Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
  • C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
  • C07D307/937—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans with hydrocarbon or substituted hydrocarbon radicals directly attached in position 2, e.g. prostacyclins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present invention relates to novel 7- year-old proprostaglandins and a method for producing the same.
• the present invention relates to a basically known 7-full-year prostaglandin using the novel 7-full-year prostaglandins.
• 1 class 2 novel production methods are also Oh Ru since about 0 back one scene technology of
• R 1Q in OR 12 is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms
• R 11 and R 12 are each a hydrogen atom or the same or different protecting group
• R 5 is a linear or branched alkyl group, Where oz represents 1 to 1 attached to a carbon atom in the above formula C10.
• the number 15 represents the position of the carbon atom.
• Natural blanking Russia scan tag run-di down 1 Category 2 [hereinafter compound also include: you have a PGI 2) is chemically unstable and was neutral or is intends handled collected under the conditions of weakly acidic but and this is Ru difficult der, 7 represented by the above formula I0 - full O Russia profile scan tag run-di down 1 Category 2 is Oh stable also extremely under the conditions described above, or ⁇ of action o this 7 in terms of improved selectivity that have been considered to be useful - full silo profile scan tag run-di down 1 Category 2 7 - Non-mud key sheet PGrI of 2 full Tsu See Japanese Unexamined Patent Publication No. 57-16653 / 82 and Japanese Unexamined Patent Publication No. However, these methods have various problems such as low selectivity and yield, and too complicated reaction steps. Problem solved was desired o
• the present invention is 7 - full silo profile scan tag run-di down 1 2 such as an intermediate useful off Tsu fluorinated been new profile scan tag run-in for the preparation of Gins and their production methods.
• the present invention is basically known as described above, which is characterized in that the novel 7-fluoroprostaglandins are used as intermediates.
• the present invention relates to a method for producing a 7-fluoroglobulin staglandin 12 class.
• 7-PPGPP is a compound represented by the following formula [ ⁇ ].
• R 1 is water
• the number 15 represents the position of the carbon atom.
• the present invention also provides a 7-hydroxy (or trimethylsiloxy) brostagranzine (hereinafter referred to as) represented by the following formula:
• the present invention relates to a method for producing 7-F PGF represented by the above formula [I] by fluorinating and, if desired, deprotecting and / or hydrolyzing.
• ⁇ ⁇ is an alkyl group having 1 to ⁇ 0 carbon atoms
• f 7 , R 3 and R 9 are the same or different.
• the present invention is the above formula 7 represented by (I) - PPGF 3 ⁇ 4 characterized that you use via ⁇ reaction 7 represented by the following formula [II] - full silo profile scan tag run-di emissions 1 class 2 (or can the R 1 G is Ru water atom der its non-toxic salts) to produce the 7 - full silo blanking port scan tag run-di emissions Ru Nodea also about 1 class 2 novel process for the preparation of.
• R 1 is particularly preferably a methyl group or an ethyl group
• oi 2 and R 3 are the same or different protecting groups. Is preferred.
• the protecting group a trialkylsilyl group (three alkyl groups may be the same or different :), alkano Tylhydryl, tetrahydrovinyl, tetrahydrofuran ninyl, benzoyl, methoxhetoxyl, etc.
• R 6 is the same alkyl group as ⁇
• ⁇ ,, and R 9 are the same protecting groups as ⁇ 2 , I 3 , and ⁇ .
• R 8 and R 9 may be a trimethylsilyl group, but if they are trimethylsilyl groups, they may be trimethylsilyl groups.
• Application Benefits methylation Shi Li le old key Shimotoka s full Tsu Moti ⁇ in Tsu by the possibility of such stomach is Ashi ⁇ in full Tsu atom albeit stomach ⁇ especially in R 5 mosquitoes were click mouth a Le key Le group field, the I Ru 7 force s Application Benefits main Chi le Shi Li Le group der, 7 - FP X force yield is one good ⁇ decrease in GF
• Application Benefits main Chi le Shi Li In the case of a benzyl group, and R 9 are preferably a protecting group other than a trimethylsilyl group.
• R 8 , R 3 , and 1 may be common protecting groups, and similarly for R 9 and R i2 .
• R 3 is a protecting group, and then R 3 is converted to a hydrogen atom.
• O 7-XPGP £ D 7-FPGI 2 7 is preferably a protecting group different from H 8 and R 10 o Why must be converted to a hydrogen atom on the way, but ⁇ 8 is the last protecting group ⁇ 7 and this Ru der is Oh Ru ⁇ and follow in poetry, et al favored by the yield of the reaction is Shi preferred is a Ru easy protection 'Motodea this is also de-protected ⁇ 8 your good beauty R 9 nights Ku, in particular door re-ethyl Le Shi Shi preferred and Li Le Motodea Ru this is ⁇ - how, H S and R 9 is other than the door Li main Chi Le Shi Li Le based on'm beauty door Li E Chi Le Shi Li Le based on They are
• a Le key Le group 3 ⁇ 4 of 3 or more carbon atoms protecting group is suitably Dea, especially di main Chi le - t - Bed Chi le arbitrarily 0 preferred is Li Le group
• the n-amyl group or the pentopenyl group is preferable.
• the 7 - PPGI 2 new Der wherein the known example does not describe o ft 5 starve click port Bae
• the yield of is very low.o is a linear or branched (i.e., in the case of a non-cyclic alkyl group, in the fluorination of sweet high Ru Ku has [Nandea coma and this exceeds the yield 5 ⁇ ) o against thereto, 7 - when X is Application Benefits main Chi le Shi Li Le group, forces force the kind of R 5
• the yield of 7 -FPGF is high, exceeding about 60, and it is
• X is a trimethylsilyl group.
• alcoholic hydroxyl groups are fluorinated with a fluorinating agent. It is well known that nitrogen is substituted by a fluorine atom.
• a trimethylsilyl group i.e., one OS i (_CH 3 ) The substitution of a fluorine atom by fluorination of 3 ) with a fluorinating agent has been found for the first time by the present inventors.
• O Trimethyl Trialkylsilyl groups other than silyl groups are inert to fluorination and cannot be replaced with fluorine atoms. o ⁇
• Preferred as 7-represented by the formula (I) are the following compounds o
• the following 15-cyclopentyl PGF 2 ⁇ derivative is a PGP 2A derivative having no ⁇ -amyl group at the 15th position, ie, 16,
• the fluorination of 7-XP GF represented by the formula) is basically performed by a known method.o The fluorination is usually carried out by dissolving in a solvent.
• OMPI Is the o off Tsu fluorinated agent rope line by the and the child to make a full Tsu fluorinated agent in the solution R 13 N-SF 3 [R 13: even though the oxygen 3 ⁇ 4 Yes having a carbon number of 4 to 7 Bubble ring 3 ⁇ 4 formed hydrocarbon group :) or D15 ⁇ N -SF 3 [, R 15 : same or
• the preferred fluorinating agents are piperidinol salfate-rich rides, etc. Nosulfur trifluoride; Ride-type fluorine-containing tj o Aminosulfur trifluoride as a fluorinating agent
• a fluorinating agent when X is a hydrogen atom, it is preferable to use a base in combination, for example, pyridin, triethylamine, dimethine.
• X can be used 0
• X is a trimethylsilyl group
• fluorination occurs when a base is present 0
• Halogenated hydrocarbons such as salt, methylene, dichloromethan, chloromethane, carbon tetrachloride, benzene and toluene.
• hydrocarbons, tetrahydrofuran, ethers such as various alkyl ethers, and other solvents ⁇
• the reaction temperature is 110 ⁇ t; 50 C is appropriate.
• the product obtained by the above method is as desired.] Perform deprotection and hydrolysis.
• the protecting group is a trialkylsilyl group
• deprotection is carried out using tetraalkylammonium, such as tetrabutylammonamide. ⁇ It is appropriate to use the multi-purpose rider o Tetra trial
• -Palladium fluoride can be used in combination with a base such as trialkylamine.
• O Solvents such as tetrahydrofuran Ether is appropriate o
• the protecting group is an acyl group, etc.
• deprotection is appropriate by hydrolysis with alkyl alcohol o ', and fi 1 is an alkyl group
• the same alcohol hydrolysis can be converted to a hydrogen atom.
• Alkali hydrolysis can be sodium hydroxide, hydration power, and other alcohols.
• the production of 7-FPG "I 2 represented by the formula [I] is carried out by subjecting the compound represented by the formula [I] to a cyclization reaction.
• the hydroxyl group at the 9-position represented by the formula (I) has been deprotected. That is, it is preferable that R 2 is a hydrogen atom) or a alkyl group.
• the basic reaction of cyclization is well known] 9, and is described in "J-Amer. Chera Soc.”, Vol. 104, pp. 5842-5844 [1982].
• 7 - JP P 1 2 is or or a R 10 force A Le key group, changing the by R 10 in the hydrolysis was or a hydrogen atom, if there is a protecting group I line deprotection, known Same as 7-FPGI 2.
• R 1Q is a hydrogen atom
• 7-FPGI 2 reacts with various bases to form a non-toxic salt, This can be used as a medicine.
• the base may be a hydroxide of alkaline metal, a hydroxide, a carbonate of alkaline earth metal, a hydroxide of alkaline earth metal, ammonia, mono or alkali. It is appropriate to use normal or o
• a feature of the present invention is that the use of the preferred fluorinating agent causes the fluorination of the carbon atom at the 7-position to occur at an extremely high selectivity, resulting in an extremely high yield. .
• the reason for this is that This is probably because the xy group is adjacent to a carbon atom having a triple bond (carbon atom at position 6 ) and is activated. For example, if the 5- and 6- positions are a double bond or a single bond, the elimination reaction will give priority to the formation of the olefin and the yield will be extremely low.
• R 5 , R 6 , _R 3 , and R 9 are the same as those in formula [II].
• a trimethylsilyl group is introduced into the 7th hydroxyl group, and the 9th hydroxyl group is a trimethylsilyl group due to the difference in reactivity between the two hydroxyl groups. And can be carried out under difficult conditions.
• 7-XP GF in which X is a trimethylsilyl group can be obtained.
• Application Benefits main Chi le sheet by only re Le group and this deprotection is a hydroxyl group 7 - are obtained.
• ⁇ X is a trimethylsilyl group 7-XF G F is obtained o
• R 5 is an n-amyl group
• R 3 is a methyl group
• R 8 and R 9 are dimethyl-t-butyl-butyryl groups.
• Trimethylsilyldiethyl amide 490 ⁇ C2.59mo1 was added dropwise to the solution (C 8MS) at 140 C, and the mixture was stirred under the same conditions for 2 hours. 0 Pour the mixture into an ice-cooled saturated aqueous solution of sodium hydrogen carbonate (2 ⁇ m £) and pour the aqueous layer twice with ethyl ether (107 7).
• 7 - FPGP will have a -A o 13 C -NMRCCDC 1 3, TMS, ppm): 5 6 1. 5 CC - 7), 7 2. 5 C - 1 1), 7 3. 2 CC - 1 5) , 7 7.2 CC-9)
• THP acetic acid-tetrahydrofuran
• water 8: 8: 1 A mixture of acetic acid-tetrahydrofuran (hereinafter referred to as THP) -water 8: 8: 1) is placed in a reaction vessel containing the above product 25 3 C 0.319 771 moi).
• THP acetic acid-tetrahydrofuran
• 3.2 Addition at ⁇ C o
• low-boiling components were reduced at 0 C.
• ⁇ Residues were added with ethyl ⁇ 1 1 1 m and saturated hydrogen peroxide
• the water station was extracted three times with ether (C 5 ⁇ £) using 10 sodium aqueous solution. Washed with organic saline solution, dried with magnesium sulfate anhydride and reduced and then compressed.
• Example 7 The compound obtained in Example 7 was subjected to a cyclization reaction by the method of Example 3 to obtain a compound having a 7-phenylene-15-cyclopentanoline PG "I2methylenol PG" Estenole L1, I5-vis C dimethyl-t-butyl) Manufacture of silyl ether o According to the ram chromatograph Later yield was 74 ⁇ .
• R 5 is a cyclopentyl group
• R 6 is a methyl group
• R 3 and R 9 are dimethyl-t-butylsilyl groups
• the R-113 solution of the above-mentioned product was mixed with a pyridinosulfone trifluoride (58, 0.58 mmo IJ).
• Triol which is the final product of Example 11, was cyclized.
• triethylamine 85 ⁇ C 0.608-71 mo 1) cool at 178 C, and hydrate sodium borohydride 1 15 (3.

Landscapes

• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Pharmacology & Pharmacy (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Priority Applications (1)

Applications Claiming Priority (1)

Publications (1)

Family

ID=14339318

Family Applications (1)

Country Status (5)

Cited By (2)

Families Citing this family (4)

Citations (3)

Family Cites Families (1)

• 1983
  • 1983-06-10 JP JP58102885A patent/JPS59227888A/ja active Granted
• 1984
  • 1984-06-07 EP EP84902214A patent/EP0148953B1/en not_active Expired - Lifetime
  • 1984-06-07 US US06/702,790 patent/US4699989A/en not_active Expired - Fee Related
  • 1984-06-07 DE DE8484902214T patent/DE3483314D1/de not_active Expired - Lifetime
  • 1984-06-07 WO PCT/JP1984/000294 patent/WO1984004917A1/ja not_active Ceased

Patent Citations (3)

Also Published As

Similar Documents

Legal Events