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    • 专利摘要:
    Novel method optically active oxazaphosphorin derivatives represented by the general formula (I), <IMAGE> (I) wherein R1, R2 and R3 are respectively different from each other and are hydrogen atom(s), lower alkyl group(s), aralkyl group(s), or aryl group(s); and X is a halogen atom. The novel oxazaphosphorin derivative is prepared by reacting an optically active amino alcohol derivative represented by the general formula (II), <IMAGE> (II) wherein R1, R2 and R3 are the same as defined above, with a phosphorus compound represented by the general formula (III), POX3 wherein X is the same as defined above. The novel optically active oxazaphosphorin derivatives are useful as intermediates for preparing optically active cyclophosphamide derivatives which are useful therapeutical agents for curing against follicular lymphoadenopathy, lymphosarcomatosis, Hodgkin's disease, lymphosarcoma cell leukaemia, reticulum-cell sarcoma or the like.
    公开号:SU867314A3
    申请号:SU792769753
    申请日:1979-05-25
    公开日:1981-09-23
    发明作者:Сато Тадао
    申请人:Оцука Фармасьютикал Ко.Лтд (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the chemistry of heterocyclic organophosphorus compounds, namely to a method for the preparation of new optically active derivatives of oxazaphosphorin of the general formula R-SI-C G where R is phenyl; R is lower alkyl or phenyl substituted lower alkyl which can be used as intermediates for the preparation of optically active cyclo phosphamide derivatives, which are valuable therapeutic agents in the treatment of follicular lymphadenopathy. Known methods for producing cyclic ethers or amides of phosphoric acid by reacting diodes or diamines with phosphorus oxychloride or its organic derivatives 1. It is also known to prepare cyclic phosphoric esters of amides, for example cyclophosphamide, of the formula CHg-0 0. / CHf- №G KfcHaCHjd-b from the corresponding amino alcohol and phosphoric acid chloride, which has antitumor activity 12. However, optically active oxazaphosphorine derivatives of the formula T and methods for their preparation are not described in the literature. The purpose of the invention is to develop an accessible method for producing cyclic phosphoric acid esters of general formula I. A post &amp; aim is achieved by preparing a method for producing optically active oxazaphosphorine derivatives of the formula I, which means that the optically active amino alcohol of the general formula C-I-I and I
    where R is phenyl; R is lower alkyl or phenyl-substituted lower alkyl, is reacted with phosphorus oxychloride at a temperature of minus 70 to plus 50 ° C.
    The process is carried out in an inert organic solvent — a saturated hydrocarbon, a halogenated aliphatic hydrocarbon, an aromatic hydrocarbon, or an ether — preferably in the presence of a basic compound — a tertiary amine or an inorganic basic compound — anhydrous potassium or sodium carbonate.
    In the reaction of a compound of the general formula HG with phosphorus oxychloride, the ratio of the two compounds used is not limited and can be selected over a wide range. A ratio of at least 1 mol of the latter compound to 3 mol of the first compound, preferably 1 mol of the latter to 1.5 mol of the first, is usually used. The reaction can be carried out with or without the presence of a solvent. As the latter, any known solvent that does not adversely affect the reaction can be used, for example, a halohydrocarbon (methylene chloride, chloroform or 1,2-dichloroethane), an aromatic hydrocarbon, for example benzene, toluene or xylene, an ether, for example dimethyl, diethyl or isopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme, triglyme, etc., a saturated hydrocarbon, such as n-heptane, n-hexane, cyclohexane, isooctane, and the like.
    Preferably, the reaction is carried out in the presence of a basic compound, but it can proceed without it. As a basic compound, any of the known non-adverse effects can be used, preferably a tertiary amine, for example triethylamine, triisopropylamine, N N-dimethylaniline, pyridine, or quinoline, basic inorganic compounds, for example anhydrous potassium carbonates, on three . The amount of the basic compound is not limited and can be selected in a wide range. Usually, 2-5 mol, preferably 2-3 mol of the basic compound are used per 1 mol of the compound of the general formula IG. The reaction is carried out at a temperature of from -70 to + 50 ° C for a period of from 10 minutes to 10 hours.
    The compound of general formula I thus obtained can be easily isolated and purified by recrystallization.
    Since the compound of the general formula T contains in the molecule one
    an asymmetric phosphorus atom and one asymmetric carbon atom, it includes the R, R-oKca3a-phosphorine derivative, the R-S-oxazaphosphorin derivative, the S-R-oxazaphosphorin derivative, and the S-S-oxazaphosphorin derivative. The symbols R and S, which stand first, show the absolute configuration of the asymmetric phosphorus atom, and the symbols in second place show the absolute configuration of the asymmetric carbon atom.
    If R-amino alcohol is chosen as the starting material from 1 compounds of the general formula: TI, only derivatives of R-R-oxazaphosphorin and S-R-oxazaphosphorin can be obtained from the compound of the general formula G
    , and one of them is formed selectively in large quantities (generally 60% or more, usually 80% or more) than the other. If Saminospirt is chosen as the starting material from compounds of general formula II, then only compounds of RS-oxazaphosphorine and SS-oxazaphosphorine can be obtained from compounds of general i of formula I, and one of them is formed in large quantities (usually 60% or more usually 80% or more) than another. This is reflected in the examples.
    The configuration of an asymmetric phosphorus atom can be reversed when an SN-type reaction is carried out at a PCB. (molecular nucleophilic substitution by reacting a compound of general formula D with a nucleophilic reagent (e.g., azide ion, cyanidion, p-nitrophenoxyion, p-nitrothiophenoxion, or the like), which can be easily leaving group in the reaction according to
    R ca-ff
    R-CH-fl
    but
    I y-y
    / N-p
    ABOUT
    0 1
    R
    Black / white
    in which NU is azide, cyanide, p-nitrophenoxide or p-nitrothio | a) an enoxide group, and R and R have; Driven values.
    In an SN-type substitution reaction (inversion reaction), the ratio of the amount of a compound of general formula G to the amount of a nucleophilic reagent compound is not limited and can be selected over a wide range. 1-5 moles of nucleophilic reagent are used, preferably 1-2 moles of the latter per 1 mole of the compound of general formula I.
    The SNj type substitution reaction can be successfully carried out by using an alcohol, for example, methanol, ethanol, propanol, butanol, and the like, an ether solvent, for example.
    5 dioxane, tetrahydrofuran, 1,2-diomethoxyethane, diglyme, triglyme, etc. an aprotic polar solvent, for example dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-Me tylpyrrolidone, hexamethylphosphoryltriamide. and the like. The reaction usually takes place at a temperature of from -30 to preferably from -10 to 100 ° C. minutes to approximately 30 hours. The derivative of oxazaphosphorine of general formula G can be introduced into optically active diclophosphoramide of general formula VI, as shown in the following P-CH-RI reaction scheme (U SSSNa SNg OH; O., G. R-SJ-R : J. SCHSN ,, CH20L) g G1-0 D gh / v) (. Op "p; - L..4 -7- Hydrogen from 0 -iiKCHjCH as) in the reaction of a compound of general Form I with diethanolamine, the wallpaper ratio of the compounds used is not limited and can be selected in a wide range. Usually, 1-10 mol, preferably 1-5 mol of diethanol are used per 1 mol of the compound of formula 1. The reaction is carried out in the presence or absence of a solvent; water, alcohols, such as methanol, ethanol, propanol, butanol can be used as solvents. , etc., halocarbons, such as methyl chloride, chloroform, 1,2-dichloroethane, etc., ether solvents, for example diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme, triglyme, aprotic polar solvents, for example dimethylformamide, dimethylacetamide, dimethylsulfs xyd, N-methylpyrrolidone, methylphosphoryl triamide hexa, etc. The reaction can be carried out in the presence of a basic compound in the reaction system or without it. As examples of basic compounds, tertiary amines can be used, for example, diethylamine or N, N-dimethylaniline. The reaction can be carried out at a temperature from room temperature to, preferably from room temperature to. Typically, the reaction is completed within a period of 30 minutes to 10 hours. The compound of the general formula IV is chlorinated using conventional chlorination by using thionyl chloride, phosphorus trichloride, phosphoric chloride, phosphorus pentachloride, hydrochloric acid, hydrochloric acid mixture as chlorinating agents and zinc chloride, hydrochloric acid, a mixture of hydrochloric acid with ecamethylphosphoramide, three phenylphosphorine with carbon tetrachloride, triphenylphosphoric chloride or risdimethylamine phosphine with carbon tetrachloride . The amount of chlorinating agent used can be from 1 mol, to an excess; preferably from 1 to 5 mol per 1 mol of the compound of the general formula IV. Conventional solvents can be used as solvents for this reaction, for example halohydrocarbons (chloroform, methylene chloride, 1,2-dichloroacetone), ether solvents, for example | diethyl ether, tetrahydrofuran, dioxane, 1,3-dimethoxyethane, diglyme, triglyme. The reaction can be carried out at a temperature from room temperature to, preferably from room temperature to 50 ° C. The reaction is completed in a period of from about 30 minutes to 6 hours. The hydrogenolysis of a compound of general formula V is carried out by using a catalyst, for example palladium. on coal, palladium black, rhodium catalyst, Rene nickel, etc. , in conditions of catalytic hydrogenation, which can be carried out in a solvent, for example in water, methanol or ethanol, at a temperature from room temperature to, preferably, from room temperature to 60 ° C. Usually the reaction ends in a period. from 30 minutes to about 30 hours, preferably from 30 minutes to 20 hours. The pressure of hydrogen gas is sub-. keep usually at the level of the atmosphere; ferrous to 150 atm, preferably I from atmospheric to 100 atm. By the end of the reaction: the thus obtained cyclophosphamide of general formula VI is separated from the reaction mixture by filtration to remove insoluble substances, and the solvent is distilled off in order to obtain the product and recrystallize it from a suitable solvent selected from the group consisting of ether, a mixture ether - hexane, isopropyl ether, mixtures of benzene hexane, carbon tetrachloride hexane, benzene - isooctane, etc. The thus obtained cyclophosphamide of general formula VI contains (S) - {- J, -cyclophosphamide and (R) - (+) - cyclophosphamide. (S) - (-) - cyclophosphamide is known as a compound with remarkable pharmacological activity compared to ( R) - (+) - cyclophosphamide.
    With proper reactions, S - (-) - cyclophosphamide can be obtained from optically active oxazaphosphorine of general formula I. Thus, S - (-) - cyclophosphamide can be obtained by any of the following methods.
    1. A compound of the S-S form of the general formula D is converted by applying a reaction of the type SNj (bimolecular nucleophilic substitution) into compounds of the general formula g, then the result
    reacting it with ethanolamine of the general formula GGG in order to obtain a compound of the form R-S of the general formula
    IV, Then the compound of the form R-S of general formula IV is chlorinated to obtain the compound of the form R-S of general formula
    V, after which it is subjected to hydrogenolysis to obtain 3 - {-) - cycrphosphamide.
    2. Compound form R — S of the general formula T is brought into contact with ethanolamine of the general formula.
    1GG in order to obtain a compound of Form R-S of general formula IV, then it is chlorinated to obtain a compound of Form R-S of general formula V, which is hydrogenolized to obtain S - (-) - cyclophosphamide.
    3. The compound of the RR form of the general formula I is reacted with ethanolamine of the general formula 1GG to obtain the compound of the form RR of the general formula IV, then it is chlorinated to obtain the compounds of the form RR of the general formula V, which is hydrogenolized to obtain S - (-) - Diklo, phosphamide.
    4. The compound form S-R of the general formula D is converted by the reaction
    type aSN2 (bimolecular nucleophilic substitution) into a compound of general formula g, which is reacted with ethanolamine of general formula G11 to obtain a compound of the form R-R of general formula IV, then hydrolyzed to obtain 8 - (-) - cyclophosphamide.
    In addition, R - (+) - cyclophosphamide can be obtained from an optically active derivative of oxazaphosphorine of general formula 1, obtained by the proposed method. So, R - (+) - tsrfklofosfamid can be obtained by any of the methods 5 - 8.
    5. Compound form R - R of the general formula T is converted into a compound of general formula g by applying a reaction of the type BYL (bimolecular nucleophilic substitution), then it is reacted with ethanolamine of the general formula THG to obtain the compound S-R total
    of formula IV, then chlorinated to obtain a compound of the form S-R of general formula V and subjected to hydrogenolysis to obtain R - (+) - cyclophosphamide.
    6. Compound SR form of general formula D is first reacted with ethanolamine-general formula III to produce compound SR of general formula IV, which is then chlorinated to obtain compound SR of general formula V, which is subjected to hydrogenolysis to obtain R- (+) - Cyclophosphamide.
    7. Compound form S-S of general formula 1 is reacted
    with ethanolamine of general formula III to obtain a compound of Form S-S of general formula IV, which is then chlorinated to obtain a compound of Form S-S of general formula V. The latter compound is hydrogenated to obtain R - (+) - cyclophosphamide.
    8. The compound of the R-S form of the general formula D is converted into a compound of the general formula g using an SN-type reaction (bimolecular nucleophilic substitution), then it is reacted with ethanolamine of the general formula 111 with a view; receiving; Compounds of form S-S of general formula IV, which are hydrogenated to form R - (+) - cyclophosphamide.
    As indicated above, R - (+) - cyclophosphamide can be obtained from any of the compounds of general formula I.
    S - (-) - cyclophosphamide has a better antitumor effect on PCb tumor than R - (+) - cyclophosphamide and the racemic form of cyclophosphamide on hl210 and P388 tumors (in mice). However, when testing the antitumor effect on hl210 tumor, which is a different type of tumor, R - (+) - cyclophosphamide exhibits a better antitumor effect than S - (-) - cyclophosphamide and the racemic form of cyclophosphamide. In addition, R - (+) - cyclophosphamide exhibits less acute toxicity (in mice) than S - (-) - cyclophosphamide and p &amp; cemic form of cyclophosphamide. These facts show that R - (+) - cyclophosphamide and S - (-) - cyclophosphamide are better; therapeutic efficacy than the racemic form of cyclophosphamide (depending on the type of tumor).
    With the introduction of any of R - (+) - and S - (-) - cyclophosphamide, a remarkable antitumor activity can be expected with fewer side effects than with the racemic form of cyclophosphamide.
    Method of determining anti-tumor activity.
    Lymphocytic-leukemic tumor of the type P388 is transplanted (1x10 cells) into the abdominal cavity
    In the male BDF live weight of about 20 g. Activity is assessed according to the IhS method (increase in life expectancy).
    Similarly, a lymphocytic leukemic tumor of solid type P388 is transplanted (1x1 O cells) subcutaneously into the back area of BDF male mice with a live weight of about 22 g. Mice are killed 10-11 days after transplantation, and the inhibitory effect on tumor proliferation is assessed by determining its weight.
    Lymphoid-leukemic tumor of solid type 141210 is transplanted (1x10 cells) in the subcutaneous region of the back of male BDF mice with live weight
    Tests for tumors L 121-0
    approximately 22 g. Mice are killed 10–11 days after transplantation and the suppressive effect on tumor proliferation is assessed by determining its weight.
      ,
    5, 10, 20, 50, 100 mg of the test compounds were dissolved in physiological sodium chloride solution (5 mg / kg concentration) and administered intraperitoneally (ER) or orally (PO).
    0 For comparison, physiology is used. sodium chloride solution with a concentration of 5 mg / kg.
    The results are presented in Table 5. 1 and 2.
    Table
    R- (+) -Cyclophosphamide
    S - (-) - Cyclophosphamide
    Racemic Form of Tumor P388
    R - (+) - Cyclophosphamide IP50,824.3
    S - (-) - Cyclophosphamide IP26,314,6
    Racemic form
    cyclophosphamide IP-39,71-69
    Acute toxicity test.
    The following are the UDjormg / kg (male BDF, IP) values for R - (+; - cyclophosphamide, S - (-) - cyclophosphamide, and the racemic form of cyclophosphamide. Test compound Yudo.mg / kg
    R - (+) - Cyclophosphamide 550
    S - (-) - Cyclophosphamide 330
    Racemic form
    cyclophosphamide 440
    Example 1. A 100 MP ether solution containing 7.8 phosphorus oxychloride is cooled with ice and a solution prepared by dissolving 8.96 g of 3 - (-) - N- (3-hydroxypropyl) -o1-fe24 is added to it with stirring. 32 29
    76 104
    95
    44,143
    Table
    5Q nilethylamine and 10.3 g of triethylamine in 50 ml of ether. The reaction is continued at the same temperature for 1 hour, then the insoluble hydrochloric triethylamine is separated by filtration. The resulting filtrate
    55 are evaporated to dryness under reduced pressure to obtain 11 g of a mixture consisting of 2 (S) -3 (3) -E1-phenylethyl tetrahydro-2-chloro-2H-1, 3,2-oxazaphosphorin-2-oxide, and 2 ( R) -3- (3) -C1-phenyl60 ethyl tetrahydro-2-hl6p-2H-1,3,2-oxazaphosphorin-2-oxide in the form of colorless crystals. Using the NMR spectrum, it was determined that the ratio in the mixture of the first component to
    65 second is 8: 1. This mixture is recrystallized from ether - hexane, and 8 g of 2 (3) -3-Pz) -A-phenylethyl tetrahydro-2-chloro-2H-1,3,2-oxazaphosphorin-2-oxide are obtained in the form of colorless igry-like crystals. . M.p. P5 WD + 51.5 (c 8.2, ethanol). Elemental analysis: Found,%: C 51.08; H 5.80; N 5.18; All 13.72; R 11.85. C H 5-CENO / j.P Calculated,%: C 50.88-; H 5.82; N 5.40; CP 13.65; R 11.93. The mother pacTBOD obtained by the above recrystallization is evaporated and recrystallized from isopropyl ether. 1.2 2 (R) -3- (S) -c (.- phenylethyl-tetrahydr-2-HLOR-2H-1,3,2-oxazaphosphorin-2-oxide) are obtained in the form of colorless prism-like crystals. 69-71 C. Mj, - 61.4 (from 3.01 to ethanol). Elemental analysis: Found,%: C 51.00; H 5.72; N 5.38; CE 13.68; 11, 90. (settled,%: C 50.88; H 5.82; N 5.40; ce 13.65; R 11.93. Example 2. 8.96 g (R) - (+) - N- (3-hydroxypropyl) -s1l-phenyl-1H- (4-methi-phenyl) -ethylamine, 7.8 g of phosphorus oxychloride and 10.3 g of triethylamine are taken according to the procedure described in Example 1, and 7.9 are obtained. g 2 (R) -3-G (K-c1 - phenylethyl tetrahydro-2-chloro-2H-1, 3,2-oxazaphosphorin-2-oxide in the form of colorless needle crystals. T. 71 -73 ° C. Rd: -51.6 (c 8.5, ethanol). Elemental analysis: Found,%: C 50.98; H 5.76; N = 5.45; se 13.68; P 11 , 95. 5-CENOiP Calculated,%: C 50.88; H 5.82; N 5, -40; c 13.66; P11.93. According to the procedure described in Example 1, i, 4 g 2 ( S) -3-G (K) -L-Phenylethyl tetrahydro-2-chloro-2H-1,3,2-oxazaphosphorin-2-oxide in the form of colorless prism crystals from the mother liquor obtained by recrystallization. T. p 69-7 + 61.6 (c 6.83, ethanol). Elemental analysis: Found,%: C 51.01; H 5.75; N 5.36; NE 13.69; R 11.91. I &amp; N,%: C 50.88; H 5.82; N 5.40; All 13.65; R 11.93. Example 3. A 20 ml solution of methylene chloride containing 1.6 g of phosphorus oxychloride is cooled with ice and, with stirring, a solution prepared by dissolving 1.8 g of (S) - (-) - N- (3-hydroxypropyl) is added to it. ) -oL-phenylethylamine and 2.1 g of triethylamine in 10 ml of methylene chloride. The reaction is carried out for 30 minutes at 40-50 seconds, after which triethylamine hydrochloride is removed by filtration. The obtained filtrate is concentrated under reduced pressure, evaporating it to dryness, to obtain 2.1 g of a mixture consisting of 2 (S) -3- (S) -oL-phenylethyl-J-tetrahydro-2-chlr-2H-1, 3.2 -oxazaphosphorin-2-oxide and 2 (R) -3- (5) - (1-phenylethyl) -tetrahydro-2-chloro-2H-1, 3,2-oxazaphosphorin-2-oxide in the form of colorless crystals. The mixture obtained is determined by means of an NMR spectrum and it is determined that the ratio of the first compound to the second is 8: 2. This mixture is recrystallized from hexane ether to obtain 1.5 g of 2-oxide-2- (S) -3-L-phenylethyl-tetrahydro-2-HLOR-2H-1, 3, 2-oxazaphosphorine in the form of colorless needle crystals . M.p. 71 - 73 ° C. rci. | f 51.7 (c 9.1, ethanol). The mother liquor obtained by recrystallization is then concentrated and recrystallized from isopropyl ether to obtain 0.1 g of 2-oxide-2- (R) -3-G (3) -c (.-Phenylethyl-3-tetrahydro-2-chloro -2N-1, 3,2-oxazaphosphorine in the form of colorless prismatic crystals, mp 69 -. - 61.2 (with 3.1, ethanol). Example 4. 50 ml of solution in cyclohexane containing 3.9 g phosphorus oxychloride, cooled with ice, to it with stirring, add a solution prepared by dissolving 4.5 g of (S) - {-) - N-3- (3-hydroxypropyl) - (i-phenylethylamine and 10.3 g of triethylamine in a 25 ml cycle The reaction was continued at the same temperature for 1 hour. After completion of the reaction, the solvent was removed from the Reaction Mixture by distillation under reduced pressure, the mixture was brought to dryness. The residue thus obtained was dissolved in 100 ml of diethyl ether and the ether layer was washed with water , dried with anhydrous sodium sulfate and filtered. The obtained filtrate is concentrated under reduced pressure to dryness and obtain 5.1 g of a mixture consisting of 2 (S) - (S) -oL-phenylethyl-tetrahydro-2-hlop-2H-1 , 3,2-oksazazafosfopin-2-oksida and .2 (R) -3- (S) - (i-phenyl) -tetrahydro-2-chloro-2 1, 3,2-oxazaphosphorin-2-oxide in the form of colorless crystals. The resulting mixture is determined by the NMR spectrum and it is recognized that the ratio of the first compound to the second is 8: 1. This mixture is recrystallized from hexane ether to obtain 3.7 g of 2 (8) -3-G (5) -c1-phenylethyl} tetrahydro-2-HLOR-2H-1, 3,2-oxazaphosphorine 2-oxide, in the form colorless needle crystals. T. pl. 71 -. Cd-J + 51, (c 8.5, ethanol). The resulting mother liquor after recrystallization is concentrated and recrystallized from isopropyl ether to obtain 0.5 g of 2-oxide-2- (R) -3-G (3) -a1-phenylethyl -2-HLOR-2H-1, 3, 2-oxazaphosphorine in the form of colorless prismatic crystals. T. pl. 69 - 71 ° C Go1 - 61.6 (c 3.2, ethanol) Example 5. A solution of 50NUi in diethyl ether containing 3/9 g of phosphorus oxychloride is cooled with ice and pacfBOp prepared by dissolving 4 is added to it with stirring, 5 g of (S) - (-) - N- (3-hydroxypropyl) -i-phenylethylamine and 9.3 pyridine in 25 ml of diethyl ether. The reaction is continued at the same temperature for 1 after which the insoluble, pyridine hydrochloride is filtered off. The obtained filtrate is concentrated under reduced pressure to dryness to obtain 5.7 g of a mixture consisting of 2 (S) -3-HS) -d-phenylethyl-tetrahydr -2-HLOR-2H-1, 3,2-oxazaphosphorin-2 -oxide and 2 (R) -3-C (S) "i- -phenyl-ethyl-tetrahydro-2-chloro-2H-1,3,2-oxazaphosphorin-2-oxide in the form of colorless crystals. The mixture obtained is determined by NMR and the ratio of the first to the second compound is 8. The mixture is recrystallized from hexane ether to obtain 3.8 g of 2-oxide-2 (S) -3 - C (S) -o (, -phenylethyl -tetrahydro-2-chloro -2H-1,3,2-oxazaphosphorine in form-like colorless needle crystals. So pl. 71-73 ° C. + 51.7 (with 8.5, ethanol). Obtained with the recrystallization described, the mother liquor is concentrated and recrystallized from isopropyl ether to give 0.5 g of 2-oxide-2- (K) -3- (S) -o1. -phenylethyl-tetrahydro-2-chloro-2H- 1, 3,2-oxazaphosphorine in the form of colorless prismatic crystals, mp 69 - 71 ° C. C. “A. - 61.8 ° (c 3.0, fl, anol) Example 6. 100 ml of solution in diethyl an ether containing 3.9 phosphorus oxychloride is cooled with ice and further stirring; a solution prepared by dissolving 4.5 g of (8) - (-) - s- (3-hydroxypropyl) -s1-phenylethylamine and 5 , 4 g of anhydrous potassium carbonate.The reaction is continued at the same temperature for 1. h, after which the insoluble substances are removed by filtration. The obtained filtrate is concentrated under reduced pressure to dryness to obtain 5.3 g of a mixture consisting of 2 (S) -3- (8) -1-phenylethyl} -tetrahydro-2-HLOR-2H-1, 3,2-oxazaphosphorus; in-2-oxide and 2 (R) -3- (S) - i-phenylethyl-tetrahydro-2-chlorop-2H-1, 3,2-oxazaphosphorin-2-oxide, in the form of colorless crystals. The NMR spectrum of the mixture obtained shows that the ratio of the first compound to the second is 8: 1. This mixture is recrystallized from hexane ether to obtain 3.8 g of 2-oxide-2 (S) -3- (8) N-phenylethyl-tetrahydro-2-chloro-2H-1, 3,2-oxazaphosphorine in the form of colorless acicular crystals. T. pl. 71 - 73С. UoL +51,4 ° (c 8.1, ethanol). . The mother liquor obtained by recrystallization is then concentrated and recrystallized from isopropyl ether to obtain 0.5 g of 2-oxide-2 (R) -3- (S) -dL-phenylethyl-2-tetrahydro-2-chloro-2H-1, 3.2 -oxazaphosphorine in the form of colorless prismatic crystals. M.p. 69 - 71 ° C. but. - 61.6 (with 3.4, ethanol). Example 7. 7.7 g of phosphorus oxychloride are dissolved in 100 ml of toluene and cooled with ice, after which a solution of 27 g of R - (+) - N- (3-hydroxypropyl) - (1 -Phenylethylamine in 100 MP of toluene. The reaction is continued at the same temperature for 30 minutes, the reaction mixture is then washed with 10% hydrochloric acid, then water and dried over anhydrous magnesium sulfate. Toluene is removed from the resulting reaction mixture by distillation under reduced pressure to obtain 6.4 g of a mixture consisting of 2 (R) -3-QR) -s1-phenylethyl-tetrahydr -2-chloro-2H-1, 3,2-oxazaphosphorin-2-oxide and 2 (S) -3-KR) -1-phenylethyl-tetrahydro-2-chloro-2H-1, 3,2-oxazaphosphorin-2 -oxide. The resulting mixture was recrystallized from diethylhexane ether to obtain 5.1 g of the first compound in the form of colorless needle-like crystals. M.p. 71-73 ° C. , - 51.5 ° (c 8.0, ethanol). The mother liquor obtained after recrystallization is purified by silica gel column chromatography. A mixture of benzene - chloroform - acetone (50: 5: 1) is used as eluent. 200 mg of crystals of the first and 700 mg of a second compound are obtained in the form of prismatic crystals. T. pl. 69 - 71 ° C. Gs). + (from 6.51, ethanol). Example 8. 18.3 g of oxychloride phosphorus is cooled to approximately -40 in a bath with a mixture of dry ice and acetone, after which the hardened phosphorus oxychloride is poured, drop by drop with a glass rod, with a solution of 26.9 g of R - (+) - N - (3-hydroxypropyl) - 1-phenylethylamine in 56 ml of triethylamine. The resulting resinous mixture is stirred at 5 for 30 minutes, after which 200 ml of water is added to the mixture to decompose unreacted phosphorus oxychloride and extracted with toluene. The toluene layer was washed with 10% hydrochloric acid (aqueous solution), with water, using an aqueous solution of sodium bicarbonate in this sequence, then it was separated and dried over anhydrous magnesium sulfate. After that, toluene was removed by distillation. 36 g dark purple but brown oily product which is purified by column chromatography on silica gel. A mixture of benzene chloroform - acetone (50: 5: 1) was used as the eluent. I get 2.7 g of 2-oxide-2 (S) -3- (R) -aL-phenylethyl-tetrahydr-2-chloro-2H-1, 3,2-oxazaphosphorin in the form of colorless prism-like crystals. M.p. 69 - 71 ° C. + 61.5 ° (c 8.7, ethanol). Then, 18.9 g of 2-oxide-2 (R) -3-C (R) -H1 Phenylethyl-tetrahydro-2-HLOR-2H-1, 3,2-oxazaphosphorin in the form of colorless needle-like crystals are isolated. T. pl. 71 - 73 ° C. - 51.7 (from 8.5, ethanol). Elemental analysis: Found,%: C 51.01; H 5.75; | N 5.36; All 13.69; R 11.91. C.HijCENOjP Calculated,%: C 50.88; H 5.82.;. N 5.40; All 13.65; R 11.93. Example 9. Obtaining cyclophosphamide. . . a) 3.5 g of 2 (S) -3-G (S) -aL-нилGnylethyl т tetrahydro-2-hlop-2. H-1, 3,2-oxazaphosphorin 2-oxide is dissolved in 35 ml of dioxane. Then 3 g of diethanolamine was added and heated under reflux for 2.5 hours. After distilling off the dioxane under reduced pressure, the resulting residue was dissolved in methylene chloride and the solution was washed with a 15% aqueous solution of hydrochloric acid in a saturated sodium chloride solution. The organic layer is separated, dried over anhydrous magnesium sulphate and filtered. The filtrate is evaporated to dryness under reduced pressure. The crystals obtained are crystallized from ethyl acetate and 3.2 are obtained. g 2 (5) -Z-fSwe (2-hydroxyethyl) (S) -A-phenylethyl tetrahydro-2H-1, 3,2-oxazaphosphorin-2-oxide in the form of colorless lamellar crystals. M.p. 104 - YubS. Gu13 | - 55.2 ° (c 6.54, ethanol). Elemental analysis: Found,%: C 55.18; H 7.53; N 8.42; R 9.38. Calculated,%: C 54.87; H 7.67; N 8.53; R 9.41. c) 3 g of thionyl chloride is dissolved in 10 ml of chloroform and a solution containing 3 g of 2 (3) -2-G5is - (2-hydroxyethylamine) -3-G (8) -ot-phenylethyl Gtetrahydro-2n is added dropwise. The -1,3,2-oxazaphosphorin-2-oxide obtained above, with stirring at room temperature, is then heated under reflux for 1 hour. After cooling the reaction mixture, the chloroform layer is washed with a saturated aqueous solution of sodium bicarbonate and water. The chloroform layer is then dried over anhydrous magnesium sulphate and filtered. The obtained filtrate is evaporated under reduced pressure and obtain 3.1 g of 2 -. (S) (2-chloroethyl) amineJ-3 (3) -1-phenylethyl} tetraHYDRO-2H-1, 3,2-oxazaphosphorin-2-oxide in as a colorless oily substance. tcL - 62.4 ° (c 5.7, benzene). c) -7.3 g of 2 (8) -2-G5iu (2-chloroethyl) -amine -3- (S) -c-phenylethyl2 tetrahydro2H-1, 3,2-oxazaphosphorin-2-oxide is dissolved in 100 ml of ethanol and catalytically reduced in the presence of 800 mg of 10% palladium on carbon at a hydrogen pressure of 20 atm and a temperature of 40-45 ° C. At the end of the reaction, insolubles were separated by filtration, the filtrate was evaporated under reduced pressure, and 4.6 g of crude Cristachols of R - (+) - cyclophosphamide were obtained. To obtain a purified substance, it is recrystallized from benzene-hexane. 1 + 2, (c 12.5, methanol). The IR spectrum and the NMR spectrum of this compound are exactly the same as those of the samples obtained previously. When testing a mixed sample, a lower melting point is not observed. I'll try it on. a) 3.5 g of 2 (R) -3- (R) - i-phenylethyl tetrahydro-2-chloro-2H-1, 3,2-oxazaphosphorin-2-oxide, prepared in Example 9, is reacted with diethanolamine, as described in example 9, and get 3.1 g 2 (K) -2-G5is (2-hydroxyethyl) (R) -eL-phenylethyl (tetrahydro-2H-1, 3,2-oxazaphosphorin-2-oxide in the form colorless lamellar crystals, mp 104–106 ° С. Go .: + 56.1 (p 6.23, ethanol) Elemental analysis: Found,%: C 55.15, H 7.56, N 8.43; R 9.39. C 5Ha5Na04P Calculated: C 54.87; H 7.67; 8.53; P 9.41.
    c) 3.0 g of 2 (R) (2-hydroxyethyl) -amin-3- (E) -s1-phenylethyl tetra-J HYDRO-2H-1,3,2-oxazaphosphorin-2-oxide obtained in Example 9 a, is reacted with 3 g of thionyl chloride according to the method described in Example 9, and 3.2 g of 2 (K) -2-G5is (2-chloroethyl) amic-3-QR) phenylethyl-3-tetrahydro are obtained. -2H-1, 3,2-oxaaphosphorin-2-oxide as an oily substance.
    U3 | 5 + 63.4 ° (c 5.6 benzene).
    c) 7.3 g of 2 (K) -2-G5ms (2-chloroethyl) amine-3-t (R) - (i-phenylethyl) tetra. 2H-1, 3,2-oxazaphosphorin-2-oxide, obtained in the example 9, is catalytically reduced by the method described in Example 9, and 4.5 g of (8) -cyclophosphamide are obtained in the form of colorless prismatic crystals, mp 65-66, ..
    GAS -2.08 (, 5, benzene).
    权利要求:
    Claims (3)
    [1]
    1. A method for preparing optically active oxazaphosphorin derivatives of general formula T
    flf-CH-R, x ".
    N,
    where k is phenyl; R is lower alkyl or phenyl substituted lower alkyl, meaning that the optically active amino alcohol of the general formula 11
    -CHR
    R
    I.
    Yes
    HLN
    where R and R have the indicated meanings, they are reacted with chlorine, phosphorus oxide at a temperature of minus 70 to plus.
    five
    [2]
    2. A method according to Claims 1, 3 a and l and h a and c with the fact that the process is conducted in an environment of an inert organic solvent — a saturated hydrocarbon, a halogenated aliphatic carbon, hydrogen, an aromatic hydrocarbon, or an ether.
    [3]
    3. Method according to paragraphs. 1 and 2, 3 and to the effect that the process is carried out in the presence of a basic compound — a tertiary amine or an inorganic basic compound — anhydrous potassium or sodium carbonate.
    Sources of information, 0; taken into account in the examination
    1.Purdela D. Vilchanu R. Chemistry of organic compounds of phosphorus. M., Himi, 1972, p. 678-679.
    2. In the same place 565.
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    同族专利:
    公开号 | 公开日
    SE7904595L|1979-11-30|
    NL7904215A|1979-12-03|
    SE446189B|1986-08-18|
    FR2427339A1|1979-12-28|
    CH646710A5|1984-12-14|
    FR2427339B1|1984-09-14|
    GB2021591A|1979-12-05|
    DE2921057C3|1981-11-26|
    CA1108175A|1981-09-01|
    US4239709A|1980-12-16|
    NL183141C|1988-08-01|
    AU4747779A|1979-12-06|
    DE2921057B2|1981-01-15|
    GB2021591B|1982-09-08|
    AU516429B2|1981-06-04|
    IT7968144D0|1979-05-28|
    IT1120976B|1986-03-26|
    NL183141B|1988-03-01|
    ES481026A1|1980-02-01|
    JPS54157580A|1979-12-12|
    BE876578A|1979-11-28|
    JPS5761360B2|1982-12-23|
    DE2921057A1|1979-12-06|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE1203268B|1961-10-26|1965-10-21|Farmochimica Cutolo Calosi S P|Process for the preparation of 2-chloro-3, 4-dimethyl-5-phenyl-1, 3, 2-oxazophospholidin-2-one|
    US3732340A|1966-07-11|1973-05-08|Asta Werke Ag Chem Fab|N',o-propylene phosphoric acid ester diamides|
    GB1235022A|1969-06-04|1971-06-09|Laeaeke Ag|A new method for the production of cyclophosphamide|
    DE2201675A1|1972-01-14|1973-07-19|Asta Werke Ag Chem Fab|1,3,2-oxaza phospha-cyclic sulphonic acid alkyl esters - - as immuno-suppressors|
    PL100390B1|1975-10-06|1978-09-30|METHOD FOR THE PRODUCTION OF 2-OXIDE-2- / BIS / 2-CHLOROETHYL / -AMINO / -1- / OXO-3-AZA-2-PHOSPHACYCLOHEXANE / CYCLOPHOSPHAMIDE / OPTICAL|DE3111428C2|1981-03-24|1990-06-13|Asta Pharma Ag, 6000 Frankfurt, De|
    US5229162A|1984-01-20|1993-07-20|Biocompatibles Ltd.|Article having biocompatible surface|
    GB8401534D0|1984-01-20|1984-02-22|Royal Free Hosp School Med|Biocompatible surfaces|
    US5380904A|1984-01-20|1995-01-10|Biocompatibles Ltd.|Process for rendering a surface biocompatible, and articles containing the same|
    ZA851062B|1984-03-01|1985-11-27|Asta Werke Ag Chem Fab|Salts of oxazaphosphorine derivatives and process for their production|
    FR2567129B1|1984-07-06|1986-12-05|Adir|NOVEL OXAAZAPHOSPHORIN DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|
    US5258538A|1985-08-26|1993-11-02|Applied Biosystems, Inc.|2,3-disubstituted-1,3,2-oxazaphosphacycloalkanes as nucleic acid linking agents|
    KR900013763A|1989-02-28|1990-09-05|안시환|Document Feeder for Copying Machine|
    DE19739159C1|1997-09-06|1999-01-28|Asta Medica Ag|Preparation of oxazaphosphorine-2-amine used as, and to prepare, cytostatics and immunosuppressants|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP53064681A|JPS5761360B2|1978-05-29|1978-05-29|
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