JPS5910577A - Preparation of 7-hydroxyprostacycline derivative - Google Patents

Abstract

PURPOSE:To prepare the titled compound useful as pharmaceuticals or their intermediates, from an easily available raw material, in high efficiency, by reacting a 7-hydroxyprostaglandin F2alpha derivative with a mercury compound in an inert organic medium, and treating the product with a borohydride compound. CONSTITUTION:The compound of formula III can be prepared economically by reacting the compound of formula I [the dotted line is a bond which may be present or absent; G is CO2R<5>, etc.; R<5> is H, 1-10C alkyl, etc.; R<1> is H, CH<3>, CHidenticalCH, etc.; R<2> is 5-8C alkyl, alicyclic group, etc.; R<3> and R<4> are H, 2- 7C acyl, tri(1-7C hydrocarbon group)-silyl, etc.; the configuration between the 8 and 9 positions is trans.] with a mercury compound, preferably a mercury salt of carboxylic acid (e.g. mercury acetate), a mercury halide (especially mercury chloride) or mercury oxide, in an inert organic medium, and reacting the reaction product preferably with a borohydride compound of formula II (M is alkali metal; R8 is 1-6C alkyl, 1-6C alkoxy, or CN; m is integer of 1-4), especially sodium borohydride, etc.

Description

[Detailed description of the invention]

The present invention relates to a novel method for producing 7-hydroxyprostacyclin derivatives. The details button on the rainbow shows that the present invention uses a 7-hydroxyprostaglandin F, α derivative as a raw material, reacts it with a mercury compound, and then treats it with a borohydride compound. This relates to a method for efficiently producing 7-hydroxyprostacyclin derivatives, which are also important as synthetic intermediates for pharmaceuticals. It has attracted attention from

Prostacyclin is a compound that has various physiological activities, but one of the key points in using it as a drug is that prostacyclin has a variety of physiological activities. In addition, the enol ether bond contained in prostacyclin's skeleton is extremely susceptible to hydrolysis by water, and this is also the reason why the development of prostacyclin as a drug has been difficult and hectic. The present inventors paid attention to this point and found that a 7-hydroxyprostacyclin derivative having a hydroxyl group introduced at the 7-position exhibits extremely high resistance to hydrolysis [ring nai et al., tetrahet a7 L'Tars (Tetra
hedron Letters) 122.1417~
1420 (1981)]. Ij! By reacting with a fluorinating reagent such as ethylacinosulfur trifluoride, the 7-hydroxyprostacyclin derivative can be prepared at the 5- or 7-position.
It has been found that the 5- or 7-fluoroprostacyclin derivatives obtained by introducing a fluorine atom into the position are extremely stable and highly active, and have been reported previously. A separate application has been filed (see the figure below). 7-Hydroxyprostacyclin derivatives are thus useful as themselves as stabilized prostacyclin derivatives, and are also useful as raw materials from which other stabilized prostacyclin derivatives such as fluorinated booster cyclin derivatives can be derived. is produced from prostacyclin by the route shown in the reaction formula below (Japanese Patent Application Laid-Open No. 57-9598
Publication No. 0). (Prostaglandins, etc.) (7-Hydroxyprostacyclin derivatives) This production method involves a large number of steps, and it requires multiple steps to obtain the prostacyclin used as a raw material compound, making it difficult to obtain. Therefore, the above production method cannot be used industrially as a method for producing 7-hydroxyprostacyclin derivatives. Therefore, as a result of intensive research into a method for efficiently producing a 7-hydroxyprostaglan S conductor using raw material compounds that can be easily obtained by hand, the present inventors found that a 7-hydroxyprostaglan hα derivative was used as a raw material compound. ,
It was found that the target 7-hydroxyprostacyclin derivative can be more easily produced than the 7-hydroxyprostaglandin Fed derivative by reacting the compound with a mercury compound and then treating it with a borohydride compound. It has been reached. That is, represented by the following formula CI)
α11 is treated with a mercury compound in an inert audible medium, and then with a borohydride compound. This is a method of manufacturing conductors. The above formula (I) which is a raw material compound in the production method of the present invention
7-hydro p-xyprostaglandin F, an
The conductor consists of the four carbons (8, 9, 11) of the cyclopentane ring.
, 12th position) and two carbons at the 7th and 15th positions are asymmetric carbons, of which the 8th and 9th positions on cyclopentane are asymmetric carbons.
It includes all diastereotypes and Evimers except those in which the bonds (substituents) at the positions are in a trans relationship with each other. Since it can be fully predicted that the chemical reaction in the production method of the present invention proceeds without any conformational change, the conformation of the resulting 7-hydroxypustacycline derivative represented by formula C11) is different from that of the raw material. Certain compounds of formula CI), namely 7-hydroxyptetrastaglandin Fl,
f) The conformation is exactly the same as that of the derivative. The above formula [! ], the symbol between the 13th and 14th positions =
represents that there is a double bond or triple bond between the 13th and 14th positions. G represents 100, R@ or -CONR'R', where ytl is a hydrogen atom, a C1-C3 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted alicyclic group, Substituted or unsubstituted phenyl (C*~Cm
) 7 Alkyl group or tri(c, -ay) hydrocarbon-silyl group. Examples of the alkyl group of c, ""' C1@ include,
Methyl, ethyl, n-propyl + 1so-propyl. n-butyl + 5ee-butyl + t+rt-butyl, n-pentyl, n-hexyl, n-heptyl, n-
Mention may be made of linear or branched ones such as octyl, n-nonyl and n-decyl. Examples of the substituent for the substituted or unsubstituted phenyl group include a halogen atom and a human mixi group. C, -C, acyloxy group, C1-C4 alkyl group optionally substituted with a hagen atom, C3-C, flukoxy group optionally substituted with a halogen atom. A nitrile group, a carboxyl group, a (C, to c6) alkoxycarboxylic group, etc. are preferred. As the halogen atom, fluorine, #1 element, bromine, etc., and particularly fluorine or chlorine are preferable. Examples of the C1-C, acyloxy group include 7cetoxy, propionyloxy, n-butyryloxy+1
so-butyryloxy, n-valeryloxy, l5o-
Mention may be made of valeryloxy, cab-yloxy, enantyloxy or benzoyloxy. Examples of the C1-C4 alkyl group optionally substituted with halogen include methyl, ethyl, n-propyl + Igo
Preferred examples include -propyl+n-7'thyl, chloromethyl, dichloromethyl, trifluoromethyl and the like. Examples of the C2-C, phenoxy group which may be substituted with nitrogen include methoxy, ethoxy, n-proboxy+1so-p4poxy, and n-dutoxy. Chloromethoxy. Preferred examples include dichloromethoxy and trifluoromethoxy. (C
Examples of the 1-C6) flukoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl, and the like. The substituted phenyl group can have 1 to 3, preferably 1 substituent as described above. Substituted or unsubstituted alicyclic groups include saturated or unsaturated C, -C groups, preferably 01 to 0 cm, particularly preferably C0 groups, substituted with the same substituents as mentioned above or unsubstituted. , for example cyclopentyl, cyclohexyl, cyclohexyl. Examples include cycloheptyl and cyclooctyl. Examples of the substituted or unsubstituted phenyl (C, -C,) alkyl group include benzyl, α-7enethyl, and β-phenethyl, in which the phenyl group is substituted with the same substituent as above or unsubstituted. . )! Examples of the (C1-cy) hydrocarbon silyl group include dove dimethylsilyl. Triethylsilyl. (such as t-butyldimethylsilyl group)! I (C, ~
C1) Preferred examples include alkylsilyl, diphenyl(C1-C4)alkylsilyl such as 1-butyldiphenylsilyl, tribenzylsilyl, and dimethyl-(2,4,6-tri-t-butylphenoxy)silyl. be able to. R' and R' of -CONR'R' are the same or different, and are a hydrogen atom, a C0 to C8 alkyl group, or R6 and R7 together with the nitrogen atom to which they are bonded further contain a heteroatom. C represents an optionally substituted or unsubstituted ring of 5 to 6 #i. Here, the C1-C1° alkyl group includes the same alkyl groups as mentioned above. Further, examples of the substituent in the above-mentioned substituted or unsubstituted ring include the same substituents as those mentioned above, and examples of the hetero atom include nitrogen, sulfur, or oxygen atoms. Examples of the above-mentioned ring include 1-pyrrolidyl and thiazolyl. 1-piperidyl, morpholyl, piperazyl or 5.6-
Examples include cyhydrophenanthridyl group. As G, ns is C, ~C,,'y alkyl group, special methyl group, CO! R11 is preferred. R1 is a hydrogen atom, a methyl group, an ethynyl group (-CmiCH)
or a protected ethynyl group. Protected ethynyl groups include, for example, trimethylsilylethynyl, t-/
/Tyldimethylsilylethynyl group etc. are preferred. Among these σ), a hydrogen atom or a methyl group is preferred. W is an unsubstituted C1-C8 alkyl group; an optionally substituted phenyl group, a phenoxy group IC, a substituted C1-C, furkyl group substituted with a C, -C6 alkoxy group or a C3-C6 cycloalkyl group: or a substituted or unsubstituted alicyclic group. The unsubstituted furkyl group of C6-C, may be either linear or branched. For example, n-pentyl, n-hexyl, 2-methyl-
1-hexyl, 2-methyl-2-hexyl, n-heptyl, n-octyl, etc., preferably n-pentyl. n-^, xyl, 2-methyl-]-hexyl, 2-methyl-2-hexyl, and the like. Replacement 01~
The C, alkyl group may be linear or branched, such as methyl, ethyl, n-propyl, 1so-propyl. i-Butyl* l1ee-butyl. t-butyl. n-
Examples include pentyl. These substituted alkyl groups include phenyl group; phenoxy group; methoxy, ethoxy, n-propoxy, 1so-propoxy, n-butoxy+15o-butoxy. C1-C6 alkoxy group of t-butoxy, n-pentoxy, n-hexoxynato; cyclopentyl. Substituted with a C6-C6 cycloalkyl group such as cyclohexyl. These substituents may also be substituted by the aS group listed as a substituent for the substituted phenyl group of KR'. Examples of substituted C3-C, alkyl groups include C3-C, substituted by a phenoxy group or a phenyl group, which may be substituted with a fluorine atom, chlorine atom, metal, ethyl or trifluoromethyl group; Furkyl group, or propoxymethyl, ethoxyethyl, norboxyethyl. Methoxymethyl, methoxypropyl, 2-ethoxy-1
, 1-dimethylethyl, propoxydimethylmethyl, or cyclohexylmethyl, cyclohexylethyl, cyclohexyldimethylmethyl, 2-cyclohexyl-1,
1-dimethylethyl and the like are preferred. As the substituted or unsubstituted alicyclic group, the same groups as those listed for R'K can be mentioned. RM is preferably n-pentyl, 2-methyl-1-hexyl, cyclopentyl or cyclohexyl group. W and W are the same or different and are hydrogen atoms. C! A group that forms an acetal bond with an oxygen atom of a ~C,7 syl group, a tri(C1~C,) hydrocarbon-silyl group, or a hydroxyl group. C! -C, the acyl group is, for example, acetyl. Bupionyl, n-butyryl + igo-butyryl. n-valeryl, 1so-valeryl, caproyl. Enantyl, benzoyl, etc. may be mentioned. Among these, C1-C6 aliphatic acyl groups such as 7-cetyl, n- or 1so-butyryl, caproyl, or benzoyl are preferred. As the tri(C,~cy)hydrocarbon-silyl group, R1
The same things as those mentioned above can be mentioned. Groups that form a 7-cetal bond with the oxygen atom of a hydroxyl group include, for example, methoxymethyl, l-ethoxyethyl,
2-methoxy-2-propyl, 2-ethoxy-2-propyl, (2-methoxyethoxy)methyl, benzyloxymethyl. 2-tetrahyto-pyranyl, 2-tetrahytomifuranyl, 4-(4-methoxy-tetrahydropyranyl) group or 6,6-dimethyl-3-oxa-2-oxo-bicycou(3,1,0) hekis- Mention may be made of the 4-yl group. Among these, 2-tetrahydropyranyl, 2-tetrahydro7ranyl, l-ethoxyethyl, 2-methoxy-2-propyl, (2-methoxyethoxy)methyl,
4-(4-methoxytetrahyFropyranyl) group or 6.
6-dimethyl-3-oxa-2-oxobicic o(3
, 1,0) hex-4-yl group is particularly preferred. These silyl groups, acyl groups, and groups forming an acetal bond should be understood to be hydroxyl group-retaining groups. As R3 or R4, these t-pthyldimethylsilyl group, 2-tetrahydropyranyl group, acetyl group, and 1-methyl-1-hexyl group are preferable. The 7-hyF-roxyprostaglandin F, α derivative represented by the above formula CI) used as a raw material compound can be easily produced by a method separately filed by the present inventors (see the figure below). 00H0HOH OR'' By reacting the 7-hydroxyprostaglandin F'*cL derivative represented by the above formula (I) with a mercury compound in an inert organic medium, and then treating it with a borohydride compound, the objective can be achieved. A 7-hyphenyl-'-xyprostacychryso derivative ["] is obtained. The inert organic medium used in this case is an aprotic organic medium such as ethyl ether, isopropyl ether, tetrahydrofuran, dioxane. Ether-based organic media such as dimethoxyethane; hagenated hydrocarbon-based organic media such as chloroform, methylene chloride, and carbon tetrachloride are preferably used. Among the mercury compounds, mercury carboxylates and mercury halides are preferred. Mercury oxide is preferred. Examples of mercury carboxylate salts include mercury acetate, mercury trifluoroacetate, and examples of mercury halides include mercury chloride, mercury bromide, and mercury monomeride. , mercury acetate, mercury trifluoroacetate, and mercury chloride are preferable.The mercury compound has 0,9 to I
The amount used is s times equivalent, preferably 1.0 to 3 times equivalent. The reaction temperature is -50°C to ]OO'C1 preferably -30°C
The temperature range is 50°C. The reaction time usually ranges from 5 minutes to 2 hours. The reaction can be carried out by adding a solution or mixture of the mercury compound in an inert organic medium, the raw substrate, or a solution dissolved in the same or different inert organic medium used to dissolve the mercury compound in the raw substrate; Begin by adding inversely. It is thought that an intermediate represented by the following formula (A) is probably produced by this first-stage reaction. 7-hydroxyprostaglandin py a of formula [I]
The derivative is reacted with a mercury compound in an inert organic medium and then treated with a borohydride compound. It is thought that the HgX residue of the compound of formula (A) is reductively eliminated by such treatment. The mercury compound used here has the following formula [1■
] A borohydride compound represented by M(R,)4-mBHm ==·C111 is preferred. Here, M is, for example, sodium or potassium. Preferred examples include alkali metal atoms such as lithium, and R
Examples of 8 include methyl, ethyl, n-propyl, n
Preferred examples include C, -C, alkyl groups such as -butyl + 5ee-butyl + n-pentyl group (amyl group); C, -06 flukoxy groups such as methoxy, ethoxy, pupoxy, and butoxy groups. Examples of such borohydride compounds include sodium borohydride, lithium borohydride, and lithium triethylborohydride. Sodium triethylborohydride, triethylborohydride fl
ee-Sodium butylboronate, hydrogenated Toso 1111
Su-butylboron lithium, hydrogenated tree l! ee-
Butyl boron potassium, tris7mil boron hydride potassium, sodium trimethoxy boron hydride, lithium trimethoxy boron hydride, sodium triethoxy boron hydride. Examples include lithium triethoxyborohydride, sodium tripropoxyborohydride, sodium cyanoborohydride, and the like. Among these, sodium borohydride, sodium tritoxyborohydride, and sodium triethoxyborohydride are particularly preferred. The amount of the borohydride compound used is 7-hydroxyprostaglandin Fva Fh! of formula (I). The molar amount is usually 1 to 50 times that of the l-isomer. Treatment with borohydride compounds, i.e. reductive mercury (
The HgX ) elimination reaction is carried out in the same inert organic medium used in the first stage reaction with the mercury compound, preferably a protic medium. Examples of the protic medium include methyl alcohol, ethyl alcohol, inpropyl alcohol, water, and mixtures thereof. When treating with a borohydride compound, the following method is employed. That is, the inert organic medium used in the first step may be removed using a method such as distillation under reduced pressure, and then the protic medium may be added, or the protic medium may be added without performing the removal operation. Good too. At this time, the amount of protic medium used is preferably 1 to 10 times (by volume) the inert organic medium used in the first step. When using water as the protic medium, for example, alkaline water prepared using sodium hydroxide or the like may be used. The reaction time is usually 30 minutes to 24 hours. The crude reaction product obtained can be post-treated according to a conventional method. For example, hexane or pentane. Addition of an organic solvent soluble in water and Ca such as petroleum ether or ethyl ether, or After directly concentrating the reaction mixture under reduced pressure, the organic mixture obtained by the same operation was washed with brine, anhydrous magnesium sulfate and anhydrous sodium sulfate. After drying with a desiccant such as anhydrous potassium carbonate, the organic medium was removed under reduced pressure. A crude product is obtained. The crude product can be purified, if desired, by a purification means such as column chromatography, thin layer chromatography, liquid chromatography, etc. Stacyclin derivatives affected by monohydro-σ-xib can be easily and efficiently produced. Specific examples of 7-hydroxyprostacyclin derivatives produced by the present invention include the following: (1) 7- Hydroxyprostacyclin +2115
-Cyclopentyl-7-hydroxyprostacyclin + 3115-cyclohexyl-7-hydroxyprostacycline (4) 17-methyl-7-hydroxyprostacyclin + 5115-methyl-7-hydroxyprostacyclin + 61 (Methyl ester of 11 to (5) (71
fll~f5117) ethyl ester (81 +61
11.15-Bisuptyldimethylsilyl ether (11th position of 91 +61 is methoxyinpropyl group. 15th position is protected with t-butyldimethylsilyl group (11th position of 11 +e+ is t-butyldiphenylsilyl group) A compound protected with a t-butyldimethylsilyl group at the 15th position (Ill (a compound protected with a 4-(4-methoxytetrahydropyranyl) group at the 11th position of 61 and a monobutyldimethylsilyl group at the 15th position) (12+6117) 11th place is '))chik( 2, 4.
6-) lyt-7'tylphenyloxy)silyl group. A compound in which the 15th position is protected with a t-butyldimethylsilyl group. The present invention is useful as a stabilized prostacyclin derivative, and is also useful as a raw material for the production of other stabilized prostacyclin derivatives, such as 7-fluorobrostacyclin derivatives and 5-fluoroprostacyclin derivatives. The purpose of the present invention is to provide a method for easily and efficiently producing 7-hydroxyprostaglandin F,a derivatives, which are 7-hydroxyprostaglandin F,a derivatives, and its significance is in the production of useful pharmaceuticals. It's immeasurable in terms of what I do. The present invention will be illustrated below with reference to Examples, but it is not limited thereto. Example 1 (78,8R,98,IIR,158)-5,6-dihydro-dihydroxyprostaglandin F, 11,15-bis-butyldimethylsilyl ether of α-methyl ester (200 μ) was added to 40 ml of tetrahydrofuran (1K).
The dissolved solution was mixed with mercury trifluoroacetate or 3 #l of tetrahydrofuran under argon atmosphere and cooling with water. added to the solution. The water bath was removed, and the mixture was allowed to react at room temperature for 10 minutes, and then 62 In9 of sodium borohydride was added again with 4 parts of methanol while cooling with water. When the addition was completed, the aqueous solution was removed and the mixture was stirred for 1 hour. The mixture was filtered through Celite. 150 d of ether was added, washed three times with saturated sodium chloride water, and dried and distilled over anhydrous potassium carbonate-anhydrous magnesium sulfate. /3) K and purify 7S, 8R, 9S, IIR. 11. of l5S)-7-hydroxyp-stazycline methyl ester. Is-bis-t-methyldimethylsilyl ether 116# was prepared. The spectral data of this product were as follows. 'H-nmr(CDCA'@) a ;5.48(2H
, m), 4.75 (IH, m) 4, 4ty (IH, t
, J=7Hz), 4.27 (IH,s). 4.07 (IH, m), 3.83 (IH, m). a, an (3H, @). C-1 anmr (ppm); ■'4.4.158.7.135.9.128.6゜9
9, 2.82.7.77, 9.77.5.72.8°5
3.5.51.4.41.6.38.5.33.6゜3
1, 8.25.9.25.8.25.1.25.0゜2
4.7.22.6. IJ 2.1B, 0.14. O
. -4,7,-4,6,-4,5,-4,2゜Mass(
) Limethylsilyl ether) 70 eVm/e; 6s
z(M+), 625,551,533 Example 2 (7R,8R,9S,11R,15s)-5,6-dihydro-twohydroxyprostaglandin R (11.15-bis-t-of t-methyl ester Butyldimethylsilyl ether 95Tv was dissolved in tetrahydrofuran 2- and treated in the same manner as in Example 1 using a solution of mercury(II) trifluoroacetate 7:I tq in tetrahydrofuran 1.5 wJ. The crude product was subjected to 70 lysyl column chromatography (n-hexane-ethyl acetate-
Purify with 1% triethylamine 100/IK and obtain the desired product (7R98R+ 9S# 11R* ”S
) '-Hydroxyprostacyclin methyl ester II. 15-bis-butyldimethylsilyl ether 54
I got it right away. The spectrum 7'-ta of this product was as follows. H-nmr (CD (Jl) δ; 5.38 (2H+ mL 4.73 (IH 1 mL 4, 5
0 (I H+ d+ J""' Hz). 4, 39 (IH, t, J=+7Hz). C-xanmr (ppm); 174.3.158.9.134.9, 129.6°9
7.4,83 2. F8,9,73,2,71.9゜51,4.150+2.49.9.41.9.38.3
゜311.7.31.8.25.9.25.2.25.
0°24, 7.22.6.18.3.14.0. -4.
2°-4+6. -15.0°Mas s (70sV) ()! 682 (M+), 62B, 651
, 838° Meio side 3 The hydroxyl groups at the 11th and 15th positions were protected with a methoxyisopropyl group and a t-butyldimethylsilyl group, respectively (7S
, 8R,98,IIR,158)-5,6-dehyF0-
7-human roxypsistaglandin F,. A solution of 45 μm of methyl ester in 1d of tetrahyfuran was mixed with mercury chloride (
[1] 24 W#p was added to a tetrahydro 7-run mixture at room temperature and allowed to react for 15 minutes at room temperature.The crude product obtained by the same procedure as in Example 1 was subjected to turidyl column chromatography. (n-hexane-ethyl acetate-1% triethylamine) K and purified, and the hydroxyl groups at the 11th and 15th positions were protected with a methoxyisopropyl group and a t-butyldimethylsilyl group, respectively. 28 das of methylester were obtained. The spectral data of this product were as follows. nmr CCDCl@ ) δ; s, 5r (211, m). 4.80 (IH, rnL4゜53 (I H* L J=7Hz L 4.30 (I
Hls)+4.20-3.80(2H,rn), 3.6
8 (3H, I). 3.20 (3H, s). Example 4 (7R8, [lR, 98111R, 158)-11,6
-dehyde 0-15-cyclopentyl-7-human oxygen 16. ! 11, 18- of 7,18,19.20-pentatrue prostaglandin hα methyl ester
Using 100 da of bis-1-,/tyldimethylsilyl ether, the reaction was carried out in the same manner as in Utility Model 1, followed by post-treatment to obtain the desired (7R8, SR, 98, IIR. 153) -1Is-cip Ope. 7-k-7-human-xyprostacycline methyl ester 11°15
-Bis-t-butyldimethylsilyl ether (55) was obtained. The spectral data of this product were as follows. 'H-nmr (CD (Js) δ; 5.30 (IHls), 4.77 (IH, m). 4, 5orin, to J=7Hz), 4.27 (
IH, I). 4, 02 (IH+ nl), 3.90 (11 (+ mL)
3.65 (3H, 8). Mass (20eV) m/@; 60g (M+), 55
1. Example 5 CTR8* 8R, 9B, IIR, 158)-5,6-
DehyF-15-cyclohexyl-7-hyF-1
6,17,18,39,20-pentanorp p-staglandin F'ta methyl ester l 1. I S-bis-t-7' methyldimethylsilyl ether compound 85■ was reacted in the same manner as in Example 1 to obtain the desired product (7R8,
8R,98,IIR,IFlB) -15-cyclohexyl-7-hydroxyprostacycline methyl ester, 15-bis-t-butyldimethylsilyl ether 40M4I, etc. The spectral data of this product was of first order. 'H-nmr (CDC/1) J es, 4
g (2L m), 4. 78 (I Hl
mL4, 45 (IH, t, J=7Hz), 4.2
15 (IH,,). 4, o (tH, mL 3.9 (IHI m). a, as (sH, s). Mass (20 eV) m/e; 622 (M+). (7R8, SR, 98, IIR, 5ss) -s , e-dehydro-7-human-xy-17.20-dimethylregrostaglandin avian alpha methyl ester of 115-t-7'
Tyldimethylsilyl ether-11-i-butyldiphenylsilyl ether 60 was reacted in the same manner as in Example 1 to obtain the desired product (7R8°SR,9S, IIR,1
1i3) - Fuhi FC! 15-4-7'Tyldimethylsilyl ether-tt-t-butyldiphenylsilyl ether of xy-17,20-dimethyl booster cycline methyl ester was obtained. The spectral data of this product was as follows. 'H-nmr(CD(1,)J; 5,511(21(,m), 4°9~11.8(SR
,I? IL3.70 (3[,s). Mass (2 (leV) m/e; 762 (M+) Example f()R8I 8R198, 11R, 15S) -5,6-
1s-1-Butyldimethylsilyl ether of zohydro 7-hydroxybrostaglandin bα methyl ester 1l-(4-(4-methoxytetrahydropyranyl))
The ether form goIn9 was reacted in the same manner as in Example 1 to obtain the desired reaction (7R8°SR, 9L IIR, 15
9)-15-t-Butyldimethylsilyl ether of fuhyyroxyprostacychlisomethyl ester 11-[
4-(4-methoxytetrahydropyranyl)]ether compound 301v was obtained. The spectral data of this product were as follows. 'H-nmr CCDCl, ) J ;s, S (
2H, m)e 4. e~s,s (aH). 3,70('4H,t, J-5H$), 3.68(
Ile 8). 3.25 (3H, I) Mass (1!O*V) m/e; 15113 (M±57
) Example 8 (7R8,SR,98,1JR,j!1s)-! i, 6
-dehyde 0-7-hydroxyprostaglandin F, α
Methyl ester 1s-t-7' tildimethylsilyl ether 13-(2-tetrahydropyranyl) ether 100~ is reacted with Example 1 to obtain the desired (7R8l 8R, ossllR, 1519) - 7
-S+ of hyF roxypustacycline methyl ester
5-t-//Tyldimethylsilyl ether 11-(,2
-tetrahuman 1-pyranyl) ether 15sq was obtained. The spectral data of this product were as follows. 'H-nm r (CDCIg) a; 5, Is
5 (2H, m), 5. O-3,7(8H)*s, 5s
(sH, s and m). Mass (20eV) m/a; 523 (M”-57)
. Example 9 15-1-Butyldimethylsilyl ether 11-dimethyl (L4.6-) of H0H (7R8,8R,98,IIR,15B)-5,6-dihydro-twohydroxy prostaglandin F, alpha methyl ester The desired product (7R8, 8R, 9s, II
R,1158)-7-Hydoxyp 1 stacycline methyl ester 15-t-fuldimethylsilyl ether 11-dimethyl(2,4,6-)-t-butylphenyloxy)silyl ether 62~ Ta. The spectral data of this product were as follows. 'H-nmr (CDCIg) δ: y, aa (aH, s), s, as (2H, m). 5, O-3,7(5H), 3.6[i(3)ilg,)
-Mass (20eV) m/@; 757 (M-57). Procedural amendment dated January/2nd, 1982, Director General of the Japan Patent Office 1, Indication of the case, Patent Application No. 117791/1982, 2, Title of the invention 7 - Process for producing p-stazycline derivatives of hydroxyplast 3
Relationship with the case of the person making the amendment Patent Applicant 1-11 Minamihonmachi, Higashi-ku, Osaka (300) Representative Tokusue Tomo Teijin Co., Ltd. e) 0) Scope of Claims in the Specification ” shall be corrected as shown in the attached sheet. (2) Vc on page 12, line 10.31j to line 5 of the specification [The bonding hands (substituents) at the 8th and 9th positions on the cyclopentane ring are mutually trans. "The 8- and 9-position bonds (substituents) on the cyclopentane ring are cis. ] Correct. (3) On page 12, line 10, the following is corrected. (4) On page 12, lines 11 and 12, "In the formula, a, nl, R", W, and n; are the same as defined above. ” is replaced by [in the formula, symbol 3, G ,
R, +, FL”, R”. R84 is the same as defined above. ” he corrected. (5) Page 5, line 8 ll'c [where G, R' ~
The statement "R' is the same as the above definition" is corrected to "In the formula, the symbols G, R'-n,' are the same as the above definition." (6) Add the following sentence next to the bottom line of page 45. (7R,) -s, 6-dihydro-15-cyclopentyl-7-hydroxy-16,17,18゜19,
20--<7 tanol prostaglandin F. 85 g of lj, 15-diacetate of methyl ester was dissolved in 2111K dry tetrahydrofuran and heated at -30°.
It was cooled to Mercury (11) Refluoroacetate 11
A dry solution of Terolahitro 7 run 1y of 589 was added and stirred for 5 minutes, then sodium boron hydride 3489 and methanol lil were added and stirred at the same temperature for 1 hour. 3 od of ethyl ether was added, and the organic layer was washed with saturated brine and dried by trapping anhydrous potassium carbonate and anhydrous magnesium sulfate. After filtration, add a small amount of triethylamine to reduce EIE WI
It was purified by silica glucuronidography (-,
Xane-ethyl acetate = 7:3 (contains 0, i% triethylamine). 631117 (7B)-η-hydroxyprostacyclin (7R,)-15-cyclobenthyl-7-hydroxyl 16, 17°18, 19, 2
0-Pentatulprostacyclin methyl ester 1
1,15-diacetate was obtained. The spectral data of this product were as follows. l-1 (coating, ゛): 3 7 7 0,
1 7 3 5cWL-'NMR (0004) J
: 1.98, 2.02 (6H, 2s), 3
．． 67 (3H, l) 4.1-5+2 (5H, m)
, 5.50-5.75 (2H, m) (1B)-5,6-dihydro-15-cyfrobenthylhydrohydro-16,17,18,19,20-pentatulu prostaglandin F , 11 of a methyl ester
, Example 10 from 20011 g of 15-diacetate
Similarly, (78)-15-cyclopentyl-7-
Hydroxy 16, 17, 18, 19, 20-
11 of pentatulprostacyclin methyl ester
, 15-diacetate compound 1211119 was obtained. The spectral data of this product were as follows. IR (painted): 3470.1740cm-'NMR (0
001m) δ: 1. es, 2.00 (6H
. 2 S), 3.65 (3H, 8) 4.2
8 (I H, 8), 4.50 (I H, t. J = 7 Hri 4.6 0 - 5.3 0 (3H, m)
, 5.4 0 -5.6 5 (2H, m) (7R)-"+'-Dehydro 7-hydroxyprostaglandin F, 11°15-diacetate of α-methyl ester 220 mfl dry tetrahydrofuran 58
1 (220 μ of mercury (■) trifluoroacetate was added to the 1+ solution under water cooling, and after 10 minutes, 5 ml of methanol and 90 μ of sodium hydride were added, and the mixture was stirred at room temperature for 1 hour. 100 ml of ethyl ether was added, and saturated brine was added. After washing, it was dried over anhydrous potassium carbonate and anhydrous magnesium sulfate, and then evaporated under reduced pressure, and purified by fusilidyl columnar hymatogelafie (cyclohexane-ethyl acetate-9=1. containing 0.3% triethylamine). 120 TRfl (7R)
The 11,15-diacetate form of -7-hydroxyp-stacycline methyl ester was 1%. The spectral data of this product were as follows. IR (coating): 3460, 17350-1SMR (Co
(]/,)δ: 2. o o (6ft,
S). 3.65 (3H, 8), 4.22-5.35 (5H1m
), 5,4 5 5.7 5 (2H
tm) (78)-5,6-zohydro-7-hydroΦsibrostaglandin F-methyl ester 11,15-diacetate 200149 was reacted in the same manner as in Example 12 to obtain (78)-7- of 12089. The 11,15-diacetate of hydroxy-p-xyprostacyclin methyl ester was obtained. The spectral data of this product were as follows. IIL (paint): 3470, 1740 (!++1-'N
MrL((5001,)δ: 1.98, 2.00
(6H. 28), 3.66 (3H, 8) 4.25 (I
H, 8), 4.52 (I H. t, J=7) 1z) 4.60-5.30 (3H, m), 5,3S
-5,60(2H,m) J Claim 1: 7-hydroxyprostaglandin F, α represented by the following formula [l]
reacting the derivative with a mercury compound in an inert organic medium;
1. A method for producing a 7-hydroxyprostacyclin derivative represented by the following formula [1], which is then treated with a borohydride compound. 2. The method for producing 7-hydroxyprostacyclin IIIM# according to claim 1, wherein the mercury compound is a mercury carboxylate salt, a mercury halide, or a mercury oxide. 3. The method for producing a 7-hydroxyprostacyclin derivative according to claim 2, wherein the mercury carboxylate salt is mercury acetate or mercury trifluoroacetate. 4. The method for producing a 7-hydroxyprostacyclin derivative according to claim 2, wherein the mercury halide is mercury chloride. 5. The borohydride compound has the following formula [■]M (&),
-mBHm ・・・・・・・・・・・・ Claim 1 which is a boron hydride compound represented by [drunk]
A method for producing the 7-hydroxyprostacyclin derivative according to any one of Items 1 to 4. 6. The method for producing a 7-hydroxyprostacyclin derivative according to claim 5, wherein the borohydride compound is sodium borohydride, sodium trimethoxyborohydride, or sodium triethoxyborohydride. 7. Any one of claims 1 to 6, wherein G in the above formula [1] is a methoxycarbonyl group
A method for producing a 7-hydroxyprostacyclin derivative according to X. 8. In the above formula CD, [R1 is n-pentyl group, 2-
8. A method for producing a 7-hydo-1-sib-1-stacycline derivative according to any one of claims 1 to 7, which is a methyl-1-hexyl group, a cyclohexyl group, or a cyclopentyl group. 9. In the above formula (i) ttc, R8 and R4 are the same or different, t-butyldimethylsilyl group, 2-tetra and dropyranyl group, 7 cetyl group, 1-methoxy-I-methylethyl, 4.4- (4-methoxytetrahydropyranyl) group, 6,6-dimethyl-3-oxa-2-oxobicyclo[3,1,0]hex-4-yl group or dimethyl (2,4,6-tri-t-butyl A method for producing a 7-hydroxyprostacyclin derivative according to any one of claims 1 to 8, wherein the 7-hydroxyprostacyclin derivative is a phenyloxy)silyl group.

Claims (1)

[Claims] 1. 7-hydroxyprostaglandin F1α represented by the following formula CI) OR'
A rust conductor is reacted with a mercury compound in an inert organic medium,
A method for producing a 7-hydro-p-xyprostacyclin-bound conductor represented by the following formula (IF), which is then treated with a borohydride compound. 2. 7-- of claim 1, wherein the mercury compound is a mercury carboxylate salt, mercury chloride, or mercury oxide.
Method for producing hydroxyprostacyclin derivatives. 3. The carboxylic acid mercury salt is mercury acetate or trifluoro-
7-Hydroxyprostacyclin derivative according to claim 2, wherein the 7-hydroxyprostacyclin derivative is mercury acetate; and the method for producing a 7-hydroxyprostacyclin derivative according to claim 2, wherein the halogenated water is mercury chloride. 1 The borohydride compound has the following formula [■]M(R@)4-
Claims 1 to 3 are boron hydride compounds represented by mBHm...''...--(III)
4. The method for producing a 7-hydroxyprostacyclin derivative according to any one of t. 6. The borohydride compound is sodium borohydride,
6. The method for producing a 7-hydroxyprostacyclin derivative according to claim 5, wherein the 7-hydroxyprostacyclin derivative is sodium trimethoxyborohydride or sodium triethoxyborohydride. 7. The method for producing a 7-hydroxyprostacyclin derivative according to any one of claims 1 to 6, wherein in the above formula CI), G is a methoxycarbonyl group.艮 Formula CI) [wherein R7 is an n-pentyl group. A method for producing a 7-hydro-xyprostacycline derivative according to any one of claims 1 to 7, wherein the derivative is a 2-methyl-1-hexyl group, a cyclohexyl group, or a cyclopentyl group. 9. In the above formula (I), R3 and R4 are the same or different; pyranyl)
group, 6,6-dimethyl-3-oxa-2-oxobicyclo(3,1,0)hex-4-yl group or dimethyl(2
+L6-) Lee t-7'chiruhueni! A method for producing a 7-hydroxyprostacyclin derivative according to any one of claims 1 to 8, which is a leoxysilyl group.