FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - An improved process for the preparation of
Azetidine-3-carboxylic Acid

2. Applicant(s)
(a) NAME :
(b) NATIONALITY
(c) ADDRESS :

ALEMBIC LIMITED
An Indian Company.
Alembic Campus, Alembic Road, Vadodara - 390 003, Gujarat, India.

3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

Field of the invention:
The present invention relates to an improved process for preparation of Azetidine-3 -carboxylic Acid represented by a structural formula (I) as given below.

Background of the invention:
The molecular formula of Azetidine-3-carboxylic Acid is C4H7NO2 and molecular weight is 101.104. CAS registry No. of Azetidine-3-carboxylic Acid is [36476-78-5]. Azetidine-3-carboxylic Acid, a P-amino acid used for the preparation of a variety of pharmaceutically active compounds, including CCR5 receptor modulators, procollagen C-proteinase inhibitors, tryptase inhibitors, IL-5 inhibitors, growth hormone secretagogues and others.
Various process has been described in the literature. US4665197 discloses preparation by reacting compound of formula (a) with nitric acid at reflux and then subjecting the resulting initial azetidine carboxylic acid product to acid condition at 80°C to produce acid addition salt of Azetidine-3 -carboxylic Acid which can be converted to free acid.

US4639334 discloses a process for preparation of Azetidine-3-carboxylic Acid as shown in the Scheme-I.
2

OH

TEA HID ^ OMsv
ICM; \ . <**ssi methane sulfonyl \ ,
ci HN^ >^ ^ tetrabutylammoniun^ [—| I 1 chloride. TEA. . I
iodide, reflux N-^-^ dichloromethane, LN
Npr?pSSrin0"1"Chl0r° N-benzylazetidin-3-ol 1-benzylazetidine-3-ol
NaCN.water, DMF,
60°C
H00C i)saturated solution NC
H°°\ methanol, Vn ffS , °f Ba(OH)2, reflux \ ^
UH '5%p^H- Lw c^r^ L»^JU
(I) azetidine-3-carboxylic acid
C02 gas
1 -benzylazetidine- 1 -benzyl-3-cyano
3-carboxylic acid azetidine
Scheme-I

In the above process, the productivity was not high and it relied on the use of highly toxic starting material such as sodium cyanide and reagents which are difficult to handle at an industrial scale.
The other route of synthesis is reported by Anderson and Lok in J. Org. Chem. 1972, 37, 3953. However, double displacement of dibromide (b) with benzhydrylamine gave only monodisplacement and elimination product and not the required azetidine product as shown in the Scheme-II.
Ar
^ NH COOR
Ar-CH2-NH2
O—R //
H2C 0—R
y<
,. . L. . » 1-benzylazetidine-
ehmination product 3-carboxylic acid
Scheme-II
Another route of synthesis is reported in synthetic communications, vol. 33,19,2003, p3347-3353 as shown in the Scheme-Ill.
3


TfO-EtOOC-
-COOEt
TfO—' (HI)
HO—
EtOOC
HO— (I")
HOOC
(I)

Tf20,
iPr2NEt
HOOC
PcKOHyc, H2,
NH 60°C, 40psi

-COOEt
(VII)

BnNH2,^ iPr2NEt*
HzO, *" reflux

COOEt
EtOOC-
(IV)
INaOH, , 2.HCI
COOR
COOR-
V: R=Na VI: R=H

Scheme-Ill
In the above process, compound (VII) is not isolated. The isolation is very difficult as it is not easily filterable material. Moreover the isolation from water can not be done using high temperature due to possibility of opening of the azetidine ring.
Hence, there is a need to develop a process which not only overcomes disadvantages of the prior art process but also provide a process which is simple and which provides high purity of Azetidine-3-carboxylic Acid.
The present inventors have directed their research work towards developing a process which increases purity and reduces the number of steps as compared to the prior art. They developed an improved process for preparation of Azetidine-3-carboxylic Acid which overcomes problems of existing art and also gives purity level higher than 99%.
Object of the invention:
The primary object of the present invention is to provide an improved process for the preparation of Azetidine-3-carboxylic Acid (I).
Another object of the present invention is to provide an improved process for the preparation of Azetidine-3-carboxylic Acid (I) having purity greater than 99%.
4

Detailed description of the invention:
Accordingly, the present invention provides a process for preparation of Azetidine-3-carboxylic Acid (I)
HOOC
-NH

(i)

(I)
comprising steps of
reacting diethyl bis(hydroxymethyl) malonate (II) with triflic anhydride in the
absence of base to give bistriflate derivative (III);
TfO—i EtOOC-
-COOEt
-COOEt
TfO—' (IN)

(ii) reacting bistriflate derivative (III) obtained in step (i) with benzylamine in the presence of base to give diester (IV);
COOEt

EtOOC-
(IV)
(iii) purifying the diester (IV) obtained in step (ii);
(iv) heating diester (IV) obtained in step (iii) with sodium hydroxide in methanol to give disodium salt (V);
COONa

NaOOC-
(V)
(v) reacting the disodium salt (V) obtained in step (iv) with cone. HCl in water at elevated temperature to give monoacid (VII);
HOOC.

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(VII)

(vi) isolating the monoacid (VII) by lyophilization;
(vii) hydrogenating the monoacid (VII) obtained in step (vi) in the presence of noble metal catalylst to give the Azetidine-3-carboxylic Acid (I).
In the process of present invention, diethyl bis(hydroxymethyl)malonate (II) is reacted with triflic anhydride in the absence of base in acetonitrile at low temperature preferably in the range of -15 to -8°C to give bistriflate derivative (III) which is reacted further with benzylamine in the presence of base such as N,N-diisopropylethylamine to give diester (IV). The base is taken five equivalent of the diethyl bis(hydroxymethyl)malonate (II). The reaction mixture is heated to reflux temperature for 3 to 4 hours. The reaction is monitored on thin layer chromatography (TLC). After completion of the reaction, toluene and DM water is added and product is extracted. The organic phase is separated and washed with brine solution. The solvent is evaporated from the organic phase by distillation under reduced pressure to give brown oil.
The crude oil is purified by the methods known in the art. For the purpose of this specification, the meaning of the term "purification" as used hereinabove includes any method known to a person skilled in the art such as column chromatography on silica or purification from single solvent or combination of solvents by dissolving the compound optionally at elevated temperature and precipitating the compound by cooling the solution or removing solvent from the solution or both. It further includes methods such as solvent/antisolvent or precipitation. In the preferred embodiment, the crude oil diester (IV) is purified by column chromatography on silica using hexane grading to 10% ethylacetate in hexane to give pure diester (IV).
The diester (IV) is dissolved in methanol and reacted with aq. ION NaOH to form the slurry. It is heated at 70°C to reflux temperature for lh. Additional aq. NaOH was added and heating is continued for further 22h. The reaction mixture is cooled to room temperature and solid was filtered. The solid was washed with diethyl ether and suck dried. The solid was dried under vacuum to give disodium salt (V) as an off-white solid.
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The disodium salt (V) is dissolved in water to prepare a homogeneous solution. Cone. HC1 was added to it to give suspended solid-diacid (VI) which is heated to reflux at 100-105°C for 7 to 8 hours. The reaction mixture was cooled at room temperature and solid sodium bicarbonate was added to bring the pH to 5-6. Water was evaporated under vacuum at -80°C by lyophilization to afford monoacid along with other inorganic salts as off-white to pale yellow solid. The obtained solid was heated to reflux with absolute alcohol to remove insoluble inorganic solid. The filtrate was used as such in the next step for hydrogenation.
For the purpose of this specification 'lyophillization' is defined as "A stabilizing process in which a substance is first frozen and then the quantity of the solvent, generally water is reduced, first by sublimation and then desorption to values that will no longer support biological activity or chemical reactions"
The hydrogenation is carried out in the presence of noble metals catalylst. The noble metal catalylst are selected from group of palladium, platinum, nickel, cobalt, rhodium, ruthenium, molybdenum, tungsten and the like. The example of noble metal catalyst mentioned hereinabove includes but not limited to Pd(OH)2/C, Pt/C, Pd/C, PtO2, raney Ni or mixture thereof. The hydrogenation is carried out at 40-45°C at 40psi for 20 to 22 hours. The mixture was filtered through hyflo bed and the bed was washed with alcohol. The combined filtrates and washings were concentrated under reduced pressure to a minimum volume, approximately one third of the original volume. The solid was filtered and washed with ethyl acetate followed by with diethyl ether to get white to off-white solid. The solid was dried under vacuum to give the product azetidine-3-carboxylic acid
(I )-
The following examples illustrate the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual example but rather to the scope of the appended claims.
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Example-1
Preparation of Diester (IV):
To a cooled solution of diethyl bis(hydroxymethyl)malonate (l00g, l.0eq.) in acetonitrile (1500ml) at -15°C, was added dropwise triflic anhydride (156.4ml, 2.1eq.) by maintaining the temperature below -8°C. The reaction mixture was stirred at 0 to -5°C till bis-triflate formation is over. The reaction was monitored on TLC. N,N-Diisopropylethylamine (393ml, 5.0eq.) was added slowly at 0°C. Temperature rose up to 30°C. Benzylamine (74.3ml, 1.5eq.) was charged to it at the same temperature and refluxed at 70°C for 3h. The reaction mixture was cooled to room temperature. Water (3.0Lit) and toluene (2 x 1250ml) was added and extracted. Combined organic phase was washed with brine (1.5 lit) and concentrated under vacuum to give brown oil, which was purified by column chromatography using hexane grading to 10% ethylacetate in hexane to give diester (80g). Yield: 60%
Example-2
Preparation of Disodium salt (V):
To a stirred solution of diester (IV) (80g) in methanol (625ml), was added aq. NaOH
(ION, 50.2ml) in one lot at room temperature. The resultant slurry was heated at 70°C for
lh. Additional aq. NaOH (ION, 5ml) was added after lh and heating continued at the
same temperature for 22h. The reaction mixture was cooled to room temperature and the
solid was filtered. The solid was washed with diethyl ether (300ml x 2) and suck dried.
The solid was dried under vacuum to give disodium salt (52g) as an off-white solid.
Yield: 67%
Example-3
Preparation of monoacid (VII):
To a homogeneous solution of disodium salt (V) (52g) in water (208ml), was added cone. HC1 (45.5ml) at room temperature. The suspended solid-diacid (VI) was heated to reflux at 100-105°C for 7h. The reaction mixture was cooled at room temperature and solid sodium bicarbonate was added to bring the pH to 5-6. Water was evaporated under
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vacuum at -80°C by lyophilization to afford monoacid (20-30g) along with other inorganic salts as off-white to pale yellow solid. The obtained solid was heated to reflux with absolute alcohol (l.0lit) to remove insoluble inorganic solid. Collected filtrate was used as such in the next step.
Example-4
Preparation of azetidine-3-carboxylic acid (I):
The monoacid (VII) in absolute alcohol was hydrogenated with Pd(OH)2 on charcoal at 40°C and 40psi hydrogen pressure for 20h. After completion of the reaction, the mixture was filtered through hyflo bed and the bed was washed with alcohol. The combined filtrates and washings were concentrated under reduced pressure to a minimum volume (approximately one third of the original volume). Separated solid was filtered and washed with ethyl acetate (50ml x 2) followed by with diethyl ether (25ml x 2) to get white to off-white solid (4.0g), which was dried under vacuum. Yield: 21% based on Disodium salt
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We claim:
1. A process for preparation of Azetidine-3 -carboxylic Acid of formula (I)
HOOC
-NH

(i)

(I)
comprising steps of
reacting diethyl bis(hydroxymethyl) malonate (II) with triflic anhydride in the
absence of base to give bistriflate derivative (III);

HO—| TfO
EtOOC— —COOEt EtOOC
HO—' TfO

-COOEt

(ID

(III)

(ii)
(iii) (iv)

reacting bistriflate derivative (III) obtained in step (i) with benzylamine in the presence of base to give diester (IV);

-N
COOEt EtOOC—
(IV)
purifying the diester (IV) obtained in step (ii);
heating diester (IV) obtained in step (iii) with sodium hydroxide in methanol to
give disodium salt (V);

COONa

NaOOC-

(v)

(V)
reacting the disodium salt (V) obtained in step (iv) with cone. HCl in water at elevated temperature to give monoacid of formula (VII);
HOOC


(VII)
(vi) isolating the monoacid (VII) by lyophilization;
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(vii) hydrogenating the monoacid (VII) obtained in step (vi) in the presence of noble metal catalylst to give Azetidine-3-carboxylic Acid (I).
2. The process as claimed in claim 1, wherein the base is selected from N,N-Diisopropylethylamine.
3. The process as claimed in claim 1, wherein the step (iv) heating is performed at temperature of about 70°C to reflux temperature.
4. The process as claimed in claim 1, wherein hydrogenation is carried out in the presence of noble metal catalyst.
5. The process as claimed in claim 4, catalyst includes one or more metals selected from the group consisting of palladium, platinum, nickel, cobalt, rhodium, ruthenium, molybdenum, tungsten.
6. The process as claimed in claim 1 or 5, wherein hydrogenation is carried out in the presence of noble metal catalyst selected from a group comprising of Pd(OH)2/C, Pt/C, Pd/C, PtO2, raney Ni.
Dated this 22nd day of August 2007
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Title : AN IMPROVED PROCESS FOR THE PREPARATION OF AZETIDINE-3-CARBOXYLIC ACID
ABSTRACT
The present invention relates to an improved process for preparation of Azetidine-3 -carboxylic Acid represented by a structural formula (I) as given below.