Use of silyl ester and enamine protection for an efficient alternate synthesis of (1S,2S,5R,6S)-2-[(2′S)-(2′-amino)propionyl] aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride (LY544344·HCl)

Article abstract of DOI:10.1055/s-2006-942487

An alternate synthesis of title compound (5) using N-(2-methoxycarbonyl-1- methylvinyl)-L-alanine sodium salt (6) and 2-aminobicyclo[3.1.0]hexane-2,6- dicarboxylic acid (1) was successfully completed. Incorporation of silyl ester protection and the use of an enamine-protecting group allowed for the elimination of several processing steps. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942487

PAPER
2659
Use of Silyl Ester and Enamine Protection for an Efficient Alternate Synthesis
of (1S,2S,5R,6S)-2-[(2¢S)-(2¢-Amino)propionyl]aminobicyclo[3.1.0]hexane-2,6-
dicarboxylic Acid Hydrochloride (LY544344·HCl)
Use of Sil
a
yl Ester
a
nd
r
Enamin
e
e
Protectio
d
n
W. Fennell,* Michael J. Semo, David D. Wirth, Radhe K. Vaid
Chemical Product Research and Development, Tippecanoe Laboratories, Eli Lilly and Company, Lafayette, IN 47902, USA
Fax +1(317)2764507; E-mail: Fennell_Jared_W@Lilly.com
Received 28 February 2006
nal product. Our goal was to simplify the process and
Abstract: An alternate synthesis of title compound (5) using N-(2-
eliminate the tert-butyl chloride impurity in the final prod-
methoxycarbonyl-1-methylvinyl)-L-alanine sodium salt (6) and 2-
uct. The utility of silyl groups as temporary protection of
carboxylic acid groups and amine protection as an enam-
aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (1) was success-
fully completed. Incorporation of silyl ester protection and the use
of an enamine-protecting group allowed for the elimination of sev- ine in the form of Dane salts have been well established in
eral processing steps.
the syntheses of peptides, cephalosporins and carba-
cephs.3 Therefore, our approach was to incorporate the ac-
Keywords: acylations, protecting groups, amino acids, drugs, pro-
cess development
tivation of Dane salt 6, derived from L-alanine,4 in the
form of mixed carboxylic–carbonic anhydride 7 and pro-
tection of 1 as silyl ester 9 (Scheme 2). This manuscript
describes our efforts that resulted in an efficient synthesis
that eliminates the tert-butyl chloride impurity.
(1S,2S,5R,6S)-2-[(2¢S)-(2¢-Amino)propionyl]aminobicy-
clo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride,
LY544344·HCl (5), is a new chemical entity under inves-
tigation by Eli Lilly & Company as a potential treatment
for symptoms related to disorders of the mammalian cen-
tral nervous system.1 The original synthesis of 5 from
(1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicar-
boxylic acid (1)2 involved the protection of carboxylic ac-
ids in the form of methyl esters and activation of tert-
butoxycarbonyl-L-alanine using isobutyl chloroformate
(Scheme 1). This process involved various solvent ex-
changes, pH adjustments, multiple extractions, isolation
of intermediates, and also generated the tert-butyl chlo-
ride impurity that has to be controlled at 10 ppm in the fi-
Use of N-(2-methoxycarbonyl-1-methylvinyl)-L-alanine
sodium salt (6), the Dane salt of L-alanine, eliminated the
byproduct tert-butyl chloride produced during t-Boc
group cleavage. In addition, compound 6 was prepared
from readily available and inexpensive starting materials,
methyl acetoacetate, L-alanine, sodium hydroxide, in
methanol following the literature procedure.3 Cleavage of
this enamine moiety, like the trimethylsilyl ester protect-
ing groups, can be easily accomplished under mildly acid-
ic aqueous conditions (pH 3.5) to unveil the amine
functionality.
H
MeO2C
H
H
HO2C
H
MeO2C
H
b
a
H
Me
NH CO2Me
H2N CO2H⋅5H2O
BocHN
H2N CO2Me
O
2
1
3
H
H
HO2C
HO2C
d
c
H
H
Me
Me
NH CO2H
NH CO2H
+
BocHN
Cl–
H3N
O
O
4
5
Scheme 1 Previous synthesis of 5. Reagents and conditions: (a) i) SOCl2, MeOH, 50 °C; ii) vacuum distillation; iii) aq NaOH, CH2Cl2; (b)
i) Boc-L-alanine, NMM, IBCF, CH2Cl2, < –5 °C; ii) aq HCl; (c) i) THF, aq NaOH, 40 °C; ii) EtOAc, aq HCl; iii) EtOAc, heptane, crystallization;
(d) i) anhyd HCl, EtOAc, crystallization; ii) H2O, acetone, crystallization.
SYNTHESIS 2006, No. 16, pp 2659–2664
x
x.
x
x
.
2
0
0
6
Advanced online publication: 12.07.2006
DOI: 10.1055/s-2006-942487; Art ID: M01106SS
© Georg Thieme Verlag Stuttgart · New York

2660
J. W. Fennell et al.
PAPER
H
TMSO2C
CO2Me
CO2Me
NH
CO2
CO2Me
NH
c
a
H
CO2TMS
CO2i-Bu
HN
O
Na
b
O
N
H
O
6
7
8
H
TMSO2C
d, e
1
H
CO2TMS
H2N
5
9
Scheme 2 Synthesis of 5 using silyl ester and enamine protection. Reagents and conditions: (a) N-Methylmorpholine, isobutyl chloroformate,
DMF, < –40 °C; (b) HMDS, reflux, CH2Cl2, cool to –10 °C; (c) 9 added to 7, warm to 0 °C; (d) i) HCl, CH2Cl2, ii) acetone crystallize (MeCN);
(e) acetone–water recrystallization.
To determine the appropriate reaction conditions for for-
mation of 7, a screen was conducted evaluating various
solvent systems and operating temperatures. It was found
that the Dane salt readily dissolved in polar aprotic sol-
vents. The screened reactions were conducted between
–15 °C and –65 °C and were monitored to obtain both a DMF
yield of mixed anhydride 7 as well as its stability over
Table 1 Solvent-Screen Results for Formation of 7 Done at Tem-
peratures < –42 °C
Solvent
Solvent volumes
Yield (%) of 10
(mL/g 6)
10
> 97
97
78
72
50
32
79
55
60
60
DMF
3.0
2.0
40
time under the reaction conditions. The percent yield of
anilide 10 formed from a derivatization reaction
(Scheme 3), was used as an indirect measurement of the
percent yield of 7. Table 1 provides derivatization results
that show N,N-dimethylformamide used at temperatures
below –42 °C provides the best conditions with approxi-
mately 97% yield of the anilide.
DMF
THF
THF
5.0
4.0
3.5
3.5
3.5
3.5
CH2Cl2
20% THF in DMF
40% THF in DMF
20% MeCN in DMF
40% MeCN in DMF
H2N
1.
2.
H
H+
N
+
Cl–
H3N
7
O
10
Scheme 3
Knowing N,N-dimethylformamide would be a challeng-
ing solvent from which to isolate the final product as an
HCl salt and that mixes of various organic solvents with
N,N-dimethylformamide were not successful, attempts
were made to minimize the solvent volumes. Direct infor-
mation about the mixed carboxylic–carbonic anhydride 7
stability was obtained from in situ monitoring of the anhy-
dride absorption spectrum using in situ IR. The intensity
profile of absorptions at 1822 cm–1 (carbonyl stretch) and
1091 cm–1 (CO–O–CO stretch) were recorded for reac-
tions performed in 3.5 mL/g 6 and 8 mL/g 6 of N,N-di-
methylformamide at –60 °C for one hour. The profile in
Figure 1 shows no change in intensity over one hour once
the intermediate is formed. This led to the suggestion that
7 is stable under these reaction conditions.
Figure 1 In situ IR absorption profile of 7 at –60 °C at 3.5 mL/g 6
of N,N-dimethylformamide
Synthesis 2006, No. 16, 2659–2664 © Thieme Stuttgart · New York

PAPER
Use of Silyl Ester and Enamine Protection
2661
Further analyses of reaction mixtures run at 3–4 mL/g 6 of advantage of the different solubility properties of the reac-
N,N-dimethylformamide (Table 2) reveal in situ acylation tion products. First, deprotection and adjustment of the
yields of 90% or better for conversion of 6 to 8.
solvent composition is achieved such that NaCl will pre-
cipitate from the crude reaction mixture. After filtration
and adjustment of the filtrate composition, 5 is crystal-
lized and collected as technical material.
Initially, silylation of 1 to afford 9 was accomplished in
refluxing dichloromethane with five equivalents of both
trimethylsilyl chloride (TMSCl) and N-methylmorpholine
(NMM). This protocol afforded 90% crude acylation The enamine and silyl groups of 8 are removed using
yields with 7; however, the reactions produced large aqueous HCl conditions. Adjustment to pH < 1.0 avoids
amounts of relatively insoluble NMM·HCl and NaCl reaction between the deprotected amine and methyl ace-
salts. Our attention moved toward 1,1,1,3,3,3-hexameth- toacetate, the product of enamine hydrolysis, by convert-
yldisilazane (HMDS) as a means of silylation without the ing the amine product to the HCl salt. Empirical
generation of large quantities of insoluble salt by-prod- observations showed that when an excessive amount of
ucts. The development of silylation conditions using HCl is used and/or the reaction mixture is not adequately
HMDS allowed for forward processing of the silylated es- chilled during the enamine cleavage, N,N-dimethylform-
ter intermediate 9 removing the need for isolation of the amide hydrolysis was observed as evident by the forma-
protected species. An additional advantage was the by- tion of dimethyl ammonium chloride detected by 1H NMR
products of HMDS are inert and volatile. Once acylation (d = 2.61 ppm, D2O) in 5. The identity of this peak was
occurs, the trimethylsilyl ester groups are easily depro- confirmed to be dimethyl ammonium chloride by DEPT-
tected to unveil the carboxylic acid groups using standard HSQC and HMBC NMR correlation experiments and a
aqueous workup conditions.
spiking study. Therefore, the aqueous HCl deprotection/
hydrolysis of 8 is performed as a chilled dilute solution
prior to removal of dichloromethane. Further, to achieve
successful rejection of NaCl from the reaction solution re-
quires appropriate adjustment of the solvent volumes and
addition of the appropriate anti-solvent. Both acetone and
acetonitrile were investigated for their ability to precipi-
tate NaCl in the presence of 5.
Table 2 provides results of acylation reactions using 9
with 7. The adopted protocol refluxes 1 in 3.8 mole equiv-
alents of HMDS for three hours followed by vacuum dis-
tillation of the excess HMDS. The clear, colorless oil
product is prepared for addition to 7 by dilution with 16–
20 mL/g 1 of dichloromethane and cooled to –50 °C to
–65 °C. The acylation yields were 90% or greater when a
–40 °C to –60 °C dichloromethane solution of silylated in- Figure 2 provides the solution compositions required to
termediate (9) was added to a –48 °C to –60 °C N,N-di- precipitate approximately 1.2 equivalents NaCl. At these
methylformamide solution of 7. The reverse addition of 7 compositions, 5 was completely soluble as determined by
to a solution of 9 resulted in approximately 10% lower HPLC. The graphs show that acetone can more effectively
acylation yields. It was observed after workup that re- achieve the NaCl rejection using less solvent. Additional-
maining HMDS reacts with 7 to form the corresponding L- ly, acetonitrile does not consistently provide a filterable
alanine amide 13, therefore, excess HMDS should be re-
moved prior to acylation reaction. Data also suggested
H
slow addition of 9
HMDS
that fast addition of 9 and low temperature of 7 is required
to inhibit the formation of carbamate 14 by the undesir-
able reaction of 9 with 7 (Scheme 4).
HO2C
7
CO2H
Oi-Bu
H2N
CONH2
13
H
H
HN
14
O
Enamine 8 Cleavage and Work Up Strategy: Workup
strategy involved isolating the desired material by taking
Scheme 4 Observed side-reactions involving intermediate 7
Table 2 HMDS Silylation of 1 Followed by Acylation with 7
Acylation yield
(%)
HMDS
(molar equiv)
Solvent
reflux time (h)
Other conditions studied
75
90
90
97
92
4.2
3.7
3.8
3.8
3.8
MeCN (0.75)
MeCN (4.5)
Neat (2.5)
Concentrate to low volume, dilute with MeCN, add to
7 at –55 °C over 1 h warm over 2 h.
Concentrate to low volume, dilute with CH2Cl2, add to
7 at –40 to –55 °C over 5–10 min, warm over 2 h.
Concentrate to low volume, dilute with CH2Cl2, add at r.t. to
7 at –58 to –65 °C over 5–10 min, warm over 3 h.
Neat (3.0)
Concentrate to low volume, dilute with CH2Cl2, add at r.t. to
7 at –59 to –65 °C over 5–10 min, warm over 2 h.
Neat (3.0)
Concentrate to low volume, dilute with CH2Cl2, add at r.t. to
7 at –45 to –49 °C over 5–10 min, warm over 2 h.
Synthesis 2006, No. 16, 2659–2664 © Thieme Stuttgart · New York

2662
J. W. Fennell et al.
PAPER
recovery that acetonitrile affords. Therefore, due to low
throughput of 5 with acetone, acetonitrile was selected for
isolation. The addition of reaction filtrate dropwise to a
volume of anti-solvent over 2.5 hours at room temperature
provides a product of desirable physical characteristic.
The white slurry obtained was cooled and filtered to give
technical material in the range of 75–78% yield having 1H
NMR, IR, and HPLC retention time matching to authentic
standards of 5. The potency of technical 5 ranges from
95.5% to 98.6% with greatest related substances at 2.31%.
Recrystallization of Technical 5 to Purified 5: An ace-
tone–water system was chosen for recrystallization based
upon the knowledge that alcoholic solvates can form. Be-
cause LY544344·HCl has extremely high water solubili-
ty, the solvent composition in this procedure was critical
for recovery. Table 3 provides quality data for 5 isolated
using acetone as an anti-solvent. All identified impurities
are at 0.04% or less in 5 with the exception of a lot that has
0.14% NaCl.
Figure 2 Composition required to precipitate NaCl from N,N-di-
methylformamide–solvent–H2O systems
solid but can give an oily biphasic system. Experience has
shown best results are achieved when 10 mL/g 1 of ace-
tone is added. If less acetone is used, the soluble NaCl is
carried through the process and contaminates the final
product.
The successful use of enamine protection for amine and
trimethyl silyl group protection for carboxylic acid func-
tionality was demonstrated successfully in the synthesis
of LY544344·HCl. This approach delivers 5 in a more
straightforward fashion while eliminating the tert-butyl
chloride issue in a 74–76% overall yield with excellent
quality.
Crystallization of 5: The filtrate composition is adjusted
to crystallize technical 5 first by the addition of water. The
quantity of water in the filtrate must be adjusted to 10%
by weight prior to anti-solvent dilution.5 Once the filtrate
has been added completely to the anti-solvent, the solvent
composition is 2–3% by weight water. It is important that
the water content be in the range of 2–3% by weight in this
N,N-dimethylformamide–acetonitrile–water system to al-
low 5 to crystallize (Figure 3) while maintaining the bulk
of related substances in solution.
The 1,1,1,3,3,3-hexamethyldisilazane (HMDS), methyl acetoace-
tate, isobutyl chloroformate (IBCF), L-alanine, methyl acetoacetate,
N-methyl morpholine (NMM), methane sulfonic acid (MSA),
aniline, dimethyl formamide, NaOH pellets and dichloromethane
were all used as received from commercial supplier without purifi-
cation. FT-IR analyses were conducted using a Process IR MP™
As far as anti-solvent choice, both acetone and acetonitrile
provided material of acceptable quality (> 94% potency).
However, acetone requires twice the amount to obtain the
1
utilizing the ReactIR™ software application. H and 13C NMR
spectra were recorded on a Bruker Avance spectrometer at 300
MHz and 75 MHz respectively. Chemical shifts are reported in ppm
downfield from TMS.
Synthesis of 5
(a) Synthesis of 9 by Silylation of 1
To a 250 mL 3-necked round-bottomed flask attached with a reflux
condenser, temperature probe, and mechanical stirrer were added
LY354740·H2O (12.18 g, 59.9 mmol), HMDS (48.0 mL, 228
mmol), and a catalytic amount of (NH4)2SO4 (55 mg, 0.40 mmol).
The slurry was stirred and heated to reflux at 124–135 °C (Note: a
homogeneous solution was obtained after 1.25 h at reflux). The so-
lution was refluxed at 130–135 °C for 3 h before the contents were
allowed to cool to ambient temperature. Excess HMDS (25–27 mL)
was removed under vacuum (2–4 torr) at 20–30 °C before CH2Cl2
Figure 3 Solubility of 5 in acetonitrile–N,N-dimethylformamide–
water
Table 3 LY544344·HCl (5) Yield and Quality Data
Overall yield (%) Potency (%)
Impurities (%)
0.49
L-Alanine (%)
<0.10
1 (%)
<0.02
<0.02
<0.02
<0.02
13 (%)
0.04
14 (%)
0.02
NaCl (%)
<0.01
0.14
77
76
73
72
97.5
99.5
98.7
97.9
0.47
<0.10
<0.02
<0.02
<0.02
<0.02
0.04
0.27
<0.10
<0.01
<0.01
0.05
<0.10
<0.02
Synthesis 2006, No. 16, 2659–2664 © Thieme Stuttgart · New York

PAPER
Use of Silyl Ester and Enamine Protection
2663
(250 mL) was added and the contents were cooled to –65 °C under
a nitrogen atmosphere.
washed with warm acetone (100 mL). The collected product was
dried overnight in a vacuum oven at 65 °C to give LY544344·HCl
(5.76–5.90 g; 96–98% recovery).
(b) Preparation of the Mixed Carboxylic–Carbonic Anhydride
(7)
1H NMR (300 MHz, D2O): d = 3.98 (q, J = 7.0 Hz, 1 H), 2.44 (dd,
J = 2.8, 6.3 Hz, 1 H), 2.17 (m, 1 H), 1.90–2.07 (3 H), 1.63 (dd, J =
2.9, 2.9 Hz, 1 H), 1.44 (d, J = 7.1 Hz, 3 H), 1.33–1.43 (m, 1 H).
To a 500 mL 3-necked round-bottomed flask attached with a me-
chanical stirrer and temperature probe were added the Dane salt of
L-alanine (15.11 g, 72.3 mmol) and DMF (60 mL, 4.0 volume). The
slurry was stirred for 20–25 min at ambient temperature under a ni-
trogen atmosphere to obtain a clear solution, then chilled to –60 °C.
NMM (0.17 mL, 1.5 mmol) and IBCF (9.25 mL, 71.1 mmol) were
added sequentially while maintaining the temperature at –55 °C to
–60 °C during addition (IBCF addition causes an exothermic reac-
tion). After 15 min, MSA (0.1 mL, 1.5 mmol) was added to the re-
action and stirring was continued at –58 °C to –64 °C until the later
of 15 min or until the silylated amine preparation was complete.
1H NMR spectrum is consistent with the corresponding data of 5 al-
ready reported in the literature.6
Synthesis of l-Alanine Anilide (10)
To a 250 mL 3-necked round-bottomed flask attached with a tem-
perature probe and mechanical stirrer were added DMF (96 mL)
and L-alanine Dane salt (6.1 g, 29 mmol) and chilled to –45 °C.
NMM (0.1 mL) and IBCF (3.8 mL, 29 mmol) were added while
maintaining the temperature below –40 °C during the additions. Af-
ter 10 min of stirring, a CH2Cl2 solution (12 mL) of aniline (29
mmol) was added while maintaining the solution temperature below
–43 °C. This solution was allowed to stir and warm to r.t. over 1 h.
The crude reaction mixture was poured into a separatory funnel
containing H2O (110 mL) and CH2Cl2 (50 mL) and the layers were
separated. The aqueous layers were extracted with additional
CH2Cl2 (2 ×). To the combined CH2Cl2 extracts were added aq
KOH and EtOAc in sufficient quantity to give an upper organic lay-
er. The organic layer was collected, dried over MgSO4, filtered, and
concentrated under vacuum to give an oil. The oil was taken up as
a THF solution and concd HCl (25 mL) was added. Acetone was
added to the solution as anti-solvent to crystallize the L-alanine anil-
ide·HCl salt from solution.
(c) Acylation Reaction
The pre-formed 9 was transferred via cannula using nitrogen pres-
sure over 4–6 min to the pot containing the mixed anhydride of L-
alanine Dane salt 7 while maintaining the reaction temperature be-
tween –54 °C to –64 °C. The flask previously containing the silylat-
ed LY354740 was rinsed with CH2Cl2 (10–30 mL) and transferred
to the acylation pot. The reaction mixture was allowed to stir and
gradually warm to –30 °C over 2 h, then warm to near r.t. over 2 h,
then finally warmed to ambient temperature.
(d) Enamine Cleavage/NaCl Rejection/Crystallization of 5
The reaction mixture was cooled to 0–2 °C and a solution of DI H2O
(10 mL) and concd HCl (8.5 mL) was added over 20 min through
an addition funnel while maintaining the temperature of –4 °C to 2
°C. The contents were then stirred at this temperature for an addi-
tional 30 min. The reaction was concentrated under vacuum to 72–
76 g of remaining material. Acetone (155 mL) was added and the
contents were stirred at 0–2 °C for 1 h. The precipitated NaCl was
filtered by passing the contents through a paper filter on Büchner
funnel and was washed with 3% H2O in acetone (10 mL, v/v).
Weight of solid collected was 4.3 g. Total weight of filtrate was
187 g (KF = 1.55% which is equivalent to 2.9 mL H2O in the fil-
trate). H2O (5.1 mL) was added to the filtrate to make the total water
content equal to 8.0 mL (10 wt%).
1H NMR (300 MHz, DMSO-d6): d = 10.77 (s, 1 H, NH), 8.34 (br s,
3 H, NH3), 7.64 (m, 2 H, CH-arom.), 7.34 (m, 2 H, CH-arom.), 7.10
(m, 1 H, CH-arom.), 4.06 (br m, 1 H, CH-Ala), 1.46 (d, J = 7.0 Hz,
3 H, CH3-Ala).
1H NMR agrees with literature report.7
Acknowledgment
The authors would like to thank Dr. Scott Coffey, Mr. Steve Peder-
son for assistance on the project and Mr. Dallas Hallberg for provi-
ding NMR assistance. Thanks are due to Dr. Doug Kjell, Prof.
William Roush, and Prof. Marvin Miller for suggestions and helpful
discussions.
To another 500 mL 3-necked round-bottomed flask attached with a
mechanical stirrer, temperature probe, and a pressure-equalizing ad-
dition funnel containing the crude reaction mixture was placed
MeCN (280 mL) seeded with prodrug. The crude reaction mixture
was added to the MeCN at r.t. over 2.5 h with stirring. The white
slurry obtained was then cooled to 0–5 °C and stirred for 45 min be-
fore it was collected in a Büchner funnel and washed with acetone
(100–120 mL). The solid product was dried in the vacuum oven at
55 °C overnight. Dry weight = 13.66 g; potency = 98.6%; yield =
76.8%.
References
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homogeneous filtrate was added acetone (11 mL, 1.83 volume) and
warmed to r.t. where it was seeded with 544344·HCl and stirred for
1 h. Acetone (140 mL) was added over 3 h to the suspension at r.t.
followed by heating the contents to 48 °C for 1 h. The warm con-
tents were poured onto a Büchner funnel to collect the product and
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J. W. Fennell et al.
PAPER
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W.; Wuts, P. G. M. Protection for the Amino Group, In
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New York, 1991, Chap 7. (e) Barton, J. W. In Protective
Groups in Organic Chemistry; McOmie, J. F. W., Ed.;
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(5) KF analysis was used to determine quantity of water to add
to obtain a 10% by weight solution of water prior to addition
to anti-solvent.
(6) Coffey, D. S.; Hawk, M. K. N.; Pedersen, S. W.; Ghera, S.
J.; Marler, P. G.; Dodson, P. N.; Lytle, M. L. Org. Process
Res. Dev. 2004, 8, 945.
(7) Bryant, B. P.; Leftheris, K.; Quinn, J. V.; Brand, J. G. Amino
Acids 1993, 4, 73.
Synthesis 2006, No. 16, 2659–2664 © Thieme Stuttgart · New York