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Bisphosphonate Prodrugs. Selective Synthesis of (1-Hydroxyethylidene)-1,1-bisphosphonate Partial Esters

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Bisphosphonate Prodrugs. Selective Synthesis of (1-Hydroxyethylidene)-1,1-bisphosphonate Partial Esters
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  PAPER633 Synthesis 2000, No. 4, 633–637ISSN 0039-7881© ThiemeStuttgart·New York Bisphosphonate Prodrugs. Selective Synthesis of (1-Hydroxyethylidene)-1,1-bisphosphonate Partial Esters Petri A. Turhanen, a * Markku J. Ahlgren, b  Tomi Järvinen, c  Jouko J. Vepsäläinen a a University of Kuopio, Department of Chemistry, P. O. Box 1627, 70211, Kuopio, Finland b University of Joensuu, Department of Chemistry, P. O. Box 111, 80101, Joensuu, Finland c University of Kuopio, Department of Pharmaceutical Chemistry, P. O. Box 1627, 70211, Kuopio, FinlandFax +358(17)163259; E-mail: Petri.Turhanen@uku.fi  Received 31 October 2000 Abstract : Selective methods for the synthesis of (1-hydroxyeth-ylidene)-1,1-bisphosphonate tri-, P,P  -di-, P,P-di- and mono estershave been developed. Preparation is started from selected symmet-ric or unsymmetric tetraesters of etidronate using alkalimetal saltsor trimethylsilyl iodide as dealkylating agents. Synthesis of H 3 CC(OH)[P(O)(OH) 2 ][P(O)(OH)(OHex)] starting from trimethylester of etidronate is also described. 1 H, 13 C and 31 P NMR data arereported including 1  J  CP , 2  J  CP  and 2  J  PP  couplings. The solid statestructure is given for [1-(dimethoxyphosphinyl)-1-hydroxyethyl]-1-phosphonic acid monomethyl ester monopotassium salt ( 1a ). Key words : bisphosphonate, etidronate, partial esters, synthesis,prodrug Bisphosphonate compounds, which are characterised by aP-C-P bridge, are analogues of pyrophosphates. 1  They arewidely used in the treatment of diseases associated withincreased bone resorption and bone metastases. 2  They arealso the most effective inhibitors of osteoclastic bone re-sorption and are, therefore, useful drugs to treat and pre-vent osteoporosis. 3  Etidronate, clodronate andpamidronate are examples of these drugs used in variousbone diseases. 1,2  Etidronate, (1-hydroxyethylidene)-1,1-bisphosphonicacid (HEBPA) disodium salt, is highly hydrophilic likeother tetraacidic bisphosphonates and its oral bio-avail-ability is poor, only 3   7% of the drug dose. 4  Masking oneor more ionizable groups of etidronate, as shown belowwith derivatives 1   4 , by using the prodrug approachwould increase the lipophilicity of the molecule and leadto better absorption. Prodrug is a derivative, which shouldrelease the parent drug after chemical and/or enzymatichydrolysis. 5  Prepared partial ester derivatives 1   4  areused as model molecules to develop synthesis strategies of more complicated prodrug systems. Figure 1 The knowledge about preparation of etidronate partial es-ters (PEs) is rather limited since previously, based on CASsearch, only P,P   -dimethyl ester 2a  is documented. 6  The-oretically HEBPA PEs can be synthesised by severalroutes, but according to our earlier results from clodronatePEs, tetraester is the best starting material, if a gooddealkylation reagent is available. 7–9  A common strategy toprepare selectively methylene- (MBP) and (dichlorometh-ylene)bisphosphonate (Cl 2 MBP) partial esters is dealkyla-tion of tetraester with amines. 9  However, this approachcan not be used in the case of etidronate tetraesters be-cause of the rearrangement problem. Under basic condi-tions, rearrangement of HEBPA tetraesters to tetraalkylphosphono phosphate is observed and the same reactioncan occur if the temperature of the reaction mixture is toohigh (Scheme 1). 10   Scheme 1 An alternative strategy to prepare HEBPA PEs is identicalto MBP PEs if a selected mixed tetraester with the desirednumber of methyl groups is used as starting material,since methyl esters are selectively hydrolysed over otheralkyl groups, if trialkylsilylhalide is used as dealkylationreagent under controlled conditions. 7,8  However, the limi-tation of this method is the availability of required mixedHEBPA tetraesters and synthesis of partial methyl esters,e.g., 1a . This is the first systematic study for the preparation of dif-ferent types of HEBPA PEs including identification byNMR, and containing also the first crystal structure of etidronate PEs. Here, we report a general and selectivemethod for the synthesis of tri-, P , P   -di-, P , P -di- and mo-noesters from readily available tetraesters using selectedalkali metal salt or silane as dealkylating agent. A general synthesis strategy for HEBPA PEs 1   2  isshown in Scheme 2 and the results with 31 P chemicalshifts and 2  J  PP  coupling constants are listed in the Table.                                                                                                                                                 634 P. A. Turhanen et al. PAPER Synthesis 2000, No. 4, 633–637ISSN 0039-7881© ThiemeStuttgart·New York The starting tetraesters 6a   d , and 7a   c  were synthesisedas reported earlier from the selected monophosphorousspecies. 12 Reagents and conditions: i) KI ( 1a , b , d , e ), NaI ( 1c , f  ); ii) NaI ( 2a ),LiCl ( 2b , d ), LiI ( 2c , e ) Scheme 2 The above mentioned rearrangement, which occurs if pHor temperature is too high, is the major difficulty in pre-paring compounds 1   4 . Rearrangement was observed inwater solution even at pH 7.4 for tetramethyl ester 6a . 11 Based on the preparation of 2a , 6  alkali metal salts werefirst examined as potential dealkylation reagents. Howev-er, the rearrangement was still a problem if the tempera-ture was too high. Compound 6a  yielded approx. 8% of rearranged 1a  during reflux in acetone, but at approx.50   C, sideproducts were not observed. Also, ethanol andmethanol were tested as solvents because they dissolve al-kali metal salts better than acetone, but these solutions didnot lead to PEs. The major benefit for the developed routeis the easy removal of the products from the reaction mix-ture by filtration, and the purity of the products withoutfurther purification steps. Trials to find a selective reagent to prepare 1a  from 6a lead to quite surprising results with potassium iodide.When potassium iodide was used as dealkylating agent,only one methyl group was selectively removed from 6a and 1a  was the only product as verified by X-ray analysis(Figure 2), even if 4 equivalents of potassium iodide wasused. The same selectivity was found for NaI, but now theproduct was P,P   -dimethyl ester 2a , as Van Gelder et al. 6 have reported. Potassium iodide was also tested with tet-ramethyl esters of methylene- and dichloromethylene bis-phosphonic acids, but the reaction proceeded directly toP,P   -diester without any selectivity to triester stage. As aconclusion from the tests with other esters, lithium, sodi-um or potassium salts can only remove methyl or n-alkylgroups from tetra esters of HEBPA, and isopropyl andphenyl groups did not react under these conditions. Figure 2 Crystal structure of 1a Using the above method, it was only possible to preparetriesters and P , P   -diesters of HEBPA; another strategy tothe synthesis of P , P -diester 3  and monoesters 4a  b  had tobe developed. An obvious solution to prepare 3  is dealky-lation of the methyl groups with silylhalides, if required Table Prepared Partial Esters of HEBPA with 31 P NMR shifts, 2  J  PP  couplings and Yields a Yields were not optimised.Com-poundZ RR   P   P ′ 2  J  PP Yield a  (%) 1a K + MeMe28.4316.6634.488 1b K + EtEt26.2415.8134.649 1c Na + PhPh19.8412.6138.245 1d K + EtMe26.1417.1034.495 1e K + Pr i Me23.7517.4035.454 1f  Na + PhMe20.3515.9237.186 2a Na + MeMe21.05   94 2b Li + EtEt20.31   31 2c Li + PhPh17.46   55 2d Li + EtMe21.5920.0931.640 2e Li + PhMe20.9318.1534.275 3 H + Et   23.5919.6640.5100 4a 2H + , Li + Et   20.6519.9034.554 4b H + Hex   22.2021.1640.398  PAPER Selective Synthesis of (1-Hydroxyethylidene)-1,1-bisphosphonate Partial Esters 635 Synthesis 2000, No. 4, 633–637ISSN 0039-7881© ThiemeStuttgart·New York methyl containing mixed tetraester is available, since thereaction order of silylation depends on the ester as fol-lows: Me>1 o -alkyl>2 o -alkyl>>Ar, while the order of hy-drolysis is: Me 3 Si>>Bu t  >2 o -alkyl>>1 o -alkyl. 8  Mixedtetraesters of HEBPA are rather easy to prepare from cor-responding monophosphorous species, e.g., P , P -dimethyl P   , P   -dialkyl esters ( 7a   c ) were obtained fromHP(O)(OMe) 2  and MeCOP(O)(OR) 2 . Previously, this si-lylation method has been successfully applied for the me-thyl containing mixed Cl 2 MBP tetraesters. 7,8  Our targetwas more challenging: can the silyl reagent selectively re-move only methyl groups over other n-alkyls, e.g., ethylones? Based on the 31 P NMR results from the reactionmixture, a small but clear step between dealkylation of methyl and ethyl esters was observed under the developedconditions and only methyl groups were cleaved from de-rivative 7a  to give 3  with approx. 100% yield (Scheme 3). Reagents and conditions: i) NaI/ClSi(CH 3 ) 3 ; ii) MeOH; iii) LiI Scheme 3 Synthesis of monoesters 4a   b  was more difficult sincethe required trimethyl starting esters were in some casescomplicated to prepare because a mixed monophospho-rous species, HP(O)(OMe) 2  and MeCOP(O)(OR)(OMe)are required, and also during the bisphosphonate forma-tion some unexpected side-reactions were observed. 12 Based on the results for 2b   e , we treated 3  with lithiumiodide and surprisingly 4a  was the only product.To avoid the preparation of 4b  via mixed methyl ester 5 ,an alternative route to monoesters of HEBPA was devel-oped using trimethyl ester 1a  as starting material. It isknown that it is possible to esterify MBP compounds viasilver salts using alkyl halides as alkylating agents. 7  As anexample of this approach, mono hexyl ester 4b  was pre-pared by this method (Scheme 4). Preparation was startedfrom the potassium salt of 1a , which was first liberated tothe free acid using concentrated HCl and then convertedto the silver salt with silver carbonate. Addition of hexyliodide to the reaction mixture gave the intermediate mixedtetraester 5  with 83% yield. The methyl groups from 5 were selectively removed by trimethylsilyl iodide usingthe method developed earlier 7  to give 4b  with 81% yield(from 1a ). This developed alkylation method also offers anew way to prepare various mixed tetraesters of HEBPA. 1 H and 31 P NMR spectroscopy were used to follow theformation of partial esters of HEBPA. Disappearance of alkyl groups were easily detected from the 1 H NMR spec-tra and formation of unsymmetric partial esters from thesymmetric tetraesters were readily followed by 31 P NMRspectroscopy. In the case of symmetric PEs ( 2a   c ),   -car-bons (in 2b  also   -carbons) appears as virtual triplets (seeexperimental). Due to chirality of the P-C-P backbone inthe case of 1  and 3 , the   - and   -groups appear as unequalchemical shifts. On comparing the unsymmetric HEBPAPEs ( 1a   f  , 2d   e , 3  and 4a   b )   to Cl 2 MBP PEs, the mostsignificant differences in the coupling constants were 2  J  PP couplings, which were about two fold greater in HEBPAPEs than Cl 2 MBP PEs. 7,9a In conclusion, four selective methods for the synthesis of various partial esters of HEBPA have been described. Tri-esters and P , P   -diesters are prepared from n-alkyl tet-raesters using potassium, sodium and lithium salts asdealkylation reagents. P , P -dialkyl esters are preparedfrom mixed methyl containing tetraesters using silylha-lide as demethylation agent. Monoesters are synthesisedeither from P , P -diesters with LiI, or from trimethyl ester,which is alkylated via silver salt to the mixed tetraesterand demethylated using silylhalide. Alkali metal salts used in reactions were dried at 120     C for at least2 h before use. Solvents were high-purity reagent-grade materialsand used without further purification. Starting tetraalkyl esters of HEBPA were synthesised earlier. 12  CaCl 2 -tubes were used to pro-tect reactions from outside humidity. 1 H,  31 P   and 13 C NMR spectrawere recorded on Bruker AM 400 spectrometer operating at 400.1MHz, 162.0 MHz and 100.6 MHz, respectively; TSP or TMS (forCD 3 OD solutions) was used as an internal standard for 1 H and 13 Cmeasurements; 85% H 3 PO 4  as an external standard for 31 P measure-ments. 3  J  HH  couplings are indicated by the letter “  J  ” and all  J   valuesare given in Hz. Number of protons on each carbon were detectedfrom DEPT-135 experiment and are marked after each carbon usingletters d, t or q. n  J  CP  couplings were calculated from carbon spectraand are given in Hz. In the case of symmetric structure, only thesums of the  J  CP  couplings (    J  CP , the width of the virtual triplet) aregiven, since the satellite lines were unambiguous to detect from thebackground. Elemental analyses were determined for some repre-sentative compounds. The purity of products were determined from 1 H and 31 P NMR spectra and was    95%, unless stated otherwise.Yields were not optimised. Crystallographic data of 1a  were col-lected on a Nonius KappaCCD diffractometer. The structure wassolved and refined with full matrix least-squares analysis usingSHELXS-97 13  and SHELXL-97. 14   [1-(Dimethoxyphosphinyl)-1-hydroxyethyl]-1-phosphonic Acid Monomethyl Ester Monopotassium Salt (1a); Typical Proce-dure (1-Hydroxyethylidene)-1,1-bisphosphonic acid tetramethyl ester( 6a ) (3.65 g, 13.9 mmol) and KI (2.3 g, 13.9 mmol) were dissolvedin acetone (20 mL) and stirred in an oil bath at 50   C for 1 h. Theformed precipitate was filtered, washed twice with acetone andEt 2 O, and dried in vacuo to give 1a  (3.5 g, 88%) as a white powder. Reagents and conditions: i) concd HCl/acetone; ii) Ag 2 CO 3 ; iii)HexI; iv) NaI/ClSi(CH 3 ) 3 ; v) MeOH Scheme 4  636 P. A. Turhanen et al. PAPER Synthesis 2000, No. 4, 633–637ISSN 0039-7881© ThiemeStuttgart·New York 1 H NMR (D 2 O):   =3.86 (d, 3H, 3  J  HP =10.5), 3.85 (d, 3H, 3  J  HP =10.6), 3.68 (d, 3H, 3  J  HP =10.1), 1.61 (dd, 3H, 3  J  HP =14.5, 3  J  HP  =17.5). 13 C NMR (D 2 O):   =74.51 (dd, 1  J  CP =149.1, 1  J  CP  =153.3), 57.23(qd, 2  J  CP =7.6), 57.11 (qd, 2  J  CP =7.6), 55.89 (qd, 2  J  CP =6.6), 22.69(q). Anal. Calcd for C 5 H 13 KO 7 P 2 : C, 20.98; H, 4.58. Found: C, 21.21; H,4.55. Crystal and refinement data for C 10 H 26 K 2 O 14 P 4 , K2( 1a )2: colourlesscrystals were obtained by slow evaporation of MeOH/EtOH (5:1)solution at r.t. M=572.39, monoclinic, space group C  2/  c ,a=28.4122(5), b=7.7524(1), c=25.1112(5) Å, U=4821.71(14)Å 3 , T=120K, Z=8,   =0.71073 Å,    (Mo-K   )=0.718 mm   1 ,8869 reflections collected, 4629 unique (R int =0.0106). Final  R 1=0.0247 [I > 2   (I)] and wR 2=0.0668 (all data). [1-(Diethoxyphosphinyl)-1-hydroxyethyl]-1-phosphonic Acid Monoethyl Ester Monopotassium Salt (1b) Prepared from 6b  (415 mg, 1.30 mmol), KI (216 mg, 1.30 mmol)and acetone (5 mL), reaction time was 16 h. Compound 1b  (210 mg,49%) was obtained as a white powder. 1 H NMR (D 2 O):   =4.237 (m, 2H), 4.234 (m, 2H), 4.04 (m, 2H),1.60 (dd, 3H, 3  J  HP =14.5, 3  J  HP  =17.4), 1.35 (t, 6H,  J  =7.1), 1.27 (t,3H,  J  =7.1). 13 C NMR (D 2 O):   =74.22 (dd, 1  J  CP =148.7, 1  J  CP  =153.3), 67.24(td, 2  J  CP =7.6), 67.22 (td, 2  J  CP =7.7), 65.19 (td, 2  J  CP =6.7), 22.63(q), 19.15 (qd, 3  J  CP =5.3), 18.63 (qd, 3  J  CP =5.2). [1-(Diphenoxyphosphinyl)-1-hydroxyethyl]-1-phosphonic Acid Monophenyl Ester Monosodium Salt (1c) Prepared from 6c  (550 mg, 1.23 mmol), NaI (184 mg, 1.23 mmol)and acetone (6 mL), reaction time was 3 h. The precipitate waswashed with Et 2 O/acetone (1:2) to give 1c  (250 mg, 45%) as a whitepowder. 1 H NMR (D 2 O):   =7.38   7.33 (m, 6H), 7.27   7.14 (m, 9H), 1.98(dd, 3H, 3  J  HP =14.9, 3 J HP  =18.8). 13 C NMR (D 2 O):   =154.49 (d, 2  J  CP =9.0), 152.62 (d, 2  J  CP =11.2),152.59 (d, 2  J  CP =11.1), 132.83 (d), 132.42 (d), 128.70 (d), 126.89(d), 123.76 (dd, 3  J  CP =3.7), 74.42 (dd, 1  J  CP =153.9, 1  J  CP  =155.4),22.77 (q). [1-(Diethoxyphosphinyl)-1-hydroxyethyl]-1-phosphonic Acid Monomethyl Ester Monopotassium Salt (1d) Prepared from 7a (250 mg, 0.86 mmol), KI (143 mg, 0.86 mmol)and acetone (5 mL), reaction time was 48 h. Compound 1d  (256 mg,95%) was obtained as a white powder. 1 H NMR (D 2 O):   =4.23 (m, 4H), 3.68 (d, 3H, 3  J  HP =10.1), 1.60(dd, 3H, 3  J  HP =14.6, 3  J  HP  =17.4), 1.35 (t, 6H,  J  =7.1). 13 C NMR (D 2 O):   =74.36 (dd, 1  J  CP =148.8, 1  J  CP  =153.9), 67.34(td, 2  J  CP =7.4), 55.79 (qd, 2  J  CP =5.7), 22.69 (q), 18.64 (qd, 3  J  CP =5.2). {1-[Bis(1-methylethoxy)phosphinyl]-1-hydroxyethyl}-1-phos-phonic Acid Monomethyl Ester Monopotassium Salt (1e) Prepared from 7b  (162 mg, 0.51 mmol), KI (81 mg, 0.49 mmol) andacetone (4 mL), reaction time was 25 h. Compound 1e  (90 mg,54%) was obtained as a white powder. 1 H NMR (D 2 O):   =4.77 (m,2H), 3.67 (d, 3H, 3  J  HP =10.1), 1.58(dd, 3H, 3  J  HP =14.5, 3 J HP  =17.3), 1.37 (m, 12H). 13 C NMR (D 2 O):   =76.42 (dm, 2  J  CP =7.8), 74.21 (dd, 1  J  CP =148.4, 1  J  CP  =156.8), 55.66 (qm), 26.30 (q), 25.89 (qm), 22.72 (q). [1-(Diphenoxyphosphinyl)-1-hydroxyethyl]-1-phosphonic Acid Monomethyl Ester Monosodium Salt (1f) Prepared from 7c  (212 mg, 0.55 mmol), NaI (165 mg, 1.10 mmol)and acetone (4 mL), reaction time was 25 h. Compound 1f   (185 mg,86%) was obtained as a white powder. 1 H NMR (D 2 O):   =7.43   7.38 (m, 4H), 7.31   7.26 (m, 2H), 7.19   7.15 (m, 4H), 3.75 (d, 3H, 3  J  HP =10.2), 1.88 (dd, 3H, 3  J  HP =14.4, 3  J  HP  =18.9). 13 C NMR (D 2 O):   =152.60 (d, 2  J  CP =11.1), 132.87 (d), 128.74 (d),123.80 (dd, 3  J  CP =3.3), 74.57 (dd, 1  J  CP =149.1, 1  J  CP  =153.9), 56.08(qd, 2  J  CP =3.7), 22.80 (q).Anal. Calcd for C 15 H 17 NaO 7 P 2 : C, 45.70; H, 4.35. Found: C, 46.26;H, 4.36. (1-Hydroxyethylidene)-1,1-bisphosphonic Acid  P ,  P  -Dimethyl Ester Disodium Salt (2a) Prepared from 6a  (7.0 g, 0.027 mol), NaI (8.1 g, 0.054 mol) and ac-etone (30 mL), reaction time was 30 h. Compound 2a  (7.0 g, 94%)was obtained as a white powder. 1 H NMR (D 2 O):   =3.67   3.64 (m, 6H), 1.53 (t, 3H,  3  J  HP =15.1). 13 C NMR (D 2 O):   =75.16 (t, 1  J  CP =146.8), 55.45 (qt,    J  CP =6.6),23.43 (q). (1-Hydroxyethylidene)-1,1-bisphosphonic Acid  P ,  P  -Diethyl Es-ter Dilithium Salt (2b) Prepared from 6b  (1.0 g, 3.1 mmol), LiCl (0.27 g, 6.4 mmol) andacetone (13 mL), reaction time was 72 h. The precipitate waswashed with EtOH to give 2b  (270 mg, 31%) as a white powder. 1 H NMR (D 2 O):   =4.05 (m, 4H), 1.53 (t, 3H, 3  J  HP =15.1), 1.26 (t,6H,  J  =7.0). 13 C NMR (D 2 O):   =74.97 (t, 1  J  CP =144.9), 65.19 (tt,    J  CP =6.5),22.90 (q), 19.23 (qt,      J  CP =5.3). Anal. Calcd for C 6 H 14 Li 2 O 7 P 2 : C, 26.30; H, 5.15. Found: C, 26.12;H, 5.39. (1-Hydroxyethylidene)-1,1-bisphosphonic Acid  P ,  P  -Diphenyl Ester Dilithium Salt (2c) Prepared from (1-hydroxyethylidene)-1,1-bisphosphonic acid P,P  -methyl phenyl ester (49 mg, 0.13 mmol), LiI (33 mg, 0.25 mmol)and acetone (3 mL), reaction time was 1 h. Compound 2c  (26 mg,55%) was obtained as a white powder. 1 H NMR (D 2 O):   =7.40   7.35 (m, 4H), 7.27   7.24 (m, 4H), 7.19   7.15 (m, 2H), 1.75 (t, 3H, 3  J  HP =15.6). 13 C NMR (D 2 O):   =154.76 (t,    J  CP =8.8), 132.35 (d), 126.67 (d),124.08 (d), 74.96 (t, 1  J  CP =150.0), 23.12 (q). (1-Hydroxyethylidene)-1,1-bisphosphonic Acid  P -Monoethyl-  P  -monomethyl Ester Dilithium Salt (2d) Prepared from 7a (2.5 g, 8.6 mmol), LiCl (728 mg, 17.2 mmol) andacetone (20 mL), reaction time was 72 h. The precipitate waswashed with MeOH/Et 2 O (4:1) to give 2d  (890 mg, 40%) as a whitepowder. 1 H NMR (D 2 O):   =4.05 (m, 2H), 3.67 (d, 3H, 3  J  HP =9.9), 1.54 (t,3H, 3  J  HP =15.1), 1.27 (t, 3H,  J  =7.1). 13 C NMR (D 2 O):   =75.03 (t, 1  J  CP =145.5), 65.18 (td, 2  J  CP =6.3),55.66 (qd, 2  J  CP =6.7), 23.02 (q), 19.21 (qd, 3  J  CP =3.6). (1-Hydroxyethylidene)-1,1-bisphosphonic Acid  P -Monophenyl-  P  -monomethyl Ester Dilithium Salt (2e) Prepared from 6d  (435 mg, 1.4 mmol), LiI (375 mg, 2.8 mmol) andacetone (6mL), reaction time was 24 h. Compound 2e  (308 mg,75%) was obtained as a white powder. 1 H NMR (D 2 O):   =7.41   7.36 (m, 2H), 7.26   7.16 (m, 3H), 3.70(d, 3H, 3  J  HP =10.0), 1.65 (t, 3H, 3  J  HP =15.4).  PAPER Selective Synthesis of (1-Hydroxyethylidene)-1,1-bisphosphonate Partial Esters 637 Synthesis 2000, No. 4, 633–637ISSN 0039-7881© ThiemeStuttgart·New York 13 C NMR (D 2 O):   =154.65 (d, 2  J  CP =9.0), 132.36 (d), 126.75 (d),123.94 (dd, 3  J  CP =3.9), 74.93 (dd, 1  J  CP =145.6, 1  J  CP =148.9), 55.85(qd, 2  J  CP =6.6), 22.99 (q). [1-(Diethoxyphosphinyl)-1-hydroxyethyl]-1-phosphonic Acid (3) Compound 7a (353 mg, 1.2 mmol), trimethylsilyl chloride (317 mg,2.9 mmol) and NaI (365 mg, 2.4 mmol) were dissolved in MeCN(8 mL) and mixture was stirred at r.t. for 24 h. After filtration, thefiltrate was evaporated to dryness, MeOH (5 mL) was added andstirring was continued for 2 h. The mixture was evaporated in vacuoto give 3  (318 mg, 100%) as a slightly yellow solid. 1 H NMR (CD 3 OD):   =4.26   4.18 (m, 4H), 1.64 (t, 3H, 3  J  HP =16.2), 1.342 (t, 3H,  J  =7.1), 1.338 (t, 3H,  J  =7.0). 13 C NMR (CD 3 OD):   =71.91 (t, 1  J  CP =156.0), 64.93 (td, 2  J  CP =7.3), 64.78 (td, 2  J  CP =7.6), 20.64 (q), 16.82 (qd, 3  J  CP =5.4),16.79 (qd, 3  J  CP =5.4). [1-(Dihydroxyphosphinyl)-1-hydroxyethyl]-1-phosphonic Acid Monoethyl Ester Monolithium Salt (4a) Prepared similarly to 1a , from 3 (92 mg, 0.35 mmol), LiI (42 mg,0.31 mmol) and acetone (3 mL). Compound 4a  (41 mg, 54%) wasobtained as a white powder. 1 H NMR (D 2 O):   =4.06 (m, 2H), 1.55 (t, 3H, 3  J  HP =15.4), 1.26 (t,3H,  J  =7.1). 13 C NMR (D 2 O):   =74.32 (dd, 1  J  CP =142.6, 1  J  CP  =145.4), 65.53(td, 2  J  CP =6.6), 22.65 (q), 19.27 (qd, 3  J  CP =5.0). [1-(Dihydroxyphosphinyl)-1-hydroxyethyl]-1-phosphonic Acid Monohexyl Ester (4b) Prepared similarly to 3 , from 5  (188 mg, 0.57 mmol), trimethylsilylchloride (189 mg, 1.74 mmol) and NaI (249 mg, 1.66 mmol). Com-pound 4b  (160 mg, 98%) was obtained as a slightly yellow solidwith 92% purity. 1 H NMR (CD 3 OD):   =4.14 (m, 2H), 1.68 (m, 2H), 1.64 (t, 3H, 3  J  HP =16.0), 1.41 (m, 2H), 1.32 (m, 4H), 0.91 (m, 3H). 13 C NMR (CD 3 OD):   =71.71 (dd, 1  J  CP =152.7, 1  J  CP  =153.6),68.46 (td, 2  J  CP =7.3), 32.65 (t), 31.88 (td, 3  J  CP =5.5), 26.37 (t),23.68 (t), 20.58 (q), 14.40 (q). [1-(Dimethoxyphosphinyl)-1-hydroxyethyl]-1-phosphonic Acid Methyl Hexyl Ester (5) Compound 1a  (208 mg, 0.73 mmol) was suspended in acetone(8 mL), concd HCl (250   L) was added and the mixture was stirredfor 10 min at r.t. The mixture was filtered and the filtrate was evap-orated to dryness in vacuo. The residue was dissolved in acetone(5 mL), Ag 2 CO 3  (100 mg, 0.36 mmol) and hexyl iodide (154 mg,0.73 mmol) were added and mixture was stirred in the dark, in anoil bath at 60   C for 32 h. The mixture was filtered and filtrate wasevaporated to dryness in vacuo to give 5  (colourless oil, 200 mg,83%) as a pair of diastereomers (ratio 50:50). 1 H NMR (CD 3 OD):   =4.16 (m, 2H), 3.87   3.84 (m, 9H), 1.69 (m,2H), 1.67 (t, 3H, 3  J  HP =16.6), 1.40 (m, 2H), 1.33 (m, 4H), 0.92 (m,3H). 31 P NMR (CD 3 OD):   =23.84 (d, 2  J  PP =44.0), 22.33 (d) and 23.83(d, 2  J  PP =42.9), 22.49 (d). 13 C NMR (CD 3 OD):   =72.93 (t, 1  J  CP =160.3), 72.91 (t, 1  J  CP =160.6), 69.11 (td, 2  J  CP =10.8), 69.04 (td, 2  J  CP =10.9), 55.11   54.88 (m), 32.48 (t), 31.67   31.59 (m), 26.25 (t), 23.62 (t), 20.77   20.71 (m), 14.36 (q). Acknowledgement The elemental analyses were performed at the University of Joen-suu (Finland). We would like to thank Mrs. Maritta Salminkoski fortechnical assistance. References  (1)Fleich, H. Bisphosphonates in Bone Disease: From the Laboratory to the Patient; The Parthenon Publishing Group Inc.: New York, 1995. (2)Fleich, H.  Drugs   1991 , 42 , 919. (3)Papapoulos, S. E.; Landman, J. O.; Bijvoet, O. L. M.; Löwik, C. W. G. M.; Valkema, R.; Pauwels, E. K. J.; Vermeij, P.  Bone   1992 , 13 , S41.Yates, A. J.; Rodan, G. A.  DDT    1998 , 3 , 69.Socrates, E.; Papapoulos, M. D.  Am. J. Med.   1993 , 95 , 48S.Giannini, S.; D'Angelo, A.; Sartori, L.; Passeri, G.; Garbonare, L. D.; Crebaldi, C. Obstet. Gynecol.   1996 , 88  , 431. (4)Recker, R. R.; Saville, P. D. Toxicol. Appl. Pharmacol.   1973 , 24 , 580. (5)Sinkkula, A. A.; Yalkowsky, S. H.  J. Pharm. Sci.   1975 , 64 , 181.Stella, V. J.; Charman, W. N. A.; Naringregar, V. H.  Drugs   1985 , 29 , 455.Balant, L. P.; Doelker, E.; Buri, P.  Eur. J. Drug Metab. Pharmacokin. 1990 , 15 , 143. (6)Van Gelder, J. M.; Breuer, E.; Ornoy, A.; Schlossman, A.; Patlas, N.; Golomb, G.  Bone   1995 , 16  , 511. (7)Ahlmark, M. J.; Vepsäläinen, J. J. Tetrahedron   1997 , 53 , 16153. (8)Vepsäläinen, J. J.; Nupponen, H.; Pohjala, E. Tetrahedron    Lett.   1993 , 34 , 4551. (9)a) Vepsäläinen, J. J.; Kivikoski, J.; Ahlgren, M.; Nupponen, H. E.; Pohjala, E. K. Tetrahedron   1995 , 51 , 6805.b) Vepsäläinen, J. J.; Nupponen, H.; Pohjala, E. Tetrahedron    Lett.   1996 , 37  , 3533.(10)Fitch, S. J.; Moedritzer, K.  J. Am. Chem. Soc.   1962 , 84 , 1876.Nicholson, D. A.; Vaughn, H.  J. Org. Chem.   1971 , 36  , 3843.Ruel, R.; Bouvier, J.-P.; Young, R. N.  J. Org. Chem.   1995 , 60 , 5209.(11)Niemi, R.; Turhanen, P; Vepsäläinen, J.; Taipale, H.; Järvinen, T.  Eur. J. Pharm. Sci.   2000 , 11 , 173.(12)Turhanen, P. A.; Ahlgren, M. J.; Järvinen, T.; Vepsäläinen, J.  J. Phosphorus, Sulfur and Silicon,  accepted.(13)Sheldrick, G. M. SHELXS-97, Program for Crystal Structure Determination, University of Göttingen, Germany, 1997.(14)Sheldrick, G. M. SHELXL-97, Program for Crystal Structure Determination, University of Göttingen, Germany, 1997.Article Identifier:1437-210X,E;2001,0,04,0633,0637,ftx,en;P07400SS.pdf 
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