Method for preparing phosphonic acid ester

Abstract

Provided is a method for preparing specific bisphosphonate compounds and their ester derivatives. In this method, specific bisphosphonate compounds such as medronic acid are prepared via the reaction of the corresponding isopropyl ester with (i) trimethylsilyl bromide or trimethylsilyl iodide or (ii) trimethylsilyl chloride and an alkali metal iodide or bromide; followed by treatment with a liquid containing water. The above method surprisingly gives the desired compounds despite the relatively bulky ester group such as isopropyl in the starting bisphosphonate ester.

Description

Technical Field

[0001] The present disclosure generally belongs to the field of organic synthetic chemistry. Specifically, the present disclosure relates to a method for preparing medronic acid, which can be further derivatized to its corresponding ester.

Background Art

[0002] Medronic acid, CAS No. 1984-15-2, is a useful diphosphonate compound that has been used in complexes with radioactive technetium in nuclear medicine. Known methods generally result in low yields and involve the use of reagents that are sensitive to air and moisture.

Summary of the Invention

[0003] In summary, the present disclosure provides a method for preparing certain bisphosphonate compounds and their ester derivatives. In this method, certain bisphosphonate compounds such as medronic acid (where z is 1 in the following formula) are prepared via the reaction of the corresponding isopropyl ester with (i) trimethylsilyl bromide or trimethylsilyl iodide or (ii) trimethylsilyl chloride and an alkali metal iodide or bromide; followed by treatment with a liquid containing water. The above method surprisingly gives the desired compounds despite the relatively bulky ester groups such as isopropyl in the starting bisphosphonate ester.

Modes for Carrying Out the Invention

[0004] As used in this specification and the appended claims, unless the context clearly dictates otherwise, the singular forms "a", "an", and "the" include plural referents. As used in this specification and the appended claims, unless the context clearly dictates otherwise, the term "or" is generally used in the sense of "and / or".

[0005] The term "about" generally refers to a range of numbers that are considered equivalent to the stated value (e.g., having the same function or result). In many instances, the term "about" may include numbers rounded to the nearest significant digit.

[0006] Numerical ranges expressed using endpoints include all of the numbers within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5).

[0007] In a first aspect, the present disclosure provides a method for preparing a compound of formula (I) TIFF2025523862000001.tif35170 [wherein z is an integer from 1 to 12], the method comprising contacting a compound of formula (A) TIFF2025523862000002.tif46170 with (i) trimethylsilyl bromide or trimethylsilyl iodide or (ii) trimethylsilyl chloride and an alkali metal iodide or bromide, and subsequently treating with a liquid containing water.

[0008] In the above method, the compound of formula (A) is commercially available. For example, when z is 1, the CAS No. is 1660 - 95 - 3 and it is available from Sigma Aldrich. Exemplary alkali metal iodides or bromides include sodium iodide, potassium iodide, sodium bromide, and potassium bromide. When trimethylsilyl bromide or iodide is utilized, the above method is generally carried out at a high temperature, e.g., about 60 - 80 °C. When a combination of trimethylsilyl chloride and an alkali metal iodide is utilized, the above method can be carried out from room temperature to about 70 °C. Further, the compound of formula (A) may be reacted with (ii) trimethylsilyl chloride and a Group II or Group X iodide or bromide (e.g., MgBr2, NiI2, etc.).

[0009] In any case, generally, a polar aprotic solvent, e.g., acetonitrile or dichloroethane, can be utilized.

[0010] In the above second step, the trimethylsilyl phosphate intermediate is hydrolyzed in situ using a liquid containing water, such as water containing alcohol(s). In one embodiment, the trimethylsilyl phosphate is treated with water at room temperature.

[0011] In a further aspect, the present disclosure provides that the compound of formula (I) is further treated with an alkylating compound of formula HC(OR)3, wherein R is a primary or secondary C1-C8 alkyl group, to give a compound of formula (II) TIFF2025523862000003.tif40170 to form a compound.

[0012] In this aspect, suitable alkylating agents include trimethyl orthoformate, triethyl orthoformate, tri(n-octyl) orthoformate, etc.

[0013] Existing methodologies for generating the compound of formula (I) involve treating the compound of formula (A) with phosphorus pentachloride (PCl5) to give a tetrachlorinated intermediate, which is then reacted with an alcohol in the presence of an amine such as triethylamine. In this existing method, phosphoryl chloride (POCl3) is generated in situ. Advantageously, the method of the present disclosure does not utilize phosphorus pentachloride. Thus, the above method provides a compound of formula (I) (and a compound of formula (II)) that is essentially free of contaminants of formula PO(OR)3 and their partially chlorinated equivalents in one embodiment. In certain embodiments, the compounds of formula (I) and (II) have less than about 1000 ppm of PO(OR)3, less than about 700 ppm of PO(OR)3, less than about 500 ppm of PO(OR)3, less than about 250 ppm of PO(OR)3, less than about 100 ppm of PO(OR)3, less than about 75 ppm of PO(OR)3, less than about 50 ppm of PO(OR)3, less than about 25 ppm of PO(OR)3, less than about 10 ppm of PO(OR)3. In this regard, PO(OR)3 can be measured by HPLC (high performance liquid chromatography).

Examples

[0014] General procedure: All operations were carried out under an inert atmosphere unless otherwise specified. NMR analysis was carried out in air. NMR measurements were performed on a Bruker 400 MHz.

[0015] Diphosphonic acid synthesis Example 1: Tetraisopropyl methylenediphosphonate (36 mL, 112 mmol) was added to a 250 mL three-necked round-bottom flask and heated to 50 °C. Bromotrimethylsilane (70 mL, 530 mmol) was added and the mixture was heated at 75 °C for 2 h. The mixture was cooled to 30 °C and the volatiles were removed in vacuo. Analysis of the mixture by NMR showed complete conversion to the intermediate tetrakis(trimethylsilyl) methylenediphosphonate. 1 1H NMR (400 MHz, CDCl3): δ = 2.29 (t (br), 2H, 2 J PH = 21 Hz, CH2), 0.27 (s (br), 36H, SiCH3). 13 13C{ 1 1H} NMR (100 MHz, undiluted): 30.58 (t, 1 J PC = 139.7 Hz, CH2), 1.04 (s, SiCH3). 31 31P{ 1 1H} NMR (162 MHz, undiluted): δ = 2.29 (br).

[0016] Water was added to the mixture and stirred at room temperature for 1 h. The layers were separated and the organic layer was discarded. The water was removed by trituration with isopropanol (4 × 30 mL), then filtered, washed further with isopropanol (20 mL) and dried in vacuo to give a white powder (18.3 g, 92% yield). 1 1H NMR (400 MHz, D2O): δ = 2.29 (t 2H, 2 J PH = 21 Hz, CH2). 13 13C{ 11H NMR (100 MHz, D2O): δ = 26.9 ppm (t, 1 J CP = 130 Hz). 31 31P{ 1 1H} NMR (162 MHz, undiluted): δ = 18.1 ppm. 31 31P{ 1 The purity by 1H analysis was 99.8%. 1 The purity by 1H analysis was 98.0%.

[0017] Example 2: Add a slurry of NaI (4.5 eq) in dichloroethane (20 mL) to a flask. Add tetraisopropyl methylenediphosphonate (5.0 mL, 15.6 mmol) at 50 °C, followed by trimethylsilyl chloride (TMSCl) (9.0 mL 4.5 eq). Stir the mixture at 70 °C for 24 h, cool to room temperature, filter, and wash with dichloroethane (2 × 20 mL). Then remove the volatiles under vacuum. From here, after the addition of water, workup is carried out in the same manner as in Example 1. Medronic acid was obtained in 21% yield. The low yield is due to the air sensitivity of the tetrakis(trimethylsilyl) methylenediphosphonate intermediate as a rubbery solid formed during the initial filtration.

[0018] Example 3: Add a slurry of LiI (9.4 g, 4.5 eq) in DCE (20 mL) to a flask. Add tetraisopropyl methylenediphosphonate (5.0 mL, 15.6 mmol) at 50 °C, followed by TMSCl (9.0 mL 4.5 eq). Stir the mixture at 70 °C for 50 h, cool to room temperature, further dilute with DCE (20 mL), filter under nitrogen, and wash with DCE (3 × 10 mL). Then remove the volatiles at 60 °C under vacuum. From here, after the addition of water, workup is carried out in the same manner as in Example 1. Medronic acid was obtained in 89% yield.

[0019] Example 4: Add a DCE (20 mL) slurry of KBr (8.4 g, 4.5 equivalents) to the flask. Add tetraisopropyl methylenediphosphonate (5.0 mL, 15.6 mmol), followed by TMSCl (9.0 mL, 4.5 equivalents) at 50 °C. Stir the mixture at 70 °C for 50 hours, then, 31 31P NMR (D2O) showed 77% conversion to medronic acid (based on the -OiPr groups converted to -OH). The mixture was discarded.

[0020] Example 5: Add a MeCN (20 mL) slurry of KI (11.6 g, 4.5 equivalents) to the flask. Add tetraisopropyl methylenediphosphonate (5.0 mL, 15.6 mmol), followed by TMSCl (9.0 mL, 4.5 equivalents) at 50 °C. Stir the mixture at 50 °C for 21 hours, cool to room temperature, further dilute with DCM (40 mL), filter, and wash with DCM (3 × 10 mL) under nitrogen. Then, remove the volatiles at 60 °C under vacuum. From here, perform post-treatment in the same manner as in Example 1 after adding water. Medronic acid was obtained in a 77% yield.

[0021] Example 6: Add a MeCN (20 mL) slurry of MgBr2 (6.3 g, 2.2 equivalents) to the flask. Add tetraisopropyl methylenediphosphonate (5.0 mL, 15.6 mmol), followed by TMSCl (9.0 mL, 4.5 equivalents) at 50 °C. Stir the mixture at 70 °C for 24 hours, then add an additional MgBr2 (1.1 equivalents) and TMSCl (2.25 equivalents). After a total of 65 hours at 70 °C, 31 31P NMR (D2O) showed that the analytical complex mixture contained only 6% medronic acid (confirmed by spiking). The mixture was discarded.

[0022] Example 7: Add a slurry of ZnI2 (11.9 g, 2.4 equiv) in MeCN (20 mL) to the flask. Add tetraisopropyl methylenediphosphonate (5.0 mL, 15.6 mmol), followed by TMSCl (9.0 mL 4.5 equiv) at 50 °C. Stir the mixture at 70 °C for 43 h, then, 31 31P NMR (D2O) showed 98% conversion to medronic acid (based on the -OiPr groups converted to -OH).

[0023] Example 8: Add a slurry of CaI2 (5.5 g, 2.4 equiv) in MeCN (20 mL) to the flask. Add tetraisopropyl methylenediphosphonate (5.0 mL, 15.6 mmol), followed by TMSCl (9.0 mL 4.5 equiv) at 50 °C. Stir the mixture at 70 °C for 43 h, then, 31 31P NMR (D2O) showed that the complex mixture contained only 8.8% medronic acid (confirmed by spiking) by analysis. The mixture was discarded.

[0024] Example 9: Perform the same procedure as in Example 1 using tetraethyl ethylenediphosphonate. 1,2-Ethylenediphosphonic acid was obtained in 53% yield (0.65 g). 1 H (400 MHz, D2O): δ = 1.84 (m, 4H). 13 C{ 1 H} NMR (100 MHz, D2O): δ = 20.0 ppm (m). 31 P{ 1 H} NMR (162 MHz, D2O): δ = 28.4 ppm

[0025] Example 10: Perform the same procedure as in Example 1 using tetraethyl dodecylenediphosphonate. 1,12-Dodecylenediphosphonic acid was obtained in 43% yield (0.65 g). 1 H (400 MHz, MeOH-d4): δ = 1.33 - 1.73 ppm (m, 24H). 13 C{ 11H NMR (100 MHz, MeOH-d4): δ = 31.8 (d, 2 J PC = 16 Hz), 30.7 (s), 30.5 (s), 30.3 (s), 28.2 ppm ( 1 J PC = 138 Hz), 23.9 ppm ( 3 J PC = 5.8 Hz). 31 31P{ 1 1H} NMR (162 MHz, MeOH-d4): δ = 30.2 ppm

[0026] Diphosphonate synthesis Example 11 Medronic acid (17.4 g, 98.8 mmol) and trimethyl orthoformate (56 mL, 511 mmol) were added to a 250 mL flask equipped with a stir bar and a water-cooled distillation apparatus. The mixture was heated to 90 °C for 2 h and then cooled to 40 °C. The distilled by-products were discarded and another aliquot of trimethyl orthoformate (46 mL, 420 mmol) was added. The distillation apparatus was heated to 100 °C and then gradually to 120 °C over 2.5 h. 31 31P{ 1 1H} NMR indicated that the reaction was complete after an additional 1 h at 120 °C. The distilled by-products were discarded and all other volatiles were removed at 60 °C in vacuo. The product was distilled at 110 - 118 °C / 540 - 570 mTorr to afford tetramethyl methylenediphosphonate as a clear, colorless liquid (20.4 g, 89.1% yield). 1 1H NMR (400 MHz, CDCl3): δ = 3.74 (d, 12H, 3 J PH = 11 Hz, CH3), 2.31 (t 2H, 2 J PH = 21Hz, CH2). 13 13C{ 1 1H} NMR (100 MHz, CDCl3): δ = 52.58 (m), 22.92 (t, 1 J PC = 136.5 Hz, CH2) 31 31P{1 1H NMR (162 MHz, CDCl3): δ = 21.9. 31 P{ 1 The purity by 1H analysis was 99.8%. 1 The purity by 1H analysis was 99.1%.

[0027] Example 12 Medronic acid (0.50 g, 2.84 mmol) and triethyl orthoformate (10 mL, 21 equivalents) were combined and heated at 120 °C for 2 days. The volatiles were removed at 50 °C in vacuo to afford tetraethyl methylenediphosphonate as a yellow oil in essentially quantitative yield (0.82 g). 1 1H NMR (400 MHz, CDCl3): δ = 4.18 ppm, (m, 8H, CH2-O), 2.44 ppm (2H, t, 2 J PH = 20.9 Hz), 1.34 ppm (12H, t, J = 7.0 Hz), 88% analysis. 13 13C{ 1 1H} NMR (100 MHz, CDCl3): δ = 62.5 ppm (m), 25.5 ppm (t, 1 J PC = 136 Hz, CH2), 16.3 (m) 31 31P{ 1 1H} NMR (162 MHz, CDCl3): δ = 19.4 (99.8% analysis).

[0028] Example 13 Medronic acid (0.50 g, 2.84 mmol) and triisopropyl orthoformate (13 mL, 20 equivalents) were combined and heated at 120 - 140 °C for 3 days, after which 31 31P NMR (CDCl3) showed 98% conversion to tetraisopropyl methylenediphosphonate. Example 14 (hypothetical)

[0029] The same procedure as in Example 13 is used with tributyl orthoformate as the alkylating agent. 31 31P NMR (CDCl3) 31 31P{1 1H NMR (162 MHz, CDCl3): According to δ = 19.5, 98.5% conversion to tetrabutyl methylenediphosphonate was achieved.

[0030] Example 15 The same procedure as in Example 12 is used with ethylenediphosphonic acid as the substrate. Tetramethyl ethylene-1,2-diphosphonate was obtained as a yellow oil in quantitative yield. 1 1H NMR (400 MHz, CDCl3): δ 3.72 (m, 12H, CH3), 1.96 (m, 4H, CH2), 92% analysis. 13 13C{ 1 1H} NMR (100 MHz, CDCl3): δ = 52.4 ppm (m, CH3), 18.0 ppm (m, CH2) 31 31P{ 1 1H} NMR (162 MHz, CDCl3): δ = 32 (95.2% analysis).

[0031] Example 16 The same procedure as in Example 12 is used with dodecylenediphosphonic acid as the substrate. Tetramethyl dodecylene-1,12-diphosphonate was obtained as a sticky solid in quantitative yield. 1 1H NMR (400 MHz, CDCl3): δ 3.72 (t, J = 5.4hz, 12H, CH3), 1.96 (m, 4H, CH2), 92% analysis. 13 13C{ 1 1H} NMR (100 MHz, CDCl3): δ = 52.5 (d, 2 J PC = 6.6Hz, CH3), 30.5 (d, 2 J PC = 17 Hz), 29.5, 29.3, 29.1, 24.6 (d, 1 J PC = 140 Hz, P-CH2), 22.2 (d, J = 5.5 Hz), 31 31P{ 11H NMR (162 MHz, CDCl3): δ = 35.2 (89.8% analysis).

[0032] Aspect In a first aspect, the present disclosure provides a method for preparing a compound of formula (I) TIFF2025523862000004.tif35170[wherein z is an integer from 1 to 12], comprising contacting a compound of formula (A) TIFF2025523862000005.tif46170with (i) trimethylsilyl bromide or trimethylsilyl iodide or (ii) trimethylsilyl chloride and an alkali metal iodide or bromide; and subsequently treating with a liquid containing water.

[0033] In a second aspect, the present disclosure provides the method of the first aspect, wherein the compound of formula (A) is reacted with trimethylsilyl bromide or trimethylsilyl iodide.

[0034] In a third aspect, the present disclosure provides the method of the first aspect, wherein the compound of formula (A) is reacted with (ii) trimethylsilyl chloride and an alkali metal iodide or bromide.

[0035] In a fourth aspect, the present disclosure provides the method of the third aspect, wherein the alkali metal iodide is sodium iodide.

[0036] In a fifth aspect, the present disclosure provides the method of the third aspect, wherein the alkali metal iodide is potassium iodide.

[0037] In a sixth aspect, the present disclosure provides the method according to any one of aspects 1 to 5, wherein the compound of formula (I) contains less than about 1000 ppm of a compound of formula PO(OR)3.

[0038] In a seventh aspect, the present disclosure provides the method according to any one of aspects 1 to 6, wherein the compound of formula (I) contains less than about 100 ppm of the compound of formula PO(OR)3.

[0039] In an eighth aspect, the present disclosure reacts a compound of formula (I) with an alkylating compound of formula HC(OR)3 [wherein R is a primary or secondary C1-C8 alkyl group] to form a compound of formula (II): TIFF2025523862000006.tif40170 and further includes the step of forming the compound of. The present disclosure provides the method according to any one of aspects 1 to 7.

[0040] In a ninth aspect, the present disclosure provides the method according to the eighth aspect, wherein R is selected from methyl, ethyl, n-pentyl, n-octyl, and isopropyl.

[0041] In a tenth aspect, the present disclosure provides the method according to the eighth aspect, wherein z is 1 and R is methyl.

[0042] In an eleventh aspect, the present disclosure provides the method according to any one of the eighth to tenth aspects, wherein the compound of formula (II) contains less than about 1000 ppm of the compound of formula PO(OR)3.

[0043] In a twelfth aspect, the present disclosure provides the method according to any one of the eighth to eleventh aspects, wherein the compound of formula (II) contains less than about 100 ppm of the compound of formula PO(OR)3.

[0044] In a thirteenth aspect, the present disclosure provides a compound of formula (I) TIFF2025523862000007.tif35170 [wherein z is an integer from 1 to 12] prepared by the method according to any one of aspects 1 to 7.

[0045] In a fourteenth aspect, the present disclosure provides a compound of formula (I) Provide a compound of TIFF2025523862000008.tif35170 [where z is an integer from 1 to 12].

[0046] In a fifteenth aspect, the present disclosure provides a compound according to the fourteenth aspect, containing a compound of the formula PO(OR)3 of less than about 100 ppm.

[0047] In a sixteenth aspect, the present disclosure provides a compound according to the fourteenth aspect, containing a compound of the formula PO(OR)3 of less than about 10 ppm.

[0048] In a seventeenth aspect, the present disclosure provides a compound of formula (II) containing a compound of the formula PO(OR)3 of less than about 1000 ppm: TIFF2025523862000009.tif40170 [where R is a primary or secondary alkyl group of C1 - C8].

[0049] In an eighteenth aspect, the present disclosure provides a compound according to the seventeenth aspect, containing a compound of the formula PO(OR)3 of less than about 100 ppm.

[0050] In a nineteenth aspect, the present disclosure provides a compound according to the seventeenth aspect, containing a compound of the formula PO(OR)3 of less than about 10 ppm.

[0051] With some illustrative embodiments of the present disclosure described as above, those skilled in the art will readily understand that other embodiments can be made and used within the scope of the appended claims. Many advantages of the present disclosure targeted by this document are described in the foregoing explanation. However, it will be understood that the present disclosure is merely illustrative in many respects. The scope of the present disclosure is, of course, defined by the language in which the appended patent claims are expressed.

Claims

1. A compound of formula (A) is contacted with (i) trimethylsilyl bromide or trimethylsilyl iodide or (ii) trimethylsilyl chloride and an alkali metal iodide or bromide to form a mixture; The mixture is treated with a liquid containing water, whereby a compound of formula (I) [wherein z is an integer from 1 to 12] is formed, a method comprising.

2. The method according to claim 1, wherein the compound of formula (A) is reacted with trimethylsilyl bromide or trimethylsilyl iodide.

3. The method according to claim 1, wherein the compound of formula (A) is reacted with trimethylsilyl chloride and an alkali metal iodide or bromide.

4. The method according to claim 3, wherein the alkali metal iodide used is sodium iodide.

5. The method according to claim 3, wherein the alkali metal iodide used is potassium iodide.

6. The method according to claim 1, wherein the compound of formula (I) contains a compound of formula PO(OR) of less than about 1000 ppm ３ ​

7. The compound of formula (I) contains less than about 100 ppm of the compound of formula PO(OR) ３ The method according to claim 6, wherein the compound of formula (I) contains less than about 100 ppm of the compound of formula PO(OR).

8. The compound of formula (I) is reacted with an alkylating compound of formula HC(OR) ３ [wherein, R is a primary or secondary C １ -C ８ alkyl group] to give a compound of formula (II) The method according to claim 1, further comprising forming the compound of.

9. The method according to claim 8, wherein R is selected from methyl, ethyl, n-pentyl, n-octyl and isopropyl.

10. The method according to claim 8, wherein z is 1 and R is methyl.

11. The method according to claim 9, wherein z is 1 and R is methyl.

12. The method according to claim 8, wherein the compound of formula (II) contains a compound of formula PO(OR) less than about 1000 ppm ３ ​

13. The compound of formula (II) contains less than about 100 ppm of the compound of formula PO(OR) ３ The method according to claim 8, wherein the compound of formula (II) contains less than about 100 ppm of the compound of formula PO(OR).

14. A compound of formula (I) prepared by the method according to claim 1 [wherein z is an integer from 1 to 12].

15. A compound of formula PO(OR) less than about 1000 ppm ３ containing, of formula (I) [wherein z is an integer from 1 to 12] a compound.

16. A compound according to claim 15, containing a compound of formula PO(OR) of less than about 100 ppm ３ ​

17. A compound of formula PO(OR) less than about 1000 ppm ３ containing, of formula (II): [In the formula, R is a primary or secondary alkyl group of C １ to C ８ of the compound.

18. A compound according to claim 17, containing a compound of formula PO(OR) of less than about 100 ppm ３ ​

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