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    • 专利摘要:
    2-Substituted-1,3-propylidenediphosphonates of formula (I), where A, R1 and R2 are defined in claim 1, are therapeutically active compounds, namely for the treatment of cardiovascular diseases. They can be prepared by reacting phosphonating agents with 1,3- dibromopropanes or ditosylates of 1,3-propanediols substituted in position 2. <IMAGE> (I) .
    公开号:SU1375141A3
    申请号:SU853926752
    申请日:1985-07-17
    公开日:1988-02-15
    发明作者:Нгюэн Монг Лэн；Ньезор Эрик；Бентцен Крэйг；Гийон-Желлэн Ив；Калатакис Кириякос；Трюнг Фан Хье；Россье Жан-Робер
    申请人:Симфар С.А. (Фирма)；
    IPC主号:
    专利说明:

    f- (2} B (iJ} (
    (o) fifCcH2v;
    f; H3 (CH2it ,, (cH2) fo CHj-;
    Gui 2 N 2 H2
    SNg№2 th
    CHaCCHjlnl -tCHjlC O.
    / y
    ,,
    SNS (.CH2) p
    ilt-lCR lirOk CH V
    Tf
    CHHcH V
    one
    This invention relates to the chemistry of organophosphorus compounds with a G-P-bond, and specifically to a process for the preparation of new derivatives of 1,3-propipeniphosphonic acids of the general formula
    gh
    CH7.-R OHOYA {) ()
    dpU
    CHT ORiUOI V j
    where RI and Rj; - the same or different; C, -C j-apkyl, C-C-alkenyl, cyclopentylmethyl, cyclohexylmethyl;
    A selected from the following radicals radical:
    Сн н, ь И: p2: (Q} m (СН2 V-;
    O - ((SNGCH-;
    ShzX ...
    (0) rfri-CH, -; Y |} - (OV (CH,) jf i CHy 1 N
    (, h
    t
    where b, m, n, k, t are integers; B 3-16; m O or 1; n O - 8; k O - 4; t 1 - 4j X, Y, Z - the same or different: H, F, Cl, Bg, CF CHF, CHj,, j. CH, CH-CH ,, M-CjH ,, iso-C Ht, H-, iso- or trvt "h: H ,, OH,,, OS-C4-alkyl, SCHj, W ,, N (C, - C-alkyl). 8 tab.

    ten
    five
    .CO) ;-(
    /: CNP;
    , .1I-CCH2 -; / -O / SNG--.
     . .n
    b (0) rir (,) tx l: r QV GH 4-
    Uo
    ABOUT
    Y, Z
    0
    ; 0 / СНг1п4cHiV-H
    (0) T (CH 2) n - 0 i tЧсНг) г (О) т№г) г
    z to
    ) nl-, N- (CH2) rON-lCHiVOm - /
    CH (CH2 OH (CH2)
    20
    gb-osh SNG) g
    -
    CH3 (CH2) l
    ;-( CH24-i25
    CH- (CHi) t, -;
    Y
    ")), VO")) nd- (SNg) nd-;
    (Jh,
    jQ-CCrtfirC-CHa-; Y sh
    ;% (cHiiu (Q) (CHjln-;
    The compounds of formula (I) may be
    used as therapeutic agents for treating cardiovascular diseases such as angina pectoris and hypertonia.
    The purpose of the invention is to develop a method for producing 1,3-propylene diphosphonic acid derivatives which have therapeutic properties.
    The structure of the compounds of formula (l) is decayed from elemental analysis, IR spectrum, mass spectrum, and spectrum. The purity of the compounds is determined by thin layer chromatography on sy-
    five
    0
    five
    0
    35
    40
    45
    ...
    gel (under usual conditions of elution with a mixture of CHCl j - CH jOH in a ratio of 95; 5 to 80: 20 (v / v) and gas-liquid chromatography on a column filled with 3% Silar, 150 cm long, with an inner diameter of 3 mm, under general conditions of chromatographic analysis: 120 C (exposure 2 min), 4 ° / min to 200 - (30 min).
    All compounds of formula (l) show absorption lines of the IR spectrum belonging to phosphonate functional groups: 1240 cm (P 0) and 1070 - 990 (P - O - C).
    The NMR spectrum of 2-substituted I, 3-pro:: i-lendiphosphonates (l) also gives a characteristic picture:
    Н С - РОЗК2
    / n
    A-C-NS
    P hb
    The paired methylene protons H and H are diastereotopic drames and form absorption lines at two different chemical shifts: cf 2.3 - 2.0 and (/ 2.10 - 1.8. The lower n absorption region is a doublet doublet (dxhdxhd) with three interaction constants:
    JH H 7 Hz
     (fresh
    interaction) 16GTSI-R 19-20 Hz. In the higher absorption region, a similar multiplet (g. X g. X g.) Is additionally split by the interaction of the far limit with the second, the phosphorus atom. The proton methine H is absorbed as a broad multiplet adjacent to cG 2.5.
    Example 1. Tetraztil-2-benzyl-1. , 3-propylene diphosphonate
    , CH2.-P (0) (OC2H5) 2
    i
    CH, -R (OChOSg, H5) 2
    A solution of diethylbenzylmalonate (106 g, 0.43 mol) in 300 ml of dry dystil zirr is introduced in a nitrogen atmosphere in a slurry of 24.5 g (0.65 mol) of lithium aluminum (LiAlHj in 220 MP of dry α-sfir so that weak boiling with swelling of reflux. The reaction mixture is heated under reflux for another 2 hours after stopping the reagent. Excess LiAlH is destroyed, sequentially entering 50 ml of ethyl acetate, 50 ml of water and 600 ml of 15% sulfuric acid. The ether phase is extracted with a saturated bicarbonate sodium and a saturated solution of chloride n and evaporate the solvent, after evaporation of the solvent, a white solid is obtained and purified by recrystallization with ether.
    45.8.g (0.28 mol) of 2-ben zyl-1,3-propanediol are obtained (yield 64%), m.p. 65-67 C.
    IR spectrum (KBG), cm: 3300 (OH), 1450 (OH); 1030 (C-O).
    In a solution containing 114 g (0.6 mol) of p-toluenesulfonyl chloride (chloride chloride) in 200 ml of dry pyridine, cooled to, is introduced a solution of 45 g (0.27 mol) of 2 benzyl -1,3-propanediol in 40 ml of dry pyridine. The mixture is stirred at 2 hours and then at room temperature overnight. The reaction mixture is cooled to −25 ° C. for 2 hours and then 500 ml of ice water are poured. The white solid is separated, recovered by filtration and purified by recrystallization in acetone.
    104 g (0.22 mol) of 2-benzyl-1,3-propanediol ditosylate (yield 80%) are obtained, m.p. 88-90 ° C.
    IR spectrum (KBG), 1360; 1170 (-S0.5-).
    Then a 3.5 M solution of sodium diethyl phosphite is prepared as follows.
    9.0 g of 80% sodium hydride dispersion in mineral oil (0.30 mol) is suspended in 15 ml of tetrahydrofuran. After stirring for 5 minutes, a solid precipitated out. The surface layer is removed with a pipette. Then, sodium hydride is resuspended in 30 ml of dry tetrahydrofuran and 45 g (0.33 mol) of diethyl phosphite is added dropwise. Intensive hydrogen evolution is observed, accompanied by progressive consumption of sodium hydride. The mixture is stirred at room temperature even in those Q 5
    0
    5 o
    five
    0
    five

    1 hour and then diluted to total volume with tetrahydrofuran (85 ml
    A completely clear solution is obtained which contains about 3.5 mol / L sodium diethyl phosphite.
    A solution of 33 g (O, O7 mol) of 2-beisyl-1,3-pr-pandial ditosylate dissolved in 85 ml of 1,4-dirxane is introduced dropwise into the solution of sodium diethyl phosphite. Soon after the reaction mixture was heated to reflux temperature (approximately), a massive white precipitate separated. After heating under reflux for 4 hours, the reaction mixture is evaporated in vacuo and partitioned between 50 MP of water and 300 ml of chloroform, the chloroform phase is dried over MgSO4 and evaporated. The result is a pale yellow oil. The volatiles are removed by heating the raw mixture to 150 ° C under a vacuum of 0.05 mm Hg. The residual product is then purified by a T-molecular partition in apparatus with a round bottom flask and tube.
    21 g (52 mmol) of tetra- and ethyl-2-6eH3HJrl, 3-propylene diphosphonate are obtained in the form of a colorless oil (yield 74%), mp, 153-1554 0.05 mm Hg.
    Calculated,%: C, 53.20; H 7.94; R 15.24.
    C, gHjiO Pa
    Found,%: C 53.49; H 8.18; R 15.00.
    IR spectrum (liquid film), cm 3050 (aromatic C – H); 2990 (aliphatic C — H); 1240 (P 0); 1170 (P-O-C Hj); 1030 (P-O-C); 790 (aromatic C — H).
    NMR spectrum (CDCl1), f: 7.30 - 7.15 (m, 5H, aromatic H); 4.15-3.95 (m, 8H, P-OCHjCHg); 2.90 (d, J = 7 Hz, 2H, Ph-CHa); 2.58, - 2.40 (m, 1H, Ph — CH, —CH); 2.04 dx x ddc to d., J 7; 16 and 19 Hz, 2H, diastereotopic - C (H °) (n) - POjEt); 1.83 (finely divided d, X d. X d., 2H, diastereotopic H S –C (H) () t); 1.28 and 1.30 (two tons, J = 7 Hz, I2H, P-0-CH, -CH3),.
    This compound can also be obtained by chemically reacting 2-6eH3Hjr-1,3-dibromopropane with triethylphosphite. .
    Phosphorus tribromide (13.0 g, 48 mmol) is introduced into 2-benzyl-1,3-propaidiol
    (0.8 g, 48 mmol), cooled to, The reaction mixture is stirred for five days at room temperature. This viscous mass is heated at 100 ° C for 2 hours and poured into ice water.
    After extraction with ether and vacuum distillation, 7.8 g of 2-benz1-1,3-dimer) opane are obtained (yield 56%), mp. 79-83 C (0.05 mm Hg).
    Mass spectrum, m / e: 294 (M + 4); 292 (M + 2Y, 290 (M).
    A mixture of 5 g (17 mmol) of the indicated dibromide and 17 g (00 mmol) of triethyl phosphite is heated under reflux for 20 hours. After removing an excess of triethyl phosphite, followed by distillation using a round bottom flask and tube, 4.8 g are obtained (yield 70%) of tetraethyl-2-benzyl-1,3-proxydiphosphonate. This compound and the material obtained by the chemical interaction of 2-benzyl-1,3-propanediol ditosylate with sodium diethyl phosphite have identical IR and NAN spectra.
    Example 2. Tetraetch-2-1fe Nil-1,3-propylene diphosphonate
    XH2-P (0) (OC2H5l2 XH2-P (0) (OC2H5 2
    2 Phenyl, 1,3 dibromoprolane is produced by the chemical interaction of 2-ene-1-1,3-propane diol with phosphorus tribromide.
    To a solution of sodium diethyl phosphite, obtained by chemical interaction of 9.42 g (68 mmol) of diethyl phosphite with 1.84 g (61 mmol) of an 80% dispersion of sodium hydride in mineral oil in 17 ml of tetrahydrofuran, was injected with a solution of 4 g (14 , 4 mmol) of 2-phenyl-1,3-dibromo | 1-propane in 17 ml of dioxane. When the reaction mixture is heated for 2 hours, sodium bromide is added. The organic solvents are evaporated and the residual evaporation product is partitioned between ether and water. The volatiles are removed by heating the organic extracts to a pressure of 0.05 mm Hg. Analysis by gas-liquid chromatography shows that the high boiling residue is
    5 5
    0
    0
    0
    five
    five
    five
    0
    is a mixture of two products (gas chromatography conditions: 3% Silar-2100, 150 ml column, 3 mm internal diameter, temperature: 120 ° C (extract 2 min), up to 200 ° C (extract 30 min).
    The two compounds were separated by silica gel column chromatography using chloroform as eluant.
    The first compound (1.0 g, 18% yield), which is eluted from the column, is determined by IR and NMR spectroscopy as tetraethyl-1-methyl-1-phenyl-1, 2-ethylene diphosphonate of the formula
    SNG
    -C-CH2-P (0) (OC2H5) 2 P (0) (OC2H5) 2
    IR spectrum (liquid film), cm: 3060 (aromatic C – H); 2980 (aliphatic C — H); 1240 (P 0); 1165 (P-0-Et (Et-ethyl); 1040 (P-O-C); 790 - 690 (aromatic C-H).
    NMR spectrum (CDCl,), G: 7.55-7.2 (m, 5H, aromatic H); 4.0j 3.85; 3.70 and 3.50 (four separate meters, 8H P-O-CH, -CH3); 2.93 (t.d., J 8; 17 and 25 Hz, 1H, diastereotope -C (H) () - PO, Et,); 2.36 (finely split, etc., 1 H, dystereotope H: C- (H °) (n) —PoJEt; 1.85 (d, J 18 Hz, 6H, branched CHO, -group ); 1.25; 1.10; 1.0 and 0.94 (four separate t., J 7 Hz, 12H,).
    The second product (1.3 g, 24% yield) is similar to the first one using IR and. NMR spectroscopy is defined as the target compound, tetraethyl-2-phenyl-1,3-hopopylenediphosphonate.
    IR spectrum (liquid film), 3050 (aromatic C – H); 2980 (aliphatic C — H); 1240 (p - 0); 1165 (P-0-Et); 1030 (P-O-C); 780 - 690 (aromatic C — H).
    NMR spectrum (CDC1), J: 7.30 - 7.16 m., 5H, aromatic H; 3.95-3.76 (m, 8H, P-G-CH 1, -CH g); 3.52 - 3.38 (m, 1H, Ph — CH); 2.43-2.30 (d. X d. X d., J 6; 16 and 19 Hz, 2H, diastereotopic H °: -C (n) (H) -,) ;. 2.18-2.05 (d. X d. X d., J 9; .16 and 22 Hz, 2H, diastereotopic (H °) (H) -PO, E-g); 1.15
    and 1.16 (two tons, J = 7 Hz, 2H, - P-O-CHj-CHj).
    Example 3. Tetraisopropyl-2-benzyl 1,3-propylenediphosphonate
     // -sn -sn
    SI2-P (0) (0-СзН7-изО) 2 -I
    CH2-P (0) (0-CzN7-iso) 2
    This compound is obtained by chemically reacting a solution of 10.6 g (22 mmol) of dithyloxylate 2 benzyl 1,3-propanediol in 25 ml of diocene with 25 ml of a 3.5 M solution of sodium diisopropylphosphite in tetrahydrofuran. After this treatment, the reaction mixture is distilled in a round bottom flask and tube. The result is 5.5 g (yield 54%) of tetraisopropyl - 2-benzyl -1,3-propylenediphosphonate as a colorless oil.
    This compound is also obtained by heating a mixture of 1.8 g (6 mmol) of 2- -benzyl-1,3-dibromopropane and 14.2 g (60 mmol) of triisopropshtofosfite during 6 hours.
    After distillation, 1.9 g (70%) of pure tetraisopropyl-2-benzyl-1,3-propylene diphosphonate are obtained, b.p. 160 -, 03 mm Hg).
    IR spectrum (liquid film), 3040 (aromatic C — H); 2980 - 2940 (aliphatic C — H); 1390 - 1380 (isopropyl group); 1240 (Р 0) j 990 Р-О-С).
    NMR spectrum (CDCl1), s: 7.3-7.15 (m, 5H, aromatic H); 4.65 (finely split semiplet, J 7 Hz, 4H, POi (CHMe j),); 2.90 (d, J = 7 Hz, 2H, Ph — CH, —CH); 2.55-2.40 (m, 1H, Ph-CH7-CH); 2.0 (d. X d. X x d., J 7; 16 and 19 Hz, 2H, diastereotopic H (C (H) (H) -PO x Pr,)) 1.75 (finely split d. X dxd diastereotope H: C (H °) (H) - POjiPr); 1.25-1.35 (several superimposed d., J 7 Hz. 24H, RHZ (CH - (CHj),),) .
    Example 4. Tetrabutyl 2-ben ZIL-I, 3-propylene diphosphonate
    , CH2-PCO) (0-H-CiiH9) 2 55
    Ш2-Р (0) (0-Н-С% Н9) 2
    0
    five

    five
    0
    five
    Prepare a 2 M solution of sodium dibutyl phosphite in tetrahydrofuran as in Example 2.
    A solution of 15 g (32 mmol) of ditosylate 2 - beisyl-1,3 propanediol in 40 ml of dioxane is introduced into 40 ml of a 2 M solution of sodium dibutylphosphite in a tetrahydrophore. When the mixture is heated, massive sodium precipitate forms. tosylate This temperature is maintained for 15 hours, after which the reaction mixture is evaporated in vacuo. The evaporation residue is distributed between chloroform and water. The organic phase is evaporated. The residual product is evaporated cleaned by distillation in an apparatus with a round bottom flask and tube.
    Tetrabutyl-2-benzyl-1,3-propylene diphosphonate is obtained as a colorless oil (10.0 g, 60% yield).
    This compound is obtained by chemical interaction of 8.8 g (30 mmol) of 2-benzidg-, 3-dibromopropane with 50 ml of a toluene solution containing 120 mmol of sodium dibutylphosphite. The mixture is heated under reflux for 5 hours,
    Tetrabutyl 2-benzyl-1,3-propylene diphosphonate is obtained (yield 55%), b.p. 175-180 With (0.05 mm Hg),
    IR spectrum (liquid film), cm: 3040 (aromatic C – H); 2960 - 2940 (aliphatic C-); 1600-1500 (aromatic C-C); 1240 (P 0); 1070-1020 - 980 (Р-О-С).
    NMR spectrum (SBS1e), f 7.3-7.15 (m, 5H, aromatic H); 4.06 - 3.94 (m., 8H, P-0-CH,; - CH, CH3); 2.90 (d, J = 7 Hz, 2H, Ph — CH, —CH); 2.55- 2.4 (multiplet, 1H, Fh-CH-CH); 2.02 (d. X d. X d., J Hz, 2H diastereotope H: C (H °) (H) - POjBu j (Bu-butyl); 1.85 (distorted d. X d. X d., 2H, diastereotope (n) () - ROSVi2); 1.42 (m, 8H, P-0-CHg-CH, ; -CH5-CH3); 0.90 (s, J = 7 Hz, 12H, P-O-CH-CH.; - CH ,, - CH e).
    Example 5. Tetrabutyl-2- (3- -phenylpropyl) -1,3-propylene diphosphononate
    / CH2-P (0) ((- H-CitH9) 2
    O- (CH2) s-CH
    CH2-P (0) (. 0H-C H9) 2
    Distilmalonat (211 g, 1.32 mol) is added to a solution of 30.3 g (1.32 mol).
    1113
    sodium in 1500 ml of anhydrous ethanol. Then, nilpropyl bromide (249 g, 1.25 mol) is introduced into this solution. The mixture was kept under stirring for 15 hours. The ethanop was partially removed in vacuo and the residue was partitioned between water and dichloromethane. The dried organic phase is evaporated.
    282 g of diethyl 3 phenylpropylmalonate are obtained (yield 80%), b.p. 110- (0.05 mm Hg).
    IR spectrum (film), 1750 and 1730 (); 1300-1150 (C-O).
    The said compound (170 g, 0.61 mol) was introduced dropwise into a suspension of 25.8 g (0.68 mol) LiAlH in 650 m

    simple ether. Reaction mixture of at-20 phatic C-CH1); 1600 - 1500 (heated under reflux for 15 hours. Excess LiAlH, decompose, sequentially injecting 50 ml of ethyl acetate, 40 ml of water and 850 ml of 15% -
    Math C-C); 1240 (P 0); 1070-1040 (P-O-C).
    NMR spectrum (CDCl,), 7.3-7.15 (m, 5H, aromatic H); 4.05 oi sulfuric acid. The ether phase is 25 3.95 (m, 8H, R: H) -CH g-CH g-CH g-CH i);
    soaring to dryness, the evaporation residue is recrystallized from a mixture of diethyl ether and petroleum ether.
    2.60 (t, J = 7 Hz, 2H, Ph — CH —CH —CH, -); 2.34-2.17 (m, GN, Ph- (CH7) 3-CH-); 2.03 (d. X. d. X d., J 7; 16 and 19 Hz, 2H, diastereotopic H
    58 g (49%) of 2- (3-phenylpro ZO C (H) (H) -PO, B,) are obtained; 1.84 (distorted
    X d ..
    drank) -, 3-propanediol, so pl. 35-37 ° C. dxhd
    40
    IR spectrum (KBG), cm 1030 (C-O).
    A solution of this dihydric alcohol (57.5 g, 0.296 mol) in 50 ml of dry pyridine was injected into a solution of 135 ml (0.71 mol) of tosyl chloride dissolved in 250 ml of dry pyridine. The reaction mixture is stirred at room temperature overnight and poured into 500 ml of ice water. The separated viscous mass is recrystallized from acetone-petroleum ether.
    96 g (65% yield) of ditosid5 lata 2-C3-phenylprocil) -1,3-propanediol are obtained, m.p. 54-56 ° C.
    IR spectrum (KBg), cm: 1360 and 1170 (-SOrt-).
    A solution of sodium dibutylphosphite is prepared; 60 g (0.31 mol) of dibutyl phosphite are introduced into a suspension of 9.0 g (0.30 mol) of 80% sodium hydride dispersion in mineral oil in 100 ml of tetrahydrofuran. In this re-
    2H, diastereotopic
    3300 (OH); cue (H °) () - POiBuJ; 1.70-1.58 (m., 12H, (Ph — CH — CH — J, F — O — CH — CH — CH — CH,); 1.40 (six-year, J, 7 Hz, 8H,
    35 p-o-CH, i-CHj, -CH, i-CH3); 0.92 (t, J
     7 Hz, 12Н, Р-О-СН Mr. -СН-СН, - СН з).
    EXAMPLE 6. Tetrabutyl-2- (3- -cyclohexylpropyl) -, 3-propylene; phosphonate
    / Ш2-Р (оХО-н-с
    g - 7- (CH2) s-CH
    / - CH2-P (0) (0-H-C4H9h
    50
    3-Cyclohexylproduct chloride (70 g, 0.44 mol) is reacted with a solution of 0.64 mol sodium diethyl malonate in ethanol (270 ml) at 60 s for 15 h.
    Diethyl-3-cyclohexyl propromalonate is obtained in the amount of 62 g (50%).
    IR spectrum (film), cm: 1730 (), 1300-1100 (C-O).
    The specified connection (20 g, 70 mmol) is subjected to interaction
    the agent is injected with a solution of 51 g (0.10 mol), with a suspension of LiAlH (3.5 g, 92 mmol of 2- (3-phenylpropyl) -1 ditosylate, E-pro in 80 ml of dry tetrahydrofuran with a pan-yol in 100 ml dioxane. After heating at 80 ° C for 15 h
    reflux for 4 h. The reaction mixture is
    one
    12
    the reaction mixture is evaporated in vacuo and the residual product is distributed between dichloromethane and water. The dried organic phase is evaporated and the oily residue is purified by distillation in a round bottom flask and tube.
    39 g (yield 70%) of tetra-b are obtained from tyl-2- (3-phenylpropyl) -1,3-pr-diphosphonate, b.p. 185-190 C (0.05 mm Hg).
    Calculated,%: C 61.54} H, 9.52; R 11.38.
    C gHsjOjP,
    Found,%: C 61.26; H 9.72; R 11.54.
    IR spectrum (liquid film), cm: 3040 (aromatic C – H); 2970 (alimatical C-C); 1240 (P 0); 1070-1040 (P-O-C).
    NMR spectrum (CDCl,), 7.3-7.15 (m, 5H, aromatic H); 4.05 3, 95 (m., 8H, R: H) -CH g-CH g-CH g-CH i);
    2.60 (t, J = 7 Hz, 2H, Ph — CH —CH —CH, -); 2.34-2.17 (m, GN, Ph- (CH7) 3-CH-); 2.03 (d. X. d. X d., J 7; 16 and 19 Hz, 2H, diastereotopic H
    C (H) (H) -RO, B,); 1.84 (distorted
     ,) 1.84 (distorted
    2H, diastereotopic
    ) -POiBuJ; 1.70-1.58 J, F-O-CH —CHj — stiplet, J 7 Hz, 8H,
    3-Cyclohexylproduct chloride (70 g, 0.44 mol) is reacted with a solution of 0.64 mol sodium diethyl malonate in ethanol (270 ml) at 60 s for 15 h.
    Diethyl-3-cyclohexyl propromalonate is obtained in the amount of 62 g (50%).
    IR spectrum (film), cm: 1730 (), 1300-1100 (C-O).
    The specified connection (20 g, 70 mmol) is subjected to interaction
    with a suspension of LiAlH (3.5 g, 92 mmol in 80 ml of dry tetrahydrofuran with
    with a suspension of LiAlH (3.5 g, 92 mmol in 80 ml of dry tetrahydrofuran with
    reflux for 4 h. The reaction mixture is
    evaporated and the residue diluted with 150 ml of ether. Excess LiAlH is decomposed with 6 ml of water and 100 ml of HjSO4.
    After evaporation to dryness, 9 g (49%) of 2 (3-cyclohexylpropyl) -1.1,3 propanediol are obtained, mp. 47-48 C.
    IR spectrum (KBG), 3250 (OH); 1030 (C-0).
    The specified dihydric alcohol (8 g, 40 mmol) is reacted with tosyl chloride 19.1 g, 100 mmol in pyridine (40 ml).
    18.8 g (yield 92%) of 2 - (3-cyclohexylpropyl) -1.3-propanediol ditosylate are obtained, m.p. 68-70 ° C.
    IR spectrum (KBG), cm 1350 and 1170 (-80, -).
    A solution of 8 g (15i, 7 mmol) of the indicated ditosylate in a mixture of 20 ml of tetrahydrofuran and 80 ml of dioxane is reacted at 75 ° C with a solution of 63 mmol of sodium dibutylphosphite in 60 ml of tetrahydrofuran. After this treatment, vacuum stripping is carried out.
    6.0 g (69% yield) of tetrabutyl 2- (3-cyclohexylpropyl) -, 3- propylene diphosphonate are obtained, b.p. 190 - 195 ° C (0.05 mm Hg).
    IR (KBg), 2960 (aliphatic C – H); 1240 (P 0); 1040-980 (P-O-C).
    NMR spectrum (CDCl1), /: 4.1-3.96 (m, 8H, P-O-CH, -CH, -CH, -CH,); 2.33-2.14 (m, 1H, C H „ČSN) s-CH-); 2.03 (d. X d. X d., J Hz, 2H diastereotope H: C (n) (H) - FOjBu,); 1.84 (distorted d. X d. X x d., 1H, diastereotopic C (H) (H °) - DIZVi); 1.74 - 1.60 (m, 12I): -CH, - (CHj) + P-0-CH2-); 1.6-1.52 (q, 2H, C H "-CH); 1.40 (six-year-old, J 7 Hz, 8H, P-O-CH-CH-CH-CH3); 1.35-1.10 (broad m., 11H, 0.92 (t, J 7 Hz, 12H, P-O-CHg CH,).
    Example 7. Tetrabut-2- (2-phenoxyethyl) -, 3-propylene diphosphonate
    CH2-P (0) (0-H-C H9) 2 fyO-lCHnlo-CH CH2-P (0) (0-H-C4H9) 2
    2-phenoxyethyl bromide (84 g, 0.42 mol) is subjected to interaction
    with a solution of 0.42 mol of sodium diethyl malonate in 400 ml of ethanol.
    85 g (72% yield) of diethyl -2 -2-phenoxyethyl malonate are obtained, b.p. 130- (0.05 mm Hg).
    IR Spectrum (film), 1730 (); 1300-1150 (C-0).
    The indicated compound (70 g, 0.25 mol) is reduced by slurry of 10.92 g (0.28 mol) of LiAlH + in 420 ml of dry ether.
    Obtain 44 g (yield 62%) 2- (2- - enoxyethyl) -1, Zpropanodio l a, t :. square 71-72 C.
    IR spectrum (KBG), cm 3300 (OH); 1030 (C-0).
    This dihydric alcohol (30 g 0.15 mol) is reacted with 80 g (0.46 mol) of tosyl chloride in 180 ml of dry pyridine.
    62 g (82% yield) of 2- (2-phenoxyethyl) -1,3-propanediol ditosilate are obtained, m.p. S9-70 C.
    IR spectrum (KVg), cm% 1370 and 1170
    C-sOj-).
    a solution of ditosylate (20 g, 40 mmol) in a mixture of tetrahydrofuran (50 ml) and dioxane (150 mol) is introduced into a solution of 190 mmol sodium dibutyl phosphite in 100 ml of tetrahydrofuran. The resulting mixture is heated at overnight. After this treatment, distillation is carried out in an apparatus with a round bottom flask and tube.
    12 g (yield 55%) of tetrabutyl 2- (2-phenoxyethyl) -1,3-propyne diphosphonate are obtained.
    The same yield is obtained when the phosphonation reaction is detected in dimethoxyethane.
    A solution of 160 mmol of sodium dibutylphosphite in 80 ml of dimetok of seethane is prepared by chemical interaction of 35.2 g (180 mmol) of dibutylphosphite with 4.8 g (170 mmol) of 80% sodium hydride. To this solution, enter a solution of 20 g (39.6 mmol) of 2- (2-phenoxyethyl) -1,3-propanediol ditosylate in 70 ml of dimethoxyethane. The resulting reaction mixture is heated under reflux overnight.
    After this treatment, 17.4 g (yield 60%) of tetrabutyl-2- (phenoxynethyl) -1,3-propylene diphosphonate are obtained, b.p. 205-210-C (0.05 mm Hg).
    IR spectrum (liquid film), cm 2970 (aliphatic C – H); 1600 aro
    magic CH); 1240 (P 0); 107O-980 (P-O-C).
    NMR spectrum (SBSI3), f: 7.3-7.24 and 6.95-6.85 (m, 5H, aromatic H); 4j, p9-3.95 (m, 8H, PO-CH-CHj-CHj-CHj + PhO-CHi), 2.62-2.44 (m, 1H, PhO - (CH,) - CH- ); 2.20-2.06 (m, 4H, di-, astereotopic H: C (H) (H) + + PhO-CH, -CH,); “2.0 (distorted doublet of the doublet of the doublet, 2H diaste-rheotopic (n) (n) -ROSVi ,; 1.63 quintet, 8H, P-O-CH-CH, -CH CH); 1.40 (six-fold, J = 7 Hz, 8H, P-O-CH-CHj-CHj-CHj); 0.92 (t, J is 7 Hz, 12H, P-O-CH, -CH3).
    Example 8. Tetraethyl-2- (1-.-Naphthylmethyl) -, 3-propylene diphosphonate
    CH-CH2-P (0) COC2H5b
    Diethyl malonate (91 g, 0.57 mol) was introduced into a solution of sodium ethoxide, obtained by dissolving 13.1 g (0.57 mol) of metallic sodium in 460 ml of anhydrous ethanol. The resulting mixture was stirred at 50 ° C for 1 hour, then a solution of 100 g (0.57 mol) of 1-chloromethylnaphthalene in 50 ml of ethanol was added dropwise to it. Soon a white precipitate of sodium chloride is released. The reaction mixture is heated at 60 ° C overnight. The ethanol solution of the mixture is evaporated in vacuo and the residue is partitioned between diethyl ether and water. The dried ether solution is evaporated. The residual oil is slowly cured.
    After recrystallization from diethyl ether, 120 g (0.4 mol) of diethyl- (1-naphthyl) -methyl-malonate are obtained (yield: 70%), mp. 27-28 c.
    IR spectrum (KBG), cm 1750 and 1730 (); 1280 - 1150 (C-O).
    A suspension of 19.8 g (0.52 mol) of lithium aluminum hydride in 500 ml of dry diethyl ether is injected with a solution of 120 g (0.4 mol) of diethyl 2- (1-naphthyl) methylmalonate in 80 ml of diethyl ether and the resulting mixture is heated under reflux for 12 hours. Excess LiAlH is decomposed by sequential addition of 70 ml of water and 110 ml of 15% H 0 4. The separated ether phase is washed
    about s
    0
    5 days
    .

    0
    with a saturated solution of sodium bicarbonate and dried over MgSOv. After evaporation of the ether, the residual solid is recrystallized from a mixture of diethyl ether and petrol ether in a ratio of 95: 5.
    35 g (0.16 mol) of white crystals of 2- (1-naphthylmethyl) -1,3-propane diol (yield 40%) are obtained, mp. 78-81 S.
    IR spectrum (KBG), cm: 3250 (OH); 1040 (C-O); 790 (naphthyl CH).
    A solution of 30 g (0.14 mol) of 2- (1-naphthylmethyl) -, 3-propanediol in 50 ml of pyridine is injected into a solution of 78 g (0.41 mol) of tosyl chloride dissolved in 110 ml of pyridine. The reaction mixture is stirred at room temperature for 15 hours and then poured into 500 ml of ice-cold water. The semi-solid mass is viscous. This mass is dissolved in 50 ml of cold diethyl ether and the result is a white solid.
    After recrystallization from a mixture of acetone and petroleum ether, 46 g (yield 62%) of 2- (1-α-naphthylmethyl) -, 3-propane diopita ditosylate, m.p. 90-91 C.
    IR spectrum (KBG), 1380 and 1180 (SOj-); 830 and 770 (naphthyl CH).
    A solution of 10 g (19 mmsl) of the indicated ditosylate in 20 ml of dioxane is introduced into a solution containing 65 mmol of sodium diethyl phosphite in 20 ml of tetrahydrofuran. The reaction mixture is heated at 100 seconds for 3 hours, then the solvent mixture is removed by evaporation. The resulting evaporation residue was partitioned between chloroform and water. After evaporation of the dried organic phase, a viscous oil is obtained, which is purified by distillation in an apparatus with a round bottom flask and tube.
    Tetraethyl-2- (l-naphthylmethyl) -l, 3-propylene diphosphonate (5.2 g, 11.4 mmol) is obtained as a pale yellow viscous oil (yield 60%), b.p. 195-200 ° C (0.05 mm Hg).
    Calculated,%: C 57.89; H 7.46; P 13.60.
    CiiH4406Pi
    Found,%: C 57.92; H 7.72;
    P 13.40.
    IR spectrum (liquid film), cm: 3060 (ap, omatic C – H); 2990 (aliphatic); 1240 (P 0); 1060-1040 (P-O-C); - 800 (naphthyl).
    17
    NMR spectrum (CDCl1), tf: 8.28, 7.83 and 7.73 (three d., J 8 Hz, 3N, aromatic protons from the substituted phenyl core); 7.55 - 7.26 (m ,, 4H, aromatic protons from the condensed benzene core); 4.10- 3.90 m., 8H, P-O-CH-CH /); 3.35 (d, J, 7 Hz, 2H, CtoH — CHj — CH); 2.75 - 2.58 (m, 1H, C ,, - CH); 2.14 (d. X d. X d., J 7; 16 and 19 Hz, 2H, diastereotope n: -C (n) (H) - POjEt); 1.87 (distorted d. X d. X x d., 2H, diastereotope H: -C (H) (H) -P03Et ,,) ;; 1.24 and 1.18 (two tons, 7 Hz, 12H. P-O-CH-CHj).
    Example 9. Tetrabutyl 2 13 - (3 pyridyl) propyl -1,3-propylene di-phosphonate
    15
    .CH2-P (OKO-H-CitH9l2
    0 (CH,.) 2
    N
    3- (3 Pyridyl) propylchloride hydrochloride is obtained by chemically reacting 3- (3-pyridyl) propanal with phosphorus chloroxylate in ethnacetate at reflux temperature. This free base is obtained by dissolving said chlorohydrate in a 10% solution of sodium hydroxide and extracting it with an organic solvent (toluene or ether).
    Diethyl malonate (156 g, 0.98 mol) was reacted with a solution of 66.5 g (0.98 mol) of sodium ethyl acetate in 400 ml of ethanol. Then, 100 g (0.65 mol) of 3- (3-pyridyl) propyl chloride is introduced into the reaction mixture. The reaction mixture is heated at overnight. Ethanol is evaporated. The evaporation residue is distributed between chloroform and water.
    After distillation in an apparatus with a round-bottom flask and tube, 90 g (50% yield) of diethg-3- (3-tshrimyl) propylmalonate in the form of a pale yellow oil are obtained, b.p. 135 - 140 C (0.05 mm Hg).
    IR spectrum (film), 1720 (C 0); 1300 - 1150 (C-0).
    The specified malonate in an amount of 20 g (72 mmol) was introduced into drops in suspension of 3.9 g (103 mmol) of LiAlH4 in 70 ml of dry tetrahydrofuran. Reak137514118
    The mixture is heated under reflux for 4 hours. Excess LiAlH4 is decomposed by adding 8 ml of water. The precipitated hydroxide is filtered off. After evaporation of tetrahydrofuran, 11.5 g of orange oil are obtained, which is purified by chromatographic separation on a column of silica gel with elution with a mixture of chloroform: methanol (8: 2). Receive (3-pyridyl) propyl -1, 3-propanediol in the amount of 7.7 g (yield 55%), so pl. 45-. .
    IR spectrum (KBG), cm: 3300 (OH); 1020 (C-0).
    Tosyl chloride in the amount of 18.4 g (96.6 mmol) dissolved in 20–30 ml of dry pyridine was introduced into a solution of 6.3 g (32.3 mmol) of the indicated dihydric alcohol in 20 ml of pyridine, after which the reaction mixture was stirred at a temperature of 0 ° C overnight. The crystalline pyridine hydrochloride is filtered off, after which the pyridine solution is poured with simultaneous stirring in 500 ml of ice water. The solid solid pro- duct 30 SOAc is recrystallized from an acetone-ether mixture.
    9.8 g (60%) of ditosylate (3-pyridyl) propyl propan-1,3-diol are obtained, m.p. 85-86 ° C.
    IR spectrum (KBg), 1360 and 1170 ().
    In a solution containing 28.8 mmoles of sodium dibutyl phosphite and 20 ml of tetrahydrofuran, a solution of the indicated ditosylate (3.4 g, 6.8 mmol) in a mixture of tetrahydrofuran (10 ml) and di-ocean (30 ml) is introduced. The reaction mixture is heated at 90 ° C, during which sodium tosylate is recovered. After heating at 90 ° C for 15 hours, the reaction mixture is partitioned between water and chloroform. After evaporation of the dried organic phase, the oil is heated to vacuum at 0.05 mm Hg. to remove volatile matter. The residual product is purified by separation in a chromatography column with silica gel using as a eluent a mixture of chloroform and methanol 55 in a ratio of 9: 1.
    2.8 g (75% yield) of 1,3-protic diphosphonate are obtained in the form of a pale yellow oil.
    35
    40
    45
    50
    IR spectrum (liquid film) i 2970 (aliphatic C – H); 1240 () 1020 - 980 (Р-О-С).
    NMR spectrum (CDCl1), s: 8.46, 7.6, and 7.3 (m, 4H, heteroaromatic H); 4.05-3.95 (m., 8H, -CHH-CH3-CH3); 2.65 (t, J = 7 Hz, 2H CsH; N-CHs-CH-CHj); 2.35-2.0 (m, 1H, (CH ,,) j-CH-); 2.03 (d. X X d. X d., J 7; 16 and 19 Hz, 2H,. Di astereotopic n: C (n) (H) - POjBuj); 1.84 (distorted d. X d. X x d., 2H, diastereotopic C (H) (, Bu,); 1.72 - 1.60 (m, 12H, Cd H 4N-CH g- (CH ,) j, ,,); 1.40 (six-fold, J 7 Hz 8H, P-OCHzCHjCHjCH,); 0.95 (t, J 7 Hz, 12H, R-OCH, CH, CH, CH g).
    Hydrogen chloride gas is introduced into a solution of this compound in diethyl ether. After evaporation of the solvent, a chlorohydrate salt of tetrabutyl 2- 3- (3-pyridyl) propyl is obtained: 1-1,3-propylene diphosphonate,
    IR spectrum, cm% 2970 (aliphatic C – H); 2500 - 2200 (NNH-ammonium-- wah salt); 1240 (P 0); 1020 - 980 (Р-О-С).
    Example 10. Tetraamyl 2- (3- -phenylpropyl) -1,3-propylene di-sponate
    (
    CH2-P (0) (0-H C5Hiil2
    CH2-PCO) (0-H-G5Hii) 2
    A solution of sodium di-amylphenyl phosphite is prepared by adding 80 g (0.36 mol) of di-H-pentyl phosphite to a suspension of 8.6 g (0.29 mol) of 80% sodium hydride in 150 ml of tetrahydrofuran, after which the mixture is heated at 60 ° C until sodium hydride is completely consumed. 40 g (0.08 mol) of 2- (3 Fench1propyl) -1,3-propanediol ditosylate dissolved in 150 ml of dioxane are introduced into this solution. The resulting mixture was heated overnight, then distilled in an apparatus with a round bottom flask and tube.
    38 g (yield 79%) of tetraamgshg-2- (3-phenylpropyl-1, 3-propyl-1g diphosphonate, bp. 210-215 C (0.05 mm Hg) are obtained.
    IR spectrum (liquid film), 3050 (aromatic C – H); 2960 (aliphatic C — H); 1240 (P 0); 1050-1000 ().
    NMR spectrum (CDCl1): 7.3-7.15 (m, aromatic H); 4.05-3.95 (m, 8H, F-G-CHj-C H,); 2.60 (t, J = 7 Hz, 2H, Ph-CHj-CCHj),); 2.35-2.18 (m, 1H, Pb (CH3) s-CH); 2.05 (d. X d. X d., J 7; 16 and 19 Hz, 2H diastereotope H: C (n) (H) - POj (,) j); 1.85 (distorted d. X x d. X d., 2H, diastereotopic, C (H «) (HM-POj (CjH ,,) J; 1.65 (m, 12H, Ph-CHj (CH, ) + pwO-CH7-CH3- -CjHi); 1.35 (m, 16H, P-O- (CHg), - - (CHg) g- (Shz); 0.92 (distorted t., J 7 Hz, 12H, P-0- (CH j) -CHj).
    Example 11. TeTpareKCHjr 2- - (Z-phenylpropyl) -1,3-proshshendifos background t
    Lx, / CH2-PCO) (0-H-CgHB),
    (.) s-n
    - CH2-P (0) (0-H-SbN1e) ;,
    0 5
    0
    five
    ,
    .
    obtained by reacting 20 g (0.04 mol) of 2- (3-phenylpropyl) -, 3-propanediol ditosylate dissolved in 80 ml of dioxane with a solution of sodium dihexyl phosphite, obtained by chemically reacting 4.2 g (0.14 mol) 80% sodium hydride with 40 g (0.16 mol) of dihexyl phosphite in 80 ml of tetrahydrofuran.
    After distillation in an apparatus with a round-bottomed flask and tube, 11 g (yield 42%) of tetrahexyl 2- (3- -phenyl flux) -, 3-propylene diphosphonate, b.p. 225-230 C (0.05 mm Hg).
    IR spectrum (liquid film), 3040 (aromatic C — H); 2960 (aliphatic C — H); 1240 (P 0); 1050-990 (Р-О-С).
    NMR spectrum (CDCl,), f: 7.3-7, .15 (m, aromatic H); 4.05 - 3.95 (m., 8H, P-O-CH-CdH ,; 2.63 (t., J 7 Hz, 2H, Ph-CH} - (CH2),); 2.35 - 2.20 (m, 1H, Pb- (CH,) e-CH); 2.04 (d. X d. X d., J 7; „16 Hz, 2H, dias-hereotopic H: C (H () - POj (); 1.85 (distorted d. X X d. X d., 2H, diastereotopic (.) () - PO, (,;),); 1.65 (m, 12H, Ph-CH., - (CH.j), + P-0-CH, -CH,. ,,); 1.42 - 1.26 (broad m., 24H, P-0- - (CE: j ) j- (j 0.90 (distorted m., J 7 Hz, 12H, PO- (CHj) 5- -CHj).
    Example 12. Bis (ethyl, amyl) - -2- (W-ynylpropyl) -, 3-pro saw or phosphonate
    .tf
    Čsn CHCHi-PtoXOCzHsXO-H-CsHu
    : CHi HOKOCiH5) ((Hl-C5Hu
    Amount of 44.1 (0.5 mol) amyl alcohol was slowly introduced into 103.0 g (0.75 mol) of cooled-to-PClj. The resulting gaseous hydrogen chloride is removed from the reaction mixture with a stream of nitrogen. Stir up the thief and stir additionally for 1 hour at room temperature. A vacuum is then created by means of a water vacuum pump to remove residual gas.
    Amide of dichlorophosphite in the amount of 50 g (53%) is distilled at 66–70 ° C (15 mm Hg).
    IR spectrum (liquid film), 2930 (aliphatic C-H); 1000 (Р-О-С).
    39.0 g (0.21 mol) of amyldichlorophosphate in 10 ml of anhydrous ether are added dropwise to a solution of 19.0 g (0.41 mol) of ethanol in 90 ml of ether, at. The mixture is stirred overnight at room temperature. The ether solvent is evaporated. The evaporation residue is distilled off in vacuo.
    10.0 g (27%) of ethylamyl phosphite are obtained, b.p. 85-100 ° С 5 mmHg
    IR spectrum (liquid film |, 2930 (aliphatic C – H); 1250 (P 0); 970 ().
    Mass spectrum, t / e: 179 (M-D); 83 (main peak).
    A solution of sodium ethyl pentyl phosphite prepared from 5.76 g (32 mmol) of ethyl amyl phosphite and 0.90 g (30 mmol) of 80% sodium hydroxide dispersion in mineral oil in 40 ml of anhydrous tetrahydrofuran was added to a solution of 4.0 g ( 8 mmol) ditosylate 2- (3-phenylpropyl) -I, 3-propane diol in 40 ml of anhydrous dioxane. After refluxing for 15 hours, the reaction mixture is evaporated in vacuo and the residual product is partitioned between chloroform and water. The dried organic phase is evaporated and the residual evaporation product is fractionated by distillation in an apparatus with a round bottom flask and tube.
    0.5 g (yield 2%) of bis (ethyl, amyl) -2- (3-feshspropyl) -1.3---propylene diphosphonate is obtained, b.p. 195 - 200 C (0.05 mm Hg).
    five
    0
    five
    0
    five
    0
    five
    0
    five
    IR spectrum (liquid film), cm: 3040 (aromatic C-fl); 2930 (aliphatic C — H—); 1240 (P 0); 1020 (Р-О-С).
    NMR spectrum (CDCl1), of: 7.3-7.15 (m, 5H, aromatic H); 4.15-4.05 (m., 4H, P-O-CH, - CH}); 4.05-3.95 (m, 4H, P-0-CHj- (CH,) j-CH3); 2.60 (t, 22H, Ph-OTj-CH, -CH,); 2.35-2.20 (m, 1H, Pb- (CH) s-CH); 2.03 (d. X x d. X d., 2H, diastereotopic (H) (H) -P (0) (OS, H) (OS, H, J); 1.85 (distorted d. X d x d., 2H, diastereotopic (H) (H) - P (0) (OS, H5). (OS, H „)); 1.65 (m, 8H, PhCHj - (CH,) 2- CH + P-OCH, CH j (CH.,), CH h); 1.35 (m, 8H, P-0-CH CH2 (CH2), - CH3); 1.16 (t., 6H, P-0-CHj-CHj); 0.92 (t,;, 6H, P-0- (CH,) «- CH3).
    Mass spectrum, t / e: 518 (M); 179 (-P (0) (OC, Hj) (OC5H ,,)).
    Example 13. Bis (etch1, amyl.) - -2-benzyl-1,3-propylene diphosphonate
    ,, Mr. R OSOSgN XO-N-CzNi ch2-P (o) (os2az) {rn-S9NyH
    A solution of 25.0 g (0.132 mol) of pentile-dichlorophosphite. In 50 ml of hexane is added dropwise to a stirred solution of 12.2 g (0.265 mol) of stanol and 20.9 g (0.265 mol) of pyridine in 100 ml of hexane. . During this introduction, the mixture is maintained at a temperature below by means of an ice bath. Stirring is continued for an additional 3 hours at room temperature; The resulting massive precipitate of the pyridine hydrochloride salt is filtered, washed with hexane and the filtrate is evaporated to dryness. The residue is fractionated by separation in a VigreiLK column.
    8.0 g (yield 29%) of diethylpentylphosphite are obtained, b.p. 85 - (15 mm Hg).
    IR spectrum (liquid film), 2940 (aliphatic C-H); 1030 (P-O-C).
    2-Benzyl-1,3 dibromopropane was prepared according to example 1,
    A mixture of 1.0 g (3.4 mmol) of 2-basyl--1,3-dibromopropane and 3.6 g (17.0 mmol) of diethylamyl phosphite is heated under reflux c. nitrogen atmosphere at 180 ° C for 4 h. The reaction mixture obtained is fractionated by distillation in an apparatus with a round-bottomed calboy and tube.
    23137514
    0.4 g (24%) of bisCethyl, amyl) -2-benzyl-1,3-propylenediphosphone is obtained, b.p. ISe-igO C (0.05 mm Hg),
    IR spectrum (liquid film),, 2960 (aliphatic C – H); 1250 (P 0); 1050 (Р-О-С).
    NMR spectrum (CDCl 3), about: 7.32 - 7.18 (m, 5H, aromatic H); 4.15-4.00 (m, 4H, P-O-CH-CH g); 4.00 - U 3.90 (m, 4H, P-0-CH .- (CHg) e-CHE 2.90 (d. 2H, Ph-CH-CH); 2.50 (m, 1H , Ph-CHj-CH); 2.03 (d. X d. X d., 2H, diastereotopic H °: C (n) (H) - P (0) (OC, H5) (OC5H „)); 1.85 (distorted-15th d. X d. X d., 2H, diastereotopic (H) () - P (0) (OS, H5) (OS, H "); 1.65 (m, 4H, P-0-CHiCH (CH), CH jh 1.35 (m, 8H, P-0-CH2CH (CH,) CH,); 1.30 (t. 6H,, CH,); 0, 90 (t, 20 6H, P-0- (CH, g) f-CH3).
    Mass spectrum, t / e: 490 (M).
    Example 14, Bis (butyl, ethyl) -2- (3 phenylpropyl) -1.3 propylenediphos phonate 25
    CH2-P (0) (OC2H5) (0-H-C Nd NM2-P (0) (OC2H5) CO-H-C H9)
    Tetrabutyl 2- (3-fenshchropyl) -1,3-propylene diphosphonate (10 g, 18 mmol) dissolved in 120 ml of solution of NaOH in n butanol, heated at 60 ° C for 2 h. Solvent
    soar. The evaporation residue is distributed between water and dichloromethane. The organic phase is evaporated and the residual evaporation is dissolved in 15 ml of 20% HC1 solution. The aqueous acid solution is evaporated, 20 ml of ethanol are introduced and the mixture is filtered to remove the NaCl.
    After evaporation of the solvent, 6.0 g (77% yield) of bis (butyl hydrogen) -2 3-phenylprosh -1,3-propylene diphosphonate is obtained.
    IR, cm: 2900 - 2300 (wide ROH); 1600 (Р (М1); 1240 (Р 0); 1030 (Р-О-С + Р-Ш)).
    The indicated compound (5 g, 11.5 moles) was dissolved in 10 ml and a fivefold excess amount of a solution of diazoethane in simple ether was added. After being left at room temperature for 1 h, the solvent is evaporated and a pure one is obtained (as shown by gas-liquid chromium).
    24
    tograph) bis (butyl, ethyl) -2- (3-phenylpropyl) -, 3-propylene diphosphonate (5.6 g, yield 100%), bp. 195 -200 ° C (0.05 mm Hg).
    IR spectrum (film), 2960. (aliphatic C – H); 1250 (P 0); 1050 - 980 (Р-О-С).
    The chemical interaction of bis- (butyl, hydrogen) -2- (3-phenylpropyl) -I, 3-propylene diphosphonate (5 g, 11.5 mol) with triethyl orthoformate gives 4.2 g (yield 75%) bis (butyl, ethyl) -2- (3-phenylpropyl) -1,3-propylene diphosphonate, b.p., 195 - (0.05 mm Hg, cent.),
    Thin-layer chromatography and ha-liquid chromatography show that this compound is identical to the product obtained by the reaction of bis (butyl, hydrogen) -2- (3-phenyl-propyl) -1,3-propylenediphosphonate with diazoethane.
    Example 15, Tetrabutyl-2-5- - (3-ox-1-4-hydroxymethyl-2-methyl) pyridine-1-methyl methyl 1,3-propylene diphosphonate
    0
    five
    d
    five
    0
    BUT
    h
    CHO / SNg-P (0) (0-H-C Ne) g HD..JvCH2-CH
    CH, L CH2-P (0) (0-H-C H9) 2
    A mixture of 50 g (0.243 mol) of pyridoxine hydrochloride in 400 ml of dry acetone and 55 ml of concentrated HjSO4 is stirred overnight at KOIT-sodium temperature. The acidic solution is neutralized to pH 7 with sodium hydroxide and evaporated to dryness. The evaporation residue is dissolved in CHClI, dried and filtered.
    51.0 g (100% yield) of isopropylidenepyridoxine are obtained, b.p. 90 - 92 ° C
    IR spectrum (KBg), cm: 1380 (d ,, (SNE)., C),
    A solution of thionyl chloride (77.4 g, 0.65 mol) in 50 ml of benzene was introduced into a warm solution of this compound (88 g, 0.325 mol) in 500 ml of benzene. The mixture was heated under reflux for 15 minutes. The precipitate is filtered and the ethanol is recrystallized from the mixture. A simple solution after filtration of the solid is made alkaline with 15% -Hfc f NaOH, -extracted with CHClI and
    dried over potassium carbonate. After evaporation of the solvent, 30 g (yield 41%) of 3.4 isogophoply (methyl chlorine) (methyl methyl) -2-methylpyridine are obtained. Analysis by gas-liquid chromatography shows that this compound is a pure product.
    A solution of this chloride (30 g, 0.132 mol) in 100 ml of absolute ethanol is reacted with a solution of sodium diethyl malonate (0.132 mol) in 120 ml of ethanol for 15 h.
    After removing an excess amount of diethyl malonate, 34.3 g (74% yield) of crude diethyl 5- (3,4-α-isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-pyridylmethylmalonate) are obtained.
    IR spectrum (film), cm: 1740 (C 0); 1200 (C-0).
    Substituted malonate (34.3 g, 98 mmol) in 100 ml of absolute dy-. ethyl ester is reduced with a suspension of 4.8 g (0.127 mol) LiAlHi in 250 ml of ether. After this treatment, the crude mixture is stirred with cold ether. 9.5 g (36% yield of 2-15- - (3,4-isopropylidene-3-hydroxy-4 hydroxymethyl-2-methyl) pyridylmethyl} -1,3-pro pandiol, t.cl. 127- 128 C.
    IR spectrum (KBg), cm: 3380 (СН,), С
    As a result of tosylation of this dihydric alcohol (8.15 g, 31 mmol) in 40 ml of pyridine with a solution of 12 g (63 mmol) of tosyl chloride in 50 ml of pyridine, the corresponding ditosylate is obtained as a brown oil, which is purified by chromatographic separation in a column SiO /, eluting with a mixture of CHClg-MeOH in a ratio of 8: 2.
    3.4 g (yield 19%) of ditosylate are obtained,
    IR spectrum (film), 1350 and 1170 (SOi).
    A solution of this ditosylate (2.7 g, 4.7 mmol) in 40 ml of dioxane is reacted with a solution of sodium butyl phosphite (18.8 mmol) in 40 ml of tetrahydrofuran in the usual way. After removing the volatile substances by distillation in an apparatus including a round bottom flask and a tube, the resulting residue is purified on a SiOci chromatography column, eluted with a mixture of CHCl j - MeOH in a ratio of 95: 5.
    Tetrabutyl-2-t5- (3,4-α-isopropylidene-3-hydroxy-4-oxymethies JH-2-methyl) pyridylmethyl -1, 3-propylenediphosphonate is obtained as a yellow oil (1.5 g yield: 52%). .
    IR spectrum (film), cm-: 2980 (aliphatic C – H); 1380 (d., (CHj-j); 1240 (P 0); 1060 - 970 (P-O-C).
    Mass spectrum, t / e: .619 (M).
    NMR spectrum (CDCl1), f 7.82 (s, 1H, pyridyl H); 4.87 (s., ZN, -CH, -0, -C (CH3),); 4.0 (m, 8H, P-0-CH, e); 2.76 (d, J 7 Hz, 2H, -CHj-CH- (CH, P03Bu) j); 2.40 (s, IH, 2-CHj — pyridyl); 2.45-2.30 (m. 1H, -CH- (CH-ROSViD 2.10 (d. C..D. X d., 2H, diastereotope n: C (n) (H) -R05Vi ,); 1.84 (d. X d. X d., 2H, diastereotopic n: C (n) () - ROSVi.,); 1.70 - 1.60 (m, 8P, P- O-CH, -CH j-CH, -CH,); 1.55 (s, 6H, isopropylidene H); 1.44 1.34 (m, 8H, P-O-CH,); 0, 95 (t., J 7 Hz, 12H, P-O-CH - -CHi-CHj-CH ,,).
    Deprotection of the isopropylidene derivative is carried out by heating to 55 ° C of the indicated compound (g, 1.16 mmol) in 13 ml of 1 N. HCl. The reaction mixture is neutralized (pH 7-8) with a saturated sodium bicarbonate solution and extracted into warm benzene.
    After purification in a chromatographic column on SiO with elution. with a mixture of CHClg - MeOH in the ratio of 9: 1, 0.2 g (yield 30%) of tetra-butyl-2-15- (3-hydroxy-4-hydroxymethyl-2-methylphen-methylmethyl-, 3-propylene diphosphonate, t. mp 43-44 ° C.
    Calculated,%: C 55.95; H 8.87; R 10.68.
    C ,, H5, NOePi
    Found,%: C 55.87; H 76.1; R 10.49.
    IR spectrum f film) cm: 3200 (OH); 2980 (C – H); 1230 (P 0); 1040 - 970 (Р-О-С).
    NMR spectrum (CDC1,), 7.75 (p. 1H, pyridyl H); approximately 5.85 (broad s, substitution, hydroxy H); 4.03-3.85 (i., 8H, P-O-—CH j — CH j — CHs — CH j); 2.8 (d, J, 7 Hz, 2H, -CH, -CH- (CH, 2P03BUj)); 2.45 (s., NN); 2.50-2.35 (m., W,
    -CH- (CH, -ROSVi, () .;); 2.0 (d. X d. X x d., 2H, diastereotopic C (n) (n) -ROSVi,); 1.76 (d. X d. Xd. 2H, diastereotopic (H) (H),); 2.65-2.55 (m, 8H, -CHj-CH, -CH,); 1.27 (split six-fold, J = 7 Hz, 8H, P-SKSH, -CH; j-CHjCHj); 0.94 (several triplets, J 7 Hz, 12H, P-0-CH -CH, CHijCH
    Example 16. Tetrabutyl-2-C4- - (4-phenylpiperazinylmethyl) -benzyl - 1,3-propylenediphosphonate
    OSZ goGa ™
    TYPR (,
    4-Phenylpiperazinyl (41.4 g, 0.26 mol) was introduced into a solution of 4-bromomethyl benzonitrile (25 t, 0.13 mol) in 60 ml of ethanol, and the mixture was heated under reflux for 1 hour. Filtration of the precipitated I-fenschiperzine bromide filtrate is evaporated. The evaporation residue is recrystallized in chloroform-acetone.
    Obtain 28.6 g (79% yield) 4- (4-phenylpiperazinylmethyl) benzonitrile, so pl. 154-156 ° C.
    IR spectrum (KVg) 2200. cm
    The said nitrile (28.0 g, 102 mmol) was dissolved in 150 ml of hot 1-propanol, 60 ml of 10 N are introduced into it. sodium hydroxide solution. The resulting mixture is heated under reflux overnight. After cooling, the sodium carboxylate precipitate is filtered off, dissolved in 60 ml of water, and 60 ml of 37% hydrochloric acid is added at 0 ° C. The precipitate formed is filtered and dried under vacuum at. 24 g (yield 62%) of 4- (4-fensh piperazinylmethyl) benzoic acid, m.p. 250-253 ° C (with decomp.).
    IR spectrum (KBG), 3000 - 2500 and 1720 (COOH).
    A suspension of lithium aluminum hydride (11.5 g, 303 mmol) in 240 ml of tetrahydrofuran was added dropwise to a suspension of this acid (24 g, 65 mmol) in the same solvent. This mixture is heated under reflux for 5 hours. After this treatment, 12 g (yield 65%) of 4- (4 fenshpiperazinylmethyl) benzyl alcohol are obtained, m.p. 109-111 C.
    IR spectrum (KVg),: 3600 (OH).
    Phosphorus tribromide (14.9 g, 55 mmol) is slowly added to a solution of alcohol (12 g, 42 mmol) in 60 ml of anhydrous benzene. This mixture is heated under reflux for 3 hours. After filtration, 16.6 g (yield 92%) of crude 4- (4-α-phenyl piperazismethyl) benzyl bromide hydrobromide are obtained. This compound (16 g, 36 mmol) reacts with a solution of 100 mmol sodium-diethyl malonate in ethanol (PO ml) at 60 ° C for five hours.
    After distillation in a round bottom flask (Kugelrohr) apparatus, 5.3 g (35% yield) of diethyl - - (4-phenylpiperazinylmethyl) benzyl malo Nata are obtained in the form of a pale yellow oil that slowly crystallizes, mp. 210 C (0.05 mm Hg).
    IR spectrum (film), cm: 1750 and 1730 (C 0); ISO - 1150 (C-0).
    The indicated compound (5.0 g, 11.8 mmol) is reduced by suspension of 0.58 g LiAlH (15.4 mmol) in 60 ml of dry tetrahydrofuran. After this treatment, 3.0 g (yield 75%) of 2-C4- (4-phenylpiperazins-metsh1) benzyl-1,3-propanediol are obtained, m.p. 135-137 C (acetone - simple ether).
    IR spectrum (KBG), cm; 3250 (OH); 1030 (C-0).
    The indicated dihydric alcohol (3 g, 8.8 mmol) is reacted with tosyl chloride 4.9 g, 26 mmol in 20 MP of pyridine.
    4.3 g (75% yield) of ditosylate (4-phenylpiperazinylmethyl) benzyl-, 3-propanediol are obtained, mp. 153-154 C (in acetone)
    IR spectrum (KBG), cm: 1350 and. 1170 (-S0, j.-).
    A solution of this ditosylate (3.6 g, 5.6 mmol) in 10 ml of dioxane was introduced into a solution of 23 mmol of sodium di-butylphosphite in 10 ml of tetrahydrofuran. The resulting mixture is heated under reflux for 24 hours. After this treatment, the residual product is purified in a chromatographic column (adsorbent: SiO, eluent: CHC1-MeOH mixture in a ratio of 99: 1).
    1.5 g (yield 39%) of a white oil are obtained, which is tetrabuyl-2 4 4-feshpiperazinylmethyl benzyl J-1, 3-h1 propylene di-phosphonate.
    29
    IR spectrum (film), cm: 2960 (aliphatic C – H); 1600 (aromatic C-C) j 1240 (P 0); 1060 - 970 (P-O-C); 690 - 750 (aromatic H).
    Nuclear Magnetic Resonance Spectrum (CDCl1), ": 7.35- 6.18 and 6.90 - 6.85 (total, 9H, aromatic H); 4.1-3.96 (m, 8H, P-0-CHj-CH ,, -CH, -CH3); 3.56. (s., 2H,,); 3.25 and 2.65 (two distorted triplets, 8H,); 2.93 (d, 7 Hz, 2H, CH, -CH (CH ,, fOj),); 2.60-2.45 (m, 1H, -CH- (CH, POj)); 2.08 (d. X d. X d., 2H, diastereotopic (H) () POjBu2); 1.88 (d. X d. X d., 2H, diastereotopic (H) (H 0 -Roz-Bi, 1.7.0 - 1.60 (m, 8H, P-0-CH, (CH3); 1.44 (six-fold, 8H, P-O-CH; SNgHH1375141; 30 IR spectrum (film), 3400 (OH 1030-1050 (C-0).
    As a result, according to the standard procedure (tosyl chloride in pyridine), 7 g (70% yield) of ditosylate (2-methyl-1,3-dioxolan-2-yl) propyl -1,3-pro- pandiol - in the form of a viscous oil, 10 IR spectrum (film), 1360, 1190 - 1170 (-SO., -).
    A solution of this ditosylate (4 g, 7.8 mmol) in 15 ml of dioxane is reacted with a solution of 15 mmol sodium dibutylphosphite in
    15 ml of tetrahydrofuran at reflux for
    16h After fractionation in an apparatus with a round bottom flask and tubes (CH3); 0.98 (t, 12H, P-O-CH.; -, 20 which gives 1.8 g (yield 41%) of tetra-CH 3). butyl-2- 3- (2-m8TSh1-1,3-dioxol-2-EXAMPLE 17. Tetrabutyl 2-yl) -propyl -}, 3-propylene diphosphonate, (2-methyl-1,3 -dioxolan-2-yl) pro-bp. 200 C (0.05 mm Hg). Z-propylenediphosphonate.
    IR spectrum (film), cm: 2980
    25 (aliphatic C — H); 1240 (P 0); 970, 1030, 1050 (Р-О-С).
    CH2-P (0) (0-H-C / .Ne QH
    CH2-P (0) CO-H-C H9) 2
    NMR spectrum (CDCl1), f: 4.08-3.96 (m, 8H, -P-O-CH2-CHj-CH, -CH3); 3.96- 3.90 (m., 4H,, - (CH g)); 2.33-2.14 (m, 1H, -CH- (CH ,, PQ5Bu ,,)); , 96 (m, 4H, diastereotopic H °: C (H) (HV) -POjBu.j + C, (CH,) -); 1.86 (distorted d. X d. Xd 2H, diastereotopic n: C (n) (H
    2- (3-Chloropropyl) -2-methylg-, 3-diox-, solane (27 g, 0.164 mol) is reacted overnight at reflux temperature with an equal polar amount of sodium diethyl
    malonate in 100 ml of absolute ethano-Ro Bi,); 1.65 (partially overlapped la. After distillation in an apparatus with a circle ...
    22 g (47% yield) of diethyl 3- (2-methyl--1,3-dioxolan-2-yl) propyl malonate, mp. 140 C (0.05 mm Hg).
    IR spectrum (film), 1740 (C 0); 1200 C-0).
    A solution of this compound, 22 g, 76 mmol) in 30 MP diethyl ether, is introduced into a suspension of 3.8 g (100 mmol) LiAlH 4 in 150 mp diethyl ether. The mixture obtained is
    40
    45
    quintet, 12H, - (CH,):, - CH (, Wi, :), + P-O-CH -CH-CHj-CH,); 1.42. (six-fold, .8JH, P-O-CH CH CH CH,); 1.33 (s., SN,, (CH3)); 0.95 (t, 12H, P-0-CH-CH, -CH, -CH,).
    Example 18. Tetraethyl-2- (5- -phenyl-1, 3-dioxan-2-yl-methyl) -1,3-propylene diphosphonate
    : Y.sn, -y5 - "°
    CH2-P (0) (OC2H5) 2
    stitched at room temperature for 4 hours. Introduced a 10% solution of NaOH, which decomposes the excess
    Synthesize 2-bromomethyl-5-fench -1,3-dioxane by chemical
    amount of hydride. Essential solution 0 mode 1,2-dibromometshtsetseat
    decanted from hydroxides.
    After evaporation of the ether phase and then distillation in an apparatus with a round-bottomed flask and tube of evaporation, 4 g 55 (yield 26%) (2-methyl-1,3-dioxolyl-2-yl) propyl -1.3 are obtained. -propanediol, bp. 105-120 ° C (0.05 mm Hg).
    5141 30 IR spectrum (film), 3400 (OH 1030-1050 (C-0).
    As a result, according to the standard procedure (tosyl chloride in pyridine), 7 g (70% yield) of ditosylate (2-methyl-1,3-dioxolan-2-yl) propyl -1,3-pro- pandiol - in the form of a viscous oil, 10 IR spectrum (film), 1360, 1190 - 1170 (-SO., -).
    A solution of this ditosylate (4 g, 7.8 mmol) in 15 ml of dioxane is reacted with a solution of 15 mmol sodium dibutylphosphite in
    15 ml of tetrahydrofuran at reflux for
    16h After fractionation in an apparatus with a round-bottomed flask and tube, 1.8 g (yield 41%) of tetra-butyl-2- 3 - (2-m8TC-1-1,3-dioxyl-2-yl) -propyl -} are obtained, 3-propylene diphosphonate, b.p. 200 C (0.05 mm Hg).
    IR spectrum (film), cm: 2980
    (aliphatic CH); 1240 (P 0); 970, 1030, 1050 (Р-О-С).
    NMR spectrum (CDCl1), f: 4.08-3.96 (m, 8H, -P-O-CH2-CHj-CH, -CH3); 3.96- 3.90 (m., 4H,, - (CH g)); 2.33-2.14 (m, 1H, -CH- (CH ,, PQ5Bu ,,)); , 96 (m, 4H, diastereotopic H °: C (H) (HV) -POjBu.j + C, (CH,) -); 1.86 (distorted d. X d. Xd., 2H, diastereotopic n: C (n) (N)
    Ro Wee,); 1.65 (partially overlapped ...
    Ro Wee,); 1.65 (partially overlapped ...
    quintet, 12H, - (CH,):, - CH (, Wi, :), n + P-O-CH -CH-CHj-CH,); 1.42. (six-fold, .8JH, P-O-CH CH CH CH,); 1.33 (s., SN,, (CH3)); 0.95 (t, 12H, P-0-CH-CH, -CH, -CH,).
    Example 18. Tetraethyl-2- (5- -phenyl-1, 3-dioxan-2-yl-methyl) -1,3-propylene diphosphonate
    : Y.sn, -y5 - "°
    CH2-P (0) (OC2H5) 2
    Synthesize 2-bromomethyl-5-phenyl -1,3-dioxane by chemical interaction
    1,2-dibromoethyl acetate
    (prepared according to the reaction of vinyl acetate with bromine in carbon tetrachloride) with 2-phenyl-1,3-propavdiol (obtained by reducing diethylphenylmalonate with lithium aluminum hydride).
    2-Bromomethyl-5-phenyl-1,3-dioxane is condensed with diethyl malonate, in pe-
    As a result, the corresponding substituted malonate is obtained, which is reduced to 2- (5-phenyl 1,3-dioxane 2 yl-methyl) -, 3 propanediol with LiAlH4 in diethyl ether. The tosylation is carried out in the usual manner using tosyl chloride in pyridine. A solution of ditosylate 2- (5-phenyl 1,3-dioxane 2 Br1-molsht) -1,3-propanediol (4.5 g, 80 mcl) in 20 ml of dioxane is reacted at room temperature for 15 hours with a solution of 20 mmol sodium diethyl phosphite in 20 ml of tetrahydrofuran.
    After distillation in an apparatus with a round-bottom flask and tube and subsequent separation in a chromatographic column on SiOj with elution with a mixture of CHY CHCl j - MeOH in a ratio of 95: 5, 2.0 g (yield 50%) of tetraethyl ™ -2- (5 -phenyl 1,3-dioxan-2-yl-methyl) -1,3-propylene diphosphonate.
    IR spectrum, 2980 (aliphatic C — H); 1240 (P 0); 1165 (P-0-Et 1040 (P-O-C); 790 (aromatic C-H).
    Example 19 2-Benzyl-1,3-diphosphonic acid tetramethyl ester
    .SN ROSSNZ)
    A mixture of 5 g (17. mmol) of 2-benzyl--1,3-dibromopropane, prepared as described in Example D, and 12, 4 g (100 mmol) of three methylphosphite are boiled with a reflux condenser at I 10 ° C for 24h
    1.43 g (4.1 mmol) of 2-benzyl-, 3-diphosphonic acid tetramethyl ester as a white oil (24% yield) are obtained by distillation using a bead tube.
    Calculated,%: C 48.00; H 6.91; R 17.68.
    C ,, H ,, OjPi
    Found,%: C 48.35; H 6, P 17.40.
    Example 20. 2-Benzyl-1,3-diphosphonic acid tetrabutyl ester
    CHfCH
    / СН2РОз (СН2РОз () 2


    A mixture of 5 g (17 mmol) of 2-benzyl--1,3-dibromopropane prepared in Example 1 and 25 g (100 mmol) of tributyl phosphite is heated for 10 hours at 200 C. The excess tributite 1 phosphite is distilled off and fractionated using a ball. tube.
    4.1 g (8 mmol) of 2-benzyl-1,3-diphosphonic acid tetrabutyl ester are obtained (yield 47%).
    Calculated,%: C 60.22; H 9.33; R 11.95.
    C7 (.480tPl
    Found,%: C 60.48; H 9.01; R 11.65.
    Example 21
    .СН2РОзСС.Нд) 2 СН2РО ()
    A solution of sodium dibutyl phosphite is prepared from 1.05 g (36 mmol) of 80% sodium hydride and 7.7 g (40 mmol) of dibutyl phosphite in 50 ml of tetrahydrofuran (THF) at reflux temperature (66 ° C). To this reagent was added 5 g (9.9 mmol) of 2-benzyl-1,3-propandiol ditosylate, dissolved in 50 ml of THF, and the resulting mixture was heated at reflux (6b C) for 15 hours.
    After refining and distillation using a bead tube, 2.6 g (5 mmol) of 2-benzyl-1,3-propylene phosphonate tetrabutyl ether (50% yield) are obtained.
    Calculated,%: C 60.22; H 9.33; R 11.95.
    CitH gOfeP
    Found,%: C 59.88; H 9.69; R 11.52.
    Example 22. Using n-heptane as a typical solvent for the reaction.
    Tetrapropyl ester of 2- (phenoxyethyl) -, 3-diphosphonic acid.
    A solution of sodium dipropyl phosphite is prepared from 8 g (48 mmol) of dipropyl phosphite and 1 g (43 mmol) of metallic sodium in 40 ml of n-heptane. To the resulting solution, 5 g (10 MMOjjb) of 2- (2-phenoxyethyl) -1,3-propanediol ditosylate, dissolved in 40 ml of THF, are added to the resulting mixture
    boil under reflux overnight.
    3.2 g (6.5 mmol) of tetrapropyl ether 2 (2 phenoxyethyl) -1.3 diphosphonic acid are obtained by distillation using a bead tube, mp. 195 -200 with (0.05 mm Hg).
    IR spectrum, cm: 3040 (aromatic C — H); 2980 - 2940 (aliphatic C — H); 1240 (P 0); 990 (Р-О-С).
    NMR (CDClI), t /: 7.3-7.24 and 6, .95- 6.85 (m, 5H, aromatic H); 4.09 3.95 (m., 8H, P-O-CH-CH CHa + PhO- -CH,); 2.62-2.44 (m, 1H, PhO- (CH ,,) -CH-); 2.20-2.06 (m, 4H, diastereotropic H °: C (H) (H) -POjPr ,, + PhO -); 2.0 (deformed d. X X d. X d., 2H, diastereotropny N: C (n) (H) -RoZRg1); 1.63 (sextet 8H, P-0 CHy-CHj-CHj-); 0.92 (t, J 7 Pc, 12H, P-O-CH-CH-CH,).
    Elemental analysis of compounds (l).
    Example 1. 2-Benzyl-I tetraethyl ester, 3-propylene diphosphonic acid.
    Calculated,%: C, 53.20; H 7.94; R 15.24.
    C, 8 N, p.,
    Found,%: C 53.49; H 8.18; R 15.00.
    Example 2. 2-Phenyl-1,3-propylenediphosphonic acid tetraethyl ester
    Calculated,%: C 52.04; H 7.71; R 17.79.
    SP1CH ,,
    Found,%; C 52.24; H 7.53; R 15.41.
    Example 3. 2-Benzyl-1,3-pro pelenediphosphonic acid.
    Calculated,%: C 40.83; H 5.48; R 21.06.
    CfcH, 0, P
    Found,%: C 40.52; H 5.09; R 21.00.
    Example 4 Tetraisopropyl ester of 2-benzyl-1,3-propylene diphosphonic acid.
    Calculated,%: C 57.13; H 8.72; R 13.39.
    .
     Found,%: C 57.01; .H 8.81; R 13.06.
    Example 5. 2-benyl-I, 3-propylenediphosphonic acid tetrabutyl ester.
    0
    five
    0

    0
    five
    0
    five
    Calculated,%: C 60.22; H 9.33; R 11.95.
    Found,%: C 59.91; H 9.71; R 11.70-.
    Example 6. 2- (3-Phenylprosh) -, 3-propylene diphosphonic acid tetrabutyl ester.
    Calculated,%: C, 61.54; H 9.52; R 11.36.
    C, VN5.0, P,
    Found,%: C 61.26; H 9.72; R 11.54.
    Example7. Tetrabutyl ether 2 (3-cyclohexylpropyl) -1,3-propylene diphosphonic acid.
    Calculated,%: C, 60.85;; H, 10.58; R 11.21.
    CnHjjO P,
    Found,%: C 60,58; H 10.64; R 11.05.
    Example 8. Tetrabutyl ester 2 (2 enoxyethyl) -1,3-propylene diphosphonic acid.
    Calculated,%: C 59.11; H 9.19; R 11.29.
    C, 7 5o07l.
    Found,%: C 58.88; H 9.21; R 11.40.
    Example 9. (1 Naphthylmethyl) -1 tetraethyl ester, 3 propylene diphosphonic acid.
    Calculated,%: C 57.21; H 7.46; P 13.60.
    Cj, H 1
    Found,%: C 57.92; H 7.72; P 13.40.
    Example 10. (3-Pyridyl) propyl 1,3-propylene diphosphonic acid tetrabutyl ester.
    Calculated,%: C 59.21; H 9.39; H 11.31.
    Cj, Hj, NO, P,
    Found,%: C 59.44; H 9.41; R 10.90.
    Example 11. 2- (3 Fench 1 Propyl) -1,3-propylene diphosphonic acid tetraamyl ester.
    Calculated,%: C, 63.76 ;, H, 10.03; R 10.28.
    Cj
    Found,%; C, 63.76; H 9.95; F 10.02.
    Example 12. 2- (3-Phenyl) opyl-1, 3-propane-diphosphonic acid tetrahexyl ester.
    Calculated,%: C 65.63; H 10.40; R 9.40.
    35
    CjtHtgOtP
    Found,%: C 65.41; H 10.21; R 9.68.
    Example 13. Bis (ethyl, amyl) 2- () enylpropyl) -1.3 propyl diphosphonate.
    Calculated,%: C 60.22; H 9.33; R 11.94.
    Cj, H ,,,.
    Found,%: C 60.49; H 9.00; R 11.61.
    Example 14. Bis (ethyl,. Amyl) -2 -2-benzyl-1,3-hopopylenediphosphonate.
    Calculated,%: C 58.76; H 9.04; R 12.63.

    Found,%: C 59.09; H 9.39; R 12.29.
    Example 15. (3-Hydroxy-4-hydroxymethyl-2-methyl) -pyridylmethyl 1 tetrabutyl ester, 1) phosphonylphosphonic acid.
    Calculated,%: C 55.95; H 8.87; R 10.68.
    , y, N08P
    Found,%: C 55.87; H 8.76; R 10.49.
    Example 16. (4-Phenylpiperizinylmethyl) benzyl -, 3-propylene diphosphonic acid tetrabutyl ether.
    Calculated,%: C 64.14; H 9.02; R 8.94.
    C ,, 0, P,
    Found,%: C 65.00; H 9.39; P 8.60.
    Example 17. Tetraboutsh1-2-Z-C2-methyl-1,3-dioxolan-2-yl) propyl - - 1, 3-propylene diphosphonate, - -
    Calculated,%: C 56.00; H 9.94; R 11.11.
    Found,%: C 55.88; H 9.60;
    P 11.01.
    Example 18. Tetraztil 2- (5-phenyl-l, 3-dioxan-2-yl-methyl) -1, 3- -pr opil dendiphosphone t.
    Calculated,%: C 59.59; H 9.00; R 10.24.
    ha
    Found,%: C 59.20; H 9.40; P 10.01.
    The overall properties of 1,3-diphosphonates of the formula (l) are given in tab. one.
    Studies have shown that 1,3-diphosphonates of formula (l) have a significant vasodilating effect. These compounds investigated
    ) with s-
    ten
    ) -
    15
    20 and-
    25
    ZOR Z- - 40
    45
    -
    35
    50
    .
    4136
    also with a view to detecting their activity with respect to modulating the binding of n-trendipine to the brain cells; inhibition of tracheal contraction in rats caused by KC1; changes in an isolated pre-rat; hypotonic activity of the cr {c.
    The results of biological and pharmacological studies in vivo and in vitro show that 1,3-diphosphonates are calcium antagonists, and that they have a strong pharmacological effect, as they can affect the excitability of the cells to be reduced. Compounds of this specific class alter the activity of the calcium channels of eicari otic cell membranes and, therefore, can be used to treat diseases caused by or associated with dysfunctions of these channels, for example, to treat heart diseases, hypertension, angina pectoris, arrhythmias, asthma and disorders gastrointestinal activity.
    The mechanism of action of calcium antagonists.
    Fluctuations in the content of free Ca in cells regulate various processes, such as muscle contraction and secretory functions. In plasma shells and in intracellular organelles, calcium input and sequestration processes take place. These functional processes create an increased Ca concentration during the excited state and maintain and maintain a low concentration of intracellular Ca in a quiescent state. Mobilization during cell tissue contraction can be initiated by both intracellular and extracellular sources. The extent of this initiation depends on various factors. Drugs that reduce the effect of calcium ions on cellular functions, such as tiny reduction, are called calcium antagonists; Classic examples of such drugs are nifedipine, verapamil and diltiazem, which with very high specificity inhibit slow internal currents (or impulses) of the action potential.
    Heart rate is regulated and caused by sinus cells.
    heart node, atrioventricular sinus and nodal cells. Because of the dependence on calcium, the sinus nodes of the heart are sensitive to drugs blocking calcium. In these cells, calcium is partly responsible for creating the potentials of the sinus node of the heart and for the conductivity of the signal, carries partly the current causing elevated and in-depth phases (gshato and depression phases), and also stabilizes the heart membranes and inhibits activity in furkinje columns.
    All drugs that are Ca channel inhibitors have a strong negative inotropic and chromotropic effect.
    The ability of drug blocking to affect the function of contractile cell tissues is manifested to a very large extent in vascular smooth muscles and visceral smooth muscles (muscles of the trachea of the intestine, uterus and ureter). The hemodynamic result of blocking the Ca channel in the vascular smooth muscle is vasodilation, leading in some cases to hypotension. The ability to block calcium in arterial smooth muscle is particularly significant in the coronary arteries, in which they create deep vasodilation.
    The inhibitory effect of 1,3-diphosphonates on the contraction of the masonry muscle cells (trachea), as well as hypotonic activity, were determined by appropriate tests.
    I. Modulation of C-N-Nitrendipine Binding to the Cells by means of 1,3-diphosphonates
    . Materials
     N-nitrenpine, flunarnzin, prenylamine lactate, nifedipine, vrrapamil, dlnthiazemchlorhydrate.
    Water-insoluble compounds are dissolved in absolute ethanol, yielding 10 or 2.5 mM basic solutions. Appropriate dilutions are carried out in a 50 mM Tris-HCl buffer solution (pH 7.4) containing 150 mmol WaCl and 1 mmol. The concentration of ethanol in the final analytical sample never exceeds 0.1%.
    The purity of the radioligand and various agents tested
    g 5
    0 5 Oh,
    ABOUT
    .
    five
    „
    five
    Trolled by thin layer chromatography on silica gel plates.
    2о Methods.
    Adult male rats Vestar weighing 250-300 g are anesthetized with carbon dioxide, and then beheaded. The brain is removed and immersed in ice-cooled 0.32 M sucrose and washed 2-3 times with fresh solution. The cerebral cortex is crushed and homogenized (in a Potter-Elvehijem homogenizer) in 10 volumes of an ice-cold sucrose solution. The homogenate is centrifuged (4 ° C) at 100 rpm for 15 minutes. Then the resulting surface layer was centrifuged at 90000 rpm (30 minutes) and the granules were washed twice with 20 ml of ice-cold 50 mM Tris-HCl (pH 7.4). The final granules are again suspended in 50 1 Tris-HCl (pH 7.4); protein concentration is 4 mg / ml.
    The shell suspension is in ice before use. Binding assay is performed under dim light to prevent decomposition of dihydropyridine. The envelope protein (400 mg / tube) is incubated in a 50 mM Tris-HC1 buffer solution (pH 7.4) containing 150 mM NaCl and 1 mM CaC, with the indicated concentrations of radioligand and the tested compound or known calcium antagonists (general nd volume 2 ml).
    After some time, the reaction ceases as a result of rapid filtration through Whatman 6F filters - E glass fiber (2.4 cm in diameter) on a Millipore filter. The test tube is washed with 2 ml of ice-cold 50 mM Tris-HC (pH 7.4), the precipitate is further washed with the same buffer solution (2 x 5 ml). The filters are dried in a heating lamp and extracted with 10 ml of a liquid scintillation cocktail (toluene – Triton X-100 2: 1, containing 4 g of omnifluole / 1), after which tritium is determined at a reference efficiency of 48%.
    The value of non-specific binding is determined in the presence of 1, O micromole of unlabeled nifedipine and subtracted from the total value of binding, with the result that the value of binding, called
    3913751
    specific bonding. Analyzes were performed two or three times. The data are expressed as a percentage of the specific binding of N nitrendipine from the established control value.
    The activity of the compound in the analysis of the binding of H-nitrin- dipin is determined using the following criteria: tO
    a) H-nitreidipine binding at a final concentration of 1.0 µmol or below 95% or above 105% of the control value, which was determined in the absence of a compound.
    b) the ratio obtained by dividing the amount of specifically bound H -nitrenedine at a final concentration of a compound of 0.1 µmol by 20 the final value obtained at a concentration of the test compound of 1 µmol is less than 0.9
    or more than 1.1. This ratio is an indication of the relationship with the response to the dose within the analyzed concentration of the compound, when this value is markedly different from 1.0. In some experiments, 30 Pll 200 110, a commercially available specific dihydropyridine, is used instead of H-nitrendipine. The results are comparable with those obtained with N-nitrenpine.
    3. Results.
    The amount of specifically bound N-nitrenepipine is measured in the presence of 1 µmol of known calcium antagonists used as reference standards. The following results are obtained in Q,% of nitrendipine: TMB-8 95; fpunarizin 55, prenyl amine 57; verapamip 44; and nifedipine 0.
    From tab. 2 it can be seen that among the test, 1,3-diphosphonates there are strong inhibitors (compounds 38; 79; 88; 68; 113, 117, 83, 73, 75) and activators (compounds 55 and 56) C Hl-nitrendipine. When used In the formulation of more specific dihydropyridine t HJ-PN 200 110 (Table 3), similar results are obtained with compound 79, used as quality. ve internal standard. In addition, some compounds have been found that have the same potency as nifedipine (compounds 90, 93, 92, 89, and 106). Many 1,3-diphosphonates
    35
    41
    40
    0
    50
    Q
    ,
    five
    with more active than the listed standard calcium antagonists. These results are evidence of the interaction of .1,3-diphosphonates with the calcium channel and / or control points. The compounds exhibit a full range of modulation of the binding of H-nitr endipine.
    II Inhibitory effect of 1,3-diphosphonates on the reduction of the trachea, rats, caused by depolarization of KC1 (Table 4).
    1. Preparation of tissue.
    In this study, male rats with spontaneously induced hypertension (SHR), Okamoto Aoki strain weighing 300-400 g were used. Rats were killed by bleeding after anesthesia with pentobarbital (Nembutal, abbott Co), 40 mg / kg. The trachea is quickly completely removed and freed from fat and connective tissue in Krebs-Ringer's solution. Prepare a strip (4x40 mm) by cutting the trachea in a spiral. This strip is immediately suspended in 50 MP of Krebs-Ringer solution, through which the Ojf / COj mixture in a ratio of 95: 5 is continuously passed in the form of puzzles. The bath temperature is maintained at 37 +. The composition of the Krebs-Ringer solution, modified by Nghiem, is the following, mmol: NaCl 118.0; KC1 4.7; CaCl 2, MgCl, 1.18; NaHCO, 12.5; KH, P04 1.18; glucose 5.5 in double distilled water (pH 7.4). Each strip is leveled at an initial tension of 1.5-2 g for 1-2 hours. The bath solution changes every 30 minutes. The reaction occurring in contraction or pdc weakening is isometrically measured by a force displacement sensor (Ugo-Basile) and recorded on a polygraph (Beckmann).
    2. Relaxing action of 1,3-diphosphonates.
    After aligning the strip, KCl is introduced into the bath, so that its final concentration is 65 mmol. This concentration leads to the maximum reduction of the trachea. Under these conditions, the plateau phase, showing a tonic steady cut, is reached within 30 minutes. 30 minutes after reaching the plateau phase, drugs are administered (final concentration 1.0 µmol). Volume injected
    41
    drug solutions do not exceed 100 μl. The residual tracheal contraction is recorded 40 minutes after the drug is introduced into the liquid bath. The initial contraction caused by KC1 is considered the maximum response to KC1 (100%). Results are expressed as% of maximum reduction. Nifedipine, preminamine, flunarizin and diltiazem are used as reference standards to validate this analysis.
    3. Compounds and drugs.
    All 1, 3-diphosphonates and drugs are dissolved in saline (0.9% NaCl) with the exception of water-insoluble preparations, which then dissolve in 2% ethanol. Determined that. the final concentration of ethanol does not affect the results of the analysis.
    4.Statistical analysis. Results are average.
    13
    values + S EM. DP statistical analysis using student t-test. Compounds that reduce the maximum reduction (100%) caused by KC1, to at least 95%, are considered to show activity,
    5. Results.
    The selected models of the compound 25, 37, 55, 73, 40, 74, 75, 79, 83, 38, 87, 88, 1 17 show high pharmacological activity. These results confirm the possibility of using 1,3-diphosphonates as medications for relaxing smooth muscle, for example, in the treatment of asthma.
    III The effect of 1.3 dkfosfonatov on the rhythm of the Atria.
    1, Methods
    Males of rats with spontaneously induced hypertomy (SHR), Strain (Okamoto - Aoki) are anesthetized with pento-barbital (Nembutal Abott), 60 mg / k intraperitoneally. The heart is quickly cut out, both atria are separated from the adjacent cardiac tissue. The atrium is immediately immersed in 50 ml of Krebs-Ringer bath solution of the following composition, mmol: WaCl 120, Oj KCl 5.63; CaCl 2.0; MgCl 2.10; NaHCOj 25.0; glucose 9.7 (pH 7.4). A mixture of 7 (95: 5) is continuously bubbled through the solution.
    ten

    25
    15
    20

    g 7314142
    The temperature of the solution is maintained at 37 + 1 ° C. The atrium is fixed to an optical displacement sensor (IITC, U.S.A.) at a steady-state tension of 1 g to measure atrial rhythm. The system is brought to equilibrium within 40 w. The integral dose-response curves for each test compound (0.5-5 µmol / L) are then determined. Dp of each concentration, the maximum effect usually reaches with within 30-40 minutes.
    2. Connections.
    The main solutions are usually prepared in a 0.9% strength solution, water-insoluble compounds in 50% ethanol. The final concentration of ethanol does not significantly affect the atrial rhythm. When testing compounds with a concentration of 0.5 x X 10-mol, a decrease in atrial rhythm by more than 5% is considered significant.
    3.Results.
    All data are presented as a percentage of the decrease in the initial p itm of the dose of Erdi (average from 30 i SEM). A strong negative chromotropic effect was found in all tested compounds (Table 5) .- By the activity shown in this analysis, determined the possibility of using 1,3-diphosphonates for the treatment of heart disease and arrhythmias.
    Iv. The hypotonic effect of 1,3-diphosphonates, illustrated in rats.
    Intravenous hypotonic action.
    1. Methods.
    Male Wistar rats are anesthetized with pentobarbital (Nembutal 60 mg / kg, intraperitoneal injection) and heparin 5 mg / kg (intraperitoneal injection) is administered. After the tracheotomy of the right carotid artery, a cannula (PE 50 catheter) is inserted, the blood pressure is measured by a pressure transducer (Statham P 23 dB) and recorded on a polygraph (Vecman).
    2. Compounds and drugs. Animals receive a dose of subjects.
    compounds 0.5 and 1.5 mg / kg. Less than 100 µl of the test compounds dissolved in 0.9% saline were injected into the vein. Water insoluble compounds are suspended in 2% 35
    40
    45
    55
    Mr. Twin-IN. The introduction of only the drug base does not lead to a noticeable hypotonic action.
    2. Results
    The results presented are expressed as a percentage of the decrease in the initial mean blood pressure (mean + S EM). A certain hypotonic activity is clearly manifested in all tested 1,3-diphosphonates. Compounds 73, 75, and 82 show a hypotonic effect that exceeds the hypotonic effect of classical hypotonic drugs and calcium antagonists used as reference standards (Table 6).
    Hypotonic effect, manifested in rats with hypertension, with the introduction of drugs through the mouth,
    Since calcium antagonists are hypotonic drugs, rats with spontaneously induced hypertension (SHR) are used additionally as a model to demonstrate the hypotonic activity of 1,3-diphosphonates when administered through the mouth. Some selected compounds are ingested through the mouth into rats with spontaneous hypertension (SHR) and regulate blood pressure using the tail caff method. When all rats are tested, the hypotonic activity of 1,3-diphosphonates is constant and constant. The results were obtained 2 h after dose administration (Table 8). The studies illustrate the possibility of using 1,3-diphosphonates for the clinical treatment of hypertension in people when administered through the mouth. Some compounds (79, 90, 93, 92, 89, and 91) reduce blood pressure to the same extent as noted calcium antagonists used as reference drugs, the clinical use of which as antihypertensive drugs have already been confirmed. .
    The decrease in mean blood pressure depending on the drug administered is given in Table. 7
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining derivatives of 1.3 g of the product of diphosphonic acids of the general formula
    CHo-P (0) (ORi) (OR2l A-CHS
    (0) (ORi40P2l,
    where RJ and R-, are odiyacovye or different; Cj-Cg-alkyl, C, -Cg-alkenyl, cyclopentenylmethyl, cyclohexylmethyl;
    A selected from the following group of radicals: f
    . -. . :: rv ow-ccH v- /
    (0) (Gfii) -. (.CH2) h- ..N- (CHiV 0
     ,
    . °% CH,), H
    X.Q
    ) t-; Z. -
    trS / CH ln-;
    -four
    CCHzVH
    X
    Y - €) - (. ((CH, - Z Isf
    .N4CH,) jr (O) m (
    CH3 (CH) (CH2) r 0 -O-
    ,), - O) - (CH, V-;
    d
    55
    CHjCCHx P CHSSSN - CH),
    SCN, (cH, v- (Ob (CH,) iСНз (СН2) п
    : N- (CH) K-Offl CH., 4-;
    , CH- (SNg) pY
    Ob (ofe (CH, V
    rV (CH-2) (CH2yt-;
    (Ob (CH2) tr
    Y
    CH,
    yO- (0) s-cHg-; sns
    X ...
    ) nZ N
    0 (o) - (cH, V
    Y
    B is an integer from 3 to 16; m is O or 1;
    n is an integer from O to 8;
    k is an integer from 0 to 4;
    Z is an integer from 1 to 4j X, Y and Z are the same or different, such as H, F, C1, Br, CF, CHF, CH, CjHs, CH CH-CHg, H-CjH, iso-, H-C4H5, iso-C4Nd, tert-CH, OH, CHjOH, -O-CHj-O-, OCHj, OCjHy,. OSNN7, SCH ,, NH. , NCCH,) ,, NCCjH,) ,, consisting in that 1,2,3-propane of the general formula
    15
    A-sns ;,
    . CH201
    where A has the indicated meanings; Q - bromine or, is subjected to interaction with the alkali metal salt of diorganophosphite, formed as a result of treatment of diorganophosphorous acid with lithium, sodium or potassium, or with a hydride or amide of an alkali metal, at a molar ratio of alkali salt of diorganophosphite and 1,2,3-substituted propane 2 , 5-4,8: 1 at temperature
    65-PO C, or with triorganophosphite
    at a molar ratio of triorganophosphite and 1,2,3-3-positioned propane, equal to 5.0–10.0: 1 at a temperature of 110–200 ° C and the process is carried out in an environment
    an aprotic solvent selected from the group consisting of hexane, heptane, benzene, toluene, dimethoxyethane, tetrahydrofuran or dioxane, or in a mixture of any two of these solvents.
    CaiticTMft 1,
    XMrP (0) (ORt) (OR24 fHKOUORiMOfi)
    ((Schg-. (
    (HC2hH- Sn, V
    ,,
    l and ,,
    SJ1
    Ci "r
    s, n,.
    c, c,
    c, n,
    s, n.
    Table 1
    153-135
    2900-2300 (oshroknny R-ON
    1500 (arsmattv OS) 1200-1130 (R. O) 1000-950 (R-OH)
    750 (arokatachesk OY)
    2980 (an | fap1ch skaA S-H ()
    1240 (P - 0)
    1195 (RO-CH)
    1030 (Р-О-С)
    2980 (aliphatic C — H) ,,, (
    1160 (Р-О-С, Иj) 1030 (Р-О-С)
    49
    ,
    / - (CHtH.,. (CH.v
    w- (cHiH
    OCHJ-OCH, C, H,
    C, H. C, H,
    C, H,
    C, H,
    C, H,
    C, Hy
    ct-q-chich
    o- (cH7V
    SNS
    C, H,
    C, H,
    32 (3 L-O-SNGN-c, H,
    CHi) i-,
    Q- (HcHjV
    c.Hj
    C, H,
    35
    -o chngngcc, H,
    CHjO
    ShGC, H,
    37
    Cfh
    i
    1375141
    50 Continuation of table 1
    2980 (aliphatic C — H)
    1240 (P - 0)
    1160 (R-FM:, N)
    1030 (P-O-C)
    2980 (almfk-ppvek CB)
    1240 (F 0) 1160 (RChS, H,)
    1030 (P-O-C) 790 (aromatic C – H)
    2980 («аиФалпмк С-Я) 1240 (Г 0)
    1160 (,)
    1030 (Р-О-С)
    790 (“ronalrgrski si-n)
    se
    5G
    58
    . (cHih-iWcH sH
    CNP E165-170 (0.05) 2980 (aliphatic OH) I390-1385 (neoprslil)
    185-188 (0.05) 1240 (P - 0)
    990 (Р-О-С) 185-190 (0.05) 750 (aromatic C-C)
    xso-cjh
    HSO-CjH,
    59
    o-CjH,
    w F-O-o- cHiV
    e-C, H,
    -O-CCHiH- Cl
    ((CNG) g-: i
    (- / IЖI
    -CH,
    O-o-cch h €
    O-o-CcHji Cl Cl
    ,,
    ™ -cH-cHr
    (SNGY, s,
    H-CjH,
    ir-C, H,
    HSO-CjH,
    ii30-C, H
    6 / :: ± (sn2CH70
    /:
    .N-whiv
    71x5.-CGHtH0
    ii-C.H,
    72Clir:, H,
    73
    Ls, n,
    .200-205 (0.05)
    195-200 (0.05)
    195-200 (0.05) 1240 (P - 0)
    1000-990 (P-O-C) 210-215 (0.05).
    195-200 (0.05) 1390-1385 (iaopropp)
    210-215 (0.05) 1240, 990
    29SO (aaifatkcheeky C-H) 1240 (P - 0)
    1070-980 {Р-О-С)
    185-190 (0.05) 175- “80 (0.05)

    (CNGN .4 (СНа) G d - (/
    Shaiv /
    H
    rf:, n.
    to",
    a.v,
    Continuation of table 1
    2980 (tpple M (H) (P - 0) ()
    ""
    L
    59
    1375141
    60
    Continuation of table 1
    Continued table. 2
    Continuation of table 3
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    同族专利:
    公开号 | 公开日
    DK324185A|1986-01-19|
    JPS6140294A|1986-02-26|
    EP0173041A1|1986-03-05|
    FI79327C|1989-12-11|
    GR851767B|1985-11-26|
    KR930005390B1|1993-06-19|
    KR860001117A|1986-02-22|
    DE173041T1|1986-06-12|
    YU117185A|1987-10-31|
    HU193791B|1987-11-30|
    PT80820B|1988-04-21|
    CS262421B2|1989-03-14|
    AU4511485A|1986-01-23|
    US4696920A|1987-09-29|
    ES545330A0|1986-12-16|
    DK324185D0|1985-07-17|
    CS530585A2|1988-07-15|
    AT38991T|1988-12-15|
    IL75807D0|1985-11-29|
    IL75807A|1989-09-10|
    NO852822L|1986-01-20|
    HUT38950A|1986-07-28|
    NZ212768A|1988-06-30|
    FI852806L|1986-01-19|
    PT80820A|1985-08-01|
    CH664158A5|1988-02-15|
    DE3566545D1|1989-01-05|
    EP0173041B1|1988-11-30|
    ES8702427A1|1986-12-16|
    CA1284320C|1991-05-21|
    ZA855357B|1986-02-26|
    AU581442B2|1989-02-23|
    FI852806A0|1985-07-17|
    FI79327B|1989-08-31|
    引用文献:
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    NZ226378A|1987-10-08|1989-12-21|Colgate Palmolive Co|Packaged dental cream containing polyoxyethylene/polyoxypropylene block copolymer|
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    US5332743A|1992-06-12|1994-07-26|Mcneilab, Inc.|Benzyl and benzhydryl alcohols|
    EP0663919A1|1992-10-09|1995-07-26|PHARMACIA &amp; UPJOHN COMPANY|Pyrimidine bisphosphonate esters as anti-inflamatories|
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    AU3718501A|2000-02-29|2001-09-12|Medicure Int Inc|Cardioprotective phosphonates and malonates|
    WO2002004421A2|2000-07-07|2002-01-17|Medicure International Inc.|Pyridoxine and pyridoxal analogues: cardiovascular therapeutics|
    US6548519B1|2001-07-06|2003-04-15|Medicure International Inc.|Pyridoxine and pyridoxal analogues: novel uses|
    US6897228B2|2000-07-07|2005-05-24|Medicure International Inc.|Pyridoxine and pyridoxal analogues: new uses|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    CH3488/84A|CH664158A5|1984-07-18|1984-07-18|DERIVATIVES PROPYLIDENEDIPHOSPHONATES-1,3 SUBSTITUTED IN POSITION 2, THEIR PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.|
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