A practical process for the preparation of azetidine-3-carboxylic acid

Article abstract of DOI:10.1081/SCC-120023992

A practical and convenient synthesis of azetidine-3-carboxylic acid (1) that proceeded in 55% overall yield from commercially available diethylbis(hydroxymethyl)malonate (3) is reported. Azetidine ring-formation was achieved in high yield by cyclization of bistrifiate of the diol (3) and benzylamine. Decarboxylation under carefully pH-controlled conditions gave the mono acid azetidine that was hydrogenated to give the title compound.

Full text of DOI:10.1081/SCC-120023992

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A Practical Process for the Preparation of Azetidine-3-
carboxylic Acid
Ross A. Miller a , Fengrui Lang a , Benjamin Marcune a , Daniel Zewge a , Zhiguo J. Song a &
Sandor Karady a
a Department of Process Research , Merck Research Laboratories , Rahway, New Jersey, USA
Published online: 15 Aug 2006.
To cite this article: Ross A. Miller , Fengrui Lang , Benjamin Marcune , Daniel Zewge , Zhiguo J. Song & Sandor Karady (2003)
A Practical Process for the Preparation of Azetidine-3-carboxylic Acid, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 33:19, 3347-3353
To link to this article: http://dx.doi.org/10.1081/SCC-120023992
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 19, pp. 3347–3353, 2003
A Practical Process for the Preparation of
Azetidine-3-carboxylic Acid
*
Ross A. Miller, Fengrui Lang, Benjamin Marcune,
Daniel Zewge, Zhiguo J. Song, and Sandor Karady
Department of Process Research, Merck Research
Laboratories, Rahway, New Jersey, USA
ABSTRACT
A practical and convenient synthesis of azetidine-3-carboxylic acid
(1) that proceeded in 55% overall yield from commercially available
diethylbis(hydroxymethyl)malonate (3) is reported. Azetidine ring-
formation was achieved in high yield by cyclization of bistrifiate of
the diol (3) and benzylamine. Decarboxylation under carefully
pH-controlled conditions gave the mono acid azetidine that was
hydrogenated to give the title compound.
Key Words: Amino acid; Azetidine.
*Correspondence: Ross A. Miller, Department of Process Research, Merck
Research Laboratories, P.O. Box 2000, Mail Stop 800-B369, Rahway, NJ
07065, USA; E-mail: ross_miller@merck.com.
3347
DOI: 10.1081/SCC-120023992
Copyright & 2003 by Marcel Dekker, Inc.
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3348
Miller et al.
b-Amino acids are found in peptidic natural products possessing
pharmacological properties and are commonly substituted for a-amino
acids in peptidomimetics by medicinal chemists. Hydrolytic stability to
peptidases overthe a-amino acid derivatives gives these unnatural deriva-
tives an advantage overthe natuarl ones. As such, new and better
syntheses of challenging b-amino acids are important to the synthetic
chemistry community.[1] Azetidine-3-carboxylic acid (1), a b-amino acid
used for the preparation of a variety of pharmaceutically active com-
pounds, including CCR5 receptor modulators, procollagen C-proteinase
inhibitors, tryptase inhibitors, IL-5 inhibitors, growth hormone secreta-
gogues, and others.[2] However, only one literature report has appeared
on the preparation of this compound.[3a] This approach was based on the
condensation of epichlorohydrin with benzhydrylamine followed by a
cyanide displacement. The productivity of this lone literature synthesis
was not high and relied on the use of highly toxic starting materials and
reagents that are not readily available. We therefore investigated
alternate syntheses that would be practical for large scale preparation.
Herein we report the results of our studies.
Different routes to give azetidine acid has been tried previously
(Sch. 1). As reported by Anderson and Lok,[3a] double displacement of
dibromide (2) with benzhydrylamine gave only monodisplacement and
elimination products (Sch. 1); therefore, this approach was not a viable
alternative route.
To prevent this elimination problem, we used a malonate ester during
the azetidine ring-forming step. Simple hydrolysis/zthermal malonate
decarboxylation would then generate the desired mono-acid. The
required starting material, diethyl bis(hydroxymethyl)malonate (3), is
commercially available or easily made from diethylmalonate.[4]
Conversion to the crystalline bis-mesylate proceeded in high yield using
Hunig’s base and mesyl chloride (Sch. 2). Attempted azetidine formation
using benzylamine orammonia gave eitherstarting material orcomplex
mixtures. The bis-mesylate was stable undera vairety of conditions
Scheme 1.

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Azetidine-3-carboxylic Acid
3349
Scheme 2.
tested, so a more reactive leaving group was sought. Conversion of (3) to
the bis-triflate (4) proceeded in high yield using triflic anhydride
[5]
underacidic conditions (<5% oxetane detected).
Addition of Hunig’s
base, benzylamine, and heating to reflux induced cyclization to the
azetidine ring.
Initially, the bis-triflate formation and cyclization were carried out as
two separate steps using 1.1 equiv. of benzylamine. Simply doing the two
steps in one-pot gave the desired product 5 but in about 20% loweryield
compared to the stepwise approach. The intermediate bis-triflate was
found to slowly decompose at room temperature, which makes the
one-pot process much advantageous. Further investigation confirmed
that polymerization was not a major competitive pathway to the desired
intra-molecular cyclization in the reaction between bis-triflate and
benzylamine. The one-pot process to the azetidine malonate was achieved
in comparable yield to the two-step sequence by simply increasing the
amount of benzylamine from 1.1 to 1.5 equiv. The logic in this change
was that 4 equiv. of triflic acid released during the one-step process would
be neutralized by 5 equiv. of Hunig’s base; however, benzylamine can be
competitively protonated by triflic acid thereby slowing down the desired
alkylation reaction. Under the reaction temperature (70ꢀC), the bis-tri-
flate will decompose faster than the reaction takes place, resulting in the
20% loweryield. The azetidine malonate was not sufficiently crystalline
to isolate; therefore, the malonate was hydrolyzed directly to the solid
bis-sodium salt (6) using methanolic sodium hydroxide in 74% overall
yield from (3). Subsequent methanol wash of the solid removed most
organic impurities. Acidification with HCl gave the crystalline diacid 7
in 83% isolated yield from disodium salt 6. The inorganic impurities and
sodium chloride generated from this step remained in the aqueous mother
liquor. The diacid 7 thus obtained is essentially inorganic free and
showed a 98 wt% purity by our assay.

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3350
Miller et al.
Initial studies on the decarboxylation of 7 showed that elimination to
form an acrylate (Sch. 1, 2b) would be a competing pathway. Acrylate
formation was minimal when the benzyl group of 7 was still in place
compared to the decarboxylation of the corresponding N-H compound.
Also, the high watersolubility of azetidine-3-carboxylic acid 1 could be
more easily managed when a hydrogenation was the last step. Decarboxy-
lation was carried out by heating a slurry of the isolated diacid 7 in water
at reflux. After about 6 h, the reaction was completed and the solution
was used directly in the subsequent debenzylation step. Debenzylation
was best carried out using palladium hydroxide on carbon under 40 psi
hydrogen pressure at 60ꢀC overnight.[6] Isolation of the water-soluble
azetidine-3-carboxylic acid was easily achieved by azeotropic distillation
of the ethanol–waterslury until the watercontent was less than 2% and
then simple filtration to isolate the crystalline 1. HPLC assay of the
isolated solid indicated high purity by weight (>96.8%).
In conclusion, an improved synthesis of the b-amino acid azetidine-3-
carboxylic acid was reported. The synthesis was streamlined into a three
isolation-procedure and was successfully demonstrated on large scale.
EXPERIMENTAL
General
All solvents and reagents were purchased from commercial sources
and used without purification.
Preparation of 1-(phenylmethyl)-3,3-azetidinedicarboxylic acid diethyl
ester (5). Into a 100 L flask under a nitrogen atmosphere was charged
diethyl bis(hydroxymethyl)malonate 3 (3.5 kg, 15.89 mol), 52 L of
anhydrous acetonitrile and the solution was cooled to ꢁ20ꢀC. Triflic
anhydride (5.61 L, 33.37 mol, 2.1 equiv.) was charged via addition
funnel over 50 min while keeping temperature below ꢁ10ꢀC. N,N-
Diisopropylethylamine (5.14 kg, 39.72 mol, 2.5 equiv.) was then added
slowly over 1.5 h to the reaction mixture via addition funnel while
maintaining temperature of reaction mixture below ꢁ10ꢀC. Bis-triflate
1
4 formed cleanly as checked by NMR. H NMR (CDCl3): ꢀ 1.28 (6H, t,
J ¼ 7.1 Hz), 4.29 (4H, q, J ¼ 7.1 Hz), 4.95 (4H, s). While the reaction
mixture was still at ꢁ10ꢀC, more N,N-diisopropylethylamine (5.14 kg,
39.72 mol, 2.5 equiv.) was added via an addition funnel over10 min.
Benzylamine (2.60 L, 23.84 mol, 1.5 equiv.) was then charged over
5 min, and the resulting mixture was heated to 70ꢀC (reflux) and aged
for 2 h. Completion of the cyclization reaction was confirmed by HPLC

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Azetidine-3-carboxylic Acid
3351
(<2 A% bis-triflate 4). The batch was cooled to room temperature, trans-
ferred to a workup vessel containing 52 L of toluene, and washed with
2 Â 60 L of water. Quantitative assay of the toluene layer gave a yield of
86%. The pH of aqueous layerwas 9–10 and yield loss in aqueous layers
was less than 2%. The batch was concentrated and solvent switched to of
methanol (total vol. 40 L) under reduced pressure. Amount of toluene at
the end of solvent switch was determined to be 6 v% by GC. The
methanol solution of diester 5 was directly used in the subsequent step.
5, 1H NMR (CDCl3): ꢀ 1.26 (6H, t, J ¼ 7.2 Hz), 3.65 (2H, s), 3.66 (4H, s),
4.22 (2H, q, J ¼ 7.2 Hz), 7.22–7.32 (5H, m). 13C NMR (CDCl3): ꢀ 13.9,
49.4, 59.5, 61.7, 62.7, 127.1, 128.2, 128.4, 137.2, 169.7.
Preparation of disodium 1-(phenylmethyl)-3,3-azetidinedicarboxylate
(6). To the methanol solution of diester 5 from above (quantitative
assay showed 3.98 kg of 5) at room temperature, was added 4.0 L 10 N
NaOH in one portion, and the resulting mixture was heated to 50ꢀC and
aged over 45 min. The resultant slurry was cooled to room temperature
and sampled forassay, which showed the hydrolysis was incomplete, so
an additional 400 mL 10 N NaOH was added. The slurry was aged at
50ꢀC for an additional 30 min, cooled to room temperature and filtered.
The solid was then washed with 16 L of MeOH. The wet solid was
transferred to a flask with 28 L methanol and stirred overnight at room
temperature. The slurry was filtered and the wet cake washed with
2 Â 12 L methanol. The product was dried in a vacuum oven at room
temperature overnight giving 3.61 kg (approximately 90 wt% pure,
1
3.25 kg pure basis) disodium salt 6 as an off-white solid 6, H NMR
(D2O): ꢀ 3.54 (4H, s), 3.62 (2H, s), 7.24–7.37 (5H, m). 13C NMR (D2O):
ꢀ 53.4, 60.8, 61.8, 127.5, 128.5, 128.8, 136.8, 178.9.
Preparation of 1-(phenylmethyl)-3,3-azetidinedicarboxylic acid (7).
Solid disodium salt (6) (3.33 kg) and 12 L of water were stirred approxi-
mately 10 min until homogeneity was achieved. Five normal HCl (4.77 L)
was then added via an addition funnel over45 min without cooling,
temperature rose þ7ꢀC to 30ꢀC during the addition. The mixture
became a slurry at the end of addition. The batch was then cooled with
an ice/waterbath, aged for1 h and filtered. The solid was washed with
14 L of MeOH and left to dry under a nitrogen atmosphere overnight.
A total of 2.12 kg solid (7) was obtained in 98 wt% and 83% yield
1
(corrected for purity). 7, H NMR (D2O): ꢀ 4.37 (2H, s), 4.38 (4H, m),
7.38–7.48 (5H, m). 13C NMR (D2O): ꢀ 49.0, 58.2, 58.7, 128.9, 129.3,
130.0, 130.1, 173.0, 173.1. HRMS calcd. forC 12H14NO4 (MþH):
236.0923. Found: 236.0917.
Preparation of 1-(phenylmethyl)-3-azetidinecarboxylic acid (8). To
2.12 kg (9.01 mol) of diacid (7) was charged 20 L of distilled water and

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3352
Miller et al.
the suspension was heated to reflux (internal temperature 96ꢀC). After
6 h, the reaction was complete as indicated by HPLC analysis (diacid
<1A%). The reaction mixture was then cooled to room temperature
and filtered via in-line filter to remove inorganic insolubles. The solution
1
was used directly in the next step. 8, H NMR (D2O): ꢀ 3.42 (1H, m),
4.03–4.22 (4H, m), 4.28 (2H, s), 7.34–7.46 (5H, m). HRMS calcd. for
C11H14NO2 (M þ H): 192.1018. Found: 192.1019.
Preparation of azetidine-3-carboxylic acid (1). To the monoacid 8
solution in water from the previous step was added ethanol (4.8 L and
Pd(OH)2/C (20 wt%, 212 g). The reaction mixture was hydrogenated at
60ꢀC and 40 psi hydrogen for 16 h. After completion of the reaction, the
mixture was filtered through Solka Floc, washing with 20 L of water. The
combined filtrates and washes were concentrated under reduced pressure
to a minimum volume of approximately 5 L and then ethanol was added
slowly over 30 min, during which time a slurry resulted. The distillation
was then continued until less than 2 wt% water remained, as determined
by Karl Fisher titration. The slurry was then cooled to room tempera-
ture, filtered, and washed with 12 L of ethanol. Total filtrate losses were
less than 2%. After drying overnight under nitrogen, 806.2 g of white
solid was obtained in 96.8 wt% purity. 1, 1H NMR (D2O): ꢀ 3.63
(1H, m), 4.18–4.26 (4H, m). 13C NMR (D2O): ꢀ 36.8, 49.2, 178.2.
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Azetidine-3-carboxylic Acid
3353
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Received in the USA April 3, 2003

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