Phosphine Oxides from a Medicinal Chemist's Perspective: Physicochemical and in Vitro Parameters Relevant for Drug Discovery

Article abstract of DOI:10.1021/acs.jmedchem.0c00407

Phosphine oxides and related phosphorus-containing functional groups such as phosphonates and phosphinates are established structural motifs that are still underrepresented in today's drug discovery projects, and only few examples can be found among approved drugs. In this account, the physicochemical and in vitro properties of phosphine oxides and related phosphorus-containing functional groups are reported and compared to more commonly used structural motifs in drug discovery. Furthermore, the impact on the physicochemical properties of a real drug scaffold is exemplified by a series of phosphorus-containing analogs of imatinib. We demonstrate that phosphine oxides are highly polar functional groups leading to high solubility and metabolic stability but occasionally at the cost of reduced permeability. We conclude that phosphine oxides and related phosphorus-containing functional groups are valuable polar structural elements and that they deserve to be considered as a routine part of every medicinal chemist's toolbox.

Full text of DOI:10.1021/acs.jmedchem.0c00407

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Article
Phosphine Oxides from a Medicinal Chemist’s Perspective:
Physicochemical and in vitro Parameters Relevant for Drug Discovery
Peter Finkbeiner, Joerg P. Hehn, and Christian Gnamm
J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.0c00407 • Publication Date (Web): 01 Jun 2020
Downloaded from pubs.acs.org on June 1, 2020
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Phosphine Oxides from a Medicinal Chemist’s
Perspective: Physicochemical and in vitro
Parameters Relevant for Drug Discovery
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Peter Finkbeiner,§,† Jörg P. Hehn and Christian Gnamm *
§
§
§
Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397
Biberach an
der Riß, Germany
KEYWORDS
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Phosphine Oxides, Phosphonates, Phosphinates, Polarity, Solubility, Metabolic Stability,
Permeability.
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ABSTRACT
Phosphine oxides and related phosphorus-containing functional groups such as
phosphonates and phosphinates are established structural motifs that are, still,
underrepresented in today’s drug discovery projects, and only few examples can be found
amongst approved drugs. In this account, the physicochemical and in vitro properties of
phosphine oxides and related phosphorus-containing functional groups are reported and
compared to more commonly used structural motifs in drug discovery. Furthermore, the
impact on the physicochemical properties of a real drug scaffold is exemplified by a series
of phosphorus-containing analogs of imatinib. We demonstrate that phosphine oxides are
highly polar functional groups leading to high solubility and metabolic stability, however,
occasionally at the cost of reduced permeability. We conclude that phosphine oxides and
related phosphorus-containing functional groups are valuable polar structural elements and
that they deserve to be considered as routine part of every medicinal chemist’s toolbox.
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1. INTRODUCTION
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Organophosphorus compounds have been investigated for applications in agricultural,1
2
3
veterinary, and medicinal applications for decades, and a considerable number of
phosphorus-containing drugs have achieved commercial success.4,5 The majority of
these approved phosphorus-containing pharmaceuticals contain a phosphate, a
phosphoramide or a phosphonate group, while phosphines, phosphinates and phosphine
oxides are rare. Among the successful examples of organophosphorus drug research are
the phosphorodiamidate based anti-cancer drugs cyclophosphamide (1) and ifosfamide
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(2), as well as the phosphonamidate and phosphonate containing reverse transcriptase
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inhibitors tenofovir alafenamide (3) and adefovir dipivoxil (4) to fight infectious diseases
like HIV and hepatitis B, respectively (Figure 1). Several so-called bisphosphonates
containing a phosphonic acid motif such as etidronate (5) are used for the treatment of
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osteoporosis, and the natural product fosfomycin (6) is a broad spectrum antibiotic. The
ACE inhibitor fosinopril (7) is so far the only approved phosphinate based drug on the
market and used for the treatment of hypertension.11
A major obstacle associated with the use of acidic phosphorus-containing functional
groups such as phosphates, phosphonates and phosphinates in drug discovery is their
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occurrence as charged species at physiological pH, which often leads to low cell permeability and
poor oral bioavailability.12,13 In most orally administered phosphate-containing drugs the
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phosphate constitutes a solubility-enhancing prodrug and is not part of the pharmacophore of the
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active principle itself, as for example in case of antiretroviral protease inhibitor fosamprenavir
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17
(
8), SYK inhibitor fostamatinib (9) and fospropofol (10), a widely used anesthetic (Figure 1).
Similarly, many of the drugs containing a phosphonate or phosphinate are employed as prodrugs
as exemplified e.g. by the phosphonate and phosphinate esters in adefovir dipivoxil (4) and
fosinopril (7), respectively, or the phosphonamidate in tenofovir alafenamide (3). Also Gilead’s
remdesivir (11),18 a phase III antiviral drug originally developed for the treatment of ebola virus
that is currently tested in clinical trials for efficacy against Covid-19,19 constitutes a
phosphoramidate prodrug.
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NH2
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Ph
O
P
O
O
O
O
P
N
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N
P
Cl
Cl
O
HN
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Ifosfamide (2)
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N
NH2
O
t-Bu
OH
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N
N
Etidronate (5)
O
P
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Ph
N
P
t-Bu
O
O
N
O
O
OH
O
O
O
P
O
OH
t-Bu
Adefovir dipivoxil (4)
Fosfomycin (6)
Fosinopril (7)
O OH
P
F
N
O
OH
O
O O Na+
-
O
S
HN
O
N
O
NH
-
+
N
P
O
O Na
+
O
O
P
-
O-Na+
O Na
N
O
O
O
NH
O
N
O
O
O
NH2
Fosamprenavir (8)
Fostamatinib (9)
Fospropofol (10)
Ph
O O
P
NH2
O
O
N
O
N
N
H
CN
N
O
HO
Remdesivir (11)
OH
Figure 1: Selected examples of phosphorus-containing drugs.
In light of all the difficulties associated with the use of charged phosphorus-containing
functionalities it is surprising that their uncharged counterparts, namely phosphine oxides but also
O-substituted phosphonates and phosphinates, have been largely neglected in medicinal chemistry.
Some recent examples for the application of phosphine oxides in medicinal chemistry are shown
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in Figure 2, including C-C chemokine receptor 2 (CCR2) antagonist 12, progesterone receptor
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21
(
PR) antagonist 13, potassium voltage-gated channel subfamily A member 5 (Kv1.5) inhibitor
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4, epithelial sodium channel (ENaC) inhibitor 15, methionine aminopeptidase 2 (MetAP2)
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inhibitor 16, human calpain I inhibitor 17, and histone deacetylase 1 (HDAC1) inhibitor 18.
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CCR2 antagonist 12
Progesterone receptor antagonist 13
Kv1.5 inhibitor 14
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P
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Cl
NH2
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H
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N
HN
NH2
O
N+
Ph
Ph
O
-
P
CF CO
3
2
O
ENaC inhibitor 15
MetAP2 inhibitor 16
Cl
S
Bn HN
O
O
O
NH
P
O O
O
P
N
O
H
Cl
NH2
Calpain I inhibitor 17
HDAC1 inhibitor 18
Figure 2: Recent examples for the application of phosphine oxides in medicinal chemistry.
It has been only recently that ridaforolimus (19), a dimethylphosphinic ester containing inhibitor
of mammalian target of rapamycin (mTOR), progressed into Phase III clinical studies for the
27
treatment of sarcoma, and that the anaplastic lymphoma kinase (ALK) inhibitor brigatinib (20)
became the very first drug containing a phosphine oxide motif that was approved by the U.S. FDA
for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) (Figure 3).28
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O
O
MeN
OH
P
OMe
Ridaforolimus (19)
Brigatinib (20)
Figure 3: Ridaforolimus (19) and brigatinib (20) as examples for investigational or
approved drugs with a non-charged phosphorus-containing functional group.
The reasons for the rare appearance of phosphine oxides in drug discovery are not obvious, since
they are chemically stable and their synthesis is well precedented. Additionally, they offer the
unique feature of a very strong H-bond acceptor attached to a tetrahedral center with three potential
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vectors for derivatization. Surprisingly, only few reports on the physicochemical properties and
in vitro parameters of phosphine oxides and related phosphorus-containing functional groups are
available today. 26,28a,30
With the aim to provide a better understanding of phosphorus-containing functional groups from
a medicinal chemist’s perspective, we herein describe the design and synthesis of a larger set of
phosphorus-containing tool compounds. In addition, we report selected physicochemical and in
vitro parameters and rank the phosphorus-containing functional groups among related
bioisosteres.31 Furthermore, the effects of phosphorus-containing functional groups on the
properties of analogs of the approved tyrosine kinase inhibitor imatinib (36) are presented.32
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2
. RESULTS AND DISCUSSION
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.1 Design of tool compounds 21-35 and drug-like analogs 37-45 derived from imatinib.
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In order to measure the unbiased effect of the envisaged phosphorus-containing
functional groups (Figure 4a), a 4-(trifluoromethyl)phenyl group was chosen as chemically
robust and simple platform. Initially, acyclic phosphine oxides 21a-c with increasingly
sized aliphatic residues as well as cyclic phosphine oxides 22a-g comprising different ring
sizes and heteroatoms were designed. In addition, a variety of phospinates 23a-b and
phosphonates 24a-25d was outlined and rounded off by cyclic phosphonamidates 26a-b
and cyclic phosphonamides 27a-c. Pyridines 28a-c were designed to measure the effects
of the attached phosphorus-containing functional groups on their basicity. This set of
phosphorus-containing tool compounds was then complemented by the corresponding
31
bioisosteric structural motifs (Figure 4b), comprising carboxylic acid and esters 29a-c,
carboxamides 30a-d, sulfonamides 31a-c, sulfoxide 32 and sulfone 33, but also
sulfoximines 34a-c and sulfonimidamides 35a-c.33
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a) Design of phosphorus-containing tool compounds
2
2c (X = CH2)
O
O
O
P
O
P
O
P
O
P
22d (X = O)
P Me
Me
P Et
Et
i-Pr
i-Pr
R1
R1
R1
R1
R1
R1
22e (X = NH)
X
2
2
2f (X = NMe)
2g (X = Ni-Pr)
21a
21b
21c
22a
22b
3
4
2
2
4a (R = R = H)
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O
O
3
4
O
O
O
O
4b (R = Me, R = H)
O
P Me
P OR 24c (R = Et, R = H) R1
4
3
4
P
O
R1
P
R1
P
R1
R1
2
3
3
4
OR
OR
24d (R = R = Me)
O
O
O
2
3
4
2
3a (R = H)
24e (R = R = Et)
2
3
4
25a
25b
25c
23b (R = Et)
24f (R = R = i-Pr)
O
H
N
Me
O
Me
H
Me
O
O
O
1 P
O
1 P
O
N
N
N
N
R1
P
1 P
R
1 P
1 P
R
R
R
R
O
NH
MeN
O
O
HN
MeN
25d
26a
26b
27a
27b
27c
O
O
O
1
5
R =
R =
P Et
Et
P Me
OEt
P OEt
OEt
R5
R5
R5
N
F3C
28a
28b
28c
b) Design of bioisosteric tool compounds
O
O
O
O
O
O
O
R1
R1
OMe R1
Ot-Bu R1
29c
NH2 R1
NHMe R1
30b
NMe2 R1
OH
9a
NHt-Bu
2
29b
30a
30c
30d
O O
S
O O
O
S
O O
S
O O
O NH
S
O NMe
S
S
R1
R1
S
NH2
R1
NMe2
R1
Me R1
R1
R1
NHMe
Me
Me
Me
31a
31b
31c
32
33
34a
34b
O
S
N
O NMe
S
R1
O NH
S
O NMe
S
R1
R1
NHMe R1
NHMe
NMe2
34c
35a
35b
35c
Figure 4: Design of a) tool compounds bearing phosphorus-containing functional groups
and b) bioisosteric functional groups.
Finally, the effects of phosphorus-containing functional groups were explored in the
context of a drug-like substrate. As small molecule kinase inhibitors with their usually flat
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and polyaromatic core structures often lack aqueous solubility and bioavailability, they
were considered to be an ideal showcase. To this end, tyrosine kinase inhibitor imatinib
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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9
0
1
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8
9
0
1
2
3
4
5
6
7
8
9
0
32
(
36) was selected as a reference and imatinib analogs 37a-45c including phosphorus-
containing or classical functional groups were designed (Figure 5).
O
O
O
O
O
Ar
N
NMe
Ar
OH
Ar
OEt
Ar
NH2
Ar
NHMe
38b
Ar
NMe2
38c
Imatinib (36)
37a
37b
38a
O
S
O O
S
O NR
O O
S
S
1
Ar
Me
Ar
Me
Ar
Me
Ar
NR R2
1
2
39
40
41a (R = H) 42a (R = R = H)
Ar =
O
41b (R = Me)
1
2
4
2b (R = H, R = Me)
1
2
42c (R = R = Me)
HN
O
P
Me
O
O
Me
P
OR
Me
P
OR1
N
Ar
Ar
Ar
OR2
Me
N
NH
43
44a (R = Et)
4b (R = H)
1
2
4
4
4
5a (R = R = Et)
4
1
2
N
5b (R = H, R = Et)
1
2
5c (R = R = H)
Figure 5: Design of imatinib analogs containing phosphorus-, sulfur- and carbon-based
functional groups.
2.2 Chemistry. General synthesis of aryldialkylphosphine oxides and related
arylphosphinates and -phosphonates. The synthesis of aryl-phosphorus compounds is
well-precedented and still a thriving field of research.34 Symmetric tertiary
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aryldialkylphosphine oxides I can be synthesized in numerous ways, most conveniently
starting from corresponding phosphorus(V) H-phosphine oxide precursors via transition
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
5
metal catalyzed cross coupling methodologies (Scheme 1, A). Alternatively, nucleophilic
36
arylation of dialkylphosphinoyl chlorides (Scheme 1, B) and double nucleophilic addition
of organometallic species to arylphosphoryl dichlorides37 and arylphosphonic acid
esters38 (Scheme 1, C) have been described. In addition, P(III)-precursors like
dialkylphosphinyl chlorides39 and aryldichlorophosphines are reported to react with
4
0
C-nucleophiles (Scheme 1, D and E), and arylphosphines can be alkylated using alkyl
41
halides (Scheme 1, F). However, when P(III) intermediates are employed, a subsequent
oxidation of the intermediate tertiary phosphines to the phosphine oxides I is required.
Scheme 1: Synthetic pathways for the construction of aryldialkylphosphine oxides I.
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
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4
4
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5
5
5
5
6
O
Cl
R P
R
P R
R
H
A
Ar
X
D
Ar
M
O
Ar
M
O
R
R
R M
Cl
Cl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
oxidation
Ar
P
Ar P
P R
R
P R
R
I
Cl
B
Ar
C
E
(R = alkyl)
R M
F
R
Br
O
P
H
Ar
P
X
X
Ar
H
X = Cl, OMe
Similar to the preparation of phosphine oxides, a large number of methods exists for
the synthesis of aryl phosphinates42 and aryl phosphonates.43 Acyclic dialkyl
arylphosphonates II are accessed by the Arbuzov reaction between trialkylphosphites and
aryl halides (Scheme 2, A). While electron-poor aryl halides can undergo direct S Ar-type
N
44
reaction with trialkylphosphites at elevated temperatures, their electron-rich congeners
4
5
46
47
48
49
require either radical initiators or Ni-, Pd-, Cu-, or photoredox-catalysis. The Pd-
catalyzed cross coupling of H-phosphonates and aryl halides was pioneered by Hirao and
5
0
co-workers, and is still inspiration to modern synthetic methodologies utilizing poorly
activated aryl pseudohalides,51 -amides and -esters (Scheme 2, B).52 In addition,
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H-phosphonates are capable to react with nucleophiles like arylboronic acids,53
-
sulfinates,54 -silanes,55 and C(aryl)-H bonds under oxidative coupling conditions.56
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
C(aryl)-P bond construction via nucleophilic addition of aryl Grignard reagents to acyclic
dialkyl chlorophosphates is well precedented (Scheme 2, C).57
In contrast, the synthesis of cyclic alkyl arylphosphonates III by the reaction of a
nucleophilic aryl-metal species with a corresponding cyclic chlorophosphate is rather
5
8
59
60
challenging (Scheme 2, D). However, cyclic alkyl arylphosphonates III, -amidates IV,
6
1
and -amides V are readily accessible by the reaction of arylphosphonyl dichlorides with
diols, aminoalcohols, and diamines (Scheme 2, E).
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 2: Synthetic pathways for the construction of a) aryldialkylphosphonates II and
b) cyclic arylphosphonates III, -amidates IV, and -amides V.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a) Synthesis of symmetric acyclic aryldialkylphosphonates II
OR
P
O
O
Ar
X
Ar M
P OR
OR
P OR
Cl
OR
RO
OR
Ar
A
C
II (R = alkyl)
Ar
X
H
B
O
P OR
OR
b) Synthesis of cyclic arylphosphonates III, -amidates IV, and -amides V
XH
O
O
P
O
Ar
M
YH
P O
O
X
P Cl
Ar
Cl
Cl
Ar
Y
D
E
III (X = Y = O)
IV (X = O, Y = NR)
V (X = Y = NR)
Synthesis of acyclic and cyclic tertiary phosphine oxides 21 and 22. Our synthetic efforts
aimed at the installation of the arene-phosphorus bond as the final step of every reaction
sequence allowing an easy and modular exchange of aromatic moieties. The synthesis
of tertiary acyclic phosphine oxides 21 was achieved through Pd-catalyzed coupling of
4-(trifluoromethyl)phenyl iodide with secondary phosphine oxides to deliver the desired
products 21a-c in 44-93% yield (Scheme 3a).35c
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Scheme 3: Synthesis of a) acyclic, b) cyclic, and c) cyclic nitrogen-containing phosphine
oxides.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a) Synthesis of acyclic phosphine oxides 21a-c
O
Pd (dba) (2.5 mol%)
2
3
I
O
Xantphos (5 mol%)
P R
R
21a (R = Me), 62%
21b (R = Et), 93%
21c (R = i-Pr), 44%
+
P R
R
H
Et3N, dioxane, rt
F3C
F3C
b) Synthesis of cyclic phosphine oxides 22a-d
O
P
O
P
Br
O
P
NH H PO
2
i) (COCl)2
4
2
[
]n or
HO
O
Br
Z
HMDS
Z
ii) 4-(CF )PhMgX
3
F3C
22a (n = 0), 20%
F3C
THF, 0 °C
(X = Br, I)
4
4
4
6a (Z = CH2)
6b (Z = [CH ] )
6c (Z = [CH ] )
46d (Z = CH O CH )
22d, 24%
2
2
2
2b (n = 1), 32%
22c (n = 2), 35%
2
3
2
2
c) Synthesis of cyclic N-containing phosphine oxides 22e-22g
-(CF )PhI (1 equiv.)
4
3
Pd(OAc) (2.5 mol%)
Xantphos (5 mol%)
O
P
O
P
2
O
P
i) RNH2
EtO
H
NR
NR
DIPEA, DMF
ii) LAH
F3C
4
4
4
7a (R = Bn)
7b (R = Me)
7c (R = i-Pr)
48 (R = Bn), 81%
22e (R = H)
2f (R = Me), 56%
22g (R = i-Pr), 47%
Pd/C, H (65%)
2
2
Cyclic tertiary phosphine oxides are usually more challenging to synthesize. In view of
the designed compounds 22a-g, two distinct synthetic approaches were envisioned
(Scheme 3b and 3c). The first route relies on the addition of aryl Grignard reagents to
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2
2
2
2
2
2
2
2
2
3
3
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3
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4
4
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6
2
phosphinoyl chlorides derived from cyclic phosphinic acids (Scheme 3b). In our case,
the barely functionalized phosphinic acids 46a-d62b-c were most conveniently accessed by
a robust double-Arbuzov reaction of alkyldihalides with ammonium phosphinate and
hexamethyldisilazane (HMDS). Activation of the phosphinic acids using oxalyl chloride
gave the corresponding phosphinoyl chlorides which upon treatment with 4-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
3
(
trifluoromethyl)phenylmagnesium halide furnished cyclic aryl phosphine oxides 22a-d
in 20-35% yield (over 2 steps).
The second route provides nitrogen-containing cyclic phosphine oxides via
Pd-mediated cross coupling of cyclic secondary phosphine oxides with aryl halides
(Scheme 3c). Precursors for phosphine oxides 22e-g were assembled by double-Michael
addition of primary amines to ethyl divinylphosphinate.64,65 Reduction of the
corresponding cyclic ethyl phosphinates (structure not shown) using lithium aluminium
hydride (LAH) afforded cyclic secondary phosphine oxides 47a-c,65b which smoothly
reacted in Pd-mediated cross coupling reactions with 4-(trifluoromethyl)phenyl iodide to
give cyclic phosphine oxides 48 (and 22e after subsequent hydrogenation), 22f and 22g
in good yields (47-81%).
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Synthesis of arylphosphinates 23 and acyclic arylphosphonates 24. Phosphinates can
be synthesized by palladium-mediated cross coupling, occasionally accompanied by
undesired transesterification events or base-promoted dealkylation.42c,66 The reaction of
ethyl methylphosphinate with 4-(trifluoromethyl)phenyl iodide directly delivered the
phosphinic acid 23a in 42% yield when a mixture of DMF and ethylene glycol was used
as solvent, while similar conditions using toluene as solvent furnished ethyl phosphinate
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
23b in 37% yield (Scheme 4a).
Dimethyl phosphonate 24d was prepared by an Cu-catalyzed oxidative coupling of
-(trifluoromethyl)phenylboronic acid and dimethyl phosphite in 35% yield (Scheme 4b).53
4
Dialkyl phosphonates 24e and 24f were obtained through Pd-mediated cross coupling
67,
c
with 4-(trifluoromethyl)phenyl halides in 90% and 74% yield, respectively. 42 However,
when dimethyl phosphite was employed, the partially dealkylated methoxyphosphinic
68
acid 24bwas obtained in 69% yield. Diethyl phosphonate 24e was selectively converted
to the ethoxyphosphinic acid 24c in 75% yield using aqueous NaOH, or to phosphonic
acid 24a in 85% yield upon treatment with trimethylsilyl bromide (Scheme 4c).69
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2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
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5
5
5
5
5
5
5
6
Scheme 4: Synthesis of a) phosphinates 23 and b) phosphonates 24, and c) selective
hydrolysis of diethyl phosphonate 24e.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a) Synthesis of phosphinates
4
-(CF )PhI (1.0 equiv.)
4-(CF )PhI (1.0 equiv.)
3
3
O
Pd(OAc) (2 mol%)
2
Xantphos Pd G3
(10 mol%)
O
Xantphos (2.2 mol%)
O
P Me
OH
P Me
OEt
P Me
OEt
DIPEA
DMF/ethylene glycol (9:1)
H
DIPEA
Toluene, 100 °C
F3C
F3C
1
15 °C
23a, 42%
23b, 37%
b) Synthesis of phosphonates
OH
B
Cu O (5 mol%)
1,10-phen (10 mol%)
2
O
O
P OMe
OMe
OH
+
P OMe
OMe
H
DIPEA, MeCN
air, rt
F3C
F3C
24d, 35%
Pd(OAc) (2 mol%)
dppf (4 mol%)
2
O
Br
O
P OR1
+
2
P OR
OR
OR
H
KOAc (10 mol%)
DIPEA, THF, reflux
F3C
F3C
1
2
R = Me, Et
24b (R = Me, R = H), 69%
4e (R = R = Et), 90%
1
2
2
Pd(OAc) (2 mol%)
dppf (2.2 mol%)
O
2
I
O
P Oi-Pr
Oi-Pr
+
P Oi-Pr
H
F3C
Oi-Pr
DIPEA
DMF/DME (9:1)
reflux
F3C
2
4f, 74%
c) Phosphonate hydrolysis
O
O
O
P OH
OEt
4M NaOH
EtOH, rt
P OEt
OEt
TMSBr
P OH
OH
DCM, rt
F3C
F3C
F3C
2
4c, 75%
24e
24a, 85%
Synthesis of cyclic phosphonates 25, phosphonamidates 26, and phosphonamides 27.
For the synthesis of cyclic phosphonates 25a-d, phosphonamidates 26a-b and
phosphonamides 27a-c, arylphosphonic acid 24a was converted into the corresponding
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phosphonic acid dichloride 49 by treatment with oxalyl chloride, and the crude product
was directly reacted with the selected diols, aminoalcohols, or diamines (Scheme 5). The
attempted synthesis of arylphosphonic acid ethylene ester 25a38,70 however was sluggish
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
71
and resulted in the isolation of hydrolyzed compound 24g (20%) as the sole product. In
contrast, the dioxaphosphinane-2-ones 25b and 25c were obtained in good yields of 49%
and 81%, respectively. Dioxazaphosphocan-2-one 50 was isolated in 49% yield and
subsequent cleavage of the Boc protecting group (HCl/dioxane) afforded compound 25d
as a hydrochloride salt in quantitative yield. In the same manner, arylphosphonamidates
26a-b and arylphosphonamides 27a-c were prepared in 68-95% yield and 22-86%,
respectively.
Scheme 5: Synthesis of cyclic phosphonates 25, cyclic phosphonamidates 26 and -
amides 27.
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O
P
O
(COCl)2
O
P
XH
YH
X
P OH DMF (cat.)
Cl
Cl
Y
OH
THF
0 °C - rt
DCM, reflux
F3C
25 (X = Y = O)
F3C
F3C
2
4a
49
2
6 (X = O, Y = NR)
7 (X = Y = NR)
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
P O
O
O
O
P
O
O
O
P OH
O
P
OH
O
O
F3C
F3C
F3C
F3C
2
5a (not observed)
24g, 20%
25b, 49%
25c, 81%
R
R
O
O
O
P
O
O
N
P
N
N
P
P
NR
O
O
N
RN
F3C
F3C
F3C
F3C
5
2
0 (R = Boc), 49%
5d HCl (R = H)
HCl
(quant.)
26a (R = H), 95%
26b (R = Me), 68%
27a, 86%
27b (R = H), 22%
27c (R = Me), 71%

Synthesis of pyridine derivatives 28a-c. Pyridine derivatives 28a-c were synthesized by
Pd-catalyzed coupling of 4-bromopyridine hydrochloride with diethylphosphine oxide,
ethyl methylphosphinate or diethyl phosphite in moderate to excellent yields of up to 87%
(
Scheme 6).
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Scheme 6: Synthesis of pyridines bearing phosphorus-containing functional groups.
Pd (dba) (10 mol%)
2
3
Xantphos (20 mol%)
diethylphosphine oxide (1 equiv.)
DIPEA (2.2 equiv.)
O
P
Et
Et
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
1,4-dioxane, 80 °C, 2 d
28a, 43%
Pd(OAc) (2 mol%)
2
Xantphos (2.2 mol%)
ethyl methylphosphinate (1.2 equiv.)
DIPEA (2.3 equiv.)
O
Br
P Me
OEt
Cl
HN
N
toluene/DME (4:1), 80 °C, 2 d
28b, 87%
Pd(OAc) (2 mol%)
2
dppf (4 mol%)
diethyl phosphite (1.2 equiv.)
DIPEA (2.3 equiv.)
O
P OEt
OEt
N
THF, 70 °C, 24 h
28c, 73%
Synthesis of imatinib analogs 37-45. The imatinib analogs 37-45 were synthesized
7
2
starting from a commercially available aniline building block 51, which was coupled
(HATU) with the corresponding benzoic acids bearing the desired functional group (FG)
in para position (Scheme 7). For carboxylate 37b and carboxamides 38a-c the coupling
reactions proceeded smoothly with yields of up to 94% (Scheme 7a). However, mixed
results were obtained for derivatives with sulfur containing functional groups (Scheme
7
b). Sulfoxide 39 and sulfone 4073 were obtained in 92% and 91% yield, respectively,
whereas sulfoximines 41a-b and sulfonamides 42a-c were isolated in lower yields of 20-
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
7
4
6
9% (conditions not optimized). Phosphine oxide analog 43 was isolated in 91% yield
after HATU coupling (Scheme 7c). The low yielding synthesis of ethyl phosphinate 44a
and phosphinic acid derivate 44b is the result of an unselective hydrolysis of ethyl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
-[ethoxy(methyl)phosphoryl]benzoate and was not optimized.75 Diethyl phosphonate
4
5a was obtained in a good yield of 83%, and subsequently converted under standard
conditions to the ethoxyphosphinic acid 45b and phosphonic acid 45c in 62% and 38%
yield, respectively.
Scheme 7: Synthesis of imatinib analogs bearing a) carbon-, b) sulfur-, or c) phosphorus-
based functional groups.
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9
FG
Me
O
H N
HN
2
FG
HATU, Et N
3
N
N
Me
+
O
DMF
N
NH
N
NH
OH
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
N
5
1
36-45
a) Carbon-based functional groups
O
O
OR
1 2
NR R
1
2
3
3
7b (R = Et), 90%
7a (R = H)
38a (R = R = H), 86%
38b (R = H, R = Me), 81%
38c (R = R = Me), 94%
LiOH (80%)
1
2
1
2
b) Sulfur-based functional groups
O O
S
O NR
O O
S
O
S
S
1 2
Me
Me
NR R
Me
1
2
3
9, 92%
40, 91%
4
1a (R = H), 20%
41b (R = Me), 20%
42a (R = R = H), 69%
42b (R = H, R = Me), 55%
42c (R = R = Me), 23%
1
2
1
2
c) Phosphorus-based functional groups
O
O
O
2
P Me
Me
P Me
OR
P OR
1
OR
1
2
4
3, 91%
44a (R = Et), 6%
4b (R = H), 17%
45a (R = R = Et), 83%
1
2
NaOH (62%) TMSBr
4
45b (R = H, R = Et)
(38%)
1
2
4
5c (R = R = H)
2
.3 Physicochemical and in vitro properties of tool compounds 21-35. For all synthesized
phosphorus-containing compounds the relevant physicochemical and in vitro pharmacokinetic
parameters such as lipophilicity (logD), dissociation constants (pK /pK , where appropriate),
a
b
76
aqueous solubility (HPLC and shake flask assay), stability in human liver microsomes and
Caco-2 permeability were measured (Table 1). The same set of data was also determined for the
collection of compounds containing more classical functional groups (Table 2).
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Journal of Medicinal Chemistry
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 1: Physicochemical and in vitro parameters of phosphorus-containing tool
compounds 21-28.a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Chemical
stability:
decomposition
after 7 days [%]
Stability in
human liver
pK or pK
a b
microsomes
Aqueous solubility
Caco-2
permeability
logD
(pH 6.8) [µg/mL]
Compound Structure
pH
2
pH
11
T
[min]
1/2
HPLC
Shake
P
AB
Efflux
pH
<1
pH
>10
%Q
H
−
6
assay flask assay [10 cm/s] ratio
O
21a
P
Me
Et
1.5
1.1
2.0
n.d.
n.d.
>130 <23
>130 <23
>52
>60
>30,000
22,500
82
88
0.5
0.7
<10
<10
<10
<10
R1
R1
Me
O
2
1b
P
2.3
Et
O
2
1c
P
i-Pr
i-Pr
3.1
1.8
2.0
2.8
1.6
1.7
n.d.
n.d.
n.d.
>130 <23
>130 <23
>130 <23
>61
>53
>59
22,200
24,500
24,500
110
78
0.5
0.8
0.7
<10
<10
<10
<10
<10
<10
R1
O
22a
P
R1
O
2
2b
R1
P
69
O
P
22c
R1
2.4
1.4
0.0
0.0
0.2
2.0
1.1
0.5
0.9
2.0
n.d.
n.d.
>130 <23
>130 <23
>130 <23
>130 <23
>130 <23
>66
>65
>61
>66
>68
7,700
>30,000
28,000
>30,000
23,000
49
65
13
52
84
1.1
0.7
1.1
0.7
0.5
<10
<10
<10
<10
<10
<10
<10
<10
<10
<10
O
P
2
2d
R1
O
O
P
2
2e
R1
pK
b
b
b
6.9
NH
O
P
22f
R1
pK
6.3
NMe
O
P
2
2g
R1
pK
7.0
2.0
Ni-Pr
O
P
OH
23a
Me
1.3 −1.3
pK
a
>130 <23
>130 <23
n.v. n.v.
>130 <23
>49
n.v.
>54
>60
>8,900b#
n.d.
<5
69
-
1.0
-
<10
n.d.
<10
<10
<10
n.d.
<10
<10
R1
O
2
3b
P
Me
OH
OH
OH
2.5
2.3
n.d.
R1
OEt
O
P
OH
pKa1 <2.0
pKa2 6.8
2
4a
0.6 <−1.6
17,800b*
27,300b§
n.v.
n.v.
R1
O
2
4b
R1
P
1.3
n.v.
n.v.
-
OMe
O
P
OEt
2
4c
1.9 −0.8
2.5 2.2
n.v.
n.d.
>130 <23
>130 <23
>64
50
28,000b$
10,100
10
85
<0.1
0.5
<10
<10
<10
<10
R1
O
2
4d
R1
P
OMe
OMe
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Chemical
stability:
decomposition
after 7 days [%]
Stability in
human liver
pK or pK
a b
microsomes
Aqueous solubility
(pH 6.8) [µg/mL]
Caco-2
permeability
logD
Compound Structure
pH
pH
11
T
[min]
1/2
HPLC
Shake
P
AB
Efflux
pH
<1
pH
>10
%Q
H
−
6
2
assay flask assay [10 cm/s] ratio
O
2
4e
4f
P
OEt
OEt
3.4
3.2
4.2
n.d.
n.d.
>130 <23
>130 <23
>61
29
1,300
400
95
84
0.6
0.5
<10
<10
<10
<10
R1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
2
R1
P
Oi-Pr
Oi-Pr
4.3
O
P
OH
O
R1
>28,500b$
8,800
24g
n.v. n.v.
n.d.
n.d.
n.v. n.v.
>130 <23
>63
>66
n.v.
95
-
<10
<10
<10
OH
O
P
O
R1
O
>90c
2
5b
2.1
3.1
1.5
2.6
0.4
O
O
R1
P
2
5c
n.d.
>130 <23
>67
2,800
73
0.6
<10
>90c
Me
O
Me
O
O
R1
P
70d
2
5d
0.5
2.0
1.5
1.3
pK
b
6.0
>130 <23
>130 <23
66
>10,000
n.v.
63
57
0.7
0.7
<10
O
NH
O
P
H
N
R1
>90c
>90c
2
6a
n.v.
>60
O
O
P
Me
N
R1
>90c
2
6b
2.5
n.v.
n.v.
1.9
2.0
1.1
n.d.
n.d.
n.v.
>130 <23
n.v. n.v.
>130 <23
53
7,500
>30,000
12,300
64
n.v.
42
0.5
-
<10
<10
<10
O
O
P
Me
R1
N
>90c
>90c
>90c
2
7a
>64
>61
MeN
O
P
H
N
R1
2
7b
0.7
HN
O
P
Me
N
R1
2
7c
3.0
2.7
n.d.
>130 <23
>68
11,100
81
0.5
<10
MeN
O
28a
P
Et
Et
<−1.8 −1.0
−1.1 −0.7
pK
b
b
b
<2
>130 <23
>130 <23
>130 <23
>46
>45
>50
11,600
>30,000
29,500
19
54
66
0.6
0.6
0.7
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
R2
O
P
OEt
2
8b
Me
pK
<2
<2
R2
O
P
OEt
2
8c
OEt
0.0
0.2
pK
R2
a
1
2
R = 4-(CF )-phenyl; R = 4-pyridyl; n.d.: not determined; n.v.: no valid data; color-
3
b
coding: green: desirable, yellow: acceptable, red: undesirable. Buffer capacity exceeded:
#
*
§
$
c
d
sample measured at pH 5.9, pH 2.3, pH 2.0 and pH 2.1. Result after one day. 20%
decomposition observed under neutral conditions.
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Journal of Medicinal Chemistry
Page 28 of 108
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 2: Physicochemical and in vitro parameters of bioisosteric tool compounds 29-35.a
Stability in human Aqueous solubility
Caco-2
permeability
logD
liver microsomes
(pH 6.8) [µg/mL]
Compound
Structure
a b
pK or pK
HPLC Shake flask
P
AB
Efflux
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
pH 2 pH 11
T
1/2 [min] %Q
H
[10− cm/s] ratio
6
assay
assay
O
2
9a
9b
9c
0a
0b
0c
0d
1a
1b
1c
n.v.
n.v.
n.v.
1.5
1.9
2.3
n.v.
n.v.
n.v.
n.v.
1.6
pK
a
3.5
>130
n.v.
<23
>48
>10,000
15
n.v.
n.v.
68
1.3
-
R1
OH
OMe
Ot-Bu
O
2
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.v.
n.v.
n.v.
<23
<23
<1
7
20
20
R1
O
2
n.v.
-
R1
O
3
n.v.
>44
>51
>54
300
200
700
1.0
0.9
0.6
R1
NH2
NHMe
NMe2
O
3
>130
>130
56
R1
R1
R1
O
3
2.1
83
O
3
3.8
n.v.
n.v.
3.4
3.7
n.v.
n.v.
n.v.
>130
>130
>130
n.v.
<23
<23
<23
n.v.
14
>48
>49
47
10
800
900
90
56
83
0.7
0.6
0.9
-
NHt-Bu
O
O
3
S
pK
pK
a
9.4
R1
NH2
O
O
3
S
a
10.7
36
R1
NHMe
O
O
3
S
n.d.
n.d.
n.d.
n.v.
R1
NMe2
O
3
2
3
S
S
1.7
n.v.
0.8
0.7
1.4
n.v.
0.9
1.7
n.v.
n.v.
n.v.
n.v.
<23
<23
>46
>47
>50
>54
11,100
300
n.v.
n.v.
88
-
R1
O
Me
O
3
-
R1
Me
NH
O
34a
4b
34c
5a
35b
5c
S
pK
b
2.5
>130
>130
9,100
2,400
0.7
1.0
R1 Me
O
NMe
3
S
n.d.
67
R1
Me
O
R1
N
S
0.1
1.8
pK
pK
b
b
3.8
2.4
>130
<23
>59
4,700
84
0.7
O
NH
3
S
0.8
0.7
2.2
1.0
1.8
2.9
47
45
>54
>57
49
6,900
1,200
1,200
70
81
70
0.9
0.5
0.8
R1
NHMe
O
NMe
S
n.d.
n.d.
>130
>130
<23
<23
R1
NHMe
NMe
O
3
S
R1
NMe2
a
1
R = 4-(CF )-phenyl; n.d.: not determined; n.v.: no valid data; color-coding: green:
3
desirable, yellow: acceptable, red: undesirable.
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Page 29 of 108
Journal of Medicinal Chemistry
1
2
3
4
5
6
7
8
9
Lipophilicity (logD). Amongst the phosphorus-containing compounds that are not ionized at
physiological pH, phosphine oxides such as 21a and 22a are the most polar ones, exhibiting a
7
7
polarity comparable to sulfoxide 32, sulfoximine 34a and sulfonimidamide 35a (Figure 6). As
expected, the lipophilicity of phosphine oxides can be fine-tuned by the size of the aliphatic
residues (21b-c, 22b-c) and polarity can be increased by introduction of additional heteroatoms
like in ether 22d or amines that are considerably protonated at physiological pH, such as 22e-g.
Dialkyl phosphonates 24d-f are about one log unit more lipophilic than their phosphine oxide
congeners 21a-c, while the cyclic phosphonate 25b is more polar than the corresponding
phosphine oxide of identical ring size 22c. In comparison to the cyclic phosphine oxide 22c (logD
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
.0 at pH 11), the corresponding phosphonamidate 26a and phosphonamide 27b are more polar
with logD values of 1.3 and 1.1, respectively, while the methylated analogs 26b, 27a and 27c show
comparable or higher lipophilicity with logD values of 1.9 - 2.7. The phosphinic and phosphonic
acid derivatives 23a and 24a are predominantly ionized at physiological pH and represent the most
polar phosphorus-containing functional groups covered by this study as indicated by their low
logD values at pH 2 (1.3 and 0.6) and at pH 11 (–1.3 and <–1.6), respectively.
ACS Paragon Plus Environment
29