throbber
(19)
`
`Japanese Patent Office (JP)
`
`(11)
`
`Unexamined Patent
`Application (Kokai) No.
`
`(12) Unexamined Patent Gazette (A)
`
`56-122328
`
`Int. Cl.3
`(51)
`C 07 C 59/46
`51/43
`59/62
`31/557
`177/00
`
`A 61 K
`C 07 C
`
`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)
`(22)
`(72)
`
`(72)
`
`(72)
`
`(72)
`
`(71)
`
`(74)
`
`Application No.:
`Date of Filing:
`Inventor:
`
`Inventor:
`
`Inventor:
`
`Inventor:
`
`Applicant:
`
`Agent:
`
`1. Title of the Invention
`
`55-25726
`February 29, 1980
`Kawakami, Hajime
`Takarazuka-shi, Hyōgo-ken 2-chome, 14-ban, 7-go
`Ono, Keiichi
`Osaka-shi, Higashiyodogawa-ku, Higashiawaji 1-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
`
`CRYSTALLINE AMINE SALT OF METHANOPROSTACYCLIN DERIVATIVE,
`MANUFACTURING METHOD THEREOF, AND PURIFYING METHOD THEREOF
`
`JP 56 –122328 A
`
`Page 1
`
`Liquidia - Exhibit 1012 - Page 1
`
`

`

`2. Claims
`
`(1) A dicyclohexylamine salt of a methanoprostacyclin derivative expressed by the
`general formula
`
`(where R1 is a trityloxymethyl group, 3-trityloxy-trans-1-propenyl group, or the group expressed
`by the general formula
`
`(where R2, R3, and R4 are each a hydrogen atom or a methyl group)).
`
`(2) A method for manufacturing a dicyclohexylamine salt of a methanoprostacyclin
`derivative expressed by the general formula
`
`(where R1 is a trityloxy group, 3-trityloxy-trans-1-propenyl group, or a group expressed by the
`general formula
`
`JP 56 –122328 A
`
`Page 2
`
`Liquidia - Exhibit 1012 - Page 2
`
`

`

`(where R2, R3, and R4 are each a hydrogen atom or a methyl group)), characterized in that a
`mixture of a methanoprostacyclin derivative expressed by the general formula
`
`(where R1 is the same as above) and a 7-Z isomer thereof is converted to a crystalline salt by
`dicyclohexylamine and is further recrystallized as needed.
`
`3. Detailed Description of the Invention
`(Field of Industrial Utilization)
`
`The present invention relates to a crystalline dicyclohexylamine salt of a
`methanoprostacyclin derivative, a manufacturing method thereof, and a purifying method
`thereof.
`
`Methanoprostacyclin [II] was discovered as a stable derivative of prostacyclin (PGI2), a
`natural bioactive substance having a strong blood platelet 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 PGI2, and is
`an extremely useful compound in the treatment of arteriosclerosis, 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, but all the reported methods use a Wittig
`reaction between a ketone derivative [III] and an ylide derivative [IV], as shown below.
`
`JP 56 –122328 A
`
`Page 3
`
`Liquidia - Exhibit 1012 - Page 3
`
`

`

`This reaction has an excellent yield but has a serious drawback of typically producing an
`unnecessary 7Z isomer [II'] as a byproduct (the generation rate is [II]:[II'] = 7:2, Tetrahedron
`Letters, 433 (1979)). In addition, the properties of the two are extremely similar (Rf value is 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 compound is fairly low (68°C to 69°C, Tetrahedron
`Letters, 3743 (1978)), and crystallization is therefore severely impeded by the admixing of trace
`impurities.
`
`On the other hand, the 7Z isomer [II'] has an extremely low pharmacological activity
`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, establishment of an efficient and industrially viable method of separating isomers
`of methanoprostacyclin derivatives is essential in the development of these derivatives as
`pharmaceutical products.
`
`In view of the above, the inventors conducted an examination of various separation and
`purification methods after 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 and to a novel dicyclohexylamine salt of
`a methanoprostacyclin derivative [I] obtained thereby.
`
`JP 56 –122328 A
`
`Page 4
`
`Liquidia - Exhibit 1012 - Page 4
`
`

`

`The methanoprostacyclin derivative in which any of R2, R3, or R4 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), and a
`methanoprostacyclin derivative in which R1 is a trityloxymethyl group or a 3-trityloxy-trans-1-
`propenyl group is important as an intermediate of methanoprostacyclin synthesis (Japanese
`Patent Application Nos. 54-29233 and 54-29236).
`
`According to the present invention, a dicyclohexylamine salt of a methanoprostacyclin
`derivative expressed as methanoprostacyclin derivative [I]
`
`(where R1 is a trityloxymethyl group, 3-trityloxy-trans-1-propenyl group, or the group expressed
`by the general formula
`
`(where R2, R3, and R4 are each a hydrogen atom or a methyl group))
`
`can be obtained in the following manner. Specifically, the dicyclohexylamine salt is obtained by
`mixing a methanoprostacyclin derivative [I] or a methanoprostacyclin derivative [I] containing
`the corresponding 7Z isomer [I']
`
`JP 56 –122328 A
`
`Page 5
`
`Liquidia - Exhibit 1012 - Page 5
`
`

`

`(where R1 is the same as above) with dicyclohexylamine in an appropriate solvent at an
`appropriate amount (0.7 to 1.2 molar multiples), the mixture is cooled as needed, and the
`precipitated crystals are filtered out.
`
`The dicyclohexylamine salt of the methanoprostacyclin derivative [I] thus obtained
`generally has fairly high purity, and the purity can be further improved by recrystallization 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 dicyclohexylamine salt 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 dicyclohexylamine salts of compounds that can be easily
`obtained according to the present invention.
`
`2-β-trityloxymethyl-3α-hydroxy-7E-(4'-carboxybutylidene)-bicyclo[3,3,0]octane
`
`2-β-(3'-trityloxy-trans-1-propenyl)-3α-hydroxy-7E-(4'-carboxybutylidene)-
`bicyclo[3,3,0]octane
`
`JP 56 –122328 A
`
`Page 6
`
`Liquidia - Exhibit 1012 - Page 6
`
`

`

`2-β-(3'α-hydroxy-trans-1'-octenyl)-3α-hydroxy-
`7E-(4'-carboxybutylidene)bicyclo[3,3,0]octane
`
`2-β-(3'α-hydroxy-4', 4'-dimethyl-trans-1'-octenyl)-3α-hydroxy-
`7E-(4'-carboxybutylidene)bicyclo[3,3,0]octane
`
`2-β-(3'α-hydroxy-3'β-methyl-trans-1'-octenyl)-3α-hydroxy-
`7E-(4'-carboxybutylidene)bicyclo[3,3,0]octane
`
`The invention will now be described in greater detail using examples.
`
`Example 1
`
`0.8 g of a 7-E, Z mixture of raw 2β-trytyloxymethyl-3α-hydroxy-
`7-(4'-carboxybutylidene)-bicyclo[3,3,0]octane obtained by a Wettig reaction between
`4-carboxybutylene triphenylphosphorane and 2-β-trityloxymethyl-3α-hydroxy-
`bicyclo[3,3,0]octan-7-one was dissolved in acetone, an equimolar amount of 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 amount of acetone to obtain
`a dicyclohexylamine salt of 2β-trityloxymethyl-3α-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 2β-(3'α-hydroxy-trans-1'-octenyl)-3α-hydroxy-
`7E-(4'-carboxybutylidene)-bicyclo[3,3,0]-octane containing a 7-Z isomer was dissolved in
`acetone, an equimolar amount of dicyclohexylamine was additionally injected under stirring, the
`stirring was conducted for two hours, the solution was then allowed to stand at room
`temperature, and the precipitated crystals were filtered out, whereby a dicyclohexylamine salt of
`2β-(3'α-hydroxy-trans-1'-octenyl)-3α- hydroxy-7E-(4'-carboxybutylidene)-bicyclo[3,3,0]octane
`was obtained.
`
`Melting point: 105.5°C to 106.5°C
`
`JP 56 –122328 A
`
`Page 7
`
`Liquidia - Exhibit 1012 - Page 7
`
`

`

`The dicyclohexylamine salt was neutralized in a 0.5N aqueous solution of KHSO4 and
`extracted with ether. The ether layer was then washed and dried, and the solvent was distilled out
`under reduced pressure, whereby 2β-(3'α-hydroxy-trans-1'-octenyl)-3α- hydroxy-7E-
`(4'-carboxybutylidene)-bicyclo[3, 3, 0]octane crystals were obtained.
`
`Melting point: 66.5°C to 68°C
`
`JP 56 –122328 A
`
`Page 8
`
`Liquidia - Exhibit 1012 - Page 8
`
`

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