(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property

Organization
International Bureau
(10) International Publication Number
(43) International Publication Date WO 2016/192694 Al
8 December 2016 (08.12.2016) P O PCT

(51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY,
C12P 41/00 (2006.01) C07C 317/28 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM,
C07C 315/04 (2006.01) C12P 13/02 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
C07C 317/18 (2006.01) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR,
KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG,
(21) International Application Number: MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM,
PCT/CZ20 16/000061 PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC,
(22) International Filing Date: SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN,
2 June 2016 (02.06.2016) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.

(25) Filing Language: English (84) Designated States (unless otherwise indicated, for every
kind of regional protection available): ARIPO (BW, GH,
(26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ,
(30) Priority Data: TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU,
PV 2015-383 5 June 2015 (05.06.2015) cz TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE,
DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU,
(71) Applicant: ZENT A, K.S. [CZ/CZ]; U Kabelovny 130, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK,
102 37 Praha 10 (CZ). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
GW, KM, ML, MR, NE, SN, TD, TG).
(72) Inventors: DOUBSKY, Jan; Rymarovska 434, 199 00
Praha 9 (CZ). KLVANA, Robert; Sladkovicova 11, 140 Declarations under Rule 4.17 :
00 Praha 4-Krc (CZ). RICHTER, Jindrich; Hurka 173,
— as to applicant's entitlement to apply for and be granted a
530 03 Pardubice (CZ). LEHNERT, Petr; Hugo Haase 1,
patent (Rule 4.1 7(H))
152 00 Praha 5 (CZ).
Published:
(74) Agents: JIROTKOVA, Ivana et al; Rott, Ruzicka &
Guttmann, Vinohradska 37, 120 00 Praha 2 (CZ). — with international search report (Art. 21(3))
(81) Designated States (unless otherwise indicated, for every
kind of national protection available): AE, AG, AL, AM,

(54) Title: A PROCESS FOR PREPARING THE KEY INTERMEDIATE OF APREMILAST, USING ENZYMATIC RESOLU
TION OF THE RACEMIC AMINES

(SM (S)-2

(57) Abstract: The invention relates to a preparation method of (S)-l-(3-ethoxy-4-methoxyphenyl)- 2-(methylsulfonyl)-ethyl-amine

(S)-l, or its N-acyl derivatives of general formula (S)-2. The amine (S)-l is the key intermediate in the synthesis of (S)-{2-[l-(3-eth -
oxy-4- methoxyphenyi)-2-methyisulfonylethyl]-4-acetylaminoisoindolin-l ?3-dione, known as Apremilast. In this synthesis, the
¾ amine (S)-l, or its respective salts, are subjected to condensation with 3-acetamidophthalic anhydride 4, providing the desired
product 3 (Scheme 1).
A process for preparing the key intermediate of apremilast, using enzymatic resolution
of the racemic amines

Technical Field

The invention relates to a preparation method of ( S)-l-(3-ethoxy-4-methoxyphenyl)-

2-(methylsulfonyl)-ethyl-amine )-l , or its N-acyl derivatives of general formula S -2

(S>-2

Figure 1

The amine (S )-l is the key intermediate in the synthesis of (5)-{2-[l-(3-ethoxy-4-

methoxyphenyl)-2-methylsulfonylemyl]-4-acetylaminoisoindolin-l,3-dione 3, known as
Apremilast. In this synthesis, the amine -l , or its corresponding salts, are subjected to
condensation with 3-acetamidophthalic anhydride 4, providing the desired product 3 (Scheme
7).
Racemic 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl-amine (rac)-l
actually consists of an equimolar mixture (1:1) of two opposite enantiomers (S)-l and (R )-l.
Reactions catalyzed by enzymes are generally characterized by high stereoselectivity with
respect to the substrates. Therefore, in the presence of a suitable enzyme and the acyl donor 5
derivatization of just one of the two enantiomers preferentially occurs. The product of this
reaction is either a mixture of the desired chiral amine (S)-l and N-acyl derivative (R)-2
(method , Scheme 1), or a mixture of the amine (R)-l and N-acyl derivative of the desired
amine -2 (method ii, Scheme 1).
Scheme 1

In the first case (method i), the optically pure amine (S)- l can, after separation from
the respective derivative (R )-2, be directly used for the synthesis of Apremilast 3. In the
second case (method ii), after enzymatic resolution and separation of the products, the desired
amine ( )-l is chemically released from the corresponding derivative S -2.
The said enzymatic resolution only makes it possible to achieve max. 50% yield
because the contents of each of the two opposite enantiomers S -l and (R)-l in the racemic
amine r c)- are just 50%. However, in the presence of a suitable racemization catalyst
continuous mutual conversion of the S and (R) isomers occurs, which makes it possible to
theoretically achieve up to 100% yield of the desired isomer, or its derivative. This method is
generally known as the enzymatic dynamic kinetic resolution (hereinafter only: DKR; Figure
2).
Thus, the present invention represents a very efficient, economically advantageous
and in addition environment-friendly preparation method of the key intermediate of the
synthesis of Apremilast 3, i.e. (5)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl-
amine
 catalyst

Figure 2

Background Art

Apremilast 3 {Scheme 1) is an orally available inhibitor of phosphodiesterase 4

(PDE4), which inhibits spontaneous production of the tumor necrosisfactor a (TNF- ), thus
exhibiting an anti-inflammatory activity. It can be used for the treatment of psoriatic arthritis
and it is also being tested for the treatment of other inflammatory diseases.
Apremilast 3 was first described as a racemic mixture of active pharmaceutical
ingredients (WO 2000/25777 Al; EP 1126839 B). A few years later, in an application (WO
2003/080049) a particular enantiomer, (5)-isomer, commonly only referred to as Apremilast 3
was described, which is the carrier of the biological activity as such. Thus, it is the chiral
amine (S) - l that is the key intermediate for the synthesis of Apremilast 3. An application
(WO 2003/080049) describes the procedure of chiral resolution of the racemic amine (rac)-l
with the use of N -acetyl-L-leucine and subsequent use of the corresponding salt 6 for the
synthesis of Apremilast 3 (Scheme 2).
Using this procedure, the desired enantiomer (S )- l was isolated in the yield of 44%, or 89%
(based on the theoretical content of 50% of formula (S )- l in the racemic amine (rac)- X)
Also, later applications (US 2008/0234359 Al; EP 2431371 Al) make use of the use N-
acetyl-L-leucine, or derivatives of chiral amino acids in general, for chiral resolution of the
racemic amine (rac)-l and subsequent use of the corresponding salt 6 for synthesis of
Apremilast 3 (Scheme 2).
Besides the above mentioned ones, a number of asymmetrical syntheses of the desired
enantiomer of formula (5)-l have been described that use chiral catalysts of transition metals,
e.g. rhodium (US2013/217919 Al; US2014/81032 Al). However, these procedures are not
suitable for industrial production of (5)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-
ethylamine (S)-l, or Apremilast 3, in economic terms.

At present, Dynamic Kinetic Resolution (DKR, Figure 2) belongs to well-established

and frequently used methods not only in the laboratory, but also in the industrial scale (P.
Hoyos, V. Pace, A. R. Alcantara: Adv. Synth. Catal. 2012, 354, 2585-2611; A. Schmid, J. S.
Dordick, B. Hauer, A. Kiener, M . Wubbolts, B . Witholt: Nature 2001, 409, 258-268; A .
Kamal, M. A. Azhar, T. Krishnaji, M . S. Malik, S. Azeeza: Coord. Chem. Rev. 2008, 252,
569-592; . Kirk, and M . W. Christensen: Org. Process Res. Dev. 2002, 6, 446-451). In the
industrial scale, this method is also used for a number of amines of the benzyl type, i.e. for
compounds that are structurally close to the racemic amine (rac)-l.
Enzymes that are generally usable for enzymatic resolution or for DKR belong to the
wider group of so-called hydrolases (international identification EC 3), comprising e.g.
lipases, esterases, peptidases etc. Besides free enzymes or cell cultures, enzymes
immobilized on solid carriers can be advantageously used as they make it possible to carry
out the above mentioned reactions also in organic solvents without the presence of water or
other additives. One of the most commonly used immobilized enzymes is Novozym 435®,
which is lipase B of the Candida antarctica (CAL-B) yeast, usually bound to polymers of the
acrylate type.

Suitable N -acyl donors 5 (Scheme 1 ; Y-donor in Figure 2) are most frequently esters
of carboxylic acids 5a, less frequently free carboxylic acids 5b and their corresponding
anhydrides 5c, or more rarely also derivatives of carbonic acid 5d (Figure 3) (C. E. Hoben, L.
Kanupp, J.-E. Backvall: Tetrahedron Lett. 2008, 9, 977-979).
In the case of DKR, complexes of some transition metals are most frequently used as
the racemization catalysts, especially those of ruthenium, iridium, palladium, rhodium or
vanadium (Figure 4), or even pure transition metals, possibly adsorbed on suitable carriers
(e.g. Pd/C, Pd/CaC0 3, Pd/BaS0 4, Rh/C, Rh/Al20 3 etc.).

= Me, Et, CF3, MeOCH 2, and the like

R z = alkyls and aryls (also substituted in any manner)

R = Me, Et, t-Bu, PhCH , allyl, and the like

Figure 3
 7a Ar = Ph "shv0 8 10

7b Ar = 4-MeOC 6 H A = Ph, PhCH , 4-CF C H , 4-F-C H

Ph SiCT VOSi
OSiPI¾

11 X =C, 12

Figure 4

Disclosure of Invention

The invention provides a process for preparing (iS)-l-(3-ethoxy-4-methoxyphenyl)-2-

(methylsulfonyl)-ethyl-amine (S)-l, or its N-acyl derivatives of the general formula (S)-2,
generally using enzymatic resolution of the corresponding racemic amine (rac)-l (Scheme 3)

Scheme 3
 Racemic 1-(3-ethoxy-4-memoxyphenyl)-2-(methylsulfonyl)-ethyl-amine (rac)-l
consists of the equimolar mixture (1:1) of two opposite enantiomers and In the
presence of a suitable acyl donor 5 and a suitable enzyme from the group of so-called
hydrolases (international identification EC 3), comprising e.g. Upases, esterases, peptidases
etc., derivatization of one of both the enantiomers preferentially occurs. Then, the product of
such a reaction is either a mixture of the desired chiral amine and N -acyl derivative (R)-
2 (method i, Scheme 3), or a mixture of the amine (R)-l and N -acyl derivative of the desired
amine (5)-2 (method , Scheme 3).
Suitable acyl-donors 5 (Figure 3 and Figure 5) usable for enzymatic resolution of the
racemic amine {rac)-\ are generally the following compounds: a) esters of carboxylic acids
5a, b) carboxylic acids 5b, c) anhydrides of carboxylic acids 5c or d) esters of carbonic acid
(referred to as carbonates) 5d. In the case of al these compounds, R is R3 independently
stand for H (except 5c and 5d), a C -Ci alkyl, aryl or heteroaryl with one or more
heteroatoms, wherein all these groups may be further substituted by any functional groups.
For the purposes of this invention, the term "any functional group" refers to: (a) halogens,
(b) hydroxy, alkoxy or aryloxy groups, (c) amino and nitro groups, (d) CHO and acyl groups
(i.e. ketones), (e) derivatives of carboxylic acids. In the case of the esters 5a, the R2 group
may also stand for any alkenyl group (i.e. so-called enol esters).

Figure 5

The derivatives 5a-5c can advantageously be used, wherein R stands for the ¾ .ηΧ
group (n = 1 to 3), wherein X is any C -C alkyl, any halogen (F, C , Br and I), or alkoxy
group OR4, wherein R4 stands for any Ci- alkyl or C -C 10 aryl. Concerning the esters 5a,
the enol esters can also be preferentially used, i.e. compounds wherein R2 is a vinyl or
isopropenyl. Suitable carbonates 5d are compounds wherein R 3 independently stands for a
Ci-Cig alkyl, aryl or heteroaryl with one or more heteroatoms, wherein all these groups may
be further substituted by any functional groups in the sense of the above mentioned
definition. Preferably, especially the carbonates 5d, wherein R3 is a -C alkyl, phenyl,
benzyl or a y .
Enzymes usable for the above mentioned enzymatic resolution {Scheme 3) can be any
enzymes belonging to the wider group of so-called hydrolases (international identification
EC 3), comprising e.g. lipases, esterases, peptidases etc. Besides free enzymes or cell
cultures, enzymes immobilized on solid carriers can be advantageously used as they also
make it possible to carry out the above mentioned reactions in organic solvents without the
presence of water or other additives. Out of immobilized enzymes, the following enzymes
can especially be advantageously used: Novozym 435® (E.C. 3.1.1.3; lipase B from Candida
antarctica CAL-B yeast, bound to a polymer of the acrylate type), Subtilisin (E.C. 3.4.21.62;
protease from Bacillus species, covalently bound on an amino-acrylate polymer), or
Penicilin-G amidase (E.C. 3.5.1.11; amidase from Escherichia coli, immobilized on an
epoxy-acrylate polymer).
It has been unexpectedly found out that especially the carbonates 5d (R3 = C1-C3)

provide, in the presence of the immobilized lipase Novozym 435®, the desired enantiomer of
the amine in the form of the respective carbamates (S )-2a (Scheme 4), in high chemical
yields and in addition with high chiral purity. A clear advantage of this transformation is the
possibility to use the respective carbonates 5d not only as the acyl donors, but also directly as
the reaction media. In addition, the carbonates 5d are commonly commercially available,
cheap and entirely environment-friendly compounds. In terms of industrial production, its
economy and environmental aspects, these are all significant innovative elements.

(rac)-1 5d (S)-2a

Scheme 4

Enzymatic resolution also offers another prospective advantage, which is the above
described enzymatic dynamic kinetic resolution (Figure 2). In the presence of suitable
racemization catalysts, continuous mutual conversion of the enantiomers ( S -1 and (R )-l can
be achieved with the use of this method, which makes it possible to theoretically achieve up
to 100% yield of the desired isomer, or its derivative while without the presence of
racemization catalysts the maximum yield can only be 50%. In terms of industrial production
and its economy this fact also represents a substantial advantage.
It has been surprisingly found out that under the conditions of enzymatic resolution of
the racemic amine (rac)-X, in the presence of suitable racemization catalysts, mutual
conversion of the two enantiomers (S )-l and (R)-l (represented in the racemic amine in the
molar ratio of 1:1) can be efficiently achieved, i.e. the chemical yield of the desired
enantiomer (5)-l in the form of the respective derivatives (5)-2 can exceed 50% (Scheme 5).
Especially complexes of some transition metals, preferably complexes of ruthenium -
referred to as the Shvo catalysts 7a and 7b (Figure 4) have proved to be suitable racemization
catalysts for this transformation (Figure 4).

Scheme 5

Detailed description of the invention

The invention provides a process for preparing (S)-l-(3-ethoxy-4-methoxyphenyl)-2-

(methylsulfonyl)-ethyl-amine S - l , or its iV-acyl derivatives of the general formula (S )-2,
generally using enzymatic resolution of the corresponding racemic amine (mc)-l. In another
aspect, the invention provides a process for preparing (5)-l-(3-ethoxy-4-methoxyphenyl)-2-
(methylsulfonyl)-ethyI-amine S -l , or its N -acyl derivatives of general formula S -2,
generally using the enzymatic dynamic kinetic resolution (Figure 2, Scheme 5), i.e. enzymatic
resolution in the presence of any racemization catalysts. Still another aspect of the invention
provides conversion of the derivatives of general formula (S -2 to the chiral amine (S)-l and
its use for the preparation of apremilast 3 (Scheme 1).
 Racemic 1-(3-emoxy-4-methoxyphenyl)-2-(memylsulfonyl)-emyl-amine (rac)-l
consists of the equimolar mixture (1:1) of two opposite enantiomers S -l and (R)-l. In the
presence of a suitable acyl-donor 5 and a suitable enzyme from the group of hydrolases
(international identification EC 3), derivatization of preferentially only one of the two
enantiomers occurs. Such reaction produces either a mixture of the desired chiral amine (5 )-l
and the N -acyl derivative R -2 (method i, Scheme 3), or a mixture of the amine (R)-l and N-
acyl derivative of the desired amine (S)-2 (method ii, Scheme 3).

Saa = MeOCH ; R = M 5da R = Me

Sab R, = MeOCH 2 ; R = /-Pr 5db = Et
5ac R = CH3 ; R = Et 5dc R = CH Ph
5ad R, = CH3 ; R = /-Pr
5ae R, = CH3 ; R = CH=CH2
5ae R, = CH3 ; R = C(CH3 )=CH
Saf R = CF ; R = Et

Figure 6

Suitable acyl-donors 5 {Figure 6) usable for enzymatic resolution of the racemic amine (rac)-
1 are generally the following compounds: a) esters of carboxylic acids 5a, b) carboxylic acids

5b, c) anhydrides of carboxylic acids 5 c or d) esters of carbonic acid (referred to as

carbonates) 5d. In the case of all these compounds, R R R independently stand for H
(except 5 c and 5d), a -C alkyl, aryl or heteroaryl with one or more heteroatoms wherein
all these groups may be further substituted by any functional groups. For the purposes of this
invention, the term "any functional group " refers to: (a) halogens, (b) hydroxy, alkoxy or
aryloxy groups, (c) amino and nitro groups, (d) CHO and acyl groups (i.e. ketones), (e)
derivatives of carboxylic acids. In the case of the esters 5a, the R 2 group may also stand for
any alkenyl group (i.e. enol esters).
Either esters of the general formula 5a, in the particular case esters Saa - Saf, or
carbonates of the general formula 5d, in particular the compounds 5da - Sdc, can be
preferably used {Figure 6). All the above mentioned acyl donors 5a and 5b are liquid
substances, commonly commercially available and, in addition, inexpensive, so they can be
advantageously used not only as acyl donors, but also as reaction media (solvents), which
are, moreoverm environment-friendly.

The enzymes usable for the above mentioned enzymatic resolution {Scheme 3) can be
any enzymes belonging to the wider group of hydrolases (international identification EC 3),
comprising e.g. lipases, esterases, peptidases etc. Besides free enzymes or cell cultures,
enzymes immobilized on solid carriers can be advantageously used as they also make it
possible to carry out the above mentioned reactions in organic solvents without the presence
of water or other additives. Out of immobilized enzymes, the following enzymes can
especially be advantageously used: Novozym 435® (E.C. 3.1.1.3; lipase B from Candida
antarctica CAL-B yeast, bound to a polymer of the acrylate type), Subtilisin (E.C. 3.4.21.62;
protease from Bacillus species, covalently bound on an amino-acrylate polymer), or
Penicilin-G amidase (E.C. 3.5.1.1 1; amidase from Escherichia coli, immobilized on an
epoxy-acrylate polymer).
It has been surprisingly found out that especially the carbonates 5d (R 3 = C -C ,
preferably the dimethyl carbonate 5da, and also the esters of carboxylic acids 5a, preferably
especially the esters of methoxyacetic acid 5aa and 5ab, provide, in the presence of
immobilized lipases, preferably the immobilized lipase Novozym 435®, the desired
enantiomer (S )-l in the form of the respective derivatives (S )-2aa, or (5)-2ba {Scheme 6) in
high chemical yields and in addition with high chemical purity.

Scheme 6

Immobilized lipases are highly resistant to the environment of common solvents as

well as to elevated temperatures. Thus, the above mentioned reactions {Scheme 6) can be
conducted either without the presence of any solvents (the acyl donors 5 serve as a solvent at
the same time), or in a wide range of commonly available solvents. Applicable solvents
comprise aliphatic or aromatic hydrocarbons and their halo derivatives, ethers, alcohols,
derivatives of carboxylic acids (e.g. amides and nitriles), or sulfur derivatives, such as
sulfones and sulfoxides. Advantageously, especially ethers can be used as f-butyl methyl
ether (MTBE), cyclopentyl methyl ether (CPME), or cyclic 2-memyltetxahydrofuran
(MeTHF).
However, in economical and environmental terms it is even more advantageous to
carry out the above mentioned enzymatic resolution (Scheme 6) without the use of solvents.
Especially, dimethyl carbonate (DMC) can be preferably used, which serves, in the particular
case, not only as an acyl donor 5, but also as a solvent. DMC is well-known and frequently
recommended as a cheap and at the same time environment-friendly solvent.
The reaction itself can be carried out in a wide temperature range. The temperature of
the reaction mixture mainly influences the reaction rate: with an increased temperature the
reaction gets accelerated, i.e. the reaction time gets shorter. It is suitable to carry out the
above mentioned reactions at elevated temperatures (depending on the use of a possible
solvent and its physical characteristics), preferably in the temperature range of 50 to 125°C.
It has been surprisingly found out that under the conditions of enzymatic resolution of
the racemic amine (rac)~l, in the presence of suitable racemization catalysts, mutual
conversion of the two enantiomers (S -l and (R )- l (represented in the racemic amine in the
molar ratio of 1:1) can be efficiently achieved, i.e. the chemical yield of the desired
enantiomer ( -l in the form of the respective derivatives (S)-2 can exceed 50% (Scheme 5).
A number of complexes of transition metals as well as pure transition metals, both free, or
adsorbed on various carriers, have turned out to be suitable racemization catalysts for this
transformation (Figure 4).
Advantageously, the so-called "Shvo catalysts" 7a and 7b can mainly be used in
combination with the acyl donors 5aa, 5ab and 5da and with immobilized lipase Novozym
435® as the enzyme (Scheme 7). Under these conditions, the respective derivatives (S)-2 of
the desired amine (S ) l can be obtained n chemical yields of up to 90% (i.e. 40% of the
undesired enantiomer (R)- l transformed) while the chiral purity achieves up to 97%.
Scheme 7
To be able to use the protected derivatives (S)-2 for the preparation of apremilast 3
{Scheme 1), it is first necessary to convert them, in a suitable way, to the desired free amine
(S)-l (method ii, Scheme 1), The RCO acyl groups belong to groups that are commonly used
to protect amines. Thanks to this, a number of methods and agents have been described,
enabling carrying out such transformations even under very moderate conditions.
In the particular case of the derivatives (5)-2aa and (S )-2ba, either strong acids, or
strong bases can be used equally successfully for the conversion to the free amine (S)-l
{Scheme 8). Suitable acids are any strong mineral acids, preferably HC1, HBr or H S0 4 . As
the strong bases, for example, hydroxides of alkali metals or alkaline earth metals can be
used, preferably LiOH, NaOH, KOH and Ba(OH) 2. Further, also some carbonates, preferably
Na C0 3 and K2C0 3 .

(S)-2aa (S)-2ba (SH

Scheme 8

In both the above mentioned cases (use of acids or bases), the reactions can be
conducted in a wide temperature range, preferably at the temperatures from 50 to 150°C,
depending on the used agent and solvent. As the solvents, for both the approaches mainly
protic polar solvents can be used, including water, or their mixtures with aprotic polar
solvents, preferably, e.g., with ethers such as dimethoxyethane, tetrahydrofuran and dioxane.
Suitable protic solvents are: a) water; b) alcohols of the general formula OH, wherein R4
stands for any C -C alkyl (branched as well as unbranched); c) diols of the general formula
HO-R -OH, wherein R stands for (CHR )n, wherein n = 2-4 and R 6 independently stands for
H, a C C3 alkyl or CH OH; d) diols of the general formula HO-R -OH, wherein R5 stands
for [( C]¾)n Z(CH2)n]m, wherein independently: n = 1-4, m = 1-4 and Z stands for O, S or
NR7, wherein R 7 is H or any Ci-C 8 alkyl, possibly substituted by another hydroxy group; e)
liquid carboxylic acids of the general formula R COOH, wherein R 8 stands for H or any C -
C alkyl. Out of the above mentioned protic solvents, especially water, methanol, ethanol,

propanols, butanols, ethylene glycol, propylene glycols, diethanolamine and triethanolamine

can be advantageously used.
In the case of the carbamate (S)-2aa, other specific agents can also be used for its
transformation to the free amine (S )-l, such as trialkyl halo silanes of the general formula
(R )3 SiX, wherein R9 independently represents a Ci-C 6 alkyl and X may be Cl, Br or I.
Especially, trimethyl si y iodide e S (TMSI) can be preferably used; the reaction itself
can be conducted in various polar solvents, preferably in dichloromethane or in acetonitrile.
The invention is clarified in a more detailed way using the examples below. These
examples, which illustrate the improvement of the procedure in accordance with the
invention, only have an illustrative character and do not restrict the scope of the invention in
any respect.

Experimental part

General:
The chemical purity of all the said compounds was determined by means of high-
performance liquid chromatography (HPLC equipped with a UV/VIS detector). The analyses
were conducted in an XSelect® HSS C18 SB column (100x4.6 mm; 2.5 µη stationary phase)
using an acetonitrile/10 mM phosphate buffer mixture (pH = 2.5) as the mobile phase
(temperature 45 °C; flow 0.8 m min; detection at 230 run).
The chiral purity (general stereometric purity) of all the said compounds was
determined by means of high-performance liquid chromatography (HPLC equipped with a
UV/VIS detector). The analyses were conducted in a Chiracel® OZ-3 column (150x4.6 mm;
3 µ η stationary phase) using a hexane/ethanol 75:25 mixture as the mobile phase
(temperature 35 °C; flow rate 1.2 ml/min; detection at 280 nm).
The term "laboratory temperature" refers, for the purposes of the text below and
above, to the temperature range from 22 to 26°C. Unless indicated otherwise, the term
"equivalent" (or abbreviated "equiv.") always means "molar ratio" in the text and tables
below. The indication ee means "enantiomeric excess" (i percent) of a pure isomer (R or S
in its mixture with the racemate RS mixture, and its calculation is based on the equation: ee
= \R - S\)/(R + S -100 = %R -%S\ [%].

Abbreviations and names of the chemical compounds:

(rac)-l 1-(3 -Emoxy-4-memoxyphenyl)-2-(memylsulfonyl)-ethyl-amine
( S)-l (5)- 1-(3-Emoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl-amine
(i )-l (R)- 1-(3 -Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl-amine
2aa Methyl (1-(3 -ethoxy-4-methoxyphenyl)-2-(methyl sulfonyl)ethyl)carbamate
(5)-2aa Methyl (S)-(l -(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-
carbamate
(S )-2ba (5)-N -(l-(3-emoxy-4-memoxyphenyl)-2-(memylsulfonyl)-ethyl)-2-
methoxyacetamide
Novozym 435 Lipase B from Candida antarctica yeast (E.C. 3.1.1.3; CAL-B) immobilized
on methacrylate polymer (>5000 U/g).
TMSI Trimethyl silyl iodide
DMC Dimethyl carbonate
MeTHF 2-Methyltetrahydrofuran
MTBE /-Butyl methyl ether
CPME Cyclopentyl methyl ether

Examples

Example 1
Methyl (5 -(1-(3 -emoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)carbamate (5)-2aa

0.13 g (0.48 mmol) of the racemic amine {rac)-\ is suspended in a mixture of CPME
(0.4 ml) and dimethyl carbonate (0.1 ml). Novozym 435 (60 mg) is added to the white
suspension and the mixture is maintained at a temperature of 85-90°C, being moderately
stirred. After 43 hours, the reaction mixture contains 44% of the starting amine 1 and 53% of
the carbamate 2aa. The reaction mixture is filtered in a hot state a d the filtrate is
concentrated at a reduced pressure. The concentrated product is stirred up in 2M aqueous HC1
and extracted with 2 x 3 ml of dichloromethane. The combined organic extracts are
concentrated. The process provides 75 mg of the carbamate 2aa (47%) containing 92% of
(S)-2aa.

Example 2
Methyl (S)-(l-(3-emoxy-4-memoxyphenyl)-2-(methylsulfonyl)ethyl)carbamate (S)-2aa

0.13 g (0.48 mmol) of the racemic amine (rac)~l is suspended in a mixture of CPME
(0.4 ml) and dimethyl carbonate (0.1 ml). Novozym 435 (60 mg) and 5% Pd on CaC0 3 (16
mg) are added to the white suspension. The mixture is maintained at 80°C, being moderately
stirred. After 24 hours, the reaction mixture contains 45% of the starting amine 1 and 53% of
the carbamate 2aa. The reaction mixture is filtered in a hot state and the filtrate is
concentrated at a reduced pressure. The concentrated product is stirred up in 2M aqueous HC1
and extracted with 2 x 3 ml of dichloromethane. The combined organic extracts are
concentrated. The process provides 75 mg of the carbamate 2aa (47%) containing 82% of
(5)-2aa.

Examples 3-7
Methyl (5)-(l-(3-ethoxy-4-methoxyphenyl )-2-(methylsulfonyl)ethyl)carbamate ( -2aa

The procedure described in Example 1 was precisely repeated in the subsequent

experiments. All, and the only, changes (solvent type, temperature, reaction time, or addition
of a catalyst) are specified in Table 1.
Table 1. a Content of the carbamate 2aa in the reaction mixture (according to HPLC);
* Content of (S)-2aa in the isolated carbamate 2aa (according to HPLC).

Example 8
Methyl (5)-( 1-(3-emoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)carbamate ( -2aa

0.13 g (0.48 mmol) of the racemic amine (rac)-\ is suspended in dimethyl carbonate
(0.5 ml). Novozym 435 (60 mg) is added to the white suspension. The mixture is maintained
at 70°C, being moderately stirred. After 40 hours, the reaction mixture contains 25% of the
carbamate 2aa. The reaction mixture is filtered in a hot state and the filtrate is concentrated at
a reduced pressure. The concentrated product is stirred up in 2M aqueous HC1 and extracted
with 2 x 3 ml of dichloromethane. The combined organic extracts are concentrated. The
process provides 35 mg of the carbamate 2aa (22%) containing 92% of ( S -2aa.

Example 9
Methyl ( S -( 1 -(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)carbamate (S)-2aa

0.13 g (0.48 mmol) of the racemic amine (rac)-l is suspended in dimethyl carbonate
(0.5 ml). Novozym 435 (60 mg) is added to the white suspension. The mixture is maintained
at 90°C, being moderately stirred. After 18 hours, the reaction mixture contains 44% of the
carbamate 2aa. The reaction mixture is filtered in a hot state and the filtrate is concentrated at
a reduced pressure. The concentrated product is stirred up in methanol (5 ml). The white
crystalline product is aspirated and dried. The process provides 44 g of the carbamate 2aa
(28%) containing 92% of (S)-2aa.

Example 10
Methyl (5)-(l-(3-emoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)carbaniate (S)-2aa

0.13 g (0.48 mmol) of the racemic amine (rac)-l is suspended in dimethyl carbonate
(0.5 ml). Novozym 435 (100 mg) is added to the white suspension. The mixture is maintained
at 90°C, being moderately stirred. After 5 hours, the reaction mixture contains 46% of the
carbamate 2aa. The reaction mixture is filtered in a hot state and the filtrate is concentrated at
a reduced pressure. The concentrated product is stirred up in methanol (5 ml). The white
crystalline product is aspirated and dried. The process provides 40 mg of the carbamate 2aa
(25%) containing 97% of (S)-2aa.

Example 1
Methyl (5)-(l-(3-emoxy-4-memoxyphenyl)-2-(methylsulfonyl)ethyl)carbarnate (S)-2aa

0.13 g (0.48 mmol) of the racemic amine {rac)-\ is suspended in dimethyl carbonate
(0.5 ml). Novozym 435 (100 mg) and 52 mg (0,048 mmol) of the racemization catalyst 7a are
added to the white suspension (Figure 4). The mixture is maintained at 90°C, being
moderately stirred. After 5 hours, the reaction mixture contains 90% of the carbamate 2aa.
The reaction mixture is filtered in a hot state and the filtrate is concentrated at a reduced
pressure. The concentrated product is stirred up in methanol. The white crystalline product is
aspirated and dried. The process provides 108 mg of the carbamate 2aa (68%) containing
97% of (S)-2aa.

Example 12
(S)-N-( 1-(3 -ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl)-2-methoxyacetamide (S)-
2ba

50 mg of Novozym 435, 20 ml of CPME; 0.87 ml (8.757 mmol) of methyl methoxy

acetate 5aa are added to 0.342 g (1.251 mmol) of the racemic amine ( )-l and the reaction
mixture is stirred at 105 °C for 37 h . The resulting mixture containing 48% of the respective
amide 2ba is filtered, concentrated at a reduced pressure on an evaporator and the product is
isolated with the use of column chromatography on silica gel (an ethyl acetate/hexane
mixture as the mobile phase). The process provides 199 mg (46%) of the crystalline
compound (S )-2ba with the chiral purity of ee 97% and chemical purity of 99.3% (HPLC).

Example 3
{S)-N-( 1-(3 -emoxy-4-memoxyphenyl)-2-(memylsulfonyl)-ethyl)-2-methoxyacetamide (5)-
2ba

50 mg of Novozym 435, 20 ml of CPME and 0.121 ml (8.757 mmol) of isopropyl

methoxy acetate Sab are added to 0.342 g (1.251 mmol) of the racemic amine {rac)-\ and the
reaction mixture is stirred at 105°C for 37 h. The resulting mixture containing 47% of the
respective amide 2ba is filtered, concentrated at a reduced pressure on an evaporator and the
product is isolated with the use of column chromatography on silica gel (an ethyl
acetate/hexane mixture as the mobile phase). The process provides 194 mg (45%) of the
crystalline compound (S )-2ba with the chiral purity of ee 95% and chemical purity of 99.2%
(HPLC).

Example 14
( )-N-(l-(3-emoxy-4-memoxyphenyl)-2-(^ (S)-
2ba

50 mg of Novozym 435, 136 mg (0.1251 mmol) of the racemization catalyst 7a

{Figure 4), 20 ml of CPME and 0.87 ml (8.757 mmol) of methyl methoxy acetate 5aa are
added to 0.342 g (1.251 mmol) of the racemic amine ( )-l . The reaction mixture is stirred
at 105°C for 37 h. The resulting mixture is filtered, concentrated at a reduced pressure on an
evaporator and the product is isolated with the use of column chromatography on silica gel
(an ethyl acetate/hexane mixture as the mobile phase). The process provides 346 mg (80%) of
the crystalline compound (5)-2ba with the chiral purity of ee 91% and chemical purity of
99.4% (HPLC).
Example 1
(S)-N-( 1-(3 -ethoxy-4-methoxyphenyl)-2-(memylsulfonyl)-emyl)-2-methoxyacetamide (5)-
2ba

50 mg of N voz m 435, 136 mg (0.1251 mmol) of the racemization catalyst 7b

(Figure 4), 20 ml of CPME and 0.87 ml (8,757 mmol) of methyl methoxy acetate 5aa are
added to 0.342 g (1.251 mmol) of the racemic amine ( )-l . The reaction mixture is stirred
at 105°C for 37 h. The resulting mixture is filtered, concentrated at a reduced pressure on an
evaporator and the product is isolated with the use of column chromatography on silica gel
(an ethyl acetate/hexane mixture as the mobile phase). The process provides 389 mg (90%) of
the crystalline compound (S)-2ba with the chiral purity of ee 97% and chemical purity of
99.4% (HPLC).

Example 16
(S)- 1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl-amine (S)-l

0.5 g of triethanolamine and 0.5 ml of a 50% (by weight) aqueous solution of NaOH
are added to 345 mg ( 1 mmol) of the amide (5)-2ba from Example 15. The mixture is
gradually heated up in a flask to 120°C and at this temperature the heating and stirring
continues for another 6 hours. After cooling to the laboratory temperature the reaction
mixture is diluted with water (5 ml) and extracted with toluene (3 5 ml). The combined
toluene phases are washed with water (2 5 ml) and salt brine ( 5 ml). After evaporation
at a reduced pressure on an evaporator the amount of 243 mg (89%) of the crystalline amine
(S)-l is obtained with the chiral purity o e 97% and the chemical purity of 99.7% (HPLC).

Example 17
(5)-l -(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl-amine

2 ml of ethylene glycol and 0.5 ml of a 50% (by weight) aqueous solution of KOH are
added to 331 mg ( 1 mmol) of the carbamate (5)-2aa obtained according to the process of
Example 11. The mixture is heated in a flask at 100°C for 12 hours. After cooling to the
laboratory temperature the reaction mixture is diluted with water (10 ml) and extracted with
MTBE (3 x 5 ml). The combined ether phases are washed with water (2 x 5 ml) and salt brine
(1 5 ml). After evaporation at a reduced pressure on an evaporator the amount of 249 mg
(91%) of the crystalline amine (S)-l is obtained with the chiral purity of ee 92% and the
chemical purity of 99.5% (HPLC).

Example
(5)-l-(3-Emoxy-4-methoxyphenyl)-2-(memylsulfonyl)-emyl-amine (S)-l

215 µΐ TMSI (1.5 mmol) are added to a solution of 331 mg ( 1 mmol) of the carbamate
(S )-2aa obtained with the use of the process of Example 11 in 10 ml of dry DCM and the
mixture is heated up to boil for 12 hours. The reaction mixture is then concentrated at a
reduced pressure on an evaporator, diluted with water (10 ml) and after neutralization with a
1M aqueous solution of NaOH it is extracted with MTBE (3 5 ml). The combined ether
phases are washed with water ( 5 ml) and salt brine ( 1 5 ml). After evaporation at a
reduced pressure on an evaporator the amount of 211 mg (77%) of the crystalline amine (S)-l
is obtained with the chiral purity of ee 94% and the chemical purity of 99.7% (HPLC).

Example
(S)-l -(3-Emoxy-4-me oxyphenyl)-2-(methylsulfonyl)-ethyl-amine (S )-l

2 ml of a commercial solution of HBr in acetic acid (33% solution - by weight) are

added to 331 mg ( 1 mmol) of the carbamate (S )-2aa obtained with the use of the process of
Example 11 and the mixture is stirred at 25 °C for 24 hours. The reaction mixture is
concentrated at a reduced pressure on an evaporator, diluted with water (10 ml) and after
neutralization with a 1M aqueous solution of NaOH it is extracted with MTBE (3 5 ml).
The combined ether phases are washed with water (2 x 5 ml) and salt brine ( 1 5 ml). After
evaporation at a reduced pressure on an evaporator the amount of 257 mg (94%) of the
crystalline amine (S )-l is obtained with the chiral purity of ee 94% and the chemical purity of
99.2% (HPLC).
Example 20
S - {2- [1-(3 -ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl] -4-acetylaminoisoindoline- 1,3-
dione (3)

137 g (0.5 mmol; 97% ee) of (S)-l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-

ethylamine (S)-l (see Example 16), 108 mg (0.525 mmol) of 3-acetamidophthalic anhydride
4 and 5 ml of glacial acetic acid were charged into a 25ml flask. The mixture was refluxed
overnight and then cooled down to the laboratory temperature. Then, the mixture was
concentrated at a reduced pressure and the residue was dissolved in 25 ml of ethyl acetate.
The obtained solution was washed with water (2 x 5 ml), saturated aqueous solution of
NaHCC 3 (2 5 ml), salt brine ( x ml) and dried with sodium sulfate. The solvent was
evaporated at a reduced pressure and the rest was crystallized from a mixture of ethanol /
acetone 2:1 (by volume). The separated crystals were isolated by filtration on frit, washed
with ethanol and dried at a reduced pressure (0.5 kPa) at 60°C. The process provided 194 mg
otApremilast 1 (yield 84%, 97% ee, HPLC 99.8%)

Example 1
(S)- {2-[1-(3 -ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl] -4-acetylaminoisoindoline- 1,3-
dione (3)

1.21 g (4.43 mmol; 97% ee) of (S)-l-(3-ethoxy-4-methoxyphenyl)-2-

(methylsulfonyl)-ethylamine (S)-l (obtained using the process of Example 16), 954 mg (4.65
mmol) of 3-acetamidophthalic anhydride 4 and 18 ml of glacial acetic acid were charged into
a 50ml flask. The mixture was refluxed for 3 h and cooled down to 20°C. After that, 35 ml of
water was gradually added, under continuous stirring the mixture was inoculated with
crystals of Apremilast 3 (10 mg) and stirred at 20°C for another 15 hours. The separated
crystals were aspirated, washed with a mixture of acetic acid - water (volume ratio 2:5) and
dried at a reduced pressure. The amount of 1.875 g of yellowish crystals of the product 3 was
obtained (yield 92%, 98% ee, HPLC 99.1%).
Claims

1. A process for preparing apremilast, (S)~{2-[l-(3-ethoxy-4-methoxyphenyl)-2-

memylsmfonylethyl]-4-acetylaniinoisoindoline-l,3-dione of formula 3

characterized in that it comprises a reaction of the racemic amine of formula ( )-l

wherein Me is methyl and Et is ethyl,

with N-acyl donors of formula 5

wherein R is H a Ci-Cig alkyl, C - 4 aryl or Ci-Cg heteroaryl with one or more heteroatoms,
or a C1-C18 alkoxy group, wherein all said groups can be further substituted by any functional
groups; the donor is OH, any C -Cig alkoxy, C1-C9 aryloxy, C alkylthio group or a C -
C acyloxy group;
in the presence of an enzyme from the group of hydrolases, preferably in the presence of a
racemization catalyst,
which produces either (i) directly the chiral amine of formula (S)-i,
or (ii) iV-acylated amine of formula (S)-2,

which is converted, by treatment with a base or an acid in the presence of a solvent, to the
chiral amine (S)-l, wherein the amine (S)-l obtained in step (i) or (ii) is further subjected to a
reaction with 3-acetamidophthalic anhydride of formula 4,

thus producing apremilast of formula 3 .

2. The process according to claim 1, characterized in that the N -acyl donor is selected
from esters of carboxylic acids of formula 5a, carboxylic acids of formula 5b, anhydrides of
carboxylic acids of formula 5c or derivatives of carbonic acid of formula 5d, preferably in the
form of esters of carboxylic acids of formula 5a and derivatives of carbonic acid of formula
5d, wherein l, R2, R3 are independently H, except formulae 5c and 5d, a -Ci alkyl, aryl
or heteroaryl with one or more heteroatoms, wherein all these groups may also by further
substituted by any functional groups.
3. The process according to claims 1 and 2, characterized in that the N-acyl donor is an
ester of carboxylic acids of formula 5a and is selected from methyl methoxyacetate, isopropyl
methoxyacetate, ethyl acetate, isopropyl acetate, vinyl acetate, isopropenyl acetate or ethyl
trifiuoroacetate, preferably methyl methoxyacetate.

4. The process according to claims 1 and 2, characterized in that the N-acyl donor is a
derivative of carbonic acid of formula 5d, selected from dimethyl carbonate, diethyl
carbonate or dibenzyl carbonate, preferably dimethyl carbonate.

5. The process according to claims 1-4, characterized in that the enzyme from the group
of hydrolases is selected from lipases, esterases or peptidases, which are free or immobilized
on solid carriers, the enzyme preferably being Novozym 435, i.e. lipase B from Candida
Antarctica yeast, preferably bound to polymers of the acrylate type, Subtilisin or Penicilin-G
amidase.

6. The process according to claims 1-5, characterized in that the reaction of the racemic
amine of formula ( c)-l with the N-acyl donor of formula 5 is carried out in the presence of
a racemization catalyst, which is a transition metal, selected from Ru, Ir, Pd, Pt or Rh, which
is free or adsorbed on a carrier, selected from active carbon, aluminium oxide and calcium
carbonate, or said catalyst is complexes of transition metals selected from Ru, Ir, Pd, Rh or V,
preferably complexes of transition metals, especially the Shvo catalysts.

7. The process for preparing apremilast according to any one of the preceding claims,
characterized in that it comprises a reaction of the racemic amine of formula (rac)-i with
dimethyl carbonate under treatment with Novozym 435, preferably in the presence of a
racemization catalyst, producing methyl-(S)-(l-(3-ethoxy-4-methoxyphenyl)-2-
(methylsulfonyl)ethyl)carbamate of formula (S)-2aa.
8. ( S)-(l-(3-emoxy-4-memoxyphenyl)-2-(memylsulfonyl)emyl)carbam ( -2aa.

9. The process for preparing apremilast according to any one of the preceding claims,
characterized in that it comprises a reaction of the racemic amine of formula ( )-l with
methyl methoxyacetate or isopropyl methoxyacetate under treatment with Novozym 435,
preferably in the presence of a racemization catalyst, producing (5)-iV-(l-(3-ethoxy-4-
methoxyphenyl)-2-(methylsulfonyl)ethyl)-2-methoxyacetamide of formula ( -2ba.

10. (S)-N-( 1-(3 -emoxy-4-methoxyphenyl)-2-(memylsulfonyl)-e1ihyl)-2-methoxyacetamide

(S)-2ba.

11. Use of (5)-(l-(3-ethoxy-4-methoxyphenyi)-2-(methylsulfonyl)ethyl)carbamate of

formula (S)-2aa or 5 -N -(l-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl)-2-

methoxyacetamide of formula ( -2ba for the preparation of apremilast.

1 . The process for preparing apremilast according to claims 1-7 and 9, characterized in
that the N -acyled amine of formula ( -2 is converted, in the presence of a solvent, to the free
amine (5)-l by treatment with an acid selected from hydrochloric, hydrobromic, and sulfuric
acid, or a base selected from L OH, KOH, NaOH, Ba(OH) 2, Na2C0 , and K2C0 3.
13. The process according to claim 12, characterized in that the N-acyled amine of
formula ( )-2 is selected from methyl-(5)-(l-(3-ethoxy-4-methoxyphenyl)-2-
(methylsulfonyl)ethyl)carbamate or (S)-N-( 1-(3-ethoxy-4-methoxyphenyl)-2-
(methylsulfonyl)-ethyl)-2-methoxyacetamide.

14. The process for preparing apremilast according to claims 1 to 7, 9 and 12,
characterized in that the solvent is selected from protic polar solvents such as water, C -
alcohols, diols, C1-C8 carboxylic acids or their mixtures with aprotic polar solvents selected
from ethers such as dimethoxyethane, THF and dioxane, a preferred solvent being water,
methanol, ethanol, ethylene glycol, propylene glycol, diethanolamine, dimethoxyethane,
THF, dioxane or their mixtures.

15. The process according to any one of claims 1 to 7, 9 and 1 to 14, characterized in
that the reaction of the amine of formula (S)- l with 3-acetamidophthalic anhydride of
formula 4 is conducted in the presence of water, an organic solvent, or their mixtures, said
organic solvent being preferably selected from the group comprising C2-C5 carboxylic acids,
especially acetic acid, nitriles of C2-C5 carboxylic acids, especially acetonitrile, and polar
aprotic solvents such as dimethyl foraiamide, dimethyl acetamide, dimethyl sulfoxide, and
further hydrocarbons, preferably e.g. toluene, xylenes, α,α,α-trifluorotoluene, chlorobenzene
and n-butyl chloride.

16. The process for preparing apremilast according to claim 1, characterized in that it
comprises a reaction of the racemic amine (rac)-l with dimethyl carbonate, under treatment
with Novozym 435, producing methyl (S)-(l-(3-ethoxy-4-methoxyphenyl)-2-
(methylsulfonyl)ethyl)carbamate of formula ( S -2aa , preferably in the presence of a
racemization catalyst, , the resulting carbamate being converted, with the use of hydrobromic
acid in the presence of acetic acid, to the chiral amine of formula (S -l , which provides,
through the subsequent reaction with 3-acetamidophthalic anhydride of formula 4 in glacial
acetic acid, the desired (S)-{2-[l-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-
acetylaminoisoindolin-l,3-dione of formula 3 .
A . CLASSIFICATION O F SUBJECT MATTER
INV. C12P41/00 C07C315/04 C07C317/18 C07C317/28 C12P13/02
ADD.

According to International Patent Classification (IPC) o r t o both national classification and IPC

B . FIELDS SEARCHED
Minimum documentation searched (classification system followed b y classification symbols)
C12P C07C

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)

EPO-Internal , CHEM ABS Data, WPI Data

C . DOCUMENTS CONSIDERED T O B E RELEVANT

Category* Citation o f document, with indication, where appropriate, of the relevant passages Relevant to claim No.

WO 03/080049 Al (CELGENE CORP [US] ; 1-5

SCHAFER PETER H [US] ; MULLER GEORGE W
[US] ; MAN HON) 2 October 2003 (2003-10-02)
c i ted i n the appl i cati on
c l aims ; f i gure 1 6-16

EP 2 431 371 Al (TIANJIN HEMAY BIO TECH CO 1-16

LTD [CN] ; TIANJIN MICHELE SCI TECH DEV CO
LT) 2 1 March 2012 (2012-03-21)
c i ted i n the appl i cati on
paragraphs [0168] , [0169]

US 2013/217919 Al (CONNOLLY TERRENCE J 8 , 10

[US] ET AL) 22 August 2013 (2013-08-22)
c i ted i n the appl i cati on
paragraphs [0017] , [0231] , [0236] ;
c l aims ; exampl e s 3 ,6,8

-/-

X| Further documents are listed in the continuation of Box C . See patent family annex.

* Special categories of cited documents :

"T" later document published after the international filing date o r priority
date and not in conflict with the application but cited to understand
"A" document defining the general state of the art which is not considered
the principle o r theory underlying the invention
to b e of particular relevance
"E" earlier application o r patent but published o n o r after the international
"X" document of particular relevance; the claimed invention cannot b e
filing date
considered novel o r cannot b e considered to involve a n inventive
"L" documentwhich may throw doubts o n priority claim(s) orwhich is step when the document is taken alone
cited to establish the publication date of another citation o r other
"Y" document of particular relevance; the claimed invention cannot b e
special reason (as specified)
considered to involve a n inventive step when the document is
"O" document referring to a n oral disclosure, use, exhibition o r other combined with one o r more other such documents, such combination
means being obvious to a person skilled in the art
"P" document published prior to the international filing date but later than
the priority date claimed "&" document member of the same patent family

Date of the actual completion of the international search Date of mailing of the international search report

9 September 2016 16/09/2016

Name and mailing address of the ISA/ Authorized officer
European Patent Office, P.B. 5818 Patentlaan 2
N L - 2280 HV Rijswijk
Tel. (+31-70) 340-2040,
Fax: (+31-70) 340-3016
Boeker, Ruth
C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

HOBEN ET AL: " Practi cal chemoenzymati c 1-16

dynami c k i neti c resol uti on of primary
ami nes v i a transfer of a readi l y removabl e
benzyl oxycarbonyl group" ,
TETRAHEDRON LETTERS, PERGAMON , GB,
vol . 49 , no. 6 ,
8 December 2007 (2007-12-08) , pages
977-979 , XP022417897 ,
ISSN : 0040-4039 , D0I :
10. 1016/J .TETLET. 2007 . 12 .017
c i ted i n the appl i cati on
the whol e document

US 5 981 267 A (WONG CHI -HUEY [US] ET AL) 1-5

9 November 1999 (1999-11-09)
c l aims ; f i gure 1 8 , 10

EP 1 870 475 Al (EVONI K DEGUSSA GMBH [DE] ) 1-5

26 December 2007 (2007-12-26)
c l aims 8 , 10
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