`
`Japanese Patent Office (JP)
`
`(11)
`
`Unexamined Patent
`Application (Kokai) No.
`
`(12) Unexamined Patent Gazette (A)
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`56-122328
`
`Int. Cl.3
`(51)
`C 07 C 59/46
`51/43
`59/62
`31/557
`177/00
`
`A61 K
`C 07 C
`
`Classification
`
`Internal Office
`
`Symbols
`
`AEL
`
`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
`
`Application No.:
`
`55-25726
`
`February 29, 1980
`
`Kawakami, Haj ime
`Takarazuka-shi, Hyogo-ken 2-chome, l4-ban, 7-go
`Ono, Keiichi
`Osaka-shi, Higashiyodogawa—ku, Higashiawaji l-chome, 5-ban, 3-
`530-go
`Sugie, Akihiko
`Toyonaka—shi, Sonehigashinocho, 2-chome, 10-ban, 1-116-go
`Katsube, Sumimoto
`Toyonaka—shi, Machiganeyama-cho, 10-20
`Sumitomo Chemical Co., Ltd.
`Osaka-shi, Higashi—ku, Kitahama, 5-chome, 15-banchi
`Katsuya Kimura, Patent Attorney
`
`SPECIFICATION
`
`(21)
`
`(22)
`
`(72)
`
`Date of Filing:
`
`Inventor:
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`(72)
`
`Inventor:
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`(72)
`
`Inventor:
`
`(72)
`
`Inventor:
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`(71)
`
`Applicant:
`
`(74)
`
`Agent:
`
`1. Title of the Invention
`
`CRYSTALLINE AMINE SALT OF METHANOPROSTACYCLIN DERIVATIVE,
`
`MANUFACTURING METHOD THEREOF, AND PURIFYING METHOD THEREOF
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`JP 56 —122328 A
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`Page I
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`SteadyMed - Exhibit 1007 - Page 1
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`Liquidia's Exhibit No. 1048
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`IPR2020-00770 - Page 001
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`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 001
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`
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`2. Claims
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`(1) A dicyclohexylamine salt of a methanoprostacyclin derivative expressed by the
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`general formula
`
`On
`HG:
`
`(where R1 is a trityloxymethyl group, 3-trityloxy-trans-l-propenyl group, or the group expressed
`
`by the general formula
`
`HE R5
`I
`I
`"CH=CH-?—?-UHECH2E5H2UHS
`on n4
`
`(Where R2, R3 , and R4 are each a hydrogen atom or a methyl group)).
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`(2) A method for manufacturing a dicyclohexylamine salt of a methanoprostacyclin
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`derivative expressed by the general formula
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`CORE
`
`‘: ‘Rl
`
`m5
`
`(where R1 is a trityloxy group, 3-trityloxy-trans-l-propenyl group, or a group expressed by the
`
`general formula
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`JP 56 —122328 A
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`Page 2
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`SteadyMed - Exhibit 1007 - Page 2
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`Liquidia's Exhibit No. 1048
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`IPR2020-00770 - Page 002
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`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 002
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`F2 R3
`‘
`J
`—— CH = CH -- c — : — 0H2(1512(:ngcn3
`I
`OH H‘
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`(where R2, R3, and R4 are each a hydrogen atom or a methyl group)), characterized in that a
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`mixture of a methanoprostacyclin derivative expressed by the general formula
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`0021i
`
`‘3 Bl
`
`no
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`(where R1 is the same as above) and a 7-2 isomer thereof is converted to a crystalline salt by
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`dicyclohexylamine and is further recrystallized as needed.
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`3. Detailed Description of the Invention
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`(Field of Industrial Utilization)
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`The present invention relates to a crystalline dicyclohexylamine salt of a
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`methanoprostacyclin derivative, a manufacturing method thereof, and a purifying method
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`thereof
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`Methanoprostacyclin [II] was discovered as a stable derivative of prostacyclin (PGIZ), a
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`natural bioactive substance having a strong blood platelet coagulation-inhibiting action
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`(Tetrahedron Letters, 2607 (1979)). Methanoprostacyclin [II] is by far more chemically stable
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`than prostacyclin, has the same strong blood platelet coagulation-inhibiting action as PGIz, and is
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`an extremely useful compound in the treatment of arteriosclerosis, heart failure, thrombosis, and
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`the like. Total synthesis of methanoprostacyclin and derivatives thereof has been reported by the
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`inventors and several other groups of researchers, but all the reported methods use a Wittig
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`reaction between a ketone derivative [III] and an ylide derivative [IV], as shown below.
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`JP 56 —122328 A
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`Page 3
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`SteadyMed - Exhibit 1007 - Page 3
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`Liquidia's Exhibit No. 1048
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`IPR2020-00770 - Page 003
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`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 003
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`
`i.
`
`-.
`
`.-'
`
`03 2“
`
`1102 o
`
`)3 _
`
`+ in“;
`
`(n1 1
`
`“9
`
`9“
`r. H J
`
`11d:
`
`bu
`[ll ’1
`
`(PhhHQfiflI—lgtmgffififriul-l
`
`r. N 1
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`This reaction has an excellent yield but has a serious drawback of typically producing an
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`unnecessary 7Z isomer [II'] as a byproduct (the generation rate is [II]:[II'] = 7:2, Tetrahedron
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`Letters, 433 (1979)). In addition, the properties of the two are extremely similar (Rf value is 0.14
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`for 7E, and 0.17 for 72; Tetrahedron Letters, 433 (1979)), making separation and purification
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`very difficult. Also, the melting point of this compound is fairly low (68°C to 69°C, Tetrahedron
`
`Letters, 3743 (1978)), and crystallization is therefore severely impeded by the admixing of trace
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`impurities.
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`On the other hand, the 72 isomer [II'] has an extremely low pharmacological activity
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`compared with methanoprostacyclin [II]. For example, the blood platelet coagulation-inhibiting
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`action of II' is about 1/100 of II (Tetrahedron Letters, 433 (1979)).
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`Thus, establishment of an efficient and industrially viable method of separating isomers
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`of methanoprostacyclin derivatives is essential in the development of these derivatives as
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`pharmaceutical products.
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`In view of the above, the inventors conducted an examination of various separation and
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`purification methods after achieving success in the synthesis of methanoprostacyclin, and finally
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`succeeded in inventing an extremely simple and industrially viable purification method. The
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`present invention relates to this novel purifying method and to a novel dicyclohexylamine salt of
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`a methanoprostacyclin derivative [1] obtained thereby.
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`JP 56 —122328 A
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`Page 4
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`SteadyMed - Exhibit 1007 - Page 4
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`Liquidia's Exhibit No. 1048
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`IPR2020-00770 - Page 004
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`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 004
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`
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`The methanoprostacyclin derivative in which any of R2, R3 , or R4 in general formula [I]
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`is a methyl group has excellent blood platelet coagulation-inhibiting action in the same manner
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`as methanoprostacyclin (Japanese Laid-open Patent Application No. 54-119444), and a
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`methanoprostacyclin derivative in which R1 is a trityloxymethyl group or a 3-trityloxy-trans-l-
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`propenyl group is important as an intermediate of methanoprostacyclin synthesis (Japanese
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`Patent Application Nos. 54-29233 and 54-29236).
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`According to the present invention, a dicyclohexylamine salt of a methanoprostacyclin
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`derivative expressed as methanoprostacyclin derivative [1]
`
`0023
`
`‘\
`
`(I)
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`(where R1 is a trityloxymethyl group, 3-trityloxy-trans-l-propenyl group, or the group expressed
`
`by the general formula
`
`R2 R3
`|
`I
`—'CH=CH “Ll?“- E] "‘ CHZCHECHBUHS
`OH R4
`
`(where R2, R3 , and R4 are each a hydrogen atom or a methyl group))
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`can be obtained in the following manner. Specifically, the dicyclohexylamine salt is obtained by
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`mixing a methanoprostacyclin derivative [1] or a methanoprostacyclin derivative [1] containing
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`the corresponding 72 isomer [1']
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`JP 56 —122328 A
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`Page 5
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`SteadyMed - Exhibit 1007 - Page 5
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`Liquidia's Exhibit No. 1048
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`IPR2020-00770 - Page 005
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`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 005
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`
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`H020 .
`
`H0
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`(where R1 is the same as above) with dicyclohexylamine in an appropriate solvent at an
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`appropriate amount (0.7 to 1.2 molar multiples), the mixture is cooled as needed, and the
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`precipitated crystals are filtered out.
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`The dicyclohexylamine salt of the methanoprostacyclin derivative [1] thus obtained
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`generally has fairly high purity, and the purity can be fiirther improved by recrystallization as
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`needed with the use of an appropriate solvent.
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`Examples of appropriate solvents that can be used in the present invention include
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`alkanols (e. g., ethanol, n-propanol, and iso-propanol) and alkanones (e. g., acetone, methylethyl
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`ketone, diethyl ketone, and methyl-isobutyl ketone), and acetone, methylethyl ketone, and the
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`like are particularly preferred.
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`The dicyclohexylamine salt obtained by the present invention can be easily reverted to a
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`free methanoprostacyclin derivative [1] by conventional methods, and the resulting
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`methanoprostacyclin derivative exhibits excellent crystallinity compared with substances not
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`purified according to the present invention.
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`Following are examples of dicyclohexylamine salts of compounds that can be easily
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`obtained according to the present invention.
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`2-[5-trityloxymethyl-3 a—hydroxy—7E-(4'—carboxybutylidene)—bicyclo[3,3,0]octane
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`2-[3-(3'—trityloxy—trans— l -propenyl)-3 a—hydroxy—7E—(4'—carboxybutylidene)—
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`bicyclo[3,3,0]octane
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`JP 56 —122328 A
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`Page 6
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`SteadyMed - Exhibit 1007 - Page 6
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`Liquidia's Exhibit No. 1048
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`IPR2020-00770 - Page 006
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`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 006
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`2-B-(3 'u—hydroxy—trans- l '-octenyl)—3 a—hydroxy—
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`7E-(4'-carboxybutylidene)bicyclo[3 ,3 ,0] octane
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`2-[3—(3 'u—hydroxy—4', 4'-dimethyl-trans- l '-octenyl)-3 (x—hydroxy-
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`7E-(4‘-carboxybutylidene)bicyclo[3 ,3 ,0] octane
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`2-B-(3 '(x-hydroxy-3 'B—methyl-trans-l '-octenyl)-3 a—hydroxy—
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`7E-(4'-carboxybutylidene)bicyclo[3 ,3 ,0] octane
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`The invention will now be described in greater detail using examples.
`
`Example 1
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`0.8 g of a 7-E, Z mixture of raw 2B-trytyloxymethyl-3 a—hydroxy—
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`7-(4'-carboxybutylidene)—bicyclo[3,3,0]octane obtained by a Wettig reaction between
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`4-carboxybutylene triphenylphosphorane and 2-B-trityloxymethyl-3 a—hydroxy—
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`bicyclo[3,3,0]octan—7-one was dissolved in acetone, an equimolar amount of dicyclohexylamine
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`was additionally injected under stirring, stirring was fiirther conducted at room temperature, and
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`the precipitated crystals were then filtered out and washed in a small amount of acetone to obtain
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`a dicyclohexylamine salt of ZB-trityloxymethyl-3 a—hydroxy—7E-(4'-carboxybutylidene)—
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`bicyclo[3,3,0]octane.
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`Melting point: 69°C to 71°C
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`Example 2
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`0.39 g of a brown oily substance of 20-(3'a—hydroxy—trans—l'-octeny1)-3a—hydroxy—
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`7E-(4'-carboxybutylidene)—bicyclo[3,3,0]-octane containing a 7-Z isomer was dissolved in
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`acetone, an equimolar amount of dicyclohexylamine was additionally injected under stirring, the
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`stirring was conducted for two hours, the solution was then allowed to stand at room
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`temperature, and the precipitated crystals were filtered out, whereby a dicyclohexylamine salt of
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`ZB-(3 'a—hydroxy—trans— 1 '-octenyl)-3 (x- hydroxy- 7E—(4'-carboxybutylidene)—bicyclo [3 ,3 ,0] octane
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`was obtained.
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`Melting point: 105.5 °C to 106.5 °C
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`JP 56 —122328 A
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`Page 7
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`SteadyMed - Exhibit 1007 - Page 7
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`Liquidia's Exhibit No. 1048
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`IPR2020-00770 - Page 007
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`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 007
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`The dicyclohexylamine salt was neutralized in a 0.5N aqueous solution of KHSO4 and
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`extracted with ether. The ether layer was then washed and dried, and the solvent was distilled out
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`under reduced pressure, whereby 2B-(3'a—hydroxy—trans-l'-octenyl)-3 a— hydroxy—7E—
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`(4'-carboxybutylidene)—bicyclo[3, 3, 0]octane crystals were obtained.
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`Melting point: 665°C to 68°C
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`JP 56 —122328 A
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`Page 8
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`SteadyMed - Exhibit 1007 - Page 8
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`Liquidia's Exhibit No. 1048
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`IPR2020-00770 - Page 008
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`Liquidia's Exhibit No. 1048
`IPR2020-00770 - Page 008
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