Ralf Sonnenburg

Darstellung von Bis-(2-chlorethyl)amino-substituierten Diazaphosphorinonen. Reversible oxidative Addition von Hexafluoraceton an σ3λ3-Phosphor-Verbindungen. Synthese von σ5λ5-Spirophosphoranen und deren Zersetzung

Durch Umsetzung von 1-Methyl-pyrido[3,2-e]-3,1-oxazin-2,4-dion (1) mit Benzylaminen wurden die Aminonicotinsaureamide 2–4 gebildet. Die anschliesende Umsetzung mit Phosphortrichlorid lieferte die P-Chlor-pyridodiazaphosphorinone 5–7, die durch Umsetzung mit Bis-(2-chlorethyl)ammoniumchlorid/Triethylamin in die entsprechenden P-bis-(2-chlorethyl)amino-substituierten Pyridodiazaphosphorinone 8–10 uberfuhrt wurden. Das P-Chlor-benzodiazaphosphorinon 11 wurde mit 2-Chlorethylammoniumchlorid/Triethylamin zum 2-Chlorethylamino-substituierten Derivat 12 umgesetzt. Durch Oxidation der σ3Diazaphosphorinone 8, 9, 12 und 13 mit dem Harnstoff-Wasserstoffperoxid-(1 : 1)-Addukt wurden die entsprechenden Phosphorylderivate 14–17 erhalten. Die oxidative Addition von Hexafluoraceton (HFA) an das σ3-Diazaphosphorinon 18 fuhrte unter Abspaltung von Methylchlorid zu dem tricyclischen Phosphoran 19 b. Die Spirophosphorane 21–23 wurden durch Reaktion der Verbindungen 8, 9 und 13 mit HFA gebildet. Es wurden NMR-Untersuchungen hinsichtlich der Zersetzung der bicyclischen Phosphorane 20 a, 22 und 23 unternommen. Die oxidative Addition von HFA an Diazaphosphorinone stellte sich dabei als reversibel heraus. Von den Verbindungen 17 und 19 b wurden Rontgenstrukturanalysen angefertigt, die die erwartete Konnektivitat bestatigen. Verbindung 17 weist kurze C–H…O-Wasserstoffbrucken auf (H…O 234 pm). Verbindung 19 kristallisiert mit zwei unabhangigen Molekulen, die sich u. a. in der Ausrichtung der Chlorethylgruppen unterscheiden. Synthesis of Bis-(2-chloroethyl)amino-substituted Diazaphosphorinones. Reversible Oxidative Addition of Hexafluoroacetone to σ3λ3-Phosphorus Compounds. Synthesis of σ5λ5-Spirophosphoranes and their Decomposition The reaction of 1-methyl-pyrido[3,2-e]-3,1-oxazin-2,4-dione (1) with benzylamines led to the aminonicotinic acid amides 2–4. Their reaction with phosphorus trichloride furnished the P-chloro-pyridodiazaphosphorinones 5–7, which, upon reaction with bis-(2-chloroethyl) ammonium chloride/triethylamine, were converted into the P-bis-(2-chloroethyl)amino-substituted pyridodiazaphosphorinones 8–10. The P-chloro-benzodiazaphosphorinone 11 was allowed to react with 2-chloroethylammonium chloride/triethylamine to form the 2-chloroethylamino-substituted derivative 12. The σ3-diazaphosphorinones 8, 9, 12 and 13 were oxidized with the urea-hydrogen peroxide-(1 : 1)-adduct to the corresponding phosphoryl derivatives 14–17. The oxidative addition of hexafluoroacetone (HFA) to the σ3-diazaphosphorinone 18 led, with abstraction of methyl chloride, to the tricyclic phosphorane 19 b. The spirophosphoranes 21–23 were formed by reaction of compounds 8, 9 and 13 with HFA. NMR-studies were made on the decomposition of the bicyclic phosphoranes 20 a, 22 and 23. The oxidative addition of HFA to diazaphosphorinones was found to be reversible. Single crystal X-ray determinations were conducted on compounds 17 and 19 b. They confirm the expected connectivity. Compound 17 was found to exhibit short C–H‥ O-hydrogen bonds (H…O 234 pm). Compound 19 crystallises as two independent molecules which differ, e. g., in the orientation of the chloroethyl groups.

N-PHOSPHORYLATED NITROGEN MUSTARDS; PREPARATION OF 2-CHLOROETHYL- AND BIS(2-CHLOROETHYL)-AMIDES WITH THE BENZODIAZAPHOSPHORINONE RING SYSTEM

Abstract The reaction of isatoic acid anhydride 1 with NaH/BrCH2CH2Cl furnished the N-(2-chloroethyl) substituted derivative 2, which was allowed to react with methylamine to form N-(2-chloroethyl)-N′ methylanthranilamide 3, Treatment of 3 with PCI3 furnished the 1,3,2-diazaphosphorin-4-one 4, which reacted with bis(2-chloroethyl) amine hydrochloride to form the P-bis(2-chloroethyl) amino derivative 5 by substitution at phosphorus. Oxidation of 5 with the hydrogen peroxide/urea 1:l adduct led to the phosphoryl species 6, Theσ4P-derivative 7 was formed by hydrolysis of 4 with small amounts of water. Treatment of the P-chloro derivative 8 with (CH3)3SiOCH3 furnished the methoxy-substituted compound 9, which formed the phosphoryl derivative 10 upon reaction with SO2Cl2. The previously known bis(2-chloroethyl)amino-substituted 1,3,2-benzodiazaphosphorin-4-on-2-oxide 11 was synthesized by reaction of 10 with bis(2-chloroethyl) amine hydrochloride/triethylamine. The P-2-chloroethylamino-substituted derivative 1...

PREPARATION OF N-PHOSPHORYLATED NITROGEN MUSTARDS WITH THE BENZODIAZA- AND OXAZAPHOSPHORINONE RING SYSTEMS;HYDROLYSIS OF 2-CHLORO BENZODIAZAPHOSPHORINONES

Abstract The reaction of N-p-ethoxyphenylanthranilic acid 1 with phosphorus trichloride furnished the 2-chloro-1,3,2-benzoxazaphosphorin-6-one 2, which was allowed to react with bis-(2-chloroethyl)amine hydrochloride to form 3 by substitution at phosphorus. Treatment of 3 and the previously known N-p-fluorobenzyl-, N-p-chlorobenzyl- and N-o-chlorobenzyl-substiuted 1,3,2-benzodiazaphosphorin-4-ones 4–6 with the hydrogen peroxide/urea 1:1 adduct led to the phosphoryl species 7–10. The phosphoryl derivatives 14–16 were obtained by hydrolysis of the previously known λ3P-chloro derivatives 11–13 with small amounts of water. For the N-p-fluorobenzyl substituted compound 14 a single crystal X-ray structure determination showed a weak intermolecular P—H … O contact.

A New Method for the Preparation of Ifosfamide and Cyclophosphamide

The reaction of 2-chloro-3-(2-chloroethyl)-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide 1 and 2-chloro-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide 2 with 2-(trimethylsilyloxy)ethylamine 3 and bis-[2-(trimethylsiloxy)ethyl]amine 4, respectively, yielded the trimethylsilylated compounds 5 and 6, analogous to ifosfamide and cyclophosphamide. The reaction of 5 and 6 with 2-chloro-1,3,5-trimethyl-1,3,5-triaza-2-phosphorin-4,6-dione 7 led to the diphosphorus compounds 8 and 9 which could be transformed to ifosfamide 11 and cyclophosphamide 12 by treatment with sulfuryl chloride. This synthesis shows that the alkylating agents 2- chloroethylammonium chloride and bis-(2-chloroethyl)ammonium chloride can be avoided and the chlorine atom can be introduced in the final reaction step of the synthesis of 11 and 12.

Beiträge zur Chemie des 4,5-Benzo-3-methyl-1,3,2-oxazaphosphorinan- 6-on Ringsystems: Röntgenstrukturanalysen an einem Bis(2-chlorethyl)amino- und einem Acetamido-substituierten Derivat / Chemistry of the 4,5-Benzo-3-methyl-1,3,2-oxazaphosphorinan-6-one Ring System: X-Ray Crystal Structure Analysis of a Bis(2-chloroethyl)amino- and of an Acetamido-Substituted Derivative

Abstract The reaction of 4,5-benzo-2-chloro-3-methyl-1,3,2-oxazaphosphorinan-6-one 1 with 1,2-bis- (trimethylsiloxy)ethane led to the bisphosphoryl species 2a and to the isomeric bisphosphite derivative 2b. The reaction of 1 with heptamethyldisilazane furnished the expected diphosphorus compound 3, with two λ3P(III) atoms linked by a methylamino group. Substitution of the chlorine atom of 1 by the 2-chloroethylamino and bis(2-chloroethyl)amino group led to the oxazaphosphorinanones 4 and 6. By oxidation of 4 with the hydrogen peroxide/urea 1:1-adduct, the phosphoryl compound 5 was formed. Oxidation of 4,5-benzo-2-diethyl- amino-3-methyl-1,3,2-oxazaphosphorinan-6-one 7 [1] with hydrogen peroxide, sulfur and selenium led to the corresponding phosphoryl, thiophosphoryl and selenophosphoryl compounds 8-10. Analogously, the reaction of the dimethylamino- and acetamido-substituted derivatives 11 and 13 [1] with elemental sulfur furnished the thiophosphoryl compounds 12 and 14. X-ray crystal structure determinations of 4 and 14 confirmed the molecular structures, proposed in accord with NMR spectroscopic and mass spectrometric data. The heterocyclic rings are essentially planar. In 14 a hydrogen bond N-H···O (amide) is observed.

A New Method of Preparation of Ifosfamide and Cyclophosphamide; Synthesis of Side Products

Abstract This study focusses on the preparation of ifosfamide (1; R1=CH2CH2Cl, R2=NHCH2CH2Cl) and cyclophosphamide (2 R1=H, R2=N(CH2CH2Cl)2), standard drugs in tumor therapy, in order to avoid the alkylating educts like 2-chloroethylamine by introducing chlorine in the final reaction step. The reaction of the trimethylsilyl compounds (3; R1=CH2CH2Cl, R2=NHCH2CH20SiMe3) and (4; R1=H, R2=N(CH2CH20SiMe3)2), respectively, with 2-chloro- 1,3,5-trimethyl-1,3,5-triaza-σ3λ3-2-phosphoM-4,6-dione, followed by chlorination of the resulting product with sulphuryl chloride, furnished the cytotoxic drugs (1) and (2) [l].

Zur Chemie der 4,6-Dioxo-1,3,5,2 λ3-triazaphosphinane. / On the Chemistry of 4,6-Dioxo-1,3,5,2 λ3-triazaphosphinanes.

In the reaction of phenylisocyanate, 1, with 1,3-dimethylurea, 2, and 1,3-diphenylurea, 4, 1,3-dimethyl-5-phenyl biuret, 3, and 1,3,5-triphenylbiuret, 5, respectively, were obtained. The reaction of 3, 5 and of 1,3,5-trimethylbiuret 6 with a range of P(III) chloro compounds has furnished the new 4,6-dioxo-1,3,5,2 λ3-triazaphosphinanes, 7-16. The characterization of 7-16 rests, especially, on their 1H, 13C and 31P NMR, and mass spectra.