S: 1.5067.

Example 15

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

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

2ί It is then heated to boiling for 2 hours, cooled, the triethylamine-HCI filtered off with suction and the mother liquor concentrated in vacuo. The residue is used in 20 times the amount of abs. Ether dissolved, adjusted to neutral with HO ether, filtered through charcoal and im

concentrated to vacuum.

Yield: 22.2 g = 80% of theory,
n ?: 1.5128.

Example 16

"2- (2-chloroethylamino) -3- (2-chloroethyl) -5,5-dimethyl-2-oxo-1,3,2-oxazaphosphorinane

20.2 g of 2,2-dimethyl-N- (2-chloroethyl-aminopropanol- (1,3) -hydrochloride (1/10 mol) are suspended in 160 ml of absolute chloroform, 31 g of triethylamine ( ³ / ₁₀ moles) added in portions. 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- (2-chloroethyl) -phosphorsäureamid dichloride (V ₁₀ mol) are added dropwise to 120 ml of absolute chloroform, the mixture is stirred for a further 2 hours at 40 ° C., the solvent is evaporated off in a water-jet vacuum and the semi-solid residue is mixed with 100 ml of ether, the oily one

so part goes into solution, the crystalline consists of triethylamine hydrochloride. The filtrate is concentrated and the oil is purified by extraction with ether / petroleum ether (3: 1) in the perforator. The clear, colorless oil is soluble in alcohol, chloroform, dioxane and acetone.

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

n ?: 1.5011

The oil can be kept solid if it is in

CHCl ₃ dissolved, with -r! R HQ, 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 filled with HOg 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 aminopropanol- (l, 3) hydrochloride ( ^l / _l0 mol) in 150 ml of abs is added with stirring and cooling. Chloroform in portions with 31 g of triethylamine ( ³ Ao mol). The resulting clear solution is poured from a dropping funnel over a period of 50 minutes at 25 ° C. into a solution of 25.9 g of N, N-bis (2-chloroethyl / phosphoric acid amide dichloride mol) in 130 ml of abs. Flow in CHCIj. After 2 hours stirring at 40 ⁰ C 150mf ether is added to complete precipitation of triethylamine hydrochloride, and allowed to stand for 20 hours in the refrigerator. The hydrochloride is separated off, the filtrate is concentrated in a water jet vacuum and the oily residue is extracted in a Feifuraiur rnii ether / pure ether (i: 2). Then the oil is dissolved in CH ₂ Cl ₂ , successively with ^ q HCl, 5% NaHCO ₃ solution and water

washed and dried _{over Na 2} SO _4. 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).

n ?: 1.5067.

Crystallize with cooling in an acetone-CO ₂ mixture.

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

In a solution of 9.4 g of 2-chloro-3- (2-chloroethyl) -6-propyl-2-oxo-1,3.2-oxa7: aphosphorinan 4.2 g of 2-chloroethylamine-H ('l were suspended in 50 ml of methyl chloride and a solution of 7.3 g of triethylamine in 20 ml of methylene chloride

It was then heated to boiling for 2 hours, after cooling the reaction mixture: with water, dilute hydrochloric acid, water, dilute Soda solution and washed again with water. After drying with sodium sulfate was im

- '"Vacuum concentrated. The oily residue was dissolved in a little ether and, while cooling, with a Brought dry ice-acetone mixture to crystallize. It was suctioned off and in a vacuum Dried at room temperature. White crystals.

r> Yield: 6.7 g = 61.4% of theory.
M.p .: 40-41 "C.

Example 18

2- (2-chloroethylamino) -3- (2-chloroethyl) -6-ethyl-2-oxo-l , 3,2-oxazaphosphor.nan

In a solution of 10.5 g of 2-chloro-3- (2-chloroethyl) -6-ethyl-2H-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-HCI is filtered off with suction. The mother liquor is washed with water, dil. 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 with a little ether and left

Example 20

_{J ()} 2- [bis- (2-chloroethyl) amino] -3- (2-chloroethy!) - 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

r> chloride and a solution with stirring of 35.3 g of triethylamine in 30 ml of methyl chloride are added dropwise. It was then boiled for 3 hours heated, and after cooling the reaction mixture with water, dilute hydrochloric acid, Water, dilute soda solution and washed again with water. The methylene chloride phai ^ was dried over sodium sulfate and concentrated in vacuo. The oily residue was purified by column chromatography on silica gel with mobile solvent

4) zol to acetone = 1: 1 purified.

Yield: 26 g = 71% of theory.
Light oil: nl ': 1.5060.

Claims (1)

Claims: 1. 2-Oxo-l, 3,2-oxazaphosphorinane of the formula R, R ₂ NC Z ₁ Z ₂ NP = OCZ ₁ Z ₂ ίο R ₃ O-CZ ₁ Z ₂