A practical synthesis of alendronate sodium through counterattack reaction

Article abstract of DOI:10.1055/s-0031-1290947

An efficient synthesis of alendronate sodium, an osteoporosis drug, has been developed through counterattack reaction' involving treatment of the respective acyl phosphonate with (MeO) and TMSBr followed by deblocking with aqueous HCl.

Full text of DOI:10.1055/s-0031-1290947

1556▌
SHORT PAPER
short paper
A Practical Synthesis of Alendronate Sodium through Counterattack Reaction
Synthesis of Alendronate Sodium
Masahiko Seki*
Mitsubishi Tanabe Pharma Corporation, 2-6-18, Kitahama, Chuo-ku, Osaka 541-8505, Japan
E-mail: seki.masahiko@mm.mt-pharma.co.jp
Received: 13.02.2012; Accepted after revision: 14.03.2012
reported. However, they have not been applied to the syn-
Abstract: An efficient synthesis of alendronate sodium, an osteo-
thesis of 2 and moreover the phosphites are too expensive
porosis drug, has been developed through ‘counterattack reaction’
to be used in the commercial production of 2.
involving treatment of the respective acyl phosphonate with
(MeO)3P and TMSBr followed by deblocking with aqueous HCl.
O
(i) PCl3, H3PO3
Key words: drugs, green chemistry, nucleophilic addition, elimina-
tion, phosphorus, protecting groups
H2N
2
OH
(ii) H2O
Scheme 1 A conventional synthesis of 1-hydroxy-1,1-bisphosphon-
ic acid derivatives
1-Hydroxy-1,1-bisphosphonic acid derivatives 1 have re-
ceived considerable attention as efficient osteoporosis
drugs to restore the bone balance, that is, to prevent abnor-
mal calcification and excessive bone destruction.1 Among
them, (4-amino-1-hydroxybutylidene)bisphosphonic acid
monosodium salt (alendronate sodium, 2) (Figure 1) was
launched first by Merck in 1996 as a therapeutic agent and
represents one of the most efficient drugs of this series be-
cause of the high efficacy and long duration period.1b
As a part of our program directed towards the develop-
ment of practical synthesis of drugs and related com-
pounds,5 an efficient synthesis of alendronate sodium (2)
has been explored.
The ‘counterattack reaction’, where once the liberated
leaving group participates again in the reaction, is effi-
cient in terms of atom economy and a number of practical
syntheses classified in the category have been reported.6
With the concept in mind, the author came up with an idea
for the synthesis of 2 (Scheme 2). If acyl phosphonate 4
readily obtained7 from the corresponding carboxylic acid
38 is treated with TMSBr and (R2O)3P, O-silylation and
addition of (R2O)3P to the activated carbonyl group fol-
lowed by ‘counterattack reaction’ of once liberated Br– to
R2 group would take place to form 1-trimethylsiloxy-1,1-
bisphosphonate 5. The key O-silylation of the carbonyl
oxygen in 7 is supposed to be driven by high affinity of
silicon atom to oxygen atom.9 Removal of the protecting
groups in 5 by acid hydrolysis followed by formation of
sodium salt would provide the target compound 2.
OH
O
H2N
OH
O
P
ONa
P
OH
OH
P
R
OH
P
OH
OH
O
O
OH
OH
•3H2O
alendronate sodium (2)
1
Figure 1 1-Hydroxy-1,1-bisphosphonic acid derivatives 1 and alen-
dronate sodium (2)
The literature precedents for the preparation of 2 had em-
ployed γ-aminobutyric acid as the starting material by al-
2
lowing it to react with PCl3 in H3PO3 (Scheme 1).
Although it consists of very simple combination of re-
agents and procedure, they have fundamental drawbacks
of poor yields and especially lack of easy operation: inef-
fective stirring of the reaction mixture due to the forma-
tion of sticky syrup during the reaction. These
disadvantages have prohibited facile access to this impor-
tant class of drug, especially in large scale. To address the
challenge, Merck reported the addition of MeSO3H,3a and
others employed sulfolane,3b anisole,3c or p-cresol3d as a
co-solvent, which gave moderate to high yields (49–
90%). However, we still encountered difficulty in han-
dling the reaction mixture. As an alternative approach, the
use of tris(4-methoxybenzyl)phosphite4a and tris(trimeth-
ylsilyl)phosphite4b as the phosphonating reagent has been
counterattack
TMS
O+
Br–
O
O
OR2
OR2
(R2O)3P
TMSBr
R1
OR2
OR2
P
R1
R1
P
OH
O
3
••
O
R2
P
OR2
O
4
OR2
R1 = AcNH(CH2)3
OR2
OR2
OTMS
OR2
OR2
O
(i) H+
P
R1
2
– R2Br
(ii) NaOH
P
O
5
Scheme 2 Synthesis of alendronate sodium (2) through counterat-
tack reaction
SYNTHESIS 2012, 44, 1556–1558
Advanced online publication: 19.04.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1290947; Art ID: SS-2012-F0112-OP
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Synthesis of Alendronate Sodium
1557
According to the strategy described above, compound 3 In conclusion, a practical synthesis of alendronate sodium
was first converted to its acid chloride by treatment with (2) was worked out via counterattack reaction as the key
oxalyl chloride, which was reacted with (EtO)3P to give step. Although it involves four operations, the intermedi-
acyl phosphonate 4 (R2: Et). Without isolation, 4 was ates were not isolated (telescoping) and the reactions are
treated with (EtO)3P and TMSBr to afford 1-trimethylsi- conducted under easy-to-perform mild conditions, which
loxy-1,1-bisphosphonate 5, which was subjected to acid might offer considerable advantage over the previous
hydrolysis as shown in Table 1. Neither the use of aque- method.
ous HCl nor MeSO3H (reflux, 17 h) provided any desired
product 6 (Table 1, entries 1 and 2). More nucleophilic
Melting points are uncorrected. All solvents and reagents were used
48% aqueous HBr was then tested (reflux, 17 h). By this
treatment, 6 was obtained, albeit in poor yield (22%, Ta-
ble 1, entry 3). To improve the yield, the ester group of the
phosphonic acid was switched from ethyl ester to more la-
bile methyl ester. For valeric acid 7 as a model substrate,
the same reaction sequence with (MeO)3P in place of
(EtO)3P was examined. Gratifyingly, the desired product
8 was obtained quantitatively via deblocking with aque-
ous HCl (Table 1, entry 4). This protocol was applied to
the synthesis of alendronate sodium (2) using 3 as the sub-
strate. Following the same reaction sequence employing
(MeO)3P, the desired compound was obtained in 70%
yield as monosodium salt trihydrate 2 (alendronate sodi-
um) by adjusting the pH value of the final aqueous reac-
tion mixture with aqueous 1 M NaOH (pH 4.3) and
crystallization (Table 1, entry 5). It should be noted that in
the procedure the reaction was carried out without any
scale up issues in operation, such as effective stirring. The
target compound 2 was obtained in more than 25 gram
scale without any difficulty. As an alternative substrate N-
phthaloyl-γ-aminobutyric acid (9) was tested. However,
the yield was poor possibly because of the difficulty in re-
moving the phthaloyl group under acidic conditions.
as received.
(4-Amino-1-hydroxybutylidene)bisphosphonic Acid Monosodi-
um Salt Trihydrate (Alendronate Sodium, 2)
To a mixture of N-acetyl-γ-butyric acid (3; 20 g, 138 mmol) in
CH2Cl2 (100 mL) was added oxalyl chloride (22.5 mL, 276 mmol)
at a temperature lower than 10 °C. After the addition of DMF (1
drop), the mixture was stirred at 25 °C for 2 h, and then the mixture
was evaporated. To the residue dissolved in CHCl3 (100 mL) was
added (MeO)3P (17.1 g, 138 mmol) at –10 to 0 °C and the mixture
was stirred at 25 °C for 1 h. Then, (MeO)3P (17.1 g, 138 mmol) and
TMSBr (18 mL, 138 mmol) were added at –10 to 0 °C. After stir-
ring the mixture at 25 °C for 1 h, the mixture was evaporated. To the
residue was added aq 6 M HCl (160 mL) and refluxed for 17 h. The
mixture was evaporated and the residue was dissolved in H2O (100
mL) and pH of the mixture was adjusted to 4.3 with aq 1 M NaOH.
The resulting solids were filtered and the filtrate was stirred at 25 °C
for 17 h. The solids formed were collected and washed with H2O
(10 mL) and EtOH (10 mL) to give the crude product (24.77 g).
From the mother liquor was obtained 12.08 g of crude 2. The solids
were combined (36.85 g) and dissolved in H2O (100 mL) and stirred
at 25 °C for 17 h. After adding EtOH (100 mL) to the mixture, the
solids formed were collected, washed with H2O (10 mL) and EtOH
(10 mL), filtered, and dried to give 2 (26.84 g, 70%) as colorless
crystals; mp 261–264 °C (Lit.3a mp 257–262.5 °C).
IR (Nujol): 1649 cm–1.
1H NMR (400 MHz, D2O): δ = 3.0–3.1 (m, 2 H), 1.95–2.10 (m, 4
H).
Table 1 Synthesis of 1-Hydroxy-1,1-bisphosphonic Acid Deriva-
MS: m/z = 248 [M – Na – 3H2O]+.
tives through Counterattack Reaction
Anal. Calcd for C4H12NNaO7P2·3H2O: C, 14.78; H, 5.58; N, 4.31.
Found: C, 14.50; H, 5.62; N, 4.21.
(i) (COCl)2, DMF (cat.), CH2Cl2,
r.t., 3 h
R1
OH
O
(ii) (R2O)3P, .r.t, 1 h
O
P
OH
(iii) (R2O)3P, TMSBr, r.t., 1 h
R1
OH
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(iv) method A: aq 6 M HCl, reflux, 17 h
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P
OH
3 R1 = AcNH
7 R1 = Me
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O
OH
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M. Seki
SHORT PAPER
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© Georg Thieme Verlag Stuttgart · New York