(12) United States Patent
`Bader et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,687,646 B2
`Mar. 30, 2010
`
`US007687646B2
`
`(54) POLYIVIORPHIC FORIWS OF OLOPATADINE
`HYDROCHLORIDE AND METHODS FOR
`PRODUCING OLOPATADINE AND SALTS
`THEREOF
`
`GB
`GB
`-'1’
`W0
`
`6/1977
`1 476 215
`8/1977
`1 481 866
`1/1995
`07002733
`10/2007
`WO 2007/119120 A2
`OTHER PUBLICATIONS
`
`.
`Inventors: Thomas Bader, Zurich (CH);
`HanS_Uh.ich Bichsela Hérhausen (CH);
`Bruno Gilumenfi Zurich (CH); Imelda
`Meyer_“,ilmes, Haag (CH); Mark
`Sundermeier’ Dusseldorf
`
`.
`Asslgneesi Azad Pharmaceutical lngredients’AG>
`Schaffliausen (CH); UniVe"Sitit Zfirich:
`Zurich (CH)
`
`Subject to any disclaimer, the term of this
`patem is extended or adjusted under 35
`U.S.C. 154(1)) by 599 days.
`
`11/392 098
`’
`Mar. 28, 2006
`
`Prior Publication Data
`US 2007/0232814 A1
`Oct. 4, 2007
`
`Int CL
`
`Liu ct al., Zhongguo Xinyao Zazhi, 2006, 150.3), 2045-2046*
`Xue et al., Z110I1ggLl(:y2i.0VVllHLl£i.i‘£LltiZ3.Z111, -2004, 14(6), 363-g‘)_64,*
`]Core1}/Pet
`al1.,
`-Hlgifiy-1§€aCé1tV€.
`Equivzfiilenés
`(Elf all Sfliflin
`11p ieny
`iospioianes
`01
`ie . eieospeci
`c
`yii iesis o
`,-
`Dienes by Cis-Ole Fination of Hindered Aldehydes,” Tetrahedron
`,
`1. 26,N .47, 5747-5748 1985 .
`L tt
`Efstiedsallfshima :t al., “Synthesis( and )Antiallergic Activity of
`11—(Aminoalkylidene)—6, 1 1—dihydrod1'benz[b,e]oxepin Derivatives.”
`J. Med. Chem. 35, 2074-2084 (1992).
`Daniel E. Aultz et al., “Dibenz[b,e]oxepina1kanoic Acids as
`N onsteroidal Antiinflarrimatory Agents. 3. u)-(6,11-Dihydro-11-
`oxodibenz[b,e]oxepin-2-yl)a11<anoic Acids," Journal of Medicinal
`Chernistry, vol. 20, No. 11, 1499—1501(1977).
`_
`_
`Daniel E. Aiiltz et al., “Dibenz[b,e]oXep11ialkai1oii: Acids as
`Nonsteroidal Antiinflamrnatory Agents.
`1.
`6,11-Dihydro-11-
`oxodjbenz[b,ejoxepin-2-acetic Acids,” Journal of Medicinal Chem-
`istry, vol. 20, No. 1, 66-70 (1977).
`“6, 1 1—Dihydro—1 1-
`al.,
`Katsujiro
`Ueno
`et
`A1"fl
`:11
`b3
`'
`'A'd 'lP
`::i1\Ilii:1’1’Z.ioii1ii]:i)1{e§ill\jI::$:1na1Efieiiiiiirv ifimig
`7”’3iIi“.B°i§
`1.19751
`_
`_
`_
`Xue et al., “Study on the Synthetic Process of a Novel Anti-Allergic
`Agent Olopatadine Hydrochloride,” Chinese Journal of Medicinal
`Chemistry, vol. 14, No. 6, 2004, 363-367.
`Y. Liu et al., “Synthesis of a New H1, Receptor Antagonist
`Olopamdinegy, Chinese New Drugs Journal, Vol. 15, N0 23, 2006,
`20454045,
`
`* cited by examiner
`
`Primary E_mminer—D. Margaret Seaman
`Assistant Examiner—Niloofar Rahmani
`(74) Attorney, Agent, or Firm—Roberta L. Hastreiter; Scott
`B. Feder; Locke, Lord, Bissell & Liddell LLP
`
`(57)
`
`ABSTIMCT
`
`1,
`h._f
`1
`1
`.d H
`.
`.
`V
`h
`€SdI10\/6 P0 yII10I'p IL UHIIO
`T €pI'€S€I1i1I1V€I1i]0I1pI'0\’l
`olopatadine hydrochloride ([(Z)-3-(dimetliylaniino)propy-
`lidene]-6,1 1-dihydrodibenz[b,e]oxepin-2-acetic acid hydro-
`chloride), a selective histamine H1—receptor antagonist that is
`used for the treatment ofocular symptoms of seasonal allergic
`conjunctivitis. The present invention also provides novel
`methods for producing olopatadine on a large scale, and 111.8
`manner that is cost effective, provides a low level of impuri-
`ties and eliminates the need to use the costly and dangerous
`base, butyllithium, which is used in prior art reactions for
`making olopatadine. The present invention further provides
`novel processes for carrying out a large scale production of
`3—dimethylaminopropyltriplienylphosphoiiium bromide and
`its corresponding hydrobromide salt. which are employed in
`the production of olopatadine, and pharniaceutically accept-
`Z1316 salts Of olopatadine.
`
`45 Claims, 2 Drawing Sheets
`
`(200601)
`C07D 313/10
`U.S. Cl.
`.................................................... .. 549/354
`Field of Classification Search ................ .. 549/354
`See application file for complete search history.
`R f
`C't d
`C crcnccs
`1 0
`U.S. PATENT DOCUMENTS
`11/1967 Tretter ...................... .. 260/240
`4/1970
`260/333
`8/1972
`260/249.8
`10/1978 McFaddcncta1.
`.. 260/333
`
`*
`
`.. 260/544
`H 562/473
`548/2 52
`N 549/354
`.. 514/450
`.. 549/3 54
`~- 514/450
`
`7/1979 McFaddenetal.
`11/1979 McFadden etal‘ .
`3/1931 Rckach at 31.
`11/1933 Lee et 31,
`...... N
`4/1986 1-Ielsley et al.
`10/1989 Lever, Jr. el al
`5/1992 051111113 9‘ 31~
`FOREIGN PATENT DOCUMENTS
`
`3’354‘155
`3,509,175
`3,681,337
`4,118,401
`4,160,781
`4,175,209
`4,282,365
`4,417,063
`4,585,788
`4,871,865
`5,116,863
`
`>>>i>>>>>i>>>
`
`2435613
`2442060
`7-000703
`3716230
`3
`0069810
`0 351 887
`0214779
`0235795
`
`0235796
`
`2/1975
`5/1975
`7/1975
`10/1977
`
`12/1986
`1/1990
`4/1990
`9/1991
`
`9/1997
`
`APOTEX EX1026
`
`Page 1
`
`

`
`U.S. Patent
`
`Mar. 30, 2010
`
`Sheet 1 of2
`
`US 7,687,646 B2
`
`F_ig-_l
`
`XRD (CuKa): Polymorphic form B of Olopatadine-HCI
`
`inte ns ity
`5000
`
`4500
`
`4000
`
`3500—
`
`3000
`
`2500
`
`2000
`
`1 500
`
`,;.JLJ1 Am .L._;.u.J
`
`5
`
`10
`
`Zthetaldegrees
`
`Page 2
`
`Page 2
`
`

`
`U.S. Patent
`
`Mar. 30, 2010
`
`Sheet 2 of2
`
`US 7,687,646 B2
`
`Fig. 2
`
`XRD (Cl.|Ka.)2 Polymorphic form A of Olopatadine-HCI
`
`intensity
`8000
`
`7000
`
`6000—
`
`5000
`
`4000
`
`3000
`
`2000
`
`1000
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`Zthetaldegrees
`
`Page 3
`
`Page 3
`
`

`
`US 7,687,646 B2
`
`1
`POLYMORPHIC FORMS OF OLOPATADINE
`HYDROCHLORIDE AND METHODS FOR
`PRODUCING OLOPATADINE AND SALTS
`THEREOF
`
`BACKGROUND OF THE INVENTION
`
`1. Field of the Invention
`
`The present invention is directed to a novel polymorphic
`form of olopatadine hydrochloride, and to novel methods for
`producing olopatadine, and pharmaceutically acceptable
`salts thereof.
`
`2. Background and Related Art
`Olopatadine-HCl
`([(Z)-3-(dimethylamino)propylidene]-
`6,1 1-dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride)
`is a selective histamine H1 -receptor antagonist that is used for
`the treatment of ocular symptoms of seasonal allergic con-
`junctivitis. The compound may be administered in a solid oral
`dosage form or as an ophthalmic solution.
`
`NMe2*HCl
`
`2
`
`Olopatadine is stated to be an effective treatment for symp-
`toms of allergic rhinitis and urticaria (e.g., sneezing, nasal
`discharge and nasal congestion), as well as in the treatment of
`various skin diseases, such as eczema and dermatitis.
`
`10
`
`15
`
`Olopatadine and its pharmaceutically acceptable salts are
`disclosed in EP 0214779, U.S. Pat. No. 4,871,865, EP
`0235796 and U.S. Pat. No. 5,116,863. There are two general
`routes for the preparation of olopatadine which are described
`in EP 0214779: One involves a Wittig reaction and the other
`involves a Grignard reaction followed by a dehydration step.
`A detailed description of the syntheses of olopatadine and its
`salts is also disclosed in Ohshima, E., et al., J. Med. Chem.
`20 1992, 35, 2074-2084.
`
`COOH
`
`25
`
`o
`
`Olopatadine-HCl
`[(Z)_-3 - (D1methyla.r_n1no)propyl1d_ene]- 6 ,1 1 -d1hyd.ro-
`dibenz[b,e]oXep1n-2-acetic acid hydrochloride
`
`Scheme 1:
`
`EP 0235796 describes a preparation of olopatadine deriva-
`tives starting from 1 1-oxo-6,1 1-dihydroxydibenz[b,e]ox-
`30 epin-2-acetic acid, as well as the following three different
`synthetic routes for the preparation of corresponding dim-
`ethylarninopropyliden-dibenz[b,e]oxepin
`derivatives,
`as
`shown in schemes 1-3 below:
`
`SOC12
`
`o
`
`iHa.1MgCH2CH2CH2NMe2
`
`—N
`
`.:
`
`HO
`
`0
`<\
`N
`
`Y
`
`o
`
`ROH
`
`
`
`Page 4
`
`Page 4
`
`

`
`US 7,687,646 B2
`
`-continued
`
`N /
`
`H \
`
`Y—COOR
`
`Y : —(CH2)m
`m : 0, 1, 2, 3, 4
`R : H, alkyl group
`Hal : halogen
`
`Scheme 2:
`
`O
`
`O
`
`O
`
`Y—COOH
`
`HO
`
`Y—CH2OH
`
`LiAlH4T»
`
`O
`
`R1OHor
`RZCI
`
`R10
`
`Y? CHZORZ
`
`0
`
`Y jCH2OR2
`
`oxidationCT
`
`0
`
`O
`
`HalMgCH2CH2CH2NMe2
`
`R1 : R2 : alkyl group
`R1 : H, R2 : trityl group
`
`HO
`
`Y—CH2OR2
`
`_H2O
`Z»
`
`H
`
`\
`
`Y—CH2OR2
`
`Page 5
`
`Page 5
`
`

`
`US 7,687,646 B2
`
`\
`N /
`
`-continued
`
`\
`N /
`
`H
`
`X
`
`Y—CooH
`
`Cm
`oxidation
`
`H
`
`X
`
`Y—CH2OH
`
`Scheme 3:
`
`O
`
`0
`
`Ph3P
`
`+ Hal/\/\Ha1
`
`G)MPh3P
`
`Hal
`
`Ph$/X/\N/
`
`Wimg reactmn
`
`Scheme 4:
`
`O
`
`15
`
`-continued
`\N /
`
`20
`
`25
`
`R3 : COOH, etc.
`
`The syntheses of several corresponding tricyclic deriva-
`tives are disclosed in the same manner in EP 0214779, in
`which the Grignard addition (analogous to Scheme 1) and the
`35 Wittig reaction (analogous to Scheme 3) are described as key
`reactions.
`The synthetic routes shown above in Schemes 2 and 3 for
`the preparation of olopatadine are also described in Ohshima,
`E., et al., J. Med. Chem. 1992, 35, 2074-2084 (schemes 4 and
`40 5 below). In contrast to the above-identified patents, this
`publication describes the separation ofthe Z/E diastereomers
`(scheme 5).
`
`O
`
`COOH
`
`HO
`
`CHZOH
`
`LiA1H4T»
`98%
`
`CH2OCPh3
`
`KMNO4‘j
`81%
`
`O
`
`65%lPh3CCl
`HO
`
`o
`
`O
`
`0
`
`o
`
`8l%lClMgCH2CH2CH2NMe2
`
`CH2OCPh3
`
`Page 6
`
`Page 6
`
`

`
`/
`jN
`
`HO
`
`O
`
`US 7,687,646 B2
`
`-continued
`
`\ Z
`
`CHZOCPH3
`
`TSOH X H20
`T»
`
`H
`
`\
`
`CHZOH
`
`O
`
`E/Z : 9/1
`after recrystallization:
`E/Z 2 99/1
`yield: 68%
`
`oxidation 7
`
`N /
`
`H
`
`COOH
`
`A significant disadvantage of the synthetic route depicted
`in Scheme 4 is the diastereoselectivity of the dehydration
`step, which gives up to 90% of the undesired E-isomer. The 40
`last step (oxidation) is not described in this publication.
`Scheme 5 below depicts a prior art method disclosed in
`Ohshima, E., et al., supra.
`
`Scheme 5:
`
`Bra
`WW
`Ph3P
`
`N/
`| X HBr
`
`1. BuLi
`2
`'
`
`O
`
`COOH
`
`O
`
`3. MeOH, TsOH
`61%
`
`
`
`COOCH
`
`3
`
`O
`
`E/Z : 1/2
`
`yield?lNaOH
`
`Page 7
`
`Page 7
`
`

`
`US 7,687,646 B2
`
`10
`
`\
`N1 x TsOH
`
`-continued
`
`N/
`
`COOH
`
`H
`
`coon
`
`TsOH<
`separation of the
`diastereomers by
`fractional crystallization
`62%
`
`o
`
`E/Z - 1/2
`
`O Z
`
`-isomer
`
`H
`
`\
`
`49% N HCO
`
`(2 steps)i
`
`3'
`
`3
`
`{
`
`x HCI
`
`coon
`
`‘ O
`
`O Z
`
`-isomer
`
`N”’
`
`H
`
`T»
`COOH SNHO
`
`H
`
`\ 80%
`
`O Z
`
`-isomer
`
`Each of the prior art methods for synthesis of olopatadine
`have significant cost and feasibility disadvantages. Specifi-
`cally with the respect to the method set forth in Scheme 5, the
`disadvantages include:
`
`(1) the need for excess reagents, e. g. 4.9 equivalents Wittig
`reagent and 7.6 equivalents of BuLi as the base for the
`Wittig reaction, which can be expensive;
`
`(2) the need to use Wittig reagent in its hydrobromide salt
`form, so that additional amounts of the expensive and
`dangerous butyllithium reagent are necessary for the
`“neutralization” of the salt (i.e., excess butyllithium is
`required because of the neutralization);
`
`(3) because 7.6 equivalents of the butyllithium are used
`(compared to 9.8 equivalents of the (Olo-IM4) Wittig
`reagent), the Wittig reagent is not converted completely
`to the reactive ylide form, and thus more than 2 equiva-
`lents of the Wittig reagent are wasted;
`
`(4) the need for an additional esterification reaction after
`the Wittig reaction (presumably to facilitate isolation of
`the product from the reaction mixture) and the purifica-
`tion of the resulting oil by chromatography;
`
`(5) the need to saponify the ester and to desalinate the
`reaction product (a diastereomeric mixture) with ion
`exchange resin, prior to separating the diastereomers;
`
`(6) the need, after the separation of the diastereomers, and
`liberation of the desired diastereomer from its corre-
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`sponding pTsOH salt, to desalinate the product (olopata-
`dine) again with ion exchange resin;
`
`(7) the formation of olopatadine hydrochloride from olo-
`patadine is carried out using 8 N HCl in 2-propanol,
`which may esterify olopatadine and give rise to addi-
`tional impurities and/or loss of olopatadine; and
`
`(8) the overall yield of the olopatadine, including the sepa-
`ration of the diastereomers, is only approximately 24%,
`and the volume yield is less than 1%.
`
`As noted above, the known methods for preparing olopata-
`dine in a Wittig reaction use the intermediate compounds
`6,1 1-dihydro-1 1 -oxo-dibenz[b,e]oxepin-2-acetic acid and
`3-dimethylaminopropyltriphenylpho sphonium
`bromide
`hydrobromide. Preparation of these chemical intermediates
`by prior art syntheses present a number of drawbacks that add
`to the cost and complexity of synthesizing olopatadine.
`
`One known method for preparation of the compound 6,1 1-
`dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid is depicted
`in Scheme 6, below. See also, U.S. Pat. No. 4,585,788; Ger-
`man patent publications DE 2716230, DE 2435613, DE
`2442060, DE 2600768; Aultz, D. E., et al., J. Med. Chem.
`(1977), 20(1), 66-70; and Aultz, D. E., et al., J. Med. Chem.
`(1977), 20(11), 1499-1501.
`
`Page 8
`
`Page 8
`
`

`
`Scheme 6:
`
`COOEt
`
`NB S
`benzoylperoxideT»
`CCI4
`
`US 7,687,646 B2
`
`COOEt
`
`COOEt
`
`Br
`
`HQ
` >
`KZCO3
`KI
`MEK
`
`COOEt
`
` £
`
`COOEt
`0{%
`
`KOH
`
`COOH
`
`EtOH, P4010
`sulfolan or
`
` acetic acid
`alternative:
`PPA or
`PPA in acetic acid
`
`COOH
`
`O
`
`COOH
`
`O
`
`0
`
`6,11-dihydro-11-oXo-dibenz-
`[b,e]oXepin-2-acetic acid
`
`cyclization
`
`SOCIZ
`
`COCI
`
`O
`
`COCI
`
`In addition, U.S. Pat. No. 4,417,063 describes another
`method for the preparation of 6,1 1-dihydro-1 1 -oxo -dibenz[b, 40
`e]oxepin-2-acetic acid, which is shown in Scheme 7.
`
`Scheme 7:
`
`COOEt
`
`Br
`
`O
`
`o
`
`+ H0
`
`CHO W
`
`COOH
`
`WC
`‘_
`
`O
`
`o
`
`6,11-dihydro-11-oXo-dibenz-
`[b,e]oXepin-2-acetic acid
`
`COOEt
`
`0
`
`Cl
`
`COOH
`
`BnN(Et)3Cl
`CHC13,
`50% NaOH
`
`
`CH0
`COOH
`
`O
`
`1. soc12
`2. AICI3
`
`COOH
`
`OH
`
`1. soc12
`2. AlCl3
`
`Page 9
`
`Page 9
`
`

`
`13
`
`US 7,687,646 B2
`
`-continued
`
`HO
`
`SOCIZ
`
`O
`
`COOH
`
`(1976), 19(7), 941,
`.I. Med. Chem.
`Ueno, K., et al.,
`describes yet another prior art method for preparing 6,11-
`dihydro-ll-oxo-dibenz[b,e]oxepin-2-acetic acid, which is
`shown below in Scheme 8.
`
`Scheme 8:
`
`COONa
`
`T»
`1. 1so—225° C.
`2. H2O,HC1
`59%
`
`coon
`
` /L
`
`coon
`O
`
`PPA(frorn
`H3PO4,
`P205)
`
`80° C.
`43%
`
`COOH
`
`O
`
`O
`
`6,1l-dihyd.ro-ll-oXo-dibenz-
`[b,e]oxepin-2-acetic acid
`
`Further, as depicted in Scheme 9, below, U.S. Pat. Nos.
`4,118,401; 4,175,209; and 4,160,781 disclose another
`method for the synthesis of 6,1 l-dihydro-l l-oxo-dibenz[b,e]
`oxepin-2-acetic acid.
`
`COOH
`
`OH
`
`Scheme 9:
`
`O
`
`S, HN
`O
` ,l40—l45° C.
`
`15
`
`20
`
`25
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`0
`
`-continued
`COOH
`
`OH
`
`BnBrT»
`KZCO3, MEK
`
`S N
`{/0
`
`COOBn
`
`OBn
`
`S
`
`/W
`0/0
`
`l. KOH
`2. HCl4»
`
`COOH
`
`O
`
`O
`
`OH
`
`PPA
`l50—200° C.
`alternative
`SOCIZ, AlCl3
`
`O
`
`COOH
`
`O
`
`6, l l -dihydro-l l-oxo-dibenz-
`[b,e]oxepin-2-acetic acid
`
`JP 07002733 also describes the preparation of 6,1 l-dihy-
`dro-l l-oxo-dibenz[b,e]oxepin-2-acetic acid, as follows in
`Scheme 10, below.
`
`Page 10
`
`Page 10
`
`

`
`US 7,687,646 B2
`
`Scheme 10:
`
`O
`
`O +
`
`H0
`
`COOH
`
`0
`
`COOH
`
`NaOMe in
`L,DMF
`100—130° C.
`95.2%?
`
`COOH
`
`cyclization
`(not described)4»
`
`O
`
`COOH
`
`O
`
`O
`
`6,11-dihydro-11-oxo-dibenz-
`[b,e]oxepin-2-acetic acid
`
`Specific methods and reagents for performing the intramo-
`lecular Friedel-Crafts reaction for cyclizing 4-(2-carboxy-
`benzyloxy)-phenylacetic acid to form 6,1 1-dihydro-1 1-oxo-
`dibenz[b,e]oxepin-2-acetic acid are described in (1) EP
`0068370 and DE 3125374 (cyclizations were carried out at
`reflux with acetyl chloride or acetic anhydride in the presence
`of phosphoric acid, in toluene, xylene or acetic anhydride as
`solvent); (2) EP 0069810 and U.S. Pat. No. 4,282,365 (cy-
`clizations were carried out at 70-80° C. with trifluoroacetic
`
`anhydride in a pressure bottle); and (3) EP 0235796; U.S. Pat.
`No. 5,116,863 (cyclizations were carried out with trifluoro-
`acetic anhydride in the presence of BF3.OEt2 and in methyl-
`ene chloride as solvent).
`Turning to the Wittig reagent for use in preparing olopata-
`dine, 3-dimethylaminopropyltriphenylphosphonium bro-
`mide-hydrobromide and methods for its preparation are
`described in U.S. Pat. Nos. 3,354,155; 3,509,175; 5,1 16,863,
`and EP 0235796, and depicted in Scheme 11 below.
`
`Scheme 11:
`
`Ph3P
`
`+ Br/\/\Br —>
`
`6Br
`
`(9 /\Z\ HNMe2
`Ph3P
`Br —>
`
`(*3 /V\
`Ph3P
`
`NMe2*HBr
`
`Corey, E. J ., et al., Tetrahedron Letters, Vol. 26, No. 47,
`5747-5748, 1985 describes a synthetic method for the prepa-
`ration of 3-dimethylarninopropyltriphenylphosphonium bro-
`mide (free base), which is shown below in Scheme 12.
`
`Scheme 12:
`
`Ph3P
`
`+ Br
`
`M benzene
`Br m
`
`9
`1.HNMe2
`Br
`QM 2. extraction
`Ph3P
`Br
`'
`
`BIO
`O
`’ Ph3P/\/\NMe2
`
`The prior art methods for preparing olopatadine and the
`chemical intermediates 6,1 1-dihydro-11-oxo-dibenz[b,e]ox-
`epin-2-acetic
`acid,
`and
`3-dimethylaminopropyltriph-
`enylphosphonium bromide-hydrobromide (and its corre-
`sponding free base) are not desirable for synthesis of
`olopatadine on a commercial scale. For example, due to high
`reaction temperatures and the absence of solvents, the syn-
`thesis described in Ueno, K., et al., J. Med. Chem. (1976),
`19(7), 941 and in U.S. Pat. No. 4,282,365 for preparation of
`the intermediate 4-(2-carboxybenzyloxy)phenylacetic acid is
`undesirable for a commercial scale process, although the
`synthesis described in JP 07002733, and set forth in Scheme
`13 below, is carried out in an acceptable solvent.
`
`S cheme 13:
`
`H0
`
`COOH
`
`1. NaOMe (30% in MeOH) >
`DMF
`100—130° C.
`2. HCl
`
`COOH
`
` ;
`
`COOH
`O /
`
`Olo—IM1
`
`The processes described in the literature for the intramo-
`lecular Friedel-Crafts acylation used to prepare 6,11-dihy-
`dro-11-oxo-dibenz[b,e]oxepin-2-acetic acid are undesirable
`for commercial scale synthesis because they generally
`require either drastic conditions in the high boiling solvents
`(e.g. sulfolane) or they require a two step synthesis with the
`corresponding acid chlorides as intermediate. Furthermore
`the procedures for synthesizing 6,1 1-dihydro-1 1-oxo-dibenz
`[b,e]oxepin-2-acetic acid as set forth in European patent
`documents EP 0069810 and EP 0235796 use excess trifluo-
`
`roacetic anhydride (see Scheme 14), and are carried out with-
`out solvent in a pressure bottle at 70-80° C. (EP 0069810) or
`at room temperature in methylene chloride using catalytic
`amounts of BF3.Et2O (EP 0235796).
`
`Page 1 1
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Page 11
`
`

`
`US 7,687,646 B2
`
`Scheme 14:
`
`COOH
`
`O
`
`O10-1M1
`
`COOH
`
`TFAA
`f»70-80 C.
`
`O
`
`COOH
`
`O
`
`O10-1M2
`
`According to the teachings in EP 0235795, a suspension of
`3-bromopropyltriphenylphosphonium bromide (Olo-1M4) in
`ethanol was reacted with 13.5 equivalents of an aqueous
`dimethylamine solution (50%) to provide dimethylaminopro-
`pyltriphenylphosphonium bromide HBr. After this reaction,
`the solvent was distilled off and the residue was recrystallized
`(yield: 59%).
`U.S. Pat. No. 3,354,155 describes a reaction of 3-bro-
`mopropyltriphenylphosphonium bromide with 4.5 equiva-
`lents dimethylamine. The solution was concentrated and the
`residue was suspended in ethanol, evaporated and taken up in
`ethanol again. Gaseous hydrogen bromide was passed into
`the solution until the mixture was acidic. After filtration, the
`solution was concentrated, whereupon the product crystal-
`lized (yield of crude product: 85%). The crude product was
`recrystallized from ethanol.
`A significant disadvantage of the prior art processes for
`making 3-dimethylaminopropyltriphenylphosphonium bro-
`mide hydrobromide involves the need for time consuming
`steps to remove excess dimethylamine, because such excess
`dimethylamine prevents crystallization of the reaction prod-
`uct. Thus, to obtain crystallization, the prior art processes
`require, for example, repeated evaporation of the reaction
`mixture (until dryness), which is undesirable for a commer-
`cial scale synthesis of olopatadine.
`Corey, E. J ., et al., Tetrahedron Letters, Vol. 26, No. 47,
`5747-5748 (1985) describes the preparation of 3-dimethy-
`laminopropyltriphenylphosphonium bromide (free base)
`from its corresponding hydrobromide salt. But the prepara-
`tion of the free base, which uses an extraction step with
`methylene chloride as the solvent, is undesirable for commer-
`cial production because of the poor solubility of the free base
`in many of the organic solvents that are desirable for com-
`mercial production of chemical products, and because of the
`high solubility of the free base in water, causing low volume
`yields and loss of material. Furthermore according to this
`publication, the work up procedure gave an oil, which crys-
`tallized only after repeated evaporation in toluene.
`It would be desirable to provide processes for preparing
`olopatadine on a large scale, e.g., on a commercial scale, in a
`manner that is cost efiicient and provides olopatadine that has
`a low level of impurities, including a low level of the undes-
`ired diastereomer.
`It further would be desirable to eliminate the need to
`
`derivatize the olopatadine product of the Wittig reaction, e.g.,
`by esterification, in order to separate the olopatadine from the
`reaction mixture. It would be especially desirable to provide
`
`18
`a method for preparing olopatadine that allows for isolation of
`olopatadine directly from the reaction mixture.
`It would also be desirable to eliminate the need for the
`
`costly and dangerous base, butyllithium, that is used in pre-
`viously described Wittig reactions for making olopatadine.
`It would also be desirable to provide improved methods for
`preparing chemical intermediates used in the synthesis of
`olopatadine via a Wittig reaction.
`In the description of the various aspects of applicants’
`invention that follows, reference may be made to the chemical
`intermediates, final products and byproducts in accordance
`with the nomenclature set forth immediately below.
`The chemical names and structures for compounds that are
`discussed herein are set forth below in Table 1.
`
`TABLE 1
`
`Structures, chemical names and abbreviations
`Abbreviation for
`Chemical name
`
`Chemical name/structure
`
`Phthalide
`
`0
`
`None
`
`10
`
`15
`
`20
`
`25
`
`CgH5O2
`Exact Mass: 134.04
`M01. Wt.: 134.13
`
`30
`
`4-Hyd.r0xypheny1acetic acid
`COOH
`
`None
`
`HO
`
`35
`
`C8H8O3
`Exact Mass: 152.05
`M01. Wt.: 152.15
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4- (2-Ca.rb0xybenzy10xy)-phenylacetic acid
`COZH
`
`COOH
`
`O10-1M1
`
`O
`
`C1sH1405
`Exact Mass: 286.08
`M01. Wt.: 286.28
`
`6,11-Dihyd.r0-11-0x0-dibenz[b,e]0xepin-
`2-acetic acid
`
`COOH
`
`O
`
`0
`
`C1sH1204
`Exact Mass: 268.07
`M01. Wt.: 268.26
`
`Triphenylphosphine
`Ph3P
`
`CISHISP
`Exact Mass: 262.09
`M01. Wt.: 262.29
`
`O10-1M2
`
`None
`
`Page 12
`
`Page 12
`
`

`
`US 7,687,646 B2
`
`19
`
`TABLE 1-continued
`
`20
`
`TABLE 1-continued
`
`Structures, (chemical) names and abbreviations
`
`Structures, (chemical) names and abbreviations
`
`Abbreviation for
`Chemical name
`
`None
`
`Olo-IM3
`
`Olo-IM4
`
`Chemical name/structure
`
`1,3.Dibromopropane
`
`Br/\/\ Br
`C3H5B1‘2
`Exact Mass: 199.88
`Mol. Wt.: 201.89
`
`3- 3romopropyl-
`tri ahenylphosphonium bromide
`I
`
`Br/\/\B
`C3H5B1‘2
`Exact Mass: 199.88
`Mol. Wt.: 201.89
`
`3- )imethylaminopropyl-
`tri ahenylphosphonium bromide
`hydrobromide
`9
`Br
`(9
`P
`N x HBr
`\ /V\ /
`Ph/ \
`
`Ph
`
`C23H28Br2NP
`Exact Mass: 507.03
`Mol. Wt.: 509.26
`
`3-Dimethylaminopropyl-
`triphenylphosphonium bromide
`
`Olo-IM4 (free base)
`
`Olo-IM4 ylide
`
`C23H27BrNP
`Exact Mass: 427.11
`Mol. Wt.: 428.34
`
`3-Dimethylamino-propylidene-
`triphenylphosphine
`Ph
`
`Ph/
`
`N
`l
`
`P\
`
`Ph
`C23H2sNP
`Exact Mass: 347.18
`Mol. Wt.: 347.43
`
`Triphenylphosphine oxide
`Ph 0
`\|lP—Ph
`/Ph
`
`CISHISOP
`Exact Mass: 278.09
`Mol. Wt.: 278.28
`
`Abbreviation for
`Chemical name
`
`Olo-IM4 BP1
`
`Olo
`
`Chemical name/structure
`
`3-Dimethylaminopropyl-
`diphenylphosphine oxide
`
`Ph
`
`if/X/\
`>P
`Ph
`
`N/
`|
`
`C17H22NOP
`Exact Mass: 287.14
`Mol. Wt.: 287.34
`
`(Z)-11-[3 -Dimethylamino-
`propylidene]- 6 ,11-dihydro-
`dibenz[b,e]oxepin-2-acetic acid
`Olopatadine
`
`\Nm
`
`COOH
`
`O
`
`C21H23NO3
`Exact Mass: 337.17
`Mol. Wt.: 337.41
`
`(E)-11-[3-Dimethylamino-
`propylidene]- 6 ,11-dihydro-
`dibenz[b,e]oxepin-2-acetic acid
`
`Olo-BP1
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`/N
`
`55
`
`COOH
`
`None
`
`60
`
`65
`
`O
`
`C21H23N03
`Exact Mass: 337.17
`Mol. Wt.: 337.41
`
`Page 13
`
`Page 13
`
`

`
`21
`
`TABLE 1-continued
`
`US 7,687,646 B2
`
`22
`
`Structures, chemical names and abbreviations
`Abbreviation for
`Chemical name
`
`Chemical name/structure
`
`Olo-HBr
`
`Olo-HCl
`
`(Z)-11-[3-Dimethylamino-
`propylidene]-6,1 1-dihydro-
`dibenz[b,e]oxepin-2-acetic acid
`hydrobromide
`
`H
`
`<§N/ Bro\
`
`COOH
`
`COOH
`
`
`
`O
`
`C21H24BrNO3
`Exact Mass: 417.09
`Mol. Wt.: 418.32
`
`(Z)-11-[3-Dimethylamino-
`propylidene]-6,1 1-dihydro-
`dibenz[b,e]oxepin-2-acetic acid
`hydrochloride
`H
`31¢ Cl 9\
`
`X
`
`O
`
`C21H24ClNO3
`Exact Mass: 373.14
`Mol. Wt.: 373.87
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is an XRD profile of the polymorphic Form B of
`olopatadine hydrochloride.
`FIG. 2 is an XRD profile of the polymorphic Form A of 50
`Olopatadine-HCl.
`
`DESCRIPTION OF THE INVENTION
`
`In one aspect, a process ofthe invention concerns a process 55
`for preparing olopatadine or a salt thereof, comprising:
`(a)
`reacting
`1 1-oxo-6,1 1-dihydrodibenz[b,e]oxepin-2-
`acetic acid, a Wittig reagent selected from the group consist-
`ing
`of
`3-dimethylamino -propyltriphenylpho sphonium
`halides and salts thereof, and a suitable base, under Wittig
`reaction conditions, to provide a reaction mixture containing
`olopatadine;
`(b) adding an amount of water sufiicient to protonate
`residual ylide present in the reaction mixture to provide a
`hydrolyzed reaction mixture;
`(c) adjusting the pH of the hydrolyzed reaction mixture, or
`aqueous phase thereof, to a pH ofabout pH 12 or higher, ifthe
`
`65
`
`60
`
`reaction mixture of step (b) is not at least about pH 12, to
`convert excess 3-dimethylamino-propyltriphenylphospho-
`nium halide, or salt thereof, into 3-dimethylamino-propyl-
`diphenylphosphine oxide;
`(d) extracting the solution of step (c) with a suitable solvent
`to provide a solution containing a diastereomeric mixture of
`olopatadine and (E)-1 1-[3 -dimethylaminopropylidene] -6,
`1 1-dihydrodibenz[b,e]oxepin-2-acetic acid and having a sub-
`stantially reduced amount of 3-dimethylamino-propyldiphe-
`nylphosphine oxide;
`(e) adjusting the pH of the solution obtained in step (d) to
`a pH between about pH 4 and pH 5 to provide acid-addition
`salts of olopatadine and (E)-11-[3-dimethylaminopropy-
`lidene]-6,1 1-dihydrodibenz[b,e]oxepin-2-acetic acid;
`(f) extracting the acid-addition salts of olopatadine and
`(E)-1 1-[3-dimethylarninopropylidene] -6,1 1-dihydrodibenz
`[b,e]oxepin-2-acetic acid with a water-miscible solvent
`selected from the group consisting of (i) n-butanol; and (ii)
`mixtures ofmethyl-THF and a C1 -C4 alcohol; provided that if
`the selected solvent is a mixture of methyl-THF and a C1-C4
`alcohol, then the solution is evaporated and the residue is
`taken up in n-butanol/water;
`(g) concentrating by azeotropic distillation the n-butanol/
`water solvent containing the acid-addition salts of olopata-
`dine and (E)-1 1-[3-dimethylarninopropylidene]-6,11-dihy-
`drodibenz[b,e]oxepin-2-acetic acid; and
`(h) fractionally crystallizing the acid-addition salt of olo-
`patadine.
`In another aspect, a process of the invention concerns a
`process for preparing olopatadine or a salt thereof, compris-
`ing:
`1 1-oxo-6,1 1-dihydrodibenz[b,e]oxepin-2-
`reacting
`(a)
`acetic acid, a Wittig reagent selected from the group consist-
`ing
`of
`3-dimethylarnino-propyltriphenylphosphonium
`halides and salts thereof, and a suitable base, under Wittig
`reaction conditions, to provide a reaction mixture containing
`olopatadine;
`(b) adding an amount of water sufiicient to protonate
`residual ylide present in the reaction mixture to provide a
`hydrolyzed reaction mixture;
`(c) adjusting the pH of the hydrolyzed reaction mixture, or
`aqueous phase thereof, to a pH ofabout pH 12 or higher, ifthe
`reaction mixture of step (b) is not at least about pH 12, to
`convert excess 3-dimethylamino-propyltriphenylphospho-
`nium halide, or salt thereof, into 3-dimethylamino-propyl-
`diphenylphosphine oxide;
`(d) extracting the solution of step (c) with a suitable solvent
`to provide a solution containing a diastereomeric mixture of
`olopatadine and (E)-1 1-[3 -dimethylaminopropylidene] -6,
`1 1-dihydrodibenz[b,e]oxepin-2-acetic acid and having a sub-
`stantially reduced amount of 3-dimethylamino-propyldiphe-
`nylphosphine oxide;
`(e) adjusting the pH of the solution obtained in step (d) to
`a pH of from about pH 6.5 to pH 8.0 to provide a solution
`containing olopatadine and (E)-11-[3-dimethylaminopropy-
`lidene]-6,1 1-dihydrodibenz[b,e]oxepin-2-acetic acid;
`(f) extracting the solution obtained in step (c) with n-bu-
`tanol to provide an n-butanol/water solution of olopatadine
`and
`(E)-1 1-[3-dimethylaminopropylidene]-6,1 1-dihydrod-
`ibenz[b,e]oxepin-2-acetic acid;
`(g) adjusting the pH of the solution obtained in step (f) to a
`pH of from about pH 4 to about pH 5 to provide acid-addition
`salts of olopatadine and (E)-11-[3-dimethylaminopropy-
`lidene]-6,1 1-dihydrodibenz[b,e]oxepin-2-acetic acid;
`
`Page 14
`
`Page 14
`
`

`
`US 7,687,646 B2
`
`23
`(h) concentrating by azeotropic distillation the n-butanol/
`water solvent containing the acid-addition salts of olopata-
`dine and (E)-l l-[3-dimethylarninopropylidene]-6, l l -dihy-
`drodibenz[b,e]oxepin-2-acetic acid;
`(i) fractionally crystallizing the acid-addition salt of 010-
`patadine.
`In other embodiment of the process, optionally the acid-
`addition salt of olopatadine may be treated with a sufficient
`
`24
`
`amount of base to liberate olopatadine free base, and option-
`ally converted from the free base to a pharmaceutically
`acceptable salt.
`
`The general route for the preferred synthesis of the salt
`olopatadine hydrobromide (e.g., using HBr in step (e) to
`lower the pH to between about pH 4 and pH 5) and separation
`of the diastereomers is shown below in Scheme 15.
`
`Scheme l5:
`
`9
`
`eq.
`.
`a
`—
`)
`1 N H (7 8
`Br
`®/\/\ / THF, 50—60° C.
`Ph3P
`N X HBr
`l
`
`2.7 equivalents
`Olo—lM4
`
`O
`
`COOH
`
`2_
`
`/
`/1/\
`
`Ph3P
`
`/
`
`N
`|
`
`o1 (I)M2
`
`0.
`20 300 C
`'
`
`-
`
`Bre
`
`Olo—lM4 ylid
`
`(*3/\/\
`
`Ph3P
`
`TX
`
`l. NaH (3.5—4 eq.)
`
`THF, 50—60° C.
`
`2.7 equivalents
`Olo-IM4 (free base)
`
`N /
`
`H
`
`0
`Z/E = 70/30
`
`C00Na
`
`+ P113?/\/\T/ +
`9Br
`
`POPh3
`
`+
`
`Ph3P
`
`N
`|
`
`l. +H2O
`pH = 12-13
`2. evaportion ofTHF and benzene
`
`N /
`
`N /
`
`-
`
`‘
`
`H
`Q
`
`O
`
`Z/E = 70/30
`
`COW
`+ small amounts of
`byproducts
`
`W?z::::3:;;/
`LHBHOH
`
`\
`
`H
`t
`
`O
`
`Z/E = 70/30
`
`COW <3
`/
`4“ Ph2P/\Z\N 4“ POP113
`l
`
`aqueous layer
`
`aqueous layer
`
`+ HBr
`extraction at pH : 4.2-4.6 with THF
`or MeTHF/iPrOH or BuOH
`
`Page 15
`
`Page 15
`
`

`
`25
`
`26
`
`US 7,687,646 B2
`
`-continued
`
`COOH
`
`Z/E : 70/30
`
`organic layer
`
`(azeotropic) distillation and
`crystallization from BuOH >
`
`COOH
`
`O
`
`Z-isomer
`Olo-HBr
`Olopatadine-HBr
`yield: up to 55%
`Z/E-isomer ~ 98.5/1.5
`
`It will be appreciated that the ylide is the reactive species in
`the Wittig reaction and may be conveniently prepared from
`3-bromopropyltriphenylphosphonium bromide HBr, or its
`corresponding free base, or other 3-dimethylpropytripheny-
`phonium halides and hydrohalide salts thereof, where the
`halogen is bromine, chlorine or iodine. A preferred way to
`provide the ylide entails reacting 3-dimethylpropyltriph-
`enylphosphonium bromide HBr (Olo-IM4), or its corre-
`sponding free base, bromopropyltriphenylphosphonium bro-
`mide (Olo-IM4 free base) with NaH in a suitable solvent
`under a N2 atmosphere. Preferably the NaH or other base is
`present at a molar excess as described herein. The reaction to
`form the ylide preferably may be carried out at a temperature
`in the range of 10-70° C. A preferred reaction is carried out at
`a temperature in the range of 10-40° C., more preferably
`20-30° C., for about 40 minutes, followed by elevating the
`temperature to about 40-70° C., more preferably 55-60° C.,
`for about 3 hours. The ylide containing reaction mixture then
`may be cooled to a temperature below 10° C. and may be
`concentrated prior to initiating the Wittig reaction by careful
`addition of a solution of 6,11-dihydro-11-oxo-dibenz[b,e]
`oxepin-2-acetic acid (Olo-IM2). After addition, the reaction
`mixture is stirred, preferably at 20-25° C. for about 20-30
`hours, then cooled to <10° C., followed by addition of water
`to quench the reaction. Suitable solvents for carrying out the
`Wittig reaction, including the step ofylide formation, include
`anhydrous solvents such as tetrahydrofuran (THF), dimeth-
`ylformamide (DMF), N-methylpyrrolidone (NMP) and tolu-
`ene.
`
`We have found that the dangerous and expensive butyl-
`lithium reagent, which is used in the prior art reactions, can be
`advantageously replaced with sodium hydride (NaH). Alter-
`native bases including LiH, NaOtBu, NaOtPent, KOtBu,
`Scheme 16:
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`NaOMe, NaOEt, and KHMDS, as well as mixtures of these
`bases, even when used in various solvents including THF,
`DMF, NMP and toluene, and mixtures thereof, were found to
`be substantially inferior to either butyllithium or NaH. Bases
`other than butyllithium and NaH resulted in incomplete con-
`version, isomerization of olopatadine into the undesired (E)-
`diastereomer (especially ifthe base was used in excess) or the
`formation of numerous byproducts.
`We have found that within 30 hours at room temperature a
`reaction using about 2.7 equivalents of 3-dimethylaminopro-
`pyltriphenylpho sphonium bromide hydrobromide (Olo -IM4)
`and not more than about 7-8 equivalents of NaH gave an
`almost quantitative conversion of 6,11-dihydro-11-oxo-
`dibenz[b,e]oxepin-2-acetic acid (Olo-IM2) to a diastereo-
`meric mixture of olopatadine with a (Z)/(E) ratio of about
`70:30. Use of the free base, 3-dimethylaminopropyltriph-
`enylphosphonium bromide, requires only about 3.5-4 equiva-
`lents ofNaH. See Scheme 16 below. The reaction yield for the
`(Z)-isomer was up to 67%. The novel Wittig reaction using
`NaH is stable and robust. Neither excess NaH, nor higher
`temperatures (up to 30° C.), were found to have an adverse
`influence on the selectivity and yield of the reaction.
`The ylide is formed almost quantitatively by heating a
`mixture ofNaH and the Wittig reagent (3 -dimethylaminopro-
`pyltriphenylphosphonium bromide or
`its corresponding
`hydrobromide salt) in THF for 2.5 to 3 hours at 55-60° C.
`Then, 6,11-dihydro-1 1-oxo-dibenz[b,e]oxepi