RU2450012C2 - Method of producing adamantylalkyl and adamantyloxyalkyl ethers of tosyloxymethyl-phosphonic acid - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing adamantylalkyl and adamantyloxyalkyl ethers of tosyloxymethyl-phosphonic acid of formula

,

used in synthesis of pharmaceutical preparations having antiviral activity, from compounds of formula

, where X is absent, R=H, R'=H, n=1; or X is absent, R=H, R'=H, n=2; or X is absent, R=H, R'=CH₃, n=1; or X=O, R=H, R'=H, n=2; or X=O, R=C₂H₅, R'=H, n=2; Ts denotes tosyl (n-toluene sulphonyl). The method involves treatment of a solution of O,O-diethyl(tosyloxymethyl)phosphonate in methylene chloride with bromotrimethylsilane, followed by reaction of the formed bis-trimethylsilyl ether with oxalyl chloride in the presence of catalytic amounts of N,N-dimethylformamide in ratio of 3 mole oxalyl chloride to 1 mole O,O-diethyl(tosyloxymethyl)phosphonate. The formed dichlorophosphonate is then treated with two equivalents of alcohols of formula II in the presence of Et₃N.

EFFECT: method with improved reaction selectivity and use of readily available reagents simplifies and reduces cost of production.

5 ex

Description

The invention relates to a method for producing adamantylalkyl and adamantyloxyalkyl esters of tosyloxymethylphosphonic acid. Tosyloxymethylphosphonic acid alkyl and alkoxyalkyl esters are used for the synthesis of pharmaceutical preparations with antiviral activity (cidofovir, adefovir, tenofovir and their analogues).

CHIMERIX INC [US]; UNIV CALIFORNIA [US] Patent WO 2007/130783 A2, Metabolically stable alkoxyalkyl esters of antiviral or antiproliferative phosphonates, nucleoside phosphonates and nucleoside phosphates, 11/15/2007.

Beadle J.R., Wan W. B., Ciesia S. L. et al. // J. Med. Chem. 2006. V. 49. N 6. P. 2010-2015.

This invention solved the problem of creating lipophilic modifiers of synthetic nucleoside analogs, which, due to the presence of a lipophilic adamantane fragment, will provide high bioavailability of nucleoside phosphonate, with the ability to penetrate into the cell and gradually release the active nucleoside. This will allow to maintain an intracellular concentration of the drug, sufficient for a therapeutic effect for a long time, and, thus, reduce a single dose of the drug and frequency of administration.

A known method for the synthesis of tosyloxymethylphosphonic acid dimethyl ester (Holy A. // Coll. Czech. Chem. Commun. 1982. V.47. N 12. P.3447-3463), tosyloxymethylphosphonic acid diethyl ester (Barral K., Balzarini J., Neyts J. et al. // J. Med. Chem. 2006. V. 49. N 1. P. 43-50. Farrington GK, Kumar A., Wedler FC // J. Med. Chem. 1985. V. 28. N 11. P.1668-1673), tosyloxymethylphosphonic acid diisopropyl ester (Hammerschmidt F., Kaehlig H., Mueller N. // J. Chem. Soc., Perkin Trans. 1991. N 2. P.365-369 , Holy A. // Coll. Czech. Chem. Commun. 1993. V.58. N 3. P.649-674, Kelley JL, Linn JA, McLean Ed.W, Tuttle JV // J. Med. Chem. 1993. V.36. N 22. P.3455-3463) by reaction of the corresponding alkyl esters of hydroxymethylphosphonic acid lots with tosyl chloride in the presence of an organic base. However, the esters obtained do not have lipophilic fragments in their composition; therefore, they themselves cannot be used as lipophilic nucleoside modifiers.

The closest in technical essence to the claimed method is a method for producing sodium salts of O-alkoxyalkyl (tosyloxymethyl) phosphonates from O, O-diethyl (tosyloxymethyl) phosphonate by treating the latter with bromotrimethylsilane in a solution of methylene chloride followed by reaction of the resulting bistrimethylmethylsilylmethylsilyl in the presence of , N-dimethylformamide and the reaction of the obtained dichlorophosphonate with alkoxyalkanols (12-methyltridecyloxypropan-1-ol, 13-methyltetradecyloxypropan-1-o ohm, 14-methylpentadecyloxy-propan-1-ol, 15-methylhexadecyloxypropan-1-ol, 17-methyl-octadecyloxyethan-1-ol and 15-methylhexadecyloxyethan-1-ol) taken in the ratio of 0.73 mol per 1 mol of the initial O, O-diethyl ( tosyloxymethyl) phosphonate in the presence of pyridine.

CHIMERIX INC [US]; UNIV CALIFORNIA [US] Patent EP 2012799 (A2) Metabolically stable alkoxyalkyl esters of antiviral or antiproliferative phosphonates, nucleoside phosphonates and nucleoside phosphates, 01/14/2009.

CHIMERIX INC [US]; UNIV CALIFORNIA [US] Patent WO 2007/130783 (A2) Metabolically stable alkoxyalkyl esters of antiviral or antiproliferative phosphonates, nucleoside phosphonates and nucleoside phosphates, 11/15/2007.

The method consists in the fact that 175 mmol of bromotrimethylsilane was added to a solution of 29.5 mmol O, O-diethyl (tosyloxymethyl) phosphonate in 150 ml of methylene chloride and the reaction mixture was stirred at room temperature for 18 hours. Then, methylene chloride and excess bromotrimethylsilane were removed in vacuo, non-volatile residue dissolved in 150 ml of methylene chloride and cooled the resulting solution to 0 ° C; 0.5 ml of DMF was added to it, and then a solution of 175 mmol of oxalyl chloride in 50 ml of methylene chloride was added dropwise over 30 minutes. After all oxalyl chloride was added, stirring was continued for 5 hours. Methylene chloride was distilled off and the remaining oil was dissolved in 100 ml of diethyl ether. To the resulting ether solution, a solution of 21.5 mmol of the corresponding alkoxyalkanol and 10 ml of pyridine in 50 ml of diethyl ether was added with stirring and stirred for 3 hours. After this, the reaction mixture was poured into a cold saturated solution of sodium bicarbonate and stirred for 1 hour. The organic layer was separated, dried with magnesium sulfate and ether was removed in vacuo. The crude product thus obtained was purified by chromatography using eluent methylene chloride - 15% ethanol.

The specified method has a number of significant disadvantages:

1. A large excess of oxalyl chloride is used (5.9 mol per 1 mol of the initial O, O-diethyl (tosyloxymethyl) phosphonate), the regeneration of which from distillation with methylene chloride is difficult, which leads to the complexity of the process and is not justified from an economic point of view.

2. The reaction of tosyloxymethyldichlorophosphonate with 0.73 equivalents of alcohols is not sufficiently selective, since, in addition to the target O-alkoxyalkyl (tosyloxymethyl) chlorophosphonate, complete tosyloxymethylphosphonic acid esters are formed at this stage and the initial dichlorophosphonate remains, which leads to a decrease in the yield of the target dichlorophosphonate. Therefore, it seems more appropriate to synthesize complete tosyloxymethylphosphonic acid esters as lipophilic nucleoside modifiers as a more selective process.

3. Branched alkoxyalkanols used as lipophilic modifiers are very difficult to obtain and multistage synthesis is required to obtain them.

EFFECT: selective method for producing adamantylalkyl and adamantyloxyalkyl esters of tosyloxymethylphosphonic acid of the general formula I

where X is absent, R = H, R '= H, n = 1 (Ia); X is absent, R = H, R '= H, n = 2 (Ib); X is absent, R = H, R '= CH ₃ , n = 1 (Iv); X = O, R = H, R '= H, n = 2 (Ig); X = O, R = C ₂ H ₅ , R '= H, n = 2 (Id); Ts - tosyl (n-toluenesulfonyl),

as more affordable lipophilic nucleoside modifiers; extension of the method to the synthesis of complete tosyloxymethylphosphonic acid esters.

The technical result is achieved by the fact that in the method for producing tosyloxymethylphosphonic acid esters at the stage of dichlorophosphonate synthesis, a smaller excess of oxalyl chloride (3 mol per 1 mol of the initial O, O-diethyl (tosyloxymethyl) phosphonate) is used, and the dichlorophosphonate is esterified with two equivalents of alcohols of the general formula II adamantanes

where X is absent, R = Н, R '= Н, n = 1 (IIa), X is absent, R = Н, R' = Н, n = 2 (IIб), X is absent, R = Н, R '= CH ₃ , n = 1 (IIc), X = O, R = H, R' = H, n = 2 (IIg), X = O, R = C ₂ H ₅ , R '= H, n = 2 (IIe).

Features:

1. The addition of oxalyl chloride at the rate of 3 mol of oxalyl chloride per 1 mol of the original O, O-diethyl (tosyloxymethyl) phosphonate.

2. The use of alcohols of the adamantane series for the synthesis of tosyloxymethylphosphonic acid esters.

3. Synthesis of complete tosyloxymethylphosphonic acid esters by adding 2 equivalents of the adamantane alcohols of the general formula II to the dichlorophosphonate formed after the reaction with oxalyl chloride.

4. The use of triethylamine as the organic base in the reaction step of dichlorophosphonate with alcohols.

5. The use of petroleum ether - ethyl acetate system as an eluent at the stage of chromatographic isolation of compounds Ia-d.

6. The use of recrystallization for the final purification of compounds Ia-b.

The claimed invention has the following advantages:

The extension of the method specified in the prototype to the synthesis of complete esters of tosyloxymethylphosphonic acid formed with higher selectivity.

The use as lipophilic modifiers of alcohols of the adamantane series, which are more accessible and possess antiviral activity.

Reducing the amount of oxalyl chloride.

Examples of the method

The analysis was performed on a Finnigan Trace DCQ gas chromatography mass spectrometer using a SGE capillary column BPX-5 30 0.32 at an ionizing electron energy of 70 eV.

NMR spectra were recorded on Brucker AC200 and Brucker AM300 instruments using the solvent CDCl ₃ (200.13, 300.13 ( ¹ N), 50.32, 75.47 ( ¹³ C) and 121.49 MHz ( ³¹ P)). The measurements were carried out without the use of additional standards with reference to the frequency of the signal of the deuterated solvent.

Example 1

O, O-Bis (adamant-1-ylmstil) (tosyloxymethyl) phosphonate (Ia)

All operations were carried out in an argon atmosphere. To 10.6 g (33.0 mmol) of O, O-diethyl (tosyloxymethyl) phosphonate in 215 ml of methylene chloride, 28.5 g (186 mmol) of trimethyl bromosilane was added and the reaction mixture was stirred at room temperature for 16 hours. The solvent and excess trimethyl bromosilane were removed in vacuo. The residue was dissolved in 200 ml of methylene chloride, cooled to 0 ° C, 0.25 ml of DMF was added, and 12.7 g (100 mmol) of oxalyl chloride in 15 ml of methylene chloride was added dropwise with stirring, maintaining the temperature at 0-5 ° C. After adding all the necessary amount of oxalyl chloride, the reaction mixture was stirred at the same temperature for 6 hours. The solvent was removed in vacuo. The residue was dissolved in 60 ml of absolute diethyl ether, filtered. To the resulting ether solution of dichlorophosphonate, a solution of 7.0 g (69.3 mmol) of triethylamine and 11.0 g (66.0 mmol) of adamant-1-ylmethanol (IIa) in 120 ml of ether was added dropwise with stirring. The mixture was kept at 0 ° C for 12 h, poured into 500 ml of cold water. The ether layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution (2 × 150 ml), dried with sodium sulfate. The solvent was distilled off. The residue was chromatographed on silica gel with a grain diameter of 60-200 μm using eluent petroleum ether (40-70 ° C) - ethyl acetate with a gradual increase in polarity (0-20% ethyl acetate). The product was recrystallized from 100 ml of a mixture of petroleum ether and ethyl acetate. Yield: 7.28 g (39.2%). T. pl. 132 ° C. Mass spectrum m / z (%): 563 [M] ⁺ , 407 (13), 150 (16), 148 (100), 135 (32), 107 (14), 93 (22), 91 (25) 79 (21), 67 (14), 55 (6). NMR ¹ H, δ, ppm: 1.50 s. (12H, CH ₂ , Ad), 1.65 q. (12H, CH ₂ , Ad), 2.00 s. (6H, CH, Ad), 2.45 s. (3H, CH ₃ , p-Tol), 3.60 m. (4H, Ad CH ₂ O), 4.20 d. (2H, CH ₂ O, ² J _HP 7.0 Hz), 7.35 d., 7.8 d. (4H, p-Tol, AB system); δ _C 21.71 s. (CH ₃ , p-Tol), 27.98 s. (CH, Ad), 33.93 d. (C, Ad, ³ J _CP 6.0 Hz). 36.91 sec (CH ₂ , Ad), 38.77 s. (CH ₂ , Ad), 60.99 d. (CH ₂ O, ¹ J _CP 169.8 Hz), 63.97 d. (AdCH ₂ O, ² J _CP 32.5 Hz), 128.25 s. (m-CH, p-Tol), 130.03 s. (o-CH, p-Tol), 131.95 s. (i-C, p-Tol), 145.47 s. (nC, p-Tol); δ _P 16.05 ppm

Example 2

O, O-Bis (2- (adamant-1-yl) ethyl) (tosyloxymethyl) phosphonate (IB)

To 14.8 g (46.0 mmol) of 0-diethyl (tosyloxymethyl) phosphonate in 300 ml of methylene chloride was added 40.6 g (265 mmol) of trimethyl bromosilane and the reaction mixture was stirred at room temperature for 16 hours. The solvent and excess trimethyl bromosilane were removed in vacuo. The residue was dissolved in 270 ml of methylene chloride, cooled to 0 ° C, 0.34 ml of DMF was added, and 17.7 g (139 mmol) of oxalyl chloride in 20 ml of methylene chloride was added dropwise with stirring, maintaining the temperature at 0-5 ° C. After adding all the necessary amount of oxalyl chloride, the reaction mixture was stirred at the same temperature for 6 hours. The solvent was removed in vacuo. The residue was dissolved in 80 ml of absolute diethyl ether, filtered. To the resulting ether solution of dichlorophosphonate, a solution of 9.76 g (96.6 mmol) of triethylamine and 16.6 g (92.0 mmol) of 2- (adamant-1-yl) ethanol (IIb) in 170 ml of ether was added dropwise with stirring. The mixture was kept at 0 ° C for 12 h, poured into 700 ml of cold water. The ether layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution (2 × 210 ml), dried with sodium sulfate. The solvent was distilled off. The residue was chromatographed on silica gel with a grain diameter of 60-200 μm using eluent petroleum ether (40-70 ° C) - ethyl acetate with a gradual increase in polarity (0-20% ethyl acetate). The product was recrystallized from 140 ml of a mixture of petroleum ether and ethyl acetate. Yield: 9.53 g (35.0%). T. pl. 67 ° C. Mass spectrum m / z (%): 591 [M] ⁺ , 435 (12), 273 (12), 267 (33), 163 (100), 135 (74), 105 (31), 91 (37) 79 (36), 67 (16), 55 (11). NMR ¹ H, δ, ppm: 1.45 t. (4H, Ad CH ₂ CH ₂ O), 1.49 s. (12H, CH ₂ , Ad), 1.65 q. (12H, CH ₂ , Ad), 1.95 s. (6H, CH, Ad), 2.45 s. (3H, CH ₃ , p-Tol), 4.12 m. (4H, CH ₂ O), 4.19 d. (2H, CH ₂ O, ² J _HP 8.2 Hz), 7.35 d., 7.8 d. (4H, p -Tol, AB-system); δ _C 21.77 s. (CH ₃ , p-Tol), 28.60 s. (CH, Ad), 31.84 s. (C, Ad), 37.01 s. (CH ₂ , Ad), 42.54 s. (CH ₂ , Ad), 44.28 d. (Ad CH ₂ CH ₂ O, ³ J _CP 6.03 Hz), 61.20 d. (CH ₂ O, ¹ J _CP 167.5 Hz), 63.97 d. (AdCH ₂ CH ₂ O, ² J _CP 6.8 Hz), 128.32 s. (m-CH, p-Tol), 130.08 s. (o-CH, p-Tol), 131.97 s. (i-C, p-Tol), 145.52 s. (n-C, p-Tol); δ _P 18.01 ppm

Example 3

O, O-Bis (1- (adamant-1-yl) ethyl) (tosyloxymethyl) phosphonate (Ic)

To 14.8 g (46.0 mmol) of O, O-diethyl (tosyloxymethyl) phosphonate in 300 ml of methylene chloride was added 40.6 g (265 mmol) of trimethyl bromosilane and the reaction mixture was stirred at room temperature for 16 hours. The solvent and excess trimethyl bromosilane were removed in vacuo. The residue was dissolved in 270 ml of methylene chloride, cooled to 0 ° C, 0.34 ml of DMF was added, and 17.7 g (139 mmol) of oxalyl chloride in 20 ml of methylene chloride was added dropwise with stirring, maintaining the temperature at 0-5 ° C. After adding all the necessary amount of oxalyl chloride, the reaction mixture was stirred at the same temperature for 6 hours. The solvent was removed in vacuo. The residue was dissolved in 80 ml of absolute diethyl ether, filtered. To the resulting ether solution of dichlorophosphonate, a solution of 9.76 g (96.6 mmol) of triethylamine and 16.6 g (92.0 mmol) of 1- (adamant-1-yl) ethanol (IIc) in 170 ml of ether was added dropwise with stirring. The mixture was kept at 0 ° C for 12 h, poured into 700 ml of cold water. The ether layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution (2 × 210 ml), dried with sodium sulfate. The solvent was distilled off. The residue was chromatographed on silica gel with a grain diameter of 60-200 μm using petroleum ether (40-70 ° C) - ethyl acetate with a gradual increase in polarity (0-20% ethyl acetate) using eluent. The product was recrystallized from 140 ml of a mixture of petroleum ether and ethyl acetate. Yield: 1.35 g (4.97%). T. pl. 165 ° C. Mass spectrum m / z (%): 591 [M] ⁺ , 273 (25), 267 (84), 162 (89), 135 (100), 107 (30), 93 (44), 79 (37) , 67 (17), 55 (12). NMR ¹ H, δ, ppm: 1.20 d. (6H, CH ₃ ), 1.40-1.75 m. (24H, CH ₂ , Ad), 2.0 s. (6H, CH, Ad), 2.45 s. (CH ₃ , p-Tol), 4.22 m. (2H, CH ₂ O, 2H, CHO), 7.35 d., 7.8 d. (4H, p-Tol, AB system); δ _C 15.0 s. (CH ₃ ), 21.50 s. (CH ₃ , p-Tol), 28.18 s. (CH, Ad), 36.68 s. (C, Ad), 37.01 s. (CH ₂ , Ad), 37.70 s. (CH ₃ , Ad), 62.54 d. (CH ₂ O, ¹ J _CP 170.0 Hz), 83.00 d. (Ad CH CH ₃ ) O, 128.27 s. (m-CH, p-Tol), 129.98 s. (o-CH, p-Tol), 131.97 s. (i-C, p-Tol), 145.39 s. (n-C, p-Tol); δ _P 14.16 ppm

Example 4

O, O-Bis (2- (adamant-1-yloxy) ethyl) (tosyloxymethyl) phosphonate (Id).

To 6.98 g (21.7 mmol) of O, O-diethyl (tosyloxymethyl) phosphonate in 140 ml of methylene chloride was added 19.3 g (126 mmol) of trimethyl bromosilane and the reaction mixture was stirred at room temperature for 16 hours. The solvent and excess trimethyl bromosilane were removed in vacuo. The residue was dissolved in 130 ml of methylene chloride, cooled to 0 ° С, 0.17 ml of DMF was added, and 8.34 g (65.7 mmol) of oxalyl chloride in 10 ml of methylene chloride was added dropwise with stirring, maintaining the temperature at 0-5 ° С. After adding all the necessary amount of oxalyl chloride, the reaction mixture was stirred at the same temperature for 6 hours. The solvent was removed in vacuo. The residue was dissolved in 40 ml of absolute diethyl ether, filtered. To the resulting ether solution of dichlorophosphonate, a solution of 4.60 g (45.6 mmol) of triethylamine and 8.50 g (43.4 mmol) of 2- (adamant-1-yloxy) ethanol (IIg) in 80 ml of ether was added dropwise with stirring. The mixture was kept at 0 ° C for 12 h, poured into 210 ml of cold water. The ether layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution (2 × 100 ml), dried with sodium sulfate. The solvent was distilled off. The residue was chromatographed on silica gel with a grain diameter of 60-200 μm using eluent petroleum ether (40-70 ° C) - ethyl acetate with a gradual increase in polarity (0-50% ethyl acetate). The product was recrystallized from 70 ml of a mixture of petroleum ether and ethyl acetate. Yield: 5.23 g (38.7%). T. pl. 53-55 ° C. Mass spectrum m / z (%): 624 [M-H] ⁺ , 579 (5), 293 (5), 268 (5), 155 (7), 135 (100), 121 (7), 107 ( 12), 93 (22), 91 (19), 79 (17), 67 (7). NMR ¹ H, δ, ppm: 1.52 sq. (12H, Ad), 1.70 s. (12H, Ad), 2.12 s. (6H, Ad), 2.45 s. (3H, CH ₃ , p-Tol), 3.58 m. (4H, AdO CH ₂ CH ₂ O), 4.15 m (4H, AdOCH ₂ CH ₂ O), 4.30 d. (2H, CH ₂ O, ² J _HP 8.2 Hz), 7.35 d., 7.80 d. (4H, p-Tol, AB system); δ _C 21.66 s. (CH ₃ , p-Tol), 30.47 s. (CH, Ad), 36.36 s., (CH ₂ , Ad), 41.39 s. (CH ₂ , Ad), 59.09 s. (AdO CH ₂ CH ₂ O), 61.74 d. (CH ₂ O, ¹ J _CP 169.8 Hz), 67.02 d. (AdOCH ₂ CH ₂ O, ² J _CP 7.55 Hz), 72.62 s. (C, Ad), 128.26 s. (m-CH, p-Tol), 129.92 s. (o-CH, p-Tol), 132.01 s. (iC, p-Tol), 145.24 s. (n-C, p-Tol); δ _P 18.15 ppm

Example 5

O, O-Bis (2- (3-ethyladamant-1-yl) ethyl) (tosyloxymethyl) phosphonate (Ie)

To 10.6 g (33.0 mmol) of O, O-diethyl (tosyloxymethyl) phosphonate in 215 ml of methylene chloride, 28.5 g (186 mmol) of trimethyl bromosilane was added and the reaction mixture was stirred at room temperature for 16 hours. The solvent and excess trimethyl bromosilane were removed in vacuo. The residue was dissolved in 200 ml of methylene chloride, cooled to 0 ° C, 0.25 ml of DMF was added, and 12.7 g (100 mmol) of oxalyl chloride in 15 ml of methylene chloride was added dropwise with stirring, maintaining the temperature at 0-5 ° C. After adding all the necessary amount of oxalyl chloride, the reaction mixture was stirred at the same temperature for 6 hours. The solvent was removed in vacuo. The residue was dissolved in 60 ml of absolute diethyl ether, filtered. To the resulting ether solution of dichlorophosphonate, a solution of 7.0 g (69.3 mmol) of triethylamine and 14.8 g (66.0 mmol) of 2- (3-ethyladamant-1-yloxy) ethanol (IIe) in 120 ml of ether was added dropwise with stirring. The mixture was kept at 0 ° C for 12 h, poured into 500 ml of cold water. The ether layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution (2 × 150 ml), dried with sodium sulfate. The solvent was distilled off. The residue was chromatographed on silica gel with a grain diameter of 60-200 μm using eluent petroleum ether (40-70 ° C) - ethyl acetate with a gradual increase in polarity (0-20% ethyl acetate). Yield: 8.70 g (38.8%). Mass spectrum m / z (%): 679 [M] ⁺ , 636 (12), 500 (7), 473 (62), 381 (7), 355 (12), 337 (22), 311 (48) , 293 (20), 267 (11), 177 (11), 162 (100), 155 (25), 149 (13), 121 (42), 107 (56), 93 (44), 91 (35) 79 (32), 55 (12). NMR ¹ H, δ, ppm: 0.80 t. (6H, CH ₃ , Et), 1.20 q. (4H, CH ₂ , Et), 1.35 s, 1.40 s, 1.63 q, 2.18 s. (28H, Ad), 2.45 s. (CH ₃ , p-Tol), 3.58 t. (4Н, AdO CH ₂ CH ₂ O), 4.15 m. (4Н, AdOCH ₂ CH ₂ O), 4.30 d. (2Н, CH ₂ O, ² J _HP 8.2 Hz), 7.35 d., 7.8 d. (4H, p-Tol, AV system); δ _C 7.18 s. (CH ₃ , Et), 21.73 s. (CH ₃ , p-Tol), 30.57 s. (CH, Ad), 35.89 s. (CH ₂ , Et), 40.99 s. (CH ₂ , Ad), 45.78 s. (CH ₂ , Ad), 59.41 s. (AdO CH ₂ CH ₂ O), 61.66 d. (CH ₂ O, ¹ J _CP 187.0 Hz), 67.09 d. (AdOCH ₂ CH ₂ O, ² J _CP 6.8 Hz), 73.69 s. (C, Ad), 128.30 s. (m-CH, p-Tol), 129.99 s. (o-CH, p-Tol), 132.06 s. (i-C, p-Tol), 145.31 s. (n-C, p-Tol); δ _P 17.18 ppm

Claims (1)

The method of producing adamantylalkyl and adamantyloxyalkyl esters of tosyloxymethylphosphonic acid of the general formula I

where X is absent, R = H, R '= H, n = 1; or X is absent, R = H, R '= H, n = 2; or X is absent, R = H, R '= CH ₃ , n = 1; or X = O, R = H, R '= H, n = 2; or X = O, R = C ₂ H ₅ , R '= H, n = 2;
Ts is tosyl (n-toluenesulfonyl), in which a solution of O, O-diethyl (tosyloxymethyl) phosphonate in methylene chloride is treated with bromotrimethylsilane, followed by reaction of the resulting bistrimethylsilyl ether with oxalyl chloride in the presence of catalytic amounts of N, N-amide amide dimethylformide 3 mol of O, O-diethyl (tosyloxymethyl) phosphonate, after which the resulting dichlorophosphonate is treated in the presence of triethylamine with two equivalents of the alcohols of formula II

,
where X is absent, R = H, R '= H, n = 1; or X is absent, R = H, R '= H, n = 2; or X is absent, R = H, R '= CH ₃ , n = 1; or X = O, R = H, R '= H, n = 2; or X = O, R = C ₂ H ₅ , R '= H, n = 2.