JPS5993070A - Manufacture of intermediate compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for the preparation of novel intermediates for novel compounds. More specifically, the present invention provides that known prostaglannes having one or two fluoro-positions on the C-16 position, that is, the carbon atom in contact with the hydroxy-substituted carbon in the methyl terminal chain, are, for example, prostaglanone E2 ( PCi[2], prostaglan 'F2 alpha and beta (PC) F2. , and PGF2β), glosstaglandin A2 (PC) A2)
, prostaglandin B2(P')B2), and all the corresponding i-'GE compounds. Each of the interstitial zolostagranes described above is a derivative of gulostanic acid with the following structure and atomic numbering.

For example, Bergstrom
), etc., Ph7-Mako Cl Dical Levii-(Ph,
armaCOl, HeV), vol. 20, p. 1 (1968
(2013) and the literature cited therein. The systematic name of brostanoic acid is 7-((2β-octyl)-cyclopent-ICX-yl]-hebutanoic acid.

PGm2 has the following structure.

P.G.F. has the following structure.

H.O. f, +F2β has the following structure.

F'JA2 has the following structure.

PGE2(d, has the following structure.

pGg, PGF. , PGM"□β, P()A engineering and Pf) It has the same structure as shown in the corresponding PG2 compound, except that the bond is replaced.

For example, PGE□ has the following structure.

In formulas ■ to ■1 and the formulas described below, the dashed line attachment to the /clopencune ring represents the alpha configuration, ie, a substituent below the plane of the cyclopentane ring.

The bold line attachment to the cyclopentane ring represents the beta configuration, ie, the configuration above the plane of the cyclopenkune ring.

The 1l-1l] chain hydroxy/ of C-15 in formulas ■ to ■ is in the Sp integrated device. For a discussion of three-dimensional prostaglandins, see Nature magazine.
), vol. 212, p. 38 (1966).

Each of the molecules of the known prostaglandins has several asymmetric centers, and can be found in either a racemic (optically inactive) form or two bilateral forms (optically active), i.e., dextrorotatory and levorotatory. It can exist. As shown in the figure, each of formulas ■ to ■ corresponds to grosstaglandin obtained from a certain mammalian tissue, such as sheep minor vesicle gland, pig lung, or human N'(':j), or its represents a particular optically active form of those obtained by reduction of the carbonyl and/or double bond of a prostaglandin, see for example Bergestrom et al., cited above.The mirror image of each of formulas 1 representing the other left and right i1'12 of the prostaglandin.The racemic form of a prostaglandin contains the same number of both left and right molecules, and one of 2■ to ■ and the mirror image of its formula is Required for proper expression of body prostaglandins.

For convenience, P()El, PGE2, PGE3, PG
F. The use of these terms refers to an optically active form of glosstaglandin having the same absolute configuration as PG, El obtained from IQ$i mammalian tissues. When it is intended to refer to the racemic form of some of those prostaglandins, the term "racemate" or "dl" precedes the prostaglandin name, thus racemic PGE, or dl-PGF'2. become that way.

PG[yo, PC)E2, and the corresponding PGF(X,
PGFβ, PGA, and PGB compounds, as well as their esters, acylates, and pharmacologically acceptable salts, have an excellent ability to elicit a variety of biological responses. For this reason, these compound knowledge are useful for pharmacological purposes. See, for example, Bergestrom et al., cited above.

Some of these biological responses include PGE and PGFβ
and P()A compounds, for example, a reduction in systemic arterial blood pressure measured in ventrinium-treated mice anesthetized (bentoparbital sodium) by placing a cannula in the aorta and right heart; A similar measured effect on increasing blood pressure in the case of smooth muscle ridges, as shown in tests with sections of the guinea pig ileum, rabbit duodenum or gerbil colon, synergistic effect of other tenotropic agents; induced by epinephrine. antagonizing the mobilization of free fatty acids,
Antilipolytic activity as demonstrated by the spontaneous release of glycerol from isolated mouse fat pads; feed or histamine in the case of PGE and PGA compounds? Inhibition of gastric secretion as shown in dogs whose secretion was stimulated by Juin; effects on the central nervous system; regulation of convulsions and ease of breathing in asthmatic conditions; platelets as shown by adhesion between platelets and crow decrease in adhesion and inhibition of platelet aggregation and thrombus formation induced by various physical stimuli, such as blood damage and individual biochemical stimuli, such as ADP, ATP, serotonin, thrombin, and collagen. Stimulation of epidermal proliferation and keratinization in the case of 'j + and PG and PGB compounds when applied to chicken embryos and mouse skin sections in culture medium.

Because of these biological responses, these known prostaglandins are commonly found in birds and mammals, including humans, useful livestock, companion animals, and zoological specimens, as well as laboratory animals, including the Lely pet and mouse. the study of a wide range of diseases and undesirable physiological conditions in rats, rabbits, and monkeys;
Useful for prevention, prevention or mitigation.

For example, these compounds and in particular the PC)E compounds are
Both are used for topical application in mammals, including humans, in a dosage range of 11 to 9, or as an aerosol spray.

FOE, P()F. and P()A compounds are of interest in the treatment of asthma. For example, these compounds are 5R3
-A, it is useful as a bronchodilator, or as an inhibitor of mediators such as histamine released from cells that are oilified by antigen-antibody complexes.

Therefore, these compounds are associated with bronchial asthma, bronchitis,
Regulates spasticity and facilitates breathing in conditions such as bronchiectasis, pneumonia, and emphysema.

For these purposes, the compounds may be administered in various dosage forms, such as orally in the form of tablets, capsules or liquids; rectally in the form of herbal medicines, parenterally, subcutaneously or Intramuscular and intravenous administration is preferred in emergency situations; in the form of a nebulized aerosol or solution for inhalation; or in powder form for insufflation. Dosage ranging from about 0.01 to 5 me) per body weight given 1 to 4 times a day
The exact dosage depends on the age, weight, and condition of the patient, as well as the frequency and route of administration. For the above applications, these glo-7-taglandins can be combined with sympathomimetic agents (isoproterenol, phenylephrine, ephedrine, etc.), xanthine derivatives (theophylline and aminophylline), and corchicosteroid tA ('
It is advantageous to combine it with other anti-asthmatic agents, such as ACTH (togredinisolone). For the use of these compounds, see South African Moeko 68/1055.

1? GE and PGA compounds have been shown to be useful for human beings and certain useful movements. When used to reduce and control excess gastric secretion in stomatids, including dogs and pigs, it reduces or prevents the formation of gastrointestinal ulcers and can cause severe damage to the gastrointestinal tract. It is useful in promoting the healing of such ulcers that already exist. For this purpose, the compounds may be injected intravenously, subcutaneously, or intramuscularly at an injection dose ranging from about 0.1 μ7 to about 500 μ2 per y of body weight per minute, or by injection or infusion per day. Approximately 0 per kg of body weight
．． The total amount in the range of 1 to about 20m9 - [Yo amount,
The precise dosage will depend on the age, weight, and condition of the patient or animal as well as the number and route of administration.

PGE, PGF, and Pt) Fβ compounds inhibit platelet aggregation, reduce platelet stickiness, and are used whenever it is desired to eliminate or prevent thrombus formation in humans and mammals, including rabbits and mice. , accelerated patency of vascular grafts after surgery, and symptoms such as atherosclerosis, arteriosclerosis, blood coagulation dysfunction due to lipemia, and the underlying etiology is associated with lipid imbalance or hyperlipidemia. It is useful in the treatment of other clinical conditions. For these purposes, these compounds may be administered systemically, e.g. intravenously, subcutaneously, intramuscularly, for sustained action (2) and for sustained action (in the form of sterile implants, especially for rapid response in emergency situations). The intravenous route of administration is preferred for 0.0 - Doses ranging from about 0.005 to about 20 mg per molar b"i are used, although the exact dosage will depend on the age of the individual or animal, Depends on body weight and symptoms, as well as frequency and route of administration.

P'JE, PG FCX, and PGFβ compounds can be used for artificial extracorporeal circulation and artificial extracorporeal circulation of these body parts, whether severed or tied to the body. It is particularly useful as an additive to blood, blood products, blood substitutes, and other fluids used for perfusion. During these circulations and blood flows, aggregated platelets tend to block the blood vessels and circulatory system.

This blocking effect is avoided by the presence of these compounds. For this purpose, the compound may be introduced gradually or in multiple doses into the circulating blood, into the blood of the donor animal, into a remote or attached body part to be perfused, into the recipient, or into the blood of the recipient animal. at a total steady-state dose of about o, ooi to 1.0 m per liter of circulating fluid. The use of these compounds for these purposes in laboratory animals such as cats, dogs, rabbits, monkeys, and mice is particularly useful for developing new methods and techniques for organ and limb transplantation.

PGE compounds are effective in producing smooth muscle stimulation, as well as other known smooth muscle stimulants such as various Nilgot alkaloids, including Oki/Totan and derivatives and analogs. It also has commercial activity in synergizing accelerators. Thus, for example, PGE2 may be used instead of or in combination with these known smooth muscle stimulants in lower doses than usual to reduce paralytic intestinal obstruction symptoms, or to aid in abortion or postpartum relaxation during placental expulsion and during the postpartum period. It is useful for controlling or preventing uterine bleeding. For the latter purpose, P()E compounds can be administered by intravenous infusion immediately after miscarriage or delivery at a rate of q body weight per minute.
Doses ranging from about 0.1 to about 50 μ2 per dose are administered until the desired effect is achieved. Subsequent doses may be given by intravenous, subcutaneous, or intramuscular injection or infusion during the perinatal period - ranging from 0.01 to 2 mg/kg molar body weight, although the exact dose may vary depending on the age of the patient or animal. , weight, and symptoms.

PGB, PGA and PGB'β compounds are useful as antihypertensive agents for lowering blood pressure in mammals including humans. For this purpose, the compounds are administered by intravenous infusion.
Administer at a rate of about 0.01 to about 50 μ7 per 4 body weight per minute, or in single to multiple doses of about 25 to 500 μ2 per kg body weight per day.

P(!-A compounds and their derivatives and salts are
Increases blood flow in the kidneys of lactating chickens, thereby increasing urine volume and electrolyte content. P()A compounds are therefore useful in controlling cases of renal dysfunction, particularly in cases of severely reduced renal blood flow, such as hepatorenal syndrome and early kidney transplant rejection. In cases of excessive or inappropriate secretion of ADH (antidiuretic hormone: vasopuntucin), the diuretic effect of these compounds is even greater. In anophretic conditions, the nosobresocin action of these compounds is particularly useful. For example, P
All GA compounds are useful, for example, in the relief and correction of cases of edema resulting from deep skin burns and in the treatment of shock. For these purposes, the PGA compound may initially be administered by total intravenous injection at doses ranging from 10 to 1000 μ2 per ky body weight, or by intravenous infusion at doses ranging from 0.1 to 20 μ7 per ky body weight per minute. It is preferable to administer the drug until the desired effect is obtained.

Subsequent doses may be administered by intravenous, intramuscular or subcutaneous injection or infusion - 0.05 to 2 kg body weight per day.
Given in mg range.

PGE, PGFo, and P()Fβ compounds can be used as an alternative to oxytocin in pregnant animals, including humans, cows, sheep, and pigs, at or near their due date, or in pregnant animals near their due date. It is useful for inducing labor in pregnant animals whose fetus has died in utero before 20 weeks. For this purpose, a dose of 0.01 to 50 μg/min of body weight is not available until the end of delivery of the fetus, or when the amniotic sac has ruptured. It is particularly useful when natural labor does not begin after 12 to 60 hours.

Another route of administration is oral.

PC) E, PGFα and PGFβ compounds are useful in regulating the reproductive cycle in human and female mammals, including animals such as cats, mice, rabbits, dogs, cats and the like. The term ovulating female emitter is
An animal that is mature enough to ovulate but not old enough to stop ovulating normally.

For this purpose, e.g. PC) F 2α is administered, advantageously during a period starting approximately at ovulation and ending approximately at or just before menstruation, in an amount of about 0.01 m2/kg body weight of the female mammal.
Administer systemically at dosage levels ranging from 0.0 m to 0.0 m. Intravaginal and intrauterine are alternative routes of administration. Alternatively, delivery of the embryo or fetus is accomplished by similar administration of the compound during the first third of normal mammalian gestation.

As mentioned above, PGE compounds are potent antagonists of epinephrine-induced mobilization of free fatty acids. Therefore, this compound is useful for understanding and preventing diseases involving abnormal lipid mobilization and high free fatty acid levels, such as diabetes, vascular disease, and thyroid dysfunction, in mammals including humans, rabbits, and mice. It is useful in experimental medicine for in vitro and in vivo studies with therapeutic intent, symptom relief, and treatment.

PC)E and P()B compounds stimulate and accelerate the growth of epidermal cells and keratin in animals, including humans, farm animals, companion animals, zoological specimens, and laboratory animals.

These compounds are therefore useful in promoting and hastening the healing of damaged skin, such as those caused by inflammation, trauma, abrasions, and post-surgical injuries. These compounds promote the adhesion and growth of skin autografts, as well as small deep (Davis) grafts that are intended to fill skinless areas by later outward growth than the initial one. It is also useful for hastening and preventing rejection of allogeneic grafts.

For these purposes, these compounds may be applied locally, at or near the location where cell growth and keratin formation are desired, advantageously as an aerosol liquid or a micronized powder dusting, in the case of a wet dressing. lotion as an isotonic 7kf liquid or in combination with conventional pharmaceutically acceptable diluents;
Preferably, it is administered as a cream or ointment.

In some cases (1) where there is substantial fluid loss, for example in the case of extensive burns or skin loss due to other causes, combined use with regular injections of blood, plasma, or their substitutes. , or separately, systemic administration by intravenous injection or injection is advantageous. Alternative routes of administration are proximate subcutaneous or intramuscular, oral, sublingual, buccal, rectal, or intravaginal. The exact dose Vk will depend on the route of administration and such factors as the age, weight, and condition of the patient. As an example, a mixed bandage for topical application for burns of 1 to 3 degrees and/or 7 degrees with a skin area of 5 to 25+ square centimeters may contain 1 to 500 μ'? /-P
This includes the use of isotonic aqueous solutions containing the GB compound or several times its concentration of the PGB compound. Particularly for topical use, these glostaglandins are compatible with antibiotics such as gentamicin, neomynon, polymycin B1 battracin, spectinomycin, and oxytetracycline, other antibacterial agents such as mafuenide salts (
g (>2 g, useful in combination with sulfadiazine, furazolium crocide, and nitrofurazone, and corticoid steroids such as hydrocortiscin, prednisolone, methylprednisolone, and fluprednisolone, each of which are used in the combination in the usual concentrations suitable for their sole use.

One object of the present invention is that the length of the side chain is 11 different and the target is
The object of the present invention is to provide a novel method for making analogs and esters. A further object is to provide new intermediates useful in this process.

]6-Fluoco and 16,16-difluoroprostagra/zine 5"-acids and Nisdels also include compounds of the following formulas and racemic compounds of each formula and its mirror image. There is.

In formulas ■ to XX■, CnH2n is alkylene of 1 to 9 carbon atoms, g is an integer of 2 to 50, M is HOH or idH△O)i, and R1 is hydrogen or 1 alkyl of ~12 carbon atoms, 7-chloroalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 12 carbon atoms, phenyl, or (1, 2, to 3 chloro, or 1 to 4 carbon atoms substituted with alkyl)
phenyl, and horse is hydrogen, methyl, or ethyl,
Or fluoro.

/..., Formula ■ represents CnH2n, 8 is methylene, 8 is 3, M is HOH, and 1 (when 1 and R2 are hydrogen, ]]6-fluoro1920-dinor-PGFlo. Formula × is C
nH2nl., or ((.R2)3, when g is 5.1 and HOH-' is methyl and R2 is fluoro, it represents 16,16-difluoro-2a,2b-dihomo-PGE2 methyl ester. Formula XX Vi cnH2n is (CH2)4
, g is 2, M is □・'\0Hr1, is hydrogen, and R2
When is methyl, it represents 16-fluoro-16-methyl-20-methyl-2-true]5β-13,14-dihydro-P()F1β.

In the example 2 above, the name rl, 9.20-ginol is P
Refers to the absence of two carbon atoms from the hydroxo-substituted side chain of the GFUcx structure. According to the atomic numbering of the brostanic acid structure, C-19 and C-20 are believed to be missing, and the methylene at C-18 is replaced by a terminal methyl group. Similarly, in the example of formula ” “trinor” or “tetranor” refers to 1, 2.3 or 4 carbon atoms from the C-2 to C-4 and C-18 to C-20 positions of the brostanic acid carbon skeleton, respectively. Show what is missing.

According to the common numbering of carbon atoms in the gulostanic acid structure, C-16 is a hydroxy-substituted carbon atom (C-]5
) refers to the carbon atom next to it.

In the example name of formula X1lt, [2a,20-dihomo] is
Refers specifically to the two additional carbon atoms in the carboxy-terminal side chain between the c-2 and c-3 carbon atoms.

There are therefore nine carbon atoms in its side chain instead of the normal seven in the brostanic acid structure.

From the end of the chain to the example double bond, these are c-1,
Identified as c-2, C-2a, C-2b, C-3, C-4, and c-5. The carbon atoms connected by the 7-s double bond are C-5 and C-6, and the carbon atoms between the double bond and the ring are c-6 and c-7.

As in the case of formulas ■ to ■, formulas ■ to XX■ when M is Ht゛・OH are ``:li PG obtained from mammalian tissue
It is intended to represent optically active brostanic acid derivatives having the same absolute configuration as E. M is...7'゛. In formulas ■ to XX'' for H, the hydroxyl is attached to the side chain in the alpha configuration.

Those included in the scope of the present invention include M or H'
This is for 15-epimer compounds of formulas I to XX] f when C-15 hydroxy 7 is in the 2-ester configuration with OH. In the following, "15β" refers to the epimer configuration. In this way, “16-fluoro-19,20-
15β-PGFlα” is 16-fluoro-
]9゜2 Region Nolou PGF. The 15-epimer compound corresponding to the example of formula (1) is identified as having a beta configuration at C-15 instead of the natural alpha configuration of . Each of Formulas 1 through XXTl plus its mirror image describes racemates within the scope of this invention. For convenience, such racemic compounds will be referred to below by the prefix "racemate" or "tilJ" before their names. 11-) without this prefix will be represented by the appropriate formula
Light represented by XX■: '/intended to refer to tongue-injectable compounds.

Regarding XX■ from the river, examples of alkyl of 1 to 12 carbon atoms are methyl, ethyl, propyl, butthorn,
Pentyl, hegythyl, hegetyl, octyl, nonyl, dinor, undecyl, dodecyl, and their isomeric forms. Examples of cycloalkyl of 3 to 10 carbon atoms including alkylkyl are cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl 2,3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl , 2-methylcyclopropyl, 3-propylcyclobutyl, 2,3.4-)! J ethyl tuclobutyl,
Cyclopentyl 2.2) Methylcyclopentyl,
2-pentylcyclopentyl, 3-otributylcyclopentyl, cycloalkyl, /l-i-tributylcyclohexyl, 3-ingrovircyclohexyl, 2.2-7methylcyclohexyl, cycloheptyl, cyclooctinopecyclononyl and cyclodecyl De Al. Examples of aralkyl of 7 to 12 carbon atoms are hensyl, phenethyl, 1-phenylethyl, 2-phenylph.

lobil, 4-phenylbutyl, 3-phenylbutyl,
2-(1-naphthylethyl) and 1-(2-naphthylmethyl). phenyl flH substituted by 1 to 3 chloro or alkyl of 1 to 11 carbon atoms
d, p-chlorophenyl, m-chlorophenyl, 0-chlorophenyl, 2,4-dichlorophenyl, 2,4.6
- ) 'J chlorophenyl, p-ryl, m-1.
Lyle, 0-tolyl, p-ethynoenyl, p-2-tributylphenyl, 2.5-dinylphenyl, 4-
Chloro-2-methylphenyl and 2,4-dichloro-
3-methylphenyl.

Examples of alkylene groups within the range -CnH2n- defined above include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, and one or more carbon atoms on one or more carbon atoms. Alkylene with more alkyl substituents, Vl'' is -CH(C
H3)-1'(CH3)2-1-CH(CH2O)f3
)-1-CA2-CH(CH3)-1-CH(CH3)
-CH(CH3)-1-CH2-C(CH3)2-1-
CH2-CH(CH3)-CH2-1-CH2-CH2
-CH(CH2-CH2CH3)- and the like.

1 ≠ ≠ I I R2 is one of the formula moieties, i.e. HO2, HO, and ~ indicates a linkage of the hydroxyl to the ring by the alpha or beta configuration -CH =CH
-, Y is cis-C)i=cH-, and CnH2n is 1
alkylene of ~9 carbon atoms, -CFR2-
has 1 to 6 carbon atoms in the chain between and the terminal methyl, g is an integer from 2 to 5, and IA is /゛·. Yumata□・
and R is hydrogen or alkyl of 1 to 1211 carbon atoms, /O-/ of 3 to 10 carbon atoms.
aralkyl, aralkyl of 7 to 12 carbon atoms, phenyl, or phenyl (substituted with 1, 2, or 3 chloro or j is alkyl of 1 to 4 carbon atoms), and R2 is hydrogen. -L4-re, -also Idon24hi-or fluoro. Those lower alkanoates and R
When 1 is hydrogen, these c4 physically acceptable salts are included.

The novel compounds of formulas 1 to XX of the present invention elicit the biological responses described above against PGE, PGFo, Each of the new compounds is intended for use in contrast to its corresponding counterpart described above, and is used for these purposes in the same manner as the above.

All known PGK, PGFo, PG%, PGA1 and PCBC gold compounds are effective in producing multiple biological responses even at low doses. For example, P()K
Both Yo and PGE2 exhibit anti-lipolytic effects, and at the same time,
Causes vasodilation and smooth muscle stimulation. Furthermore, in many cases these known grosstaglandins have a disadvantageously short period of biological action. In contrast, the more you stir, the formula ■~
XX■ Novel prostaglandin analogues and their racemic compounds are substantially more specific in their ability to elicit prostaglandin-like biological responses and exhibit substantially longer durations of biological action. have. Each of these new prostacran-/-n analogues is therefore more likely than the corresponding A(l, zuchiprone, taglandin class) to have this(·-1 shown above for the latter). For at least one pharmacological purpose, hτ is different and unexpectedly more useful because it has a different and narrower spectrum of biological potency than known prostaglandins, and 4y This is because they are more specific and cause less unwanted side effects than when using known prostaglandins for the same purpose.Furthermore, because of their long-lasting action, novel prostaglandins - Less frequent and smaller doses of the analog can often be used to achieve the desired result.

In order to achieve the optimal combination of specificity of biological response, potency, and duration of action, certain compounds within the range of formulas 1 to xx are preferred. For example, it is preferable to tlf the C-15 hydroxyl to an alpha steric.

Another preferred thing is that Cn in the hydroxy-substituted chain
The existence of an arbitrary branch at C-17 of the H2n group. General expression used here 'nn2n-CH3
Examples of such branches include -CB (CH3)
(:R3, -CH(CH3)-C3d5, -CH2-
CH(CH3)-CH3, -C(CH3)2-CH2-
CH3, -CH(CH3)-C1((CH3)-CH3
, -C(CH3)2-C(CH3)2-CH2-Cf(
3, CH(CH3)-(ClO2-CH3, and -C
(CH3)2 (CH2)5 CH3. Particularly preferred are those in which the chain length of -CnH2n-CH3 is from 3 to 51 carbon atoms.

Another preferred thing is -CFl(2- and wood;%:
CnH2n in the chain between esters is 1.2.4.5
Or when it has 6 carbon atoms, g is 3. Yet another preference is that when g is 2.4 or 5, Cn has 3 carbon atoms in the chain between -CFR2- and the wood end methyl.

Another advantage of the novel compounds of the present invention, particularly the preferred compounds described above, compared to the known prostaglandins is that these novel compounds have the above mentioned excretory potential for the uses of the known prostaglandins. In addition to the usual intravenous, intramuscular, or subcutaneous injections, intravenous, sublingual,
These compounds can be administered effectively in one infusion, one in the mouth, or one intestine. J
It makes it easier to remove uniform limescale, and patients can take it by themselves.

The 1G-fluoro and 16.16-difluor Mankuchi P (J E, P) to'α, 1- type analogues included in formulas 1 to XX'll, including arecanoates, are Used in the free acid form, ester form, or pharmacologically acceptable salt form for purposes 1 and 2. When using the ester form (where ester is within the scope of the definition of R1 above) However, Esther is 1
Preferred is alkyl of from 121 carbon atoms.

Of these alkyls, methyl and ethyl are particularly preferred for optimal absorption of the compound by the body or laboratory animal system; linear octyl, nonyl, decyl, undecyl and dodecyl are preferred for sustained action in the body or laboratory animal system. It is particularly preferable for

- These items for F-1 listed in -XX1l
The pharmacologically acceptable L4As are based on pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.

Particularly preferred metal cations are those derived from alkali metals, such as lithium, sodium, and aluminum, and from alkaline earth metals, such as magnesium and calcium, but with the exception of other metals, such as aluminum, = %jk, and cationic forms of iron also fall within the scope of the invention.

Pharmacologically acceptable amine cations are those derived from oh, oni, or oniamine. Examples of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, noclopentylamine, dicyclohexylamine,
benzylamine, dibenzylamine, α-phenylethylamine, β-phenylethylamine, engineered ethylene diamine, diethylene triamine and similar aliphatic, ring-like, and araliphatic amines containing up to about 15 carbon atoms, and hetero 4-amines, such as piperidine, morpholine, pyrrolidine, piperazine, and their lower alkyl derivatives, such as 1-methylpiperidine, i-ethylmorpholine, 1-isopropylpyrrolidine, 2-methyl Pyrrolidine, 1. -↓-Dimethylpiperazine, 2-methylpiperidine, etc., as well as amines containing hydrophilic groups or hydrophilic groups, the first row being mono-, di-, and triethanolamine, ethyljetamine, etc. Tanolamine, N-butylethanolamine, 2-amino-1-butanol, 2--7
Minnow 2-ethyl-1,3-furopanediol, 2-amino-2-methyl-1-propanediol, tris(hydroxymethyl)atumethane, 4-phenylethanolamine, I□J-(p-7 These include triamylphenyl 9 diethanolamine, galactamine, 1) J-methylpyridine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine, propyrine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium, and the like.

Compounds included in formulas ① to X
It is used in the form where H is converted to 10COCH3.

Examples of lower alkanoate moieties are acetoquine, propionyloxy, butyryloxy, haleryloxine, hexanoyloxy, heptanoyloxy, occulnoyloxy, and branched alkanoyloxy isomers of these moieties.

Among these alkanoates, acetoxy compounds are particularly preferred for the above purpose. These free hydroxy and alkanoyloxy compounds are used as free acids, as esters, and in salt form as described above.

As discussed above, compounds of formulas - X Inner, oral cavity 1.
'', administered in the form of sterile implants for sublingual, topical, 2 and sustained action. For intravenous injection or infusion, a bacterial isotonic aqueous solution lii is preferred. For this purpose, the formula ＼・III～X
,'(l[I) It is preferred that R in the compound be hydrogen or a pharmacologically acceptable cation to increase water solubility. For subcutaneous or intramuscular injection, aqueous or non-aqueous (Uses non-sparkling liquids or suspensions of the original acid, salt or ester type. Tablets, capsules, and syrups, elixirs, and simple solutions with common pharmacological carriers. Liquid preparations such as 1' are used for oral and sublingual administration. For direct or vaginal administration, herbal medicines known to the art and 2 are prepared. For tissue transplantation, sterile tablets are used. or by using silicone rubber capsules or other objects containing or impregnated with this substance.

The 1G-fluoro and 16°1+3-difluoro PGE-1PC)Fα-,゛÷Tsuji-type analogs encompassed by formulas ＼■-XxlII are made by the reactions and procedures described and exemplified below.

With reference to Figures A and B, the steps for making intermediates of XXXIV from formula xxiv will be apparent.

Figure A XXIV XXV XX\l XX\11 Age XXvl [Figure B]・, XXXX), 1), Xχn
XXXII[XXXIV
The preparation of intermediate bicyclic lactone diols of the formula XXXV has already been described by E. J. Corey et al., Journal 0
of American Chemical Society (J, Am.

Chem, Soc, ), Volume 91, 5675 (19
In 1969, he was praised as a young boy, and later E.G. Collie, etc.
J, Am, Chem, Soz,, vol. 92, 397 @
(1970) in Optical Activity No. W. From this intermediate, either racemic or optically active PCr
Conversion to E2 or PGF2α is disclosed in these seven publications.

Iodolactones of formula XX[V in Figure A are known to the art (see Collie et al., supra). These are available either in racemic form or in the active form (ten or -). The natural configuration of prostaglandins is levorotatory (
-) is used.

1st A and B, CnH2ns g '' and R2 have the same meaning as defined above, i.e. CnH2n
is an alkylene having 1 to 9 carbon atoms, and -0FR
There are 1 to 6 carbon atoms in the chain between 2- and the terminal methyl, or - or hydrogen, methyl, and Q is -CFR2CHR2nCHs, and
represents a hydroxyl with two bonds in the alpha or one haheta configuration.

The appendage of 戊XXV (Figure A) supports the Ra0 portion in the 4-position. where Rs is L7D7/L/kyl, phenylalkyl of 7 to 10 carbon atoms, or nitro, S is cello to 5, and T not exceeding 11 or 2 is (Provided that the total number of carbon atoms in T does not exceed 101 carbon atoms)
, atomic argyl), as shown), or (4) acetyl. In preparing a compound of formula XXV by replacing the hydrogen of the hydrogen group at the 4-position i with an acyl group, it is possible to prepare the compound of formula XXV by a method known in the art. When an aromatic acid of the formula R1OH, e.g.
In the presence of quick lead chloride or phosphoryl chloride, formula XXI
V compound or an aromatic acid anhydride of formula (R3) 20, such as ammonium anhydride, uses the number 1.

But preferably acyl rides, such as tf, R2
O1, for example benzoyl chloride, is removed by hydrogen chloride i'j
ll, analogy technique;! ;fi/This is carried out under various conditions using the general VL%IJ procedure. Generally mild conditions are used, e.g.
Contact is carried out in an inert solvent such as toluene or chloroform. Acyl: Acyl is present in either stoichiometric or excess amounts.

The following are available as acids (R3od), acid anhydrides ((R3)20) or acyl chlorides (R3C1). In other words, benzoyl; substituted benzoyl example! 'f(2-13- or 4-)methylbenzoyl,
(2-13-se is 4-)ethylbenzyl, (2-%
3-also u4-) isojropylbennoyl, (2-13
-↓-) O-tributylbenzoyl, 2.4-dimethylbenzoyl, 3.5-dimethylbennoyl, 2-inorobyltolyl, 2,4.6-1-limethylbenozoi inopepentamethyl Benzoyl, ・)-phenyl-(
2-13- or 4-) tolyl, (2-13- or 1d4-
) phenethylbennoyl, 2-13- or 4-nitrobenzoyl, (2,4-2,5- or 3.5- ) dinitrobenzoyl, 3,! L-dimethyl-2-nitrobenzoyl, 4,5-dimethyl-2-nitrobenzoyl, 2
-21.rho 6-phenethylbenzoyl, 3-nitro-
2-Phenethylbenzoyl: mono-esterified phthaloyl e.g. 00. 1 (1- or 2-) naphthoyl, substituted naphthoyl, e.g. (2-13
-14-15-16- or 7-) methyl-1-naphthoyl, (2- or 4-) ethyl-1-naphthoyl, 2-isopropyl-1-naphthoyl, 4,5-dimethyl-1-
Naphthoyl, 6-isopropyl-4-methyl-1-naphthoyl, 8-benzyl-1-naphthoyl, (3-14-
15:'% is 8-) Nitro-1-naphthoyl, 4.5-
7'nitro-1-naphthoyl, (3-14-16-17
-di4 is 8-) methyl-1-naphthoylthyl-2-naphthoyl and (5- or 8-)nitro-2-naphthoyl; and acetyl, thus hendiyl chloride, 4
-Nitrobenzoyl chloride, 3,5-dinitrobenzoyl chloride blue, ie the R3Cl compound corresponding to the above OF13 may be used. Where the acyl chloride is not available manually, it is prepared from the corresponding acid and silicon pentachloride as is known in the art. R3θ
H, (R3) 20, Noro is F. It is preferred that the -CI reactant does not have bulky obstacles placed on both the carbonyl and the D ring carbon atoms.

Next) The compound of this formula XX\l has a lactone ring or OF(
Reagents that do not react with the 3 parts, such as li11 lead powder,
Dehydrogenation of XXV using sodium hydride, hydrazine-palladium, hydrogen and Raney nickel or platinum, etc.
57. can be obtained. Particularly preferred is open/al
+'i'l is 2,2'-azobis(2-methylpropionitrile) and hydrogen of pentene A at 51 and 25'Q is tributylsuzo.

Compounds of formula XX\.11 can be obtained by demethylation of XXM with reagents that do not attack the 3-moiety, such as trivalent hydrogen or trivalent boron. It is recommended to carry out the reaction in a medium at about 0 to 50 ml.

Formula XX\・■ Compound has 1 it of lactone ring! It is obtained by oxidizing -(J]20H of 6 to XXVll to 1-CHO. Useful for this purpose are dichrome-1-1-sulfuric acid, Njones' reagent, 1'J of tetraacetate, etc. preferred is a coll in about 0 to 100
This is Nonz's recommendation (pyridine-Crys).

Compounds of formula XXIX are obtained by Uite-f hyalkylation reaction of XXX1 using the appropriate sodium derivatives of 2-oxo-3-fluoro (or 3,3-difluoro)-alkylphosphonates. Trans-enone lactone can be obtained stereospecifically (D.H. Wadsworth (D.H., 'Ja.isv; ortk+)
et al., J. Org. Chem. , 30=4'), 6
Page 80 (196b city) wo reference i1%4.

(want to be).

To make a compound of formula X 7) where R2 is hydrogen, methyl, ethyl, or fluoro, and L is alkyl having 1 to 8 carbon atoms. and cnH2n is a 1 to 9 carbon 4 alkylene having 1 to 6 carbon atoms in the chain between -C,PH1- and the terminal methyl.Preferred embodiments of the present invention Phosphonates in which the fluoro substituent is on one carbon atom of the carbonyl, e.g.
1 (r(50)2”CH2C-C-(CHa)2-CH3
, or 0 0F 1111 (R50)2PCB2C-C-(CH2)3-CH3C
Use H3.

The phosphonates are made by methods known in this art and used for one cycle. See Wadsworth et al., cited above. A suitable fatty acid ester is used in the presence of n-butyllithium in the form of a lower alkyl ester, preferably methyl or ethyl. The methyl ester is easily formed from the acid by reaction with diazomethane. Fatty acid chains of various chain lengths with mono- or difluoro moieties within the range of -CFR2- as described above (1) are known or applicable to this technique. It can be made by known methods.

Many fluoro-substituted acids, such as 2-fluorobutyric acid, 2
．． 2-difluorobutyric acid, 2-fluorogreen grass + 4', j
, 2-flugarohexanoic acid, 2-fluorohepanoic acid, 2-fluorooctanoic acid, 2-fluorononanoic acid, and 2-fluorodecanoic acid can be easily prepared manually. Others are obtainable by methods known in the art, for example by hydrogenation of 2-oxoaliphatic acids with tetrabutylated sulfur to give 2,2-difluoro acids. Regarding the reaction of SF4, Martin et al.
J, Org, Chem, vol. 27, p. 316, 1 (19
Please refer to 1962). For the synthesis of other fluorinated acids, see Henne et al.
Op American Chemical Society (J, Am,
C! xem, soc, ), vol. 69, p. 281 (19
Please refer to 1947). For fluorination of ketone functional groups with MoF6・BF3K, tetrahedron (Tetr
ahedron), vol. 27, p. 2965 (1971)
Please refer to Other synthetic methods include the substitution of hydroxy by fluoro (see Ayer, US Pat. Saturation of heavy bonds (Advances in Fluorine Chemistry J (Aava
nces in FJuorineChemistry
), M Stacy (M, Sta C, 3y)
Isolines, Volume 3, Butterworth Publishing, 1963, Special I'c
181-188).

Continuing further with Figure B, the compound of formula XXX is xx■
is obtained as a mixture of alpha and beta isomers. This reduction uses ester or acid groups or alternative versions of known ketone carbonyl reducing agents that do not reduce carbon-carbon double bonds when undesired. Examples of these include metal hydrides, especially sodium, potassium, and lead borohydrides, lithium hydride
Aluminum, metal trialkoxy hydrides such as thorium trimethoxy hydride, lithium hydride, diimbutylaluminum hydride, and carbon-
When reduction of carbon double bonds is not a problem, there are boranes such as dicyamylphorane.

For the preparation of PG-type compounds of natural configuration, formula XXx
The desired 15-alpha form of the compound is separated from the 15-beta form by silica gel chromatography.

The following formula XXXI compound is prepared in methanol at about 25'C
is obtained by dealanlation of XXX with an alkali metal carbonate, such as potassium carbonate.

Bis(tetrahydropyranyl) etherxxxni is
p-Toluenesulfonic acid or pyridine hydrochloride (obtained by reaction of dihydrobyran with a diol of formula XXX+ in an inert bath medium such as dichloromethane in the presence of an acid condensing agent such as p-toluenesulfonic acid or pyridine hydrochloride). It is preferably used at 4 to 10 times the theoretical amount.The reaction is usually carried out at 20 to 10 times the theoretical amount.
The 760 lactol XXXIII, which is completed in 15-30 minutes at 30'O, can be prepared by reduction of the lactone of formula XXX... or its 015j epimer in 13. ]]4
- Obtained without reducing ethylene. Hydrogenated diimbutylaluminum is used for this purpose. Reduction-
[It is preferable to use >Q or -70CI. Assignment X
The 15β-epimer of the lactone of formula XXX is
5. 7j is also easily obtained by the steps in Figure B using the sex body.

Compounds of formula XXX■ are represented by a suitable ω-carboxyalkyl
-IJ phenylphosphonium bromate, HOOC-
(CH2)g+l P(C6H5)3Br and is obtained from formula xxxu+lactol by Wittig reaction using Wittig reagent derived from striium dimethylsulfinyl carbanide. The reaction is about 25'
It is convenient to carry out at O. This compound of formula XXXIV (serves as an intermediate for making either the P()F2α type or the PGE2 type product (Figure C). Phosphonium compounds are known in the art or e.g. - It can be easily produced manually by the reaction of phylomoaliphatic acid and triphenylphosphine.

Figure C H ○ χ
with methanol-HCl at 55°C or i
It is obtained from hydrolysis with 'l'l' acid/water/tetrahyfuran, thereby avoiding the formation of PGAQ type compounds as by-products. Referring to Figure C, PG
The production of the E2 J14'j product will be apparent. Formula X
The bis(tetrahydropyranyl) ether of the PGF2α type product, designated XXIV, is oxidized at the 9-hydroxy position, preferably by Jones reagent. Finally, the tetrahydropyranyl group is replaced by hydrogen by hydrolysis as in making the PGF2α type product in Figure B. In figure C the symbols 9, M, j, +f', Q and T'HP have the same effect as in figures A and B.

Formula of the present invention ■P Gel and formula XVIII] 3.14-
Dihydro PGE1 type products are made by ethylene reduction of compounds of the formula Xu[PGEs+ type. Thickening agents useful for this conversion are known in the art. Hydrogen is thus used at atmospheric or low pressure with catalysts such as palladium on charcoal or rhodium on aluminum. The list is E.G. Collie et al., J.

Ar+,':hem,soc,, vol. 91, p. 5677 (1969) and B.Sam
uelsson), Journal 6 of Biological Chemistry (J, Eiol.

Cht;”, -+), vol. 239, p. 4091 C196
Please refer to 4th grade) and 7th grade. For PC) El type compounds, the reaction is terminated when one equivalent of hydrogen is absorbed. i3. J4-dihiy0-pGEl quasi-El type compounds are terminated when 2 equivalents are absorbed. P.G.E.I.
For type compounds, it is recommended to use catalysts such as nickel boride, which selectively reduce cis-5,6-carbon-carbon double bonds in the presence of trans-13,]4 unsaturation. preferable. It is convenient to separate the raw bat mixture by silica gel chromatography.

Instead, the bis(tetrahydropyranyl) ether of the PGE type 2 compound (formula xxx
I'm going to do it.

Figure D0 shows the conversion of the formula X The planned warrior χX~■, Xχχrz,
In xIJ and XLI, CnE 2 ns&,
Near 1, Q, and ~ are the same as in Figures A and B -
d taste, R, is hydrogen or alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, 7 to
aralkyl, phenyl, or (l,
(a) phenyl substituted with 2 to 3 o'clock chloro or alkyl of 1 to 11 carbon atoms; and (a)
or (b) x cartrans-C'H=CH- and Y is cis-CH=CH-.

N: Kairan, r, -CH=CH- and Y is -CH2
When CH21-, the formula x X X14+1 is PC
) represents an Ez type compound. When X is C''H2CH2- and Y is -CH2CB2-, the formula X\X~I11 is]
3. Represents J.1-dihydro-PGEI type compounds.

~C< is trans-CH=C)1- and Y is cis-C
I: For 1·r where i=CB-, the formula XXXλ■ is PG
Represents E2 type compounds.

In this way, the formula XXX\゛■, XXXIX, XL:l-''
and xr, H, and all compounds represented by formulas 1 to XX111.

In this way, the PC) Fβ-type compounds included in formulas X, XV, and XX are the corresponding PGE-type compounds.
, for example, by carbonyl reduction of the formulas \Tsukuda, x■, and XVI. For example, J6-fluoro-+9
+20-dinol-PGE10-carbonyl quaternary is 16-
Fluoro-19,2tJ-di/ /l/ -PGFIC
X and 16-7 Luo-1g, z□=Zinol-PGF
, giving a mixture of β.

These ring carbonyl reductions are carried out by methods known in the art, such as those of Berkström (7), in contrast to the ring carbonyl reductions of known brostanic acid derivatives.
gstrom), alky-7-chem (Arkiv K
, emi), Vol. 19, p. 563 C1963), Acta Che+n,
5cand, ), vol. 16, p. 969 (1962),
and British Patent No. 1.097,533. Reducing compounds that do not react with carbon-carbon double bonds or ester groups include sodium borohydride, potassium, and hydrides such as trimethine, potassium, and sodium borohydride, such as trimethquine. The mixture of alpha and beta hydroxy reduction products is separated into individual alpha and beta isomers by methods known in the art for the separation of similar pairs of known brostanic acid derivatives. Separated into rel.

For example, Bergström et al., Granström et al., cited above, J. Biol.
,Chem,.

240, p. 457 (1965), and Green (
J. Lipid Research, Vol. 5, p. 117 (1964). Particularly preferred separation methods are both normal phase and reversed phase pertizolyne chromatography, preparative assisted bed chromatography, and countercurrent distribution procedures.

Formula X1. XVI, and various Ps included in XXI
GA type compounds are the corresponding PGE type compounds, Example 7t
are prepared by acidic dehydration of formulas Vl, xm, and XVIII. For example, acidic dehydration of 6-fluoro-PC)E2 gives Io-fluoro-PGA2.

These acidic dehydrations are carried out by methods known in the art for the acidic dehydration of known brostanya derivatives. For example, Plke, Proc, Nobe, etc.
l Symposium I [, Stockholm (19
1966), Interscience Publishers, Inc.
New York, pp. 162-163 (1967), and British Patent Specification No. 1,097,533.

Alkanoic acids of 2 to 6 carbon atoms, especially acetic acid, are the preferred acids for this acidic dehydration. Cold aqueous solutions of mineral acids, such as hydrochloric acid, especially in the presence of a dissolving diluent such as tetrahydrofuran, are also useful as reagents for this acidic dehydration, although these reagents cause partial hydrolysis of the ester reactant.

Various PGBs encompassed by formulas xi, xvn and xxn
The type compound order can be determined by basic dehydration of the corresponding PGE type compounds encompassed by formulas ■, XIII, and XVIII, or by the pair E, PO encompassed by formulas
It is made by contacting Type A compounds with a base. For example, 1.6. H3-difluoro-13,14-
Dihydro-PGTCl and 16.16-difluoro-13
,1,1-dihydro-? ) both give 16,16-difluoro-13,14-dihydro-PGBL by treatment with base.

These basic dehydrations and double bond transfers are carried out by methods known in the art for analogous reactions of known brostanic acid derivatives. For example, Bergström et al., J. Biol, Chera, 238, 3.
See page 555 (9/963). The base is any whose aqueous solution has a pH greater than 10. Preferred bases are alkali metal hydroxides. Suitable reaction media are mixtures of water and alkali-norls mixed in the water in an amount sufficient to give a homogeneous reaction mixture. PGE-type or PGA-type compounds can be combined with PGB-type compounds.
As shown by the ultraviolet absorption near 78 mμ, PGB-type compounds are no longer formed and are thus retained in the reaction medium.

Optically active compounds are obtained from these optically active intermediates according to the method steps of Figures A and B. Similarly, optically active products can be obtained by conversion of an optically active f-hypothesis according to the method of Figures C and D. When one racemic intermediate is used to obtain a racemic product in a reaction corresponding to the process of Figures A-D, these racemic products are used in their racemic form. or, if desired, they can be resolved as optically active isomers by procedures known in the art.

For example, when the final compound \.111~xxut is a free acid, its d-form can be resolved into the d-form and the 1-form by reacting the free acid with an optically active base, such as brucine or strychnine, by known general procedures. gives a mixture of two diastereoisomers which, when separated by known general procedures, such as fractional crystallization, give the salts of the separate diastereoisomers. Optically active acids of formulas 1 to xxm are then obtained by acid treatment of the salts according to known general procedures.

As stated above, the stereochemistry of C-15 is not changed by the conversion of Figures A and B. A 15β epimeric product of formula xxxv is obtained from a 15β formula χXX reactant.

Another way to make the 15β product is to prepare PC)F with the 1.5CX configuration by methods known in the art.
, - the father is PGE, a chemical compound of the type compounds. for example·
ζiri et al., J.Org., C:lam, 34
See Vol. 3552 (1969).

(As mentioned above, methods of Figures B, C, and D), C-Σ (Rx is hydrogen) or esters (R1 is defined above as r9/ζ, alkyl, cycloalkyl , aral, phenyl, or substituted phenyl) can be reached by various routes. When an acid is made and an alkyl ester is desired, esterification is carried out by phase conversion with a suitable diazo hydrocarbon. It is advantageous to use a methyl ester, for example, when using diazomethane.

The total use of diazobutane, diazobutane, and 1-diazo-2-ethylhexane, as well as diasotecan, respectively destroys ethyl, butyl and 2-ethylhexyl, and decyl esters.

Esterification with diazo hydrocarbons is carried out by mixing a bath solution of the diazo hydrocarbon in a suitable inert solvent, preferably diethyl ether, with the surface reactant, advantageously in the same or another inert diluent. It is carried out by After the esterification reaction has ended, the core medium is removed by evaporation and, if desired, the ester is purified conventionally by evaporation, preferably by chromatography. To avoid undesirable molecular changes, the contact between the acid reactant and the diazo hydrocarbon should be no longer than necessary to effect the desired esterification, ranging from about 1 minute to about LO minutes. It is preferable that Is this technology known for diazo hydrocarbons?
Or it can be made by any method known to this technology. For example, "Organic Reactions", John Wiley & Sons, New York, N.Y., Vol. 8, 389-
See page 394 (: 19544tg).

An alternative method of esterification of the carbogicyl moiety of acid compounds consists of conversion of the free acid to the corresponding silver salt and subsequent interaction of that salt with an alkyl iodide. Examples of suitable iodides are methyl iodide, ethyl iodide, butyl iodide, inbutyl iodide, octbutyl iodide, and the like. The silver salt can be prepared by conventional methods, for example by dissolving the acid in a cold dilute ammonia water bath, allowing the excess ammonia to evaporate under reduced pressure, and then adding a stoichiometric amount of silver nitrate (.
Futakami is created.

The final free acid form produced by the method of the present invention
Compounds 1-xxm are converted into pharmacologically acceptable salts by neutralization with a suitable amount of an inorganic or organic base O, listed by way of example above and corresponding to the secondary ions and amines. These conversions are carried out in the present invention by a variety of procedures that have been found to be generally useful in the production of inorganic, i.e., metal or ammonium salts, amine acid addition salts, and quaternary ammonium salts. The selection of
Part 4 describes the solubility characteristics of the specific material to be created.]
I am impressed. In the case of inorganic salts, it is common practice to dissolve acids 2 to XXII in water containing a stoichiometric amount of hydroxide, carbonate, or bicarbonate corresponding to the desired inorganic salt. I have one room. For example, the use of sodium hydroxide, sodium carbonate, or sodium bicarbonate provides a sodium salt solution.

If a monomer inorganic salt is desired, water evaporation or addition of a water-miscible solvent of moderate polarity, such as a lower alkanol or lower alkanone, provides this form.

To make an amine salt, replace the formula
-11+1 in a suitable solvent of about -12 or low polarity. Examples of the former are ethanol, acetone, and ethyl leutoate. Examples of the latter are diethyl ether and benzene. At least a stoichiometric amount of an amine corresponding to the desired cation is then added to the solution. If the resulting salt does not precipitate, it is usually obtained in solid form by addition of a less polar overlying diluent or by evaporation. If the amine is relatively volatile, any excess is easily removed by evaporation. The use of stoichiometric bones of less volatile amines75 is preferred.

When the cation is quaternary ammonium hydroxide, the salts are prepared by mixing an acid of 2 ~ 1 ~ X created by.

The best 16 parts made by the method of the present invention ~・■~
The acid or nistil of tXllI is 1 formula ■ ~ X X 11 [
Lower alkanoyl ha
It is turned into a hem. ↑・Rie, the use of acetic anhydride gives the corresponding acedate. The use of propionic anhydride, isobutyric anhydride, and hexanoic anhydride provides the corresponding carboxyacylates.

Carboxylation is advantageously carried out by mixing the hydroxy compound and the acid anhydride, preferably in the presence of a tertiary amine such as pyridine or triethylamine. excess amount of anhydride,
Preferably, from about 10 to about 1,000 moles of anhydride are used per mole of hydroquine compound reactant. Excess anhydride serves as a reaction diluent or medium. Active, +1-organic selectors, such as dioxa-7, can also be added to the carboxylic acid produced by the reaction to neutralize the optional carboxyl groups present in the hydroxyl compound. , it is preferred to use sufficient tertiary amine.

The carboxyacylation reaction is carried out between M'J O'' and about 1θO.
It is preferable to carry out the experiment within the range of C. The required reaction time is
Reaction temperature and properties of acid anhydride and tertiary amine reactants L
It will depend on factors like 4. For a reaction temperature of 1"l'1 acid anhydride, pyridine, and 25 Q, a reaction time of 12 to 2.1 hours is expected.

The carboquine acylation product is isolated from the reaction mixture by conventional methods. For example, an acid anhydride of less than 100 ml can be decomposed with water, the resulting mixture made acidic, and then extracted with a voluminous solution such as diethyl ether.

The desired carboxyanlate is recovered from the diethyl ether extract by evaporation. Alternatively, the carboxyacylate can be loaded by conventional methods, preferably by chromatography.

By this procedure, the PGE of formulas ■, X■, and XVI
The type compounds are converted to siacanates and have the formula ■,
PGF-type compounds of X, XIV,

PC) Type B compounds of XXn are converted to monoalkanoates.

pc+=Jy/When alkanoate is converted into a PGF-type ratio compound before carbonyl reduction as shown in the diagram, PO
2 tons of F-type Sial sword Noate is formed, and 1 yen of it is either used for the above purpose or converted into Real Kaate by the above procedure. In the latter case, the alkanoyloxy group of the oyo can be before carbonyl reduction (-any two alkanoyloxy groups are the same or :rjl).

The invention may be more fully understood by the following examples.

All temperatures are in degrees.

The red n-ray M spectrum was recorded on the infrared spectrophotometer of the Birkin Elmer Motel 421. I'+41 except when specifying other
A sample with no audience is used.

The quality and size spectra are To-4 light (ionization voltage 70
av) was recorded on an Atlas cH-4 mass hectrometer.

Nuclear magnetic resonance spectra were recorded on a Norian A-1+Q spectrophotometer in deuterochloroform solution with detramethino/silane as internal standard (downfield).

The term "brine" used in the present invention A411 refers to a saturated hydrochloric solution of sulfur and lithium chloride.

A-N Example 1 3 CX-benziroxy 2β
-Carboxaltehyde 50-hydroxy-10-cyclopentane white't,! 'tγ-Lactone (
Formula XX~'III: & is Petzil) Figure A is 1l of sand
(j,.a, 135 m of pyridine in a 9-element atmosphere
Formula XXIV levorotatory f-)3CX-human o-1C5G-hydroxy-4-iodo-2β-methoxymethyl-10-cyclopentaneacetic acid γ-lactone in E. J. Corey ) etc., J.Am.
Chem, Soc, vol. 92, p. 397 (1970
year)) 75' mixture, benzoyl chloride 3 to approximately 20 to -100 (with cooling to maintain temperature)
Add 0.4me. For the complete history of stirring; continue for 30 minutes.

Toluene-C is added and the mixture is compressed under reduced pressure. The residue was dissolved in ethyl chloride and washed with 10% sulfuric acid, brine, a saturated sodium bicarbonate bath, and brine. The ethyl solution of I'-1 is dried over sodium sulfate and concentrated in vacuo to give oil 952. Crystallization of the oil gives the corresponding 30-benzoyloxy compound.

, d points 84-86, (CX), +7° (CHCl
3), infrared spectrum absorption is 1768.1722
．． 1600, 1570.1490.1273.126
5.1180, 1125.1090.1060, 1
030, 2hi 710C no 1k. The nuclear magnetic resonance peak is 2°1-3.45, :3.3.3.58.4.3
8.5.12.5.51.7.18-7.58, and 183-8.05δ.

[), the iodo group is removed as follows. Dry benzyloxy compound (6°2
) About 6 Q mg of 2'-azobis-(2-methyl propionitrile) is added to the bath at night. Mixture 15
250 ml of tributyl hydride in ether 600+ne.
and at a rate that maintains a sustained response. When the reaction is complete as indicated by thin layer chromatography, the mixture is placed under reduced pressure? t4] Concentrate with i. The oil is mixed with 600 me of Skellinurp B (mixed isomer hexane) and 600 me of water and stirred for 30 minutes.

Separate the aqueous layer containing the product and then add 450 ml of ethyl acetate.
Combine m, e and enough solid thorium chloride to saturate the aqueous layer. Separate the ethyl acetate layer, now containing the product, dry over magisium sulfate and remove the oil under reduced pressure.
In other words, it is reduced to a compound 397, which is less than 100% of iodine.

The analyzed sample gives [α)0 99° (cHcls). Infrared spectrum absorption is 1775, 1715.1
600, 1585.1490.1315, 1275
．． 1180, 1110.1070, 1055.10
25, and 715j; #shi.

The peak of nuclear magnetic field 111 is 2.5-3.0.3.25
, 3.34.4.84-5.17, 5.17-5.
4, 7.1-7.52 and 7.8-8. (+5 a
The peak of the spectrum is 290°168% 105
, and 77.

The C,2β-methoxymethyl compound is converted to a hydroxymethyl compound as follows. dichloromethane 3201
A cold (0,5'C) solution of iodine-free methoxymethyl lactone (20r) in nitrogen fluoride, dichloride in 320rnl methane, desensitized boron 24, filtrate solution. 71g, stirring vigorously, 0-5cc'
22i, -+ for 50 minutes. Stir, cool, and continue for an hour. 414 chromatography shows that when the reaction is complete, 200 m of water
e...dissolution of thorium carbonate (monohydrate 78y)? 1
Add a note. Mixture at 0-5c for 10-15
The mixture is stirred, saturated with sodium chloride, and the ethyl acids I+j are separated. The aqueous layer is extracted with ethyl RI'+-acid and combined with the ethyl RI'+-acid main bath solution. - Concentrate with 7ζ6'@ size. The analysis sample has a melting point of 1
16-118c. [CX jo 80'(CH
Cl3). Infrared radiation 7% yield u 34
60. 1735. 1708. 1600. 158
(!, 1490.

1325.1315.1280, 1205.1115
, 1090 , 1070 .

:o3=, group 25-730, and 72o0 nuclear magnetic resonance peak, yo2.1 = 3.0.3.58.4.8
3-5-12. 5.2-5, +15, 7. ．． 15-7
*55, and 7.8-8.0 c3゜゛51 table: +'
The 2β-carboxaldehyde compound of α is prepared as follows. Dry Zik Iz Rononono 150 me and Collins reagent (J, C, Co11i
n, s) Tetrahetron Recus (Tetrahe
Dron J, ett, ), 3363 (1968'Giant), 287) was heated under nitrogen (t
This is a cold (10'O) bath solution of 150 (5.0 V) for 2 hours.
k L <Add while stirring. After stirring for an additional 5 minutes, add approximately 1 of dry pensene. lme is added, the mixture is filtered and the bath is reduced under reduced pressure. Bring the capacity to about 150+n6 with benzene. A solution of the title compound of formula x xtm is used immediately. In the Tani experiment, Collins' reagent was prepared in situ with comparable results.

Following the procedure of Preparation Example 1, but substituting the racemic compound of Qζ and its mirror image (EJ Cory, J. Am.
Chem. Soc. , vol. 91, p. 5675 (196
9), a racemic compound corresponding to the assignment XX■ is obtained.

Preparation Example 2 5-Carpoxypentyltriphenylphosphonium bromide 6-bromohexanoic acid (5o?>yl, liphenylphosphine (157, LF) and acetonitrile 24O
The r5C mixture is heated under reflux for 22 hours. 160 me of acetonitrile are then removed by distillation. solution? '(+;i, then add benzene 240 me to this!L. The title compound is obtained as a crystal. Melting point 201~
203 c0 infrared spectrum absorption is 2800, 17
05, 1585, 1480°1435, 1375
．． 1225.1210, 1190, 1115.74
5, 725, and 695C1x. Nuclear magnetic resonance peaks are 1.5-1.9.2.2-2.6.3.3-4
．． 0 and 7.7-8.0 (multiplet) δ.

A"] 4q Example 3 6-Carpoxyhexyltriphenylphosphonium Bromite Following the procedure of Preparation Example 2 but using 7-bromoheptanoic acid in place of the 6-bromohexane sequence, the title compound is obtained as crystals. Melting point 185-1870, infrared absorption is 2850, 2570.2480, 1710.15
85.1485, I235.1200.1185
, 1160 , 1115.100 (1,755,725
and 695 mercenaries. The peak of the nuclear magnetic resonance spectrum is 1.
2-1.9.2.1-2.6.3.3-4.0 and 7.
7- s, o (multiplet) in δ.

Example 1 3CX-benzoyloxy-50-hydroxy-2β-(3-oxo-4-fluoro-trans-1-octenyl)-1CX-7 clopentaneacetic acid γ-lactone (formula XXV2C□H2n is -(CH2)3 -, R2 is hydrogen, circle is benzoyl) See Figure B. a. First, dimethyl 2-oxo-3-fluorohebutylphosphonate is prepared. Ethyl 2-fluorohexanoate (prepared from 2-fluorohexanoic acid and diazoethane by known methods) 372 was added to 600 ml of tetrahydrofuran precooled to 170'O.
m (3) in dimethylmethylphosphonate (6zy) and butyllithium (1,61vi solution 312 me). The reaction mixture is stirred for 2 h, then acidified with acetic acid and concentrated under reduced pressure. The residue is Partition between dichloromethane and water. The organic phase was dried, concentrated and distilled to give the desired product 46.9 F. Boiling point 116-117 C/0.21 parts m 0 and dichloromethane 30 me Naka no Ni XXI・■3α-pen 7 pyroxo 2β-carboquinaldehyde-5CX
-Hydroxy-lα-cyclobencuenacetic acid r-lacf”
A solution of (AF'A Preparation Example 1.3.OS') was prepared from dimethyl 2-oxo-3-fluorophospoly, -1
- anion (3' 1 part above, 6.69f) and sodium hydride (1,35F). The resulting reaction mixture is stirred at about 25'Q for 2 hours, then acidified with acetic acid and reduced under reduced pressure. The residue is partitioned between dichloromethane and water and the organic phase is concentrated. The residue was chromatographed on silica gel and f'i
'f: Acid ethyl skelisolve B (isomeric hexanes)
Shoot away with (1:i). The product has a melting point of 90-93o.

The peaks of the fit spectrum are 388, 368 and 299; /L; the peaks of external absorption are 1780, 1
725, I670, 1640.

I550.1420, 1190.1110b and 985 domain.

The racemic phosphonate used in Example 1-a has the formula
Seven 4-fluoroepimers or diastereomers corresponding to the title compound of X are obtained, which are separated by conventional methods, such as silica gel chromatography.

The procedure of Example 10 is followed, but instead of racemic ethyl 2-fluorohexanoate, the ethyl esters of the (+) and (-) isomers of 2-fluorohexanoic acid obtained by resolution of the racemic acid are used. Using the corresponding optical activity←
) and (-)phosphonate 1m are obtained, and then the corresponding optically active title compound order is obtained.

The procedure of Example 1 is followed, but instead of the optically active formula -XX~1■aldehyde, the racemic aldehyde obtained after Preparation Example 1 and the racemic phosphonate-1 of Example 1-1 are used.
Two pairs of 3-oxo-4-fluororacemic compounds are obtained using . It is separated into racemic pairs by methods known in the art, such as silica gel chromatography.

Following the procedure of Example 1, but substituting the optically active ← and (→ phosphonates above for the racemic aldehydes above, a pair of corresponding diastereomers is obtained from each, which is For example, by silica gel chromatography, individual isomers can be separated by
Ru.

Similarly, following the procedure of Example 1, but substituting racemic enal 2-fluorohexanoate with each of the following fatty acid esters, pair 1. -6 are obtained, optically active esters give optically active phosphonates, cyptic esters give racemic phosphonates, and then optically active esters give racemic phosphonates, and then the optical Active or racemic lactones are produced.

Methyl 2-fluorobutyrate ethyl 2,2-difluorobutyrate methyl 2-fluoro-2-methylbutyrate ethyl 2-
Ethyl fluorovalerate 2-ethyl-2-methyl fluorovalerate 2,
2-Difluorohex? /neat methyl 2-fluoro-3
-Methylheptanoateethyl 2,3-diethyl-2-fluorohexanoateethyl 4-ethyl-2-fluorohexanoatemethyl 2-fluoroheptanoatemethyl 2-fluoro-6-methylheptanoatemethyl2. 2-difluoro-3-methylheptanoate ethyl 2-fluorooctanoate methyl 2.2-difluorobutyrate methyl 2-fluoro-3-probyl nonanoate e.g. methyl 2-fluorobutyrate hashimethyl 2-oxo- 3-fluoropentylphosphonate is prepared and then 3α-benzyloxy50-hydroxy-2β-(3-oxo-4-fluoro-trans-1 of formula XX[
-hexenyl)-1CX-cyclopentaneacetic acid r-lactone is prepared. Similarly, methyl 2,2-difluoro-3-
Methylheptanoate is dimethyl 2-oxo-3,3-
Difluoro-4-methyloctylphosphonate is prepared, and then
Hydroxy-2β-(3-oxo-4,4-difluoro-5-methyl-trans-1-nonenyl)-1CX-encrohentaneacetic acid γ-lactone is prepared.

Actual symptom f'32 3 CX-benzoyloxy-5α-hydroquine-2β-(3G-hydroxy-4-fluoro-trans-1-octenyl)-1CX-7 clobenkune lactate γ-lactone (formula XXX: M is benzoyl) and 3β-hydroxy compound 7 me sodium borohydride (0,17
f) and chloride So'Je (0,76f?) (7) Stir the mixture for 2.5 hours at about 25'Q (C.
dimethyl ether of 1,2-ethanediol
3-oxo-↓-fluoro compound of formula XXI in
Example 1.0.44? ) O bath solution was added and the mixture was
．． Stir for 51 minutes. Finally: Add 3 me of water and 20 me of ethyl acetate, filter out the solid and wash the powder with brine. The organic phase was reduced to 0.57% oil under reduced pressure. Reduce by 6 with i. This material was subjected to chromatography on solica gel,
Elute with ethyl acetate and Kelisolve B (1:1);
Collect 4 ml fractions each. Fraction pottery 8
When 5 to 105 are concentrated together, 30 of formula XXX is obtained.
-Hydroxy compound 0. i41' is created. Similarly, fraction 1. Concentration of kllll~129 together yields the formula XXX 3β-hirokylated racemic 3-
Using the oxo-11-fluoro compound 1, the corresponding racemic 3-hydroxy products are obtained.

Similarly, following the procedure of Example 2, each of the optically active or racemic lactones corresponding to formula XX■ described after Example 1 was converted to an optically active or racemic compound corresponding to formula XXX. be done.

@ Shima Example 1 30i, 5α-dihydroxy-2β-(3
0-Hydroxy-4-fluoro-trans-1-octenyl)-1 α-cyclopentaneacetaldehyde r-lactol bis(detrahydride; copyranyl) ether (formula XXX+1[: 1νI′
See Tool 1, Figure B. Formula XX in anhydrous methanol 2O me
30-hydroxy-4-fluoro compound of X (Example 2,
0,9? Di and potassium carbonate (0.32/n';/ )
Stir the melt under nitrogen for 1 hour at 26'C, then (
The mixture was diluted with 25 ml of 1,2-dichloroethane. The solution is washed with brine, filtered through sodium sulfate, and concentrated under reduced pressure. The oily residue is triturated with twice the amount of Scherisolve B and dried to yield a benzoyl-free compound of formula XXXI, namely 3G,5α-dihydroquine-2β-(3α-hydroxy-4-fluoro-
trans-2-octenyl)-1cX-; noclopentane 21-lactone 0.54C] 9 is produced. The 14 addition product (0.122?) is recovered from the wash water by acidification with potassium hydrogen sulfate and extraction with dichloromethane.

2. Compound of formula XXXI from Part 1 above ((L6(
587) is pyridine (1.1 mg)
It is converted to bis(detrahydropyranyl) ether by reaction with dichlorone 2 fluoride in the presence of 10. The reaction mixture is washed with dilute aqueous sodium bicarbonate solution and dried to give the bis(tetrahydropyranyl) ether 1 of formula XXX... 0 reduction to .23ii'.

3. The title compound is prepared as follows. Diynbutylaluminum hydride (00-82 in toluene 4 rne
me), -78'OK cooled Toruev 1.
Add dropwise to the stirred solution of XXXII bis(tetrahydropyranyl) ether (1.23 g') from Part 2 above in Ome. Refresh the stir at -780 for 1 hour, then add 2ml of tetrahydrofuran and 1ml of water.
The melt? Note the night: Add deeply. After stirring the mixture for an additional 0.51 if at about 25°, it is diluted with benzeno and filtered off. The filtrate is washed with brine, dried, and concentrated to produce the same compound alpha and beta hydroquine. A mixture of 1.22 A-type isomers is obtained.

Similarly, following the above procedure or using the 3β-hydroxo-4-fluoro a form of formula XXX of Example 2,
The corresponding 3[beta]-hydroxy compound of formula XXXI is obtained, ie when ].noti is i'\HP.

Reference 7 According to the procedure of Example 1, each of the optically active or racemic compounds corresponding to the formula XXX written and amended after Example 2 was converted into the optically active or racemic compound corresponding to 2XXXl[[ be done. Both the 30- and 3, no-hydroxy intrinsic forms of formula xxxtu are thus obtained.

Sename 1 row L 1.6-Fluoro-PC) F2αJL
15-bis-C (CI-h)3-CHs).

See Figure B. 4-Carboxybutyltriphenylphosphonium promite (E.J.
．． Corey) et al., J. Am. Chem. Soc.
, vol. 91, p. 5677 (1969)) (4-
43? ) to hydrogenate thorium (57%, 0.84
r) and dimethylsulfo;
] 4 Add to the solution of sl.lium dimethylsulfinyl carbanide prepared from me. The above formula x xxm in this reagent ν dimethyl sulfoxide 5 me
of lactol is added dropwise. The mixture is stirred for 2 hours at about 25°C and then diluted with Benzeno 80me. Add potassium hydrogen sulfate (4.
Add the solution of 08r) without stirring. The organic layer is separated, washed with water, dried and evaporated under reduced pressure. The residue is triturated with diethyl ether and cooled to Q, LOQ. Separate and discard the crystals that form. # After chromatography, the liquid residue was chromatographed on silica gel, eluting with chloroform-methanol (10, 1), thin layer chromatography, shown as 1, thus leaving out the starting materials and impurities. Combine the fractions containing product. Reduction in vacuo-[J, ↓ yields the title compound 0.82 fi'.

reference angle 1J 3 1t)-Fluoro-PGF2α(
Formula XIV: C, HJI is 3 for -(CH2)3-1,
M is //, )ioHlRl and R2 are hydrogen, ~ is alf').

See Figure 3. Acetonitrile 1.5m (Formula XXX in !
A solution of IVO bis(tetrahydropyranyl) ether (acid, 0.371) is mixed with 15 ml of 66% acetic acid.

Heat the larvae at approximately .16'O for 1.5 hours, then place under vacuum. The residue is taken up in toluene and reconstituted. The residue was chromatographed on silica gel using ethyl acetate-acetone-water (ethyl acetate-acetone-water).
Elute at 8:5.1). The starting material and the fractions containing the product, as indicated by thin J-chromatography, but not containing the product, are condensed together to yield the title compound, 0.16F. The peaks in the mass spectrum are 645.640, 597.571 and 5
50: Infrared absorption peaks are 3400, 2950,
2550.1720, and 1440.

According to the discussion example and the procedure of 8, the optically active or racemic form 3α corresponding to the formula x x x m written after Qin example i0
-Each of the hydroxy compounds is converted to the corresponding bis(tetrahydropyranyl) ether and then the corresponding 1
6-(or 16.16-di)fluoro-PGF2CX type compound or racemic mixture.

Thus, the following compound structure is obtained from the 30-hydroxy isomer atom: 16-fluoro-19,20-dinol-POF 2α1
6.16-difluoro-1! J, 20-dinol-PC)
F2α+6-7 /Lz O0-16- Mef /lz
-19,20-dinol-PC) F'2α 16-fluoro-20-true PC) F2α16-ethyl-16-fluoro-20-true PGF 2α16,
]]6-difluoro-PGF2 α16fluoro-16-methyl-PGF2α16.17
-diethyl-16-fluoro-PGF'2°+8-ethyl-16-fluoro-POF2cxJ6-fluoro-2
0-Methyl-PGF 2α11i -7# Oc -2
0,20-dimethy/lz PGF 2CX16, "Leelafluoro-1F, dimethyl-PGF 2α10
-Fluoro-20-ethyl-PL)F 2αIIj,
1G-difluoro0-2Ll-propyl-PGF 2CX
10-fluoro-17,:,:0-dipropyl-PGF
2α and their racemic mixtures, e.g. c'1
l-1+3-fluoro-19,20-dinol-PGF2
α. The corresponding 157j epimers and their racemic mixtures are obtained from the corresponding 3β-hydroxy compounds of the formula X X X Ill K. For example: 1-fluoro-15β-PGF 2α16.16-difluoro-19,20-dinol-15β-PGF2゜ and di-16-fluoro0-16-y'ff1v-19,2
0-Dinol-15β-P()F1a External angle [1lJ4 j+j-Fluoro-2-TrueP
GF2α is alpha).

Figure B #1 [Se. According to the procedure in Example 3, 9 is 1-carboxyphthyltriphenylphosphonium furomite, and 3-carboxypropyltriphenylphosphonium chloride (D, B, Dennis
y ), etc., jar f /L/ ・i F・o Kanitsuku Chemistry (J, ○rg, ciqem, )
27;], p. 33404, 1962)) using the formula
, bis(tetrahydropyranyl) ether is obtained, and then a dressing is obtained.

Year standard +6-fluoro-2a-homo-PGF2α
, (2X I V 2CHH2n is -(CH2)3-1
C is ・↓, M is l゛・, R1 and & are hydrogen, ~ O
H is alpha).

4a, but using 5-carboxypentyl (5-carboxypentyl) IJ phenylphosphonium bromide (Preparation Example 2) instead of 4-carboxyptyltriphenylphosphonium bromide (Preparation Example 2), the title compound and the corresponding bis (Tetrahydropyranyl)ether is obtained.

Shoes, precedent 61 also one fluoro 2 a, 2b-dihomo-P
GF2cx (Formula X IV: CH'rIa 11
is -(CH2):5-1l・, M is 5, M is , R1] (2 is hydrogen, O
H ~ is alpha).

Follow the procedure of QJ example and 3, but substitute 1) (lt
(3-carpoquinhexyltriphenylphosphonium bromate (Preparation Example 3))
-, 7 and the corresponding bis(tetrahydropyranyl)
Ether is obtained.

Following the steps in Ambient Light Example 3 and using each of the carboquinoalkyltriphenylphosphonium halide reactants in Examples 1, 5, and 6, convert idea ~ into the formula xxxn+ listed after the example. 1. Each of the corresponding optically active or racemic 3α-hydroxy compounds is the corresponding bis(tetrahydropyranyl) ether ((, then The corresponding 16-(also 1dIti, 16-di)fluoro-P
C) F2α type compounds or caries mixtures, such as 16-fluoro-2,1-), 2u-)linol-PO
F"2aJ6.16-difluoro-2a-homo-1shi]
, addition-dinolGF2tx 16-fluoro-16-methyl-2a,2b-dihomo-19,20-dinol-P()F2CX16-fluoro-2,20-dinol-PGF2α'6-ethyl-16-
16.16-difluoro-2a,2b-dihomo-PG
F2(xJ6-fluoro-]]6-methyl-2-truePOF2CX]617-diethyl-16-fluoro-2
a-Homo-PGF2゜18-ethyl-16-fluoro-2a, 2 b-cibomo, P()F2CX 16-fluoro-20-methyl-2-true POF2α
"6-fluoro-20',20-dimethyl-2a-homo-PC) F1a 16.16-difluoro-17,20-dimethyl-2a
, 2b-dihomo-PGF2α 16-fluoro-20-ethyl-2-true POF 2
α16, 0-DinluorozO-propyl-2a-homoPGF” 2α 1(]-Fluo’-L’7.IO-Nobrovir-2a
, 2b-dihomo-PGF 2α and their racemic mixtures β, such as al-16
-Fluoro-2,19,::0) Rhinoru? OF
'It will turn into 2α. 3β-hydroxy XXXl1
[From the compounds, the corresponding 15β epimers are first converted into bis-(tetrahydrohyranyl) ethers and then as P
C) Racemic mixture of F2α type produced by Z′L et al.
aHj, +6-difluoro0-2a-homo-19,2L)
-Dinol-15β-P()F1a and dl-16-fluoro-16-methyl-2a,2b-dinol-15β-PGF2α.

Yu m j (n-fluoro PGE2, ratio 15-hi'
(Tetrahydropyranyl) ether (Formula XXXVI: , ; is 3, i, 4' is /゛, H0
THPゝQ is 10-(CH2)3-CH3).

■Refer to Figure C. Acetone l□ me O formula X X XIV
O bis(tetrahydropyranyl) ether (Example 4
．． 0-45 f) was cooled to 1 ml of 0-45 f), and added with Jaws reagent (chromic anhydride 2.1 ml).
ii', 6 m of water (,, and 1.7 rne of 0 edible sulfuric acid
) is fed until the excess of reagent is t='a<< for 3 minutes.

2-Add two or three cylinders of propatool and concentrate the mixture under reduced pressure. Partition between the remainder 'm'+/Jk dichloro 2 ivy/ and water. Drying the organic phase and applying i+ff1L yields the title compound, which is free of starting material by 15 points of thin layer chromatography.

Kotoki (column 8 ]] 6-FluoroP) F2 (Formula XI
II: C111 (2n is -(CH2)3-1g is 3
,■・(ha, l゛・2i0Hゝtortoise and le are hydrogen).

See Figure C. Acetonitrile 1. sd middle O2: 1FXX
■Bis(tetrahydropyranyl) ether (Case 7)
．． 0.1 f
Mix with.

The mixture is heated at 15-18 C for 2 hours and then concentrated under reduced pressure. The residue was taken up in toluene and poured into four tubes again. The residue was chromatographed on silica gel and dissolved in ethyl acetic acid-Skerisolve B (-5'1) with vinegar.
41'n body heki f, 7 stones) - Water ('X): 20
: 5['l : 100)'s upper layer (thereby separated by 4. Thin layer chromatography shows that Vζ contains product by 'l-1', but the starting [) river and the impurity-free fraction are combined. When concentrated, the proverbial compound sleep 02
7 is 43, fl, ru. The two degrees of the mass spectrum are 571.566.497 and 81.

15fi, according to examples 7 and 8, hand 1ii18i, each of the kataki series and the 3 glues and the other IA series, ■, in 6, the corresponding bis-tetrahydropyranyl) ether, white Ib-(or J6.]6-G)Fluoro-POIΣ2L1:! racemic mixture of compounds or
For example, "6-fluoro-4q,3Q-dinol-PGE2
and al-16-fluoroU-19,20-dinol-
P GE 2 i/ko+j is compared. 15p-epimers and the corresponding 15β-p OR2 type epimers, such as 16-fluoro-1! l, J-dinol-15β-P
GE2 and di-16-fluoro-IQ, 20-dinol-15β-PGE2 are obtained. As per example q, moatless PGk2! The W compound 4 is obtained in both cases.

Foreign bird example 9 J(5-fluoro-P()?2β(formula χ
V: C! IH2□1 is -(cH2)a-1g is 3,
゛・i is/゛・HoHゝR1 and R2 are hydrogen).

Trace the plan. Water-cooled methanol (a solution of 300n+4 sodium borohydride in 5ml was heated to -50 methanol 3O
16-fluoro-PGE2 in rne (s-s example &,
650 rnq). Mixed I#I
Let stand for an additional 5 minutes, acidify slightly with acetic acid, and concentrate to a reduced volume. The residue was extracted with dichloromethane and the phases were washed with water, dilute aqueous sodium bicarbonate and brine, then dried over sodium sulfate and evaporated under reduced pressure. Shrink. The residue was dissolved in ethyl acetate with a damp solution.
(Chromatographed on packed silica gel and separated with 2, 4, 7.5% and 10% ethanol in ethyl acetate. The title compound was isolated as shown by thin layer chromatography. However, when the starting material and the impurity-free fraction are concentrated by filtration 7b, the title compound of formula XV is produced.

According to z example γ's move + Bg, write C after external world example B
16-(or 16.16-di)fluoro-P()E2
Each of the typed products, their I5β epimers and racemic compounds has a corresponding 16-(or]6.n,;-
G): '7 Luo C1-pO, i'2 β-type compound or ■5 β epimer or racemic thermophilic compound.

u 16-7 Luoro PGA2 (Formula XVI:
C] IH211 is -(CH2)3, g is 3, M is /
\HOHゝR1 and i are hydrogen).

See diagram. 16-Fluoro-PGE2 (Cow example 8.
300 mQ), 4 ml of tetrahydrofuran, and 0.5 N"jA lν4 mB overnight for 25 min.
Leave it in Q for 5 days. Add brine and dichloromethane-ether (1:3) and stir the mixture. Separate the M phase, dry and concentrate. The residue is dissolved in ether and the solution is extracted with a saturated aqueous solution of heavy carbon.

The aqueous phase is acidified with dilute salt and then extracted with dichloromethane.

Drying and condensation of this extract yields the compound entitled Formula XVI.

According to the procedure in Reference Z Example 10, 1 described after Fuyuu Example 8
Each of the 6-(or 16.16-di)fluoro-PGEZ type compounds, [5β epimers and racemic compounds represents the corresponding 16-(or 16.16-di)fluoro-PGA type 2 compound or [5β Converted to epimers or racemic mixtures.

4.N case 17. 16-Fluoro-PGE2 (Formula X
VI: CnHzn is -(CH2)3-, g is 3.
2boha/゛・) [OHゝh and horse are hydrogen).

See diagram. 50% ethanol water bath with potassium hydroxide ratio e:':J1 ft k? b-Fluoro-P()R2 (4% e.g."' in 100 ml, 200
A solution of 250 mq) is kept under nitrogen for 10 hours. The bath solution is then cooled to 10°C and neutralized by addition of 3N hydrochloric acid at 10°C. The resulting solution is extracted repeatedly with ethyl acetate and the combined 11-ethyl acetate extracts are washed with water and then with brine, dried and concentrated to yield the title compound of formula xvn.

Follow the steps in Example 1 (for horse mackerel soup) and prepare [
6-(or 16.16-di)fluoro-P GE 2
Each of the 15β epimers and racemization notices of the type compounds and compounds, the corresponding 16-(nu is 1.6.1
6-di) fluoro-PGBZ type compounds or 15β epimers or racemic compounds (′ζ converted).

Participation example 12 16-fluoro-PC)El (Formula ■:
CHH2H is -(cn2)3-1g is 3, M is /゛・H
OH' 1 (1 and R2 are hydrogen) and]6-fluoro-]3.1
・↓-dihydro P()El (Formula XVIII: CnH2
n is -(CH2)3-1g is 3, h-4 is /゛・, R
↓ and R2 are hydrogen).

0H 1G-7/L/Olow PGE2 formula XXXVI bis(
Tetrahydropyranyl) ether (base example, 220m
9), 5-line rhodium catalyst on alumina (110 l)
, and ethyl 1'1 acid, 16 ra5, is stirred under 1 atmosphere of hydrogen with an approximately OCv trowel until substantially all of the starting material has been consumed, as indicated by Yayumi chromatography. Filter the mixture to remove the catalyst and concentrate the filtrate. The residue is dissolved in 1 me of tetrahydrofuran and 6 me of 66% acetic acid and the mixture is warmed to 50 DEG C. for 2.5 hours. The mixture is concentrated under reduced pressure and the residue is chromatographed on lica gel, eluting with the upper layer of a mixture of ethyl acetate-acetic acid-Skelinorub B (isomeric hexanes)-water (90:20:50:100). . Thin layer chromatography shows that the mixture containing no title compound and Q containing no starting materials and impurities is concentrated by filtration to yield the title compound.

Following the steps in Example 12-, cross over the cow and horse example? Each of the PGE type 2 bis(tetrahydropyranyl) ethers described after is the corresponding 16-(or]6,16-di)fluoro-PGE type 1 or 1.3.14-dihydro-PG 1 type compound. ,■5β epimer, father is racemic compound vko1
Signed.

l j+'month 3 16-fluoro-13-dihydro-
PC)El 16-fluoro-PGEz in ethyl acetate 1IJrne
(Reference example?, 100111ri) m version on charcoal.
In the presence of Tei palladium (15 m9) (about 1 at 250
Shake with atmospheric hydrogen. consumes 2 equivalents of hydrogen,
After this, the hydrogenation is stopped and the catalyst is removed by filtration. The filtrate was concentrated under reduced pressure and the residue was chromatographed on Solicazul with 50-100 ml of ethyl acetate.
% range of 1) 11"1: Acid ethyl chloride Resolve B (
Elutes with isomeric hexanes). The desired product is obtained as shown by thin chromatography, but when the starting material A-4 and the impurity-free fraction are concentrated, the title compound is obtained.Example 9, +q,
According to the procedure of ++, 3 yohi sono 7 ni 6 ki r + 戊's 16- (or +6j6-shi) Nororo P
Each of the 11 of the OEI type or 13j4-dihydro-PC) El type compounds, 15β epimers or racemic compounds is the corresponding 16- (or 16.16-di)
Fluoro-PGE, -PGF, β, -PGA1-
PC) Bl type 7 Koha J6- (or 16,1.6-di)
Fluoro-13,1,! -Dihitko PC) F, α, -
POF, β, -PGAx or -POBl type attachment, 15
Converted to epimeric or racemic compounds.

9 people (yl J b-Fluoro-PGF2α methylnisder (Formula XIV: Cn112H is -(CH2
) 3-1st position is 3, lνd is /゛＼, 1 (1 is methyl,
)X OH is hydrogen, ~ is alpha).

Diazomethane in diethyl ether 2E,me (approx.
51? ) was dissolved for 7 nights in methanol and diethyl ether (
1;
−? Add to the δ solution of OF2cx (row 3, 50 m long). The mixture is allowed to stand at about 25'C for 5 minutes and then placed under vacuum F to yield the title compound.

Other j6- containing 15β mono-epimerite or racemic compounds added above according to the procedure of
Fluoro and 16. ] ] Each of the 6-difluoropah'-form, PC)E-form, P()A-form and PC)E-form radical acids is converted to the corresponding methyl ester.

Similarly, following the procedure of Ginnoreki 1+ but using diazoethane, diazobutane, 1-diaso-2-ethylhexane and diasodecane' instead of diazoethane, the corresponding J6-fluoro-P()F1a ethyl, butyl, γ - Ethylhexyl, and deflu esters are obtained. In the same manner, other 16-fluoro and 16.16-difluoro PGF--q, P
GE-type, Pt) A-type and PGB-type Yu, 'Fu IK
Each of 3fi (・1, corresponding ethyl, butyl, 2-
The mixture was soaked in dinalhexyl and dichloroester for 11 hours.

Example/Da 16-Fluoco PC) F1a Thorium salt water-ethanol mixture 'Pl! 7 (12l) 5
0σ16A+7N6-Fluoro-PG4i°tα($
K Example 3,100 me,))) (cooled overnight, ('1.1 N 7J (sodium oxide aqueous solution 1)
- Neutralize with the amount of Neutral bath 71k is concentrated with residue 7 of the title compound.

Follow the procedure for 1 cup of water, but substitute 1 part of sodium for water! For 7, use hydroxide power υram, calcium hydroxide, tetramethylammonium hydroxide, water 1benzenetrimethylammonium suboxide, 1-, and the corresponding 16-fluoro
- Salts of PCtF2α are obtained.

Similarly, following the procedure in Example 8], but as defined above,
β-epimers 4 include racemic compounds, IG-fluoro and 16j6-difluoroPt)
The salts for N-F-type, PO bar-type and POB-type salts are converted to sodium, potassium, calcium, tetramethylammonium oyohypendyltrimethylammonium salts.

Example 3 16.16-Difluoro-PGF 2◇Methylnisder (Formula XIV: C11HzH is -(CH
2) a-1g is 3, M is /゛・, R is methyl, I-
10H Turtle is fluoro) Please refer to Figure B. a. Initially, dumenal-2-oxo-3,3
-Nofluoroheptylphosphone+-=make. Following the procedure of Example 1-a, methyl 2,2-difluorohexanoate (klOF(5·reaction with BF3) is thus prepared from methyl 2-oxohexanoate, boiling point 6
1~66 C/III)? Reaction with 1I-dimethylmethylphosphonate 1 produces the desired raw LM.

Boiling point 93-6070.4mm, quality
Nobby is 2581.238, 202, 151.1
09, and 79°1), Formula XX■07 /1/7
'HiM (1itA[!uf!l l, n, a point 115-117 '0) is reacted with the above phosphone-1 following the procedure of Example 1-b to form the corresponding formula XX
■ A difluoro intermediate, melting point 70-72'C, is produced.

According to C0 Example 20 Hand 11ffl, the above formula xxg
All corresponding 3-oxo-4,4-difluoro compounds
The XXJ 3-human axy-4,11-difluoro compound is isolated by caloric chromatography. 3α-hydroxy isomer is 0.5
It has an Rf value of 0 (D:, II: layer chromatography) with ethyl acetate and Resolve B (1:l) on a silica gel plate.

The 3β-hydroxy isomer has an Rf value of 0.43.

d, snoring 4 fil 1. Accordingly, when the benzoyloxy group of the 3o-hydrogino compound XXX is replaced with hydrogen, the corresponding compound XXF (ethyl acetate-Skelif/L/B (2:l) with Rf value of 0; 37) is obtained. iK is generated and converted into formula XXX14. -L-Zinfluoro intermediate (ethyl acetate) in Kelisolp B (1:l)
0.6) and then converted to formula XXX1[difluorolactol.

e, calyx z Following the procedure of example 2, the formula for the 7 elephant winter example - xx
2-X above instead of χlil monofluorolactol
X
88.57i, 472 and 363, +lJ, +b-difluoroP OF2α of (trimethylsilyl visiting conductor)
is obtained.

Finally, following the procedure of Example 1+, the mass spectrum peaks are 605, 6 (10, 589, 585, 530
, 513, 510, 440, 423, and 217 (
) The title compound of 1 rimethersilyl is obtained.

The present invention further includes the following 1 fortune telling form.

1. The method according to claim 1, wherein R2 is water debris.

14, where CnH2n is -(CH2), - and g is 3! J rye method according to the first term.

Claims (1)

[Claims] R30' is alkyl of 4 carbon atoms, phenylalkyl of 7 to 10 carbon atoms, or nido Qf, and the total number of carbon atoms in T is 10 carbon atoms (where 4 is or (4) acetyl defined on alkyl of 1 to 4 carbon atoms, or racemic compounds of this formula and its mirror image, in which Cn H2n is 1 to 9 alkylene of 1 carbon atoms in the chain between -CFR2- and the terminal methyl;
CnH3n, R2 and A process for preparing an optically active compound, as defined above, or a racemic compound of this formula and its mirror image. 30 Alkyl of 4 carbon atoms, phenylalkyl of 7 to 10 carbon atoms, or nitro, and the total number of carbon atoms in T is 10 (where R4 is a carbon atom of 1 to 4 carbon atoms) alkyl is defined above) and u (4
) acetyl] or a racemic compound of this formula and its mirror image, [wherein Cn H3n is alkylene of 1 to 9 carbon atoms, and -CF, R2- and the terminal methyl with 1 to 6 carbon atoms in the button between, R2 is hydrogen or fluoro, and R5 is alkyl of 1 to 8 carbon atoms. , "2 and R3 are as defined above"
or a racemic compound of this formula and its mirror image, treating this with a reducing agent and subsequently separating the alpha and beta isomers [wherein CnH2n, R2 and R3 are as defined above, and ~ represents a bond of the hydroxyl group to the side chain in the alpha or beta configuration. ], or a process for producing a racemic compound of this formula and its mirror image.