JPS59148761A - Prostaglandin and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R<1> is H, or 1-10C alkyl; R<2>-R<4> are H, or protective group; R<5> is 3-7C straight-chain or branched-chain alkyl, or 3-7C alicyclic hydrocarbon residue). EXAMPLE:5,6-Dihydro-7-fluoro-PGF2alpha. USE:An intermediate for synthesizing 7-fluoroprostaglandin I2 shown by the formula II (R<10> is H, or 1-10C alkyl; R<11> and R<12> H, or protective group). A compound shown by the formula I is subjected to ring formation reaction to give a compound shown by the formula II in high yield. PREPARATION:A prostaglandin shown by the formula III (R<6> is 1-10C alkyl; R<7>-R<9> is protective group) is fluorinated, and, if necessary, deproteced and/or hydrolyzed to give a compound shown by the formula I . Fluorination is carried out by reacting the compound shown by the formula III usually dissolved in a solvent with a compound shown by the formula IV (R<13> is hydrocarbon forming 4-7C ring which may contain oxygen), etc. as a fluorinating agent.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 7-fluoroprostaglandins and a method for producing the same.

Furthermore, the present invention relates to a novel method for producing basically known 7-fluoroprostaglandins of type 2 using these new 7-fluoroprostaglandins.

7-fluoroprostaglandins represented by the following formula (4)! 7-fluoroprostacyclin (7-fluoroprostacyclin)
or its non-toxic salt when R10 is a hydrogen atom) are known, for example, JP-A-57-99580, JP-A-57-165382, JP-A-57-1719.
It is described in Publication No. 88, etc.

Crystal U Note that the numbers 1 to 150 attached to carbon atoms in the above formula 1 represent the positions of the carbon atoms.

Natural grosstaglandins (hereinafter referred to as PG-2, including synthetic products) are chemically unstable and difficult to handle under neutral or weakly acidic conditions, but the above formula (3)
7-fluoroprostaglandins (hereinafter referred to as 7-FPG) represented by ) are extremely stable even under the above conditions, and are considered to be useful in improving the selectivity of pharmacological action. This 7FPG engineering is 7-hydroxyP
It is produced by the fluorination of G-2 (see the above-mentioned Japanese Patent Application Laid-Open No. 57-165382) or the method described in the above-mentioned Japanese Patent Application Laid-Open No. 57-171988. However, these methods have serious problems such as low selectivity and yield, and overly complicated reaction steps, and a solution to these problems has been desired.

The present inventor has conducted various research studies on the method for producing 7-F PGI1, and has discovered an excellent method for producing a novel fluorinated prostaglandin. Furthermore, the present invention relates to a method for producing the basically known 7-FPGIs as described above, which is characterized in that the novel 7-fluoroprostaglandins are used as intermediates.

The novel 7-fluoroprostaglandins (hereinafter referred to as 7-1p PGF) of the present invention are compounds represented by the following formula (1).

In addition, in the above formula (1), 1 to 15 attached to the carbon atom
The number represents the orientation of the carbon atom.

The present invention also provides 7-hydroxyprostaglandins (hereinafter referred to as ?-0HPGF) represented by the following formula 1.
t-Fluorinated, optionally deprotected and/or hydrolyzed to produce 7-F PGF represented by the above formula (1)
It relates to a method of manufacturing i.

11sR@ Furthermore, the present invention provides 2-PP represented by the above formula [0]
Through a cyclization reaction characterized by using GIPt-7-FPG: (, (or R10
The present invention relates to a novel method for producing 7-FPGI, in which 7-FPGI is a hydrogen atom and 7-FPGI is a non-toxic salt thereof.

In the structural formulas such as the above formulas [0 to (I[ll], the tapered line (g) indicates a substituent in the β-orientation (on the plane of the molecule), and the dotted line (---) indicates the α-orientation ( (below the plane of the molecule) and the wavy line (Hebe is α-Vh is β-oriented or a mixture of these isomers) indicates a substituent that is 0. Also, these are optical isomers, racemates, It includes other types of compounds.

In 7-FPGI2 represented by the above formula (1), R
1 is particularly preferably a methyl group or an ethyl group,
R" and R' are preferably the same or different protecting groups. Examples of the protecting group include trialkylsilyl 2iI
I (the three alkyl groups may be the same or different), an alkanoyl group, a tetrahydropyranyl group,
Tetrahydrofuranyl group.

There are benzoyl groups, methoxyethoxyethyl groups, and others. Particularly preferred as the protecting group is a trialkylsilyl group having the same or different alkyl groups having 1 to 4 carbon atoms. R11 is particularly preferably a straight-chain alkyl group, particularly an n-amyl group. 7-OHP expressed in the formula
In GF, R6 is an alkyl group similar to R1,
R? , Ha, and Re are also protective groups similar to R'', R'', and R', 0, that is, when R1-R9 are hydrogen atoms,
Unlike R1-R6 in the substitute symbols, these should not be hydrogen atoms, since that moiety is affected by the fluorination reaction. Is it represented by a formula circle? -For F'PG engineering 3, 11
0. R11 and R11l may be the same groups as R1, R3, and R4 in 7-FPGF of formula [0, or may be converted into different groups.

Preferred specific compounds as 7-FPGF represented by formula CI) are the following compounds.

a, 5,6-dihydro-twofluoro-P()F, α.

1), 5.6-TEH)”Rho7-Fluoro-PGF2α
Methyl ester.

a, 5.6-tehydro 7-fluoro PGII
', alpha ethyl ester.

a, 5.6-y human low 7-fluoro-PGF,
α Methyl ester 11.15-bis(dimethyl-t-butyl)silyl 9- ) U ethylsilyl ether.

e, 5.6-7'hydro-7-fluoro-PGF2α methyl ester 11.15-diacetate 9-triethylsilyl ether.

f, 5.6-tehydro7-fluoro PGF, α
Methyl ester 11.15-bis-tetrahydropyranyl ether 9-)! J Ethylsilyl ether.

Fluorination of 7-OHPGF represented by the symbol can be performed by a known method. Fluorination is usually carried out using 7-
Fluorinating agent in 0HPGF? This is done by adding. Examples of the fluorinating agent include amino acids such as '-ゝ＼ RlB N-day F3 (R11: a ring-forming hydrocarbon group having 4 to 7 carbon atoms and optionally containing oxygen) and an alkyl group having 1 to 5 carbon atoms). Sulfur trifluoride fluorinating agents, polyfluoroolefin-dialkylamine fluorinating agents (e.g. CF3CHFCF, NE
j2. CHC:IFcF2NFtt2).

8F4.5eF4. PhSF3. PhPF4,
Ph3, PF2, etc. can be used. Preferred fluorinating agents are aminosulfur trifluoride-based fluorinating agents such as piperidinosulfur trifluoride and diethylaminosulfur trifluoride.

When using an aminosulfur trifluoride-based fluorinating agent as a fluorinating agent, it is preferable to use a base in combination, such as pyridine.

Triethylamine, dimethylaniline, etc. can be used. As the solvent, halogenated hydrocarbons such as methylene chloride, dichloromethane, chloroform, and carbon tetrachloride, hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran and various alkyl ethers, and other solvents can be used. A suitable reaction temperature is -100°C to 50°C. If necessary, extraction and purification by chromatography are performed to obtain compound 7-FPGF represented by Narita.

The product obtained by the above method may be subjected to deprotection or hydrolysis, if desired. For deprotection, when the protecting group is a trialkylsilyl group, a method using a tetraalkylammonium fluoride such as tetrabutylammonium fluoride is suitable. Tetraalkylammonium fluoride can also be used in combination with a base such as a trialkylamine. Ethers such as tetrahydrofuran are suitable as solvents. When the protecting group is an acyl group, hydrolysis with an alkali is suitable for deprotection. Furthermore, when R1 is an alkyl group, it can be converted to a hydrogen atom by similar alkaline hydrolysis. The alkaline hydrolysis is preferably carried out using an aqueous solution of sodium hydroxide, potassium hydroxide, or another alkali, and optionally in combination with a water-soluble organic solvent such as a dialcohol. These fluorination, deprotection, and hydrolysis reactions are basically known and are described in, for example, the above-mentioned Japanese Patent Application Laid-Open No. 165382/1982. This basically known method can also be employed in the present invention.

7-FPGP2O3 represented by formula (5) is produced by using 7-F PGF f: represented by formula (1) and undergoing a cyclization reaction. For this purpose,
7-FPGF represented by the formula [D is preferably a compound in which the 9-position hydroxyl group is deprotected (that is, R2, R3, and R4 are hydrogen atoms), and is preferably a ul n alkyl group. preferable.

The basic reaction of cyclization is known," J. Amer,
Chem.

soc, Vol. IO4, pp. 5842-5844 (1982). 1! ! (]The desired 7-FPGP2O3 can be produced by cyclization with mercury trifluoroacetate and then freezing with a water bulking agent.Instead of trifluoroacetic acid, cyclized mercuric or acetic acid Mercury or the like can be used, and as a hydrogenating agent, sodium borohydride (Na B H4
), zinc borohydride (Zn(BH4)*) or the like may be used. The desired product, 7-FPG, is obtained from the reaction product by washing, extraction, purification, etc., if desired.

7-FPGP2O3lG can be used as an alkyl group or by hydrolysis to change R10 to a hydrogen atom, and if there is a protective group, deprotection is performed, and as in the case of the known 7-FPG technology, it can be used as a variety of pharmaceuticals. It can be used for various purposes. When R is a hydrogen atom, it can be reacted with 7-FPGP2O3 types of bases to form a non-toxic salt, which can also be used as a medicine. Bases include alkali metal hydroxides and (bi)carbonates.

Alkaline earth metal hydroxides, ammonia, mono- or dialkanolamines, etc. are suitable.

A feature of the present invention is that by using the above-mentioned preferred fluorinating agent, fluorination of carbon atoms at the K-Schiff position occurs with an extremely high selectivity, resulting in an extremely high yield of 7-FPIF. The reason for this is thought to be that the hydroxyl group in 7-OHPGF is activated adjacent to a carbon atom having a triple bond (carbon atom at position 6). For example, 5
．． When the 6th position is a double bond or a single bond, the production of olefins and dienes by elimination reaction takes priority, and the yield of 77PGF becomes extremely low. On the other hand, the 7-FPGP2O3 ratio in the cyclization reaction of 7-F PGF can also achieve a high yield similar to the above-mentioned known cyclization reaction of 5.6-dehydro PGFjα, and overall, The production of No. 3 has extremely high selectivity compared to the above-mentioned known series.

In addition, 7-OHPGF expressed by the formula is the following formula (
Compounds represented by lνJ, such as 5,6-dihydro-dihydroxy-PGF, α-alkyl ether
It can be obtained by selectively protecting only the hydroxyl group at the 9-position, rather than a compound in which the hydroxyl group at the 9-position and the 15-position hydroxyl group is protected.

However, it is difficult to introduce a protecting group only into the hydroxyl group at the 9-position in one step. For example, it is difficult to introduce a protecting group R'' such as a trimethylsilyl group into the hydroxyl group at the 7-position first, which reduces the reactivity of the two hydroxyl groups. Depending on the difference, the hydroxyl group at position 9 can be protected with a trimethylsilyl group), and then the hydroxyl group at position 9 is protected by a protecting group R such as triethylsilyl group.
A protecting group R7 having higher deprotection resistance than 16 is introduced, and then only the protecting group R16 is deprotected to obtain 7-
OHPGF. Note that both protecting groups R8 and Ro must have higher deprotection resistance than protecting group R16, and for example, dimethyl-t-butylsilyl group is suitable. Note that the compound represented by the above composition is, for example, “Tetrahedron Letter
s', 23 volumes.

It is a known compound described on pages 5563 to 5566 (1982).

EXAMPLES The present invention will be specifically explained below using Examples, but the present invention is not limited to these Examples.

Reference Example Synthesis of the compound represented by the symbol 5, e-tehydro-7-hydroxy-PGF2α methyl ester 11.15-bis(dimethyl-t-7-tyl)
Silyl ether (in formula (1), R5 is an n-amyl group.

Compound where R6 is a methyl group and R8 and R@ are dimethyl-t-butylsilyl groups) 205■ (0,336 mmo
490 μA of trimethylsilyldiethylamide in an anhydrous acetone solution (8d) of l) at -40°C! (2,59 mmo
1) was added dropwise, and the mixture was stirred for 2 hours under the same conditions. This was poured into an ice-cooled saturated aqueous sodium bicarbonate solution (20me), and the aqueous layer was extracted twice with metal ether (10rrtl). After washing the organic layer with saturated brine and drying over anhydrous magnesium sulfate, low-boiling components were removed under reduced pressure.5.
6-dihydro-two-trimethylsiloxy-PGF, α-methyl ester 11.15-bis(dimethyl-1-butyl)silyl ether obtained as a colorless viscous liquid fc
(Yield: 230 square meters, yield approximately 100 qb).

The above product was dissolved in anhydrous methylene chloride (2d), and triethylsilyldiethylamide 3zsp was added to this solution at 0°C.
1 (1,34rn mob), then 20 μl (0,134 mfiQl) of itetriethylsilyl tetralide was added dropwise. After stirring under the same conditions for 30 minutes, ethyl ether (1
0 mJ, then saturated aqueous sodium hydrogen carbonate solution (10
d) Added t'. The aqueous layer was extracted twice with ethyl ether (10 m?), the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the low-boiling components were removed under reduced pressure to give a yield of about 95 yen. 6-dihydro-two-trimethylsiloxy-PGF, α-methyl ester 11.15-
Bis(dimethyl-t-butyl)silyl 9- ) IJ ethyl silyl/lz ether kf obtained. ”C-NMR (C:D
C13°TM8, ppm): δ61.15(C
-7), 7L5 (C-11).

7&2 (C-115), 77.2CC-9) Into a reaction vessel containing the above product 253 tq ('0.319 mmol) f, acetic acid-tetrahydrofura/(hereinafter THF)
')-water (8:8:1) mixture 3.2WLl
was added at 0°C. After stirring at room temperature for 40 hours, low boiling components were removed under reduced pressure at 0°C. To the residue were added 10 d of ethyl ether and 10 ml of a saturated aqueous sodium bicarbonate solution, and the aqueous layer was extracted three times with ethyl ether (511 t&'). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. Purified by silica gel column chromatography (hexane/ethyl acetate = 7073'0), the pure target compound 5,6-dihydro-twohydroxy
PGF2α methyl ester 11.15-bis(dimethyl-t-butyl)silyl 9-)IJ ethylsilyl ether (in formula -t-Butylsilyl group compound) was obtained. The total yield from the starting material (compound of formula 1) was about 85%.

"C-NMR (CDCI8. TMS, ppm)
: δ63.2 (C-7).

77.0 (C-9), 81.1 (C-5), 84.
8 (C-6) Implementation Ml (Synthesis of compound represented by formula (J)) Piperidinosulfur trifluoride 3
7pi (0,3'12mrno1), Virigiy 30
pl (0,372 mmol) and methylene chloride 1
A solution of 134 g (0,186 mmol) of the final product obtained in the above reference example in methylene chloride (ld) was added dropwise to the mixture of m at -78°C. After 5 minutes, -7 in advance
Diluted by adding 10 di of ethyl ether cooled to 8°C,
Pour into ice-cold saturated aqueous sodium bicarbonate solution LOW/.

The aqueous layer was extracted twice with ether (5d), and the ether layer was washed successively with ice-cooled 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. . The residue was purified by column chromatography (hexane/ethyl acetate = 91) to give R6-dihydro-twofluoro-PGF! , methyl ester 11.15-bis(dimethyl-t-butyl)silyl 9-triethylsilyl ether (Formula [D, R1 is a methyl group, R is a triethylsilyl group R1
and R4 is dimethyl-t-butylsilyl group, R is n-
Compound with amyl group) 82 sy (yield 61%) t
- Obtained as a colorless liquid.

”H-HMR (CDCYR* TM'e 'Ppm
): δ 5,17(111,tl, J=48,10
Hg, CHI')"C-NMR (CDCI, TM8
．． ppm); δ51.4(C-7,d, , T=
48H2) Example 2 (Compound of formula (1)) Fluorinated compound obtained in Example 1 72m (0.10m m
0.5 tsl (0.51 n mox) of a 1 molar THF solution of tetrabutylammonium fluoride was added dropwise to a THF solution (0.5 m/) at 0°C, and the mixture was stirred for 2 hours under the same conditions. Next, ice water (3 ml)
'(Add H, further add 50% saline (3 WLl vf-, and convert the product into ethyl ether: ethyl acetate (]:]) 3
Extracted 10 times with m. Organic I was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give almost pure 5,
6-dihydro-twofluoro-PC) II'2α methyl ester (Formula [0, R1 is a methyl group, R2, Ra
and a compound in which R4 is a hydrogen atom and R8 is an n-amyl group) were quantitatively obtained.

"H-NMR (CD Cl g, , TM 8
, p p Ell ): δ5.20 (I Hr
t & + J = 48 + 10 Hz +
CdanF) Example 3 (Production of compound represented by formula (5)) Fluorine-containing triol 381q obtained in Example 2
1 (0,10 mmol) of THF solution (1-) was added with trifluoromercury acetate 479 (0,111
A THF solution (o, 5d) of 11m01) was added dropwise. After stirring for 5 minutes under the same conditions, 28 μl of triethylamine (0,20
m mol) t-dropwise, followed by 38 Wq) of sodium borohydride (1,0 mmol), 4 mol of sodium hydroxide (0,10 mmol), and 1 mol of methanol.
- dropwise the mixture under the same conditions. The mixture was stirred at -78°C for 1 hour, diluted with ethyl ether, and then filtered through Celite. The r liquid was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The product was generated by column chromatography (Florisil, hexane-ethyl acetate (t:X) with 1% triethylamine) and purified as pure 7-
FluoroPG, methyl ester (in formula (6)
Compounds in which R11 is an n-amyl group, RIO is a methyl group, and Hli and R12 are hydrogen atoms) 31 towns (yield 82%)
) was obtained.

'H-NMR (CDCI, ppm): δ4.7
7(IH,t,J=yH2,cdan==C(C-5))4
, g3 (IH, bd, J=5H2,CHF)-J
N-, E-phase: March 1980 Mumuro Patent Office Commissioner Kazuo Wakasugi1, Indication of the case 1982 Patent Application No. 219952, Name of the invention Prostaglandins and their manufacturing method 3, Supplementary information Relationship with the iE case Patent applicant address: 2-1-2 Marunouchi, Chiyo 1n-ku, Tokyo Name
(004) Asahi Glass Co., Ltd. 4, Agent Address: 105 Address: Toranomon-chome-16-2, Minato-ku, Tokyo Toranomon-cho-dai [11 Building 6, Increased power by amendment 11 Number of inventions None 7, Amendment Target Claims J and Detailed Description of the Invention (Column 8, Contents of Amendment (1)) The claims on pages 1 to 4 of the specification are amended as a separate document.

(2) Specification No. 8, lines 5 to 6, “Ri is...
``...alkyl group,'' shall be corrected as follows.

"R1 is a linear or branched alkyl group having 3 to 7 carbon atoms, or a hydrocarbon residue having an alicyclic ring having 3 to 7 carbon atoms."
(3) Page 9, line 4 of the specification “Rs is...
・Correct "alkyl group" to "RI is the same as H% in the above formula CHF".

(4) "Rs is preferable because of the reason." on page 10, lines 11 to 13 of the specification is corrected as follows.

"HI may be a branched alkyl group or an alkyl group having an alicyclic group, but is preferably a straight-chain alkyl group or an alicyclic group. The alicyclic group may have an unsaturated bond, but , preferably a saturated alicyclic group.Particularly preferred RIs are n-amyl group and cyclopentyl group.'' (5) Insert the following sentence between lines 15 and 16 on page 11 of the specification. O[g, 5.6-dihydro-twofluoro-15-cyclopentyl-PGF1*.

h, 5,6-dihydro-twofluoro-15-cyclopentyl-PGFx.

Methyl ester.

i, 5.6-dihydro-twofluoro-15-cyfrobentyl-PGF, α methyl ester 11.15-bis(dimethyl-1-butyl)silyl ether j, 5.6-dihydro-twofluoro-15-cyclopentyl-FGF, α methyl ester 11.15-bis(dimethyl-t-7'thyl)silyl-9-triethylsilyl ether"o J (6) Specification No. 14, line 10 [R1, and R4J
Delete.

(7) Add the following example below the third line of page 24 of the specification.

[Example 4 Production of compound represented by [2〇]] 5.6
- Zohydro 7 - Hido Nishi Kishi 15 - Cyclope/Chill -
PGF,, methyl ester 11.15-bis(dimethyl-butyl)silyl 9-)! J Ethylsilyl ether (Formula CI) K Oite R' Cacyclopentyl group, R. is a methyl group R? is triethylsilyl group H& and R9
A compound having a dimethyl-t-butylsilyl group) was synthesized in the same manner as in the reference example.

Using 140 μ (0,194 mmol) of this compound, 5,6-dihydro-twofluoro-
15-cyclopentyl-PGF2 (1 methyl ester 1
1.15-bis(dimethyl-t-butyl)silyl9-
Triethylsilyl ether (CI) compound in which R1 is a methyl group, R1 is a triethylsilyl group, R8 and R4 are a dimethyl-t-butylsilyl group, and Rs is a cyclopentyl group) 79■ (Yield 56%) e Obtained as a colorless liquid. Ta.

"H-NMR (C!Dc13.TMS, ppm): δ
5.17 (IH, ta, J=50 + 10Hz +
OHF) Example 5 (compound represented by formula CI)) A THF solution (0.5 ml) of the compound 61'rng (0.085 mmol) obtained in Example 4 was added with 0.0 ml of detodibutylammonium fluoride at 0°C. 1 ml of 1 molar THF solution (
0.1 mmol) and triethylamine 14 μl (0
, 1 mmol) was added. After confirming the disappearance of the raw materials by thin layer chromatography, the volatile compounds were removed under reduced pressure, and saturated ammonium sulfate aqueous solution (SYG) and ethyl acetate (51
) was added, and then the aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, dried, and concentrated.
-cyclohexyl-P G F2a)f ester 11
．． 15-bis(dimethyl-1-butyl)7lyl ether was produced in a yield of 87%.

Example 6 (Production of compound represented by formula (III)) Using the compound obtained in Example 5, a cyclization reaction was carried out according to the method of Example 3 to produce 7-fluoro-15-cyclohexyl P.
G engineering 2 methyl ester 11.15-bis(dimethyl-t
-7'thyl)silyl ether was produced. The yield after purification by column chromatography was 74%.

'H-NMR (ODO13, ppm): δ4.76
(IH, t, J=7Hz.

0H=Oon C-5) δ4.93 (IH, bd, J=56Hz.

Attachment [2, Claim 1, 7-fluor prostaglandins represented by the following formula CD]

2, 7- represented by the following formula CI), which is characterized by fluorinating the glosstaglandins represented by the following formula (If) and optionally deprotecting and/or hydrolyzing them.
A method for producing fluoroprostaglandins.

01't' 3. A cyclization reaction characterized by using 7-fluoroglostaglandins represented by the following formula [■]. Or, when RIO is a hydrogen atom, a method for producing its nontoxic salt.

0 R+ 2 Procedural amendment November 2, 1980 Kazuo Wakasugi, Commissioner of the Japan Patent Office1, Indication of the case Patent Application No. 21995 of 19822, Name of the invention Prostaglandins and their manufacturing method 3, Make amendments Relationship with the patent case Patent applicant address 1-2 Sara-chome, Marunouchi, Chiyoda-ku, Tokyo Name
(004) Asahi Glass Co., Ltd. 4, Agent 6, Number of inventions increased by amendment None? , Target of amendment Section 8 of the specification "Detailed Description of the Invention" Contents of amendment (1) rJ = 5HzJ in the third line of page 24 of the specification is changed to rJ
= Corrected to 56HzJ.

that's all

Claims (1)

[Scope of Claims] 1. 7-Fluoropuros represented by the following formula [0] 2, Glostaglandins represented by the following symbols are fluorinated and optionally deprotected and/or hydrolyzed. A method for distributing 7-fluoroglostaglandins represented by the following formula CI). 1°0.8. R' λ A cyclization reaction characterized by using 7-fluoroprostaglandins represented by the following formula [0] 7-fluoroprostaglandins 2 represented by the following l
The ninth method is to produce a non-toxic salt of RIO when it is a hydrogen atom. RuR4 ()R1!