JPS6193137A - Production of optically active compound through asymmetric induction - Google Patents

Abstract

PURPOSE:To obtain an optical active intermediate for synthesizing carbacyclin without requiring optical resolution process, by using a cis-4-cyclohexen-1,2-ylene diacetic acid diamide derivative as a starting raw material, and reacting it with an achiral nucleophilic agent. CONSTITUTION:A compound shown by the formula I (T is group shown by the formula II; R<1> is lower alkyl; . mark is carbon atom or R- or S-configuration) is reacted with an alcohol shown by the formula R<2>-OH (R<2> is alkyl), a secondary amine shown by the formula R<3>R<4>NH (R<3> and R<4> are alkyl or linked to from alkylene), or an arylthiol shown by the formula R<5>-SH (R<5> is aryl) as an achiral nucleophilic agent, to form preferentially either of a compound shown by the formula III or formula VI. The prepared compound is reacted with a nucleophilic agent different from that in the reaction, so that it is converted to an unsymmetrical compound shown by the formula V or formula VI. The compounds shown by the formula III-formula VI are subjected to Dieckmann condensation reaction, the group R<6> or the group R<7> is eliminated to give a compound shown by the formula VII or formula VIII (R<8> is OR<2>, NR<3>R<4>, or SR<5>), which is converted to an optically active substance shown by the formula IX or formula X (R<9> and R<10> are H, or OH-protecting group).

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to optically active bicyclo [≠v 3
t' ] Compound is related to a method for producing a compound from an achiral raw material metal by asymmetric induction. The present invention also provides a novel raw material metal used in this method,
It also relates to novel metal compounds produced as intermediates. In recent years, prostacyclin, which has a strong platelet aggregation inhibitory effect, has been discovered and is attracting attention. However, since prostacyclin is chemically unstable, various more stable analogs have been synthesized. Among them, carbacyclin (compound/) represented by the following formula % is the most promising compound because it has excellent stability and has a pharmacological action very similar to prostacyclin (Unexamined Japanese Patent Application Publication No. (Sho 5J-ttizpi issue). There is a need for the development of an advantageous method for synthesizing carbacycline (I). The only methods for synthesizing carbacycline (I) that have been reported to date include a method of synthesizing optically active carbacycline using an optically resolved raw material, and a method of synthesizing a racemate. As an example of the former method using optically resolved raw materials, Japanese Patent Application Laid-open No. Sho ZS-6111, "Tetrahedron (Tetrahedron) J37 No.25 Ko32
1 page (year), [Journal of Org
anic chemistry) J 4' Volume A/
914' page (tyri year), same magazine Hiro ≠ volume 2110 page (I
972), “Angevante Chemie International Edition in English” (Angevante Chemie International Edition)
wandte C! hemie, international
onal Edition i, nEnglish
) The method shown in J Co. θ, vol. 104A & p.
internal of the Chemical Soc
iety) J/OA 7 pages (1999), “
Tetrahedron Letters
Letters) Jλ≠ Volume 3
), “Chemical and Pharmaceutical
Bretan (Chemical & Pharmiceu)
tical Bulletin) J J / Volume 377
There is a general review of these synthetic methods in "Now 5 synthetic roots".
+Pro@taglandin and Thromb
oxane) J Academic Press, London (
/91-). On the other hand, various methods are generally known for optical resolution, but the most widely used is a fractionation method in which diastereomeric salts are formed using a ceramic substrate and a resolving reagent. This is a method of separating by recrystallization. but,
Fractional recrystallization requires sophisticated and complicated techniques such as selection of recrystallization solvent, setting of temperature at 1m degree, and the actual yield is often considerably lower than the theoretical yield jO%. In addition, there is the disadvantage that the crystals obtained do not necessarily contain the desired isomer. As an intermediate raw material for carbacycline synthesis, a compound of or a compound of the following formula (b) [wherein R and R' may be the same or different,
[indicates a protecting group for a hydrogen atom or a hydroxyl group]] is known (JP-A-Sho ZS-TAJ+I and Tetrahedro Vol. 737, No. 2! μ).
(p. 321), and the method of synthesizing carbacycline (/') from this intermediate raw material compound is described in detail in the aforementioned Tetrahedron Vol. 37-2j, Hiroshi 3, p. 1 et seq. However, the carbacycline synthesis method that includes the complicated and low-efficiency optical resolution step at some stage, as described above,
There is a disadvantage that the overall yield of carbacycline is inevitably low. Means for Solving the Problems In view of the above, the present inventor intended to synthesize an optically active carbacycline without involving an optical resolution step at any stage. With this intention in mind, by a novel asymmetric induction reaction, formula (a), which is known as an important intermediate in carbacycline synthesis,
Research has been conducted to provide a method for synthesizing the optically active compounds (b) and (b) in an optically pure form. As a result, cis-gucyclohexene-7,-2-ylene cyacetic acid, which has a symmetrical molecular structure, was used as a raw material, and ≠('fL)- or ≠(s)-'t3-theacylysia 2- Although the diamide derivative obtained by reacting thione has a symmetrical five-molecular structure, when an appropriate achiral nucleophile is applied to it, the amide of one of the two amide groups One group has the property of having a higher reaction activity than the other, reacting preferentially, thereby forming an asymmetric derivative, and furthermore, when the first achiral nucleophile acts, the first amide group It was discovered that this compound has the property of being able to react with other asymmetric compounds. Starting from this knowledge, we have conducted extensive research and have now succeeded in developing a reaction route that can efficiently synthesize the optically active compounds of formulas (a) and (b) above in an asymmetric manner. Based on this, the present invention has been completed. Therefore, the gist of the first invention is that the following general formula (I) [wherein T is represented by the following formula≠(R)- or≠(8)-alkoxycarzenyl/,3- a thiazolidine-corchion residue, 1.
a' is a lower alkyl group, especially a methyl or ethyl group, and the configuration of the carbon atom with a fist indicates the R-or S-configuration] cis≠-cyclohexene-/, 2- , yl-ene diacetic acid diamide derivative,
As an achiral nucleophile, a lower alcohol of the following formula (m) 几2-OH(m) [wherein R2 is a lower alkyl group] or the following formula (IV) [wherein R and 几 are each an alkyl group] is a group or R3
and R together form one alkylene chain]
or a secondary amine of the following formula (V) R5-S H(V) [wherein R is an aryl group, particularly a phenyl group] to react with an arylthiol of the following formula (Ma) to obtain a compound represented by the following formula (Ma) and a compound represented by the following formula (Vlb) [wherein T is the same as above, and 几 is derived from the lower alcohol (Ill) or amine (R7) or arylthiol (v) used as the nucleophile. alkoxy group -OR,
or substituted amine group -NR3 4. or arylthio group-
8R5] is preferentially produced in a stereoselective discrimination reaction, and then the obtained compound of formula (Ma) or compound of formula (Vlb) is added to the compound of formula (Vlb) used in the above reaction. 1 nucleophile compound (Ill), (IV) or (V
) with a second nucleophile compound selected from the lower alcohol of the formula (Ill), the amine of the formula (Ili/) and the arylthiol of the formula (■) to obtain the following formula ( ■Asymmetric compound of a) or the following formula (Mlb)
an asymmetric compound [wherein R is the same as above, R
7 is an alkoxy group -OR, a substituted amino group -Nl'L'R', or an arylthio group -8R5 derived from the second nucleophile compound used, and R6 and R7 belong to the same fam. is not a group] and further directly uses a compound of formula (■2) or a compound of formula (Mlb), or a compound of formula (■a) or a compound of formula (■b
) is subjected to Dieckmann condensation reaction to remove the base hole or the base hole, and the optical activity of the following formula (■a) circular knitting A ゛00-R,8 is obtained. compound, or an optically active compound of the following formula (Mb) [wherein 几8 is the compound (Vi
Base hole 6 in a), (Mb), (■a) or (Mb)
and R, which is the one with the smaller elimination property during the Dieckmann condensation reaction, an alkoxy group -OR, a substituted amino group -NR3R', or an arylthio group -8R5] is produced by a regioselective cyclization reaction, Furthermore, after that, the expression (
■ Reduction reaction of the compound of a) or the compound of formula (Mb) of its oxo group (=0) and/or group (-Co-R8), and protection reaction of the 7 or 2 hydroxyl groups formed thereby. , oxidative cleavage reaction of the cyclohexene ring double bond,
An alkyl esterification reaction of the two carbonyl groups thus formed, a cyclization reaction by Dieckmann condensation of two side chains having two alkoxycarbonyl groups formed thereby, and a cyclization reaction of the remaining alkoxycarbonyl group. By subjecting it to a series of steps including an elimination reaction and an optional elimination reaction of the remaining hydroxyl protecting group, the compound of the formula (■a) can be converted to the compound of the following formula (]Xa), Or from the compound of formula (■Ib), the following formula (IXb). The compound [wherein R? and B10 may be the same or different and represent a hydrogen atom or a hydroxyl group. The method of the present invention will be explained below. (I) cis-gucyclohexene- of general formula (I)
7゜Coylene, diacetic acid, and diamide derivatives have a molecular structure with a plane of symmetry. For Koylene (compound 2), there are two molecules of the following formula (■') (where R2 is a lower alkyl group ε carbon number/~μ), and the configuration of the carbon atom marked with a pot is R1-coordination. It can also be prepared by condensation reaction of ≠(R)- or da(S)-alkoxycardenyl/, J-thiazolidine-corchion represented by the Fis-coordination. The compound of formula (■') acts as an asymmetric auxiliary reagent for compound Ql. Suitable examples of this include the following ≠ compounds. (I) 4! (R)-Methoxycarzenyl 1. ! −
Thiazolidine-corchion [abbreviated as μ(R)-M OT] (compound 3-(co)4'(S)-methoxycarzenyl/,!-thiazolidine-corchion [≠(S)-M OT) ] (Compound!) H0OOOH3 (J) 4'(R)-Ethoxycarbonyl-/,!-
Thiazolidine-2-thione (4' (abbreviated as BJ-EcT)) (compound 6) HO0002H5 (9)) ≠ (S)-ethoxycarzenyl/, J-thiazolidine-corchion [Hiroshi (8) -E OT abbreviation ] Compound (3), that is, 4A(R)-MOT, is condensed with the co-molecule compound Nachisouban to form an active diamide derivative (Tl
An example of a reaction formula for preparing a compound, which is an example, is as follows. S (compound) (compound 3) (compound≠) However, Me represents a methyl group. The active diamide derivative of general formula (T) has a symmetrical molecular structure, but in addition to this, general formula (I), ■ Or (■) When treated with a achiral nucleophile, the diami-r derivative [■
] The amide site with higher activity among the two amide groups is identified and reacted preferentially to form the general formula (lV
a) or (ffb) is produced. In other words, in the compound of general formula H, two amide groups have chemically identical substituents, such as -(R)-M
Although they are bonded to c T , -(s)-Mo T , etc., they are not chemically equivalent and have different reactivities. Unfortunately, in compounds, one amide group reacts preferentially with various achiral nucleophilic groups, that is, one amide bond is preferentially attacked by the nucleophilic group, while the other The amide bond has the characteristic that it is less susceptible to attack. 01) First, in the method of the present invention, a diamide compound of general formula (I) is reacted with a nucleophile compound of formula (5) or (to) to form a compound of formula (■a) or (ffb). However, various nucleophiles of general formulas (I), (IV), Cv), such as bipe IJ syn, thiophenol or Examples of reactions that preferentially occur when methanol is applied to fc are illustrated below. (Compound ≠) S (Compound P) (Compound //) In addition, the diamide compound (I) obtained by the condensation reaction of Compound ≠ and one molecule of ≠(S)-MOT (Compound YO) has the following formula ( The diamide compound (I) obtained by the condensation reaction of compound 7 with one molecule of Hiro(R)-PCT (compound t) is the compound shown by formula C) below. t
It is. For these specific diamidated metals 7 and diamide compound r, the formula (ship, (5). Piperidine or theophe is used as various nucleophiles of the lock. Shows the reaction that occurs preferentially when nol is applied. and the following formula: Su (compound/2) O (compound/3) However, in the above reaction formula, -(R)MOT is ≠(R
)-MOT residue, -(8) MOT is Hiro(S)-MOT
residue, -(■ EOT represents the residue of ≠ (b) -E OT (the same applies hereinafter). As can be seen from the above reaction formula, diamide compound 7 has an optical activity opposite to that of diamide compound 7. This compound has a different amide group from that of the compound μ in that it is attacked by a nucleophile.On the other hand, the diamide compound r has an amide group at the same position as the diamide compound ≠, which reacts with the nucleophile. , Even if the diamide compound is the same, the nucleophile compound (I), GV) is acted upon.It is recognized that when the type of (2) is different, the amide moiety that preferentially reacts with the nucleophile is different. Diamide compound of general formula (I) and formula (I), ([V
) or M with a nucleophile compound is a stereoselective discrimination reaction, but in both reactions, in addition to the main product shown in the reaction formula above, the nucleophilic attack is directed against the compound (I ), a small amount of secondary product is formed at the other amide bond. These secondary substances have diastereomeric relationships with the main substance and therefore have different chemical properties. Therefore, these two diastereomers can be easily separated and purified by conventional methods such as recrystallization, silica gel chromatography, and liquid chromatography. Diamide derivative (I) and first nucleophile compound (button, (5
) or ■, the substitution reaction is carried out using -equivalent or excess amount of nucleophile. For example, when piperidine is used as the secondary amine [), the substitution reaction with arylthiol (
When benzenethiol, i.e. thiophenol, is used as the lower alcohol (I), it is used in the presence of an organic base such as triethylamine or in the form of a lithium salt, and methanol is used as the lower alcohol (I). When used, the substitution of formula (T%'a) or (IVb) can be produced in good yield by reacting tetanium tetraisoproboxide Ti (OOH(OH3)2,]4). In order to improve the production ratio of the main product of this substitution reaction,
It may be advantageous to add the nucleophile in portions. The solvent for this substitution reaction is a conventional organic solvent, such as ethers such as tetrahydrofuran and diethyl ether, halogenated hydrocarbons such as methylene chloride and chloroform, esters such as ethyl acetate, and aliphatic hydrocarbons such as n-hexane. , alcohol is used. These solvents are commercially available products and used as they are or in an anhydrous state after being purified by a conventional method. The reaction temperature can range from -100° C. by cooling with liquid nitrogen to room temperature or higher, and the optimum reaction temperature varies depending on various factors such as the combination of nucleophile and solvent. The reaction method is usually to react the nucleophilic compound of formula (I), QV) or A solution containing the agent is added dropwise, and if necessary, the solution is left at the same temperature, and if necessary, the temperature is raised to room temperature or higher. In general, the longer the time required for the dropwise addition, the better, usually 2 to 5 hours; however, as in the reaction with benzenethiol (thiophenol) in the presence of triethylamine, the reaction progresses slowly enough, so the time required for the dropwise addition is short. In some cases, it may be better to add titanium as a solvent all at once, as in the reaction with methanol in the presence of titanium 0° tetrane propoxide. The reaction was followed by thin layer chromatography (
Stationary phase Nijiri gel plate, developing phase: n-hexane-acetate ether (,2:/)% chloroform-methanol (
JO:/), benzene-ethyl acetate (j:/)% color former niline molybdic acid j% ethanol solution, iodine, /θ
sulfuric acid solution) or #i liquid chromatography (stationary phase Nisilica gel, mobile phase: n-hexane-ethyl acetate (
3:l), Detection: UV detector (30!nm))
etc. are often used. After the above substitution reaction, the reaction solution may be diluted with mineral acids such as normal hydrochloric acid or 10% sulfuric acid, organic acids such as 44-) toluenesulfonic acid or acetic acid, or acid salts such as ammonium chloride aqueous solution. If necessary, after concentration, it is washed by normal separation operation, and then column chromatography or recrystallization method is used to obtain the formula (ffa).
) or the target product of formula (IVb) is isolated. (ilD) In the method of the present invention, the obtained compound of formula CVIm or the compound of formula (VTb) is then
fe first nucleophile compound (I) used in the above reaction,
By reacting with a nucleophile compound of +iλ selected from lower alcohols of the formula (button), amines of formula (5) and arylthiols of formula (5) excluding (■), the molecule The above formula (■a) has an asymmetric structure
Alternatively, the compound of (VI[b) is produced, but the substitution reaction in this case is exactly the same as the reaction between the diamide derivative of general formula (I) and the first nucleophile compound used initially. It can be done. Isolation and purification of the desired optically active compound (■a) or (■b) after the reaction can be carried out in exactly the same manner as before. Compound (ri) obtained in the seventh substitution reaction described above. (/θ), (//) # (/force and (I3) are further reacted with a third nucleophile compound (I, (ffl, CVl) to form a compound of general formula (■a) or (■b). An example of the reaction formula produced is as follows: (Compound/7) (Compound is) (Compound I) The optically active compound (/I) obtained here is
The steric configuration was determined based on the optical rotation of compounds whose absolute structures have been determined by X-ray crystal analysis and on the basis of compounds 1 and 11. Compound → Compound /! , [αbet n + /−ta(I(C
O6≠], chloroform) [ (chemical property 20) Q [αbo0-/J, /'(cOj, chloroform)l
lψ In the method of the present invention, the compound of the formula (Via) or the compound of the formula (Vlb) is further used immediately, or the compound of the formula (■a) or the compound of the formula (■b) is used. For cyclization, the Dieckmann condensation reaction is carried out to remove the group R or the group 81', and the optically active mold, chlorine [μ, 3
．． o] Produces hazardous nonene. At this time, the cyclization reaction occurs regioselectively. This Dieckmann condensation reaction can be carried out by a known method. Bases used in this reaction include sodium hydride, potassium hydride and 1iliy! +- Dimzyl anion (Na”0H2SOOH3, K
0H2SOCH3), inorganic bases such as calcium hydride, DBU(/, J'-diazabicyclo(I,≠,0
] organic bases such as undec-7-ene), DFIN (/, j-diazabicyclo [day, j, Q) non-o-en],
LD person (lithium diisopropylamide), lithium-
Alkali metal salts of amines such as hexamethyldisilazane,
etc. are suitable. Examples of the solvent used include DMSO (dimethyl sulfoxide), THF (tetrahydrofuran), methylene chloride, etc.The reaction temperature depends on the type of compound of general formula (■a) or (■b) used, the combination of bases used,
and other factors in the range from 7r'O to room temperature or higher. To avoid extremely high or low concentration of the tFi reaction compound used, the solvent is selected within the range of 3 times to !θ times the mass of the compound of formula (■a) or (■b) used. To isolate the desired cyclized compound (■ resistance or (■ b),
Perform the following operations. After the reaction solution is cooled, it is neutralized by adding an amount of acid equal to or several times the chemical equivalent of the base used. Examples of acids used for neutralization include mineral acids such as 0.1 m/N hydrochloric acid and 10-thiosulfuric acid, organic acids such as ≠-toluenesulfonic acid and acetic acid, and acid salts such as an aqueous ammonium chloride solution. After neutralization, depending on the solvent, it may be concentrated, followed by normal separation operations (however, base washing is not preferred), and if necessary, silica gel column chromatography.
) or (■b) cyclized compound is isolated. The optically active bicyclo [≠, 3. O]nonene compound derivatives are one of the important intermediates in the synthesis of carnocycline and its related useful physiologically active substances, but its asymmetric synthesis has not yet been carried out prior to the method of the present invention. In the Dieckmann condensation reaction step of the method of the present invention, general formula (■a)
or (■b) is characterized in that only one of the groups H, 6, or R7 can be removed regioselectively. ] The desired cyclized compound can be selectively formed. In this cyclization reaction, the group with better elimination property among 81' or B,' of compound (■) is eliminated. Compound /y, The reaction formula for carrying out this Diekmann condensation reaction in the presence of a base using io, ii and lj, the base used, and the structural formula of the raw material are illustrated below. (Compound Col) Sweet υ ( Compound 2) +1 (Compound 3) H (Compound 2≠) It is clear from the above reaction formula that the levels of elimination properties of groups a6 and R1' are in the following order. Two groups (H, 6 and R7)
When a compound having the general formula (■) in its molecule is subjected to this Diekmann reaction, the group with strong elimination property (the group on the left side) is eliminated and cyclized, and the weak group (on the right side) becomes cyclized. The remaining compound of formula (Vl! or (I'lb) is produced. (XA In the method of the present invention, the obtained compound of formula (■a) or compound of formula (■b) is then , reduction reaction of its oxo group (=0) and/or group (-Co-R8), protection reaction of the 7' (/):t hydroxyl groups formed thereby, protection reaction of the cyclohexene ring double bond. Cleavage reaction by oxidation, alkyl esterification reaction of the carxyl groups formed thereby, cyclization reaction by Dieckmann condensation of two side chains formed by this, fc, having two alkoxyalkyl groups, residual The compound of formula (Vllra) is then subjected to a series of steps including an elimination reaction of the alkoxy group and an optional elimination reaction of the remaining hydroxyl protecting group.Thus, the compound of formula (Vllra) is converted to the following formula (IXa) OH,2-OR,'. Or from the compound of formula (■b), the following formula (b
) Compound of (1) [in the formula % R''E and R, 10B may be the same or different, a hydrogen atom or a known hydroxyl group-protecting group 9, such as an aralkyl group such as a tetrahydropyranyl group or a benzyl group,
Indicates an alkoxyalkyl group such as a methoxymethyl group]
to rawhide. Compounds of general formula (■a) or (■b), such as compounds!
For Compound 21A, a series of steps including the above-mentioned reduction reaction, hydroxyl group protection reaction, oxidative cleavage of double bonds, esterification, Dieckmann condensation, decaldealkoxy reaction, etc. can be carried out by conventional methods. Through this series of steps, the compound of general formula (■a) or (■b) is converted to the compound of general formula Cr1a) or (lXb). An example of the conversion route of ζ-ni is shown in the reaction formula below. However, it is possible to take various combinations of reaction steps other than this indicated route. Namely, compound (ffa) or (IX'b
) The type and order of reactions to be carried out in the series of reaction steps to induce (t) and the appropriate combination thereof can be appropriately changed by a chemical expert based on known techniques. H (Compound 3) Compound 31 shown in the above reaction formula. Compound 3 and Compound 3 have the general formula (Ha) obtained by the method of the present invention.
This is an example of a compound. Furthermore, general formulas (la), (■b) s (■a) and (■b
) are new compounds, and as is clear from the above description, they are useful as intermediate raw materials for cal/catacycline synthesis. Therefore, the gist of the second invention is that Fi, the above formula (Vla). (VTb), (■a), and (■b) are collectively represented by the following general formula [wherein A and BFi each have a lower alkoxy group -0R2
(However, 81' is a lower alkyl group, or a substituted amine group -NRB, (However, R1 and R1 are each an alkyl group, or R and R together form one alkylene chain, or aryltheo group -8R,' (however, FL5 is an aryl group), or the formula (however, R1 is a lower alkyl group, and the configuration of the carbon atom marked with a pot has R-or Fis-orientation). Show)ノ≠
(River- or 4A(S)-alkoxycarzenyl/, J
-thiazolidine-corchion residue), and B and B are often groups belonging to the same type]. Furthermore, the compounds of general formula (r) used as starting materials for the process of the invention are also new compounds and are useful as before. Therefore, the third aspect of the present invention provides that in the following general formula (I)C, T
has the above-mentioned meaning]. The present invention will be specifically explained with reference to the following examples. In addition, the constant of each compound produced was measured and described as follows. The melting point (mp) was determined by the hot plate method (Yanagimoto Seisakusho,
Measured with a micro melting annoler (Fioo type) and is uncorrected. Optical rotation [a] 9 is measured using a quartz cell (JEOL Ltd., rhSa. DIP/10 type polarimeter) type optical meter with an optical path length of 10 crR. Nuclear magnetic resonance spectra (NMR) show H only/unless otherwise specified.
00MH! (JEOL, JMN-FX1
00 type). The absorption spectrum pattern in NMR is abbreviated as follows. S knee doublet, bs: wide doublet, d: doublet, t: triplet, q: quartet, dd: two sets of doublets, 1m: multiplet. Infrared spectra (IR) were measured using potassium bromide tablets unless otherwise specified (JEOL, JASO-A-10λ spectrometer). Moreover, the compound numbers given in the examples are the same as the compound numbers referred to above. In the formula, Me represents a methyl group, Prt represents an ethyl group, and THP represents a tetrahydropyranyl group. 22. of cis-cyclohexene/2-ylene diacetic acid, i.e. compound O). / j r (0,/12 mol), 32.A y of ≠(R)-MO'r (compound 3)
(0,2241 mol), ≠-dimethylaminopyridinco, 7 J y (ty, oλ comole) in anhydrous THF, ?
Dissolve in OOd, cool to 0°C in a water bath, and then convert to dicyclo#shi/I/force/I/ygdiimipjO,741
9 (0.24 tt-E-L) was added thereto, and the mixture was stirred for 11 minutes and further stirred at room temperature for 5 hours. When the reaction solution was analyzed by t-TLO (stationary phase Nisilica gel plate, developing phase: benzene-ethyl acetate Cj:i), coloring agent: iodine or phosphomolybdic acid 6% ethanol solution was sprayed and heated), ≠ (kawa MOT (Compound 3) (几f O,,2) disappeared, and the formation of a new yellow spora) (Rf value O, at ) was observed. After cooling the reaction solution again in a water bath, insoluble matter was removed using a glass filter, and the furnace solution was concentrated. The residue was dissolved in ethyl acetate≠00- and O0! Normal hydrochloric acid 100 times, 0, l normal sodium hydroxide aqueous solution/! Coro with θgo. After washing twice with deionized water -〇〇-, it was dried over anhydrous sodium sulfate. After removing the anhydrous sodium sulfate, the solution was concentrated to 100H11, and n-hexane was added. When O- is added, yellow needle crystals j2? (♂♂chi) is obtained. Ethyl acetate! 00tlVCj Dissolve at 0°C, filter insoluble matter, concentrate to about 200dl, and add n-hexane to,z
By adding '6, yellow needle-like crystals of the compound (4t) with even higher purity (yield 7 days) were obtained. '(c/, 0
, chloroform) elemental analysis value = C2oH24N206S
4 (molecular weight jl &, 7), the calculated value is 0416. jO, Hit, 4&', Nj, <
42. O/rjlSko ≠, ♂ko actual value 04'4.33. T(4', 7.1',
NjJ2, O/r, 7&L. Sko1.63 NMR, δ(0DO13): j, 7ko~s, to
(koH, ddJ=J. ♂Hz), J, JJ (41 (, s). -0ri~JJ (/OH), /, J gluco, Ar (7
H,1 Mass spectrometry (EI): m/e jlj (M),
33ri, /71゜l/♂ Example coSame as Example/, compound (co) and 4t(S)-MOT
Compound (7) was obtained as yellow needles from compound j) (
Yield: 7r). mp, /ko! , t~/j t, D℃ mass spectrometry (EI
): m/e jl A (M), JJri,/
7rCompound 0) Tobi(6))-EOT as in Example 1
An adduct <r) was formed from (compound t). After purification by silica gel column chromatography (developing phase: benzene-ethyl acetate (/J-:/)), ethyl acetate-n-
A pure product was obtained as a yellow amorphous powder by powdering with hexane. m p, Tat~lO1℃ Mass spectrometry (EI): m/e j4'4! (M), J
j4A, 192 Example μ Production of compound (l and (]) (by reaction with the first nucleophile)
J mol] in 2 mols of methylene chloride and cooled on ice. This is supplemented with 0.0% thiophenol as the nucleophile arylthiol (7). / / d (/, / mmol) and triethylamine 0. /! A methylene chloride solution with Ml (/,/mmol) was added and reacted at the same temperature overnight. The reaction solution was concentrated to 0, and the residue was subjected to silica gel chromatography (stationary phase: Wako gel 0-200, TJfil, developing phase: n-hexane-THF (J:/)) to obtain the target compound 00, 2/3 n! (yield u 7.3%) and its stereoisomer (c) A 7 my (yield/Hiro,
(Register) was obtained. In addition, dithiophenyl ester K 411 (2%) and 4 tons of unreacted raw material (J section) were recovered. chemical substance 00
Although it was sufficiently pure as it was, when ethyl acetate was dissolved in - and n-hexane was added, it precipitated as yellow needle-like crystals to give 1 mg. mp, dry O~ris, o℃ [α:] -72,10 (c/, 0.chloroform) Elemental analysis value C2, H23NO4S3 (molecular group≠≠2
．． 60) Calculated value as 0! rt, 10. Hj, /l,
NJ, /2,0/屹23Actual measurement value Oj A, /j,
Hj, J♂, N3,0/, O/μ, 03NMR, δ(
0DO1,5) Near, 34' (j I(,s)
, 13ri (2H. m), J, jj (jH, 5J IR, ν , /711j, /701./1!P1./
l! 2TlaX mass spectrometry (EI): m/e 1111 (M), 34
10. /71°TLO: 几fO13/(Silica gel, developing phase n-hexane-THE'(j:/)) The structure of this substance was confirmed by X-ray crystal analysis. Compound (a), which is a stereoisomer of compound αO, was obtained as a yellow oily substance. NMR, L') C0DOt3): 7. jj(jH
,s), jJ2ckoH0rr+), J,4tJ(
JH, a) El, ν, /717! , /710. /l, r7 (film method) ax mass spectrometry (El): m/e ell CM”), 3
4Ao. i'yr, iA3 'I'LG! : Rfθ, core (silica gel, developing phase: n
-Hexane-THF (j:/)) Example! Preparation of compounds α1 and □□□ 32■ (0.07j mmol) of compound (g) was dissolved in THF.
jm/ in a dry ice-acetone bath (-71°C)
It was cooled at. Especially n-butyllithium! ! ,4tμt
and the nucleophile thiophenol 1opt as THli”Jm/
The reaction was carried out under cooling at 17J"C in a syringe to form lithium thiophenoxide. This solution was added dropwise to the THF solution prepared above using a syringe over a period of 2 hours at the same temperature (-7♂°C).Dropwise addition After that, it was left at the same temperature for 2 hours, and then a THF solution of cuttoluenesulfonic acid/hydrate/Rimisaki was added dropwise over 10 minutes.Then, it was treated in the same manner as in Example G to obtain compound QO.
/7. t■ was obtained. Accounting yield t3
．． Section J. Compound 00 m p e Tahiro, j~ri 3.3°C [a] 25-7J, 2'(cO6J'7.rioo form) NMR, δ (00015): 7. J 4' (j
H-s) * j, A (:' (-2H. m), 3. A j (J H* s) Compound (a) NMR, δ(OnOt3J: 7,32 (, rH,
s), J, 12(-2H-rn), J, 4'
-2(jH#S) Mass spectrometry (EI): m/
e 1111ri (M+), 3410, / 7♂
. /lJ 2.0039 (3J I mmol) of Example B compound (4L)
f Dissolved in anhydrous THF≠O- and cooled in a dry ice-acetone bath, piperidine O, 4 t μJd (&, 4 tJ' mmol) as the nucleophile secondary amine, was added to this solution.
A THF solution (Hiroshi 7) was added dropwise over 4 hours. After the dropwise addition, the mixture was stirred at the same temperature overnight. The reaction solution was concentrated and the remaining fl
K silica gel chromatography (stationary phase: Kieselgel to, ♂02.Developing phase: benzene ethyl acetate/3:
Gradient from / to j:/) to obtain the fraction 7/4L■ (I1) containing the target compound (ri), and convert the original #+ to g! θ■ (22%) was recovered. However, the fraction containing compound (ri) was analyzed by liquid chromatography (JASCO Tri-rotor S-,! model. Stationary phase Nijiri gel, mobile phase: n-hexane-ethyl acetate (3:/), detection: UV (JOjnm)). When analyzed, it was separated into two components with a relative ratio of 1l-1,? 2:/
It was l. This is due to the contamination of stereoisomers, and when recrystallized three times from a mixed solvent of ethyl acetate and n-hexane, the compound (ri), which shows a single peak even when analyzed by liquid chromatography, appears as yellow needle-shaped crystals. Obtained. mp, f, 2~rg℃ NMJ'L, δ(CD0Ls): (AOMHz
) Yo,! ! (2H, bs) 3.71 (3H, s
), j, / 0~3.72 (complex) 7.7λ~2.
70 (complicated) /, 4L~/, 70 (complex) Mass spectrometry (EI): m/e t12a, 3u0 + compound (
41)tD! 0trpy (OJ?; remote #) f T
HF'! d, dissolved in a mixture of methanol 1id (partly acts as a nucleophile, lower alcohol surface), titanium tetraisopropoxide/, j d (4t
,/mi IJ mol) and allowed to react at room temperature for 3 days. After concentrating the reaction solution, the reaction solution was subjected to the usual separation operation and separated by silica gel column chromatography, resulting in a mixture containing compound α]) and its isomers (results of analysis by liquid chromatography in the same manner as in Example g). , compound a
The relative ratio of η and its isomers was g,l:/. ) was obtained in total yield r o. This mixture was purified by preparative liquid chromatography (manufactured by Yamamura Kagaku Seisakusho, stationary phase Nijiri gel, mobile phase: n-hexane-ethyl acetate (J:/)), and the compound αυ was converted into a yellow oil with a yield of Jr, 4L%. O [α] +10.7° (co, 77, chloroform) NMR, δ (0DO13) obtained in: j, J j (coH
, bs), JJr (JH. s), JJr (JH, s) Example g Compound (7) Obtained by reacting with thiophenol in the same manner as in all Examples≠ (yield≠, 2H). mp, Ta! ~riS, O℃ Mass spectrometry (EI): m/e u4Ari, 3170.
171 Compound (f) 3/, 3 is converted into methylene chloride 2-, and triethylamide 7 (TEA) 10j/7t is added under ice cooling. Add 7.7 μt of nucleophile thiophenol and react at the same temperature for 72 hours. The mixture was treated in the same manner as in Example 1 to obtain a mixture lO,/rrq containing compound 04) as a yellow oil. This mixture was analyzed by liquid chromatography (same as in Example t), and the relative ratio of compound α and its stereoisomer was λ, J 7 :/. Preparative liquid chromatography was carried out under the same conditions as in Example 7 to isolate a pure compound. [α]-! gu, /'(co, col, chloroform NM
R, δ (00015): 7. j 7 (j)I
, s ) , j , j r (2H.s), 2.4Ar(,2H,t), /, /7(jH,s
) Example 10 Compound 0(I)! , r 4 f (/ OJ Milimo A
) f TIP was dissolved in 10 liters and cooled to an internal temperature of -7j'C in a dry ice-acetone bath. To this, add 2.0 d of commercially available sodium methoxide-methanol solution (Kolchi) as a nucleophile! It was dripped over a period of time. While maintaining the same temperature/normal salt M/jd was added to neutralize. After concentration and separation as usual, silica gel column chromatography (developing phase: benzene-chloroform (I0:/
)) When purified with 3. / j f(rit, z%)
Compound Q7) was obtained as a colorless oil. ((I3D-J, J” (c/, 0, rioo form) NMR, δ (cDat3) near, j4t (JH
,s 几! , AOC Ko H9s), J, A! (3H,
5) -2,7~/, j (Film method mass spectrometry (BI): m/e J (7! (M) J
7j, /rij. 10 Examples/1 327 mmoles (o, r mmol) of compound 00 was dissolved in THF, and heated in a dry ice-acetone bath (bath temperature -71').
'C) Cooling [6. Ta. Piperidine as a nucleophile in this? A solution containing μt (o, 9 mmol) was added dropwise to THFJ over about 2 minutes, and then the reaction solution was returned to room temperature in about 30 minutes. After concentrating the reaction solution, column chromatography on silica gel (developing phase: n-hexane-ethyl acetate (j
:, 2)). Pure Compound 04 (Part 3) was obtained as a colorless oil. [α]20+/Otsu10 (c/, 0.chloroform)NM
R, δ (0DOt3J ”, 7J 7 (r H,
s), rj/(-! H. s), 3. AQ (44H1bs), 2. &! (, i H
, a d), -2,<< ta (t H, m
)/, jri(4tH, bsJ Mass spectrometry (BI): m/e rj7(M”), 2
<AI, /u Example 1 Compound (ri) 13! (9,3/r mmol) was dissolved in methylene chloride/- and cooled on ice. T E A 6 to this
2μt, thiophenol 1μt2 to methylene chloride/-
A solution of θ dissolved in was added dropwise over 2 minutes at the same temperature. When treated in the same manner as in Example, 1 (72%) of the compound was obtained as a colorless oil. [α)D+/7.00 (c/, 0, chloroform) NMR and mass spectrometry results were similar to the product (transformation) of Example 7. Example/3 Compound α force lμ, 3■ (o, o a 7 mmol)
was dissolved in THF O, 7 mt, and to this was added the nucleophile piperidine, tμt, and silver trifluoroacetate/0.41 g. , at ℃! After concentrating the reaction solution heated and stirred for an hour, it was subjected to silica gel column chromatography (developing phase: benzene-ethyl acetate (μ:l)) with 5iJI to give znicoki (
40%) of the compound was obtained as a colorless oil. [Q]o -/J-/' (C0-u J
, riooform]NM几,δ(ct+czs:j,j
4(2H, bs), 3.tco(jH.s), co-2IC,2H,bs), 2.30~/J2 Mass spectrometry (Fi:I): m/e 27ri(M”)
, j ur Example/4 < Compound (ri) was treated with sodium methoxide in the same manner as in Example IO to obtain compound (ri). Yield 7-2% [α)
"10/u, ri0 (cO, 4L/, chloroform) NM
R, δ(0DOt3 J: -r,! l (2H
, b s], j, J, 2(31(. 3), J, 2r(jH, bs ), ko JO ~ 1.! ko mass spectrometry (EI) 2 m/e core P (M ) , j PJ'
Example/Event Just before one reaction, 101■ (0.3 mmol) of the compound αη obtained in Example io was dissolved in THF 13- by distillation with the addition of metallic sodium, and calcium hydride was added. Add 12 μt of hexamethyl 7-osulfur triamium (MPA) distilled using
The mixture was cooled to an internal temperature of -7rC in a 77ton bath. Separately, cool in the same bath and add 0.372 μt of n-butyllithium hexane solution (Aldrich) and 0.0 μt of diisopropylamine to fcTHF'/J'-. /J'- was added and reacted to make lithium diisopropylamine (LDA, 1 solution. The above LDA solution was quickly added to the previous compound 0η T) (F'i solution) while being careful to keep it warm. Raise the internal temperature to -!O'cJ in minutes, and then raise the internal temperature to 70'C
Cooled to . Cyclized by Diekmann condensation reaction. Here, gutluenesulfonic acid-/-hydrate o,rt was added to neutralize the reaction solution, and the temperature was raised to room temperature K. After concentrating the reaction solution under reduced pressure, 1. Perform normal separation operation and perform silica gel column chromatography (Developing phase: benzene-ethyl acetate (J-O:
/)), a compound of 4A O,2rrq was obtained as a colorless oily substance. Yield jLj ratio [:a) 25- / J 4A, Ao (c /, 0,
Chloroform] NMR, δ(0DO15,): j, A
! (2H, b s ), 3.72 (JHlS)
, 3. θ! (jH, d, J = Hz). Ko, I 7 (/H, m), ,! , t~7.4
tcm-1゜el, ν, 77≠3-, /7.20,1tj3 (film method) ay Mass spectrometry (EI): m/e /ri44 (M”) /
13. //A cyclization anti-U by Diekmann reduction
When performing Erk, instead of LDA as a base,
A similar reaction was carried out using sodium hydride, potassium hydride, or a dimyl anion prepared from them, lithium hexamethyldisilazane (LHDS). Addition of HMP& is effective when LDA or LHDS is used as a base and improves the yield. The reaction conditions and yield of base 1 used here are shown in the following table. Table Sodium hydride 3.0 DMSO room temperature 3 minutes 4Lμ Potassium hydride DMSO room temperature 3 minutes 31L) (DS 3.O
T') (F-I (MP & -7IC2 hours jj Example/゛, 4 wq (0, J/j mmol) to l≠8 of compound αO of Example μ is dissolved in T) IPjdK, and after cooling l, ♂-Diazabicyclo (J,≠,O) undecane (DBU) r/1
1. f was added and the cyclization reaction was carried out at the same temperature for lJ'hours'1. The reaction solution was concentrated using 50% sulfuric acid at 70 atm, and the residue was dissolved in ethyl acetate and washed several times with saturated brine. The organic layer was concentrated and purified by column chromatography on silica gel to obtain Compound (a) of μ, ≠ Misaki as colorless needle-like crystals. Yield≠g, flathead. In addition to this, compound (a) // is a good friend. mp, AJ-bu 4℃ NMR, δ (0DOt3) near, 3 j (jH, s
) jA/(2H.s), 2. II (,2H,s), Ko, 70~
j, 244. J/4 (2H, bs). Eighty A (2H, d, J-AHz). /, rO(jH, bs) Mass spectrometry (EI): m/e J7J(M”), /43
In addition, when carrying out one cyclization reaction, DB is used as a base.
Instead of U, sodium hydride, potassium hydride, or prepared from them. A similar reaction was carried out using a wet base system of dimyl anion, calcium hydride triethylamine-DBU. The reaction conditions and yield of base 1 used here are shown in the following table. TEA-DBU 21 T HF Room temperature 3 days
39μ potassium hydride AJ THF room temperature
2 hours 4cj:. Sodium hydride /, OTHF room temperature / hour
,. Example/7 Compound 11]) of Example 7, 77,! ~(o,o guamimol) was dissolved in anhydrous THF 082-. Separately, a potassium hydride coj% oily suspension≠r, Hiroη was washed once with T) (after washing with F, it was reacted with DMSOO and CorM to obtain the dimyl anion, and the above compound was αD THF
The mixture was added to the solution and stirred at room temperature for 3 minutes to cause a cyclization reaction. After neutralizing the reaction solution with acetic acid, the organic layer was separated with ether and water, the organic layer was concentrated, and a 5-preparative TLO (silica gel plate: Merck Artoff/j, 1 plate used, developing phase: benzene-ethyl acetate <2
o:i)), the desired fraction (to) is purified as a clear oil in 6. Got the cape. Yield 4t2%. [a]+/J/, J' (cθ, μ2.chloroform)
NMR, δCCD0A5):! , tIC2H, bs),
J, 7 (3H0s), 3. Or(jH, d, J=riH
2J. Ko, J' 7 (/H, m), , 2.1~/
, 4LI R-y −/ 74' j, / 7 J
Oe / & j j (7ilm method) ax Mass spectrometry (EI): m/e/ri4t (M), /43.
//l Example it l/ ~ (0,2 mmol) of compound α9 was dissolved in TI (Fcom/m/. Separately, potassium hydride 2! oleaginous suspension/Kob Ilv/degree After washing with THF, DMSO
Dimmyl anion was prepared by reacting with O, J ml, and this was added to the THF solution of compound 09 and I
The cyclization reaction was carried out for 0 minutes. When treated and purified in the same manner as in Example 17, the target compound (c) was obtained as a colorless and transparent oily substance. 4L/(4'H. bs), 7J ~/, 70, /, 32(μH,
bs) Mass spectrometry (EI): m/e2 Hiro 7 (M) Example/ReDissolve 670 ■ (2.23 mmol) of compound ■D of Example/j in 10 td of methanol and dilute with sodium borohydrocyanide. Then, normal hydrochloric acid was added dropwise over 7 hours. After stirring at the same temperature for 7 hours to carry out the reduction reaction, the reaction solution was concentrated and subjected to silica gel column chromatography (developing phase: benzene). Ethyl acetate (≠
By purifying with :l)), the compound (a) of 309■
was obtained as a colorless oil. Yield: 33.7 This reduction reaction was carried out in ethanol with sodium borohydride 2
When an equivalent amount was added and the process was carried out at 100°C, a yield of 100% was obtained, and a total of 23% of the raw material was added. rch was collected. NM几、δ(0DOt3): j、A2(2H
, b s ), 447 (/H, dd , J=/
θ, 4 Hz) @jjjj(JH,s) Mass spectrometry (EI): m/e/lit(M”),/71
, 100 Examples-〇Example/70 tq (0.12 mmol) of the compound kanji was dissolved in 0.3 tq of methylene chloride, and 73 tq of pyridinium tosylate, dihydropyran! Add 2 μtf and 4 at room temperature.
The reaction mixture was stirred for hours to carry out a reaction for introducing a tetrahydropyranyl group (THP), and the reaction solution was treated according to a conventional method to obtain the desired compound @ as a colorless oily substance /JP■. Yield! Yu. NM几、δ(0001s)：、! , A j (-
2H, b s ), 4tA O(/H, m), Jj
2(jH,s) Mass spectrometry (]13I): m/e2J'0(M), 2
u ri, /ri 2 Example-No Example 20 compound @ of /g/■ (0,2 < 12 mmol) was dissolved in T) (F, 2-. Lithium aluminum hydride ram coheco 1nv Suspend it in THF2-, cool it in a dry ice acetone bath, and add T of the previous compound (c).
The HF solution was added dropwise, and the temperature was raised to room temperature in 30 minutes. The reduction reaction was carried out by stirring for 17 hours. Add JJm of water and 3tμ of a 15% aqueous sodium hydroxide solution to the reaction solution.
After stirring for 30 minutes, the P solution was concentrated, and the residue was dissolved in ethyl acetate and washed twice with water. Column chromatography on silica gel (developing phase: benzene-ethyl acetate (3 :/)) Purification with K gave 1/1~ of Eri chemical compound as a colorless oily substance. Yield: 7T NMR, δ(0r)Oz3) :j, A4' (j
H-b s ) -44j j (/H-m) ,
4t, 22~3.4! 0 (JH). Ko, sr~/, 0! (/μH) Mass spectrometry (EI): m/e jt, 2 (M”), 2
J4A, /61゜j Example 22 J//η (I, 23 mmol) of the compound of Example 2
D M S OO, 7rd K l! I understand. Sodium hydride 60% oily suspension t≠■ in dry benzene/
After washing twice, the DMSO solution of the above compound (c) was added 7 times to the dimyl anion solution obtained by reacting with DM80. After stirring at room temperature for j minutes, 770 μt5f of benzyl chloride was added to one reaction solution, and the mixture was stirred at the same temperature for one hour. In this way, a reaction was carried out to introduce a benzyl group into a hydroxyl group. After performing the extraction procedure as usual, silica gel column chromatography (developing phase: benzene-ethyl acetate (70:/
)) to purify the chemical compound as a colorless oily substance.
J I got 119. Yield Octopus, 7 yen NMR, δ (CjDC15): ! J J' (2H
, b s ), 4'j J(/H,mJ,4',4
'Q(η(,5)41.30~j,40(jH),3
．． 1-r(j H, t, J=AHz), 2J
4AO (#H) mass spectrum CEI): m/e 344, 217.
ri l. j Example 3 Example/! Compound 12'D of 2. t 9 f (/
j, Tamimol) was dissolved in THF & o-. 422Mg of lithium aluminum hydride in THF J O-
Suspend it in a dry ice-acetone bath to bring the internal temperature to -73°C.
After cooling to 1/C, the above THF solution was added dropwise over 2 hours. The reaction solution was heated to room temperature over about 3 hours, and then stirred for an additional hour to carry out a reduction reaction. l! IJium aqueous solution 1. After adding -1, the mixture was further stirred for 30 minutes and then heated under Pa to concentrate the P solution. The residue M' was dissolved in 30 ml of ethyl acetate, washed three times with saturated brine, and then dried over anhydrous sodium phosphate. After the desiccant is removed from the oven, the residue is purified by column chromatography on silica gel (developing phase: chloroform-methanol (20:/)) to obtain the adduct as a colorless oil.1. Ac
I got t. Yield i Lj % [cy] -0.7° (C1,
0, rioo form) NMR, δ (0DC15): jjJ
(2H,s),j,ri7(/)T. dd, J=J, 7Hz), J, Ar ~J, +
7.2 (JH), Ko,? -~/, 0 Hiro (I0H) Mass spectrometry (EI): m/e/AI, /! 0
, ? /Example 24L Compound (I) of Hibiki Example 3
It was dissolved in OOo Td and reacted with dimidyl anion prepared from a 60% sodium hydride oily suspension in the same manner as in Example 2.2, and further dissolved in pendyl chloride/J.
It was reacted with 7 μt. A benzyl group was introduced into the hydroxyl group. Column chromatography on silica gel (developing phase: benzene-ethyl acetate) was carried out in the same manner as in Example-22.
I:/)) to obtain 134tIIll of compound Gη as a colorless oil. Yield 4(j, TachiNMl'L, δ(CD(I!t3): 7.27
(j H, s ), j, 7 J (j H. d * J = -2Hz), 4', j / (,2
H, s). 4', 02 (/H* d d, J ” / /
, 7Hz). Jj7 (/H, dd, J=7.jHz). J, J (/H, t, J = Hz) 2.4tO ~ /jD, /, J (/H, t. J = 7Hz mass spectrometry (EI): m/e21! (M 2uO , /J/
. Ri l Example! Example 2) Compound 61) of Kohiro was treated with pyridinium tosylate and dihydrobilane in agglomerated methylene in the same manner as in Example 20 to obtain a chemical compound. NMR, δ(0DC3L5 N: j, j J' (2
H, b s ), u, j / (/H. m ), ! , Jri(koH,s), Let(koH,
t, J=AHz) The compound (to) of the formula shown in Example coro and Example coj could also be synthesized by the following reaction route. The chemical compound obtained by this method is a spectral example. 2! It was identical to the compound obtained in . 7.42-7Q Mass spectrometry (EICm/e 272 (Lf”) Mass spectrometry (BI 1 :m/e J, tA(M),, 27/
The reaction reagents, reaction conditions, and product yields used in each of the above reaction steps are as follows. Reaction (a) Nibenzoyl chloride (5 parts per liter), pyridine, /j°C, j hours, yield 7! eIb Reaction (b) Niedihydropyran (/, l!:), pyridinium tosylate, room temperature, 3 hours, yield P! , /忤Reaction (C): -Sodium methoxide-methanol, room temperature. 2 hours, yield 3.3% Example core ■ Chemical compound e: 0, 20 Arq (0,102 mm 17 mol) f Chloroform j Dissolved in ml, methytail 1 phosphorus oxide/. After adding j2 and stirring at room temperature for 7 hours. Extract according to the usual method. Purification by column chromatography gave Compound 1/77 as a colorless oil. Yield ratio 7 coefficient NMR, δ(CD01,): 7,,? Ko(jH,
s), jj7(koH0b s), 4',j r
(koH,s), 4A,60(jH,s), J. 2Ir
(JH.s) Mass spectrometry (EI): mle302, λ7/
, 2!7, PI Example 1 By adding the series of reaction steps described below to the compound of Example 2, which is an example of the target product (IXa) of the method of the present invention, 1 The product (IXa) of the process according to the invention (as an example chemical compound) was obtained. (Ring cleavage by oxidation) (Esterification of calzexyl group) Compound (to) The reaction conditions of the 6 reaction reagents used in each reaction step and the yield of the product are as follows. Reaction (a): -periodine N') Sodium j 6 parts Potassium permanganate 00 lfif Sodium carbonate o, r parts Dioxane-water (2.2: / ), room temperature. 3-hour reaction (b): -, quazomethane-ether. In addition, (a), (bl yield of product (g) in two steps. 1' 3,/% reaction (C) knee potassium hydride
Ko. ! equivalent DMSO, room temperature. j minutes, yield r r. r
% reaction (dl) knee HMP water (ko0:/), 171
℃. /J' minutes. Yield: 2% Physical properties of each product are as follows. Compound (to) NMR. δ(0DOt3): 7.2 0(
j H, a), 4'. j 7 (/H
. m), 830 (koH, s), j. 4u (4H,3), 3,t,r (3H.s) mass spectrometry (1
'3 I): mle 4' J 4', 4'
Oj, J4Ari,,24! j. lri3, lrj NMR. δ(0DOt3): 7,/j(
j H, s), 4', J j (/H. m), Il. <12 ( , 2H , s ) , j
jri (JH,s), J. Aj (3H,S) mass spectrometry (
DI) :mle 4tOx(M”) !70,3/
I. Compound (to) NMR, δ (00013): 7,
/ 7 (j H, s),'
ni, j7 (/H. m)', 41.4 &! (2H, s) Mass spectrometry (EI): m/e j #g (M”)
) Preparation of the compound (IXa) which is an example of the method of the present invention by subjecting the core compound (1) to the same series of reaction steps 8 as in Example (1) I got it. The reaction conditions and yield of the product are as follows: Reaction (a) Sodium periodate G, j Sodium permanganate 0.2 equivalent sodium carbonate o, as a i-dioxane-water (co, coni), room temperature, 1.! hour Reaction (b): -diazomethane-ether (-),
(b) Yield of compound (9) in two steps 7♂, 3-ti reaction (C) di-potassium hydride J, amount of Ofi DMSO,
room temperature,! min, yield 3.7 h Reaction (d): -HMP
A-Water (27):/), /rO'c, 11 minutes, pick-up vehicle irechi The physical properties of each product are as follows. Compound lead NMR, δC0DO23): 7. JJ (j)(,s
), 44. AO(2H.!), 44jko, (jH,s),g, (73(/
H,t, J=jHz), J, J7 (JHos), J,
tJ(JH,s). 3JJ (3H, s) Mass spectrometry (EI): m/e 313, J4'5',
Amount analysis of compound ■ and θ mixture (EI, ): m/e J71r, Ju7,
3JJ compound CC5 1N, δ (0D073) near, J J (,t
H,s),≠,JO(koH1s), 41. j
j (koH, s), 3. Jθ<3H,s) Mass spectrometry (EI): m/e 272. Example 30 Example of the desired product (IXa) of the process of the invention, compound I obtained by zr; 3. 'j ノ/A J, 7
Dissolve ttq (0.4t7A mmol) in methanol 3- and add pyridinium tosylate/2yyf at 53°C.
The mixture was stirred for 7 hours. By hydrolysis, TH of hydroxyl group protection
The P group was eliminated. After treatment in a conventional manner, it was purified by column chromatography on silica gel (developing phase: dichlorohexane-ethyl acetate (3:con)) to obtain compound (1) as an oily substance. Yield: 22. 2chi

[0]25+
/j, /・(e /, 0, chloroform) NMR, δ
(0DOt3): 7. j J (j H, s)
-4'j 4' (-2F(.B) ,!, //(/H,q, J=7.6Hz)J,
j 7 (/H, dd, J=l'J, jHz)
3.4A 7 (/H, dd, J=J', J',
,1',! Hz) l36. The above compound (good) can also be produced from compound (2) by another method. That is, J7Jvag(0,/
(gmmol) was dissolved in a mixture of methanol imp, water o, z-, droplets of concentrated hydrochloric acid were added, and the mixture was stirred at 10°C for 4 hours. After the reaction solution was condensed, the residue was subjected to column chromatography on silica gel (developing phase: benzene-ethyl acetate (3:co)).
The compound (goods) was purified as an oily substance and obtained as 7. Yield ro, t% of the compound thus obtained) is the compound of Example 30 obtained from compound (2).
The spectrally matched perfectly. Effects of the Invention According to the present invention, X for optically active carbacycline synthesis
It has become possible to produce essential intermediates without optical resolution. Therefore, by using the target product of this method, it became possible to produce the desired optically active carbacycline in good yield.

Claims (1)

[Claims] 1. The following general formula (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, T is the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) 4(R)- or 4(S)-alkoxycarbonyl-1,3-thiazolidine-2-thione residue as shown,
R^1 is a lower alkyl group, especially a methyl or ethyl group, and the configuration of the marked carbon atom is R-configuration or S
A cis-4-cyclohexene-1,2-ylene diacetic acid diamide derivative represented by , R^2 is a lower alkyl group] or the following formula (IV) ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (IV) [In the formula, R^3 and R^4 are each an alkyl group or R^3 and R^4 together form one alkylene chain], or a secondary amine of the following formula (V) R^5-
SH(V) [wherein R^5 is an aryl group, particularly a phenyl group] is reacted with an arylthiol to form the following formula (V
Ia) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VIa) and the following formula (VIb) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VIb) [In the formula, T is the above is the same as R
^6 is an alkoxy group -OR^2 derived from a lower alcohol (III) or amine (IV) or arylthiol (V) used as a nucleophile, or a substituted amino group -NR^
3R^4 or an arylthio group -SR^5] is preferentially produced in a stereoselective discrimination reaction,
Next, the obtained compound of formula (VIa) or compound of formula (VIb) is added to the first nucleophile compound (III
), (IV) or (V), a second nucleophile compound selected from lower alcohols of formula (III), amines of formula (IV) and arylthiols of formula (V) above, excluding (IV) or (V). By reacting with are the same, and R^7 is an alkoxy group -OR^2 derived from the second nucleophile compound used, or a substituted amino group -NR^3R
^4, or an arylthio group -SR^5, and R^6 and R^7 are not groups belonging to the same type], and further generates a compound of formula (VIa) or an arylthio group -SR^5. Using the compound immediately or using a compound of formula (VIIa) or a compound of formula (VIIb), subjecting it to a Diekmann condensation reaction with elimination of the group R^6 or the group R^7, An optically active compound of the following formula (VIIIa) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VIIIa) or an optically active compound of the following formula (VIIIb) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VIIIb) [In the formula, R^8 is the compound used (VIa
), (VIb), (VIIa) or (VIIb)
an alkoxy group -OR^2, or a substituted amino group -NR^3R^4, or an arylthio group -S, which is the one with smaller elimination property during Diekman condensation reaction among 6 and R^7
R^5] is produced by a regioselective cyclization reaction, and then, the compound of formula (VIIIa) or the compound of formula (VIIIb) is converted to the oxo group (=O) and/or group (- C
reduction reaction of O-R^8), protection reaction of one or two hydroxyl groups formed thereby, cleavage reaction by oxidation of the cyclohexene ring double bond, and reaction of two carboxyl groups formed thereby. Alkyl esterification reaction, cyclization reaction by Diekman condensation of two side chains having two alkoxycarbonyl groups formed by this, elimination reaction of the remaining alkoxycarbonyl group, and optionally By subjecting it to a series of steps including an elimination reaction of the remaining hydroxyl protecting group, the compound of formula (VIIIa) is converted to the compound of the following formula (IXa) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IXa) or from the compound of formula (VIIIb), the following formula (I
Xb) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IXb) Produces the compound [In the formula, R^9 and R^1^0 may be the same or different and represent a hydrogen atom or a protecting group for a hydroxyl group] Formula (IXa) or (
IXb) Method for producing optically active compound. 2. The following general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VII-c) [In the formula, A and B are each a lower alkoxy group -OR^2
(However, R^2 is a lower alkyl group), or a substituted amino group -NR^3R^4 (However, R^3 and R^4 are each an alkyl group, or R^3 and R^4 together (combined to form one alkylene chain) or arylthio group -
SR^5 (where R^5 is an aryl group), or formula ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (However, R^1 is a lower alkyl group, and the configuration of the carbon atom marked with ・ indicates R-or S-coordination) 4
(R)- or 4(S)-alkoxycarbonyl-1,3
- A thiazolidine-2-thione residue, and A and B are groups belonging to the same type - A 1,2-ylene diacetic acid derivative. 3. The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, T is the following formula▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (However, R^1 is a lower grade 4(R)- or 4(S)-alkoxycarbonyl-1,3-thiazolidine, which is an alkyl group, and the configuration of the marked carbon atom is R-or S-configuration) -2-thione residue].