JPH02256650A - Dicarboxylic acid monoester and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1> is alkyl, alkenyl, aryl etc.; X is O, S, O-O, (CH2)m (m is 0-4), etc.; Y is (CH2)n (n is 0-3), CR<2>=CR<2> (R<2> is H or CH3C2H5, etc.; Z is H, lower alkyl, etc.]. EXAMPLE:A (1R,2S,3S,4S)-bicyclo[2,2,1]heptane-2,3-decarboxylic acid 2-methyl ester. USE:Useful for chemical syntheses. PREPARATION:An acid anhydride of formula II is reacted with a (R)- or (S)- arylacetic acid derivative of formula III (M<1> is H or metal atom; R<5> is H, alkyl or aralkyl; Ar is aryl) into an arylacetic acid monoester of formula IV, which is then esterified to introduce R1 followed by elimination of the arylacetic acid derivative residue or reaction of the resultant ester with a compound of formula V (M<2> is alkali metal, etc.), thus obtaining the compound of the formula I.

Description

[Detailed description of the invention]

11 The present invention is useful for the asymmetric synthesis of various compounds derived from natural products, and more specifically, dicarboxylic acid mono-esters and dicarboxylic acid monoesters useful for the synthesis of optically active prostaglandins, Regarding its manufacturing method. (Leaving space below) K. GoranoO Diels-Alder reaction and enzymatic hydrolysis of the diester moiety are well-known methods for obtaining optically active dicarboxylic acid monoesters; Pure compounds can be easily produced in large quantities by forming complex reactions or using special reagents.
Moreover, it was quite difficult to obtain it at a low price. Obtaining compounds with high optical purity through asymmetric synthesis has important implications not only for the synthesis of natural organic compounds but also for the synthesis of various compounds including pharmaceuticals in a broad sense. The present invention is the result of intensive investigation into an asymmetric synthesis method that can significantly improve optical purity by allowing the reaction to proceed stereoselectively and by extremely easily removing small amounts of by-products generated during the reaction process. . Incidentally, the present invention also contemplates that the above reaction can be carried out easily and with inexpensive reagents. (Left below) As a result of extensive studies in view of the above points, the inventors have found that σ
The present inventors have discovered that dicarboxylic acid monoesters having a desired steric configuration can be selectively obtained by reacting a symmetrical acid anhydride with a (R)- or (S)-arylacetic acid derivative, and have completed the present invention. . Details will be described later, but in this reaction, by-products generated during the reaction can be easily removed by recrystallization.The asymmetric synthesis method provided by the present invention can be applied to acid anhydrides with various elongation symmetries. The resulting dicarboxylic acid monoesters are extremely important as intermediates for the synthesis of various prostaglandins, amine sugars, nucleotides, terpenes, alkaloids, steroids, and other useful compounds derived from natural products. (The following is a blank space) The present invention uses such an important intermediate with the general formula: [wherein R1 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted aryl, or a substituted Indicates an aralkyl which may be
X- is -〇--5--()-()--(CL)tll
- (In the formula, m represents an integer of 0 to 4, R2 represents hydrogen, methyl or ethyl, Rs represents hydrogen, methyl, benzyloxycarbonyl or formyl) (In the formula, n represents an integer of 0 to 3. , R2 has the same meaning as above, R4 is hydrogen,
methyl or ethyl) Z represents hydrogen, lower alkyl or penyl (provided that when m and n are both 0 and (IS. 2R,35,4R)-7-oxabicyclo[2,2,1
]Hebutane-2,3-dicarboxylic acid 2-methyl ester) , Y and 2 have the same meanings as above; (R)- or (S)-arylacetic acid derivatives represented by the general formula: (wherein, R1, XlY% 2 and Ar have the same meanings as above), and then the ester is subjected to an esterification reaction to introduce R1, and then the arylacetic acid derivative residue is removed or the ester is l to the general formula: % formula % (wherein Rt represents optionally substituted alkyl, optionally substituted alkenyl, menthyl, optionally substituted aryl, or optionally substituted aralkyl, M2 represents an alkali metal atom or an alkaline earth metal atom). The present invention provides an asymmetric synthesis method for obtaining an optically active dicarboxylic acid monoester represented by the general formula: (wherein RB, X, Y%2 and We also provide highly pure optically active arylacetic acid derivative monoesters represented by A" (has the same meaning as above). Below, a reaction process diagram is shown and the present invention will be explained in more detail. (Left below) Method for producing trans dicarboxylic acid monoester [Method A Method using co(R)-arylacetic acid derivatives-D (In the formula, R1, R', X, Y, Z, Ar and M ' has the same meaning as above.) 1.1 By reacting a brochiral cyclic anhydride with σ symmetry shown on the above compound with a (R)-arylacetic acid derivative in a solvent, the target compound 1f can be obtained. -D is obtained. The reaction is carried out at about -100 to about 50°C, more preferably at about -78°C.
It takes about several tens of minutes to several hours to complete the process at ~0''C.Solvents include tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane, 1,2-dimethoxyethane, n-hexane, DMSO, ) toluene, H
Examples include MPA. At this time, depending on the aryl acetic acid derivative used, the target product can be
There are two types of compounds, the free carboxylic acid type is l, and the ester type is l, double (I will represent the door).Compound l double m is easily crystallized and can be isolated, and impurities can be separated. Therefore, it can be subjected to the following reaction.Compound 1t
-Dmu'' is subjected to a deprotection reaction, if desired, to form compound I
It can be converted into I-D al and subjected to the next reaction. It is recommended that the deprotection reaction be carried out under neutral to acidic conditions. That is, it is necessary to deprotect while maintaining the ester bond between the arylacetic acid residue and the carbonyl bonded to the ring, but this is not suitable because the ester bond will be broken under alkaline conditions.Normally, palladium is used. - Carry out reductive deprotection reaction using carbon under neutral conditions. However, in cases where there are other easily reduced functional groups or where X and Y have a double bond, hydrogenation may become a single bond. If you wish to deprotect while retaining the functional group or double bond, deprotection can be carried out under acidic conditions using a reagent such as trifluoroacetic acid, aluminum chloride, hydrochloric acid, or zinc-acetic acid. Also LiI. The desired protecting group can be cut off by subjecting it to a thermal decomposition reaction using L(C! or NaCl, etc.).The desired compound m-D in step 221 is obtained by converting the compound l double into the general formula: % formula. % (wherein R1 or M2 has the same meaning as above) by subjecting it to a transesterification reaction and a stereoselective isomerization reaction.The compound represented by the above general formula Examples of the alkali metal or alkaline earth metal alkoxides include alkoxides, aryl oxides, alkenyl oxides, menthyl oxides, aralkyl oxides, etc. Examples of the alkali metal or alkaline earth metal alkoxides include sodium methoxide, lithium methoxide, magnesium ethoxy Examples of the alkali metal or alkaline earth metal aryloxide include sodium phenoxide, lithium phenoxide, magnesium phenoxide, sodium-α-naphthoxide, libram-β-naphthoxide, etc.Alkali metal or alkaline earth metal aryloxide Examples of similar metal alkenyl oxides include sodium allyl oxide, lithium allyl oxide, magnesium allyl oxide, etc. Examples of alkali metal menthyl oxides include sodium allyl oxide, lithium menthyl oxide, etc. Examples of alkali metal aralkyl oxides include sodium allyl oxide. Examples include benzyl oxide, lithium benzyl oxide, etc. As the solvent, methanol, ethanol, allyl alcohol, phenol, etc. are used, and if necessary, Mendelian alcohol, pyridine, tetrahydrofuran, etc. may be added.The reaction temperature is approx. The reaction is carried out at -30°C to about 150"C, more preferably at about 00C to about 80"C, and the reaction is completed in about -1 to about 10 hours. The compound LD represented by the following general formula: (wherein RB% After deprotection reaction, dicarboxylic acid, Lnie 1ju
(In the formula, R1 is hydrogen), since it remains in the mother liquor, the by-product LD can be removed 100%, and the pure target product Natsu-0 can be used in the next second step. ID and 1'-D
can be separated and purified using chromatography. Moreover, ID and I'-D in the first step can be subjected to the next reaction as a mixture without being separated. (hereinafter referred to as Kinpaku) [Method B] A method using a (S)-arylacetic acid derivative (in the formula, R1
, R', X, Y%Z%Ar and Ml have the same meanings as above. ) Compound 1 is reacted with a (S)-arylacetic acid derivative in the same manner as the first step for the (R)-arylacetic acid derivative described above to obtain the target compound 121. The obtained target product 1-L can be converted into 2 depending on the arylacetic acid derivative used.
The free carboxylic acid type and the ester type are respectively expressed as ``℃''. Compound I double crystallizes and can be easily isolated. 1 Nie 1 By reacting the compound M-L obtained in the first step above in the same manner as in the second step for the D form described above, the desired compound is obtained. (Margins below) In the first step, the following general formula: Production of cis-dicarboxylic acid monoester [compound, l[
-Production of D-2] Compound I (compound l double, I'-D, l21 or I '-L) is used. (In the formula, and Ar are the above-mentioned compounds. , the target product I is obtained from the by-product 1'-L.
It is also possible to obtain ID respectively. (Left below) (In the formula, R1%x, poly and 2 have the same meanings as above, and Ri' is substituted or optionally alkyl, optionally substituted alkenyl, menthyl, or substituted or unsubstituted alkyl. means an optionally substituted aryl or an optionally substituted aralkyl.) Kamedoko 1 This step is a step of esterifying the free carboxylic acid of the compound ID or If'-L and introducing R1. The esterification reaction is carried out while maintaining the ester bond between the arylacetic acid derivative and the ring-bonded carbonyl and the configuration at the 2-position.
For example, diazomethane, diazoethane, diphenyldiazomethane, phenyldiazomethane, etc.), alcohols (
The esterification reaction is carried out using methanol, ethanol, propatool, inpropatol, tart-butanol, benzyl alcohol, phenethyl alcohol, naphthylmethyl alcohol, menthol, phenol, nitrophenol, methylphenol, chlorophenol, methoxyphenol, aminophenol, etc.). Just follow the usual method. In order to accelerate the reaction, acids such as formic acid, p-toluenesulfonic acid, sulfuric acid, and hydrochloric acid may be used. No.”≦

[This step involves cleaving the ester bond between the aryl acetic acid derivative and the ring-bonded carbonyl to form a cis-type compound of the present invention] I
- This is the process of obtaining D-2. Since the deesterification reaction must be carried out while maintaining the steric configuration, it is usually preferable to carry out the reductive reaction using palladium-carbon under neutral conditions. (Margins below) [Production of compound 1-L-2 (wherein R1, R5', X, Y and 2 have the same meanings as above) , compound II
Compound DI-L-2 can be obtained by reacting in the same manner as in the first and second steps to obtain -D-2. As shown above, the arylacetic acid derivative monoester of the compound of the present invention represented by general formula 1 includes 11-D, I
Four stereoisomers are included: I'-D% IL and II'-L. The dicarboxylic acid monoester of the compound of the present invention represented by the general formula has 4 asymmetric carbon atoms, and a total of 8
The present invention includes all stereoisomers and optical isomers. Specifically, compounds having the configuration of the following general formula (hereinafter referred to as blank spaces) (hereinafter referred to as blank spaces) (wherein R'% X% Y and 2 have the same meanings as above) and their enantiomers are included. (In the following article) The terms used in the above definitions will be explained. Alkyl includes methyl, ethyl, isopropyl, n
-propyl, n-butyl, isobutyl, t-butyl, S
Examples include e5-butyl, pentyl, and neopentyl. As alkenyl, 2-propenyl, 2-butenyl,
3-butenyl, 2-methyl-2-propenyl, 3-methyl-3-butenyl, 2-pentenyl, 3-pentenyl,
Examples include 4-pentenyl and prenyl. Aryl includes phenyl, α- or β-naphthyl, and the like. Examples of aralkyl include benzyl, phenethyl, naphthylmethyl, and the like. The metal atoms mainly include alkali metal atoms and alkaline earth metal atoms, and the alkali metal atoms include:
Examples of alkaline earth metal atoms such as lithium, sodium, and potassium include magnesium and calcium, and zinc and the like are also used. As a bicyclo ring, the norbornane type (bicyclo[2,
2,11 to butane, bicyclo[C2,1]]buta 5
-etc.) or 7-oxabicyclo[2,2,1]hebutane, 7-oxabicyclo[2,2,11butane, etc.)
-ene, 7-azabicyclo[2,2,1]hebutane, 7
-Azabicyclo[2°2.1]butan-5-ene, 7
-thiabicyclo[2,2,1]hebutane, 7-thiabicyclo[2°2.11hebutane-5-ene and the like. The acid anhydride to be used is applicable to bicyclic or tricyclic cyclic anhydrides with σ symmetry. The substituents that may be present on the alkyl, alkenyl, aryl, and aralkyl include: Examples include the above-mentioned alkyl and 2-rukoxy, halogen, amino, amino derivatives or nitro. Examples of alkoxy include methoxy, ethoxy, propoxy, inpropoxy, butoxy, and pentyloxy. Examples of halogens include fluorine, chlorine, bromine, and iodine. Examples of amino derivatives include hydroxyamino and alkylamino. The present invention will be explained in more detail with reference to Examples and Reference Examples below, but these are not intended to limit the present invention in any way. Abbreviations used in the tables, Examples, and Reference Examples are explained below. Mc: Methyl C1t, Ph: Benzyl Et: Ethyl C11Ph, : Benzhydryl Bu Nibutyl
Ph: Phenyl THF: Tetrahydrofuran DMF Nidimethylformamide HMPA: Hexamethylphosphoramide p -Mand@: D-mandelic acid and its ester L -Mat+d@: L-mandelic acid and its ester PCC: Pyridinium chlorochromate PMB: p-methoxy Benzyl 烹Ju艷1 (Is, 2R, 3S, 4R)-bicyclo[2゜2.1]
Hept-5-ene-2,3-dicarboxylic acid 2-(benzyl D-manplate) ester D-mandelic acid benzyl ester (5,33 g, 22,0
mmol) in THF (50 ml), -78
Cool to ℃ and add n-BuLi (1,6M hexane solution 13
．． 13m1.21. On+m. 1) was added dropwise to the reaction solution and stirred for 15 minutes.
2,2,1 cohebut-5-ene-2-endo,3-endo-dicarboxylic anhydride l-1 (3,32 g, 20.
0 mmol) in THF (20 ml) is added. -7
After stirring at 8°C for 1 hour, 2N hydrochloric acid was added and extracted with ethyl acetate. After washing with water and saline and concentrating, the target product 1f-
1-Del and by-product 1'-1-Del are obtained (H-1-D(el +I['-1-D
el -9゜33g), compound 1t-1-Del
is purified by silica gel column chromatography (toluene and ethyl acetate). IR (liquid film): 3600-2400.1748.17
10.1498°1456, 1342.1257.12
08.1165°1084, 1072.912.732
．． 696'H-NMR (CDCIs-TMS) Sppm
: 1.33 (ABq, Apart. J=8.9Hz; IH), 1.48 (ABq,
Bpart, J=8.9Hz, 18). 3.16 (br, s, IH), 3.21 (
br, s, LH), 3.30 (dABq. Apart, J=3.2. 10.2Hz, 18
), 3.47 (dABq, Bpart. J=3.4Hz, 10.'2t(z, 18),
5.13(s, 2)1), 5.97(s,
IH), 6.11 (dABq, Apart,
J=2.9)1z, 5.9Hz, 1)1)
. 6.28 (dABq, Bpart, J:2.8
．． 5.9) 1z, LH), 7.13-7.5
2 (m, IOH> 衷m) In the same manner as in Example 1, the reaction was allowed to proceed as shown in the reaction formula below, and the target compound - DL = L, I The reaction conditions are shown in Table 1. (The following are blank spaces) (In the formula, R5, Y and Z have the same meanings as above. In Table 1, the target product L obtained in Example 5 -2-
A mixture of Del and the by-product M2 was subjected to silica gel column chromatography to remove toluene.
Purification with ethyl acetate yields only the target product ll-2-Del (75 g, isolated yield near 8.6%) Elemental analysis CCraHm*Oa・0.2H, O) Calculated value (%): C, 64,35; H,6,13 actual value (X): C,64,37; H,6,49'H-
NMR (CDC1a-TMS) & ppm: 1.37
~2.00 (m, 6H). 2.62 (br, s, 28), 3.06 (dAB
q, Apart, J=3.0°12.0Hz, I
H), 3.22 (dABq, Bpart, J=3
．． 0.12.0Hz, LH), 3.74(s, 3H
), 6.01(s, 111), 7.33-7.5
5(m, 5H) [α]2' = -70,2±0.6° (CHC
Is, C=1.965%) In the same way for other compounds,
Preparation of heptane-2,3-dicarboxylic acid 2-(D-MandelWa) ester 11-2-Dal was isolated. 10% palladium on carbon (0.4 g) was added to the crude product.
A methanol solution (30 ml) of DΩL U (4-06 g, 10,0 mmol) was added, and after stirring at room temperature under normal pressure and hydrogen atmosphere for 1.5 hours, the catalyst was filtered off and the reaction mixture was concentrated. Ethyl acetate and 5% aqueous sodium hydrogen carbonate solution are added to the mixture, and the aqueous layer is separated. Wash the organic layer once more with water and combine the first aqueous layers and wash with ethyl acetate. 2
Add N hydrochloric acid, extract with ethyl acetate, wash with saturated brine, and concentrate to obtain crude product I[-2-D(al) [3.14 g, yield from acid anhydride: 99%, M-
2-D(al): If'-2-D(al = 8a:
14 (by HPLC). The target compound ll- was recrystallized from ethyl acetate.
2-Dal is isolated (2.05 g. Yield: 64%). After concentrating the mother liquor, I['-2-D(al) is obtained as a by-product by recrystallizing from methylene chloride. (c + ? Hl -0-) Calculated value (
X): C, 64, 13F H, 5, 71 actual measurement value (X
): c, s3. s3; H,5,73'H-NMR
(CDC1,, rMS) Sppm: 1.46 (br,
s, 4H). 1.57-1.75 (m, IH), 1.84-2.
08 (m, 18), 2.40-2.62 (m, 2
H), 3.02 (dABq, Apart, J:3
．． 6.11.6Hz, IH), 3.29(dABq
, Bpart, J: 4.4.11.6Hz. IH), 5.86 (s, IH), 7.33-7.6
5(a+, 5H) [α Koni''=-117,1
±0.8° (MeOH,C=1.934%>11'
-2-D(al Melting point: 157-158°C Elemental analysis (as C+tH8*O*) Calculated value (X): C,64,13i H,5,71 Actual value (X): C,64,02; H ,5,57'H
-NMR (CDCIs (MS) ff ppm: 1.3
0-1.66 (m, 4H). 1.69-1.87 (m, 18), 1.96-2.
13 (m, LH), 2.60 (br. s, 2)1), 3.04 (dABq, Apart
, J=2.8.12.1Hz. IH), 3.13 (dABq, Bpart,
J=3.8. 12.1Hz, IH). 5.84 (s, IH), 7.33-7.58 (
m, 5H) [α ko ;= −81,8*0.6”
(MeO)1. C=2.005%> Thick 1111
The derivative ll-2-L(el obtained in Example 7) was subjected to the same reaction as in Example 8, and the following dicarpo was subjected to the same reaction as in Example 8 to obtain the following dicarboxylic acid 1[- 2-D(al
). Melting point: 162-164℃ [αconil'' = 4113゜2f1.5° (M
eOH, C-1,0075X) (hereinafter blank) Compound n-1-D (C3) obtained in Examples 4 and 5
and I[-2-D(e 1 ) in DMSO, LiI
By reacting, the above dicarboxylic acid ■-2-D(al)
give. (Left below) Large iLL(Is, 2R, 39, 4R)-Bicyclo[2°2.1]
Hebut-5-ene-2,3-dicarboxylic acid 2-(D-
A methylene chloride solution (60 ml) of the crude compound lt-1-D e2 (43 g) was cooled to 0°C, and anisole (18 ml) and trifluoro Add acetic acid (50 ml) and stir for 1 hour. After concentrating the reaction mixture, ethyl acetate and 5% aqueous sodium hydrogen carbonate solution are added. Separate the aqueous layer, wash with ethyl acetate, and acidify by adding 2N hydrochloric acid. Extraction with ethyl acetate, washing with saturated brine, concentration, and drying yields the crude product, L2''.
I[double double ヱ''Qmen'-1-D at =7
4:26 (by HPLC)], the target compound was obtained by recrystallization from ethyl acetate, 1 piece of L: 13-L. (13.37 g, yield 47%). Melting point: 169-171°C Elemental analysis (as C+yH+sOs) Calculated value (X): C,64,55i H,5,10 Actual value (%): C,64,46; H,5,12I
R(CHCL3): 3500-2400.1734
．． 1438.1375°1342, 1256.1168
．． 1146.1072'H-NMR (CDCIs-TM
S) Sppm: 1.36 (ABq, Apart. J=7.2Hz: IH), 1.51 (ABq, B
part, J=7.2Hz, LH>. 3.15 (br, s, 2H), 3.43 (dAB
q, Apart, J: 2.9°10.4Hz,
1M), 3.53(dABq, Bpart,
J=3.1. 10.4Hz, 11), 5.
86(s, 2H), 6.14=6.33(m,
2H). 7.32-7.62 (ms, 5) 1) [α]2':
-159,5G,0' (MeOH,C=1.99
3 χ) (space below) East m The reaction was carried out in the same manner as in Examples 1 and 8 to obtain the target product l-2-Dal. (Left below) To bicyclo[2,2,1]] Butane-2-endo-3-endo-dicarboxylic acid anhydride l-2 (1.66 g, 10.
Ommol), p-7underic acid benzyl ester (2,
66g, 11. Ommol) and n-BuLi (6
, 40 ml, 10.2 mmol), intermediate I[-
2-De2 was not purified and the hydrolysis reaction was continued to yield 2.64 g of the crude target product I[-2-Dal. [Yield: 83%/■-22-D"QμM'-2-D
al -80:20] Recrystallization from ethyl acetate yields the desired product, L2. : "Tobu" L1 - 1,47 g is obtained. (Isolated yield: 46%) Intermediate ll-2-De2 can be purified by silica gel column chromatography. 'H-NMR (CDC1, -rMs) S ppm:
1.32-1.97 (m, 6H). 2.55 (br, s, LH), 2.60 (br,
s, LH), 2.98 (dABq. Apart, J=3.7.11.6Hz, IH),
3.18 (dABq, Bpart. J=3.9.11.6Hz, LH>, 5.14(s
, 2H), 6.03(s, LH>, 7.15-
7.52 (m, 10H) Inu W (-1) The reaction was carried out in the same manner as in Example 13, and the target object 11-2 was obtained.
The six reaction conditions for obtaining -Dal are shown in Table 2.
(Margin below) (Margin below) Large m(mlヱ(IR, 29, 3S, 4S) - Bicyclo [2゜2.11
Production of hebutane-2,3-dicarboxylic acid 2-methyl ester lll-2-D-1 M@OH+THF Under nitrogen atmosphere, compound 1 [-2-Dal (5,511%
THF (40 ml), methanol (50 ml), and sodium methylate (2M/methanol, 22.0 ml, 440 mmol) were added to 17.3 mm+ol), and the mixture was refluxed for 4 hours. Add 2N hydrochloric acid, extract with ethyl acetate, wash with water and saturated brine, and concentrate. Methylene chloride is added to the resulting mixture, washed three times with water, and then concentrated to obtain 3.22 g of the target compound m-2-D-1 (yield: 94
%). Melting point = 59~60°C Elemental analysis (as Cr*Hl-Oa) Calculated value (X)
: c, so, sg+ H, 7, 13 actual measurement value (1)
: C,60,66i 14.7.08'H-NMR(
CDCIs-TMS) i! i ppm: 1.20~1
．． 74 (m, 6H). 2.59 (br, s, LH), 2.69 (br,
s, IH), 2.79 (d. J=5.4Hz, IH), 3.27 (dd, J=
3.8.5.4Hz, 1B). 3.69 (s, 3H) [α]2' = +3s, t*o, 4° (MeOH, C
= 2.002%) (blank space below)
]Hebutane-2,3-dicarboxylic acid 2-methyl ester 1[-2-L-1 Production 21 7.46 g was obtained. (
Yield near 8%) Melting point: 59-60°C [α]2' = -38°3±0.4'' (MaO
H, C=2.013%) large JILL and (Is, 2S, 3S, 4R)-bicyclo[2°2.1]
Preparation of hept-5-ene-2,3-dicarboxylic acid 2-methyl ester I [-1-D-1 The reaction was carried out in the same manner as in Example 17, and one starting material was the enantiomer of the compound of Examples 1 and 7. ni l yueee. Let's relax. For the compound 1 double 1 λ (1 s, 27 g, 48.0 o1),
Methanol ('55a+1), THF-' (60m
l), sodium methylate (2M/methanol, 60
When the reaction was carried out using the target compound 111-2-L (15 g,
47.4a+1)j, methanol (50ml), TH
When the reaction was carried out using F (100 ml) and sodium methylate (2M/methanol, 71.1 ml, 142 mmol), 7.96 g of the target product I[[-1-D-1 was obtained (yield: 93゜2 %). Melting point near 8-79℃ Elemental analysis (as C+-H+*Os) Calculated value (χ): C, 61, 2CH, 6, 17 actual value (
X): c, ao, ao; H, 6, 13IR (CH
CLs): 3400-2400.1729.170
8.143g. 1422, 1335.1311.1271.1245°1190, 1175.1162.1114.1022'
H-NMR (CDCIs-TMS) Sppm: 1.4
8 (ABq, Apart. J=8.0Hz, LH), 1.63 (ABq, B
part, J=8.0Hz, IH). 2.66 (dd, J=1.6.4.6Hz, LH)
, 3.14 (br, s, IH). 3.30 (br, s, LH), 3.43 (dd,
J:3.6.4.6Hz, LH>3.73(s,
3H), 6.14 (dABq, Apart, J-
2,9,5,5Hz. LH), 6.29 (dABq, Bpart, J=
3.15.5Hz, LH) [α]2' = +1
38.1*0.9' (MeOH, C-2,005%
) (Left below)
Manufacture of 1 liter of heptane-2,3-dicarboxylic acid 2-(D-mandelic acid) ester l double main double process + Sodium hydride (60%, 0.447 g
, 11.1 mmol) with hexane, then THF
(10 ml). D-mandelic acid benzyl ester (2,69 g, 11,1 mm
A THF solution (30 ml) of ol) was added and stirred for 30 minutes. The reaction solution was cooled to -78°C, and bicyclo[2,2
1 cohebut-5-ene-2-endo, 3-endo-dicarboxylic acid anhydride 1 unit (1,64 g, 10.0 mm
After 0 dropwise addition of THF solution (10 ml) of ol), continue stirring and raise the reaction temperature to 0°C. After post-treatment in a conventional manner, a deprotection reaction was carried out in the same manner as in Example 8 to obtain 2.04 g of the crude target product ll-2-D al (yield: 64
%). (II-2-D al :Ti'-2-D al
-59:41) (Margin below) Large 1 ■ LL top (IR, 2R, 3R, 4S) - Bicyclo [2° 2.1]
Hebut-5-ene-2,3-'; Production of carboxylic acid 2-methyl ester lll-1-L-1 (blank below) 1-1-L(al) Preparation of D-mandelic acid benzyl ester of Example 9111 Instead, L-mandelic acid paramethoxybenzyl ester is used and reacted in the same manner to obtain a crude product containing the compound l-1-L, ('21-) as the main product. The above crude product (30.6 g, 70 mmol) was dissolved in 160 ml of acetonitrile, and 35.9 ml (70 mmol) of concentrated hydrochloric acid was added.
mmol x6) and stirred at room temperature for 16 hours. Adjust the pH to 4 with a 4N NaOH aqueous solution, and add NaH to this.
The mixture is made alkaline by adding a COs aqueous solution under water cooling, and washed with ethyl acetate. The organic layer is further extracted with water, the aqueous solutions are combined, the pH is adjusted to 2 with concentrated hydrochloric acid, and the mixture is extracted with ethyl acetate. This is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crystalline residue. This crude product (1-L
aal: I'-1-L al =85:15 mixture (according to HPLC)) is recrystallized from ethyl acetate to obtain 11.12 g of compound H-1-L al (yield 50.2%). Melting point: 168-170°C. I R,'H-NHR (CDC1m) is lt-1-DΩ
Matches 11. [α]. :◆160.5±1.0°(M@a1.23℃
, c=2.002%) Compound 11-1-L-1, 345 mg (yield 92.7%) was obtained from Compound 1 (601 mg) in the same manner as in Example 17. Melting point 78-79℃, IR%NMR is Compound 1[-1
- Matches D-1. [ff]e = -140,8±0.9@(Mail,
23°C, c=2.018X)mp, 78-79°C. (Left below) Fire Jul main (IR, 2S, 3R, 48) -7-oxabicyclo[2
,2,11butane-2,3-dicarboxylic acid 2-D-
Production of mandelic acid ester 1, 1, 1, 1, 2, 3, 3, 3-D (al) compound! -3,10,5 g (62 mmol), a mixture of 1 liter of compound I and I'-3-Dal was obtained in the same manner as in Examples 1 and 8. (1
-3-D al: I'-3 Fudanko 1yu l-73:
27 (HPLC)) Compound N-3-D was obtained from this mixture.
al, 7.1 g (yield 35.8%) and I'
-3-D al 1.5 g (yield 7.6%) was isolated by recrystallization method. Compound I-l-3-D (al, 175-177°C. (Margin below) Elemental analysis (as C+ sH+ *Ot) Calculated value C%'
): C, 59,99i H, s, o4; Actual value (1)
:C,59,85:H,5,04゜'HNMR(CD
sOD-TMS) E ppm=1.55-1.88 (
m, 4H). 3.13 (ABq, A-part, J=9.6Hz
, IH), 3.19 (ABq, B-part,
J=9.6Hz, 1)1), 4.83~4.90(
m, 2H), 5.85 (s. IH), 7.35-7.65 (a+, 5) 1). IR (Nujol) νmax: 3480-2200.
1733.1712°1659, 1229.1220.
1185.1011.969.936.766°735
, 696 cll [αkoo (11,9*1.5° (MeOH, 23
°C, C = 1.013% > Compound I'-3-Da1 mp, 133-135 °C. Elemental analysis (C*, H+ *Ot・0.5H□O) Calculated value (X): C, 5g, 35; H, s, zt;
Actual measurement value (X)j C, 5g, 33j H, 5.4g. 'HNMR (CD, OD-TMS) 8 ppm:
1.55-1.90 (m, 48). 3.12 (ABq, A-part, J=9.6Hz
, IH), 3.22 (ABq, B-part,
J=9.6Hz, IH), 4.75=4.90(m
, 2H), 5.74 (s. IH), 7.35'7.65 (a+, 5H). IR (Nujol) νmax: 3680-2200
．． 1733. 171 (1 (sh). 1230.1177.1044.994,925,81
9.724 cm-'[a]I,-92,O±1.3'
(M@il, 23℃, C=1.014%>
. Tue JLLL Yu (IR, 2R, 3R, 4S)-7-Oxabicyclo[2
, 2,1-cohebutane-2,3-dicarboxylic acid 2-methyl ester II[-3-D-1 Production ■-3-D(al
) M@OH compound 1[-3-D(al
From 610 mg (1°9 mmol), compound l2-3-D-1, 190 mg (yield 50.0%) was obtained according to Example 17.
get. Melting point 134-135℃ Elemental analysis (as C*H+*Oi) Calculated value C%'): C,54,OOi l(,s,os
; Actual value <X'): C, 53,98; H, 5,97
゜'HNMR(CDC1j(MS)εppm: 1.
45-1.95 (m, 4M). 3.14 (d, J=5.1Hz, IH),
3.50 (t-d, J=5.5. 1.5Hz,
IH), 3.74 (s, 3H), 4.84 (
t, J=5.0Hz, IH). 4.92 (d, J'5.01 (z, 1) 1). IR(Nujol)νl11ax: 3400~
2480. 1736. 1725°1255, 12
15.1201. 1184. 1173.921.8
16C■-1 r (1lD+73.3*0.6@(MeOH, 24℃
, C=2.009%). Large JIL ball (Is, 28, 3S, 4R) -7-oxabicyclo[2
,2,1]Production of hebutane-2,3-dicarboxylic acid 2-methyl ester ll-3-L-1 (yield 27.5%)
. Melting point 133-134°C Elemental analysis (as CJ+sOs) Calculated value<'X): C,5too; Actual value<'X'): C,54,03il HNMR and IR indicate compound 111-3 [αcoD-73, 5*0
．． 6@ (MeOH. H, a, os; H, 6,06° Consistent with D-1. 23°C, C = 2.0131>. (Margin below) Enantiomer of compound 111-3-D-1 ~ I[ [-3
-L-1 is produced from the by-product of the cleavage reaction, compound 1-3, and 11 according to the above method. X” self q (Is, 2R, 3S, 4R)-7-oxabicyclo[2
, 2,1 cohebutane-2,3-dicarboxylic acid 2-methyl ester 1-1 to the compound 1-3-D-2.
4.5 g (14° osmmol) of the compound was treated with an ethereal solution of diazomethane in a conventional manner to obtain 4.77 g (yield: 97.5%) of the compound. Dimethyl ester Nitan W Melting point 131-132°C Elemental analysis (as C+aH**Ot) Calculated value C%”): C, 62,05i H, s, so;
Actual value (X): C, 61,87i H, 5,7g. ' HNMR (CDC1, -XMS) δppra: 1
．． 45-1.70 (m, 2) 1). 1.77-1.93 (m, 2H), 2.99 (ABq
,, A-part, J=9.6Hz. IH), 3.15 (ABq, B-part, J=
9.6Hz, IH), 3.53 (s. 3H), 3.70 (s, 3H), 4.85-4.9
3 (a+, IH), 4.95-5.03 (a, IH)
, 5.93(s, lH), 7.34=7.55(m
, 5H). IR(Nujol)νmax! 1742.1?32.
1198.1143°1055, 1009.936.7
25.695 am-' [(!1e-103,2*1.
4° (CICIs, 23.5°C, C=1.009%). Dimethyl ester 11.4, 1 eg (1
2 mmol) was dissolved in 30 ml of ethyl acetate, and 10% P
After adding 400 mg of d-C and stirring for 1 hour in hydrogen gas, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ether to give the cis half ester ll-3-D-2.
, 2,02 g (yield: 84.2%). Melting point 104-106℃ (margin below) Elemental analysis (as CeH+*Oa) Calculated value (%) + c, C4, oo; n, e, os
; Actual value (X) F C,53,83i 1(,6,04
゜'HNMR (CDCIs-TMS) Sppm++ 1
．． 45-1.60 (s, 2H). 1.73-1.93 (a+, 2H), 3.01 (AB
q, A-part, J=p, 6Hz. IH), 3.03 (ABq, B-part, J=
9゜6Hz, IH) + 3.66 (s. 38), 4.87-5.03 (m, 2H), 6.5
6 (br, s, 11). IR (Nujol) l/a+ax: 3400”248
0.1736.1731°1228, 1198.116
9.1010.996.924.900゜821C■-
1 [α]o-4,9±0.2° (MaOH, 23,5°C,
C=2.010X). [(!]ssi −7,9*0.2” (MeOH,
23.5°C, C=2.0IOX>. The [α]D value of this compound is almost the same as that of compound 111-3-D-2 reported by R. Bloch et al. [Tetrahedron Letters, No. 26
Volume, No. 34゜pages 4087-4090, 198
5 years ([α1e-3,so(MaOH. 20°C, C=2X), melting point 104°C)] (blank below) EJIL mutual (IR, 2S, 3R, 43)-7-oxabicycloC2
,2,11hebutane-2,3-dicarboxylic acid 2-methyl ester m-3-L-2 Production cleavage reaction by-product I
'-3-D al, 720 mg (7,25 mm
Compound I'-3-D was obtained according to the method used to obtain the compound I'-3-D.
, C5678 mg (yield 86.6%) is obtained. Dimethyl ester W"-3-D (e5 Melting point 115-116°C Elemental analysis (as C+sH*.0.) Calculated value (%): C, 62,05; H, s, so; Actual value (X)"C ,61,85i H,5,74゜' H
NMR (CDCI, -TMS) δppm: 1.4
5-1.70 (m, 2H). 1.74-1.95 (m, 2H), 2.97 (ABq
, A-part, , C9,6Hz. IH), 3.17 (ABq, B-part, J=
9.6Hz, IH), 3.36 (s. 3H), 3.71 (s, 3H), 4.84-4.9
5 (m, IH), 5.00-5.10 (m, IH),
5.89 (s, IH), 7.33-7.50 (m,
5H). IR(Nujol)l/max: 1753.173
7.1725.1220°1190, 1164.114
5.1056.1028.1004.817°735,
693 am" [αID -84,7*1.2@(CHCI-, 23℃
, C=1.008%). Dimethyl ester M”-3-D e5 .523mg
(1.5 mmol), compound 1[232D e
Cis half ester I [-3-L-main, 271 mg (
Yield: 90.3%). Melting point 103-105°C Elemental analysis (CsH+ *010. As IHsO) Calculated value <”X): C, 53,51i H, 6,10i Actual value C%>: C, 53,67; H, 5,90° l
HNMR and IR are completely consistent with compound lll-3-D-2. [αko, +4.4±0.2° (Meal, 24℃
, C=2.006%) [α1ssi ”7.0±0
．． 2@(MeOH, 24°C, C=2.006%). (Space below) Example 27 (IR, 2R, 3S, 48)-2-(Methyl-D-mandeloxycarbonyl)-3-methoxycarbonylbicyclo[2,2,1]hebutane 1 [nee L:'' 1 1 liter (22,72 g, 71.
3 mmol) and p-toluenesulfonic acid monohydrate (2.73 g, 14.3 mmol) in methanol (37 mmol) and p-toluenesulfonic acid monohydrate (2.73 g, 14.3 mmol)
5 ml) for 24 hours. After concentration, the mixture is separated between 5% sodium bicarbonate solution and ethyl acetate. After washing the organic layer with water, the organic layer is dried and concentrated to obtain 26.06 g of the crude target product 1-2-D (e5). Recrystallization from ether/petroleum ether yields the target product I[-2-D
(e5 is the first crystal = 18.59g (53.7mmo
l), 2nd Crystal 20. s2g (1.8mmol), tertiary crystal: 0.53g (1,
5 mmol) is obtained. (Total isolated yield/yield: 19.
74g, 79.9%). Melting point: 61.5-63.5°C. Elemental analysis (as CIJ*tO*): Calculated value C%)' C65,88,H6,40i Actual value C
%'): C65,72,H6,42°IR (KBr)
νwax: 3700-3160.2970.2885
．． 1758°1745, 1730.145? , 136
5.1345.1198.1165゜1122, 108
2.1060.1055.1042.1022.748
゜698 am'''HNMR (CDCIs-TMS) l; ppm:
L, 20-2.00 (m, 6H). 2.50-2.65 (brm, 2H), 2.96 (d
ABq, A-part, J=3.8°11.8Hz
), 3.21 (dABq, B-part, J=4
．． 3.11.8Hz). 3.54 (s, 3H), 3.70 (m, 3H), 5
．． 94 (s, IH), 7.30-7, 52 (m, 5
H). [αID-77,8±1.2°(CHCL3.23.5
°C, C=1.0OX). (Left below) Example 28 (Is, 28,3R,4R)-bicyclo[2°2.1]
Preparation of heptane-2,3-dicarboxylic acid 2-methyl ester 1-2-D-2 10% palladium on carbon (1,7
7g) to compound M-2-D e5 (17,79g
, 51.4 mmol) in ethyl acetate solution (200 ml)
and stirred at room temperature for 50 minutes under normal pressure and hydrogen atmosphere,
The catalyst is removed by filtration and concentrated. Toluene and 5% sodium hydrogen hypooxide solution are added to the reaction mixture, and the aqueous layer is separated. Wash the organic layer once again with water, wash each layer with toluene, and combine. After adding 2N hydrochloric acid and extracting with ethyl acetate,
After washing with water, drying and concentrating, the desired product 111-2-D-
2 (10.2 g: quantitative) is obtained. Elemental analysis (as C+Js40m): Calculated value (X): C60,59,H7,12i Actual value C
%): C60,42,H7,05°IR(KBr)l
/wax: 3400-2400.2960.28g0
．． 1735°1708, 1435.1356.1295
．． 1288.1132.1122゜1082, 1058
cm+-''HNMR (CDCIn-TMS) Sppm: 1.3
5-1.53 (m, 48). 1.65-1.88 (m, 2H), 2.48"2.6
4 (brm, 2H), 2.96 (dABq, A-p
art, J=3.4.11.7Hz, IH), 3
．． 03 (dABq, B-part, J=4.4.1
1.711z, 11), 3.64(s, 311). [αko +17.11.3° (MeOH, 23,
0°C, C, 2,059%). (Left below) Example 29 (IS, 2S, 3R, 4R)-2-(Methyl-L-mandeloxycarbonyl)-3-methoxycarbonylbicyclo[2,2,1]hebutane I-L21E11 The reaction was carried out in the same manner as in Production Example 28 to obtain the target product l-2-L.
-2 is obtained. (Yield: Quantitative) [α]e-17.4*o
, 3° (IIeOH, Ca2.052X, 24°C). (Left below) A reaction similar to that in Example 27 is carried out to obtain Compound 1- and Ni-Ni-L. (Yield: 87.5%) Melting point: 61.
5 #62.5℃. [ff 1m ”76, 3G, 2@(CHCIg, 2
4°C, 1.005X). Example 30 (IR, 2R, 3S, 4S)-bicyclo [2°2.1]
Production of heptane-2,3-dicarboxylic acid 2-methyl ester U double 21 (blank below) 111 Production method of arylacetic acid derivative (1) D-mandelic acid benzyl ester actual value (X)
: C,74,53; H,5,90'H-NMR(
CDCIs-TMS) S ppm: 3.44 (
d, J45.6Hz. LH), 5.14 (ABq, Apart,
J=12.3Hz, IH), 5.22 (d., C5,6Hz, IH), 5.24 (ABq,
Bpart, J: 12.3Hz, IH) 7
．． 15-7.50 (m, 10H) [(Z]+'-5
5,7*l,Qo(CHCIs, C=1.003X
) (2) D-mandelic acid 4-methoxybenzyl ester D-mandelic acid (85.1 g, 559 mmol), benzyl alcohol (65 ml, 62 Ommol) and tri-toluenesulfonic acid (1,01 gx s, a 5
mmol 1) in benzene (700 ml) for 6.5 hours, washed with water, and concentrated. Recrystallization from ether yielded 123.5 g of the target product, Uni 1. Yield: 91% Melting point: 103.5-105°C Elemental analysis (as C1, H140) Calculated value (X): C, 74,36i H, 5,82p
- mandelic acid (15,3 g, lOOmmol),
4-methoxybenzyl alcohol (15.2 g. 110 mmol) and p-toluenesulfonic acid (0
, 197g, 1.01mmol) in benzene (30
After refluxing in 0II+1) for 7 hours, the reaction solution is washed four times with water and concentrated. The obtained crude product is subjected to silica gel column chromatography, purified with toluene-ethyl acetate, and recrystallized from ether-petroleum ether to obtain 6.58 g of target product D-3. Yield: 24% Melting point near 0.5-73.5°C Elemental analysis (as C8IH0O=) Calculated value (X): C, 70,58; H, 5,92 Actual value (X): C, 70,55i H,6,OO'H
-NMR(CDC1, -TMS>8pprtr: 3.
80(s, 3H), 5.05(ABq, Apar
t, J=11.8Hz, IH), 5.19(s,
IH), 5.19 (ABq, Bpart, J=
11.8Hz, IH), 6.84(d, J=8.
7Hz, 2H), 7.17(d, J=8.7Hz
, 2H), 7.30=7.45(m, 5H) (margin below) [α]2'=-36.0 * 0.8° (CHC
IA, C=1.017%) (3) D-mandelic acid-4-nitrobenzyl ester P-mandelic acid (15゜2 g) in DMF (300 ml)
, 10 Ommol), 4-nitrobenzyl bromide (21.6 g, 10 Ommol) and triethylamine (14.0 ml, 100 mmol) and stirred at room temperature for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After washing with dilute hydrochloric acid and water, the product is recrystallized from ether-petroleum ether to obtain 6 g of target product D-419. Yield: 68% Melting point = 143-145°C Elemental analysis (as Cl* Hrs NOs) Calculated value (X): C, 62,72 + H, 4,56; N, 4
．． 88 actual measurement value (χ'): c, cz, 7s; H, 4,
61; N, 4.99'H-NMR (CDC1,-D
S) εppI11: 3.26=3.52(br, s
. 18), 5.25 (ABq, Apart, J=1
3.5Hz, LH), 5.28 (s. LH), 5.32 (ABq, Bpart, J=1
3.5Hz, LH), 7.27 (d. J=8.4Hz, 2H), 7.34-7.48 (b
r, s, 51), 8.14 (d. J=8.4Hz, 2H) [α]2'=-40.0*0.8° (CHC
(4) D-mandelic acid benzhydryl ester Dissolve D-mandelic acid (25.0 g, 164 m + 5 ol) in ethyl acetate (200 ml) and add diphenyldiazomethane with stirring at room temperature. (38.9g, 164mmol)
Add. After confirming the completion of the reaction by TLC, concentrate. Recrystallization from ether-petroleum ether yielded 47.7 g of target product D-5. Yield: 91% Melting point = 91-91.5°C Elemental analysis (C□Hr*0-) Calculated value (X)
: C, 79, 22: H, 5, 71 actual measurement value (X):
C,79,44; H,5,67'H-NMR (CD
CIs-TMS) δppm: 3.47 (d, J=
5.3Hz. IH), 5.28 (d, J=5.3Hz, 1M>
, 6.87(s, 18), 6.87-7, 46(
m, 15H) [α]2' = -57,4± 1.0° (CHCI
s, C=1.023 A reaction was carried out in the same manner as in Reference Example 1-(4), and L-mandelic acid (3G, 4K, 200mIIIol), ethyl acetate (200ml) and diphenyldiazomethane (3
8.9g, 200mmol)
54.7 g (172 mmol) are obtained. Yield: 86% Melting point: 91.5-92.0°C [α]2' +55.7 *Q, 9°
(CHCIs, c=t, ots X) Compound 1f-2-D-1 (2.80 g, 14.
An acetone solution (24 ml) of triethylamine (2,541111,18,3
mmol) and ethyl chlorosuboxide (1,7S garden 1.18.
3 gmol). A white precipitate will form immediately, but continue stirring for 15 minutes in this state and add sodium azide (
2.75g, 42.3mmol) in water (8ml)
Add. After stirring for 30 minutes under water cooling, 2N hydrochloric acid was added, extracted with ethyl acetate, and the organic layer was washed with water and brine and concentrated. Add benzene and concentrate again to completely remove ethyl acetate. The obtained oily substance was dissolved in benzene (20 ml) and 8
Heat to 0°C to carry out thermal rearrangement. When nitrogen generation has finished, add triethylamine (2.54ml 1.18, 3
mmol), benzyl alcohol (1.75ml1.16
, 9 meal) and refluxed for 1.5 hours. After the reaction, 2N hydrochloric acid was added, extracted with ethyl acetate, washed with water and brine, and concentrated. The crude product was purified by silica gel column chromatography and recrystallization to obtain the compound (3.03 g, yield near 1%).
. Melting point = 61~62℃ Elemental analysis (as C+yH□N Oa) Calculated value (X)
: C, 67,30; H, 6,99i N, 4.62
Actual measurement value (X): C, 67,46; H, 7,04;
N, 4.73'H-NMR (CDC1,-TMS
) δppm: 1.22-1.86 (m, 6H). 1.92 (dd, J=2.0.5.0Hz,
IH), 2.50 (br, s, 2H). 3.70 (br, s, 3H), 4.23 (
br, s, 1) 1), 4.90 (br. s, IH), 5.09 (br, s, 2)
M>, 7.22~7.45 (m, 51) [αKoni' = +40.1 ± 0.4° (CHC
A methanol solution (13 ml) of compound 1 (x, < 2 g, 4.67 o 1) was added to 10% palladium-carbon (0,130 g) (C=2.006X) at normal pressure, under a hydrogen atmosphere, and at room temperature. After stirring for 30 minutes to carry out hydrolysis, the catalyst is removed by filtration and concentrated. Methylene chloride (10
ml) and cooled to 0°C. Triethylamine (1.94ml 1.14.0mmol) and benzenesulfonyl chloride (0.66ml 1.5.17mmol) were added to this,
Stir for 30 minutes. Add 2N hydrochloric acid, extract with ethyl acetate, wash with water and brine, and concentrate. Purification by silica gel column chromatography yields the desired product. (1.17 g, yield: 81%) Melting point = 129-130°C Elemental analysis (as C, lH,, NO, s) Calculated value (X)
: C, 58,22; H, 6,20+ N, 4.5
2iS, 10.36 Actual value (1): c, ss, ii: H, 6,07;
N, 4.53FS, 10.09 (margin below) [α]Koni' = -0,4* 0.4° (CH
Cl,, C=0.992X) [α]::3=-36
．． 2 ± 0.8° (CHCIA, C = 0.992%) under nitrogen atmosphere, compound 2 (1.12 g, 3.62 mmol
) of lithium aluminum hydride (0,412 g, 10.9 mm.1) in THF solution (15 ml) at room temperature.
Add. After stirring for 30 minutes, ethyl acetate and water were added to the reaction solution in this order to crush the excess lithium aluminum hydride. Extracted with ethyl acetate three times and concentrated to obtain the target product 3 (1.00 g, 98.2% ). Melting point = 121-122°C Elemental analysis (CI 41 (as Im NO S) Calculated value (X): C, 59,75i H, 6,82i
N, 4.98iS, 11.39 Actual value (X): C, 59,83; H, 6,91i
N, 5.02; 5.11.33 [α]2' = 46.8 * 0.5@ (
CHCl, C=1.000X) FCC (18.4 g,
85.4 mmol) and Molecular Sheep (4A powder, 25.1 g) were added and stirred at room temperature. After confirming the completion of the reaction by TLC, inorganic substances are removed by silica gel column chromatography and concentrated to obtain an intermediate product. Since compound soil is not very stable, proceed to the next operation without further purification. Under a nitrogen atmosphere, a THF solution (160 ml) of methoxymethyltriphenylphosphonium chloride (31,20 g, 91.6 city o1) was cooled to -78°C, and n-butyllithium (1,6M hexane solution, 56°0+al) was cooled to -78°C. , 84.
After 0 dropwise addition of Ommol), the dry ice-acetone bath was changed to a water bath, and the mixture was stirred at 0°C for 25 minutes. Again, the reaction solution was cooled to -78°C in a dry ice-acetone bath, and the intermediate product beads obtained earlier (
After 0 dropwise addition of a THF solution (80 ml) of 7.27 g), the ice bath was removed and the mixture was stirred for 35 minutes. After adding ice water and extracting with ethyl acetate, the organic layer is washed with water and brine, and then concentrated. Intermediate product 5 is obtained by silica gel column chromatography, but since this compound is also not very stable, proceed to the next step without further purification. Under a nitrogen atmosphere, 90% formic acid (5.0 ml) was added to each compound (5.86 g), and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction by TLC, the mixture is neutralized with sodium hydrogen carbonate and a 5% aqueous sodium hydrogen carbonate solution. After adding water and extracting with ethyl acetate, the mixture is washed with water and brine and concentrated. Purification by silica gel column chromatography yields target compound 1 (3.30 g, yield from compound 1: 40%
). Compound 6 Melting point: 1GG ~ 103°C Elemental analysis (as C+sH,, NOsS) Calculated value (1
): C, 61, 40: H, 6, 54+ N, 4.
77; S, 10.93 Actual value (X): C, 61,39i H, 6,51i
N, 4.90: S, 11.02 [α]2'': +36.5 * 0.8°
(CHClj, C=0.994 N') Under a nitrogen atmosphere, potassium t-butyrate ( 7.55 breath, 67.3 mm+ol) is added at room temperature. After stirring at room temperature for 1 hour, the mixture was cooled to -20°C and a THF solution (20 ml) of compound 6 (3.25 g. 11 , 1 mmol) was slowly added. After continuing stirring at -20°C for about 1.5 hours, the ice bath was removed and stirring was continued for another hour. Add 2N hydrochloric acid to the reaction mixture, extract with ethyl acetate, wash with water and brine, and concentrate. Toluene and IN sodium hydroxide solution are added to the obtained crude product and the aqueous layer is separated. After washing the organic layer again with water and combining it with the aqueous layer,
Add N-hydrochloric acid. After extraction with ethyl acetate, the extract is washed with water and brine, dried over sodium sulfate, and concentrated. Purification is performed by silica gel column chromatography to obtain the desired product 7 (3.29 g, yield 79%). Melting point: 262℃ Elemental analysis (as C, H, tNO, S) Calculated value (X)
: C, 63, 63; u, 7. zt; N, 3.7
1; S, 8.49 Actual value (%): C, 63,56; H, 7,21;
N, 3. ss;S, 8.43 [α]o” ””5.3 f O,5@(CHCIs
, C=1.003%) [α]2' = +27.1±
An acetone solution (25.2 mmol) of 0.7° (MeOH, C = 1.015X)
ml) was cooled to 0 °C and diluted with triethylamine (3,90
m1.28゜Qmmol) and ethyl chlorocarbonate (2,6
5ml1.27, 7 mmol). A white precipitate will form immediately, but continue stirring in this state for 30 minutes.
Sodium azide (1.72g, 26.5mmol)
Add an aqueous solution (6 ml) of After stirring for 45 minutes under water cooling, 2N hydrochloric acid is added and extracted with ethyl acetate. The organic layer is washed with 5% sodium bicarbonate solution, water and brine, then dried and concentrated. Add benzene and concentrate again to completely remove ethyl acetate. The obtained oily substance was dissolved in benzene (25 ml) and heated to carry out thermal rearrangement. When the evolution of nitrogen was completed, benzyl alcohol (2,74+a1.26.5 mm
ol)) ethylamine (3,90ml, 28.Qmm
ol), and reflux for 75 minutes. After the reaction was completed, 2N hydrochloric acid was added and extracted with ethyl acetate.
% sodium bicarbonate solution, water and brine, then dried and concentrated. The crude product was subjected to silica gel column chromatography and purified with toluene-ethyl acetate to give the desired product 8 (3.99 g, 13.2 mmo
l) is obtained. (Yield 252.1%). Elemental analysis (CI?H,, NO, etc.) Calculated value (X)
: C, 67,31i H, 6,98; N, 4.62i
Actual value (X): C, 67,12; H, 6,96;
N, 4.63°IR(CHCl, ') νmax:
3400. 2950. 2880. 1718゜1
505.1453.1438.1358.1325,1
316,1163°1152.1080.1062,1
035.1028 am-''H-NMR (CDCIs
-TMS) & ppm: 1.32 to 1.70 (m,
6H). 2.49 (br, s, 2H), 2.93 (
dd, J=4.3Hz, and 11.1Hz. LH), 3.63(s, 3H), 3.97
~4.18 (m, IH), 5.08 (s. 2H), 6.65 ~ 6.83 (br, m, IH
), 7.28-7.44 (m, 5H) [(Z]
D=+6.1 * 0.5@(CHCls, C=1.0
10%, 23.5°C) [C1] sss s”28.
sho, 7° (CHCl,, C=L, 0IOX,
23.5°C) (margin below) Compound 8 was added to 10% palladium-carbon (0,602g).
(3.87 g, 12.8 dragon o1) in methanol solution (15 ml) was added, and the mixture was heated at room temperature under normal pressure and hydrogen atmosphere for 10 minutes.
After 6 reactions of hydrogenolysis with stirring for 0 minutes, the catalyst was removed by filtration and concentrated. Methylene chloride (10
ml) and cooled to 0°C. To this, add triethylamine (3,60ml 1.25.8ml) and phenylsulfonyl chloride (1,66+al, 13.0mmol),
Stir for 30 minutes. Add 2N hydrochloric acid, extract with ethyl acetate, wash with 5% sodium bicarbonate solution, water and brine, then dry and concentrate. Purification by silica gel column chromatography and recrystallization yielded the desired product 9 (3.20 g, 10°3 mmo
l) is obtained. (Yield: 81.0%) Melting point: 112
．． 5-113.5°C. Elemental analysis (as C, AH, #NO, S) Calculated values (1)
: c, ss, 2s; H, 6,19; N, 4.5
3jS, 10.36 Actual value (X): C, 5g, 33i H, 6, 19i
N, 4.45i5.10.0g. IR(KBr)l/wax: 3335.3270.2
965.288G. 1705, 1445.1435.1368.1352.
1330.1202゜1165, 1092.905.7
58.732.725.690.667゜586, 55
2cm-''H-NMR (CDC1,-DMS) εppm: 1
．． 22-1.76 (m, 68). 2.30 (br, s, IH), 2.43 (br,
s, 11), 2.64(dd, J=4.8Hz,
J=10.6Hz, IH), 3.51(s, 3H
), 3.611r3.82(m, 11), 6.7
4 (d, J=8.8Hz, IH), 7.42-7.5
1 (m. 3H), 7.77-7.90 (m. 2H). [αcoD=-42.1*0.8° (CHCl,,C=
1.002%, 24°C). Lithium aluminum hydride (1,54
A THF solution of the compound (3,00 g, 9.7 Ommol) (
Add 30a+1). After stirring for 2 hours, ethyl acetate and water were sequentially added to the reaction solution to decompose excess lithium aluminum hydride. After extraction with ethyl acetate three times, drying, concentration, and purification with silica gel chromatography, the desired product 10 (2.70 g) is obtained. (Yield: 99.0%) Melting point: 97.5-99.5°C. Elemental analysis (as C14HIINOsS) calculated value (X)
: C, 59,76i H, 6,81; N, 4.9
8:5.11°39; Actual value (X): C, 59,61H, 6,77; N
, 4.92;S, 11.14°IR(KBr)l/a+ax: 3840-3360.
3260.2960.2890°1482, 1463.
144g, 1340.1310.1165.1155
゜1092, 1046.955.755.718.68
8.595.575°549 c+++-''H-NMR(CDCIn-'rMs) εppm:
1.16-2.27 (m, 10H). 3.40=3.56(m, IH), 3.62(dA
Bq, Apart, J=5.0゜11.0Hz, I
H), 3.81 (dABq, Bpart, J=9
．． 0.11. Ohz. IH), 5.51=5.78(br, m, IH),
7.46-7.70 (m, 3H). 7.85-8.00 (m, 2H). Cα] o=+35. too, Bo (CHCIs, C
= 1.005%, 24.0°C) The (+) and to(-) isomers of the racemic compound can be separated by HPLC using a chiral column (ULTRONES-OVM). (Hereafter in the margins) (Hereafter in the margins) The gobaku-kake is unstable and changes gradually during the isolation procedure depending on the compound history. 'H-NMR (CDCI, -rMs) Sppm: 2
．． 58-2.66 (br, m. LH), 2.74-2.88 (m, IH), 3.
64-3.78 (d, J = 7.5 Hz. LH), 9.49 (s, 18), (Compound 11a
Only the characteristic signals are listed) Under nitrogen atmosphere, FCC (0,700g, 3.25mmo
l) and molecular sieve (4A powder, 0.703g)
Compound 10 (0,3
04g, 1.08mmol) in methylene chloride solution (
5 ml) under water cooling. After stirring for 45 minutes at 0°C, 3
Stir vigorously for 45 minutes at 0°C. After confirming the completion of the reaction by TLC, inorganic substances are removed using silica gel and the mixture is concentrated to obtain a mixture of compound Uμ and compound m. (0,301g, quantitative) Compound hookworm: Compound 11b
-9:1. Sodium methylate (0.2 N
/methanol, 1,0 ml, 0.200 mmol)
Add. After stirring at room temperature for 60 minutes, confirm the completion of the reaction by TLC. The reaction solution was once concentrated, separated with 2N hydrochloric acid and ethyl acetate, washed with water, dried, and concentrated to yield the target product 11b (0,537 g). is obtained. (yield:
97.5%) Melting point: 100-103°C Elemental analysis (as CI4HlyNOsS) Calculated value (X): C, 60, 11H, 6, 13; N, 5.
01; S, 11.48; Actual value (X): C, 60,08; H, 6,01N
, 5.11iS, 11.41°IR (KBr) l/max: 3250.2960.2
940.1712°1462, 1448.1338.1
325.1158.1145.1128°1090, 1
080.753.720.682.655.590.5
42cm-''H-NMR (CDCI, -TMS) & ppm:
1.05-1.85 (m, 68). 2.18-2.31 (m, 2H), 2.45 (
d, J=3.6Hz, LH>, 3.81~3.
94 (m, LH), 4.90-5.05 (br, m
, LH>, 7.40-7.67 (m. 3H), 7.76-7.97 (m. 2H),
9.55 (s, LH). [αko,=-47.6*0.9° (CHCl,,
C=1.009%, 24.0"C) Compound m matches the compound ball (intermediate produced in Reference Example 2 (4)), so the reaction was carried out according to Reference Example 2 (4) and (5) below. Compound 7 has a strong action as a thromboxane A receptor antagonist, and is effective against burns, trauma, acute pancreatitis, cardiac dysfunction, blood loss, sepsis, endotoxin-induced shock, and blood reperfusion. Post-ischemic shock in coronary arteries or digestive system arteries, various types of inflammation, myocardial urinary tract,
Prevention of ischemic diseases of various organs such as cerebral infarction, pulmonary embolism, renal failure, angina pectoris, thrombosis, peripheral vascular occlusive circulatory failure, heart failure, vascular constriction after subarachnoid hemorrhage, cancer metastasis, etc. It is used for prevention and treatment of blood clots after organ transplant surgery or during extracorporeal circulation such as hemodialysis and cardiopulmonary bypass, prevention of restenosis after coronary artery reconstruction surgery, and prevention and treatment of hypertension, arteriosclerosis, asthma, and allergic diseases. be able to. Patent applicant: Shionogi & Co., Ltd.

Claims (1)

[Claims] 1. General formula: ▲ Numerical formula, chemical formula, table, etc. ▼￥III￥ [In the formula, R^1 is an optionally substituted alkyl, an optionally substituted alkenyl, a substituted represents an optionally substituted aryl or an optionally substituted aralkyl,
-X- is -O-, -S-, -O-O-, -(CH_2)
m-, ▲There are mathematical formulas, chemical formulas, tables, etc.▼,▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. (represents carbonyl or formyl) Y is (CH_2)
n, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲mathematical formulas,
There are chemical formulas, tables, etc.▼ (In the formula, n represents an integer from 0 to 3, R^2 has the same meaning as above, and R^4 represents hydrogen, methyl or ethyl) Z is hydrogen, lower Optically active dicarboxylic acid monoester III represented by alkyl or phenyl (except when m and n are 0 at the same time). 2. General formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼￥ I ￥ (wherein, X, Y and Z have the same meanings as above) An acid anhydride represented by ￥ I ￥, general formula: ▲ There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, M^1 is hydrogen or a metal atom, R^5 is hydrogen,
(R)- or (S)-arylacetic acid derivatives represented by (optionally substituted alkyl or optionally substituted aralkyl, Ar represents optionally substituted aryl) are reacted to form a general Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼￥II￥ (In the formula, R＾5, Then, the ester ￥II￥ is subjected to an esterification reaction to form Rﾆ1
After introducing the aryl acetate derivative residue, the ester \II\ is converted into the general formula: R^1OM^2\IV\ (wherein R^1 is optionally substituted alkyl, substituted ￥IV￥ General formula characterized by being subjected to the reaction: ▲There are mathematical formulas, chemical formulas, tables, etc.▼￥III￥ (In the formula, R＾1, X, Y and Z have the same meanings as above) Optically active dicarboxylic acid monoester ￥III
Asymmetric synthesis method to obtain ¥. 3. General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼￥II￥ (In the formula, R^5, X, Y, Z and Ar have the same meanings as above) Optically active aryl acetic acid Derivative monoester ￥II￥.