Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
  • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
  • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
  • C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
  • C07F9/65846—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a six-membered ring which may be condensed with another ring system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

• the invention relates to a process for the preparation of racemic and diastereomeric oxazaphospho ⁇ n-2-amines (N-substituted tetrahydro-2 / - / - ⁇ 4 ⁇ 5 -1, 3,2-oxazaphosphor ⁇ n-2-am ⁇ o-2-oxides) of the general formula 1
• Ri can be H 2-bromoethyl 2-chloroethyl, 2-hydroxyethyl 2-mesyloxyethyl and 1-phenylethyl
• R 2 can be H and 2-chloroethyl and R 3 can be H, 2-bromoethyl, 2-chloroethyl and 1-phenylethyl, or R, and R 2 together with the linked N atom form an Azi ⁇ din ⁇ ng
• the compounds produced by the new process are either cytostatics or immunosuppressants themselves or starting compounds for the production of racemic and enantiomerically pure oxazaphosphorion-2-amines with cytostatic or immunosuppressive activity
• the solution to the problem according to the invention then consists in that a phosphoryl halide and two amines are reacted in an inert organic solvent and with an auxiliary base while minimizing the influence of water and alcohols and without isolating an intermediate compound to give the compounds of the general formula 1 the process is carried out as a two-stage one-pot reaction, in which the reactants are introduced into the reaction vessel one after the other
• the phosphoryl halides have the general formula 2 and the two amines the general formula 3 and 4
• R 1, R 2 and R 3 have the same meaning as in formula 1, R 4 can stand for H, or R 3 and R 4 together with the linked N atom form an azi ⁇ din ⁇ ng, X represents chlorine and bromine, where X is only bromine if R, or R 3 is 2-bromoethyl and Y is none
• Amine is therefore (R) - (+) - or (S) - (-) - 1-phenylethylamine or an N-3-hydroxypropyl derivative of (+) - or (-) - l-phenylethylamine
• reaction is carried out in inert organic solvents or solvent mixtures, for example dichloromethane, 1,2-dichloroethane, chloroform, dioxane, acetonitrile, tetrahydrofuran and toluene
• inert organic solvents or solvent mixtures for example dichloromethane, 1,2-dichloroethane, chloroform, dioxane, acetonitrile, tetrahydrofuran and toluene
• Triethylamine, pyridine and sodium carbonate are suitable as auxiliary bases or as acid-binding agents
• the concentration of the reaction mixture ie the ratio of the compound of the formula 2, 3 or 4 to the volume of the solvent, can vary between 0.1 and 6 mol per liter.
• the amines of the general formulas 3 and 4 are generally equimolar to the compound of formula 2 used, wherein an up to 5 percent deficit or 20 percent excess is possible
• auxiliary base is generally used in an equivalent amount to the amine, ie two equivalents of auxiliary base are required for the condensation of the compound of formula 3 if it is present as a salt, and one equivalent of auxiliary base if it is used as the free base for the compounds of Formula 4 is used in accordance with three or two equivalents. An up to 30 percent excess of auxiliary base is possible
• the condensation reaction of the phosphoryl halide with the nurses is exothermic.
• the reaction component with which the condensation is triggered is slowly added with cooling
• phosphoryl chloride is slowly added dropwise to an amine which is in the form of a free base, or the auxiliary base is slowly added to a mixture of phosphoryl chloride and an amine which is in the form of a salt.
• the reaction temperature in the initial phase is generally reduced by cooling in the temperature range from -40 ° C. up to 20 ° C, in particular between - 20 and + 10 ° C, kept. Halfway through the reaction, it can rise to 100 ° C or up to the boiling point of the solvent - possibly by heating
• This standard approach can be varied in the first step so that compound of formula 2 is introduced and then the amine of formula 3 is slowly added together with the auxiliary base. Furthermore, the amine of formula 3 can be introduced in its salt form in the solvent, compound of formula 2 added and then the auxiliary base is slowly metered in. Furthermore, the auxiliary base and compound of the formula 2 can be added separately at the same time slowly and slowly to the amine of the formula 3, the two additions being shifted so that the auxiliary base is excess to the compound of the formula 2
• the compound of formula 4 can also be added slowly together with the auxiliary base, or the compound of formula 4 and the auxiliary base is introduced and the reaction mixture from the first step is slowly added.
• the standard batch can be varied so that the amine of the Formula 4 is used in the first step and the amine of formula 3 is used in the second step.
• the entire auxiliary base for both stages can also be used in the first step.
• the simultaneous, slow addition of the two amines with the auxiliary base to the phosphoryl chloride provided is also possible
• the times for the addition of the four components described here are possible for the process.
• Phosphoryl chloride reacts to form defined intermediate compounds known from the literature.
• the compound 2-chlorine is formed with 3-amino-1-propanol -tetrahydro-2H-1, 3,2-oxazaphosphor ⁇ n-2-amino-2- oxide, with B ⁇ s (2-chloroethyl) amine hydrochloride the compound B ⁇ s-N, N- (2-chloroethyl) - phosphoric acid amide dichloride, with N- (2-chloroethyl) -3-hydroxypropylamine hydrochloride or 3- N-hydroxypropylazine the compound 2-chloro-3- (2-chloroethyl) -tetrahydro-2H-1, 3,2-oxazaphosphor ⁇ n-2-amino-2-oxide and the compound N- (2-chloroethyl) -phosphoric acid amide-d
• reaction solution should have a water content of less than 0.5% but better less than 0.1% or less than 0.001%
• additives can be, for example, molecular sieve, aluminum oxide in its various forms, calcium chloride (anhydrous or a hydrate form), phosphorus pentoxide and magnesium chloride between 5 g and 150 g per mole of compound of formula 2 used and the solution or suspensions is stirred for half a to 3 hours before the condensation reaction is started by adding the auxiliary base or the phosphoryl halide.
• the reaction mixture is worked up at the end of the reaction by filtering off the salts, and / or by washing with water at different pH values.
• the hydrolyzability and solubility of the oxazaphospho ⁇ n-2-amine must be taken into account, for example by short contact time with the acid or cooling of the batch.
• the water-free working up of the reaction mixture is also favorable or the neutralization the reaction solution by means of HCI gas to pH 4 to 6
• weak acids for example acetic acid and oxalic acid
• the amines of the formulas 3 and 4 can in principle also be used in non-pure form.
• N ⁇ (2-chloroethyl) -3-hydroxypropylamine hydrochloride can also be used in the presence of 15% N- (2-chloroethyl) -3-chloropropylamine hydrochloride
• Use synthesis of a compound of formula 1 see example 2) A more than 10% side reaction was to be expected, so that the recovery of the compound of formula 1 is difficult or even prevented. Surprisingly, only a minimal loss of yield occurred.
• the purification of N- ( 2-chloroethyl) -3-hydroxypropylamine hydrochloride, which is very complex, can therefore be omitted. This is an important synthetic advantage
• the compounds according to the invention also include oxazaphosphor-2-amines, which are suitable for the conversion to cyclophosphamide ifosfamide, trofosfamide and sufosfamide.
• the two diastereomers prepared in Example 5 can be separated in the manner described (K Misiura et al) (1 R, 2R) - isomer hydrogenated to (R) -ifosfam ⁇ d
• the precursor of sufosfamide ie N- (2-chloroethyl) -2- (2-hydroxyethyl) tetrahydro-2H-1 3,2-oxazaphosphor ⁇ n-2 -am ⁇ no-2-ox ⁇ d, accessible and can be directly to Sufosfamid mesy eren (see example 8)
• the yield based on phosphoryl chloride for B ⁇ s (2-chloroethyl) -phosphoric acid amide dichloride is 16 % (OM Friedman, S 657)
• the yield based on B ⁇ s (2-chloroethyl) -phosphorsauream ⁇ d- dichlo ⁇ d for cyclophosphamide monohydrate is 65-70% (DE 1 057 119 Example 10, column 9), so that an overall yield of 11%
• the yield according to the new method (example 6, 72% yield of cyclophosphamide monohydrate) is therefore considerably higher
• Sufosfamide has so far been prepared from 2-chloro-3- (2-chloroethyl) tetrahydro-2H-1, 3,2-oxazaphosphor ⁇ n-2-amino-2-oxid in a yield of 30% (DE 2 107 936 Example 9 (Columns 8 and 9) so that an overall yield of 15% based on phosphoryl chloride can be calculated. According to the new process, the yield of sufosfamide is 38% (Example 8) and is therefore more than twice as high
• Ifosfamide can be prepared according to Example 1 in such a way that 2-chloroethylamine hydrochloride in the 1 step and N- (2-chloroethyl) in the 2 step ) -3-hydroxypropylamine hydrochloride is used. This process was previously not possible. The isolation of the intermediate stage is avoided in all examples, which leads to decisive simplifications and process improvements. The new process is an enormously advantageous process for industrial synthesis in economic and ecological terms
• Dichloromethane are given 15 3 g of phosphoryl chloride with stirring at 2 to 15 ° C. After 1 day at room temperature, 17 8 g of N, N-B ⁇ s (2-chloroethyl) amine hydrochloride at 10 to 20
• Example 10 Yield 21 g (64% of theory) Melting point 50-52 ° C Rp values and NMR data correspond to those of Example 10

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Immunology (AREA)
• Engineering & Computer Science (AREA)
• Public Health (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Veterinary Medicine (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Molecular Biology (AREA)
• Biochemistry (AREA)
• Transplantation (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Priority Applications (11)

Applications Claiming Priority (2)

Publications (1)

Family

ID=7841505

Family Applications (1)

Country Status (18)

Cited By (1)

Families Citing this family (6)

Citations (4)

Family Cites Families (6)

• 1997
  • 1997-09-06 DE DE19739159A patent/DE19739159C1/de not_active Expired - Lifetime
• 1998
  • 1998-08-14 BR BRPI9814266-6A patent/BR9814266B1/pt not_active IP Right Cessation
  • 1998-08-14 HU HU0003496A patent/HU226887B1/hu not_active IP Right Cessation
  • 1998-08-14 JP JP2000510748A patent/JP4278859B2/ja not_active Expired - Fee Related
  • 1998-08-14 PT PT98945245T patent/PT1012152E/pt unknown
  • 1998-08-14 AT AT98945245T patent/ATE225797T1/de active
  • 1998-08-14 IL IL13450798A patent/IL134507A/en not_active IP Right Cessation
  • 1998-08-14 PL PL98339188A patent/PL190097B1/pl unknown
  • 1998-08-14 EP EP98945245A patent/EP1012152B1/de not_active Expired - Lifetime
  • 1998-08-14 DK DK98945245T patent/DK1012152T3/da active
  • 1998-08-14 ES ES98945245T patent/ES2185220T3/es not_active Expired - Lifetime
  • 1998-08-14 CA CA002301104A patent/CA2301104C/en not_active Expired - Fee Related
  • 1998-08-14 CN CNB988087529A patent/CN1147498C/zh not_active Expired - Lifetime
  • 1998-08-14 WO PCT/EP1998/005170 patent/WO1999012942A1/de not_active Ceased
  • 1998-08-14 DE DE59805920T patent/DE59805920D1/de not_active Expired - Lifetime
  • 1998-08-26 ZA ZA987741A patent/ZA987741B/xx unknown
  • 1998-09-01 IN IN1574CA1998 patent/IN186170B/en unknown
  • 1998-09-04 AR ARP980104431A patent/AR013467A1/es active IP Right Grant
  • 1998-09-08 US US09/149,099 patent/US6187941B1/en not_active Expired - Lifetime

Patent Citations (4)

Non-Patent Citations (5)

Also Published As

Similar Documents

Legal Events