(19)
`
`Japanese Patent Office (JP)
`
`dl)
`
`Unexamined Patent
`Application (Kokai) No.
`
`(12) Unexamined Patent Gazette (A)
`
`56-122328
`
`Int. CL?
`(51)
`C07C 59/46
`51/43
`59/62
`31/557
`177/00
`
`A61K
`C07C
`
`Classification
`Symbols
`
`AEL
`
`Internal Office
`Registration Nos.
`7188-4C
`
`7188-4C
`6617-4C
`7430-4H
`
`(43) Date of Publication: September 25, 1981
`
`Request for Examination: Not yet submitted
`
`Number of Claims: 2
`
`Total of 4 pages[in original]
`
`
`
`(54) Title of the Invention:©.CRYSTALLINE AMINE SALT OF
`METHANOPROSTACYCLIN DERIVATIVE,
`MANUFACTURING METHOD THEREOF, AND
`PURIFYING METHOD THEREOF
`
`
`
`(21)—Application No.: 55-25726
`
`February 29, 1980
`Date of Filing:
`(22)
`
`(72)—Inventor: Kawakami, Hajime
`Takarazuka-shi, Hyogo-ken 2-chome, 14-ban, 7-go
`
`(72)—Inventor: Ono, Ketichi
`Osaka-shi, Higashityodogawa-ku, Higashiawaji 1-chome, 5-ban, 3-
`530-go
`
`(72)—Inventor: Sugie, Akihiko
`Toyonaka-shi, Sonehigashinocho, 2-chome, 10-ban, 1-116-go
`
`(72)—Inventor: Katsube, Sumimoto
`Toyonaka-shi, Machiganeyama-cho,10-20
`
`(71)—Applicant: Sumitomo Chemical Co., Ltd.
`Osaka-shi, Higashi-ku, Kitahama, 5-chome, 15-banchi
`
`(74)—Agent: Katsuya Kimura, Patent Attorney
`
`SPECIFICATION
`
`1. Title of the Invention
`
`CRYSTALLINE AMINE SALT OF METHANOPROSTACYCLIN DERIVATIVE,
`
`MANUFACTURING METHOD THEREOF, AND PURIFYING METHOD THEREOF
`
`IP 56 —122328 A
`
`Page 1
`
`SteadyMed- Exhibit 1007 - Page 1
`
`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 001
`
`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 001
`
`
`
`Japanese Patent Office (JP)
`
`dl)
`
`Unexamined Patent
`Application (Kokai) No.
`
`(12) Unexamined Patent Gazette (A)
`
`56-122328
`
`Int. CL?
`(51)
`C07C 59/46
`51/43
`59/62
`31/557
`177/00
`
`A61K
`C07C
`
`Classification
`Symbols
`
`AEL
`
`Internal Office
`Registration Nos.
`7188-4C
`
`7188-4C
`6617-4C
`7430-4H
`
`(43) Date of Publication: September 25, 1981
`
`Request for Examination: Not yet submitted
`
`Number of Claims: 2
`
`Total of 4 pages[in original]
`
`
`
`(54) Title of the Invention:©.CRYSTALLINE AMINE SALT OF
`METHANOPROSTACYCLIN DERIVATIVE,
`MANUFACTURING METHOD THEREOF, AND
`PURIFYING METHOD THEREOF
`
`
`
`(21)—Application No.: 55-25726
`
`February 29, 1980
`Date of Filing:
`(22)
`
`(72)—Inventor: Kawakami, Hajime
`Takarazuka-shi, Hyogo-ken 2-chome, 14-ban, 7-go
`
`(72)—Inventor: Ono, Ketichi
`Osaka-shi, Higashityodogawa-ku, Higashiawaji 1-chome, 5-ban, 3-
`530-go
`
`(72)—Inventor: Sugie, Akihiko
`Toyonaka-shi, Sonehigashinocho, 2-chome, 10-ban, 1-116-go
`
`(72)—Inventor: Katsube, Sumimoto
`Toyonaka-shi, Machiganeyama-cho,10-20
`
`(71)—Applicant: Sumitomo Chemical Co., Ltd.
`Osaka-shi, Higashi-ku, Kitahama, 5-chome, 15-banchi
`
`(74)—Agent: Katsuya Kimura, Patent Attorney
`
`SPECIFICATION
`
`1. Title of the Invention
`
`CRYSTALLINE AMINE SALT OF METHANOPROSTACYCLIN DERIVATIVE,
`
`MANUFACTURING METHOD THEREOF, AND PURIFYING METHOD THEREOF
`
`IP 56 —122328 A
`
`Page 1
`
`SteadyMed- Exhibit 1007 - Page 1
`
`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 001
`
`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 001
`
`
`
`2. Claims
`
`(1) A dicyclohexylaminesalt of a methanoprostacyclin derivative expressed by the
`
`general formula
`
`On
`HG
`
`(where R'is a trityloxymethyl group, 3-trityloxy-trans-1-propenyl group, or the group expressed
`
`by the general formula
`
`R*® Ro
`i
`|
`~ CH = CHG 0 — OHgCHg CH20Hg
`OH R*
`
`(where R’, R*, and R* are each a hydrogen atom or a methyl group)).
`
`(2) A method for manufacturing a dicyclohexylaminesalt of a methanoprostacyclin
`
`derivative expressed by the general formula
`
`COgH
`
`Ova
`
`HO
`
`(where R’is a trityloxy group, 3-trityloxy-trans-1-propenyl group, or a group expressed bythe
`
`general formula
`
`IP 56 —122328 A
`
`Page 2
`
`SteadyMed- Exhibit 1007 - Page 2
`
`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 002
`
`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 002
`
`
`
`R* RS
`bf
`— CH=CH C —C—CHgCHgCHg CHa
`OH R#
`
`(where R’, R*, and R* are each a hydrogenatom or a methyl group)), characterizedin that a
`
`mixture of a methanoprostacyclin derivative expressed by the general formula
`
`COgH
`
`S Ri
`
`HO
`
`(where R’is the sameas above) and a 7-Z isomerthereofis converted to a crystalline salt by
`
`dicyclohexylamineandis further recrystallized as needed.
`
`3. Detailed Description of the Invention
`
`(Field of Industrial Utilization)
`
`The present inventionrelates to a crystalline dicyclohexylaminesalt of a
`
`methanoprostacyclin derivative, a manufacturing methodthereof, and a purifying method
`
`thereof.
`
`Methanoprostacyclin [II] was discoveredas a stable derivative of prostacyclin (PGI), a
`
`natural bioactive substance having a strong bloodplatelet coagulation-inhibiting action
`
`(Tetrahedron Letters, 2607 (1979)). Methanoprostacyclin [II] is by far more chemically stable
`
`than prostacyclin, has the same strong blood platelet coagulation-inhibiting action as PGl, andis
`
`an extremely useful compoundin the treatmentofarteriosclerosis, heart failure, thrombosis, and
`
`the like. Total synthesis of methanoprostacyclin and derivatives thereof has been reported by the
`
`inventors and several other groups of researchers, butall the reported methods use a Wittig
`
`reaction between a ketone derivative [III] and an ylide derivative [IV], as shown below.
`
`IP 56 —122328 A
`
`Page 3
`
`SteadyMed- Exhibit 1007 - Page 3
`
`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 003
`
`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 003
`
`
`
`COgH
`
`HOg0
`
`aq 2
`
`+i i
`
`A z
`
`o
`
`CH)
`
`HO
`
`OH
`CW)
`
`HO
`
`OH
`‘ie
`
`(Ph)P=CHGHZCHCKO0.
`
`CN)
`
`This reaction has an excellent yield but has a serious drawbackoftypically producing an
`
`unnecessary 7Z isomer[II'] as a byproduct (the generationrate is [II]:[II'] = 7:2, Tetrahedron
`
`Letters, 433 (1979)). In addition, the properties of the two are extremely similar (Rfvalueis 0.14
`
`for 7E, and 0.17 for 7Z; Tetrahedron Letters, 433 (1979)), making separation and purification
`
`very difficult. Also, the melting point of this compoundis fairly low (68°C to 69°C, Tetrahedron
`
`Letters, 3743 (1978)), and crystallization is therefore severely impeded by the admixing oftrace
`
`impurities.
`
`On the other hand, the 7Z isomer[II'] has an extremely low pharmacologicalactivity
`
`compared with methanoprostacyclin [II]. For example, the blood platelet coagulation-inhibiting
`
`action of II' is about 1/100 of II (Tetrahedron Letters, 433 (1979)).
`
`Thus, establishmentof an efficient and industrially viable method of separating isomers
`
`of methanoprostacyclin derivativesis essential in the developmentof these derivatives as
`
`pharmaceutical products.
`
`In view of the above, the inventors conducted an examination of various separation and
`
`purification methodsafter achieving success in the synthesis of methanoprostacyclin, and finally
`
`succeeded in inventing an extremely simple and industrially viable purification method. The
`
`present invention relates to this novel purifying method andto a novel dicyclohexylaminesalt of
`
`a methanoprostacyclin derivative [I] obtained thereby.
`
`IP 56 —122328 A
`
`Page 4
`
`SteadyMed- Exhibit 1007 - Page 4
`
`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 004
`
`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 004
`
`
`
`The methanoprostacyclin derivative in which any of R’, R®, or R* in general formula[I]
`
`is a methyl group has excellent blood platelet coagulation-inhibiting action in the same manner
`
`as methanoprostacyclin (Japanese Laid-open Patent Application No. 54-119444), anda
`methanoprostacyclin derivative in which R’is a trityloxymethyl groupor a 3-trityloxy-trans-1-
`
`propenyl groupis important as an intermediate of methanoprostacyclin synthesis (Japanese
`
`Patent Application Nos. 54-29233 and 54-29236).
`
`According to the present invention, a dicyclohexylaminesalt of a methanoprostacyclin
`
`derivative expressed as methanoprostacyclin derivative [I]
`
`CO gH
`
`(where R'is a trityloxymethyl group, 3-trityloxy-trans-1-propenyl group, or the group expressed
`
`by the general formula
`
`R® RS
`}
`|
`—CH=CH-t- ¢ — CHgCHeCHeCHs,
`OH R*
`
`(where R’, R*, and R* are each a hydrogen atom or a methyl group))
`
`can be obtained in the following manner. Specifically, the dicyclohexylaminesalt is obtained by
`
`mixing a methanoprostacyclin derivative [I] or a methanoprostacyclin derivative [I] containing
`
`the corresponding 7Z isomer[I']
`
`IP 56 —122328 A
`
`Page 5
`
`SteadyMed- Exhibit 1007 - Page 5
`
`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 005
`
`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 005
`
`
`
`HOaC.
`
`as*
`
`Oe
`
`HO
`
`(whereR!is the sameas above) with dicyclohexylamine in an appropriate solventat an
`
`appropriate amount (0.7 to 1.2 molar multiples), the mixture is cooled as needed, and the
`
`precipitated crystals are filtered out.
`
`The dicyclohexylaminesalt of the methanoprostacyclin derivative [I] thus obtained
`
`generally has fairly high purity, and the purity can be further improvedbyrecrystallization as
`
`needed with the use of an appropriate solvent.
`
`Examples of appropriate solvents that can be used in the present invention include
`
`alkanols (e.g., ethanol, n-propanol, and iso-propanol) and alkanones(e.g., acetone, methylethyl
`
`ketone, diethyl ketone, and methyl-isobutyl ketone), and acetone, methylethyl ketone, and the
`
`like are particularly preferred.
`
`The dicyclohexylaminesalt obtained by the present invention can be easily reverted to a
`
`free methanoprostacyclin derivative [I] by conventional methods, and the resulting
`
`methanoprostacyclin derivative exhibits excellent crystallinity compared with substances not
`
`purified according to the present invention.
`
`Following are examples of dicyclohexylaminesalts of compoundsthat can beeasily
`
`obtained accordingto the present invention.
`
`2-B-trityloxymethyl-3 o-hydroxy-7E-(4'-carboxybutylidene)-bicyclo[3,3,0octane
`
`2-B-(3'-trityloxy-trans-1-propenyl)-30-hydroxy-7E-(4'-carboxybutylidene)-
`
`bicyclo[3,3,0]octane
`
`IP 56 —122328 A
`
`Page 6
`
`SteadyMed- Exhibit 1007 - Page 6
`
`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 006
`
`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 006
`
`
`
`2-B-(3'a-hydroxy-trans-1'-octenyl)-3a-hydroxy-
`
`7E-(4'-carboxybutylidene)bicyclo[3,3,0]octane
`
`2-B-(3'a-hydroxy-4', 4'-dimethyl-rans-1'-octenyl)-30-hydroxy-
`
`7E-(4'-carboxybutylidene)bicyclo[3,3,0]octane
`
`2-B-(3'a-hydroxy-3'B-methyl-irans-1'-octenyl)-3a-hydroxy-
`
`7E-(4'-carboxybutylidene)bicyclo[3,3,0]octane
`
`The invention will now be describedin greater detail using examples.
`
`Example 1
`
`0.8 g of a 7-E, Z mixture of raw 2f-trytyloxymethyl-3a-hydroxy-
`
`7-(4'-carboxybutylidene)-bicyclo[3,3,0]octane obtained by a Wettig reaction between
`
`4-carboxybutylene triphenylphosphorane and 2-f-trityloxymethyl-3a-hydroxy-
`
`bicyclo[3,3,0]octan-7-one wasdissolved in acetone, an equimolar amountof dicyclohexylamine
`
`was additionally injected under stirring, stirring was further conducted at room temperature, and
`
`the precipitated crystals were then filtered out and washed in a small amountof acetone to obtain
`
`a dicyclohexylaminesalt of 2B-trityloxymethyl-3a-hydroxy-7E-(4'-carboxybutylidene)-
`
`bicyclo[3,3,0]octane.
`
`Melting point: 69°C to 71°C
`
`Example 2
`
`0.39 g of a brown oily substance of 2B-(3'a-hydroxy-trans-1'-octenyl)-3a-hydroxy-
`
`7E-(4'-carboxybutylidene)-bicyclo[3,3,0]-octane containing a 7-Z isomer wasdissolved in
`
`acetone, an equimolar amountof dicyclohexylamine wasadditionally injected understirring, the
`
`stirring was conducted for two hours, the solution was then allowedto stand at room
`
`temperature, and the precipitated crystals were filtered out, whereby a dicyclohexylaminesalt of
`
`2B-(3'a-hydroxy-trans-1'-octenyl)-30- hydroxy-7E-(4'-carboxybutylidene)-bicyclo[3,3,0]octane
`
`was obtained.
`
`Melting point: 105.5°C to 106.5°C
`
`IP 56 —122328 A
`
`Page 7
`
`SteadyMed- Exhibit 1007 - Page 7
`
`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 007
`
`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 007
`
`
`
`The dicyclohexylaminesalt was neutralized in a 0.5N aqueous solution of KHSO, and
`
`extracted with ether. The ether layer was then washedanddried, and the solvent wasdistilled out
`
`under reduced pressure, whereby 2B-(3'a-hydroxy-trans-1'-octenyl)-3a- hydroxy-7E-
`
`(4'-carboxybutylidene)-bicyclo[3, 3, OJoctane crystals were obtained.
`
`Melting point: 66.5°C to 68°C
`
`IP 56 —122328 A
`
`Page 8
`
`SteadyMed- Exhibit 1007 - Page 8
`
`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 008
`
`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 008
`
`
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