KR820000512B1 - Process for preparing bicylic prostaglandin - Google Patents

Abstract

2-Oxa-bicyclic prostaglandins I (R = free or esterified carboxyl, -CH2OH-, -CONRaRb-(Ra,Rb = H, C1-6 alkyl, alkanoyl, phenyl), -CN, etc.; Z1 = H, halo; p = 0-7 integer; q = 1, 2; R1 = H, OH, C1-6 alkoxy, acyloxy; Y = -CH2CH2-, -CC-; R2,R3 = H, C1-6 alkyl, C2-6 alkenyl, alkinyl, aryl, OH; R3,R4 = H, C1-6 alkyl, F; n1n2 = 0-6 integer; x = -0-, -s-; R6 = H, halo, C1-4 alkyl, etc.), exhibiting vasodilating activity, were prepd. by eliminating the amino protecting group in a reaction product of compd. IV and V followed by appropriate modifications of conventional syntheses.

Description

Method for preparing bicyclic prostaglandins

The present invention relates to a method for preparing 2-oxa-dicyclic prostaglanins of the following formula (I), which exhibits hypotensive, vasodilatory and high anti-aggregating activity.

Wherein R is (a) free or esterified carboxy group,

(b)

(Wherein each R ′ group is the same or different from each other C ₁ -C ₆ alkyl or phenyl)

(c) -CH ₂ OH,

(d)

Wherein Ra and Rb are independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl and phenyl.

(e)

(f) is obtained from a group consisting of -C≡N,

Z ₁ is hydrogen or halogen,

p is 0 or an integer from 1 to 7

q is 1 or 2,

R ₁ is hydrogen, hydroxy, C ₁ -C ₆ alkoxy, aromatic C ₁ -C ₆ alkoxy, acyloxy

및

(트랜스)(여기서 Z₂는 수소 또는 할로겐)로 구성되는 그룹으로부터 얻은 것이고,Y is -CH ₂ CH _2- , -C≡C-,

And

(Trans), where Z ₂ is hydrogen or halogen,

One of R ₂ and R ₅ is hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or aryl, the other is hydroxy, C ₁ -C ₆ alkoxy, aromatic C ₁ -C ₆ -alkoxy, or R ₂ and R ₅ together form an oxo group,

기 또는

기를 형성하기도 하며, 각각의 n₁및 n₂는 서로 같거나 다르게 0 또는 1에서 6까지의 정수이고Each R ₃ , R ₄ is the same as or different from each other, is hydrogen, C ₁ -C ₆ alkyl or fluorine, or with the carbon atom to which R ₃ and R ₄ are linked

Flag or

Each n ₁ and n ₂ are the same or different from each other or an integer from 0 to 1 to 6

X is obtained from the group consisting of -O-, -S- and-(CH ₂ ) _m where n is 0 or 1,

R ₆ is (a ′) hydrogen,

(b ′) C ₁ -C ₄ alkyl,

(c ′) C ₃ -C ₉ cycloaliphatic groups substituted or unsubstituted by one or more substituents obtained from a group consisting of C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy,

(d ′) aryl substituted or unsubstituted with one or more substituents obtained from a group consisting of halogen, halo-C ₁ -C ₆ -alkyl, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy,

(e ′) Saturated or heterocyclic, substituted or unsubstituted with one or more substituents obtained from the group consisting of halogen, halo-C ₁ -C ₆ -alkyl, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy It is obtained from a group consisting of rings.

Also optically and diastereomers such as pharmaceutical or veterinary, water-soluble salts and optical isomers, racemic mixtures of optical isomers, geometric isomers and mixtures thereof are also within the scope of the present invention.

)은 치환체가 확실한 입체 화학적 동일성을 갖지 못함, 즉 사이클로펜탄환에 속한 치환체가 α- 및 β-배치내에 위치하고, 2-옥사-이환상계에 속한 치환체는 엔도-및 엑소-배치내에 위치하며 사슬에 속한 치환체는 S- 및 R-배치내에 모두 위치함을 말한다.The broken line (……) in the structural formula of the present specification indicates that the substituent belonging to the cyclopentane ring is α-positioned, that is, the substituent belonging to the 2-oxa-bicyclic system is located in the endo-placement and the substituent belonging to the chain is S- The bold line (━) indicates that the substituent belonging to the cyclopentane ring is β-positioned, that is, the substituent belonging to the plate of the ring and belonging to the 2-oxy-bicyclic system is in the exo-battery and the substituent belonging to the chain An inverted line, indicating that it is in an R-batch

) Substituents do not have a clear stereochemical identity, that is, the substituents belonging to the cyclopentane ring are located in the α- and β-batch, the substituents belonging to the 2-oxa-bicyclic system are located in the endo- and exo-batch and Substituents belong to both S- and R-positions.

The heterocyclic ring B in the compound of formula (I) is cis-associated with the cyclopentane ring A and the two bonds represented by the dotted lines are present in the α-batch with respect to the ring A.

를 갖는 복소환 고리 B의 탄소원자는 수소원자도 함유한다.The side chain β-linked to cyclopentane ring A is in trans-batch for α-associated heterocyclic ring B and consequently an exo substituent for the 2-oxy-bicyclic system. chain

The carbon atom of the heterocyclic ring B having R also contains a hydrogen atom.

이 2-옥사-이환상계에 대해 엔도-배치내에 있을때 상기의 수소원자는 엑소치환체이고 그것의 절대배치가 β로 나타나는 반면

고리가 엑소-배치내에 있을 때 상기의 수소원자는 엔도치환체이고 그것의 절대적 배치는 α로써 나타난다.chain

When in the endo-batch for this 2-oxa-bicyclic system, the hydrogen atom is an exo substituent and its absolute configuration is represented by β

When the ring is in an exo-configuration, the hydrogen atom is an endosubstituent and its absolute configuration is represented by α.

고리가 엑소-배치내에 있고 수소원자가 α-절대배치를 반드시 갖는 B 고리와 같은 탄소원자에 연결된 본 발명의 화합물은 6αH-6,9α-옥시드(구조식(I):q=1) 및 5αH-5,9α-옥시드(구조식(I):q=2)프로스타노산 유도체로 알려져 있는 반면

고리가 엔도-배치내에 있고 수소원자가 β-절대배치를 반드시 갖는 B 고리의 같은 탄소원자에 연결된 화합물은 6βH-6,9α-옥시드(구조식(I):q=1) 및 5βH-5,9α-옥시드(구조식(I):q=2) 프로스타노산 유도체(프로스타글란딘수효)로 알려져 있다. 선택적으로 6αH-6,9α-옥시드 프로스타노산 유도체는 (2′-옥사-비사이클로 [3.3.0] 옥탄-3′-엑소-일)-알카노산 유도체로써, 5αH-5,9α-옥시드프로스타노산 유도체는 (2′-옥사-비사이클로 [4.3.0]노난-3′-엑소-일)-알카노산 유도체로써, 6βH-6,9α-옥시드프로스타노산 유도체는 (2′-옥사-비사이클로 [3.3.0]옥탄-3′-엔도-일)-알카노산 유도체로써 나타난다. 6αH-6,9d-옥시드 및 5αH-5,9α-옥시드 프로스타노산 유도체는 대응 6βH-6,9α-옥시드 및 5βH-5,9α-옥시드 유도체에 비하여 높은 크로마토그래피의 역동성(즉 높은 Rf) 및 낮은 양성 선광력([α]_D)을 지닌다.

Compounds of the invention wherein the ring is in an exo-configuration and the hydrogen atom is linked to a carbon atom, such as the B ring, which necessarily has an α-absolute, are represented by 6αH-6,9α-oxides 5,9α-oxide (formula (I): q = 2) is known as a prostanoic acid derivative

Compounds in which the ring is in the endo-configuration and the hydrogen atom is linked to the same carbon atom of the B ring that necessarily has a β-absolute are 6βH-6,9α-oxide (formula (I): q = 1) and 5βH-5,9α -Oxide (formula (I): q = 2) is known as a prostanoic acid derivative (prostaglandin number). Optionally the 6αH-6,9α-oxide prostanoic acid derivative is a (2′-oxa-bicyclo [3.3.0] octane-3′-exo-yl) -alkanoic acid derivative, which is a 5αH-5,9α-jade Cydprostanoic acid derivatives are (2′-oxa-bicyclo [4.3.0] nonan-3′-exo-yl) -alkanoic acid derivatives, and 6βH-6,9α-oxideprostanoic acid derivatives (2 ′ -Oxa-bicyclo [3.3.0] octane-3'-endo-yl) -alkanoic acid derivatives. The 6αH-6,9d-oxide and 5αH-5,9α-oxide prostanoic acid derivatives have higher chromatographic dynamics compared to the corresponding 6βH-6,9α-oxide and 5βH-5,9α-oxide derivatives. Ie high Rf) and low positive beneficiation force [[α] _D ).

Everything mentioned above relates to natural compounds. The d, l-compound is a mixture containing an equimolar amount of the nat-compound and the ent-compound of electrons having the absolute stereochemistry shown above. For ent-compounds, the stereochemical configuration is located opposite the center of all asymmetries with respect to the placement of the natural compound, and the prefix ent indicates this.

Alkyl, alkenyl, alkynyl, alkoxy and alkanoyloxy groups are branched or straight-chain groups and the preferred R is a free, salted or esterified carboxy group, preferred as aromatic-C ₁ -C ₆ -alkoxy groups is benzyl Oxy, preferred for the aryl group is phenyl, α-naphthyl or β-naphthyl, preferred for the halo-C ₁ -C ₆ -alkyl group is trihalo-C ₁ -C ₆ -alkyl, in particular trifluoro Methyl, preferably a C ₁ -C ₆ alkyl group is methyl, ethyl or propyl, a preferred C ₁ -C ₆ alkoxy group is methoxy, ethoxy or propoxy and a C ₂ -C ₆ alkenyl group is preferred. Vinyl, and a preferred C ₂ -C ₆ alkynyl group is ethynyl.

When R is an esterified carboxy group R is preferably a -COORc group wherein Rc is a C ₁ -C ₁₂ alkyl group, especially methyl, ethyl, propyl and heptyl or a C ₂ -C ₁₂ alkenyl group, especially allyl.

Z ₁ is preferably hydrogen.

When Z ₁ is halogen, preference is given to chlorine or cancellation and preference for P is an integer from 1 to 3.

Preferred when R ₁ is acyloxy is C ₂ -C ₁₂ alkanoyloxy (particularly C ₂ -C ₆ alkanoyloxy, for example acetoxy, propionyloxy) or benzoyloxy.

Preferred Z ₂ when Z ₂ is halogen is chlorine, cancellation or iodine.

Preferred R ₃ and R ₄ are each obtained from a group consisting of hydrogen, C ₁ -C ₆ alkyl and fluorine, n ₁ is preferably 0 or an integer from 1 to 3 and n ₂ preferably from 1 to 3 Is an integer.

Preferred when R ₆ is a C ₃ -C ₉ ring aliphatic group are preferably C ₃ -C ₉ cycloalkyl (cyclopentyl, cyclohexyl and cycloheptyl) or C ₃ -C ₉ cycloalkenyl groups (cyclopentenyl cyclohexenyl and cyclohep Tenyl).

R ₆ is a heterocyclic ring when R ₆ is a hetero monocycle ring or heterocyclic ring by-cycle, and contains at least one atom of the complex obtained from the group consisting of nitrogen, sulfur and oxygen. Examples of preferred heteromonocycle groups are tetrahydrofuryl, tetrahydropyranyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyls. Examples of preferred heterobicycle groups are 2-oxa-bicyclo [3.3.0] octyl, 2-oxa-bicyclo [3.4.0] nonyl, 2-thia-bicyclo [3.3.0] octyl, 2-thia Bicyclo [3.4.0] nonyl and their aromatic analogs.

Pharmaceutically or veterinarily soluble salts of the compound of formula (I) are compounds with pharmaceutical and veterinary soluble bases. Pharmaceutical and veterinary soluble bases are inorganic bases such as alkali and zinc hydroxides as well as alkali metal hydroxides and alkaline earth metal hydroxides or methylamines, dimethylamines, trimethylamines, ethylamines, dibutylamines, N-methyl-N-hexyls Amine, decylamine, dodecylamine, allylamine, cyclopentylamine, cyclohexylamine, benzylamine, dibenzylamine, α-phenyl-ethylamine, β-phenyl-ethylamine, ethylenediamine, diethylenetriamine, mor Alkyl derivatives of polylines, piperidine, pyrrolidine, pyrrazine and the last four bases, mono-, di- and tri-ethanol amines, ethyl- diethanol amines, n-methyl-ethanolamines, 2-amino-1 Butanol, 2-amino-2-methyl-1-propanol, N-phenyl-ethanolamine, galactamine, N-methyl-glucamine, N-methyl-glucosamine, ephedrine, procaine, dehydro abiethylamine, With lysine, aginine and other α or β amino acids Are the organic base of the organic amine.

Preferred salts of the present invention are salts of compounds of formula (I), wherein R is -COORd, wherein Rd is a pharmaceutically or veterinarily water soluble cation derived from one of the bases mentioned above.

Particularly preferred compounds of the present invention are 6βH-6,9α-jade of the compound of formula (I) wherein R is a free carboxy group and R ₆ is C ₁ -C ₄ alkyl, C ₅ -C ₇ cycloacyl or optionally substituted phenyl Seed and 5βH-5,9α-oxide.

The prefixes nod, dinor, trinor, tetranor and the like indicate that the side chains belonging to cyclopentane ring A are the same as those of the structural formula (I) compounds having one, two, three or four carbon atoms shorter than the analogous chains in natural prostagladins. Is used.

Specific examples of preferred compounds of the present invention include the following.

5-bromo, 5-iodine, 5-chloro analog of all 6βH-6,9α-oxide derivatives specified above, 4-bromo of all 5βH-5,9α-oxide derivatives specified above, 4 15R-epimers, 15-oxo-derivatives and 6αH- and 5αH-diastereomers of iodine, 4-chloro analogs and all compounds mentioned above.

Compounds of the present invention are prepared by the following procedure.

The following compound of formula (II) is halogenated and then removed if a known protecting group is present to give the above compound of formula (I) wherein Z ₁ is halogen, and the obtained compound is de-etherified if necessary. And / or dehalogenation yields a compound of formula (I) wherein Z ₁ is hydrogen.

In the above structural formula

p, q, r, n1, n ₂ , R ₃ , R ₄ , X and R ₆ are as defined above,

D is cis- or trans-CH = CH,

R ″ is (a ″) free or esterified carboxy group,

그룹(b ″) R 'group is as defined above

group

(c ″) —CH ₂ —R ₇ group, wherein R ₇ is a hydroxy group or a known protecting group bonded to a —CH ₂ — group by an esteric oxygen atom,

(d ″) Ra and Rb are as defined above

인 기,(e ″) structural formula

popularity,

(f ″) -C≡N

R ₁ ′ is a known protecting group bound to the ring by an oxygen atom on hydrogen, hydroxy, C ₁ -C ₆ alkoxy, aromatic-C ₁ -C ₆ -alkoxy, acyloxy or ether

One of R ₂ ′ and R ₅ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or aryl and the other is hydroxy, C ₁ -C ₆ alkoxy, aromatic-C R ₂ and R ₅ together form an oxo group, or a known protecting group bound to the chain by an oxygen atom on _1- C ₆ -alkoxy or ether.

The compound of formula (III) can be reduced to yield a compound of formula (I) wherein Z ₁ is hydrogen.

In the above structural formula

Hg⁽⁺⁾Z^(-)그룹이고(여기서 Z^(-)는 OH^(-)이거나 산의 음이온잔기이다),Q is halogen or

Hg ⁽⁺⁾ Z ^(-) group, where Z ^(-) is OH ^(-) or anionic residue of the acid,

R, P, q, R ₁ , Y, R ₂ , R ₅ , R ₃ , R ₄ , n ₁ , n ₂ , X and R ₆ are as defined above.

According to the present invention, after reacting a compound of formula (IV) with a compound of formula (V), if a known protecting group is present, R ₂ and R ₅ together form an oxo group, and Y is -CH = CZ _2. To obtain a compound of formula (I) wherein-(Z ₂ is as defined above), and if necessary, R ₂ and R ₅ together form an oxo group and Y is -CH = CZ _2- (Z ₂ is Is reduced to a compound of formula (I) wherein one of R ₂ and R ₅ is hydrogen and the other is hydroxy and Y is -CH = CZ _2- (Z ₂ is as defined above). (I) obtaining a compound, or a structural compound wherein R ₂ and R ₅ together form an oxo group, and Y is -CH = CZ _2- (Z ₂ is as defined above), wherein one of R ₂ and R ₅ If the hydroxy and the other is converted to C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or an aryl of formula (I) compounds and also necessary R ₂ and R ₅ one is hydroxy and the other is hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, C ₂ -C ₆ alkenyl or aryl, and Al, Y is -CH = CZ ₂ ( Etherylating the compound of formula (I) wherein Z ₂ (Z ₂ is as defined above), wherein one of R ₂ and R ₅ is C ₁ -C ₆ alkoxy or aromatic-C ₁ -C ₆ -alkoxy and the other is hydrogen A compound of formula (I) wherein C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or aryl and Y is -CH = CZ ₂ (Z ₂ is as defined above) And / or hydrogenation of a compound of formula (I) wherein Y is —CH═CZ ₂ (Z ₂ is hydrogen) to yield a compound of formula (I) wherein Y is —CH ₂ CH ₂ —, or as needed Dehalogenation hydrogenation of a compound of formula (I) wherein Z ₁ is hydrogen and Y is -CH = CZ _2- (Z ₂ is halogen), wherein Y is -C≡C- and Z ₁ is hydrogen Or R ₂ and R ₅ together form an oxo group, if necessary And hydrogenating a compound of formula (I) wherein Y is -CH = CZ _2- (Z ₂ is hydrogen), wherein R ₂ and R ₅ together form an oxo group, and Y is -CH ₂ CH _2- Obtain a compound or dehalogelize a compound of formula (I) wherein Z ₁ is hydrogen and R ₂ and R ₅ together form an oxo group and Y is —CH═CZ ₂ — (Z ₂ is halogel) Hydrogenation yields a compound of formula (I) wherein Z ₁ is hydrogen and R ₂ and R ₅ together form an oxo group and Y is -C≡C-, or if necessary, R ₂ and R ₅ together form an oxo group Reducing the compound of formula (I) to form to obtain a compound of formula (I) wherein one of R ₂ and R ₅ is hydrogen and the other is hydroxy, or where R ₂ and R ₅ together form an oxo group The compound of formula (I) is a compound in which one of R ₂ and R ₅ is hydroxy and the other is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl Is converted to a compound of formula (I) wherein aryl, and if necessary, one of R ₂ and R ₅ is hydroxy and the other is hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ —C ₆ alkynyl or aryl, wherein the compound of formula (I) is etherified so that one of R ₂ and R ₅ is C ₁ -C ₆ alkoxy or aromatic-C ₁ -C ₆ -alkoxy and the other is hydrogen, C _1- Obtain a structural formula (I) compound that is C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or aryl and / or convert, if necessary, a compound of formula (I) to another compound of formula (I) And / or, if necessary, salting the compound of formula (I) to obtain a free compound of formula (I) from salts and / or salts thereof if necessary, and / or separating from a mixture of isomers to a single isomer if necessary. do.

In the above structural formula

R ″, P, Z ₁ , q and R ₁ ′ are as defined above and

-그룹이고(여기서 각각의 Re 그룹은 서로 같거나 다르 알킬 또는 아릴이다),E is (C ₆ H ₅ ) ₃ P ⁽⁺⁾ -or (ReO) ₂

Is a group, wherein each Re group is the same or different from each other alkyl or aryl,

Z ₂ , R ₃ , R ₄ , n ₁ , n ₂ , X and R ₆ are as defined above.

When any one or several substituents are specifically mentioned for a compound at any stage in the process, it can be seen that other substituents mean all of the meanings indicated in advance for formula (I).

Known protecting groups, ie ether groups (acetylether, enolether and silylether) can be converted to hydroxy groups under slow reaction conditions such as acid hydrolysis.

Preferred group

(CH ₃ ) ₃ -SiO _2- ,

Wherein W is —O— or —CH ₂ — and Alk is a lower alkyl group.

Hg⁽⁺⁾Z^(-)그룹이다.In the compound of formula (III), Q is preferably obtained from a group in which Z ^(-) is an anionic residue of an acid and is composed of Cl ^(-) , Br ^(-) , I ^(-) , R ₈ -Coo ^(-)

Hg ⁽⁺⁾ Z ^(-) group.

Coo^(-)이다.Wherein R ₈ is optionally halo-substituted C ₁ -C ₁₂ alkyl group (preferably C ₁ -C ₆ alkyl or prefluoromethyl) and R ₉ is hydrogen, C ₁ -C ₆ alkyl, halogen such as cancellation, tri R ₉ which is fluoromethyl

Coo ^(-) .

COO^(-)가 바람직하다.Z ^(-) is Cl ^(-) , Br ^(-) , CH ₃ Coo ^(-) , CF ₃ COO ^(-) or

COO ^(-) is preferred.

The halocyclization reaction of the compound of formula (II) is carried out by reaction with a small amount of halogenating agent or with a small amount of halogenating agent, with or without base in the acyclic solvent. Preferred halogenating agents are iodine, cancellation, chlorine, bromo dioxane, bromopyridine, Brz-pyridine-HBr-KI ₃ , pyrrolidone-hydro tribromide, N-haloamide (N-chloro-succinimide, N Bromo-succinimide, N-iodo-succinimide, cupric halides (CuCl ₂ , CuCr ₂ ), mixed halides (ICl or IBr), mixtures of alkaline chlorides with alkaline chlorates, Mixtures of alkaline bromide and alkaline bromite, and mixtures of alkaline iodine and alkaline bromite. Suitable solvents include halogenated hydrocarbons such as CHCl ₃ , CCl ₄ , CH ₂ Cl ₂ , aliphatic hydrocarbons such as n-hexane, n-heptane, cycloaliphatic hydrocarbons such as cyclohexane, aromatic hydrocarbons such as benzene, toluene, pyridine, dioxane Cyclic or linear ethers such as tetrahydrofuran, diethyl ether, dimethoxyethane and mixtures thereof. Preferred solvents are halogenated hydrocarbons such as CH ₂ Cl ₂ because both the compound of formula II and the halogenating agent are soluble in such solvents. A stoichiometric base is required when the hydrohalide is produced during the halocyclization reaction. Such bases include alkali or alkaline earth metal oxides, inorganic bases of carbonates or bicarbonates such as CaO, CaCO ₃ and K ₂ CO ₃ , NaHCO ₃ , Na ₂ CO ₃ , organic bases of tertiary amines such as triethylamine, pyridine or alkyl Aromatic bases such as substituted pyridine or anion-exchange resins. The halocyclization reaction is carried out at a temperature between −70 ° C. and 100 ° C., preferably at room temperature. The reaction takes three to four days to a few minutes, but usually no more than two hours and a few minutes is enough to complete the reaction.

If other unsaturated bonds are present in the compound of formula II in addition to the double bonds contained in Substituent D, halogens are added to the unsaturated bonds during the halocyclization reaction. By reacting the reaction product at a reflux temperature, more preferably at room temperature, in an appropriate solvent, acetone, with alkali or alkaline earth metal iodide, the added halogen can be easily removed to reacquire the original unsaturation. The reaction time ranges from 2 to 3 hours to 2 to 3 days.

The reaction of removing a known protecting group belonging to a ring or chain by an oxygen atom on an ether is carried out under the conditions of slow acidic hydrolysis to mono, poly-carboxylic acids of formic acid, acetic acid, oxalic acid, citric acid and tartaric acid with water, acetone, tetra Treatment is carried out in a solvent such as hydrofuran, dimethoxyethane or lower aliphatic alcohol, treatment with a sulfonic acid such as p-toluenesulfonic acid in a solvent such as lower aliphatic alcohol, methanol anhydride or ethanol anhydride or treatment with polystyrene-sulfone resin. do. For example, 0.1 to 0.25 N polycarboxylic acid (oxalic acid or sirric acid) is used in the presence of a low boiling cosolvent that is miscible with water and can be easily removed under vacuum at the end of the reaction.

Hg⁽⁺⁾Z^(-)인 구조식(III) 화합물을 수득하며, 구조식(IV) 화합물을 환화하는 반응들은 그것들의 메카니즘에 있어서 동일한 반응들이며 반응혼합물에 함유되어 있는 이성질체의 수는 상기의 모든 환화반응과 동일하다. 그러므로 구조식(II) 화합물의 할로환화 반응은 4개의 구성성분의 혼합물, 즉 Z₁이 할로겐이고 엑소-배치에 측쇄

을 가지며 할로겐 Z₁의 S 또는 R 배치가 서로 다른 부분 입체 이성질체의 1쌍 및 엔도-배치에 측쇄

을 가지며 할로겐 Z₁의 S 또는 R 배치가 서로 다른 부분 입체 이성질체의 1쌍인 구조식(I) 화합물을 제공한다.All cyclization reactions described herein, for example, halocyclization of a compound of formula (II) yields a compound of formula (I)) wherein Z ₁ is halogen, and cyclization of a compound of formula (II)

The reactions of the compounds of formula (III) with Hg ⁽⁺⁾ Z ^(-) , which cyclize the compounds of formula (IV) are the same in their mechanism and the number of isomers contained in the reaction mixture is Same as the reaction. The halocyclization reaction of the compound of formula II is therefore a mixture of four constituents, i.e., Z ₁ is halogen and side chains in the exo-batch

And side chains to the endo-batch and to a pair of diastereoisomers having different S or R configurations of halogen Z ₁

Provided is a compound of formula (I) wherein the S or R configuration of halogen Z ₁ is a pair of different diastereomers.

Whereas the dynamics (Rf) of the chromatography of the endo-isomers are clearly different from the Rf of the exo-isomers, the Rf-difference between the two different endo- (or exo-) isomers only for the S or R configuration of the Z ₁ substituent is Very small

사슬이 엑소-배치에 있는 부분 입체 이성질체의 쌍은 상기의 사슬이 엔도-배치에 있는 부분 입체 이성질체의 쌍으로부터 디에틸에테르에서 분별 결정에 의해, 바람직하게는 박층 크로마토그래피, 컬럼 크로마토그래피 또는 고속 액상 크로마토그래피에 의해 분리될 수 있다. 박층 제조 크로마토그래피 또는 컬럼 크로마토그래피에 의한 분류는 용출용매로 염화메틸렌, 디에틸에테르, 이소프로필에테르, 에틸아세테이트, 벤젠, 메틸 아세테이트, 사이클로헥산 또는 그것들의 혼합물을 사용하여 실리카겔 또는 마그네슘 실리케이트를 통해 바람직하게 시행된다.

The pair of diastereomers in which the chain is in the exo-batch is obtained by fractional crystallization in diethylether from the pair of diastereomers in which the chain is in the endo-batch, preferably thin layer chromatography, column chromatography or high velocity liquid phase. Can be separated by chromatography. Classification by thin layer preparation chromatography or column chromatography is preferred via silica gel or magnesium silicate using methylene chloride, diethyl ether, isopropyl ether, ethyl acetate, benzene, methyl acetate, cyclohexane or mixtures thereof as the elution solvent. Is implemented.

Reductive dehalogenation of a compound of formula (I) wherein Z ₁ is halogen to yield a compound of formula (I) wherein Z ₁ is hydrogen is a hydrate such as first chromium acetate or tri (n-butyl) tinhydride. Reduction or by catalytic hydrogenation.

Dehalogenation is tri (n-butyl) tinhydride or first chromium acetate when generating a compound of formula (I) wherein Y is -C≡C- or -CH = CZ _2- (Z is as defined above). Only when reducing to.

When R ₂ and R ₅ together form a compound of formula (l) which forms an oxo group, the dehalogenation reaction of the compound of formula (I) wherein Z ₁ is halogen should not exceed the reaction time of 1/2 hour. When the reductive dehalogenation reaction is carried out with first chromium acetate, the solution dissolved in ethanol and aqueous sodium hydroxide or potassium is stirred under nitrogen air, and added to a cooled solution of the compound of formula (I) wherein Z ₁ is halogen. do. The reaction mixture is described in the following [J. Am. chem. Soc. 76, 5499 (1954), for 1 to 3 days at room temperature. When the dehalogenation reaction is carried out with tri (n-butyl) tinhydride, about 1.2 equivalents of reducing agent are used for each equivalent of the compound of formula (I) wherein Z ₁ is halogen. Suitable solvents for the reaction are aromatic hydrocarbons such as benzene or toluene and the reaction temperature is preferably between room temperature and 70 ° C. Preferably it is continued for about 12 hours in benzene at 55 ℃.

CH₂(CH₂)_P-R의 엑소-또는 엔도-배치에 있어 서로 다른 구조식(I)의 단지 2개의 부분 입체 이성질체의 혼합물을 수득한다.The catalytic hydrogenation of a compound of formula (I) wherein Z ₁ is halogen yields a compound of formula (I) wherein Z ₁ is hydrogen and Y is —CH ₂ CH ₂ —, such as platinum on charcoal or platinum or CaCO ₃ on charcoal. Heating the compound to room temperature or 30 to 60 ° C. in the presence of a catalyst and an ammonium salt such as ammonium acetate or propionate and a solvent such as lower aliphatic alcohol, tetrahydrofuran, dioxane, benzene, toluene under atmospheric pressure or a pressure of 1.1 to 2 atm Do it. The reductive dehalogenation reaction converts a compound of formula (I) in which Z ₁ is halogen to a compound of formula (I) in which Z ₁ is hydrogen, and the carbon atoms carrying the Z ₁ substituent during the reaction lose their asymmetry. The number of possible diastereomers contained in the mixture of the dehalogenation reaction is less than the number of diastereomers contained in the halocyclization reaction mixture. When the reductive dehalogenation reaction is carried out directly on a mixture of the four diastereomers obtained from the halocyclization process, Z ₁ is hydrogen and is branched

In the exo- or endo-batch of CH ₂ (CH ₂ ) _P —R, a mixture of only two diastereomers of different structural formulas (I) is obtained.

(여기서 Z₁은 할로겐이다)을 엑소-또는 엔도-배치에 가지며 Z₁의 S 또는 R 배치에 있어서 서로 다른 구조식(I) 화합물의 부분 입체 이성질체의 한쌍에 환원적 탈할로겐화 반응을 행할 경우 Z₁이 수소이고 엑소-또는 엔도-배치에 측쇄인

CH₂(CH₂)_P-R을 갖는 구조식(I)의 단 한 개의 이성질체를 수득한다.Branch chain

(Wherein Z ₁ is a halogen a) an exo-or endo-having the arrangement in the S or R configuration of the Z ₁ if another conducting reductive dehalogenation reaction of a pair of different structural formulas (I) diastereomer of the compound Z ₁ Is hydrogen and branched to the exo- or endo-batch

Only one isomer of formula (I) having CH ₂ (CH ₂ ) _P —R is obtained.

When a mixture of the above diastereomers is obtained, one diastereomer can be easily separated by fractional crystallization or column chromatography described above to separate the diastereomers wherein Z ₁ is halogen.

Reduction of the compound of formula (III) is carried out at a temperature ranging from room temperature to reflux temperature of the solvent used, preferably sodium, in a solvent miscible with water, ie tetrahydrofuran, dimethoxyethane or lower aliphatic alcohol (methanol or ethanol). Treatment with mixed hydrides of alkaline borohydrides such as potassium or lithium, alkaline-earth metal borohydrides such as calcium or magnesium, or treatment with tri (n-butyl) tin hydride in benzene or toluene, preferably benzene Or by treatment with hydrazine hydrate in lower aliphatic alcohols such as methanol or ethanol.

When Z ₁ is hydrogen and R ₂ and R ₅ together form an oxo group, the reduction of the compound of formula (III) changes for a short time, preferably from 5 to 30 minutes. And tri (n-butyl) tin hydride. Similar to those mentioned above with regard to the dehalogenation of the compound of formula (I) wherein Z ₁ is halogen during the reduction of the compound of formula (III), the carbon atoms carrying the Q substituent lose their asymmetry and at the end of the reduction reaction The number of possible diastereomers contained in the reaction mixture is one half of the number of diastereomers contained in the starting material.

-로서 여기서 R₂는 아릴, 바람직하게는 페닐이고, Re기 알킬일 때는 C₁-C₆알킬이 바람직하다. 구조식(IV)의 알데히드 및 구조식(V) 화합물 사이의 반응은 구조식(V) 화합물의 과량 예를들어 구조식(IV) 화합물의 각 몰당 적어도 1.01몰 당량의 구조식(V) 화합물로 처리하여 실행된다. 에틸 에테르, 테트라하이드로푸란, 디옥산, 디메톡시에탄들의 선상 및 환상에테르; n-헵탄, n-헥산, 벤젠, 톨루엔 또는 할로겐화 탄화수소(염화메틸렌, 테트라 클로로에탄)들의 지방족 또는 방향족 탄화수소 및 이러한 용매들의 혼합물과 같은 비활성 용매들이 사용된다. 반응온도는 용매의 냉동점 및 비점 사이에서 변화된다.In the compound of formula (V), E is (ReO) ₂

Where R ₂ is aryl, preferably phenyl, and C ₁ -C ₆ alkyl is preferred when Re is alkyl. The reaction between the aldehyde of formula (IV) and the compound of formula (V) is carried out by treating an excess of the compound of formula (V), for example, with at least 1.01 molar equivalents of compound of formula (V) per mole of the formula (IV) compound. Linear and cyclic ethers of ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane; Inert solvents such as aliphatic or aromatic hydrocarbons of n-heptane, n-hexane, benzene, toluene or halogenated hydrocarbons (methylene chloride, tetra chloroethane) and mixtures of these solvents are used. The reaction temperature is varied between the freezing point and the boiling point of the solvent.

-인 구조식(V) 화합물과 함께 반응을 시행할 경우 바람직한 온도는 실온 즉 10°내지 25℃의 온도이며 E가 (C₆H₅)₃P⁽⁺⁾-인 구조식(V) 화합물과 함께 반응을 시행할 경우 바람직한 온도는 용매의 환류온도이다. 구조식(IV) 및 구조식(V) 화합물 사이에서의 반응의 생성물은 Y가 트랜스-CH=CZ₂-(Z는 상기 정의된 대로이다)인 구조식(I) 화합물 및 Y가 시스-CH=CZ₂-(Z는 상기 정의된 대로이다)인 구조식(I) 화합물이 대개 90:10 및 95:5의 비를 이루는 혼합물이다.E is (ReO) _2-

- in formula (V) When underwent reaction with the compound The preferred temperature is room temperature, i.e. a temperature of 10 ° to 25 ℃ and E is _{(C 6 H 5) 3 P} (+) - in formula (V) react with the compound The preferred temperature for the reaction is the reflux temperature of the solvent. The product of the reaction between the compounds of formula (IV) and (V) is a compound of formula (I) wherein Y is trans-CH = CZ _2- (Z is as defined above) and Y is cis-CH = CZ ₂ A compound of formula (I), wherein-(Z is as defined above), is usually a mixture in a ratio of 90:10 and 95: 5.

Formula (I) compounds wherein Y is trans-CH = CZ ₂ -and Z ₂ is as defined above can be separated from the mixture by crystallization with a suitable solvent while Y is cis-CH = CZ ₂ -and Z ₂ is The compound of formula (I), as defined above, concentrates the mother liquor and successively uses silica gel or magnesium silicate as the support, and methylene chloride, diethyl ether, isopropyl ether, ethyl acetate, benzene, cyclohexane or its eluent as elution solvent. Obtained by column separation using a mixture or by chromatography such as preparative TLC chromatography. Removal of the protecting group is effected by slow acid hydrolysis, as described above, for the compounds produced by the halocyclization and reduction process.

Optionally reducing the compound of formula (I) wherein R ₂ and R ₅ together form an oxo group and Y is -CH = CZ _2- (Z ₂ is as defined above) and Y is -CH = CZ _2- ( Z is as defined above) to obtain a compound of formula (I) wherein one of R ₂ and R ₅ is hydrogen and the other is hydroxy, or R ₂ and R ₅ together form an oxo group and Y is -CH = A compound of formula (I) wherein CZ _2- (Z ₂ is as defined above) wherein Y is -CH = CZ _2- (Z ₂ is as defined above) and either R ₂ and R ₅ are hydroxy; The conversion of the other to C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or aryl compounds of formula (I) is the only reaction with 1.2 polar additions to the carbonyl group. Should be regarded as different applications. R ₂ and R ₅ together to form a compound of formula (I) wherein Y is —CH═CZ ₂ — (Z ₂ is as defined above) and one of R ₂ and R ₅ is hydrogen and the other is hydroxy Reduction of the compound of formula (I), which forms an oxo group and Y is -CH = CZ _2- (Z ₂ is as defined above), can be carried out using an alkali or 0.5 to 6 moles of reducing agent per mole of the compound of formula (I). It is preferably treated with alkaline earth metal borohydride, preferably sodium, lithium, calcium, magnesium or zinc borohydride. Reduction may be carried out with linear or cyclic ethers such as ethylether, tetrahydrofuran, dimethoxyethane, dioxane, aliphatic or aromatic hydrocarbons such as n-heptane or benzene, halogenated hydrocarbons such as methylene chloride, ethyl, methyl or isopropyl alcohol It is carried out in an aqueous or anhydrous inert solvent of a hydroxylated solvent or mixtures of these solvents. The reaction temperature varies between -40 ° C and the non-gum of the solvent used and the preferred temperature is between -20 and 25 ° C.

) 및 R(

) 알코올로부터 디에틸에테르, n-헥산, n-헵탄, 사이클로헥산으로 분별결정에 의해, 바람직하게는 CH₂Cl₂, 에틸에테르, 이소프로필에테르, 에틸아세테이트, 메틸아세테이트, 벤젠, 사이클로헥산 또는 이것들의 혼합물로 용출하는 실리카겔로 크로마토그래피 또는 마그네슘 실리케이트 컬럼 또는 제조 TLC 크로마토그래피 또는 고속 액상 크로마토그래피에 의해 하나의 에피머를 분리할 수 있음을 제공한다.The reduction reaction is two epimers S (

) And R (

) By distillation from alcohol to diethyl ether, n-hexane, n-heptane, cyclohexane, preferably CH ₂ Cl ₂ , ethyl ether, isopropyl ether, ethyl acetate, methyl acetate, benzene, cyclohexane or these It is provided that one epimer can be separated by chromatography or magnesium silicate column or preparative TLC chromatography or high performance liquid phase chromatography with silica gel eluting with a mixture of

A compound of formula (I) wherein R ₂ and R ₅ together form an oxo group and Y is -CH = CZ- (Z ₂ is as defined above), wherein one of R ₂ and R ₅ is hydroxy and the other C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or aryl and Y is —CH═CZ ₂ —, wherein Z ₂ is as defined above. The conversion to optionally is carried out by treatment with a Grignard reagent of the structure R ″ ′-MgHCl. Wherein HCl is halogen, preferably canceled or iodine and R ″ ′ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, C ₂ -C ₆ alkenyl or aryl, preferably methyl, vinyl, ethynyl, Phenyl. The Grignard reaction is usually -70 ° C in anhydrous solvents, linear or cyclic ethers such as ethyl ether, tetrahydrofuran, dioxane dimethoxyethane or aliphatic or aromatic hydrocarbons (e.g., n-heptane, n-hexane, benbene, toluene). And 1.05 to 2 moles of magnesium derivative per mole of ketone, changing to a temperature between the boiling points of the solvents used. Preferred temperatures range between -60 ° C and 10 ° C. Y is —CH═CZ ₂ — (Z ₂ is as defined above) and one of R ₂ and R ₅ is C ₁ -C ₆ alkoxy or aralkoxy and the other is hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or an aryl of formula (I) reaction to produce compounds are aryl in the presence of a catalyst such as fluoro Bor acid or boron fluoride Le ripple in an organic solvent such as dichloromethane -Optionally by reacting with substituted diazoalkanes or by reacting free or salted hydroxy groups with alkyl or allalkyl halides in the presence of a base of oxidation temperature in a solvent such as dimethylsulfoxide or dimethylformamide.

The reaction of optionally hydrogenating the compound of formula (I) wherein Y is -CH = CZ _2- (Z ₂ is hydrogen) to form the compound of formula (I) wherein Y is -CH ₂ -CH ₂ -is carried out as a catalyst in the alcohol solvent. In the presence of palladium on platinum or charcoal it is preferably carried out catalytically, varying between -40 ° and the reflux temperature of the solvent. When Z ₁ is halogen and Y is -CH ₂ -CH ₂ -to produce a compound of formula (I), it is carried out at a temperature in the range of -40 ° C to -20 ° C.

A compound of formula (I) wherein Z ₁ is hydrogen and Y is -CH = CZ _2- (Z ₂ is halogen) is optionally dehalogenated so that Z ₁ is hydrogen and Y is -C = C- The reaction for obtaining the compound is obtained from a group consisting of dimethylsulfinyl carbion diazabicyclodecene, diazabicyclononene, amide or alkoxide of an alkali metal of structure CH ₃ SOCH ₂ ^(-) using a dehalogenated hydrogenating agent. Is implemented.

1 to 5, preferably 1.5 to 1.8 molar equivalents of basic dehydrohalogenating agent are used per mole of the compound of formula (I) wherein Y is -CH = CZ ₂ -and Z ₂ is halogen.

Dehalogenated hydrogenation processes include dimethyl sulfoxide, dimethylformamide, hexamethylphosphoamide, linear or cyclic ethers (e.g. dimethoxyethane, tetrahydrofuran, dioxane), aromatic hydrocarbons (e.g. benzene, toluene) or liquid ammonia It is carried out with the blocking of oxygen in an inert solvent such as or a mixture of these solvents. The reaction temperature uses a liquid point of ammonia and a temperature between approximately 100 ° C., preferably room temperature. Depending on the solvent used, the reaction temperature and the molar ratio between the reagent and the compound, the reaction time varies from a few minutes to several periods.

And optionally, R ₂ and R ₅ together form an oxo group and Y is —CH ₂ —CH ₂ — or —C═C— to optionally reduce the compound of formula (I) so that one of R ₂ and R ₅ is hydrogen and the other The reaction to obtain a compound of formula (I) wherein the compound is hydroxy and Y is —CH ₂ —CH ₂ — or —C═C— is where R ₂ and R ₅ form an oxo group and Y is —CH═CZ ₂ — (Z ₂ is as defined above) in a similar manner as the reduction of the compound of formula (I). A compound of formula (I) wherein R ₂ and R ₅ together form an oxo group and Y is -CH ₂ -CH ₂ -or -C = C- is one of R ₂ and R ₅ is hydroxy and the other is C ₁ The reaction for converting to a structural formula (I) compound wherein -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or aryl, wherein Y is -CH = CZ ₂ -and Z ₂ is as defined above Similar conversion of the compounds of formula (I) proceeds effectively under the same reaction conditions as defined above.

One of R ₂ and R ₅ is hydroxy and the other is hydrogen or C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or aryl, and Y is —CH ₂ —CH ₂ Or any etherification of the compound of formula (-) with -C = C- wherein one of R ₂ and R ₅ is hydroxy and the other is hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl , C ₂ -C ₆ alkynyl or aryl, wherein Y is —CH═CZ ₂ — and Z ₂ is as defined above, the converting reaction of compounds of formula (I) and salting of compounds of formula (I), free from salt Preparation of compounds and separation of isomers from mixtures are carried out according to known methods. For example, a compound of formula (I) wherein one of R ₂ and R ₅ is hydrogen and the other is hydroxy can be converted by oxidation to a compound of formula (I) wherein R ₂ and R ₅ together form an oxo group. . Oxidation is carried out by treatment with an excess of activated manganese dioxide in an inert solvent, preferably a halogenated inert solvent such as dichloromethane or chloroform, varying from several hours to several days at room temperature. In addition, the reaction temperature is changed from 40 ℃ to the boiling point of the solvent and may be carried out by reacting with 1.1 to 1.2 molar equivalents of dichlorodicyano benzoquinone (DDQ) in an inert solvent such as dioxin, tetrahydrofuran, benzene or mixtures thereof. .

The compound of formula (I) wherein R is a free carboxyl group is a compound of formula (I) wherein R is a carboxyl group esterified with a C ₁ -C ₁₂ carboalkoxy group, a known method, for example an acid catalyst such as P-toluene sulfonic acid. In the presence of is reacted with a suitable alcohol, such as a C ₁ -C ₁₂ aliphatic alcohol, or converted to a diazoalkane.

The reaction in which the compound of formula (I) in which R ₁ is hydroxy is converted to the compound of formula (I) in which R ₁ is acyloxy is carried out by conventional methods, for example anhydrides or halides such as chlorides of the appropriate carboxylic acid in the presence of a base. Is carried out by treatment.

If one of R ₂ and R ₅ is hydroxy this hydroxy group is protected before acylation by one of the known protecting groups mentioned above.

The reaction in which R is an esterified carboxyl group is converted to a compound of formula (I) wherein R is a free carboxyl group is acidified after treatment with alkali or alkaline earth hydroxide in aqueous or alcoholic aqueous solution. It is carried out by a normal saponification reaction. In the compound of formula (I) wherein R is esterified carboxy and R ₁ is acyloxy, any saponification reaction is transesterification with respect to esterified carboxy, ie alcohols and alkali or alkaline earth metal alkoxides or esterifications of carboxy groups or Optionally carried out by reaction in the presence of a base such as K ₂ CO ₃ .

The reaction in which the compound of formula (I) wherein R ₁ is hydroxy is converted to the compound of formula (I) wherein R ₁ is C ₁ -C ₆ alkoxy or aralkoxy, is carried out by conventional methods, for example R ₂ and R _As defined above for the etherification of a compound of formula (I) wherein one of ₅ is hydroxy.

If only one of the various hydroxy functions present is etherified, the hydroxy group which will not be etherified is protected before etherification with the above-mentioned known protecting group, and the step of terminating the etherification reaction according to the aforementioned method Remove it from

The reaction in which R is a free or esterified carboxy group, converting the compound of formula (I) wherein R is -CH ₂ OH, reduces the ether to LiAlH ₄ in ethylether or tetrahydrofuran at reflux. Do it.

이고 Ra 및 Rb가 상기 정의된 대로인 구조식(I) 화합물로 전환하는 반응은 응축제 즉 디사이클로헥실카보이미드와 같은 카보디이미드의 존재하에서 구조식 NHRaRb의 아민으로 처리하여 시행하고, R이 에스테르화한 카복시인 구조식(I) 화합물이 R이

인 구조식(I) 화합물로 전환하는 반응은 환류온도의 적절한 유기용매내에서 2 내지 3시간 동안 구조식 NHRaRb의 아민으로 처리하여 촉진된다.A compound of formula (I), wherein R is a free carboxy group,

And the reaction for conversion to the compound of formula (I) wherein Ra and Rb are as defined above is carried out by treatment with an amine of formula NHRaRb in the presence of a condensing agent, a carbodiimide such as dicyclohexylcarbodiimide, wherein R esterification One carboxyl structural formula (I) compound is

The conversion to phosphorus (I) compound is facilitated by treatment with an amine of the formula NHRaRb for 2-3 hours in an appropriate organic solvent at reflux temperature.

인 구조식(I) 화합물로 임의 전환하는 반응은 환류온도에서 디옥산 또는 디클로로에탄에 용해한 염화티오닐 또는 염화옥살릴과 반응한 후 암모니아로 할라이드를 처리하여 아미드를 얻고 약 90℃ 내지 100℃의 온도에서 피리딘에 용해한 P-톨루엔설포닐클로라이드로 아미드를 탈수하여 니트릴을 생성한 후 마지막으로 실온 및 100℃ 사이의 온도에서 디메틸포름아미드에 용해한 나트륨 아지드 및 염화암모늄으로 처리하는 반응, 즉 카복시그룹을 대응할로겐화물, 바람직하게 염화물로 전환하는 반응에 의해 시행된다. 그러나 상기에서 언급된 카복시그룹을 -CN 또는

로 전환하는 반응은 출발물질 즉 구조식(II) 및 (IV) 화합물상에서 시행된다.A compound of formula (I), wherein R is a free carboxy group,

The reaction which is optionally converted to the phosphorus (I) compound is reacted with thionyl chloride or oxalyl chloride dissolved in dioxane or dichloroethane at reflux, followed by halide treatment with ammonia to obtain an amide, and at a temperature of about 90 to 100 Dehydration of amide with P-toluenesulfonylchloride dissolved in pyridine to form nitrile and finally treatment with sodium azide and ammonium chloride dissolved in dimethylformamide at a temperature between room temperature and 100 ° C, ie carboxyl groups By reactions which convert to halides, preferably chlorides. However, the carboxy group mentioned above may be represented by -CN or

The conversion to is carried out on the starting material, ie the compounds of formulas (II) and (IV).

Any salting of the compound of formula (I) is effected according to conventional methods.

Any separation of the optically active compound from the racemic mixture and any separation of the diastereomers or geometric isomers from the mixture are facilitated by conventional methods.

Structural formula (II) compounds are known compounds and described in E.J. Corey et al, Ann. of New York Acad. of Science 180, 24 (1971), J. Fried es al, J. Med. Chem. 16, 429 (1973), G. L. Bundy et al, Amer. Chem. Soc. 94, 2124 (1972), Gandolfi et al, II Farmaco Ea. U.S. Patent Application No. 3,935,254 by Dervent Palmdock 201717X, German Publication No. 2611788 (Dervent Palmdock 61615X), German Publication No. 2610503 (Dervent Palmdock 59717X), German Disclosure Specification 2627422 (Dervent Palm Dock 85028X), U.S. Patent No. 3,706,789, U.S. Patent No. 3,728,382, U.S. Patent No. 3,903,131, U.S. Patent No. 3,962,293, U.S. Patent No. 3,969,380, Der Bend Palm Dock 73279U , Dervent Palm Dock 31279T, U.S. Patent No. 3,890,372, U.S. Patent No. 3,636,120, U.S. Patent No. 3,883,513, U.S. Patent No. 3,932,389, U.S. Patent No. 3,932,479, Dervent Palm Dock 19594W, Dervent It is prepared as described in Palm Dock 54179U and British Patent No. 1,483,880.

Formula (III) compounds wherein Q is halogen are obtained by the same reaction already described for the synthesis of compounds of formula (I) wherein Z ₁ is halogen.

Hg⁽⁺⁾Z^(-)이고 Z^(-)가 상기 정의된 대로인 구조식(III) 화합물은 Hg⁽⁺⁺⁾이온의 존재하에서 구조식(II) 화합물을 환화하여 제조한다. Hg⁽⁺⁺⁾이온의 적절한 근원은 구조식 Hg(Z)₂의 화합물 또는 구조식 Hg(OH) Z의 화합물이다. 상기의 환화반응은 테트라하이드로푸란, 메탄올, 에탄올과 같이 둘과 혼화성인 유기용매 또는 유기용매와 물의 혼합물에서 구조식(II) 화합물의 각 몰당 1.01 내지 1.5, 바람직하게 1.2당량의 수은화합물을 사용하여 시행된다. 반응온도는 0℃ 및 반응혼합물의 비점에서 변화하며 반응시간은 5분에서 2시간 정도의 범위이다. 환화반응은 복소환고리 B에 연결되어 있는 측쇄의 배치(엔도 또는 엑소), 또는 Q 치환체의 배치(S 또는 R)에 대해 각각 서로 다른 구조식(III)의 4개의 부분 입체 이성질체의 혼합물을 제공한다.Q is

Formula (III) compounds wherein Hg ⁽⁺⁾ Z ^(-) and Z ^(-) are as defined above are prepared by cyclizing the compound of formula (II) in the presence of Hg ⁽⁺⁺⁾ ions. Suitable sources of Hg ⁽⁺⁺⁾ ions are compounds of formula Hg (Z) ₂ or compounds of formula Hg (OH) Z. The cyclization reaction is carried out using 1.01 to 1.5, preferably 1.2 equivalents of mercury compounds per mole of the compound of formula (II) in an organic solvent miscible with the two, such as tetrahydrofuran, methanol and ethanol or a mixture of organic solvent and water. do. The reaction temperature changes at 0 ° C. and the boiling point of the reaction mixture and the reaction time ranges from 5 minutes to 2 hours. The cyclization provides a mixture of four diastereomers of structural formula (III), each different for the arrangement of the side chains (endo or exo) or the arrangement of the Q substituents (S or R) linked to heterocyclic ring B. .

Separation of the diastereoisomers carried out according to the conventional methods described above from their mixtures takes place after the reduction of the compound of formula (III), if necessary.

The halogenated structural formula (IV) compound is prepared by the selective oxidation of -CH ₂ OH produced by -CHO by halocyclization of the structural formula (VI) compound and the removal of a protecting group.

In the above structural formula

R ″, P, q, D and R ₁ ′ are as defined above and

또는

, n₃이 2에서 4까지의 정수 바람직하게 2 또는 3인

또는

, -CH₂-O-CH₂-C₆H₅또는 -CH₂-O-CH₂SCH₃로 구성되는 그룹으로부터 얻은 것이다.G is a protective aldehyde group or a protective -CH ₂ OH group, preferably R ₁₀ is C ₁ -C ₆ alkyl

or

n ₃ is an integer from 2 to 4, preferably 2 or 3

or

, -CH ₂ -O-CH ₂ -C ₆ H ₅ or -CH ₂ -O-CH ₂ SCH ₃ .

The reaction in which the halo-ringing compound of formula (VI) is converted to the compound of formula (I) wherein Z ₁ is halogen is carried out using the same reaction conditions as described above.

Removal of the protecting group from aldehyde or alcoholic action is effected by complete acid hydrolysis under the same conditions detailed herein above for the removal of the protecting group (ether group) of hydroxy functioning. The selective oxidation of —CH ₂ OH to —CHO is at least 3 moles per mole of primary alcohol of dicyclohexylcarbodiimide dissolved in benzene-dimethylsulfoxide in the presence of an acid catalyst such as pyridine trifluoro acetate or phosphoric acid. It is carried out in the usual way of treating in quantities.

Hg⁽⁺⁾Z^(-)인 구조식(III) 화합물의 제조방법에 대해 이미 기술한 대로 구조식(VI) 화합물을 환화하고 연이어 수득한 화합물을 구조식(III) 화합물의 환원반응에 사용했던 동일한 반응조건을 사용하여 환원함과 같은 방법에 따라 제조된다.Of formula (IV) compound is hydrogen Z ₁ is Z ₁ is the presence of a halogen of formula (I) compound is Z ₁ is hydrogen in formula (I), or a method Hg ⁽⁺⁺⁾ ion described above for the reaction that is converted to compound Q under

The same reaction conditions as those described for the preparation of the compound of formula (III) ^, which ^is Hg ⁽⁺⁾ Z ^(-) , are obtained by cyclizing the compound of formula (VI) and subsequently using the compound obtained for the reduction of the compound of formula (III). It is prepared according to the same method as reducing using.

-인 구조식(V) 화합물은 Re, Z₂, n, R₃, R₄, X, n₂및 R₆가 상기 정의된 바와 같은 구조식(VII)의 포스포너이트를 나트륨, 칼륨, 리튬 또는 칼슘하이드라이드와 같은 알칼리금속 또는 알칼리토금속 하이드라이드, 나트륨 또는 칼륨 3급 부톡시드와 같은 알칼리알콕시드, 나트륨아미드와 같은 알칼리금속 또는 알칼리토금속아미드, 나트륨아세트아미드 또는 나트륨석신이미드와 같은 카복시이미드의 알칼리금속 또는 알칼리토금속 유도체로 구성되는 그룹으로부터 선택된 염기 일당량으로 처리하여 제조된다.E is (ReO) ₂

Formula (V) is a compound in which Re, Z ₂ , n, R ₃ , R ₄ , X, n ₂ and R ₆ are selected from the group consisting of sodium, potassium, lithium or Of alkali metals such as calcium hydride or alkaline earth metal hydrides, alkali alkoxides such as sodium or potassium tert-butoxide, alkali metals such as sodium amides or carboxyimides such as alkaline earth metal amides, sodium acetamide or sodium succinimide It is prepared by treating with a base equivalent of a base selected from the group consisting of alkali metal or alkaline earth metal derivatives.

The compound of formula (V), wherein E is (C ₆ H ₅ ) ₃ P ⁽⁺⁾ -, has a compound of formula (VIII) wherein 1 to 1.2 molar equivalents of triphenyl phosphate in an inert organic solvent such as benzene, acetonitrile, diethyl ether After reaction with the pin, the resulting triphenylphosphonium halide is prepared by treating with an equal amount of inorganic base such as NaOH, KOH, Na ₂ CO ₃ , NaHCO ₃ .

here

Z ₂ , n ₁ , R, R ₄ , X, n ₂ , R ₆ are as defined above and Hal is a halogen atom.

Structural (VI) compounds are prepared according to Tetrahedron Letters No. 42, 4307-4310 (1972). The compound of formula (VII) wherein Z ₂ is halogen is produced by halogenating the compound of formula (VII) wherein Z ₂ is hydrogen according to a conventional method as in the halogenation of β-ketoesters. Formula VII compounds wherein Z ₂ is hydrogen are described in EJ Corey et al, J. Am. Chem. Soc 90, 3247 (1968) and EJ Corey and GK Kwiatkowsky, J. Am. Chem. Soc., 88, 5654 (1966) according to known methods. Formula (VII) compounds are known compounds and are prepared according to conventional methods.

Compounds of the invention are generally used in medicine or veterinary for the same therapeutic indications as natural prostaglandins. In particular, having acetylene bonds instead of ethylene at the 13,14-position and having mono and di-substituents such as methyl and fluorine groups have excellent resistance to degradation by 15-PG-dehydrogenase which quickly inactivates natural compounds and It has the advantage of much selective therapeutic action as pointed out in.

First, to obtain a biological profile of the evi, ie to assess whether a compound of the present invention has PG-like activity or thromboxane- (TXA ₂ ) -like or PGX-like activity [Nature 223, 29 (1969)] and the piper and vane method. To increase the sensitivity of the bioassay, a mixture of antidote (Gilmore Nature 218, 1135 (1968)) was added to Krebs-Henseleit and indomethacin (4 μg / ml) to prevent resistant biosynthesis of prostaglandins. do.

To demonstrate prostaglandin-like activity, the contraction of rat colon (Re), peripheral compression (RSS) and bovine coronary artery (BCA), and relaxation of rabbit mesenteric artery (RbMA) are estimated. TXA ₂ -like activity occurs when RbMA contracts, and PGF ₂ α-like compounds also contract RbMA and thus have antiplatelet-aggregating activity that should be confirmed by inversely counteracting PGE in vitro. Finally, PGX-like activity is indicated by the relaxation of BCA and should be identified as platelet anti-aggregation activity in in vitro tests. Synthetic PGE ₂ and biosynthetic TXA ₂ and PGX are used as standard compounds. Compounds of interest are active in the concentration range of 1-5 μg / ml.

The compounds according to the invention are dissolved in a few drops of ethanol just before the experiment. The stock solution is prepared in Tris-buffer and diluted to the desired concentration with 0.1M Krebs-Hencelite at pH (1 mg / ml) 9.0. Take 13-trans-11α, 15, S-dihydroxy-6βH-6,9α-oxide-prostenoic acid compound as the parent compound and call it 6βH-6,9α-oxide, which is a diastereomer 13-trans-11α , 15S-dihydroxy-6βH-6,9α-oxide-prostenoic acid is called 6βH-6,9α-oxide. The chemical names of other test compounds are called the same as the parent compound and are tested at concentrations up to 100 mg / ml.

The results shown are usually 6βH-6,9α-oxide, dl-6βH-5-bromo-6,9α-oxide,, 6βH-6,9α-oxide-16m-CF ₃ -phenoxy-W-tetra It is shown that 9βH-diastereomers such as knots and 6βH-6,9α-oxide-16-m-chloro-phenoxy-W-tetranor compound exhibit BCA-dicyclic activity and PGX-like activity. Only dl-6βH-6,9α-oxide-16-methyl-16-butoxy-W-tetranor compound in the 6βH-eude exhibits BCA-shrinkage activity. 6αH-6,9α-oxide, dl-6αH-5-bromo-6,9α-oxide, dl-6αH-6,9α-oxide-16-methyl-16-butoxy-W-tetranor, ΑH- such as 6αH-6,9α-oxide-16-m-CF ₃ -phenoxy-W-tetranor and 6αH-6,9α-oxide-16-m-chloro-phenoxy-W-tetranor Derivatives also exhibit BCA-constrictive activity.

In general, exo-batches are associated with contraction of BCA. Moreover, the compounds according to the invention exhibited hypoglycemic activity in mammals like the natural compound PGX. However, it has the advantage of higher chemical safety over PGX and is used in pharmaceutical formulations. Hypoglycemic activity is indicated by low reflux experiments. The 6βH- and 6αH-6,9α-oxide compounds were released from 0.05 to 1 μg (about 42.5% for 6βH, about 322% for 6αH) through the left femoral artery while refluxing the left leg of the rat at constant reflux pressure. For all imperfections in the range up to), it causes a drop in the value of the average reflux pressure. Moreover, systemic pressure for heart contraction and dilation is reduced from 0.05 μg / kg to 5 μg / kg (about 45%).

The compounds according to the invention are useful for the treatment of gangrene at low points due to hypotensive and vasodilatory activity. It is well known that for these therapeutic uses these compounds are more active than PGE ₁ and PGE ₂ . They are useful for the disability of peripheral blood system and thus for the prevention and treatment of diseases such as phlebitis, liver-kidney syndrome, arterial canals, non- occlusive mesenteric hemostasis, arteritis and hemostatic ulcers of the legs.

Particularly 6βH-derivatives in the compounds according to the invention also exhibit nola anti-aggregation activity. Important compounds for increasing potency among 6βH compounds are dl-6βH-5-bromo-6,9α-oxide, 6βH-6,9α-oxide-16-m-CF ₃ -phenoxy-W-tetranor , dl-6βH-6,9α-oxide and 6βH-6,9α-oxide.

Continuation of insignificant delivery in a Born aggregometer (Born GVR, Nature (London) 194, 927 (1962)) using platelet-rich plasma (PRP) from a healthy person who has taken no medicine for at least a week 6βH-6,9α-oxide, dl-6βH-5-bromo-6,9α-oxide, 6βH-6,9α-oxide-16-m-CF ₃ -phenoxy by warning of platelet aggregation by recording It is clear that the ci-W-tetranor and 6βH-6,9α-oxide-16-m-chloro-phenoxy-W-tetranor compounds result in biosynthesis in platelet-anticoagulation. The irradiated compound is warmed in PRP for 2 or 3 minutes at 37 ° C. before adding the flocculant, arachidonic acid (0.4 mM), ADP (10 μM), collagen (38 μM) or adrenaline (15 μM). The effective rate for the compound is 1:10 for arachidonic acid flow aggregation and 1: 100 for ADP-induced aggregation compared to biosynthetic PGX.

A very interesting increase in anticoagulant potency follows 20-methyl substitution in the 6βH- and 6βH-6,9α-oxides compounds. Similarly 6βH-5-bromo-20-methyl, 6βH-5,14-dibromo, 6βH-13,14-didehydro-20-methyl and 6βH-5-bromo-13,14-didehydro compound And 6βH-5-iodo (not the 6αH-5-iodo isomer) are highly active compounds as anti-coagulants.

As such, the compounds according to the invention are particularly useful in humans for the disorder of platelet aggregation, the prevention and disorder of thrombus formation, and the reduction of platelet adhesion. It is also useful for the treatment and prevention of thrombosis and myocardial infarction, for the treatment of atherosclerosis, for the etiological syndromes associated with adipose imbalance or hyperlipidemia and for the prevention of cerebral anemia, and for long-term treatment after myocardial infarction.

When the compounds according to the invention are used as anti-aggregating agents, the route of administration is oral, intravenous, subcutaneous, intramuscular administration and the like. In case of emergency, the preferred route is intravenous injection in an amount of 0.005 to 10 mg / kg / day. The exact amount depends on the patient's weight, age and route of administration.

The compounds according to the invention also exhibit uterine contractile action in vitro and in vivo experiments against PGF ₂ α as a standard. For example, 6αH-6,9α-oxide-16-m-chloro-phenoxy-W-tetranor and 6βH-6,9α-oxide-16-m- of the uterus of mice estrused in vitro in vitro. CF ₃ - phenoxy -W- tetrahydro Nord compound is compared to PGF ₂ α has from 1.3 to 3.1 times activity. For by measuring the removal of the ovaries intrauterine pressure of rats in the in vivo test of the compound refers to the 5.9 to 8.25-fold of the activity of PGF ₂ α are described in the following table.

The table above shows higher activity in the uterus than in the gastrointestinal tract. Such compounds are useful for inducing analgesia in medicine or veterinary medicine and for relieving dead fetuses from pregnant women without the unnecessary side effects of natural prostaglandins such as vomiting and diarrhea. For this purpose the compound according to the invention is injected intravenously in an amount of 0.01 μg / kg / min until the end of analgesia. In the same amount, the compound according to the invention dilutes the cervix and promotes therapeutic abortion, and in this situation the form of vaginal or suppository is preferred.

The compounds according to the invention, in particular dl-6βH-6,9α-oxide-16-m-chloro-phenoxy-W-tetranor, have luteolin activity and are therefore useful for adjusting the fertilization rate. The 6βH-6,9α-oxides and 6αH-isomers are characterized by (a) cytoprotective activity against lesions induced by non-streptoid anti-inflammatory agents, (b) the Togagi-Okabe method [( Anti-ulcer activity induced by Jaapan J. Pharmaceut. Vol 18,9 (1968)], (C) in the gastrointestinal tract to know the anti-secretory activity according to The protective function is a common feature of all compounds.

For example, when injected subcutaneously, 6βH-6,9α-oxide is slightly more active as a gastric antisecretory agent than the standard PGE ₂ (1.5-2 times). In general, the cytoprotective activity of the 6βH compound is doubled when the acetylene bonds are present at the 13,14-position and four times when the 16-alkyl group, usually methyl, is located at the 16 (S) -configuration. As antiulcer substance, 6βH-6,9α-oxide analogue is at least equivalent to PGE ₂ and the following substitutions, 13,14-acetylene bonds, 16S or Rmethyl, 16S or R fluoro, increase the effectiveness rate (Up to 30 times). Moreover, the important oral antisecretory activity is that the methyl group has a C-15-position or 6βH-6,9α-oxide-16-methyl-16-butoxy-w-tetranor derivative of FIG. 6βH-6,9α-oxide. Appears when present in the same 16,16-dimethyl compound.

Compounds for this purpose are preferably injected intravenously or leaching, subcutaneously or intramuscularly. Intravenous infusion requires an amount of 0.1 μg four 500 μg / kg / weight / min. The total daily amount following injection or leaching is on the order of 0.1 to 20 mg / kg, but the exact dosage depends on age, weight and the condition and route of administration of the patient or animal being treated.

In addition, the compounds also have an important bronchodilator ring and are useful for treating diseases of the obstructive pulmonary artery, such as bronchial asthma. For the treatment of obstructive pulmonary artery disorders, for example bronchial asthma, the compounds according to the invention are administered orally in the form of other routes, for example, in the form of tablets, capsules, enveloped tablets or in the form of old and / or procedure, rectal administration with suppositories, intravenous Yes, intramuscularly or subcutaneously, by inhalation into aerosols or solutions through nebulizers, aeration in powder form. The dosage is 0.01-4 mg / kg, one dose four times a day. The exact amount depends on age, weight, patient's condition and route of administration.

The compounds according to the invention for use as anti-asthmatic agents are combined with sympathetic stimulants such as isoproterenol, ephedrine and the like, xanthine derivatives such as theophylline and aminophylline, or anti-asthmatic agents of corticosteroids. Doses used as hypotensive and vasodilators are the same amounts used for the anti-aggregating effect.

As mentioned above, the compounds according to the invention are given to humans and animals in various dosage forms. For example, oral administration in the form of tablets, capsules or liquids, rectal administration with suppositories, parenteral, subcutaneous or intramuscular, in an emergency, preferably intravenously, inhalation in the form of aerosols or solutions via nebulizers, Vaginal administration in the form of sterile transplants or suppositories for shouts.

Pharmaceutical or veterinary compositions containing the compounds according to the invention are prepared according to conventional methods and contain conventional carriers and / or diluents. For example, sterile aqueous isotonic solutions are preferred for intravenous injection or leaching. For subcutaneous or intramuscular injection, sterile solutions or suspensions in aqueous or non-aqueous medium are used, and for tissue transplantation, sterile tablets or silicone rubber capsules containing or infiltrating the compound are used. Conventional carriers or diluents include, for example, water, gelatin, lactose, dextrose, saccharose, mannitol, sorbitol, cellulose, lalc, stearic acid, calcium or magnesium stearate, glycols, starch, gum arabic, traga Kant rubber, alginic acid or alginate, cicithin, polysorbate, vegetable oil and the like. Suspensions or solutions of the compounds according to the present invention are used in the form of salts such as sodium salts dissolved in water for administration through the nebulizer. Alternatively the pharmaceutical formulation form is administered from a compressed container such as a nebulizer in the form of a suspension or solution of the compound according to the invention which is one of liquefied propellants such as dichlorodifluoromethane or dichlorotetrafluoroethane. If the compound does not dissolve in the propellant, it is necessary to add co-solvents and / or interfacial agents such as ethanol, dipropylene glycol to the pharmaceutical formulation.

The present invention is illustrated by the following examples and the abbreviations “THF”, “DME”, “DMSO”, “THP”, and “Et ₂ O” are tetrahydroputane, dimethoxyethane, dimethyl sulfoxide, tetrahydropyra. Neyl and ethyl ether are shown, respectively.

Example 1

1.0 g of dl-5β-hydroxymethyl-2α, 4α-dihydroxy-cyclopentane-1α-acetic acid-γ-laccon-4-P-phenyl benzoate dissolved in 8 ml of benzene // DMSO (75/25) To the solution is added 0.89 g of dicyclohexyl keybodiimide with stirring. At room temperature 1.42 ml of pyridinium trifluor acetate solution (prepared by dissolving 1 ml of trifluoroacetic acid and 2 ml of pyridine in 25 ml of 75/25 benzene // DMSO) is added. After 3 hours 19 ml of benzene are added and the mixture is treated dropwise with 0.3 oxalic acid dihydrate solution dissolved in 3.8 ml of water. After stirring usually for 15 minutes the mixture is filtered and the organic phase is washed with water until neutral and concentrated to 2 ml and diluted with 5 ml isopropyl ether. The product was isolated by filtration and crystallized from isopropyl ether to yield 0.8 g of dl-5β-formyl-2α, 4α-dihydroxy-cyclopentane-1α-acetic acid-γ-lactone-4- having a melting point of 129 four 131 ° C. Obtain P-phenylbenzoate. 800 mg of this solution dissolved in 2.8 ml of anhydrous methanol are treated with 0.62 ml of methylorthophoromate and 18 mg of P-luene sulfonic acid monohydrate. After 1 hour 0.01 ml of pyridine is added and the solution is evaporated to dryness. The residue is dissolved in ethyl acetate and washed until neutralized with 1.0N NaOH and saturated NaCl. The solvent was removed under reduced pressure and the residue was crystallized from methanol to yield 80 mg of dl-5β-dimethoxymethyl-2α, 4α-dihydroxy-cyclophen-1α-acetic acid-γ-lactone-4- having a melting point of 108 to 110 ° C. Obtain P-phenylbenzoate.

To a solution of this compound in 5.6 ml of absolute ethanol is added 60 mg of K ₂ CO ₃ . After stirring for 4 hours at room temperature, the solution is filtered. Reduce the volume and acidify with saturated NaH ₂ PO ₄ solution. Methanol is removed and the residue is treated with ethyl acetate. It was washed with saturated NaCl until neutralized, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to 480 mg of dl-5β-dimethoxymethyl-2α, 4α-dihydroxy-cyclopentane-1α-acetic acid-γ To obtain lactones.

A solution of this compound dissolved in 4 ml of CH ₂ Cl ₂ is treated with 0.32 ml of 2,3-dihydropyran and 4.8 mg of P-toluene sulfonic acid. After 4 hours at room temperature, pyridine is added and the solution is evaporated under reduced pressure. The impure reaction product was filtered through 5 g of silica gel using cyclohexane: ethyl ether (50:50) as the eluent and 380 mg of dl-5β-dimethoxymethyl-2α, 4α-dihydroxy-cyclopentane-1α-acetic acid-γ -Lactone-4-retrahydropyranyl ether is obtained.

4-ester of 5β-dimethoxymethyl-2α, 4α-dihydroxy-cyclopentane-1α, -acetic acid-γ-lactone (eg 4-P-phenyl benzoate, melting point 128-130 ° C., [α] _D = 85 °) or 4-ester of 5α-hydroxymethyl-2β, 4β-dihydroxy-cyclopentane-1β-acetic-γ-lactone (eg: 4-P-phenylbenzoate, melting point 1227 N. 129 [deg.] C, [[alpha] = + 85 [deg.] C.) following the same method, the following compound, 5 [beta] -dimethoxymethyl-2 [alpha], 4 [alpha] -dihydroxy-cyclopentane-1 [alpha] -acetic acid- [gamma] -lactone-4- Tetrahydropyranyl ether and 5α-dimethoxymethyl-2β, 4β-dihydroxy-cyclopentane-1β-acetic acid-γ-lactone-4-tetrahydro pyranyl ether are prepared. When 1,4-diox-2-ene is used instead of 2,3-dihydropyran, the corresponding 4-dioxanyl ether derivatives are obtained.

Example 2

216 mg of 5β-dimethoxymethyl-2α, 4α-dihydroxy-cyclopentane-1α-acetic acid- with [α] _D = -16 ° and [α] ₃₆₅ ° = -48 ° dissolved in 1.6 ml of dimethylformamide. The γ-lactone solution (C = 1.0 CHCl ₃ ) is treated with 0.3 ml of triethylamine and again with 291 mg of dimethyl tert-butylchlorosilane. After 1 hour the mixture is diluted with 8.3 ml of water and extracted with hexanes. The organic phase was washed with water and dried over Na ₂ SO ₄ to afford 310 mg of 5β-dimethoxymethyl-2α, 4α-dihydroxycyclopentane-1α-acetic acid-γ-lactone-4-dimethyl-tert-butylsilyl ether do.

Example 3

8 ml of benzene: dl-5β-hydroxymethyl-2α, 4α-dihydroxy-cyclopentane-1α-propanoic acid-δ-lactone-4P-phenylbenzoate (1 g) solution dissolved in DMSO (75:25) To this was added 0.86 g of dicyclohexyl-carbodiimide followed by addition of 1.37 ml of freshly prepared pyridinium trifluoro acetate (see Example 1). After 3 hours, 18 ml of benzene is added and 0.29 g of oxalic acid dihydrate solution dissolved in 3.7 ml of water is added dropwise again.

After 15 min stirring the dicyclohexylurea is removed by filtration and the organic phase is washed with water until neutral. Reduce the volume to about 2 ml and add isopropyl ether to afford 0.793 g of dl-5β-propyl-2α, 4α-dihydroxy cyclopentane 1α-propionic acid-δ-lactone-4-P-phenyl benzoate.

A solution of 780 mg of this compound dissolved in 2.7 ml of anhydrous methanol is treated with 0.59 ml of methylorroformate and 17.3 mg of P-toluene sulfonic acid. After about one hour 0.01 ml of pyridine is added and the solution is evaporated to dryness. The residue is treated in ethyl acetate and the organic phase is washed with 1N NaOH followed by neutralization with saturated NaCl. Evaporation to dryness yields 769 mg of dl-5β-dimethoxymethyl-2α, 4α-dihydroxy cyclopentane-1α-propionic acid-δ-lactone-4P-phenylbenzoate. It is dissolved in 5.4 ml of absolute ethanol and 75 mg of K ₂ CO ₃ is added. Stir at room temperature for 4 hours, filter, reduce the volume of the solution, and then acidify with a saturated solution of NaH ₂ PO ₄ . Methanol was evaporated and the aqueous phase was extracted with ethyl acetate, washed with saturated NaCl solution until the organic phase was neutralized, dried over Na ₂ S0 ₄ and evaporated under vacuum to afford crude dl-5β-dimethoxymethyl-2α, 4α- Dihydroxy cyclopentane-1α-propanoic acid-δ-lactone is obtained. A solution of this compound dissolved in 4 ml of CH ₂ Cl ₂ is treated with 0.3 ml of 2,3-dihydropyran and 44.5 mg of P-toluenesulfonic acid. After 4 hours at room temperature, 0.01 ml of pyridine is added and the solution is evaporated to dryness. The reaction product was purified by silica gel using eluent cyclohexane: aryl ether (50:50) to 480 mg of dl-5β-dimethoxymethyl-2α, 4α-dihydroxy cyclopentane-1α-propanoic acid-δ-lactone 4-retrahydro pyranyl ether is obtained.

4-ester of 5β-hydroxymethyl-2α, 4α-dihydroxy cyclopentane-1α-propanoic acid-δ-lactone and 5α-hydroxymethyl-2β, 4β-dihydroxy cyclopentane-1β-propano The following compound, 5β-dimethoxymethyl-2α, 4α-dihydroxy cyclopentane-1α-propano, following the same method from 4-ester of acid-δ-lactone (eg 4-P-phenylbenzoate) Acid-δ-lactone-4-retrahydropyranylether, 5α-dimethoxymethyl-2β, 4β-dihydroxy cyclopentane-1β-propanoic acid-δ-lactone-4-retrahydropyranyl ether To obtain.

If 1,4-diox-2-ene is used instead of 2,3-dihydropitane, the corresponding 4-dioxanyl ether derivative is obtained.

Example 4

1 g of 5β-formyl-2α-hydroxy cyclopentane-1α-γ-acetic acid-γ-lactone solution dissolved in 6.5 ml of anhydrous methanol is treated with 1.74 ml of methylorthoformate and 52 mg of P-toluene sulfonic acid. .

After about 1 hour, 0.04 ml of pyridine is added and evaporated to dryness. The residue is treated in ethyl acetate and washed with 1N NaOH and again with saturated NaCl until neutralized. Evaporation under vacuum affords 1 g of 5β-dimethoxymethyl-2α-hydroxy cyclopentane-1α-acetic acid-γ-lactone with (α) = 16 °.

According to the same method, 5β-dimethoxymethyl-2α-hydroxy cyclopentane-1α-propionic acid-δ-lactone and dl derivatives are obtained from 5β-formyl-2α-hydroxycyclopentane-1α-propionic acid-δ-lactone. .

Example 5

960 mg of dl-5β-dimethoxymethyl-2α, 4α-dihydroxy cyclopentane-1α-acetic acid-γ-lactone-4-tetrahydropyranylether solution dissolved in 16 ml of toluene cooled to -70 ° C 8.5 ml of 0.5N toluene solution of iso-butylaluminum hydride should be over 30 minutes. After 30 min of stirring at -70 ° C, 10 ml of a 2M toluene solution of isopropanol is added dropwise. Warm to 0 ° C. and then treat with 3 ml of 30% NaH ₂ PO ₄ solution. After stirring for 1 hour, 12 g of anhydrous Na ₂ SO ₄ is added. Filtration and evaporation of the solvent yielded 900 mg of dl-5β-dimethoxymethyl-2α, 4α-dihydroxy cyclopentane-1α-ethanol-γ-lactan-4-tetra hydropyranylether.

Example 6

400 mg of 5β-dimethoxymethyl-2α, 4α-dihydroxy cyclopentane-1α-acetic acid-γ-lactone-4-dimethyl-tertiary dissolved in 11 ml of toluene cooled to −70 ° C. according to the method of Example 5. -Butylsilylether solution was treated by dropwise addition of 5.9 ml of 0.5 N toluene solution of di-iso-butylaluminum hydride to 0.43 g of 5β-dimethoxymethyl-2α, 4α-dihydroxy cyclopentane-1α-ethaneal -γ-lactone-4-dimethyl-tert-butylsilyl ether is obtained.

Example 7

Di-iso in 628 mg of 5β-dimethoxymethyl-2α, 4α-dihydroxy cyclopentane-1α-δ-lactone-4-tetrahydropyranyl ether solution dissolved in 11 ml of toluene cooled to -70 ° C under nitrogen air. Treat by dropwise addition of 5.0 ml 0.5M toluene solution of butylaluminum hydride. After 30 minutes at −70 ° C., 10.9 ml of a 2M toluene solution of isopropanol is added dropwise. The temperature is raised to 0 ° C. and then ₂ ml of 30% NaH ₂ PO ₄ solution is added. After stirring for 1 hour, 8.3 g of anhydrous Na ₂ SO _{4 was added} and filtered. Evaporation of the organic phase in vacuo afforded 620 mg of 5β-dimethoxymethyl-2α, 4α-dihydroxy cyclopentane-1α-propanal-δ-lactop-4-tetrahydro pyranyl ether.

Example 8

One of the methods described in Examples 5,6 and 7 is used to prepare 4-acetal (4-tetrahydro pyranyl ether; 4-dioxanyl ether) and 4-dimethylbutylsilyl ether of the following compounds. 5β-dimethoxymethyl-2α, 4α-dihydroxy cyclopentane-1α-ethylal-γ-lactol, 5α-dimethoxymethyl-β, 4β-dihydroxy cyclo in optically active form (or nat-) Pentane-1β-ethalal-γ-lactol (or ent-form), dL and 5β-dimethoxymethyl) in optically active form (or nat-)-2α, 4α-dihydroxy cyclopentane-1α-propanal- δ-lactol, 5α-dimethoxymethyl-2β, 4β-dihydroxy cyclopentane-1β-propanal-δ-lactol (or ent-form).

Example 9

0.29 ml of anhydrous ethanol solution dissolved in 3.5 ml of toluene was cooled to 0 ° C. in 5 × 10 ⁻³ sodium (2-methoxyethoxy) aluminum hydride (1.4 ml of 70% benzene diluted with 5 ml of toluene). Solution) dropwise to the solution. 8.2 ml of alanate solution prepared above was added to 0.98 g of dL-5β-benzyloxymethyl-2α-hydroxy cyclopentane-1α-propionic acid-δ-lactone solution dissolved in 22 ml of toluene at -30 ° C. . After 45 minutes excess reagent is quenched with 6 ml of 0.5 M toluene solution of isopropanol. The mixture is warmed to 0 ° C. and 4 ml of 30% NaH ₂ PO ₄ are added and the resulting mixture is stirred for 2 hours. The inorganic salts are removed by filtration and the solution is evaporated to dryness to yield 0.94 g of dL-5β-benzyloxymethyl-2α-hydroxy cyclopentane-1α-propanal-δ-lactol.

The following compound, 5β-benzyloxymethyl-2α-hydroxy cyclopentane-1α-ethanal-γ-lactol, from the corresponding γ-rictone using either the above method or one of the methods in Examples 4-7 5β-benzyloxy methyl-2α-hydroxy cyclopentane-1α-propanal-δ-lactol, 5β-dimethoxymethyl-2α-hydroxy cyclopentane-1α-ethanal-γ-lactol, 5β-dimethoxy methyl- Prepare 2α-hydroxy cyclopentane-1α-propanal-δ-lactol.

Example 10

The reaction temperature was maintained at a temperature of 20 to 22 ° C. by stirring and external cooling, and 1.8 g of 4-carboxybutyl-triphenylphosphonium bromide and 0.38 were dissolved in a solution of 1.05 g of potassium tert-butylate dissolved in 10 ml of DMSO. To a solution of 5β-dimethoxymethyl-2α, 4α-dihydroxy cyclopentane-1α-ethanal-γ-lactol, 4-tetrahydro pyranyl ether is added dropwise. The mixture is left at room temperature for 1 hour and then diluted with 16 ml of ice / water. The aqueous phase is extracted with ether (5x8ml) and ether: benzene (70:30, 5x6ml), reextracted with 0.5M NaOH (2x10ml) and the organic phase is discarded.

The alkaline aqueous phase is acidified with 30% NaH ₂ PO ₄ to PH4.8 and extracted with ethyl ether: pentane (1: 1, 5 × 15 ml). 0.45 g of 5-cis-7- (2′α, 4′α-dihydroxy-5′β-dimethoxymethylcyclopentan-1′α-yl from the organic phase after drying over Na ₂ SO ₄ and removing the solvent ) -Hept-5-enoic acid-4'-tetrahydro pyranyl ether is obtained.

This compound is converted to the corresponding methyl ester by treatment with diazomethane in ether. 100 mg of impure product was adsorbed with 1 g of silica gel and eluted with benzene: ethyl ether (85:15) to prepare analytical specimens.

Example 11

A suspension of 0.39 g of 75% NaH oil dispersion dissolved in DMSO (13,5 ml) in dry nitrogen air is heated at 60-65 ° C. for 3.5 hours. After cooling to room temperature, the reaction mixture was kept at 20-22 ° C., 2.66 g of 3-carboxypropyltriphenyl phosphonium bromide dissolved in 6 ml of DMSO, 0.6 g of 5β-dimethoxymethyl-2α dissolved in 3 ml of DMSO, 4α-dihydroxy cyclopentane-1α-propanal-δ-lactol-4-tetrahydro pyranyl ether is added sequentially. The mixture is stirred for 3 hours and then diluted with 35 ml of water. The aqueous phase is extracted with ethyl ether (5x12ml) and ethyl ether: benzene (70:30, 7x12ml), reextracted with 0.5N, NaOH (2x15ml) and the organic extract is discarded. The mixed alkaline aqueous extract was acidified with 30% NaH ₂ PO ₄ to pH 4.3, extracted with ethyl ether: pentane (1: 1), washed until neutralized, dried over Na ₂ SO ₄ , removed solvent and 0.71 g of 4-cis-7- (2′α, 4′α-dihydroxy-5′β-dimethoxymethyl-cyclopent-1′α-yl) -hept-4-enoic acid is obtained. Treatment with diazomethane provides the corresponding methyl ester.

Example 12

Lactol produced according to the methods of Examples 4 to 8 was treated with a Wittig reagent (prepared from 4-carboxybutyl-triphenylphosphonium bromide or 3-carboxy propyl triphenylphosphium bromide) followed by diazo methane. The ester is prepared in optically active or dL form.

Example 13

5-cis-7- (2'α, 4'α-dihydroxy-5'β-dimethoxymethyl-cyclopent-1'α-yl) -hept-5-enoic acid-4 dissolved in 5 ml of methanol A solution of 1.06 g of methyl ester of '-tetrahydro pyranyl ether is added to 0.84 g of water acetate dissolved in methanol. After 30 minutes at room temperature, 250 mg of sodium borohydride solution dissolved in 2 ml of water is added with stirring and externally cooled. After stirring for 20 minutes, the mixture is acidified to pH 6.5 with aqueous sodium phosphate, the methanol is removed under reduced pressure and the residue is treated in water / ethyl ether. Removal of the solvent gave the organic phase 1.02 g of 5- (6′-exo-dimethoxy-methyl-7′-endo-hydroxy-2′-oxa-bicyclo (3.3.0) octane-3′ξ-yl) -Pentanoic acid methyl ester-7'-tetrahydro pyranyl ether is also obtained.

Example 14

1.59 g of 4-cis-7- (2'α, 4'α-dihydroxy-5'β-dimethoxymethyl-cyclopent-1'α-yl) -hept-4-eno dissolved in 6 ml of THF The acid methyl ester-4′-tetra hydropyranyl ether solution is added to 1.26 g of mercury acetate solution dissolved in 4 ml of water diluted with 4 ml of THF. The mixture is stirred for 1.5 hours until precipitation is complete. 180 mg of sodium borohydride (dissolved in 2.5 ml of water) is added and the product is stirred for 30 minutes.

The solution is poured obliquely from the precipitate and washed with THF. The aqueous / organic gradient solution is concentrated under reduced pressure and the residue is extracted with ethyl acetate. Wash with water until neutral and remove the solvent to remove 0.98 g of 4- (7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo 3.4.0 nonane-3'ξ- (I) -butanoic acid methyl ester-8'-tetrahydropyranylether is obtained.

Example 15

The ester prepared as described in Examples 9 to 11 is reacted with a mercury salt followed by a reductive mercury desorption reaction according to the method described in Examples 13 and 14 to give the following cyclic derivatives.

All these compounds are obtained in d, l, nat- and ent-forms.

Example 16

0.27 g of pyridine and 1.2 g of 5-cis-7- (2'α, 4'α-dihydroxy-) dissolved in 5 ml of methylene chloride and 0.48 g of a clear solution dissolved in 6 ml of methylene chloride cooled to 0 ° C. To the 5'β-dimethoxymethyl-cyclopent-1'α-yl) -hapt-5-enoic acid methyl ester-4'-tetrahydropyranyl ether solution is added dropwise with stirring. After stirring is continued for 10 minutes, the organic phase is washed with 5 ml of 10% buffer solution at pH 7 in sodium thiosulfate and again with water until neutralized. After drying with Na ₂ SO ₄ , the solvent was removed to remove 1.38 g of 5-bromo-5- (6′-exo-dimethoxymethyl-7′-endo-hydroxy-2′-oxa-bicyclo (3.3.0 ) Octane-3'ξ-yl) -pentanoic acid methyl ester-7'-tetrahydropyranyl ether.

Example 17

2 g of 5-cis-7- (2'α, 4'α-dihydroxy-5'β-dimethoxymethyl-cyclopent-1'α-yl) -hept-5-enoic acid dissolved in 15 ml of carbon tetrachloride 1.24 g of N-iodine succinimide is added to a methylester-4'-tetrahydro pyranylether solution. The mixture is stirred for 3 hours and then 30 ml of ethyl ether is added. The organic phase is washed with 1NNa ₂ S ₂ O ₃ and again with water until neutral. Solvent was removed to remove 2.48 g of 5-iodo-5 '-(6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo (3.3.0) octane-3'ξ -Yl) -pentanoic acid methyl ester-7'-tetrahydropyranyl ether is obtained.

Example 18

0.78 g of 4-cis-7- (2'α, 4'α-dihydroxy-5'β-dimethoxymethyl-cyclopent-1'α-yl) -hept-4-eno dissolved in 11 ml of CCl4 To the acid methyl ester-4-tetrahydro pyranylether solution is added 422 mg of N-bromosuccinimide with stirring. After stirring for 4 hours, ethyl ether is added and the solution is washed in turn until neutralized with water, 1NNa ₂ S ₂ O ₃ and water. 0.98 g of 4-bromo-4- (7′-exo-dimethoxymethyl-8′-endo-hydroxy-2′-oxa-bicyclo (3.4.0) nonane-3′ξ-yl by evaporation to dryness ) -Butanoic acid methylester-8'-tetrahydropyranyl ether is obtained.

Example 19

346 mg of 5-cis-7- (2′α-hydroxy-5′β-benzyloxymethyl-cyclopent-1′α-yl) -hept-5 dissolved in 10 ml of CCl ₄ cooled to 0-5 ° C. Suspension of 0.25 g of anhydrous CaCO ₃ in an enoic acid methyl ester solution, and then stirred in 75 mg of chlorine solution dissolved in 3 ml of CCl ₄ and added to the suspension. After stirring for 2 hours, the inorganic salts are removed by filtration. The solution is washed with 7% aqueous solution of Kl and Na ₂ S ₂ O ₃ and then washed again with water until neutralized. The evaporated dried residue was adsorbed onto silica gel and eluted with cyclohexane: ethyl ether (80:20) to give 0.27 g of 5-chloro-5- (6'-exo-benzyloxymethyl-2'-oxa-bicyclo (3.3 .0) Octane-3'ξ-yl) -pentanoic acid methyl ester.

Example 20

0.39 g of 5-cis-7- (2'α, 4'α-dihydroxy-5'β-dimethoxymethyl-cyclopent-1'α-yl) -hept-5- dissolved in 10 ml of dichloromethane The solution of enoic acid methylester-4'-dioxanyl ether and 98 mg of pyridine is cooled to -40 ° C. 81 mg of chlorine solution in 6 ml of CH ₂ Cl ₂ is added over 30 minutes. After stirring for 10 minutes, the mixture is heated to room temperature. The organic phase is washed with 7% solution of Kl and Na ₂ S ₂ O ₃ and then again with water until neutral. 0.39 g of 5-chloro-5- (6-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo (3.3.0) octane-3'ξ-yl) by removing solvent -Pentanoic acid methyl ester-4'-dioxanyl ether is obtained.

Example 21

0.39 g of 4-cis-7- (2'α, 4'α-dihydroxy-5β-dimethoxymethyl-cyclopent-1'α-yl) -hept-4-enoic acid dissolved in 10 ml of CCl ₄ 280 mg of iodine dissolved in CCl ₄ is added to a methyl ester-4'-tetrahydro pyranyl ether and 82 mg of pyridine solution.

Continue stirring until the color disappears and add 30 ml of ether.

The organic phase is washed with water and washed again until neutralized with 7% solution of Kl and Na ₂ S ₂ O ₃ and water. 0.48 g of 4-iodine-4- (7′-exo-dimethoxy methyl-8′-endo-hydroxy-2′-oxa-bicyclo (3.4.0) nonan-3′ξ-yl by removing solvent ) -Butinoic acid ethyl ester-8'-tetrahydropyranyl ether is obtained.

Example 22

To 0.34 g of 5-cis-7- (2′α-hydroxy-5′β-benzyloxymethyl-cyclopent-1′α-yl) -hept-5-enoic acid methylester solution dissolved in 6 ml of methanol 0.325 g of a second solution of mercury acetate dissolved in water: methanol (1: 9, 6 ml) was added with stirring. The mixture is stirred for 15 minutes, reduced to 3 ml in vacuo and then added to 5 ml of a saturated solution of NaCl dissolved in water. The precipitate was extracted with methylene chloride and the organic phase was washed with water and evaporated to dryness to give 0.52 g of impure 5-chloro mercurio-5- (6'-exo-benzyloxymethyl-2'-oxa-bicyclo (3.3.0) octane- 3'ξ-yl) -pentinoic acid methyl ester is obtained.

The solution of this compound dissolved in methylene chloride (10 ml) is treated with 80 mg of pyridine solution dissolved in ₂ ml of CH ₂ Cl ₂ , followed by the dropwise addition of 150 mg Br ₂ solution dissolved in CH ₂ Cl ₂ . After stirring for 20 minutes at room temperature the organic phase is washed with 7% solution of water, Kl and Na ₂ S ₂ O ₃ and again with water until neutral. Evaporation to dryness yielded 0.34 g of 5-bromo-5- (6'-exo-benzyloxymethyl-2'-oxa-bicyclo (3.3.0) octane-3'ξ-yl) -pentanoic acid methyl ester do.

Mass spectrum M ⁺ 424,426 m / e M ⁺ -HBr 344 m / e M ⁺ -CHBr (CH ₂ ) ₃ CO ₂ CH ₃ = 231 m / e

Example 23

10.5 mg of p-toluenesulfonic acid monohydrate was charged with 0.26 g of 5-iodo-5- (6'-exo-dimethoxy methyl-7'- endo-hydroxy-2'-oxy-bicyclo (3.3. 0) Octane-3'ξ-yl) -pentanoic acid methyl ester-7'-tetrahydropyranyl ether is added, and the liquid is allowed to stand at room temperature for 30 minutes. 10 mg of pyridine is added and the solution is evaporated to dryness. The residue is treated in ethyl ether / water. After drying with Na ₂ SO ₄ , the organic phase was evaporated to give 0.23 g of impure 5-iodine-5- (6′-exo-dimethoxymethyl-7′-endo-hydroxy-2′-oxa-bicyclo (3.3.0 ) Octane-3'ξ-yl) -pentanoic acid methyl ester is obtained. Silica gel chromatography using methylene chloride: ethyl ether (75:25) as the eluent gave 84 mg of 5-iodo-5- (6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxy- Bicyclo (3.3.0) octane-3′-endo-yl) -pentanoic acid methyl ester and 55 mg of 3′-exo isomers are separated.

Since spectroanalysis is used to number prostaglandins, the diastereomers are named as follows. The endo diastereomer is 6βH-6.9α-oxide-11α-hydroxy-12β-dimethoxy-formyl acetyl-W (20 → 13) tetranor-prostanoic acid methyl ester and the exodiastereomer is 6αH-6 , 9α-oxide-11α-hydroxy-12β-dimethoxy-propyl acetyl-W (20 → 13) tetrano-leprostanoic acid methyl ester.

Analysis value:

Endoparticulate isomer: TLC more polar

Mass Spectrum (m / e;% Strength Fraction):

13C-MR (TMS internal standard at 20MHZ in C ₆ D ₆ solution) ppm 172.9, 36.5 33.1, 25.6, 41.8, 81.0, 38.1, 55.5, 83.1, 41.5, 74.2, 44.6, 108.0, 54.2, 54.1, 51.0.

Axodiastereoisomers: TLC less polar

Example 24

980 mg of 4-bromo-4- (7'-enso-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo [3.4.0] nonane -3'ξ dissolved in 6 ml of anhydrous methanol The -yl) -butinoic acid methyl ester-8'-tetrahydropyranyl ether solution is treated with 48 mg of p-toluenesulfonic acid at room temperature for 30 minutes. 2% aqueous NaHCO ₃ is added and the mixture is extracted with ethyl ether. Wash until neutral and evaporate the solvent to yield 0.68 g of impure product from the organic phase. 0.3 g of 4-bromo-4- (7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa was purified by silica gel using methylene chloride: ethyl ether (80:20) as the eluent. -Bicyclo (3.4.0) nonan-3'-exo-yl) butanoic acid methyl ester and 0.29 g of 3'-endo isomer are obtained.

Example 25

Starting with the acid prepared according to the method of Example 11, the halo annular compounds described in one of Examples 16 to 22 are carried out to prepare the following halo-enhancing compounds.

Example 26

Selective acetal leaving or silyl leaving reaction of the ether described in Example 25 was carried out according to the methods of Examples 23 and 24 to obtain 3′-oxirane-hydroxy-formyl acetal derivative, and the compound was separated into the following isomers do.

Example 27

2.8 g of 5-iodine-5- (6′-exo-dimethoxymethyl-7′-endo-hydroxy-2′-oxa-bicyclo (3.3.0) octane-3′ξ-yl) -pentanoic acid Methyl ester-7′-tetrahydropyranyl ether is treated with 2.8 g of tributyline hydride solution dissolved in 8 ml of benzene with stirring.

-일)-펜타노산 메틸 에스테르-7′-테트라하이드로피라닐 에테르를 수득한다.The mixture is left at 55 ° C. for 5 hours and then again at room temperature overnight. The benzene layer is washed with 2 x 10 ml of a 5% NaHCO ₃ solution with water until neutralized again. After evaporating the solvent, the residue was adsorbed onto 10 g of silica gel and eluted with benzene and benzene: ethyl ether (85:15) to yield 1.94 g of 5- (6'-exo-dimethoxymethyl-7'-endo-hydroxy- 2'-oxa-bicyclo (3.3.0) octane-3 '

-Yl) -pentanoic acid methyl ester-7'-tetrahydropyranyl ether is obtained.

Example 28

1.98 g of 5- (6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo (3.3.0) octane-3'ξ-yl-penta dissolved in 10 ml of anhydrous methanol 60 mg of P-toluenesulfonic acid is added to a solution of methyl acid ester-7'-tetrahydropyranyl ether, and after 30 minutes at room temperature, to 20 ml of 20% aqueous NaHCO _{3 The} mixture is extracted with ethyl ether and then ether The extract was dried over Na ₂ SO ₄ and evaporated to dryness The residue was adsorbed with 100 g of silica gel and eluted with methylene chloride: ethyl ether (94: 6) to 0.64 g of 5- (6′-exo-dimethoxymethyl- 7′-endo-hydroxy-2′-oxa-bicyclo (3.3.0) octane-3′ξ-yl) -pentanoic acid methyl ester, 0.52 g of 3′-endo isomer and 0.12 g of 3′ξ- To get work.

NMR (CDCl ₃ ) endo isomer 4.6 ppm · m, 1H, 6βH, TLC more polar; Exo isomer 4.3 ppm · m, 1H 6αH, TLC less polar; 0.32 g of 3'-endo isomer is dissolved in 0.8 ml of pyridine and treated with 0.3 ml of acetic anhydride for 8 hours at room temperature. The mixture is poured into ice / water, acidified to pH 4.2 and extracted with ethyl ether.

After washing until neutralized, the extract was evaporated to give 0.315 g of 5- (6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo (3.3.0) octane-3 ' -Exo-yl) -pentanoic acid methyl ester-7'-acetate is obtained.

Example 29

1.32 g of 4- (7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo (3.4.0) nonan-3'ξ-yl)-dissolved in 10 ml of absolute ethanol Butanoic acid methyl ester-8′-tert-butylmethylsilyl ether solution is treated with 55 mg of P-toluenesulfonic acid at room temperature for 2 hours.

0.1 ml of pyridine is added and the solvent is removed under reduced pressure and the residue is treated in water / ethyl ether. After removal of the solvent 1.1 g of impure 8'-hydroxy-3'ξ-yl derivative is obtained from the organic phase. Silica gel chromatography using benzene: ethyl ether (80:20) as the eluent to afford 4- (7'-exo-dimethoxymethyl-8'-endo-hydroxy-2'-oxa-bicyclo (3.4.0) nonane -3'-endo-yl) -butanoic acid methylester (0.42 g) and 3'-exo-yl isomer (0.34 g) are obtained.

Example 30

The ether (acetal or silyl) described in Example 15 according to Examples 28 and 29 is decomposed in methane to give the corresponding free alcohol.

Example 31

0.2 g of 5-iodo-5- (6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo (3.3 with pyridine (0.6 ml) and acetic anhydride (0.3 ml) .0) Octane-3'-endo-yl) -pentanoic acid methyl ester is acetylated to yield 0.21 g of the corresponding 7'-acetoxy derivative.

The spectro analysis for 6aH isomer acetate follows respectively. 2.03 3.34 3.38, 3.66stm 4H CO ₂ CH ₃ and one of C ₅ , C ₉ 4.1m 1H, the other of C ₅ , C _{9 both} 4.2, 4.4m, 1H, 6αH, 5.1).

A 5-iodo-3'-endo-acetate solution dissolved in benzene (5 ml) was treated with 0.4 g tributyltin hydride at 50 ° C. for 10 hours. The benzene phase was washed with 5% NaHCO ₃ and water, the solvent was evaporated, and then purified with silica gel (10 g) using benzene: ethyl ether (80:20) as the eluent to prepare samples and all dots according to the method of Example 28. 0.105 g of 5- (6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo (3.3.0) octane-3'-endo-yl) -pentanoic acid methyl Obtain ester 7'-acetate.

Example 32

One of the halo-derivatives synthesized in Examples 16-26 following the procedure of Examples 27 and 31 is reduced with tributyltin hydride to yield the corresponding derivatives substituted for hydrogen in halogen. This compound is identical in several respects to the compound prepared according to the methods of Examples 15, 28, 29 and 30.

Example 33

4 g of 5- (6'-exo-dimethoxymethyl-7'-endo-hydroxy-2'-oxa-r in which 5.4 mg of hydroquinone and 1.63 g of oxalic acid solution dissolved in 48 ml of water were dissolved in 180 ml of acetone. To cyclo (3.3.0) octane-3′ξ-yl) -pentanoic acid methyl ester solution. After 12 hours at 40 ° C., acetone is removed under immersion and the mixture is extracted with ethyl acetate (3 × 25 ml). The organic extract is washed with 10% ammonium sulfate solution until neutralized and dried over Na ₂ SO ₄ . 3.21 g of 5- (6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo (3.3.0) octane-3'ξ-yl) -pentanoic acid methyl Obtain an ester. 6'-exo-formyl-6'-endo and 6'-exo-formyl-3'-exo derivatives are prepared from the corresponding respective isomers.

Example 34

The corresponding bicyclo (3.3.0) octane-6'-exo-dimethoxymethyl and bicyclo (3.4.0) nonane-7'-exo-dimethoxymethyl derivatives were treated according to the method of Example 33 to Compounds are prepared as 3′-exo and 3′-endo or 3′ξ isomers.

Example 35

Methanol: 1.2 g of 5- (6'-exo-benzyloxymethyl-2'-oxa-bicyclo (3.3.0) octane-3'ξ-yl) -pentanoic acid methyl dissolved in methyl acetate (10 ml: 10 ml) To the ester solution is added 2 ml of a 0.1 N methanol solution of HCl.

After addition of 0.15 g of PtO ₂ , the mixture is reacted with hydrogen until 1 molar equivalent of hydrogen is adsorbed at room temperature and room pressure. The gas is removed under vacuum, washed with nitrogen and the suspension is filtered, neutralized and evaporated to dryness. The residue was treated in water / ethyl acetate to give 0.84 g of 5- (6′-exo-hydroxymethyl-2′-oxa-bicyclo [3.3.0] octane-3′ξ-yl) -pentanoic acid from the organic acid. Obtain methyl ester.

The 6'-exo-propyl derivative is oxidized by the method of Example 1 using dicyclo hexylcarbodiimide dissolved in DMSO: benzene (25:75).

Example 36

18.1 g of 5β-tetrahydro pyranyloxymethyl-2α, 4α-dihydroxy-cyclopent-1α-acetic acid-γ-lactone-4-tetrahydropyranyl ether solution dissolved in 150 ml of toluene cooled to -70 ° C Add 128 ml of a 5 M solution of di-iso-butyl aluminum hydride (1.2 M / M) in 30 minutes. After 30 minutes at −70 ° C., 128 ml of a 2M toluene solution of isopropanol is added and the solution is kept at 0 ° C.

10 ml of saturated aqueous solution of NaH ₂ PO ₄ is added and stirred for 4 hours. After addition of 10 g of anhydrous Na ₂ SO ₄ and 10 g of filtration, the solution was filtered and evaporated to dryness and 18.1 g of 5β-tetrahydropyranyloxymethyl-2α, 4α-dihydroxy-cyclopent-1α-ethaneal-γ -Lactone-4-tetrahydropyranyl ether is obtained. A solution of this compound dissolved in 24 ml of anhydrous DMSO is added dropwise to an illide solution prepared as follows:

9.6 g of 80% sodium hydride solution dissolved in 300 ml of DMSO is heated at 60 ° C. for 4 hours.

The mixture is transferred to 18-20 [deg.] C. and then 67 g of 4-carboxybutyltriphenyl phosphonium bromide dissolved in 80 ml of anhydrous DMSO is added while maintaining a temperature of 20-22 [deg.] C. to give a bright red color. After stirring for 4 hours, 600 ml of water was added, followed by extraction with ethyl ether: benzene (70:30) to remove triphenylphosphine oxide. The benzene organic phase is reextracted with 0.1N NaOH and extracted again with water until neutralized and then discarded.

The aqueous alkali solution phase was acidified to pH 5 to 4.8 and then extracted with ethyl ether: pentane (1: 1) and treated with diazo methane in ether to easily convert to 21.6 g of 5-cis-7- (2α ′). , 4α'-Dihydroxy-5'β-tetrahydropyranyloxymethyl-cyclopent-1α-yl) -hept-5-enoic acid-4'-tetrahydropyranyl ether is obtained.

7.72 g of this ester dissolved in 28 ml of tetrahydrofuran are added dropwise to a tan suspension formed by adding 28 ml of THF to a solution of 6.13 mercury acetate dissolved in 28 ml of water. The mixture is stirred at room temperature for 20 minutes, then cooled in an ice water bath and 810 mg of NaBH ₄ dissolved in 14 ml of water is added dropwise. Elemental mercury is allowed to settle, the suspension is decanted and the tetrahydrofuran is evaporated under reduced pressure and the residue is extracted with ethyl ether. Remove the solvent to remove 7.5 g of 5- (6'-exo-tetrahydro pyranyloxymethyl-7'-hydroxy-2'-oxa-bicyclo (3.3.0) octane-3'ξ-yl) -penta No acid methyl ester-7′-tetrahydropyranyl ether is obtained. 0.42 g of P-toluenesulfonic acid is added to a solution of this compound dissolved in 30 ml of methanol. After 2 hours at room temperature it is concentrated in vacuo and added to water.

Extraction with ether, followed by silica gel chromatography on ethyl ether as eluent, 2.4g of 5- (6'-exo-hydroxymethyl-7'-hydroxy-2'-oxa-bicyclo [3.3.0] octane- 3'-exo-yl) -pentanoic acid methyl ester and 2.6 g of 3'-endo isomer are obtained.

Example 37

4.26 g of 5-cis-7-) 2′α, 4′α-dihydroxy-5′β-tetrahydropyranyloxymethyl-cyclopent-dissolved in CH ₂ Cl ₂ : CCl ₄ (10ml: 10ml) 2.5 g of N-iodosuccinimide was added to a 1'α-yl) -hept-5-enoic acid-4'-tetrahydropyranylether solution, followed by stirring for 4 hours. 30 ml of anhydrous methanol containing 130 mg of P-toluenesulfonic acid are added and stirring is continued for 2 hours. 0.2 ml of pyridine is added and the volume of the mixture is reduced and the residue is treated in water / ethyl acetate.

After washing with Na ₂ S ₂ O ₃ , washed again with water until neutralized, the organic phase was evaporated to dryness, adsorbed with silica gel and eluted with ethyl ether, 2.2 g of 5-iodo-5- (6′-exo-hydride). Obtain oxymethyl-7'-hydroxy-2'-oxa-bicyclo (3.3.0) octane-3'-exo-yl) -pentanoic acid methyl ester and 1.8.85 g of 3'-endo isomer.

Example 38

5-bromo-5- (6'-exo-hydroxymethyl-7'- according to the procedure of Example 37 using methyl ester, N-iodosuccinimide vs. N-synbromoacetamide instead of an acid Prepare hydroxy-2'-oxa-bicyclo (3.3.0) octane-3'-yl) -pentanoic acid methyl ester. Silicagel chromatography separates the 3'-exo and 3'-endo-isomers.

Example 39

0.86 g of pyridine and 2.2 g of 5-cis-7- (2'α, 4'α-dihydroxy-5'β-tetrahydropyranyloxymethyl-cyclopent-1 'dissolved in dichloromethane (20 ml) 0.38 g of chlorine dissolved in 10 ml of CCl ₄ : CH ₂ Cl ₂ (1: 1) after cooling the solution of α-yl) -hept-5-enoic acid methyl ester-4′-tetrahydro pyranyl ether to 30 ° C. Add. The mixture is stirred for 2 hours, warmed to room temperature, washed with 2N H ₂ SO ₄ , and washed again until neutralized with water. After evaporation of the solvent, the residue is treated with 0.1 g of P-toluenesulfonic acid, which is dissolved in methanol (10 ml). The solution is concentrated, diluted with water and extracted with ethyl acetate. The solvent was removed and the residue was purified by silica gel, followed by 0.6 g of 5-chloro-5- (6'-exo-hydroxymethyl-7'-endo-hydroxy-2'-oxy-bicyclo (3.3.0) Octane-3′-exo-yl) -pentanoic acid and 0.71 g of 3′-endo isomer are obtained.

Example 40

4.8 ml of benzene: 0.356 g of 5-iodo-5- (6'-exo-hydroxymethyl-7'-endo-hydroxy-2'-oxa-bicyclo (3.3 dissolved in DMSO (75:25)) 0.20 g of dicyclohexyl carbodiimide and 0.4 ml of pyridinium trifluoro acetate solution (see Example 1) are added in turn to .0) octane-3′-exo-yl) -pentanoic acid methyl ester solution.

After stirring for 3 hours, 8 ml of benzene and aqueous oxalic acid (94 mg in 1.2 ml) were added sequentially. The precipitate is removed by filtration and the benzene solution is washed with water until neutral. Remove solvent to remove 0.32 g of 5-iodine-5- (6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo [3.3.0] octane-3'-exo-yl ) -Pentanoic acid methyl ester is obtained.

Example 41

The 6'-exo-hydroxymethyl-7'-endo-hydroxy derivatives prepared according to Examples 36 to 39 were oxidized by the method of Example 40 to prepare the corresponding 6'-exo-formyl derivatives.

Example 42

A 3.4 g (2-oxo-heptyl) dimethoxyphosphonate solution dissolved in 50 ml of dimethoxyethane was added to a suspension of 0.45 g of 80% NaH (inorganic oil dispersion). 2.7 g of 5- (6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo (3.3.0) octane-3 dissolved in 40 ml of dimethoxyethane after stirring for 1 hour '-Al) -pentanoic acid methyl ester solution is added and diluted with 50 ml of a 30% aqueous solution of monobasic sodium phosphate in 10 minutes. The organic phase is separated, the aqueous phase is extracted again, and the organic extract is evaporated. Purify the impure product with 50 g of silica gel (cyclohexane: ethyl ether, 50:50) to give 1.1 g of 5- (6′-exo- (3 ″ -oxo-oct-1 ″ -trans-en-1 ″ -yl ) -7′-endo-hydroxy-2′-oxa-bicyclo (3.3.0) octane-3′-endo-yl) -pentanoic acid methyl ester or 13t-6βH-6 (9α) -oxide-11α -Hydroxy-15-oxo-frost-13-enoic acid methyl ester and 0.98 g of 5- (6′-exo- (3 ″ -oxo-oct-1 ″ -trans-ene-1 ″ -yl) -7 ′ -Endo-hydroxy-2′-oxa-bicyclo (3.3.0) octane-3′-exo-yl) -pentanoic acid-methyl ester or 13t-6αH-6 (9α) -oxide-11α-hydro Roxy-15-oxo- frost-13-enoic acid methyl ester is obtained 0.9 g of a 1: 1 mixture of two isomers (3'-exo and 3'-endo or 6αH and 6βH). The mixture is separated by thin layer chromatography with ethyl ether to separate two isomeric compositions.

Each of the following absorption values is shown.

=230mμ, ε=13,070 :

=228mμ, ε=12,200

= 230 mμ, ε = 13,070:

= 228 mμ, ε = 12,200

NMR (CDCl ₃ ) 0.9t 3 H C ₂₀ CH ₃ 3.68 S, 3H CO ₂ CH ₃ , 6.16

vinyl quantum in d1H C ₁₄ (J _H14 —H ₁₅ 16 Hz);

6.71q 1H C ₁₃ in vinyl quantum (J _H13 9Hz),

The same method is used to prepare the following prostenoic acid derivatives from the corresponding 5-H and 5-halo compounds;

Example 43

=220mμ, ε=11,600에서 흡수를 나타내었다.A solution of 2.16 (2-oxo-octyl) dimethylphosphonate dissolved in 20 ml of benzene in 292 mg of NaH (75% inorganic oil dispersion) dissolved in 30 ml of benzene was added dropwise. 2.6 g of 4-bromo-4- (7'-exo-formyl-3'-endo-hydroxy-2'-oxa-bicyclo [3.4.0] nonane dissolved in 20 ml of benzene after stirring for 30 minutes -3'-yl) -butanoic acid methyl ester solution is added dropwise. After stirring for 30 minutes ₂₄ ml of a 30% aqueous solution of NaH ₂ PO ₄ are added. The organic phase is separated and the aqueous phase is extracted with benzene and evaporated to dryness. The residue was purified by silica gel (50 g) using CH ₂ Cl ₂ : ethyl ether (120: 40) as the eluent to obtain 0.52 g of 4-brobo-4- (7′-exo- (3 ″ -oxo-oct-1 ″ -Trans-1 ″ -enyl) -8′-endo-hydroxy-2′-oxa-bicyclo [3.4.0] nonane-3′-endo-yl) butanoic acid methyl ester or 13-trans-4- Bromo-5βH-5 (9α) -oxide-11α-hydroxy-15-oxa-trost-13-enoic acid methyl ester and 1.45 g of 4-brobo-4- (7′-exo- (3 ″ -Oxo-oct-1 ″ -trans-1 ″ -enyl) -8′-endo-hydroxy-2′-oxa-bicyclo (3.4.0) nonan-3′-endo-yl) butanoic acid methyl ester Or 13-trans-4-bromo-5αH-59α) -oxide-11α-hydroxy-15-oxo-frost-13-enoic acid methyl ester. The methanol solution of these two compounds was analyzed by UV and lambda methanol = 230 mμ, ε = 10,640 and

Absorption was shown at = 220 mμ and ε = 11,600.

The 4-H and 4-hal bacyclo derivatives are treated in the same process to give the following prosenoic acid.

Example 44

74 mg of NaOH (75%) and 0.43 g of 5- (6 ′) dissolved in 620 mg (2-oxo-3-methyl-4-butoxybut) ylphosphonate in dimethoxymethane according to the method of Example 42 Ethyl ether: hexane (1: 1) after reaction with exo-formyl-7'-endo-hydroxy-2'-oxy-bicyclo (3.3.0) octane-3ξ-yl) -pentanoic acid methyl ester Was chromatographed with silica gel (25 g) as eluent, and 0.15 g of 13t-6αH-6 (9α) -oxide-11-hydroxy-15-oxo-16-methyl-16-butoxy-18,19,20 Trinor-frost-13-enoic acid methyl ester (λ max = 228 mμ, ε = 14,500) and 300 mg of 6βH-isomer (λ max = 227 mμ, ε = 12,280) are obtained.

Scalpel spectrum: m / e 410M m / e 392M-H ₂ O; m / e 379 M ⁺ -OCH ₃ ; m / e 295 M ⁺ -115, m / e 115

The two isomers have a similar spectra with minimal differences on secondary cleavage.

In the same procedure, 5-chloro, 5-bromo and 5-iodo-13t06ξH-6 (9α) -oxide-11α-hydroxy-15-oxo-16-methyl-16-butoxy-18,19, Obtain 20-trinor- frost-13-enoic acid methyl ester.

5Cl mass spectrum: M ⁺ 446/444, 428/426, 391, 276

5Br Mess Spectrum: M ⁺ 490/488, 472/470, 391, 276

5I Mess Spectrum: M ⁺ 536, 518, 391, 276

Example 45

Methyl 4- (7'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo (3.4.0) nonan-3'ξ-yl) -butanoic acid according to the method of example 44 The following compounds are obtained from esters and 4-iodobicyclo acid derivatives.

Example 46

45 mg of 805 N mother suspension dissolved in 10 ml of benzene was added 375 mg of (2-oxo-3,3-dimethyl-heptyl) -dimethyl phosphonate solution dissolved in 10 ml of benzene, followed by 0.305 g of 5-iodo A solution of -5- (6'-exo-formyl-2'-oxa-bicyclo (3.3.0) octane-3ξ-yl) -pentanoic acid methyl ester is added. After stirring for 45 minutes the mixture is diluted with 10% aqueous NaH ₂ PO ₄ . The organic phase is washed until neutral, dried and concentrated down to reduced volume.

Absorbed with silica gel and eluted with cyclohexane: ethyl ether (90:10), 0.12 g of 13t-5-iodo-6βH-6 (9α) -oxide-15-oxo-16,16-dimethyl-frost-13 -Enoic acid methyl ester (M ⁺ 504, M ⁺ -OCH ₃ 473, M ⁺ -99 405) and 0.095 g of 13t-5-iodo-5αH-6 (9α) -oxide-15-oxo-16, 61-dimethyl-13-enoic acid methyl ester (M ⁺ 504, M ⁺ -OCH ₃ 473, M ⁺ -99 405) is obtained.

Example 47

The following 16,61-dimethyl derivative was prepared by substituting the formyl derivative prepared according to Example 34 in the course of Example 46.

Example 48

1.55 g of (2-oxo-3 (S, R) | fluoro-4-cyclohexyl-butyl) -dimethylforce dissolved in 10 ml of anhydrous benzene in 178 mg of NaH (75% inorganic oil dispersion) dissolved in 15 ml of benzene The phonate solution is added dropwise. After stirring for 30 minutes 1 g of 5- (6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo (3.3.0) octane-3'ξ-yl) -pentanoic acid methyl Ester solution is added and stirring is continued for 1 hour. The mixture is neutralized with 30% aqueous NaH ₂ PO ₄ , the organic phase is separated, concentrated and adsorbed with silica gel.

=238mμ, ε=12,765) 및 0.31g의 6βH 이성질체 (

=238mμ, ε=9,870)를 수득한다.CH ₂ Cl ₂ : Et ₂ O (90:10) eluted with 0.62 g of 13t-6αH-6 (9α) -oxide-11α-hydroxy-15-oxo-16 (S, R) -fluoro- 17-cyclohexyl-18,19,20-trinov-frost-13-enoic acid methyl ester (

= 238 mμ, ε = 12,765) and 0.31 g of 6βH isomer (

= 238 mμ, epsilon = 9,870).

The NMR values for the former compounds are described below. (CDCl ₃ ) ppm 3.46 s 3H CO ₂ CH ₃ , 3.8m 1H C ₉ proton, 4.03q 1H C ₁₁ proton, 4.3m 1H 6αH ,, 5.00 and 5.55t, t 1 / 2H, 1 / 2H C ₁₆ proton J _HF 55 Hz 6.5 4q 1H C ₁₄ Proton 6.9q 1H C ₁₃ Proton J _H14 -H ₁₂ 3.5Hz, J _H13 H ₁₂ 7.5Hz, J _H13 -H ₁₄ 15.5Hz, The compound was treated with pyridine and acetic anhydride. Convert to 11α-acetoxy derivatives.

NMR values of 11α-acetoxy derivative (CHCl ₃ ) ppm 2.02s 3H OCOCH ₃ , 3.64s 3H CO ₂ CH ₃ , quantum of 3.8C ₉ 4.25m 1H: 6αH 4.66, 5.22t, t 1 / 2H, 1 / 2H Proton of C ₁₆ ; 4.97q 1H C ₁₁ protons; 6.51 C ₁₄ proton 6.90C ₁₃ proton;

The mass spectrum for the diastereomer of hydroxy ketone shows the following masses.

M ⁺ 424 m / e and M ⁺ -H ₂ O, M ⁺ HF, M ⁺ -CH ₃ OH / CH ₂ O, M ⁺ -CH ₂ = CHOH (basic ion) M ⁺ -115M ⁺ -44-59 and M ⁺ -(CHF-CH ₂ -C ₆ H ₁₁ ). The following masses in the mass spectrum of exo-diastereomers are particularly significant. The salient values in M ⁺ -CH ₃ OH and M ⁺ -44-28 endo-diastereomers are M ⁺ -CH ₃ O and M ⁺ -44-18s.

5-bromo, 13t-5-bromo6βH-6 (9α) -oxide 11-α-hydroxy-15-oxo-16 (S, R) -fluoro-17-cyclohexyl-18 from derivatives, Prepare 19,20-trinor-frost-13-enoic acid methyl ester.

=235mμ, ε=12,900

= 235mμ, ε = 12,900

=235mμ, ε=12,900

= 235mμ, ε = 12,900

Example 49

In the course of Example 48, a phosphonate selected from (2-oxo-4-cyclohexyl-butyl) -dimethylphosphonate and (2-oxo-4-phenyl-butyl) -dimethylphosphonate was substituted to Prepare the compound.

13t-6βH-6 (9α) -oxide-11α-hydroxy-15-oxo-17-cyclohexyl-18,19,20-trinor-frost-13-enoic acid methyl ester, lambda max 223 mμ, ε = 9,780

13t-6βH-6 (9α) -oxide-11α-hydroxy-15-oxo-17-phenyl-18,19,20-trinor-frost-13-enoic acid methylester, λ max 238 mM, ε = 9,950 and 6αH isomer, λmax 230mμ, ε = 11,950.

Example 50

1.63 g of 2-oxo-3- (m-chlorophenoxy) -propyl-dimethylphosphonate solution dissolved in 10 ml of anhydrous THF was dissolved in 178 mg of NaH (75% inorganic oil dispersion) solution dissolved in anhydrous tetrahydrofuran. It is added dropwise with stirring at ℃.

=227 mμ, ε=16,800) 및 0.11g의 6βH 이성질체(λmax=224mμ, ε=16,900)를 수득한다. 양부분입체 이성질체는 C₂₃H₂₉ClO₆과 동일한 중량 피크 m/e436을 나타낸다. 이러한 이온은 다음의 분열에 포함된다.After stirring for 30 minutes, 1 g of 5- (6'-exo-formyl-7'-endo-2'-oxa-bicyclo (3.3.0) octane-3'ξ-yl) -pentanoic acid methyl ester was added thereto. Continue stirring for an hour. The mixture is acidified with aqueous NaH ₂ PO ₄ , the organic phase is separated and the aqueous phase is reextracted with benzene. Chromatography with silica gel using CH ₂ Cl ₂ : Et ₂ O (95: 5) as eluent from organic extracts gave 0.43 g of 13t-6αH-6 (9α) -oxide-11α-hydroxy-15-oxo-16. -m-chlorophenoxy-17,18,19,20-tetranor-frost-13-enoic acid methyl ester (

= 227 mμ, epsilon = 16,800 and 0.11 g of 6βH isomer (λmax = 224mμ, epsilon = 16,900). Distereoisomers show the same weight peak m / e436 as C ₂₃ H ₂₉ ClO ₆ . These ions are included in the following cleavage.

M ⁺ -H ₂ O, M ⁺ -OCH ₃ / CH ₃ OH, M ⁺ -44, M ⁺ -(0-C ₆ H ₄ Cl), M ⁺ -H ₂ O- (OC ₆ H ₄ Cl) and M ⁺ -(CH ₂ ) ₄ -CO ₂ CH ₃ .

There are differences between the two diastereomers: Exo 6αH isomers show peaks at M ⁺ −32 and small peaks appear at M ⁺ −44. Endo 6βH isomers show peaks at M ⁺ -31 and strong peaks at M ⁺ -44.

Example 51

2-oxo-3 (m-trifluoro methylphenoxy) -propyl-dimethylphosphonate and 2-oxo-3- (P-fluorophenoxy) -propyl-dimethylphosphonate in the course of Example 50 Substitution of the phosphonate selected from the following yields the following compounds, respectively.

13t-6βH-6 (9α) -oxide-11α-hydroxy-15-oxo-16m-trifluoromethylphenoxy-17,18,19,20-tetranor- frost-13-enoic acid methyl ester,

13t-6βH-6 (9α) -oxide-11α-hydroxy-15-oxo-16-P-fluorophenoxy-17,18,19,20-tetranor-frost-13-enoic acid methyl ester and 6αH isomer.

Mass spectra of all compounds provide a structure indicating that the mass peak is M ⁺ -115.

The difference between the endo- and exo-trifluoromethyl analogs is that the mass peak, M ⁺ -CH ₃ OH and M ⁺ -CF ₃ -C ₆ H ₄ -OH, is in the exo-isomer and M ⁺ -CH ₃ O And the mass peak, M ⁺ -CF ₃ -C ₆ H ₄ -O, is in the endo-isomer.

Example 52

=229mμ, ε=12,050)을 수득한다.Replace phosphonate with (2-oxo-3s-methyl-butyl) -dimethyl phosphonate in the procedure of Example 48 to convert 13t-6βH-6 (9α) -oxide-11-α-hydroxy-15- Obtain oxo-16s-methyl- frost-13-enoic acid methyl ester and its 6αH isomer. 1.05 ml of acetic anhydride is added to a solution of 2.2 g of 6βH isomer dissolved in 2.6 ml of pyridine cooled to 0 ° C. The solution is left at 0 ° C. overnight and then added to excess cooled 0.05N sulfuric acid. Extracted with ethyl ether and evaporated to dryness, 2.3 g of 13t-6βH-6 (9α) -oxide-11α-hydroxy-15-oxo-16s-methyl-frost-13-enoic acid methyl ester-11-acetate (

= 229 mμ, ε = 12,050).

=249mμ, ε=11,450875 mg of dissolved in glacial acetic acid was added dropwise until the latter compound solution dissolved in 10 ml of glacial acetic acid appeared bright orange. 1.52 g of anhydrous potassium carbonate is added and the mixture is left at 80 ° C. for 4-5 hours to complete the precipitation of potassium embrittlement. Excess acetic acid is removed under vacuum, water is added and pH is adjusted to pH 6.3 with alkali hydrate. Extract with ethyl ether and reduce the volume of organic phase. Absorbed with silica gel and eluted with methylene chloride: ethyl ether (70:30) to give 2.01 g of 13t-6β-6 (9α) -oxide-11α-hydroxy-14-bromo-15-oxo-16s-methyl- Frost-13-enoic acid methyl ester-11-acetate is obtained.

= 249 mμ, ε = 11,450

6αH isomers are similarly prepared.

Example 53

To a suspension of 0.265 g of NaH (80% inorganic oil dispersion) dissolved in DME (10 ml) was added dropwise a solution of 2.06 g of (2-oxo-3s-methylheptyl) -dimethylphosphate dissolved in 20 ml of dimethoxy ethane. After stirring for 30 minutes, 1.6 g of N-bromosuccinimide is added and stirred vigorously for 10 minutes. 1.35 g of 5- (6′-exo-formyl-7′-endo-hydroxy-2′-oxa-bicyclo [3.3.0] octane-3′ξ-yl)-dissolved in 5 ml of dimethoxyethane Pentanoic acid methyl ester is added.

The mixture is stirred for 1 hour and then 20 ml of 30% NaH ₂ PO ₄ is added. After treatment, impure 14-bromo enone is obtained. Methylene chloride: 0.5 g of 13t-6βH-6 (9α) -oxide-11α-hydroxy-14-bromo-15-oxo-16s-methyl- separated by silica gel eluting with ethyl ether (85:15) Frost-13-enoic acid methyl ester and 0.92 g of 6αH isomer are obtained. Treatment with 0.4 ml of pyridine and 0.2 ml of acetic anhydride yields 0.205, an 11-acetoxy derivative identical in all respects with the compound produced according to the method of Example 52 from 0.2 g of 6βH isomer.

Example 54

To 54 mg of NaH (30% inorganic oil dispersion) dissolved in 5 ml of benzene, 0.43 g of (2-oxo-octyl) -dimethylphosphonate solution dissolved in 10 ml of benzene was added dropwise. When the release of H ₂ has stopped after 1 hour, 0.32 g of N-bromo-succinimide is added simultaneously. 270 mg of 5- (6'-exo-formyl-7'-endo-hydrol dissolved in 8 ml of benzene in carbanion of (1-bromo-2-oxo-octyl) -dimethyl phosphonate prepared above Add oxy-2'-oxy-bicyclo [3.3.0] octane-3'ξ-yl) -pentanoic acid methyl ester solution.

=245mμ, ε=13,500)를 수득하고 다시 6αH 및 6βH로 분리한다.After 30 minutes 20 ml of a 10% solution of NaH ₂ PO ₄ is added to cool the reaction. After washing until neutralized, 0.31 g of 13t-6ξH-6 (9α) -oxide-11a-hydroxy-14-bromo-15-oxo-20-methyl-frost-13-enemethyl ester(

= 245 mμ, epsilon = 13,500) and again separated into 6αH and 6βH.

Example 55

(2-oxo-octyl) -dimethyl phosphonate in the course of Example 54 was converted to (2-oxo-4-cyclohexyl-butyl) -dimethyl phosphonate and (2-oxo-4-phenyl-butyl) -dimethyl Substitution with phosphonate affords the following compounds.

Example 56

The formyl derivatives in Examples 53,54 and 55 were substituted with 5-iodo-5- (6′-exo-formyl-7′-endo-hydroxy-2′-oxa-bicyclo (3.3.0) octane- 3'ξ-yl) -pentanoic acid methyl ester, 4-iodo-4- (7'-exo-formyl-8'-endo-hydroxy-2'-oxa-bicyclo (3.4.0) nonane- Substituted with 3'ξ-yl) butanoic acid methyl ester, and the corresponding 4H derivative, the following compounds are obtained.

Example 57

To 0.15 g of potassium t-butylate solution dissolved in 3 ml of DMSO, 0.61 g of 2-oxo-octyl-triphenylphosphonium bromide solution dissolved in 6 ml of DMSO is added while maintaining the reaction temperature at 16 to 19 ° C. 0.27 g of 5- (6'-exo-formyl-7'-endo-hydroxy-2'-oxa-bicyclo [3.3.0] octane-3'ξ-yl) dissolved in 8 ml of anhydrous tetrahydrofuran -Pentanoic acid methyl ester is added.

After stirring for 30 minutes, an equal amount of water is added and the mixture is extracted with ethyl ether. The organic extract is washed until neutralized and the solvent is evaporated. Chromatography with silica gel (cyclohexane: ethyl ether, 40:60) yields 0.21 g of 13t-6ξH-6 (9α) -oxide-11α-hydroxy-15-oxo-20-methyl-frost-13-enoic acid. Methyl ester (M ⁺ 380, M ⁺ -H ₂ O 362, M ⁺ -OCH ₃ 349, M ⁺ -44 336, M ⁺ -C ₆ H ₁₃ 295) is obtained. Subsequent thin layer chromatography (SiO ₂ -Et ₂ O) separates the 6αH and 6βH isomers.

Example 58

D, 1-13t-6αH-6 (9α) -oxide-11a-hydroxy-15-oxo-13-enoic acid decyl ester (exoisomer having a maximum Rf value), dissolved in anhydrous ethyl ether (30 ml), (0.9 g) The solution is added dropwise to a 0.1 M solution of anhydrous ethyl ether (30 ml) with stirring for at least 15 minutes. After 2 hours, excess NaCl solution and aqueous 2N sulfuric acid are carefully added to decompose the excess reagent. The organic phase was separated, washed until neutralized, evaporated to dryness, adsorbed onto silica gel, eluted with ethyl ether, and 0.38 g of 13t-6αH-6 (α) -oxide 11α, 15R-dihydroxy-prosenoic acid. 0.42 g of d, 1-13α-6αH- (6 (9α) -oxide-11a-15s-dihydroxy-prostenoic acid methyl ester having a methyl ester in the oil phase and a melting point of 69 to 71 ° C (mass spectrum m / e 350 M ⁺ -18, 319 M ⁺ -18-CH ₃ O: 318M ⁺ -18-CH ₃ OH).

The solution of this ester in methanol (4 ml) is treated with 60 ml of lithium hydroxide and water (0.8 ml) for 8 hours at room temperature. After methanol is removed in vacuo, the residue is diluted with water and extracted with ethyl ester to remove neutral impurities. The alkaline phase is treated with an aqueous saturated solution of NaH ₂ PO ₄ until pH 5 and extracted with ethyl ether. The later organics were collected and the solvent was evaporated, followed by free acid, d, 1-13t-6αH-6 (9α) -oxide-11α, 15,15s-dihydroxy-prostenoic acid (melting point 105-106 ° C.). To obtain.

The 15R-hydroxy compound is an amorphous oil. In the same way, the nat-kero compound was reduced to Zn (BH ₄ ) ₂ to reduce melting point from 71 to 72 ° C. (α) _D = + 10.2 °, (α) ₃₆₅ ° = + 32.2 °, (CHCl ₃ ) nat-13t-6αH-6 (9α) -oxide-11α, 15s-dihydroxy-prostenoic acid methyl ester, melting point 101-102 ° C, (α) _D = 6.34 after saponification reaction °, (a) ₃₆₅ ° = + 33.2 ° (CHCl ₃ ) to give a free acid.

Starting from the endo-diastereomer (the more polar compound) the following ester, 13t-6βH-6 (9α) -oxide-11α, 15R-dihydroxy-prostenoic acid methyl ester (d, 1, mat- , ent-yu), 13t-6βH-6 (9α) -oxide-11α, 15S-dihydroxy-prostenoic acid methyl ester (d, 1, nat- [α] _D = + 24.5 °, [α] ₃₆₅ ° = + 52.9 °, (CHCl ₃ ), [α] _D = -22 °, following free acid after oil and saponification reaction, 13t-6βH-6 (9α) -oxide-11α, 15R-dihydrate Roxy-prostenoic acid (d, l, nat, ent- oil), 13t-6βH-6 (9α) -oxide-11α, 15R-dihydroxy-prostenoic acid (d, 1 oil, nat-, melting point 78 to 80 ° C), (α) _D = + 32.5 °, (α) 365 ° = + 11.6 °, (EtOH), ent-, melting point 78 to 79 ° C, (α) D = -31 ° (EtOH) To obtain.

The following experimental example is mentioned as a manufacturing method of the similar compound of a present Example.

Analogous Compound I

0.35 g of mercury acetate solution dissolved in methanol was stirred at room temperature with 0.54 g of 5C, 13t, -9α, 11α, 15S-trihydroxy-prosta dietenoic acid methyl ester-11,15-bis-THF ether (PGF ₂ α-bis-THF-ether-methyl ester). After further stirring for 15 minutes, 50 mg of sodium borohydride is added in portions. The mercury element generated is filtered off and methanol is evaporated under reduced pressure. The residue was partitioned between dichloromethane / water, washed with sodium bicarbonate and washed with water until neutralized, then the organic phase was evaporated to give 0.51 g of impure 13t-11α, 15S-dihydroxy-6ξH-6 (9α) -jade Seed-prostenoic acid methyl ester-11,15-bis-THP-ether is obtained. A solution of this compound dissolved in 10 ml of acetone is added to 8 ml of 0.2 N oxalic acid and then heated at 40-45 ° C. for 6 hours.

After removing acetone under vacuum, the aqueous suspension is extracted with ethyl acetate (3 x 15 ml). The organic phase is washed until neutralized and evaporated to dryness. The residue (about 0.45 g) was adsorbed onto silica gel (50 g), eluted with ethyl ether, and 20 ml of fractions were collected. From 13 to 11 fractions 13t-11α, 15S-dihydroxy-6αH-6 (9α) -oxide-prostenoic acid methyl ester (0.11 g, melting point 67-69 ° C.) is prepared. A mixture of diastereomers with 5 to 10 ethyl acetate was added to ethyl ether followed by 13t-11t-11α, 15S-dihydroxy-6βH-6 (9α) -oxide-prostenoic acid-methyl ester (0.16 g; Collect [α] _D = + 19.62 ° (CHCl ₃ ) The latter sample compound is determined by melting from 40 to 41 ° C. [α] _D = 25.2 °, [α] ₃₆₅ ° = 83.8 °, (CHCl ₃ ). Impure free acid indicates that [α] _D = + 18.3 ° (EtOH) The sample is crystallized from pental-ethyl ether, melting point 80 to 81 ° C., [α] _D = + 32.5 °, (α) ₃₆₅ ° = 111.6 Obtain 13t-6βH-6 (9α) -oxide-11α, 15S-dihydroxy-frost-13-enoic acid as pure crystals in degrees (EtOH) The mass spectrum of the compound shows the following peaks. (m / e, intensity, structure) 336 7% [MH ₂ O] ⁺ , 318 3% [M-2H ₂ O] ⁺ 292 100% [MH ₂ O-44] ⁺ , 264 30% [MH ₂ O- CH ₂ CHCO ₂ H] ⁺ 235 4% [MH ₂ O— (CH ₂ ) ₄ CO ₂ H].

The mass spectrum of the 6αH-diastereomer is similar.

Similar Compound 2

1. 5ml of water is dissolved in 0.3g of THF /3.0ml of 01.9g was dissolved in 2.5ml of THF to mercury acetate 5C, 13t-9α, 11α, 15S- trihydroxy-15-methyl-α- -PGF ₂ methyl ester Add solution.

After stirring for 30 minutes, 60 mg of sodium borohydride dissolved in 1.2 ml of water is added to a dark yellow suspension.

After mercury is separated, THF is removed under vacuum and the aqueous suspension is repeatedly extracted with ethyl acetate.

Washed until neutralized and evaporated to dryness to yield 0.16 g of product from organic phase and purified by thin layer chromatography to 0.04 g of 13t-11α, 15S-dihydroxy-6αH6 (9α) -oxide-15-methyl- Obtain PGF ₂ α-methyl ester ([α] _D = + 6.2 ° (CHCl ₃ )) and 0.034 g of 6βH-6 (9α) -oxide-isomer ([α] _D = + 19.62 ° (CHCl ₃ ) do.

Similar Compound 3

0.43 g of 5c, 13t-9α, 15S-dihydroxy-16R-methyl-prostadienoic acid methyl ester-15-dioxanyl ether dissolved in methanol (2.5 ml) React. The reaction mixture is left at room temperature for 15 minutes and then at 0 ° C. overnight. The crystalline precipitate formed was isolated by filtration to yield 0.36 g of 13t-15α-hydroxy-16R-methyl-6 (H-6 (9α) -oxide-5-bromomercuric prosenoic acid methyl ester Treatment with borohydride removes mercury to remove 0.12 g of 13t-15S-hydroxy-16R-methyl-6ξH-6 (9α) -oxide-prostenoic acid methyl ester) M ⁺ 366, M ⁺ -H ₂ O 218 is obtained. Column chromatography on silica gel separates the 6αH-6 (9α) -oxide and 6αH-6 (9α) -oxide diastereomers.

Similar Compound 4

To a 0.5 g mercury acetate solution dissolved in 2 ml of water / 4 ml DME is added 0.55 g of a 5C-9α, 11α, 15S-trihydroxy-prosenoic acid methyl ester solution dissolved in 7.5 ml of DME. After 15 minutes the reaction mixture is treated with 0.08 g sodium borohydride solution dissolved in 1.2 ml of water. Mercury is separated, acetone is removed under vacuum, and the residue is extracted three or four times with dichloromethane. The organic acid was evaporated to dryness, adsorbed onto silica gel and eluted with ethyl ether / ethyl acetate to give 0.21 g of 11α, 15S-dihydroxy-6αH-6 (9α) -oxide-prostenoic acid methyl ester and 0.18g of 6βH- 6 (9α) -oxide isomers are obtained. M ⁺ 368M ⁺ -H ₂ O 350M ⁺ -2H ₂ O 332M ⁺ -H ₂ OC ₂ H ₄ O 306

Similar Compound 5

116 mg 5C-9α, 11α, 15S-trihydroxy-17-cyclohexyl-20,19,18-trinor- frost-5-ene-13-inoic acid methyl ester-1,15 dissolved in 1.5 ml methanol The bis-THP-ether solution is treated with 64 mg of mercury acetate dissolved in 1.5 ml of methanol. After 10 minutes, 25 mg sodium borohydride is added. Methanol is removed under reduced pressure, mercury is separated and the product is dissolved in water / ethyl acetate. The organic acid was evaporated to dryness to give impure 11α, 15S-dihydroxy-6ξH-6 (9α) -oxide-17-cyclohexyl-20,19,18-trinor- frost-13-inosanomethyl ester-11,15 -Bis-THP-ether (100 mg) was obtained and treated with acetone (4 ml) with 2.5 ml of 0.2 N oxylic acid overnight at 40 ° C. After removal of acetone in vacuo the mixture is extracted with ethyl acetate. The solvent was evaporated to dryness and the residue was purified by silica gel (eluent: ethyl ether) to give 28 mg of 11α, 15S-dihydroxy-17-cyclohexyl-20,19,18-trinote-6αH-6 (9α) -jade Seed-frost-13-enoic acid methyl ester ((α) _D = 17.20, (α) ₃₆₅ ° = + 54 °) and 12.5 mg of 6βH-6 (9α) -oxide isomer ((α) _D = + 26.5 °, (a) ₃₆₅ ° = 84 (EtOH): M ⁺ 406, MH ₂ O + 388).

11α, 15S-dihydroxy- from 5C-9α, 11α, 15S-trihydroxy-16S-methyl-frost-5-ene-13-enoic acid methyl ester-11,15-bis-THP-ether under the same conditions 16S-methyl-6αH-6 (9α) -oxide-frost-13-enoic acid methyl ester and 6βH-6 (9α) -oxide isomers are prepared.

Mass spectrometry: M ⁺ 366 M ⁺ -H ₂ O 348, M ⁺ -2H ₂ O 330;

Similar Compound 6

0.24 g of 13t-11α, 15S-dihydroxy-6αH, 6 (9α) -oxide-16-methyl-16-butoxy-20,19,18-trinor-prostenoic acid methyl ester and 0.13 g of The 6βH-6 (9α) -oxide isomer is 1.01 molar equivalent of mercury acetate (636 ml) dissolved in 10 ml of methanol and 1.1 g of 5C, 13t 9α, 11α, 15S-trihydroxy-16-methyl dissolved in 5 ml of methanol. Obtained from the reaction of -16-butoxy-20,19,18-trinor-prostadienoic acid methyl ester-11,15-bis-THP-ether. The mercury compound prepared as described above is spontaneously reduced by carefully adding 85 ml of sodium borohydride in small amounts. The methanolic solution is decanted from the solid residue and the capacity is reduced. 10 ml of g 0.2 N aqueous oxalic acid and 20 ml of acetone are added and the resulting mixture is left at 50 ° C. for 12 hours. The organic solvent is removed under reduced pressure and the solution is saturated with sodium sulfate and extracted with ethyl acetate. The organic phase is washed with 30% ammonium sulfate (2 x 5 ml) and 2.5 ml of water, dried over Na ₂ S0 ₄ and evaporated. The residue is purified by silica gel using an eluent containing an increasing fraction of benzene-methyl acetate to give the isomers 6Hα-6 (9α) -oxide and 6βH-6 (9α) -oxide.

16-m-trifluoro methyl-phenoxy-5C, 13t-9α, 11α, 15S-trihydroxy from the above reaction treated with 16-m-chloro-phenoxy, 16-p-fluoro-phenoxy -20,19,18,17-tetranor- frost-5,13-dienoic acid methyl ester-11,15-bis-THP-ether and pseudo-methyl-18.19.20-trinor-derivative are obtained, respectively.

Similar Compound 7

16S-fluoro-17-cyclohexyl-5C, 13t-9α, 11α, 15S-trihydroxy-20,19,18-trinor-frost-5,13-dienoic acid methyl ester 11 in the course of analogous compound 6 13t-11α, 15S-dihydroxy-6αH-6 (9α) -oxide-16S-fluoro-17-cyclohexyl-20,19,18-trinor- using, 15-bis-THP-ether Frost-13-enoic acid-methyl-ester [λ] _D +18 (EtOH) and 6βH-6 (9α) -oxide diastereomer [α] _D = + 7 (EtOH) are obtained.

Example 59

While maintaining the temperature of the reaction mixture at about −5 ° to −8 ° C., gradually add 159 mg of NaBH ₄ solution dissolved in 7 ml of propan-2-ol in 0.322 g of anhydrous CaCl ₂ solution dissolved in propan-2-ol (7 ml). Add. 0.38 g of 13t-6αH-6 (9α) -oxide-11α-hydroxy-15-oxo-16- (S, R) -fluoro-17-cyclo dissolved in 3 ml of propan-2-ol after stirring Hexyl-18,19,20-trinor-frost 13-enoic acid methyl solution is added to Ca (BH ₄ ) ₂ prepared above for 40 minutes. The reaction mixture is stored with stirring at a temperature in the range of ± 5 ° C. and then 5 ml of acetone and 2 ml of water are added to decompose excess reagent. The solvent is evaporated in vacuo and the residue is partitioned in water, 0.1NH ₂ SO ₄ and ethyl acetate. The organic extracts were collected, washed until neutralized, the solvent was evaporated and the residue was chromatographed with silica gel (30 g) using CH ₂ Cl ₂ -ethyl ether (70:30) as eluent to give 0.21 g of 13t-6αH-6 ( 9α) -oxide-11α, 15R-dihydroxy-16 (S, R) -fluoro-17-cyclohexyl-18,19,20-trinor- frost-13-enoic acid methyl ester and melting point 83-83 0.14 g of 15S-epimer (from ethyl ether) at 84 ° C. is obtained.

Mass spectrometry: M ⁺ 426M ⁺ -H ₂ O408M ⁺ -H ₂ O-HF388, M ⁺ -44 382;

In the same manner, 6βH-isomer (220 mg) was reduced to 0.1 g of 13t-6βH-6 (9α) -oxide-11α15R-dihydroxy-16 (S, R) -fluoro-17-cyclohexyl-18, 19,20-trinor- frost-13-enoic acid methyl ester, melting point 63 to 64 ° C. (from isopropyl ether) and 60 mg of 15S-alcohol are obtained. A single 16S-fluoro isomer is obtained from 6βH-15S-alcohol. [a] _D = + 7 (ethanol).

Scalpel spectrum: M ⁺ 426, M ⁺ H ₂ O 408, M ⁺ -H ₂ O-HF 388M ⁺ -44 382.

The following experimental example is mentioned as a manufacturing method of the analogous compound of a present Example.

Similar Compound 1

0.54 g of 5C, 13t-9α, 11α, 15S-trihydroxy-prostadienoic acid ethyl ester-11,15-bis-tetrahydro pyranyl ether (PGF ₂ α-bis-tetrahydropyranyl ether methyl ester) To a suspension of finely divided calcium carbonate dissolved in 6 ml of methylene chloride containing was added a solution of I ₂ (0.33 g) dissolved in methylene chloride.

The reaction mixture is cooled in an ice / water bath and left to block the light. After stirring for 3 hours, the inorganic compound is removed by filtration and the organic phase is washed with 0.25N sodium thiosulfate and water. Remove the solvent to remove 0.66 g of impure 13t-5-iodo-6αH-6 (9α) -oxide-11α, 15S-dihydroxy-frost-13-enoic acid methyl ester-11,15-bis-tetrahydro Obtain pyranyl ether. A solution of this compound dissolved in 10 ml of acetone is added to 8 ml of 0.1 N oxalic acid and then heated at 45-46 ° C. for 4 hours. Acetone is removed under reduced pressure and the aqueous suspension is extracted with ethyl acetate (3 x 12 ml), washed until the organic phase is neutralized and evaporated to dryness. The residue (0.41 g) was separated with silica gel using ethyl ether as eluent. The Rf fraction was eluted with acetone to give 0.14 g of 13t-5-iodo-6αH-6 (9α) -oxide-11α, 15-S-di. Hydroxy-frost-13-enoic acid methylester [α] _D = +21 (C = 1, CHCl ₃ ), while 0.20 g of 13t-5-iodo-6βH-6 (9α) from low Rf fraction ) -Oxide-11α 15S-dihydroxy-frost-13-enoic acid methyl ester is obtained. Mes Spectrum M ⁺ 444, M ⁺ -H ₂ O 476, M ⁺ -2H ₂ O458,476-2H ₂ O, 432 476-C ₂ H ₄ O, 405 405-H ₂ O, 397M-1 ⁺ , 387 [ α] _D = + 22 (C = 1CHCl ₃ ) Methyl esters of the acids described below are similarly prepared.

Similar Compound 2

Iodine solution in CH ₂ Cl ₂ and 0.22g of pyridine were dissolved in 0.1ml 5C, 13t-9α, 13α , 15s- trihydroxy -15- dissolved in 180ml methyl α- -PGF ₂ methyl ester in methylene chloride to a solution of 10ml After the dropwise addition, the reaction mixture was stirred for 1 hour. After dilution with water and washing the organic phase with 0.1 N sodium thiosulfate and water until neutral, the solution is evaporated under vacuum to reduce capacity and adsorb onto a 0.5 mm thick silica gel plate. After developing with ethyl ether and eluting with acetone, 0.052 g of 13t-15-methyl-5-iodo-6βH-6 (9α) -oxide-11α, 15s-dihydroxy-frost-13-enoic acid methyl ester (M ⁺ 508, M ⁺ -H ₂ O490, M + -H ₂ O 472) and 0.021 g isomer of 5-iodo-6αH-6 (9α) -oxide are obtained.

Similar Compound 3

0.288 g of 5c-16,16-dimethyl-9α, 11α, 15s-trihydroxy- frost-5-enoic acid methyl ester was dissolved in 60 mmg pyridine solution dissolved in methylene chloride (8 ml), and the solution was dissolved in methylene chloride. React with 115 ml of melted cancellation. After 30 minutes the starting material disappears completely and the organic phase is washed sequentially with neutralization with 5% aqueous metabisulfite and water, the solvent is removed and purified by TLC with silica gel as eluent 0.083 g of 16,16 -Dimethyl-5-bromo-6βH-6 (9α) -oxide-11d, 15s-dihydroxy-prostanomethyl ester and 0.04 g 6αH-diastereomer. _{^{M + 478/476, M + -H 2}} O460 / 458, M + -2H 2 O442 / 440.

The following compounds are also prepared by reactions similar to the above.

Similar Compound 4

5c, 13t-9α, 11α, 15s-trahydroxy-18,19,20- dissolved in 6 ml of tetrahydrofuran in a solution of hydrotribromide pyrrolidone (1.1 molar equivalents) dissolved in anhydrous tetrahydrofuran (6 ml). A solution of Tronor-17-cyclohexyl frost-5,13-dienoic acid methyl ester-11,15-bis-tetrahydro-pyranylether (0.7 g) is added. The mixture is stirred for 12 hours and the precipitate formed is filtered off and then the tetrahydrofuran solution is diluted with its volume of acetone and treated with 4 g of potassium iodide. After 4 hours at room temperature the liberated iodine is decomposed into sodium metabisulfate. 1.5 volume of 0.1N aqueous oxalic acid is added and the mixture is heated at 48 ° C. for 4 hours. Reduce the volume of the mixture under vacuum and extract with ethyl acetate. 0.14 g of 13-t-5-bromo-6αH-6 (9α) -oxide-11α, 15s-dihydroxy-18,19,20-trinor-17-cyclohexyl-frost- 13-enoic acid methyl ester and 0.11 g and 5-bromo-6βH-6 (9α) -oxide are obtained. M + 488/486, M + -H ₂ O 470/468; The following 6 (9α) -oxide was obtained according to the preparation of analogous compounds 3 and 4. 5-Bromo-6βH-6 (9α) -oxide-11α, 15s-dihydroxy-18,19,20-trinor-17-cyclohexyl- frost-13-enoic acid methyl ester;

Similar Compound 5

A solution of 0.1 x 10 ^-3 M methyl ester prepared according to the method of analogous compounds 1 to 4 in 2 ml of methanol is treated with 1 ml of an aqueous solution of lithium hydrate (0.2 x 10 ^-3 mol). The mixture is stirred for 3 hours, almost evaporated to dryness, diluted with 5 ml of water and extracted with ethyl ether. The organic phase is washed with 0.1NLiOH (2N) and water and then discarded. The aqueous acid is acidified with 30% aqueous NaH ₂ PO ₄ to pH4.8 and then extracted with ethyl ether to give the free acid.

Example 60

0.15 g of 13t-6αH-6 (9α) -oxide-11α-hydroxy-15-keto-16-methyl-16-butoxy-18,19,20-trinor-proster dissolved in methanol (5 ml) The no acid methyl ester solution is cooled at -5 to -10 DEG C and then reduced by addition of a solution of NaBH ₄ (30 mg) dissolved in water (0.ml).

After 15 minutes, the reaction mixture is neutralized with 15% aqueous NaH ₂ PO ₄ solution and evaporated under vibration. The aqueous residue is extracted with ethyl ether to give an impure mixture of 15R, 15S-alcohol isomers. Chromatography with silica gel (CH ₂ Cl ₂ -ethyl ether (70:30) as eluent) was carried out to separate 13t-6αH-6 (9α) -oxide 11α, -15R-dihydroxy-16-methyl-16- Butoxy-18,19,20-trinor-prosenoic acid methyl ester (45 mg) (and 15S-hydroxy-epimer (62 mg) are separated Mass Mass: M ⁺ 412, M ⁺ -H ₂ O 394 , M ⁺ -2H ₂ O 376,

Example 61

13t-15αH-5 (9α) -oxide-11α-hydroxy-15-keto-16-16-methyl-butoxy-18, 19, 20-trinor-prostenoic acid under the same conditions as in Example 60 After reduction of the methyl ester, the alcohol epimer (300 mg) was chromatographed with silica gel (12 g) using methylene chloride-ethyl ether (75:25) as eluent to give 100 mg of 13t-5αH-5 (9α) -oxide-11α. -15R-dihydroxy-16-methyl-16-butoxy-18, 19, 20-trinor-prostenoic acid methyl ester and 110 mg of 15S-epimer (mass spectrum: M ⁺ 412, M ⁺ -H ₂ O 394, M ⁺ -2H ₂ O376,

를 분리한다. 검화반응 후 상응하는 유리산을 수득한다.

Disconnect. After saponification, the corresponding free acid is obtained.

Example 62

0.135 g of 13t-5-bromo-6αH-6 (9α) -oxide-11α-hydroxy-15 dissolved in ₂ ml of anhydrous Et ₂ O in 0.12 M zinc borohydride solution dissolved in ethyl ether (8 ml). Oxo-prostenoic acid methyl ester solution is added dropwise. The mixture is stirred for 2 hours and then the excess reagent is digested with water-2N ₂ HSO ₄ . The organic phase is separated, washed until neutralized and evaporated to dryness. 38 mg of 13-t-5-bromo-6αH-6αH-6 (9α) -oxide-11α, 15R-dihydroxy-pro was purified by TLC with silica gel using ethyl ether-ethyl acetate (90:10) as eluent. Stenoic acid methyl ester and 46 mg of 15S-epimer are obtained. Mass Spectra: M ⁺ 448/446, M ⁺ -H ₂ O 430/428, M ⁺ -2H ₂ O 412/410, M + H ₂ OC ₂ H ₄ 386/384, M ⁺ -Br 367.

Example 63

13t-5, 14-dibromo-6βH-6 (9α) -oxide-11α-hydroxy-15-oxo-prostenoic acid methyl ester (0.2 g) was added CH ₂ Cl ₂ -ethyl ether (60:40 Chromatograph with silica gel using a mixture of 0.056 g of 13t-5, 14-dibromo-6βH-6 (9α) -oxide-11α, 15R-dihydroxy-prostenoic acid methyl ester and 0.098 g. 15S-Isomer Mess Spectra: M ⁺ 528/526, 524, M ⁺ -H ₂ O 510/508/506, M ⁺ 2H ₂ O 492/490/488, M ⁺ -B ⁺ 447/445, M ⁺ - Remove 2Br 366. A solution of this compound dissolved in methanol is hydrolyzed with aqueous LiOH to give 72 mg of 13t-5, 14-dibromo-6αH-6 (9α) -oxide-11α, 15S-dihydroxy-prostenoic acid. .

Example 64

13t-6βH-6 (9α) -oxide-11α-hydroxy- (5-oxo-16- (m-trifluoromethyl) -phenoxy using isopropanol and NaBH 4 (45 mg) as solvent in Example 60 0.2 g of 13t-6βH-6 (9α) with [α] _D = + 33.3 ° (MeOH) by reduction of -17, 18, 19, 20-tetranor- frost-13-enoic acid methyl ester (0.47 g) -Oxide-11α, 15S-dihydroxy-16- (m-trifluoromethyl) -phenoxy-17, 18, 19, 20-tetranorprost-13-enoic acid methyl ester and 0.18 g of 15R- Obtain an Epimer The 6αH-15S-alcohol epimer is in an oil phase with [α] _D = + 12 ° (MeOH).

Example 65

A solution of 13t-16S-methyl-6αH-6 (9α) -oxide-11α-hydroxy-15-oxo-frost-13-enoic acid methyl ester (0.002 M, 0.72 g) dissolved in anhydrous ethyl ether (20 ml) was added. It is added to an ether-stirred solution of zinc borohydride (0.01 M, 100 ml). After 30-45 minutes excess reagent is dissolved by adding 2N-sulfuric acid dissolved in a saturated aqueous solution of NaCl. The organic phase is washed until neutral and evaporated to dryness. The residue was chromatographed with silica gel (25 g) using methylene chloride: ethyl ether (80:20) as eluent to give 15R-hydroxy-isomer (7.5 × 10 ^-4 M, 0.27g) and 15S-alcohol (1.1 × 10). ^-4 M, 0.38 g), 13t-16S-methyl-6αH-6 (9α) -oxide-11α, 15S-dihydroxy- frost-13-enoic acid methyl ester. Using the above procedure, the following methyl ester is obtained.

The corresponding 15-keto compound with the alcohol of the 15R-epimer is reduced and then separated by chromatography. Corresponding 15S- and 15R-alcohols are prepared from 6αH and 5αH diastereomeric 15-keto compounds. All these compounds are saponified to yield the corresponding free acid.

Example 66

13t-5-iodo-6βH-6 (9α) -oxide-16R-methyl-15-oxo-frost-13 dissolved in ethyl ether (8 ml) in a stirred solution of zinc brohydride dissolved in ethyl ether (25 ml) -Innoic acid methyl ester (0.32 g) solution is added. After 30 minutes, saturated solution of NaCl and NaH ₂ SO ₄ are added to decompose the excess reagent. The organic phase is usually treated to separate the impure residue (eluent: CH ₂ Cl ₂ -ethyl ether) and chromatographed with 0.16 g of 13t-5-iodo-6βH-6 (9α) -oxide-16R-methyl -15S-hydroxy-frost-13-enoic acid methyl ester (mes spectra: M ⁺ 492, M ⁺ -H ₂ O 474, M ⁺ -OCH ₃ 461, M ⁺ -H ₂ OC ₂ H ₄ O430) and 0.095 g of 15R-epimer is obtained. According to the above method, the corresponding 15-keto compound is reduced and then separated by chromatography to give the following methyl ester.

Example 67

The following 15S-hydroxy-9α-oxide prostenoic acid methylester is obtained by reducing the corresponding 15-keto compound using one of the methods described in Examples 58-66 with 15R-epimeric alcohol.

Similarly, the use of αH-9α-oxide-15-ketodiastereoisomers as starting materials produces diastereomeric αH-9α-oxide-15S- and αH-9α-oxide-15R-alcohols. All these esters are saponified to give the free acid.

Example 68

=229mμ, ε=11,058)를 수득한다. 에틸 에테르에 용해한 이 화합물의 용액을 에틸 에테르에 녹인 (Zn(BH₄)₂용액에 적가한다. 30분 후 과량의 시약을 H₂SO₄의 1N 용액으로 분해한 후 통상의 방법으로 처리하여 0.47g의 13t-5βH-5(9α)-옥시드-16S-메틸-11α,15-(S,R)-디하이드록시-13-프로스테노산 메틸 에스테르 11-아세테이트(메스 스펙트럼: M⁺424, M⁺-H₂O 406, M⁺-C₆H₁₃339)를 수득한다. CH₂Cl₂(5ml)에 녹인 이 화합물의 용액을 -5℃ 내지 -10℃로 냉각한 후 CH₂Cl₂에 용해한 BF₃에테르상 용액(1.2×10^-4M)으로 처리한 다음 황색이 유지될 때까지 CH₂Cl₂에 녹인 디아조메탄의 5% 용액으로 다시 처리한다. 반응 혼합물의 용량을 감압하에서

로 줄인 후 NaHCO₃의 5% 수용액으로 세척하고 다시 물로 중성이 될 때까지 세척한 다음 증발 건조하여 벤젠-에틸 에테르(85:15)를 용출제로 하는 SiO₂로 크로마토그래피하면 각각의 이성질체로 분리하는 0.47g의 13t-5βH-5(9α)-옥시드-16S-메틸-11α-하이드록시-15(S,R)-메톡시-프로스트-13-에노산-11-아세테이트(메스 스펙트럼: M⁺438, M⁺-CH₃CO₂379, M⁺-C₆H₁₃353)을 수득한다. 이와 다르게 0.21g의 15(S,R)-메톡시-유도체의 혼합물을 무수 메탄올(4ml)에 용해한 후 실온에서 4시간동안 20mg의 K₂CO₃로 처리하여 선택적 아세틸 이탈 반응시킨다. 수성 NaH₂PO₄로 희석하여 중화한 후 메탄올을 진공하에서 증발하고 잔사를 에틸에테르(2×5), 에틸 아세테이트(2×6ml)로 추출한다. 유기상을 증발 건조하여 180mg의 불순한 13t-5βH-5(9α)-옥시드-16S-메틸-11α-하이드록시-15(S,R)-메톡시-프로스테노산 메틸 에스테르(매스 스펙트럼: M⁺396, M⁺-H₂O 378, M⁺-C₆H₁₃311)를 수득한다. 상기 화합물을 CH₂Clz-에틸에테르(80:20)를 용출제로 하는 실리카겔 컬럼 크로마토그래피로 쉽게 분리하여 2개의 순수한 이성질체, 15S-에톡시 및 15R-메톡시를 수득한다. 동일한 방법에 따라 상응하는 11-아세톡시-15-케토 화합물로부터 다음의 메틸 에스테르를 수득한다.0.46 g of 13t-5OH-5 (9α) -oxide-16S-methyl-11α-hydroxy-15-oxo-frost-13-enoic acid methylester is treated with pyridine (2 ml) and acetic anhydride (1 ml). . After 6 hours at room temperature the mixture is diluted with brine, acidified to pH 4.5 to 4.8 and extracted with ethyl ether. The organic phase was evaporated to dryness to 0.48 g of 11-acetoxy-derivative (

= 229 mμ, epsilon = 11,058). A solution of this compound dissolved in ethyl ether is added dropwise to a solution of (Zn (BH ₄ ) ₂ dissolved in ethyl ether. After 30 minutes, the excess reagent is decomposed into a 1N solution of H ₂ SO ₄ and treated by conventional methods to obtain 0.47. g of 13t-5βH-5 (9α) -oxide-16S-methyl-11α, 15- (S, R) -dihydroxy-13-prostenoic acid methyl ester 11-acetate (mass spectrum: M ⁺ 424, M ⁺ -H ₂ O 406, M ⁺ -C ₆ H ₁₃ 339), a solution of this compound dissolved in CH ₂ Cl ₂ (5 ml) was cooled to -5 ° C to -10 ° C and then CH ₂ Cl ₂ Treat with BF ₃ ether phase solution (1.2 × 10 ^-4 M) dissolved in and then again with a 5% solution of diazomethane dissolved in CH ₂ Cl ₂ until yellow is maintained.

Reduced with water, washed with a 5% aqueous solution of NaHCO ₃ , washed with water until neutral, evaporated to dryness and chromatographed with SiO ₂ using eluent benzene-ethyl ether (85:15) as an isomer. 0.47 g 13t-5βH-5 (9α) -oxide-16S-methyl-11α-hydroxy-15 (S, R) -methoxy-frost-13-enoic acid-11-acetate (mass spectrum: M ⁺ 438, M ⁺ -CH ₃ CO ₂ 379, M ⁺ -C ₆ H ₁₃ 353). Alternatively, 0.21 g of a mixture of 15 (S, R) -methoxy-derivatives was dissolved in anhydrous methanol (4 ml) and then treated with 20 mg of K ₂ CO ₃ for 4 hours at room temperature for selective acetyl leaving reaction. After neutralization by dilution with aqueous NaH ₂ PO ₄ , methanol is evaporated in vacuo and the residue is extracted with ethyl ether (2 × 5), ethyl acetate (2 × 6 ml). 180 mg of impure 13t-5βH-5 (9α) -oxide-16S-methyl-11α-hydroxy-15 (S, R) -methoxy-prostenoic acid methyl ester (mass spectrum: M ⁺⁾ 396, M ⁺ -H ₂ O 378, M ⁺ -C ₆ H ₁₃ 311). The compound is easily separated by silica gel column chromatography with CH ₂ Clz-ethyl ether (80:20) as eluent to afford two pure isomers, 15S-ethoxy and 15R-methoxy. According to the same method, the following methyl ester is obtained from the corresponding 11-acetoxy-15-keto compound.

And epicyclic 15R-methoxy compounds are obtained from the corresponding 11-acetoxy-15-keto compounds.

In the above procedure, the αH-diastereomer is used instead of βH- to obtain the corresponding αH-15-methoxy compound. Diazo alkanols in diazo methane are also prepared 15-keno compounds according to methods analogous to those described above.

Example 69

0.26 g of 13t-6βH-6 (9α) -oxide-15 (S, R) -hydride in methylene chloride treated with 0.3 ml of BF ₃ ether phase solution dissolved in methylene chloride cooled to -10 to -8 ° C. To the oxy-16S-methyl- frost-13-enoic acid methyl ester solution is added a diazo ethane solution dissolved in methylene chloride until a persistent yellow color is formed.

The solvent was evaporated under reduced pressure and the residue was chromatographed with silica gel using ethyl ether-methylene chloride (10:90) as eluent to give 0.115 g of 13t-6βH-6 (9α) -oxide-15S-ethoxy-16S-methyl. Prosenoic acid methyl ester and 0.1 g of 15R-ethoxy isomer are obtained. Mes Spectra: M ⁺ 394, M ⁺ -OCH ₃ 36; a mixture of 15S, 15R-alcohols containing free 11-hydroxy groups, for example 13t-6βH-6 (9α) -oxide-11,15α ( When S, R) -dihydroxy-16S-methyl-prosenoic acid was treated according to the methods of Examples 68 and 69, co-alkylation of the 11-alcoholic functional group occurred, followed by chromatography and 13t with diazomethane. -6βH-6 (9α) -oxide-11α, 15S-dimethoxy-16S-methyl-prostenoic acid methyl ester and 15R-epimeric derivatives are isolated. Mass spectrum: M ⁺ 410, M ⁺ -OCH ₃ 379, M ⁺ -C ₂ H ₄ O 366, M ⁺ -C ₆ H ₁₃ 725; Similarly, the following 15S-alkoxy prostenoic acid derivatives are obtained.

Mass spectrum: M ⁺ 396, M ⁺ -C ₇ H ₁₅ O 281, and 15R epimers are obtained and free acid is prepared when saponified with LiOH dissolved in methanol. According to the same method, diastereomeric αH-9α-oxide derivatives are obtained.

Example 70

Stirring of 1.33 g of 13t-6αH-6 (9α) -oxide 11αhydroxy-15-oxo-frost-13-enoic acid methyl ester-11-acetate dissolved in 6 ml of toluene and 45 ml of benzene cooled to 4 ° C To the solution is added 1.67 g of iodine and methyl magnesium solution dissolved in ethyl ether. After 20 minutes, the excess reagent is decomposed with a 20% ice solution of ammonium chloride dissolved in water.

After dilution with ethyl ether, the organic phase was washed with water, sodium carbonate and water, dried over magnesium sulfate, treated with 0.1 ml of pyridine and evaporated to dryness to 1.2 g of 13t-6αH-6 (9α) -oxide-11α, 15 (S , R) -dihydroxy-15-methyl-prostenoic acid-methyl ester-11-acetate. 0.2 g of which is separated by pure silica gel thin layer chromatography using benzene-ether (60:40) as an eluent. 1 g of the mixture of the two alcohols is dissolved in anhydrous methanol (20 ml) and then treated with 0.25 g of K ₂ CO ₃ by stirring for 4 hours. The mixture is evaporated to dryness and the residue is separated between ethyl ether and 15% NaH ₂ pO ₄ aqueous solution. The organic phase is evaporated in vacuo and the residue is adsorbed onto silica gel (200 g). 0.20 g of 13t-6αH-6 (9α) -oxide-11α, 15R-dihydroxy-15-methyl-frost-13-enoic acid methyl s, dissolved in ethyl ether-isopropyl ether (80:20) Ter and 0.36 g of 15S-epimer (mass spectrum: M ⁺ 382, M ₊ -H ₂ O 364, M ⁺ -CH ₃ O 351, M ⁺ -H ₂ OC ₂ H ₄ O 320). 0.16 g of this compound is dissolved in 12 ml of methanol and treated with 0.8 mg of water and 0.2 g of K ₂ CO ₃ . After 5 hours at room temperature methanol evaporated under vacuum and the residue was treated with 20% NaH ₂ PO ₄ and ethyl acetate to give 0.14 g of 13t-6αH-6 (9α) -oxide-11α, 15S-dihydroxy- from the organic phase. 15-Methyl-frost-13-enoic acid ([α] _D (methylester) = + 6.2 ° (CHCl ₃ ) is obtained.) The corresponding 6βH-isomers are prepared in the same manner: 13t-6βH-6 (9α (Α) _D of) -oxide 11α, 15S-dihydroxy-15-methyl-frost-13-enoic acid methylester is + 19.62 ° (CHCl ₃ ).

Example 71

1.79 g of 13t-5αH-5 (9α) -oxide-11α-hydroxy-15-oxo-frost-13-enoic acid methyl ester-11-acetate solution dissolved in 20 ml of anhydrous tetrahydrofuran anhydrous tetrahydrofuran 50 ml of 0.3 M embrittled ethynyl magnesium dissolved in was added. After shaking for 1 hour, the excess reagent was removed by treatment with a saturated solution of NH ₄ Cl, and the organic phase was concentrated in vacuo and treated with ethyl ether to give 1.62 g of 13t-5αH-5 (9α) -oxide-11α, 15 (S, R) -Dihydroxy-15-ethynyl-frost-13-enoic acid methyl ester-11-acetate is obtained. The compound is dissolved in anhydrous ethanol and treated with 250 mg of anhydrous potassium carbonate while shaking for 3 hours. Evaporate under vacuum and dilute with 20% aqueous NaH ₂ PO ₄ and ethyl ether. After evaporation of the solvent 1.41 g of 13t-5αH-5 (9α) -oxide-11α, 15 (S, R) -dihydroxy-15-ethynyl-prostanoic acid methyl ester are obtained from the organic phase (mes) Spectrum: M ⁺ 392, M ⁺ H ₂ O 374, M ⁺ -C ₅ H ₁₁ 321). Chromatography with silica gel using benzene-ethyl ether (1: 1) as eluent to separate pure 15S-hydroxy and 15R-hydroxy, followed by purification of 15S-hydroxy epimer with K ₂ CO ₃ in methanol 13t- Obtain 5αH-5 (9α) -oxide-11α, 15S-dihydroxy-15-ethynyl prostenoic acid (mass spectrum: M ⁺ 378, M ⁺ H ₂ O 360, M ⁺ -C ₅ H ₁₁ 307).

Example 72

To tetrahydrofuran (25 ml) in 1.41 g of 13t-5-bromo-6βH-6 (9α) -oxide-15-oxo-frost-13-enoic acid methylester solution dissolved in anhydrous teprahydrofuran (25 ml). The rust is added 0.5M solution of embrittlement magnesium vinyl at 0-5 [deg.] C. and left for 4 hours at room temperature. Excess reagents are decomposed with a saturated solution of ammonium chloride, tetrahydrofuran is distilled under vacuum and treated with ethyl ether. The organic phase was adsorbed onto silica gel and eluted with methylene chloride-ethyl ether to give 0.41 g of 13t-5-bromo-6βH-6 (9α) -oxide-15-R-hydroxy-15-vinyl-prosenoic acid methyl ester (M ⁺ 428/426, M ⁺ -H ₂ O 410/408, M ⁺ -CH ₃ O 397/395, M ⁺ -Br 347) and 0.62 g of 15S-isomer are obtained. 0.49 g of pure 13t-5-bromo-6βH-6 (9α) -oxide-15S-hydroxy-15-vinyl-prosenoic acid (m + 414/412, m +-) after saponification with LiOH dissolved in methanol H ₂ O 396/394, M ⁺ -Br333).

Example 73

0.98 g of 13t-5-brodo-6βH-6 (9α) -oxide-11α-hydroxy-15-oxo-20-methyl-prosenoic acid dissolved in 30 ml of benzene-toluene (85:15) The methyl ester-11-acetate solution is cooled to 3-4 [deg.] C. and then to this solution is added 0.92 g of embrittled phenylmagnesium solution dissolved in ethyl ether-benzene (1: 1). After 5 hours at room temperature, the excess reagent is decomposed by treating with an ice solution of 15% NH ₄ Cl. The organic phase is washed several times with water until neutral and evaporated. The impure 15-phenyl-15 (S, R) -hydroxy derivative is dissolved in anhydrous methanol, and then 0.25 g of K ₂ CO ₃ is added and shaken for 2 hours. Evaporated to dryness and diluted with 20% aqueous NaH ₂ PO ₄ and ethyl ether, followed by evaporation of the solvent from the organic phase to 0.81 g of 13t-5-bromo-6βH-6 (9α) -oxide-11α, 15 (S, R) - dihydroxy-15-phenyl -20- phenyl-Pro stearyl acid methyl ester (meth spectra: M + 538/536, M + -H 2 O 520/518, M + -CH 3 O 507/505, M ⁺ -Br 457). Silica gel with ethyl ether as eluent separates 15S and 15R isomers, respectively.

Example 74

The corresponding methyl ester is reacted with a corresponding 15-oxo-derivative with a reagent obtained from a group of halides of methyl magnesium, ethyl magnesium, vinyl magnesium ethynyl magnesium and phenyl magnesium according to one of the methods of Examples 70 to 73. To obtain.

Similarly, the corresponding αH- (9α) -oxide-15-substituted alcohols are obtained from the αH- (9α) -oxide-15-keto compounds.

Example 75

0.5 g 13t-6βH-6 (9α) -oxide-11α, 15S-dihydroxy-14-bromo-16S-methyl-prosetanoic acid-methyl ester-11-acetate solution dissolved in 2 ml of dimethylformamide To dimethyl-t-butyl silane chloride (0.21 g) and triethylamine (0.16 g) are added. Shake for 2 hours, dilute with 4 times water and extract with ethyl ether. After washing in a conventional manner, the solvent was evaporated and filtered over silica gel with eluent cyclohexane-ethyl ether (90:10) to 0.57 g of 13t-6βH-6 (9α) -oxide-11,15S- from the organic phase. Dihydroxy-14-bromo-16S-methyl-prostenoic acid methylester-11-acetate-15-dimethyl-t. Butylsilyl ether is obtained and transfer esterified in 0.5 molar equivalents of anhydrous methanol and K ₂ CO ₃ to give the corresponding 11-hydroxy-derivative.

Example 76

0.52 g of 13t-5,14-dibromo-6βH-6 (9α) -oxide-11α, 15S-dihydroxy-prostenoic acid methyl ester solution dissolved in 10 ml of dichloromethane, 2,3-dihydro Add pyran (0.27 g) and p-toluenesulfonic acid (4 mg). Store at room temperature for 3 hours, wash until neutralized with 5% solution of KHCO ₃ and water and evaporate to dryness. 0.59 g of 13t-5, 14-dibromo-6βH-6 (9α) -oxide-11α, 15S-dihydroxy- was filtered through silica gel using cyclohexane-ethyl-ether (90:10) as an eluent. Prosenoic acid methyl ester-11,13-bis-tetragrouphydropyranyl ether is obtained.

Example 77

The 14-bromo-alcohol produced in the above example was dissolved in dimethylform amide according to the method of Example 75. Corresponding silyls when treated with butyl chlorosilane or with acetal ethers such as 2,3-dihydro-pyran-1.4-diox-2-ene, 1-ethoxy-ethyl, according to the method of Example 76 Conversion to oxy or the corresponding acetal ethers.

Example 78

0.46 g of 13t-14-bromo-6βH-6 (9α) -oxide-15S-methoxy-16S-methyl-frost-13-enomethyl methyl dissolved in anhydrous dimethyl sulfoxide (5 ml) under an atmosphere of inert gas Potassium tert-butylate (0.15 g) is added to the stirred solution of ester and stirring is continued for 30 minutes. The reaction mixture is diluted with twice the water and stirred for 15 minutes and then extracted with ethyl ether. The organic phase is reextracted with 0.2N NaOH (2 × 5 ml) and extracted again with water until neutralized and evaporated to dryness to 30 mg of 6βH-6 (9α) -oxide-15S-methoxy-16S-methyl-frost-13-ino Acid methyl ester ([α] _D = + 21 ° ethanol) is obtained. The aqueous phase is acidified to pH5.1 and extracted with ethyl ether. After evaporation of the solvent, 0.28 g of 6βH-6 (9α) -oxide-15S-methoxy-16S-methyl-frost-13-inoic acid ([α] _D = + 19 °, ethanol) is produced.

Example 79

0.34 g of trimethylsilylimidazole was removed by stirring completely to remove moisture under an inert gas stream and 0.445 g of 13t-5αH-5 (9α) -oxide-14-bromo-16R-methyl-frost-13-enoic acid To anhydrous dimethyl sulfoxide solution.

Stirring was continued for 30 minutes, and then 0.19 g of K-3-tert-butylate solution was added. After stirring for 30 minutes, the mixture is diluted with 3 times of water and stirred for another 2 hours. Acidified to pH 5.2, extracted with ethyl ether: hexane (80:20), and the organic extract was evaporated to dryness. 0.31 g) of 5αH-5 (9α) -oxide-16R-methyl-frost-13-inoic acid ([ α] _D = + 21 °, ethanol).

Example 80

13t-6βH-6 (9α) -jade dissolved in 5 ml of dimethyl sulfoxide in a solution of sodium methyl sulfinyl carbanion heated at 60 ° C. for 3 hours and suspended in 50 ml of 80% NaH in 30 ml of anhydrous dimethyl sulfoxide for 30 minutes. A solution of seed-11α, 15S-dimethoxy-14-bromo-16 (S, R) -fluoro-20-methyl- frost-13-enoic acid methyl ester (0.86 g) was added to an inert gas at 18 to 20 ° C. It is added with stirring at a temperature of.

After stirring for 40 minutes, excess 25% NaH ₂ PO ₄ was added and extracted with ethyl ether, 0.51 g of 6βH-6 (9α) -oxide-11α, 15S-dimethoxy-16 (SR) -fluoro-20 -Methyl- frost-13-ino-acid methyl ester ([a] _D = 21.4 °, ethanol) is obtained.

Example 81

13t-14-bromo-5αH-5 (9α) -oxide-11α, 15S-dihydroxy-16-m-tree dissolved in 5 ml of dimethyl sulfoxide in 80 mg of sodium amide solution dissolved in 10 ml of dimethyl sulfoxide A solution of fluoromethyl phenoxy-17,18,19,20-tetranor- frost-13-enoic acid-11,15-bis-tetrahydro pyranyl ether (0.65 g) is added. After stirring for 2 hours, diluted with water and extracted with ethyl ether. Discard the ether extract after re-extraction with alkali.

The aqueous alkaline extract was acidified to pH4.5 and extracted with ethyl ether to give 0.54 g of 5αH-5 (9α) -oxide-11α, 15S-dihydroxy-16-m-trifluoromethylphenoxy-17,18 , 19,20-tetranor- frost-13-inoic acid-11,15-bis-tetrahydro pyranyl ether is obtained. A solution of this compound (0.23 g) dissolved in anhydrous ethanol (5 ml) and 2,2-diethoxypropane (3 ml) is treated with 20 ml of p-toluenesulfonic acid. After 5 hours storage at room temperature, the solution is neutralized with aqueous NaHCO ₃ and evaporated in vacuo and the residue is partitioned between water and ethyl ether. After evaporating the organic phase and passing the residue through silica gel, 0.1 g of 5αH-5 (9α) -oxide-11α15S-dihydroxy-16-m-trifluoromethylphenoxy-17,18, 19,20-tetra To produce nor- frost-13-inoic acid ethyl ester ([α] _D = + 15 °, ethanol). 0.2 g of the product was dissolved in 5 ml of acetone, followed by acetal desorption and 0.2 N oxalic acid at 40 ° C. for 8 hours. After treatment with 3.5 ml, the acetone was evaporated under vacuum, the aqueous phase was extracted with ethyl ether, and then chromatographed with silica gel using ethyl ether: ethyl acetate (95: 5) as eluent to obtain free acid (95 mg). α] _D = + 15.5 °, ethanol)

13t-14-Chloro-6αH-6 (9α) -oxide-11α, 15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-frost-13-enoic acid-11 according to the same method 6αH-6 (9α) -oxide-11α, 15S-dihydroxy-17-cyclohexyl-18,19,20-trinor-frost-13-inoic acid from, 15-bis-saoxyyl-ether [α] _D = 27.2, ethanol). (Methyl ester [α] _D = +17.2, ethanol, (α) ₃₆₅ = + 54 °)

Example 82

0.48 g of 13t-14-bromo-6βH-6 (9α) -oxide-11α, 15S-dihydroxy-16-cyclohexyl-17,18,19,20-oxy in 3 ml of anhydrous dimethyl sulfoxide To a solution of tetranor- frost-13-enoic acid methyl ester was added a solution of 1.5-diazabicyclo (5.4.0) undec-5-ene (0.25 g) dissolved in 2 ml of anhydrous dimethylformamide after 30 minutes, followed by 65 Hold at 6 ° C. for 6 hours. Dilute with water, acidify to pH4.5 and extract with ethyl ether.

The solvent was evaporated and purified by silica gel (eluted with benzene-ethyl ether (80:20)) and then 6βH-6 (9α) -oxide-11α, 15S-dihydroxy-16-cyclohexyloxy- from the organic phase. Yields 17,18,19,20-tetranor-frost-13-inos acid methyl ester (0.29 g). (Α) _D = + 17.1, Ethanol.

Example 83

The following frost-13-inoic acid is prepared from the corresponding 13t-14-halo-frost-13-enoic acid using one of the methods described in Examples 78-82.

According to the same method, epimeric αH- (9α) -oxide-13-inosane compounds are prepared from αH- (9α) -oxide compounds.

Example 84

0.12 g of 13t-11α, 15S-dihydroxy-6βH-6 (9α) -oxide-frost-13-enoic acid petyl ester dissolved in 6 ml of methanol is reacted with a 0.5N aqueous solution of lithium hydrate (2 ml). After 6 hours the methanol is removed under reduced pressure. The residue is diluted with water (2 ml) and extracted with ethyl ether to remove neutral impurities. The aqueous alkali solution phase is acidified by treatment with ₄ ml of 30% aqueous NaH ₂ PO ₄ and extracted several times with ethyl ether. The ether extract is washed with water (2 x 1 ml) and dried. Remove the solvent to remove 91 mg of 13t-11α, 15S-dihydroxy-6βH-6 (9α) -oxide-frost-13-enoic acid (melting point 78-80 ° C., (α) _D = + 31 ° (EtOH) The ester is gumified from the previous examples to give the corresponding free acid.

Example 85

11α, 15S-dihydroxy-6βH-6 (9α) -oxide-16S-methyl- frost-13-enoic acid (0.11 g) dissolved in methylene chloride was treated with 1.5 molar equivalents of diazobetan in methylene chloride. After 15 minutes the solvent is removed under reduced pressure and the residue is adsorbed onto silica gel. 12 mg of 11α-hydroxy-15S-methoxy-6βH-6 (9α) -oxide-16S-methyl-frost-13-enoic acid methyl ester eluted with ethyl ether / benzene (70:30) ([α] _D = + 24 °, ethanol) and 78 mg of 11α, 15S-dihydroxy-6βH-6 (9α) -oxide-16S-methyl-frost-13-enoic acid methyl ester ([α] _D = + 21.5 ° , Ethanol). In the above procedure, diazo ethanol is used instead of diazomethane to obtain 11α-hydroxy-15S-ethoxy-6βH-6 (9α) -oxide-16S-methyl-frost-13-enoic acid ethyl ester.

Claims (1)

Following reaction of the compound of formula (IV) with the compound of formula (V) to remove the known protecting group, R ₂ and R ₅ together form an oxo group, and the compound of formula (I) wherein Y is -CH = CZ _2- . To obtain a compound of formula (I) wherein one of R ₂ and R ₅ is hydrogen and the other is hydroxy, or R ₂ and R ₅ form an oxo group and Y is -CH = CZ _2- A compound of formula (I) wherein one of R ₂ and R ₃ is hydroxy and the other is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or aryl Or one of R ₂ and R ₅ is hydroxy and the other is hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or aryl and Y is Ester of a compound of formula (I) with —CH═CZ ₂ — where one of R ₂ and R ₅ is C ₁ -C ₆ alkoxy or ar-C ₁ -C ₆ alkoxy and the other is hydrogen, C ₁ -C ₆ Alkyl, C ₂ -C ₆ Obtain a compound of formula (I) wherein alkenyl, C ₂ -C ₆ alkyl or aryl and Y is —CH═CZ ₂ —, or wherein Z ₂ is hydrogen and Y is —CH═CZ ₂ — Is hydrogenated to obtain a compound of formula (I) wherein Y is -CH ₂ CH _2- , or dehalogenated hydrogenation of a compound of formula (I) wherein Z ₁ is hydrogen, Z ₂ is halogen and Y is -CH = CZ _2- Obtain a compound of formula (I) wherein Y is -C≡C- and Z ₁ is hydrogen, or R ₂ and R ₅ form an oxo group, Z ₂ is hydrogen, and Y is -CH = CZ _2- Compound hydrogenation yields a compound of formula (I) wherein R ₂ and R ₅ form oxo groups and Y is —CH ₂ CH ₂ —, or Z ₁ forms hydrogen, R ₂ and R ₅ form oxo groups A halogenated hydrogenated compound of formula (I) wherein Z ₂ is halogen and Y—CH═CZ ₂ — is hydrogenated to form Z ₂ as hydrogen R ₂ and R ₅ and o is o-group, and Y is —C≡C— ) Or R ₂ and R ₅ are jade Reduction to a compound of formula (I) forming a small group to yield a compound of formula (I) wherein one of R ₂ and R ₅ is hydrogen and the other is hydroxy, or R ₂ and R ₅ form an oxo group (I) A compound of formula (I) wherein one of R ₂ and R ₅ is hydroxy and the other is C ₁ -C ₆ allyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or aryl Or one of R ₂ and R ₅ is hydrogen and the other is hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or aryl Esterification of the compound such that one of R ₂ and R ₅ is C ₁ -C ₆ alkoxy or ar-C ₁ -C ₆ -alkoxy and the other is hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl To obtain a compound of formula (I) which is C ₂ -C ₆ alkynyl or aryl.

In the above structural formula R is (a) free or esterified carboxy group (b)

(Wherein R ′ groups are the same or different, C ₁ -C ₆ alkyl or phenyl) (c) -CH ₂ OH, (d)

Wherein Ra and Rb are each independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkanoyl and phenyl) (e)

Radical, (f) selected from the group consisting of -C = N, Z ₁ is hydrogen or halogen, p is an integer from 0 or 1 to 7, q is 1 or 2, R ₁ is hydrogen, hydroxy, C ₁ -C ₆ alkoxy, ar-C ₁ -C ₆ alkoxy, acyloxy, Y is _CH ₂ CH _2- , -C≡C-,

(Cis) and

(Trans), where Z ₂ is hydrogen or halogen, One of R ₂ and R ₅ is hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or aryl, another is hydroxy, C ₁ -C ₆ alkoxy, and are -C ₁ -C ₆ alkoxy, or C ₂ and C ₅ together form an oxo group, R ₃ and R ₄ are each the same as each other; Other hydrogen, C ₁ -C ₆ alkyl or fluorine, or R ₃ and R ₄ are bonded together with a carbon atom

or

Form radicals, n ₁ and n ₂ are the same as each other or different integers from 0 or 1 to 6, X is selected from the group consisting of -O-, -S- and-(CH ₂ ) _m- , where m is 0 or 1, R ₆ is (a ′) hydrogen (b ′) C ₁ -C ₄ alkyl (c ′) C ₃ -C ₉ ring aliphatic radicals, unsubstituted or substituted with one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy, (d ′) aryl unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, halo-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy, and (e ′) Saturated or unsaturated, unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, halo-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy Selected from the group consisting of heterocyclic rings, R ″ is (a ″) free or esterified carboxy group, (b ″)

Where R ′ is the same as defined above (c ″) — CH ₂ —R ₇ group wherein R ₇ is hydroxy or a known protecting group bonded with —CH ₂ — group by an oxygen atom on an ether (d ″)

(R _a and R _b are as defined above) (e ″)

Radical, (f ″)-C≡N, R ′ is a known protecting group which is cyclically bonded with an oxygen atom on hydrogen, hydroxy, C ₁ -C ₆ alkoxy, ar-C ₁ -C ₆ alkoxy, acyloxy or ether, E is (C ₆ H ₅ ) ₃ P

-Or (ReO) 2

-A group where each of the Re groups is the same or different alkyl or aryl from each other.