FI56387C - FOERFARANDE FOER FRAMSTAELLNING AV ALKANSULFONSYRAESTRAR AV 1,3,2-OXAZAFOSFORINFOERENINGAR MED IMMUNITETSSAENKANDE VERKAN - Google Patents

Description

ΓβΙ «« ANNOUNCEMENT ς C * 5 O 7 «STa (11 ^ UTLÄGGNI NGSSKMFT ϊ> OJ g / C ^ Patent granted 10 01 1930 Patent meddelat v (51) Kv.ik.« / Int.ci. * C 07 P 9 / 65 FINLAND —FINLAND (21) PtMnttlhtkemu * - Pit * nt »n * öknlnf 1 + 1 + 5/72 (22) H» k * mltpllvl - Aineknlnftdag l8.02.72 (23) Alkupilvi — Gilti | h * ttd> { l8.O2.72 (41) Made public - Bllvit effentllg 20 08 72

Patent and Registry Managed. (44+ Nihaviksipanon |. KuLLulksiwn pvm.-

Patanfe-eeh regitterttyrelMn Anseksn utiagd och uti.skrtftea publicerad 28.09.79 (32) (33) (31) Privilege claimed — Buglrd prloritet # Q2.71 11 + .01.72 Federal Republic of Germany-Förbunds-republiken Tyskland (DE) P 21079 2201675-7 (71) Asta-Werke Aktiengesellschaft, Chemische Fabrik, 1 + 812 Brackwede,

Westfalen, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (72) Herbert Arnold, Heidelberg, Friedrich Bourseaux, Brackwede,

Jiirgen Potel, Gadderbaum, Norbert Brock, Uerentrup, Federal Republic of Germany - Förbundsrepubliken Tyskland (DE) (7I +) Berggren Oy Ab (5! +) and 1,3,2-oxazaphosphoric compounds with immunocompetence

The present invention relates to the preparation of alkanesulfonic acid esters of 1,3,2-oxazaphosphorine compounds having an immunosuppressive effect.

The compounds of the invention correspond to the general formula I

/ V * i

R-alk-N-P = 0 X I

wherein R is a chlorine atom or a lower alkylsulfonyloxy group having an alkyl group having 1 to 5 carbon atoms, R 1 and R 2 are independently hydrogen atoms or alkyl groups having 1 to 3 carbon atoms and may have a chlorine atom or a lower alkylsulfonyloxy group, wherein the molecule of formula I has at least one alkylsulfonyloxy group, alk is an ethylene or propylene group 2b 3 b / or an ethylene group substituted by a methyl or ethyl group and Z 1, Z 2 and are independently hydrogen or methyl groups.

The process according to the invention for the preparation of the compounds of the formula I is characterized in that

A) a compound of general formula IV

R 1 -alk-N-Pv = 0 IV

3 I \ R4 X1

in which formula is the same as R in formula I or is a hydroxy group, R 1 is the same as R 4 in formula I or is an alkyl group having 1 to 3 carbon atoms and having a hydroxy group, alk is the same as in formula I and is a halogen atom, preferably chlorine atom is reacted with aminopropanol of general formula V.

ΖΊΖ,

II

Rc-HN-CH2--C-CH-OH V

5 2 I

Z2 in which formula has the same meaning as R1 in formula IV and Z2, Z2 and Z2 have the same meaning as in formula I, or

B) an amine of general formula VI

R3-alk-NH VI

R4

wherein R 1 and R 2 are as defined in formula IV and alk is as defined in formula I are reacted with a compound of general formula VII

Is / N ^ V Z1 X1 - ^ z2 Z3 in which formula has the same meaning as in formula IV, has the same meaning as in formula V and Z ^, Z2 and Z3 have the same meaning as in formula I, or 3 D Ö 3 0 t

C) a compound of general formula VIII

f5 £ Γί, -ρ <ο ~ \ <Ζΐ S \ ° ~ κ 2.2 z3

wherein R 9 is as defined in formula V and Z 1, Z 2, Z 2 and alk are as defined in formula I are reacted with a compound of general formula IX

H + R3 IX

wherein R 1 is as defined in formula IV, and in the resulting compounds of formula X.

rV’1 i, Z3

in which one or more of the substituents R 1, R 2 and R 8 is a hydroxy group or contains a hydroxy group, the hydroxy groups are exchanged in a manner known per se for halogen atoms or a group -OSC 1 R 8 in which R 8 is an alkyl group having 1 to 5 carbon atoms, and in a compound of formula X none of the substituents R 9, R 4 and R 8 is a hydroxy group or does not contain such a group, and one or more of the substituents R 1, R 2 and R 8 is a halogen atom or contains a halogen atom, one or more of these halogen atoms being substituted if desired with a compound of general formula XI

Me0S02Rg XI

wherein R, has the same meaning as above and Me is periodic

O

the equivalent of a metal belonging to the first or second main or side group of the system, to the group -OSC ^ Rg.

The conversion of any hydroxy groups present into compounds of the formula X, halogen atoms or alkyl sulphonic acid groups, takes place by reacting these hydroxy compounds with 4 l υ 3 b t of halogenating agents, respectively, alkyl sulphonic acid halides, R, SO0Hal,

D Z

with wherein Rg is as defined above and Hal is a halogen atom, preferably a chlorine atom.

The reactions are preferably carried out in an inert solvent such as acetonitrile, or a low molecular weight halogenated hydrocarbon such as chloroform or methylene chloride, or an ether such as diethyl ether or dioxane, or an aromatic hydrocarbon such as benzene or toluene. In this case, work is carried out at a temperature ranging from room temperature to the boiling point of the reaction mixture.

The acid scavenger is suitably added in 1 or 2 molar equivalents. Suitable acid scavengers are several basic compounds known to those skilled in the art, such as alkali or alkaline earth metal carbonates and bicarbonates, and in particular tertiary amines, such as triethylamine or pyridine.

Halogenating agents for exchanging aliphatically bonded hydroxyl groups for halogen atoms are also known to the person skilled in the art. Useful are, for example, phosphorus halides, such as phosphorus trichloride or phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride or phosphorus oxybromide, sulfuric or sulfuric acid halides, such as sulfuryl chloride or thionyl chloride, or phosgene. Due to its ease of handling, thionyl chloride is preferably used to convert hydroxy groups to chlorine atoms.

Preferred due to their high immunosuppressive effect are the compounds of general formula II

I2 / N C [i2 \

R-alk-N-P = O CH-II

I \ ^ 2

° -CIV

wherein R, R1, R2 have the same meaning as in formula I.

5

In this case, the compounds of the formula III are very preferred

CH2CH2Cl

Ji-CH „/ 2 \

R_-SO "-O-alk-NH-P = O CH_ III

Wherein R 7 is an unsubstituted alkyl residue having 1 to 5 carbon atoms in a straight or branched chain, and alk is a residue -CH 2 CH 2 -, CHCH 2 - or -CH 2 CH-, especially a residue -CH 2 CH 2 -. ch3 c2h5 Of this group of compounds, due to its very high immunosuppressive effect, a compound of formula III is noteworthy, and therefore a compound in which alk is a residue -CH2CH2- and R7 is a methyl or ethyl group or alk is a residue -CHCH2- and R7 is a methyl group.

£ h3

The compounds of formula I have a very strong immunosuppressive effect (immunosuppression index> 1). This effect is particularly strong for the compounds of Examples 1 and 17 (see Table 1). To a lesser extent, it is present in the compounds of Examples 7, 12, 15, 18, 21 and 26. The reference substance "Busulfan"-1,4-bis- (methylsulfonyloxy) -butane, which is the main representative of the alkanesulfonic acid esters, does not show this effect in comparative experiments with the compound of Example 1 (see Table 2).

Due to the potent immunosuppressive effect, repeated use of the antigen and concomitant administration of an immunosuppressive agent can deplete the immune cell clone and induce immunotolerance in an immunologically mature animal. The compounds of Examples 1 and 17 can confer true immunotolerance, as shown in Table 3 of Example 1. The data show that the control group responded to the Brucella immunization with a primary and secondary response. In the treated animals, the formation of humoral Brucella antibodies is completely eliminated, while both groups of animals respond similarly to heterologous immunization with Listeria monocytogenes. This result is very relevant in self-aggression diseases and transplant surgery.

6 5 o 3 υ '

Commercial preparations of therapeutically used as so-called immunosuppressive agents azathioprine (6-T-methyl-4-nitroimidazol-5-yl) -thio-7-purine) and 6-mercaptopurine have been studied by Botzenhardt and Lemmel (Agents and Actions, 6 (1976) 596- 601) in various experimental models compared to the compound of Example 1.

A reduction in the primary immune response of less than 1% of the control can be achieved with a single dose of the compound of Example 1 corresponding to 5% of the dose of DL 50. In contrast, DL 50 doses of ansathioprine and 6-mercaptopurine were unable to reduce the immune response by less than 5% from control.

The secondary immune response is also reduced at non-toxic doses of the compound of Example 1 to less than 1% of the comparison, whereas even using doses of azathioprine or 6-mercaptopurine DL 50 does not provide a comparable suppressive effect.

table 1

Effect of various compounds of the invention on the formation of humoral antibodies in rats by Brucella immunization. .

after

Example Dose TE 1) Immunosuppression index 2) n; o_ mg / kg _ _ (days 7-14) _ 1 46.4 25 116 7 100 25 1.4 12 165 25 1.5 15 46.4 37 2, 8 17 34.8 25 27.4 18 46.4 14 4.5 21 62.0 25 1.4 26 150.0 37 2.6 1) TE: therapeutic units =% of DL 5Q 2) Immunosuppression index: Control group antibody titer geom.

average_

Geom of antibody titer in the experimental group. average 7.) vj 3 o t

Table 2

Dose-dependent immunosuppressive effect on humoral antibody after immunization of mice with a sheep erythrocyte count

Compound Dose TE Immunosuppression index DL 50 mg / kg __ (days 5 to 10) _ mg / kg ___ _ Henolysin Hemagglutinin _

Comparison 1 1

Example 133 15 13.1 33.9 55.5 25 89.3 144 222 88.8 40 893 288 3 15 3.5 1 "Busulfan" 5 2 5 3.5 1 20 8 40 4.6 1 8 J ϋ 3 ϋ /

E

Φ O

m - = r o o c ^ tD CM O C 'E ro oj ts r-i r-' p ....

CM- CO M M 'iH

^ o

E

ct) E

to CT)

to ^ v O

• H OJ -} t ~ - O

P t C— TO

O * rt M

E '' E ·· I TS I

aj 1 t

E CD

a) 60 CT) · Η P p

to E O

CT) CT) to o> to oj o to E ro ® io

rt E φ ·· I

P p (0 rH rH

S tO -H

thio O: cr) E

<U JE ΕΦ O

o E Φ ΕΦ to co o • Q Φ P V-JS) to -ro to

lu 60 COH TO (—1 Q (M

CT) o Ecrt ... .

»—1 P Φ · Μ i — I M i — I

rH> 5 Φ o ^ o o ^ vE E rH- ^ CT \ o X O - = r o CQ E Oj: cv) ro

ro o ct)> ·· l S) I

-H · Η -H i — t O P E: ct) • 6d X Φ (¾

Jx) E P

E T3 to "rH E · γΗ · Η

E · Η E) E O

CT) Φ O

E-1 E m p co oj • H p cm ro to -H · · l TS i

to E -H rH

E · p

CT) ij I

t-ι * H

Φ E O

| —I. * »RH O

O C0 · Η OO

PE E rH ·· I tS I

Ή p -rH i — I

EE P

E O E

E O rH

E ct) 60 oj E 60 • H tr) <O T3 ¢ 3 TS £ 3 tr)

rH CT) fO

E rH PE

Φ Φ PE

to O O E

Έ E E Φ rH E .... fl CT) CQ -rl M EE EE ro .rt ct) EM CQ · CQ o)

Ett Φ PJ. rt I — t O Φ p

g · 60 .EE

E E "rt O * rt

te CQ P · · X E

E M E I E I E

<CQ CQ '.CT) E

: ct) Φ> Φ • H ro: cr) m a ut

Φ OJ

• rl O

E Λ! «M

MM Jx) • rt E · r- ': cr) η) Φ M oj

EP E

.E E -H

> 5 Φ co cc> ω 9 56313 /

The following examples illustrate the present invention. The structure of the obtained compounds according to the invention has been determined by means of infrared spectra, in which e.g. the following characteristic lines: P = 0 - lines at wavelengths 1188-1275 cm-1, -C-SO 3 -C-lines at wavelengths 1330-1376 cm-1, 1165-1175, 905-975 787-805 cm -1, -POC- lines at a wavelength of about 1050 and 975 cm 1 and NH lines at a wavelength of 3200 to 3300 cm 1.

Example 1 2- (2-Mesyloxyethylamino) -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide

To a solution of 31.6 g of ethanolamine and 57 g of triethylamine in 300 ml of abs. dioxane, a solution of 113.2 g of 2-chloro-3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazafefin ± -5-oxide in 360 ml is added dropwise at 15-18 ° C. in abs. dioxane. After stirring for 1 hour at 30-35 ° C, the triethylamine hydrochloride is filtered off with suction and the filtrate is evaporated in a water-jet vacuum. The residue is washed 3-4 times with 100 ml of ether each time. After drying under high vacuum, 2- (2-hydroxyethylamino) -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide is obtained as a pale yellow oil.

Yield: 121.3 g = 97% of theory.

A solution of 121.3 g (0.5 moles) of the above compound and 50.6 g (0.5 moles) of triethylamine in 320 ml of dioxane is added dropwise over 30 minutes at 26-28 ° C to a solution of 57.3 g (0.5 mol) of methanesulphonic acid chloride in 340 ml of dioxane with stirring. 150 ml of ether are added to the reaction mixture and it is stirred for a further 30 minutes at 10 ° C. The precipitated triethylamine hydrochloride is separated by suction filtration and the filtrate is evaporated in a water-jet vacuum at 30-35 ° C. The oily residue coated with the ether layer crystallizes in the refrigerator after inoculation. The product is purified by dissolving in ethanol and adding ether, whereupon the compound crystallizes out in the refrigerator. Extraction on a Soxhlet apparatus with methylene chloride ether gives the title compound as beautiful colorless crystals.

Yield: 111 g = 69% of theory. Sp. 81-82 ° C.

10 5638 / '

Example 2 2- (2-Mesyloxyethylamino) -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide

To a solution of 15.3 g of 2-chloro-3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide in 150 ml of methylene chloride is suspended 8.9 g of N- (2 -chloroethyl) amine hydrochloride and 14.9 g of triethylamine are added dropwise with stirring. It is then heated to reflux for a further 2 hours and the precipitated triethylamine hydrochloride is filtered off with suction. The filtrate is washed with dilute HCl, 1% and 10% sodium hydroxide solution. After drying and evaporation of the solvent, the mixture is evaporated under normal pressure and the residue is extracted in a perforator with absolute ether. 2- (2-chloroethylamino) -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide crystallizes after seeding in a refrigerator.

Yield: 13.05 g = 71% of theory. Sp. 39-41 ° C.

A mixture of 13.05 g (1/20 mol) of the above compound and 10.15 g (1.20 mol) of silver methyl sulfonate in 80 ml of acetonitrile is heated at reflux for 8 hours. After cooling, the precipitated silver chloride is separated off by suction filtration. The acetonitrile is distilled off in a water-jet vacuum at normal temperature. the oily residue is shaken several times with ether, then dissolved in chloroform and finally re-evaporated under high vacuum. Crude yield of the title compound 11.3 g = 70% of theory.

Purification is carried out by chromatography on silica gel. Elution is carried out with a mixture of 2 parts of benzene, 1 part of chloroform and 1 part of methanol. The separated compound is recrystallized from ether.

Sp. 80-82 ° C.

Example 3 2- (2-Mesyloxyethylamino) -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide

To a solution of 22.4 g (1/10 mole) of 2- (ethyleneimino) -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide in 95 ml 11 56307 abs. ether, a solution of 9.6 g (1/10 mol) of methanesulfonic acid in 45 ml of abs is added dropwise over 20 minutes at 25 ° C. ether to form two phases. The ether phase is decanted off and the oil phase is dissolved in 50 ml of isopropanol. It is then diluted with 50 ml of ether. While standing in the refrigerator, the title compound crystallizes after inoculation.

Yield: 14.7 g = 46% of theory. Sp. 80-82 ° C.

Example 4 2- (2-Mesyloxyethylamino) -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide

A solution of 10.9 g (1/20 mol) of 2-chloro-3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide and 10.1 g (1 / 10 moles) of triethylamine in 50 ml of chloroform, is added dropwise at room temperature to a solution of 11 g (1/20 moles) of N- (methylsulfonyloxyethyl) amine hydrochloride in 50 ml of chloroform.

It is then stirred for 2 hours at room temperature and then for 2 hours at 40 ° C. After standing for 20 hours, the solvent is distilled off in a water-jet vacuum. Acetone is added to the residue and it is cooled. The insoluble triethylammonium halide mixture is separated by suction filtration. After evaporation of the acetone and after addition of ether on top of the oily residue, heat to boiling point and add enough acetone to give a clear solution. After cooling, the title compound separates as a crystalline substance.

Yield: 5.5 g = 34% of theory. Sp. 80-82 ° C.

Example 5 2- (2-Mesyloxyethylamino) -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide

To a solution of 9.8 g of N- (2-methylsulfonyloxyethyl) -phosphoric acid amide chloride in 50 ml of methylene chloride is added dropwise at 25 ° C, with stirring and occasional cooling, a solution of 6.6 g of N, N - (2-chloroethyl) - (3-hydroxypropyl) -amine hydrochloride and 11.6 g of triethylamine in 150 ml of methylene chloride.

12 56307

It is then stirred for a further 1 hour at room temperature and for 2 hours at 40 ° C. The solvent is distilled off in a water-jet vacuum and the triethylamine hydrochloride is precipitated with dioxane and filtered off with suction. The filtrate is last evaporated under high vacuum. Purification is performed in the same manner as in Example 2.

Sp. 80-82 ° C.

Example 6 2- (72-Mesyloxyethyl) -ethylamino-3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazafostorin-2-oxide

To a solution of 7.9 g of N-ethylethanolamine and 9.4 g of triethylamine in 75 ml of abs dioxane is added dropwise, with stirring at 45 ° C, a solution of 19.5 g of 2-chloro-3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide in 75 ml of abs. dioxane. It is then stirred for a further 4 hours at 45 ° C and then for 20 hours at room temperature. After separation of the separated triethylamine hydrochloride, the filtrate is evaporated in a water-jet vacuum and the residue is washed several times with ether. 2- (T2-Hydroxyethyl) -ethylamino-3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxaza-phosphorine-2-oxide is obtained as a yellow medium viscosity oil.

Yield: 21.7 g = 89.5% of theory.

To a solution of 21.7 g of the above compound and 8.4 g of triethylamine in 150 ml of abs. dioxane, a solution of 9.2 g of methanesulfonic acid chloride is added dropwise over 10 minutes with stirring at 30 ° C. The precipitated triethylamine hydrochloride is separated by suction filtration and the filtrate is evaporated in a water-jet vacuum. The residual oil is washed in a perforator for 1 hour with petroleum ether and then extracted with ether for 2 hours. After evaporation of the ether, an oil remains which is purified by column chromatography as described in Example 2. Yield of the title compound: 6 g; n ^ 1: 1.4950.

Example 7 2- (2-Mesyloxyethylamino) -3- (2-mesyloxyethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide 13 5630 7

To a solution of 13.05 g (1/20 mole) of 2- (2-chloroethylamino) -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide prepared according to Example 2 In 1 ml of acetonitrile, 20.3 g (1/10 mol) of silver methyl sulphonate are suspended. At the same time, the air is gradually heated from 20 to 100 ° C for about 50 hours, protected from moisture and light, whereby the reaction mixture is stirred well. The amount of silver chloride separated is 12.4 g = 86% of theory.

The solvent is evaporated off under a jet of water at 40 [deg.] C. and the residue is shaken five times in abs. with ether, then dissolved in abs. methylene chloride and allow to stand for 20 hours in a refrigerator. The crystallized silver methyl sulfonate precipitate is filtered off with suction and the filtrate is evaporated. The oily residue is dissolved three times in methylene chloride, filtered over activated carbon and evaporated.

After drying under high vacuum, the title compound is obtained as a thick yellow oil.

Yield: 7.4 g = 39% of theory. n ^: 1.49 55.

Example 8 2- (2-Chloroethylamino) -3- (3-mesyloxypropyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide

To a solution of 26.7 g of dipropanolamine and 42 g of triethylamine in 120 ml of abs. dioxane, a solution of 39.2 g of 2-chloroethylphosphamide dichloride in 160 ml of abs. dioxane. It is then stirred for a further 2 hours and the separated triethylamine hydrochloride is filtered off with suction. The filtrate is evaporated in a water-jet vacuum and the residue is dissolved in chloroform. It is then neutralized with HCl / ether, dried and evaporated again. 2- (2-Chloroethylamino) -3- (3-hydroxypropyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide is obtained as a tan oil. Yield: 14.4 g = 28% of theory.

To a solution of 14.4 g of the above compound and 5.7 g of triethylamine in 110 ml of abs. dioxane, is added dropwise with stirring over 30 minutes at 30 ° C a solution of 6.45 g of methanesulfonic acid chloride in 65 ml of abs. dioxane. The separated triethylamine hydrochloride is removed by suction filtration and the filtrate is evaporated in vacuo. The residue is dissolved in a mixture of 1 part of isopropanol and 1 part of ether. The mixture is allowed to stand for 2 hours in an ice bath and rubbed from time to time. The precipitated 2- (2-chloro-methylamino) -3- (3-mesyloxypropyl) -tetrahydro-2H-1,3,2-oxaza-phosphorine-2-oxide crystals are filtered off with suction, then washed with isopropanol and with a mixture of ether and then with ether alone. Purification is performed by extraction in an Soxhlet apparatus with ether.

Yield: 6.5 g = 34.6% of theory. Sp. At 72 ° C.

Example 9 2- (2-Mesyloxyethylamino) -3- (3-chloropropyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide

To a solution of 4.6 g of ethanolamine and 7.6 g of triethylamine in 55 ml of abs. dioxane, a solution of 17.6 g of 2-chloro-3- (3-chloropropyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide in 55 ml is added dropwise at 15-18 ° C over one hour: ssa abs. dioxane. After stirring for a further hour at room temperature, the precipitated triethylamine hydrochloride is filtered off and the filtrate is evaporated in a water-jet vacuum. The residue is washed several times with ether and dried under high vacuum. 2- (2-Hydroxyethylamino) -3- (3-chloropropyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide is obtained as a yellowish oil. Yield 17 g = 84.8% of theory.

To a solution of 7.6 g of methanesulfonic acid chloride in 50 ml of dioxane is added dropwise with stirring over 20 minutes at 26-28 ° C a solution of 17 g of the above compound and 6.7 g of triethylamine in 60 ml of dioxane. The precipitated triethylamine hydrochloride is separated by suction filtration and the filtrate is evaporated in a water-jet vacuum.

Purification is performed by column chromatography on silica gel using a benzene / chloroform / methanol mixture. The separated oil crystallizes on cooling and is redissolved twice in isopropanol to give an eyelid white crystals.

Yield: 7.9 g = 35.5% of theory. Sp. 92-93 ° C.

15 5638 7

Example 10 2- (72-Mesyloxyethyl) - (2-chloroethyl) -amino] -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide

To a solution of 28.3 g of N- (2-chloroethyl) -N- (2-hydroxyethyl) aminohydrochloride and 35.5 g of triethylamine in 150 ml of chloroform is added dropwise, with stirring at 28 ° C, a solution of is 38.6 g of 2-chloro-3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide in 150 ml of chloroform. After separation of the triethylamine hydrochloride and evaporation of the filtrate, the residue is extracted in a perforator with abs. ether. Evaporation of the ether gives 2- (7-chloroethyl) - (2-hydroxyethyl) -amino- 7- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide as a pale yellow oil.

Yield: 23 g = 42.5% of theory.

To a solution of 8.65 g of methanesulfonic acid chloride in 200 ml of abs. dioxane is added dropwise with stirring at 25 ° C over 20 minutes a solution of 23 g of the title compound and 7.6 g of triethylamine in 200 ml of abs. dioxane. After separation of the precipitated triethylamine hydrochloride by suction filtration, the filtrate is evaporated in a water-jet vacuum. The yellow oil obtained is extracted in a perforator with ether. After evaporation of the ether, the residue is dissolved in chloroform, washed with ice-cold, dilute ammonium hydroxide and water, dried over Na 2 SO 4 and re-evaporated. Purification of the pale yellow oil is accomplished by column chromatography on silica gel as shown in Example 2. 2- (7β-Mesyloxyethyl) - (2-chloroethyl) amino] -3- (2-chloroethyl) tetrahydro-2H-1,3,2-oxoazaphosphorine-2-oxide is obtained as a colorless oil.

21

Yield: 10.5 g; nD: 1.0526.

Example 11 2- (3-Mesyloxypropylamino) -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide

To a solution of 12.95 g of propanolamine-1,3 and 17.3 g of triethylamine in 140 ml of abs. dioxane, a solution of 37.4 g of 2-chloro-3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide 140 is added over a period of 50 minutes with stirring at 15-18 ° C. in ml abs. dioxane. After separation of the precipitated triethylamine hydrochloride 16 56387, the filtrate is evaporated in a water-jet vacuum and the residue is washed several times with ether. After drying under high vacuum, 2- (3-hydroxypropylamino) -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide is obtained as a thick clear oil. Yield: 38.6 g = 86% of theory.

38.6 g of the title compound and 15.5 g of triethylamine in 120 ml of abs. dioxane is added dropwise to a solution of 17.2 g of methanesulfonic acid chloride in 120 ml of abs. dioxane with stirring for 30 minutes at 28-30 ° C. After suction filtration of the precipitated triethylamine hydrochloride, it is evaporated in a water-jet vacuum and the oily residue is dissolved in water. The compound is liberated from impurities by means of the ion exchange resin "Duolit" (A 102). The colorless oil is extracted from the abs. ether and cooled, occasionally by rubbing, in a cooling bath to give 2- (3-mesyloxypropylamino) -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide as crystals. This is recrystallized from ethyl acetate.

Yield: 13.9 g. Sp. 59-60 ° C.

Example 12 2- [Bis- (2-chloroethyl) -amino] -3- (3-mesyloxypropyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide

To a solution of 41.8 g of dipropanolamine and 57.7 g of triethylamine in 200 ml of abs. dioxane, 45.5 g of N, N-bis- (β-chloroethyl) -phosphamide dichloride in 200 ml of abs. dioxane. After separation of the precipitated triethylamine hydrochloride, the filtrate is evaporated in a water-jet vacuum and the residue is extracted in a perforator with ether. 2- [Bis- (2-chloroethyl) -amino] -3- (3-hydroxypropyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide is obtained as a colorless, medium-viscosity oil. λ Yield: 16 g = 30.5% of theory.

16 g of the above compound and 5.5 g of triethylamine in 45 ml of abs. dioxane is added dropwise with cooling and stirring over 35 minutes to a solution of 5.75 g of methanesulfonic acid chloride in 35 ml of abs. dioxane. After suction filtration of the separated triethylamine hydrochloride, the filtrate is evaporated in a water-jet vacuum and the oil obtained is extracted in a perforator within 4 hours of abs. ether. After evaporation of the ether, the remaining residue 17 56387 is dissolved in a mixture of methanol and water and allowed to stand for 1/2 hour with "Duolit" (A-102). After filtration on activated carbon, the solvent is evaporated off under a water-jet vacuum and dried under high vacuum using P2C5. 2- [Bis- (2-chloroethyl) -amino] -3- (3-mesyloxypropyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide is obtained as a colorless oil.

Yield: 11.6 g; n ^ 1: 1.5060.

Example 13 2- [Bis- (3-mesyloxypropyl) -amino] -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide

To a solution of 38.8 g of 2-chloro-tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide in 120 ml of methylene chloride is added dropwise at 26-28 ° C over 40 minutes a solution of 26 6 g of dipropanolamine and 26.4 g of triethylamine in 100 ml of methylene chloride. After suction filtration of the precipitated triethylamine hydrochloride, the filtrate is evaporated and the residue is extracted with ether in a perforator. 2- [Bis- (3-hydroxypropyl) -amino] -tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide is obtained as a yellow oil.

Yield: 50.4 g = 99% of theory.

50.4 g of the above compound and 45 g of triethylamine in 150 ml of abs. methylene chloride is added dropwise to a solution of 46 g of methanesulfonic acid chloride in 100 ml of abs. methylene chloride with stirring for 45 minutes at 32-34 ° C. After suction filtration of the separated triethylamine hydrochloride, the filtrate is evaporated in a water-jet vacuum and the residue is dissolved in 100 ml of acetone. Filter and repeat the evaporation. The resulting oil is dissolved in 250 rtl of chloroform. It is then washed four times with 100 ml of ice water, dried over Na2SO4 and extracted with ether in a perforator. The insoluble portion of the ether is dissolved in 200 ml of methylene chloride, filtered through charcoal and evaporated. 2- [Bis- (3-mesyloxypropyl) -amino] -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide is obtained as a yellow oil.

20

Yield: 30 g; nD: 1.4947.

Example 14 2- (Bis-83-mesyloxypropyl) -amino] -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide 5638/18

To a solution of 37.5 g of bis- (3-mesyloxypropyl) -amine hydrobromide and 21.8 g of 2-chloro-3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2- oxide in 200 ml abs. dioxane, a solution of 21 g of triethylamine in 60 ml of abs. is added dropwise over 60 minutes at 35-40 ° C. dioxane. After standing for 16 hours at room temperature, the precipitated triethylammonium halide mixture is filtered off with suction and the filtrate is evaporated in a water-jet vacuum.

The oil obtained is dissolved in 200 ml of chloroform, washed five times with 50-60 ml of ice water each time, dried over Na2SO4 and evaporated again. the oil is extracted for 2 hours in a perforator abs. ether. The insoluble matter is dissolved in methylene chloride, filtered through charcoal and evaporated again under high vacuum. 2- [Bis- (3-mesyloxypropyl) -amino] -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxaza-phosphorin-2-oxide is obtained as a thick yellow oil.

Yield: 17.6 g; nj ^: 1.5050.

Example 15 2- (3-Mesyloxypropyl) - (2-chloroethyl) -amino] -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide

To a solution of 16.4 g of N- (3-hydroxypropyl) -N- (2-chloroethyl) -amine hydrochloride and 19.6 g of triethylamine in 120 ml of chloroform is added dropwise at 26 ° C over 1 hour a solution of 20 .4 g of 2-chloro-3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide in 100 ml of chloroform. After stirring for a further 2-3 hours, the precipitated triethylamine hydrochloride is filtered off with suction and the filtrate is evaporated in a water-jet vacuum. The residue is extracted in a perforator with ether. 2 - [(3-Hydroxypropyl) - (2-chloroethyl) -amino] -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide is obtained as a colorless, medium-viscosity oil .

Yield: 20.6 g = 69% of theory.

A solution of 20.6 g of the above compound and 7.3 g of triethylamine in 100 ml of abs. dioxane, is added dropwise over 30 minutes at 30 ° C to a solution of 7.45 g of methanesulfonic acid chloride in 70 ml of abs. dioxane. After suction filtration of the separated triethylamine hydrochloride, the filtrate is evaporated to half volume, 40 ml of ether are added and it is left to stand for 19 hours in a refrigerator to separate the impurities. After evaporation of the ether, the oil is washed in a perforator with petroleum ether, dissolved in chloroform and washed once with sodium bicarbonate and three times with 1N. After drying over Na2SO4, the mixture is evaporated again under high vacuum. 2- (73-Mesyloxypropyl) - (2-chloroethyl) amino] -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxaza-phosphorin-2-oxide is obtained as a yellow oil.

Yield: 20.5 g. n ^: 1 ^ 5048.

Example 16 2- (2-Chloroethylamino) -3- (2-mesyloxyethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide

To a solution of 32.9 g of 2-ethyleneimino-3- (2-mesyloxyethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide in 175 ml of abs. methylene chloride, a solution of 26.5 ml of HCl in ether (159.7 mg / ml) is added dropwise over 20 minutes at 30 ° C with vigorous stirring. After the addition, the methylene chloride-diphas is separated by decantation from the thick precipitate, filtered through charcoal and evaporated in vacuo, the oil is dissolved in methylene chloride and enough ether is added to give a solvent ratio of 1: 1. The precipitated oil is redissolved in methylene chloride and ether is added, and this treatment is repeated until the precipitated oil no longer dissolves in methylene chloride. The combined methylene chloride / ether extracts are filtered through carbon and evaporated in vacuo. The residual oil is dissolved in methylene chloride, washed three times with ice water and dried. After evaporation of the solvent, the title compound is obtained as a yellow viscous oil.

Yield: 20.8 g; n ^: 1.4967.

Example 17 2- (2-Mesyloxyethylamino) -3- (2-chloroethyl) -5-dimethyl-2H-tetrahydro-1,3,2-oxazaphosphorine-2-oxide

To a solution of 10.6 g of ethanolamine and 17.8 g of triethylamine in 130 ml of abs. dioxane, a solution of 43 g of 2-chloro-3- (2-chloroethyl) -5-dimethyl-2H-tetrahydro-1,3,2-oxazaphosphorine-2-oxide is added dropwise at 50 ° C over 1 hour. in ml of dioxane. It is then heated at 80 [deg.] C. for a further 4 hours and then allowed to stand overnight at room temperature. After suction filtration of the separated triethylamine hydrochloride, the solvent is evaporated off under a water-jet vacuum and the residue is extracted in a perforator with ether. 2- (2-Hydroxyethylamino) -3- (2-chloroethyl) -5-dimethyl-2H-tetrahydro-1,3,2-oxazaphosphorine-2-oxide is obtained as a colorless oil.

Yield: 27.1 g = 57.5% of theory.

To a solution of 11.5 g of methanesulfonic acid chloride in 90 ml of abs. dioxane, a solution of 27.1 g of the title compound and 10.2 g of triethylamine in 120 ml of abs. dioxane, within 20 minutes. 75 ml of ether are then added and the separated triethylamine hydrochloride is filtered off with suction after 1 hour. After evaporation of the solvent, the residual oil is purified in a perforator by extraction three times with a mixture of methylene chloride / ether (1: 3). 2- (2-Mesyloxyethylamino) -3- (2-chloroethyl) -5-dimethyl-2H-tetrahydro-1,3,2-oxazaphosphorine-2-oxide is obtained as a colorless thick-flowing oil.

Yield: 15.8 g; n ^: 1.4912.

Example 18 2- (2-Ethylsulfoxyoxyethylamino) -3- (2-chloroethyl) -2H-tetrahydro-1,3,2-oxazaphosphorine-2-oxide

To a solution of 12.9 g of ethanesulfonic acid chloride in 70 ml of abs. dioxane, is added dropwise over 20 minutes at 28-30 ° C with stirring a solution of 24.3 g of 2- (2-hydroxyethylamino) -3- (2-chloroethyl) -2H-tetrahydro-1,3 prepared according to Example 1. , 2-oxazaphosphorine-2-oxide and 10.1 g of triethylamine in 60 ml of abs. dioxane. After standing for 1 hour and cooling, the triethylamine hydrochloride is separated off by suction filtration. The solvent is evaporated off under vacuum, the oily residue is purified on a perforator by extraction first with ether and then with a mixture of methylene chloride and ether (2: 1). The ether phase is discarded. The title compound crystallizes from the methylene chloride / ether extract after evaporation of the solvent and standing in the refrigerator. The compound is recrystallized from methanol / ether.

Yield: 10 g. Sp. 62-64 ° C.

21 56387

Example 19 2- (2-Mesyloxyethylamino) -3- (2-chloroethyl) -6-methyl-2H-tetrahydro-1,3,2-oxazaphosphorine-2-oxide

To a solution of 2.8 g of ethanolamine and 4.6 g of triethylamine in 50 ml of abs. dioxane, a solution of 10.6 g of 2-chloro-3- (2-chloroethyl) -6-methyltetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide in 50 ml of abs. dioxane at 20 ° C. It is then stirred for a further 6 hours at room temperature and the precipitated triethylamine hydrochloride is separated off by suction filtration. The filtrate is evaporated in a water-jet vacuum and the residue is washed several times with ether. It is then extracted further in a perforator with ether. 2- (2-Hydroxy-ethylamino) -3- (2-chloroethyl) -6-methyl-2H-tetrahydro-1,3,2-oxazaphosphorine-2-oxide is obtained as a yellow oil.

Yield: 7 g = 59.4% of theory.

To a solution of 7 g of the above compound and 2.8 g of triethylamine in 150 ml of abs. dioxane, 3.1 g of methanesulphonic acid chloride in 30 ml of abs are added dropwise with stirring and cooling with water. dioxane. The precipitated triethylamine hydrochloride is filtered off with suction, filtered over activated carbon and the solvent is evaporated off under vacuum. The residue is shaken three times with ether and the ether extracts are allowed to stand in a refrigerator for several days, during which time 2- (2-mesyloxyethylamino) -3- (2-chloroethyl) -6-methyl-2H-tetrahydro-1,3,2-oxazaphosphorine-2-oxide crystallizes . It is separated by suction filtration and recrystallized from Cl 2 Cl 2 / ether (1: 1). Yield: 2 g = 22% of theory. Sp. 104 ° C.

Example 20 2- (2-Mesyloxyethylamino) -3-ethyl-tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide

To a solution of 19 g of 2-ethyleneimino-3-ethyl-tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide in 200 ml of abs. ether, a solution of 9.6 g of methanesulfonic acid is added to pH 3-4 with stirring at 5-10 ° C. After stirring for 15 minutes, the above ether solution is decanted from the separately separated oil and the oil is dissolved in abs. methylene chloride. Filtration is performed with activated carbon and evaporation in a water jet vacuum. The residue is extracted in a perforator with a mixture of 250 ml of ether-22 5 6 3 8 7 methylene chloride (1: 1). After standing in the refrigerator, the title compound crystallizes. It can be recrystallized from ether-methylene chloride.

Yield: 9 g; Sp. 104 ° C.

Example 21 2 - [(2-Mesyloxyethyl) -2- (chloroethyl) amino] -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide

To a suspension of 12 g of N- (2-mesyloxyethyl) -N- (2-chloroethyl) -phosphoric acid amide dichloride and 6.5 g of N- (3-hydroxypropyl) -N- (2-chloroethyl) -amine hydrochloride in 90 ml of methylene chloride , a solution of 11.4 g of triethylamine in 60 ml of methylene chloride is added dropwise over 15 minutes at 25 [deg.] C. with stirring and occasional cooling. It is then stirred for a further 4 hours at room temperature and then evaporated in a water-jet vacuum. Abs is added to the residue. dioxane and the separated triethylamine hydrochloride are separated by suction filtration, the filtrate is filtered with activated carbon and re-evaporated in a water-jet vacuum. The resulting oil is dissolved in methylene chloride, washed twice alternately with ice water, 0.01 N HCl and dilute NaHCO 3 solution. After drying over Na2SO4, the methylene chloride solution is evaporated in a water-jet vacuum and the oil obtained is shaken several times in abs. with ether and finally dried under high vacuum. The title compound is obtained as a pale yellow oil.

22

Yield: 5.7 g; ηβ: 1.0538.

Example 22 2- (73-Mesyloxypropyl) - (2-chloroethyl) -amino] -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide 12 g of N- (3-mesyloxypropyl) -N- (2-Chloroethyl) -phosphoric acid amide dichloride is dissolved in 60 ml of methylene chloride and suspended with 6.3 g of N- (3-hydroxypropyl) -N- (2-chloroethyl) -amine hydrochloride. A solution of 11 g of triethylamine in 60 ml of methylene chloride is added dropwise thereto with stirring and cooling at 25 ° C. It is then stirred for a further 4 hours at room temperature and the solvent is removed in a water-jet vacuum. The residue is dissolved in abs. to dioxane and the precipitated triethylamine hydrochloride is separated by suction filtration. It is then filtered through activated carbon and 23 56387 is re-evaporated in a water jet vacuum. The resulting oil is shaken three times in the abs. with ether and dried under high vacuum. The title compound is obtained as a yellowish oil.

Yield: 6.1 g; n ^: 1.5046.

Example 23 2- (2-Propylsulfoxyoxyethylamino) -3- (2-chloroethyl) -2H-tetrahydro-1,3,2-oxazaphosphorine-2-oxide

To a solution of 14.3 g of n-propylsulfonic acid chloride in 70 ml of abs. dioxane, a solution of 24.3 g of 2- (2-hydroxyethylamino) -3- (2-chloroethyl) -2H-tetrahydro-1 prepared in Example 1 is added dropwise over 15 minutes at 28-30 ° C with stirring and cooling. , 3,2-oxazaphosphorine-2-oxide and 10.1 g of triethylamine in 170 ml of abs. dioxane. Stir for a short time at 30 ° C, add 60 ml of abs. ether, cooled to 10 ° C and stirred for a further 1/2 hour. The precipitated triethylamine hydrochloride is separated by suction filtration, the filtrate is filtered through activated carbon and evaporated in a water-jet vacuum. the oily residue is extracted in a perforator with a mixture of ether-methylene chloride (1: 1). The title compound crystallizes in the refrigerator when rubbed several times. Recrystallization is performed from said solvent mixture.

Yield: 14 g. Sp. 78 ° C.

Example 24 2- [Bis- (2-mesyloxyethyl) -amino] -3- (2-mesyloxyethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide

To a solution of 16.1 g of N, N-bis- (2-chloroethyl) -phosphamide dichloride in 50 ml of chloroform is added dropwise at 20 ° C over 1 hour a solution of 10.9 g of N-2-chloroethylaminopropanol. and 20 g of triethylamine in 150 ml of chloroform. It is then heated for a few more hours, always at the boiling point, cooled to 0 [deg.] C. and the precipitated triethylamine hydrochloride is filtered off with suction. After evaporation of the filtrate, the residue is dissolved in ether, filtered and the solution is evaporated again. 2- [Bis- (2-chloroethyl) -amino] -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide is obtained as an oil which solidifies on seeding.

Yield: 16.2 g = 80% of theory. Sp. 50-51 ° C.

24 56387

A solution of 16.2 g of the above compound and 36.6 g of silver methyl sulfonate is dissolved in 150 ml of abs. acetonitrile and heated under reflux for 24 hours under protection from light. The precipitated silver chloride is separated by suction filtration and the filtrate is evaporated in a water-jet vacuum. The residue is dissolved in methylene chloride. It is then filtered and the filtrate is shaken twice in ice water in 0.01 N HCl and dilute NaHCO3 solution. After drying over Na 2 SO 4 and filtration over activated carbon, re-evaporate under high vacuum, shaking the residue several times in abs. with ether and the oil is dried under high vacuum. 2- [Bis- (2-mesyloxy-ethyl) -amino] -3- (2-mesyloxy-ethyl) -tetrahydro-2H-1,3,2-oxaza-phosphorin-2-oxide is obtained as a colorless oil.

Yield: 10.8 g; n ^: 1.4905.

Example 25 2- (2-Isopropylsulfoxyoxyethylamino) -3- (2-chloroethyl) -2H-tetrahydro-1,3,2-oxazaphosphorine-2-oxide

To a solution of 14.3 g of isopropanesulfonic acid chloride in 70 ml of dioxane is added dropwise at 28-30 ° C a mixture of 24.3 g of 2- (2-hydroxyethylamino) -3- (2-chloroethyl) prepared according to Example 1. -2H-tetrahydro-1,3,2-oxazaphosphorine-2-oxide and 10.5 g of triethylamine in 75 ml of dioxane over 25 minutes. After separation of the precipitated triethylamine hydrochloride by suction filtration, the solvent is evaporated off under a water-jet vacuum and the oily residue is washed for 2 hours with ether in a perforator. It is then extracted twice with methylene chloride-ether. After filtration on activated carbon and evaporation of the solution, the title compound is obtained as a clear yellowish and thick-flowing oil, which is purified by column chromatography using silica gel and methylene chloride.

20

Yield: 16.4 g = 47% of theory; n *: 1.4927.

Example 26 2- (2-n-Pentylsulfonyloxyethylamino) -3- (2-chloroethyl) -2H-tetrahydro-1,3,2-oxazaphosphorine-2-oxide

To a solution of 17.1 g of n-pentanesulfonic acid chloride in 75 ml of dioxane is added dropwise, with cooling and good stirring, a solution of 24.3 g of 2- (2-hydroxyethylamino) -3- (2 -chloroethyl) -2H-tetrahydro-1,3,2,5-56,387 oxazaphosphorine-2-oxide and 10.5 g of triethylamine in 90 ml of dioxane, the temperature not exceeding 35 ° C. It is then stirred for a further 1/2 hour, the precipitated triethylamine hydrochloride is filtered off with suction and the filtrate is evaporated in a water-jet vacuum. The resulting oil is dissolved in chloroform, washed with dilute HCl, NaHCO 3 solution and water and evaporated again. The residue is then extracted with ether in a perforator. The title compound crystallizes from the ether extract while standing in the refrigerator. It is recrystallized from ether.

Yield: 10.5 g = 27.8% of theory. Sp. 59-60 ° C.

Example 27 2- (2-Mesyloxyethylamino) -3- (3-chloropropyl) -2H-tetrahydro-1,3,2-oxazaphosphorine-2-oxide

To a solution of 9.8 g of N- (2-mesyloxyethyl) -phosphoric acid amide dichloride in 50 ml of methylene dichloride is added dropwise at 25 ° C, with stirring and occasional cooling, a solution of 5.1 g of dipropanolamine and 11.6 g of g of triethylamine in 150 g of methylene chloride. It is then stirred for a further hour at room temperature. The solvent is distilled off in a water-jet vacuum and the triethylamine hydrochloride is precipitated by adding dioxane and filtered off with suction. The filtrate is again evaporated under high vacuum, the oily residue is dissolved in 80 ml of chloroform without further purification and a solution of 13 ml of SOCl 2 in 20 ml of chloroform is added with stirring. After completion of the reaction, the solution is washed with 0.1 N hydrochloric acid and then with dilute sodium bicarbonate solution and dried over sodium sulfate. After distilling off the solvent, the remaining residue of the title compound is purified according to Example 9 using column chromatography.

Yield: 8 g = 60% of theory. Sp. 92-93 ° C.

Example 28 2- (2-Mesyloxy-propylamino) -3- (2-chloro-ethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide

To a solution of 25.7 g (1/10 mole) of 2- (2-hydroxypropylamino) -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide (prepared from 2-hydroxypropylamine and 2-chloro-3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide according to Example 1) and 10.5 g (1/10 mole) of triethylamine in 60 ml of abs.

26 1 6 3 8 7 dioxane, 11.5 g (1/10 mol) of methanesulphonic acid chloride in 70 ml of abs. dioxane within 20 minutes at 28-30 ° C. After removal of the precipitated triethylamine hydrochloride, the filtrate is evaporated in a water-jet vacuum. The resulting oil is extracted in a perforator with ether / methylene chloride (1: 1) for about 1 hour. Upon standing on an ice bath, the title compound separates from the solution as colorless crystals which are recrystallized from the same ether / methylene chloride solvent mixture (5: 1).

Yield: 22.4 g = 67% of theory. Sp. 100-101 ° C.

Example 29 2- (1-Ethyl-2-mesyloxy-ethylamino) -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide

To a solution of 27 g (1/10 mole) of 2- (1-ethyl-2-hydroxyethylamino) -3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxo- (prepared from 2-hydroxy-n-butylamine and 2-chloro-3- (2-chloroethyl) -tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide according to Example 1) and 10.5 g (1 / 10 moles) of triethylamine in 65 ralt. dioxane, a solution of 11.5 g (1/10 mole) of methanesulfonic acid chloride is added dropwise over 20 minutes at 28-32 ° C with stirring. After removal of the precipitated triethylamine hydrochloride, the filtrate is evaporated in a water-jet vacuum. The title compound remains as an oil which solidifies after a short time. Recrystallization is performed twice from isopropanol to give colorless crystals.

Yield: 21.0 g = 60% of theory. Sp. 129-130 ° C.

Claims (7)

27 56387 A process for the preparation of alkanesulfonic acid esters of 1,3,2-oxazaphosphorine compounds having immunosuppressive activity and having the general formula IRI 2 / NV / 1 R-alk-NP = 0 XI ^ 0 Z3 wherein R is a chlorine atom or an alkylsulfonyloxy group having 1 An alkyl group having 5 to 5 carbon atoms, R 1 and R 2 are independently hydrogen atoms or alkyl groups having 1 to 3 carbon atoms and which may have a chlorine atom or a lower alkylsulfonyloxy group, wherein the molecule of formula I has at least one alkylsulfonyloxy group and alk is an ethylene or propylene group or an ethylene group substituted by a methyl or ethyl group and Z 1, Z 2 and Z 2 are independently hydrogen or methyl groups, characterized in that A) a compound of general formula IV X 1 R 1 -alk-NP 2 = O IV 3 I \ R4 Χλ wherein R1 is the same as R in formula I or is a hydroxy group, R1 is the same as R1 in formula I or is an alkyl group having 1 to 3 carbon atoms and having a hydroxy group, alk is the same as in the formula I and is a halogen atom, preferably a chlorine atom, is reacted with an aminopropanol of the general formula VZ, Z7 II Rc-HN-CH0-C-CH-OHH1l2 wherein R1 is the same as R1 in formula IV and Z Z 1 and Z 2 have the same meaning as in formula I, or B) an amine of general formula VI 28 S 6 3 Ο 7 R.-alk-NH VI 3 A R 4 wherein R 3 and R 4 are as defined in formula IV and alk is as defined in formula I, is reacted with a compound of general formula VII wherein in formula IV, R 2 is as defined in formula V and Z 2, Z 2 and Z 2 are as defined in formula I, or C) a compound of general formula VIII * L_ / “VZl alk N - P = OV VIII \ z2 wherein R ^ represents the same as in formula V and Z ^ Z ^, Z ^ and alk have the same meaning as in formula I, is reacted with a compound of general formula IX H + R 3 IX wherein R ^ represents the same as in formula IV, and in the compounds obtained, of formula XR,. 11_, / H \ / Z1 3 i4 \ Z3 Z3 in which one or more of the substituents R1, R1 and R5 is a hydroxy group or contains a hydroxy group, one or more of these hydroxy groups are replaced in a manner known per se by a halogen atom or 29 5 6 3 8 7 or -OSO 2 R 8, wherein R 8 is an alkyl group having 1 to 5 carbon atoms, and in a compound of formula X in which none of the substituents R 1, R 2 and R 2 is a hydroxy group or does not contain such a group, and one or more of the substituents R 1, R 2 and R 2. is a halogen atom or contains a halogen atom, if desired one or more such halogen atoms are exchanged by reaction with a compound of general formula XI Me0SO2R6 XI wherein Rg is as defined above and Me is the equivalent of a metal belonging to the first or second main or side group of the Periodic Table, OSOjRg. Process according to Claim 1, characterized in that the starting materials are those in which Z 1, Z 2, Z 2 and R 2 are hydrogen, R 2 is a β-chloroethyl group, alk is a -CH 2 CH 2 group and R is a methylsulfonyloxy or ethylsulfonyloxy group . A compound for the further preparation of immunocompromised compounds of the alkanesulfonyl ester of 1,3,2-oxazaphosphoric esters with all the formulas I I2 - \ z, R-alk-NP = O \ / 1 I Z3 for R is a chlorine atom or an alkylsulfonoxy group 1-5 carbon atoms, R1 and R2 are selected from the group consisting of an alkyl atom or an alkyl group having 1-3 colaters, which may be chlorine or a lower alkylsulfonoxy group, the color being a molecule derived from an alkylsulfonoxy group, an alkyl group having an ethylene group a propylene group or a methyl group or an ethyl group substituted with an ethyl group, and Z 1, Z 2 and the corresponding groups are optionally substituted with a methyl group, the corresponding group being shown in Figure A) and having the formula IV 30 56387 R.-alk-NP = O IV A \ R4 Xj is such that R1 is selected from the group consisting of R and Formula I or a hydroxyl group, R1 is selected from the group consisting of 1-3 chapters and a hydroxyl group, alk. samma betydelse som i formel I och be tecnar en halogenatom, företrädesvis en chloro-Atom, omsättes med aminaminopropanol med denmänna formuleln V Ζ, Ζ., I1! 3 Rc-HN-CHo-C-CH-OH V Z2 där Rg har samma betydelse som R ^ i formuleln IV and Z ^, Z2 and Z ^ are selected from formula I, or B) and the amine of all formulas VI R0-alk-NH1 and VI R4 is R1 and R4 is selected from formula IV and the same is as defined in formula I, the same as in formula VII, 1 * X1 to Z2 Z3 is X ^ the same as in formula IV, R1 is the same as in formula V and Z1, Z2 and Z ^ has the same formula as in formula I, or C) in the case of all formulas VIII Rc I5 ^ / N ~ VZl alk N - P = O VIII Z 3