JPH02250852A - Arylacetic acid monoesters and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R<1> is H, 1-2C alkyl, phenyl or bonded to form alkylene, alkenylene, etc.; R<2> is H or methyl; R<3> is H, alkyl or aralkyl; X is single bond, CH2, C=O, N-R<4>, O, S, etc., (R<4> is H or amino- protecting group); Ar is aryl]. EXAMPLE:(1R,2R,3S,4S)-Bicyclo[2,2,1]heptane-2,3-dicarboxylic acid 2-(D-mandelic acid) ester. USE:Useful as a synthetic intermediate for useful compounds derived from natural substance. Providing an intermediate in high optical purity important in asymmetric synthesis of drugs such as especially prostaglandin. PREPARATION:An acid anhydride shown by formula II having sigma symmetry is reacted with an (R)- or (S)-arylacetic acid derivative shown by formula III (M<1> is H or metal) in a solvent such as THF at-100 to 50 deg.C to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is useful for the asymmetric synthesis of various compounds derived from natural products, and more specifically, it is useful for the synthesis of optically active prostaglandins. This invention relates to arylacetic acid monoesters and their production method.

As a method for synthesizing this type of optically active compound, the Diels-Alder reaction and the hydrolysis method of a diester moiety using an enzyme are well known. However, these reactions generally result in the formation of compounds with low optical purity, or even if the optical purity is high, impurities such as by-produced stereoisomers cannot be easily removed. Furthermore, in the above-mentioned hydrolysis method using an enzyme, there are difficulties in the receptivity of the enzyme to the reactant and in setting the conditions for the enzyme reaction. Therefore, it has been difficult to easily obtain optically pure compounds in large quantities and at low cost.

(Left below) A clear topic Obtaining compounds with high optical purity by asymmetric synthesis without using enzymes is not only important for the synthesis of natural organic compounds;
It has important implications for the synthesis of various compounds including pharmaceuticals in a broad sense.

The present invention is intended to provide important intermediates with high optical purity in the asymmetric synthesis of various optically active compounds, especially pharmaceuticals. The present invention also provides a method that allows the reaction to proceed and allows the slight amount of by-products generated during the reaction process to be removed very easily, thereby isolating the intermediate as an optically pure compound. Incidentally, the present invention also intends that the above reaction can be carried out easily and with inexpensive reagents.

(Left below) In view of the above points, the inventors of the present invention have conducted extensive studies and have found that:
The present invention has been based on the discovery that arylacetic acid monoesters having a desired configuration can be selectively obtained by allowing a (R)- or (S)-arylacetic acid derivative to react with a prolactyl anhydride having σ symmetry, and the present invention has been made based on the present invention. completed. The details will be described later, but in this reaction, by-products generated can be removed by recrystallization. The resulting arylacetic acid monoesters are extremely important as intermediates in the synthesis of various prostaglandins, macrolides, polyether compounds, macrolactams, amine sugars, nucleotides, terpenes, alkaloids, compactins, and other useful compounds derived from natural products. It is.

(Left below) The present invention focuses on these important intermediates of the formula: N-R',
0 or S, R1 and R2 are hydrogen or methyl at the same time), R4 is hydrogen or an amino protecting group, R1 is hydrogen or a hydroxy protecting group, and Ar is substituted or not. A method for providing and obtaining an optically active arylacetic acid monoester represented by the formula: [wherein R1 is hydrogen or optionally substituted Ct
” Ct alkyl or phenyl or taken together C8-C, alkylene, C8 or It
C4-C, alkenylene or bicyclo ring may be formed, R2 represents hydrogen or methyl, R3 represents hydrogen, optionally substituted alkyl or optionally substituted aralkyl, X is a single bond or CH,,C-0
1N-R', O%S.

CHNR', CHCHs, CHAr or CHOR' (
However, X is a single bond or CH,, C-01 (in the formula, R
1, R2 and X have the same meanings as above), and the formula: (R) - or (
S)-7 Lylylacetic acid derivative is reacted and, if desired, further subjected to a deprotection reaction.

The present invention will be explained in more detail below by showing reaction process diagrams.

(Hereinafter in the margin) Provides an asymmetric synthesis method for arylacetic acid monoester represented by the formula (wherein R1, R2, RζAr and X have the same meanings as above).

When the carboxyl group of the arylacetic acid moiety is protected, the compound (I) does not crystallize easily and is difficult to distinguish from other by-products, but it can be deprotected to form the corresponding free carboxylic acid. Then, as a stereochemically pure compound that easily crystallizes, the polar [A method] (R-aryl method (where R1, R2, R3, Ar, M' and X have the same meanings as above) ) to a brochiral cyclic anhydride having σ symmetry, (R)-
the aryl acetic acid derivative in a solvent at about -100 to about 50°C;
More preferably, the compound (I-DC) can be obtained by reacting at about -100°C to about 0°C for several tens of minutes to several hours. Examples of solvents that can be used include tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane, 1,2-dimethoxyethane, n-hexane, DMSO, toluene, hexamethylphosphoramide (HMPA), and the like.

At this time, if the arylacetic acid derivative used is a free carboxylic acid, the target compound (II-D) can be obtained directly.

On the other hand, if the carboxylic acid of the derivative is a protected ester, it can be deprotected if desired to give the target compound (I[-D)
In this specification, the target compound before deprotection may be particularly expressed as compound (I[-De).

In many cases, compound (II-De) does not crystallize, but if it is deprotected according to a conventional method to obtain the target compound (I[-D), it can be easily crystallized and isolated. The following formula slightly occurs during the reaction: (wherein, R1, R2,
The compound (I['-DC) represented by R3, Ar and X have the same meanings as above) can be removed very easily. That is, compound (I'-De) is also easily deprotected to form dicarboxylic acid (I[-D), but since this remains in the mother liquor, the by-product can be removed 100% and the pure target compound (I[-D) can be removed. II-D) can be obtained very easily. Although many asymmetric synthesis methods have been proposed so far, there is no known method that can remove the by-product diastereomers so easily.

It is recommended that the deprotection reaction be carried out under neutral to acidic conditions. In other words, it is necessary to deprotect the arylacetic acid derivative while retaining the ester bond, but this is not suitable because the ester bond will be broken under alkaline conditions.Usually, deprotection is carried out under neutral conditions using palladium-carbon. However, in cases where the reaction is carried out, but there is a functional group that is easily reduced, or when R1 together form a bicyclo ring having CI or C4-C, alkenylene or a double bond. In some cases, hydrogenation may result in a single bond. If you wish to deprotect while retaining the functional group, double bond, etc., deprotection can be carried out under acidic conditions using a reagent such as trifluoroacetic acid, aluminum chloride, hydrochloric acid, or zinc/acetic acid. Preferred conditions may be selected as appropriate depending on the type of substituent R3.

[Method B] A method using a (S)-aryl acetate derivative (in the formula, R1
, R2, R3, Ar%M' and X have the same meanings as above. ) The optically pure target compound (II-
L) is obtained.

In this specification, C, #C, which may be substituted,
Alkyl or phenyl means C, -C, alkyl or phenyl optionally substituted with lower alkylcarbonyl, lower alkyloxycarbonyl or protected formyl. Here, lower alkyl is C, -C
, means alkyl, and examples thereof include methyl, ethyl, propyl and isopropyl. Examples of the protected formyl include ethylene glyfur acetal, dimethyl acetal, diethyl acetal, and the like.

C8-C, alkylene means ethylene, propylene, phtylene, pentylene or hexylene, and as long as the σ symmetry is maintained in the acid anhydride molecule, substituents may be present on the alkylene.

C1 or C1-C, alkenylene means vinylene,
means 2-butenylene, 1,3-butadienylene, 1,4-pentadienylene, 3-hexenylene, 2,4-hexadienylene or 1,5-hexadienylene, as long as the σ symmetry is maintained in the acid anhydride molecule; Substituents may be present on the alkylene.

As a bicyclo ring, the norbornane type (bicyclo[2,
2,1]hebutane, bicyclo[2,2,1]hebutane-5
-ene, etc.), 7-oxabicyclo[2,2,1]heptane, 7-oxabicyclo[2,2,1]buta-5-
ene, 7-azabicyclo[2,2,1]hebutane, 7-
Examples include azabicyclo[2,2,1]hebut-5-ene, 7-thiabicyclo[2,2,1]hebutane, and 7-thiabicyclo[2,2,1]hebut-5-ene.

The carbonyl group (C-0) defined by X may be protected with a ketal.

As amino protecting groups, formyl, acetyl, acyl such as benzoyl, benzyloxycarbonyl, t@rt
-butoxycarbonyl, urethane type derivative forming groups such as 2-(p-biphenyl)impropoxycarbonyl, allyl, benzyl, triphenylmethyl, tetrahydropyranyl, and the like.

Hydroxy protecting groups include methyl, tart-butyl, allyl, benzyl, tetrahydropyranyl, tart
Examples include ether-forming protecting groups such as -butyldimethylsilyloxy and tart-butyldiphenylsilyloxy, ester-forming protecting groups such as acetyl and benzoyl, and sulfonic acid ester-forming protecting groups such as methylsulfonyl, p-tolylsulfonyl, and phenylsulfonyl. be able to. The amino-protecting group and the hydroxy-protecting group are not limited to these.
ive Groupsin Organic Chemi
stry+Planum Prass, 1973,
It can be selected from the protecting groups listed on pages 43 to 143.

In the term "optionally substituted aryl", aryl means phenyl or α- or β-naphdel. The substituent is not particularly limited except for esters, but examples thereof include alkoxy such as methoxy and ethoxy, and halogen such as bromine, chloro, and fluoro.

Metal atoms include alkali metal atoms such as lithium, sodium and potassium, alkaline earth metal atoms such as magnesium and calcium, and zinc.

Aralkyl, which may be substituted, includes alkyl such as methyl, ethyl, and propyl; alfoxy such as methoxy, ethoxy, and propoxy; halogen such as bromo, chloro, and fluoro; benzyl which may be substituted with nitro, etc.; It means benzhydryl or naphthylmethyl.

The (R)- or (S)-aryl acetic acid derivative used in the present invention is clear from the above definition, and among them, D- or L-mandelic acid or a derivative thereof is preferably used and is easily available. Examples of its derivatives include,
Esters of D- or L-mandelic acid with methyl, benzyl, benzhydryl, valanitrobenzyl, varamethoxybenzyl, paramethylbenzyl or parabromobenzyl are preferably used. D-Mandelic acid, its derivatives, or their residues used in the Examples and Reference Examples shown below are abbreviated as D-Mande and L-Mande.
mandelic acid, its derivatives or their residues as L-M
It is sometimes abbreviated as ande.

EXAMPLES 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.

The abbreviations used in the Examples and Reference Examples will be explained below.

Me: Methyl CHlPh: Benzyl Et: Edel
CHPh, : Benzhydryl Bu Nibutyl P
h: Phenyl THF: Tetrahydrofuran DMF Nidimethylformamide PMB: 4-methoxybenzyl (blank below)! 1011 (1st step) D-mandelic acid benzyl ester (5,
After dissolving n-BuLi (1,6 mmol) in THF (50 ml) and cooling to -78°C,
M hexane solution 13.13++1.21.0 mm.

1) was added dropwise to the reaction solution and stirred for 15 minutes.
2,2,1 cohebut-5-ene-2-endo,3-endo-dicarboxylic acid anhydride 1-1 (3,32 g, 20,
Add Ommol) of THF solution (20 ml).

After stirring at -78°C for 1 hour, 2N hydrochloric acid was added and extracted with ethyl acetate. After washing with water and saline and concentrating, compound 1
[2-Del and by-product II 2'-Del are obtained (total yield: 9.33 g) e Compound 12-Del is purified by silica gel column chromatography (toluene/ethyl acetate).

IR (liquid film): 3600-2400.1748.17
10.1498°1456, 1342.1257.12
0g, 1165°1084, 1072.912.73
2.696'H-NMR (CDC11TMS) δppm
: 1.33 (ABq, Apart.

J=8.9Hz; [1), 1.48(ABq, B
part, J: 8.9Hz, 11).

3.16 (br, s, IH), 3.
21 (br, s, IH), 3.30
(dABq.

Apart, J: 3.2.10.2Hz, LM),
3.47 (dABq, Bpart.

J=3.4Hz, 10.2Hz, LH), 5.1
3(s, 2H), 5°97(s.

LH), 6.11 (dABq, Apart, J
=2.9Hz, 5.9Hz, LH).

6.28 (dABq, Bpart, J=2.8.
5.9Hz, IH), 7.13-7.52(
(2nd step) To 10% palladium on carbon (0.4 g) was added the crude product 1[2-Del (4.06 g, 10.0 mmol) obtained previously.
) was added, and after stirring at room temperature for 1.5 hours under normal pressure and hydrogen atmosphere, the catalyst was removed by filtration and concentrated. Ethyl acetate and a 5% aqueous sodium hydrogen carbonate solution were added to the reaction mixture. , separate the aqueous layer. The organic layer is extracted once more with water and the first aqueous layers are combined and washed with ethyl acetate. Add 2N hydrochloric acid, extract with ethyl acetate, wash with saturated brine, and concentrate to obtain the crude product L1 (3.14 g, yield from acid anhydride: 99%, I[1-
D: [1'-D-86:14 (by HPLC))
.

By recrystallizing from ethyl acetate, the target compound (I[
Isolate 1-D) (2.05 g, yield: 64%)
, melting point = 164-166°C.

Elemental analysis (as CCItH-1oa) Calculated value (X): C,64,ts; H,5,71 Actual value (X): C,63,83i H,5,73'H
-NMR (CDC1$, Engineering MS) & ppm: 1.4
6 (br, s, 41).

1.57-1.75 (m, 18), 1.84-2.
08 (m, IH), 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, 18), 7.33-7.6
5 (m, 58) [α] Amase-117.1*0.8° (
After concentrating the mother liquor (MeOH, C=1.934%), it was recrystallized from methylene chloride to obtain (II
I'-D) is obtained. Melting point 157-158°C.

Elemental analysis (as C+yHtsOs) Calculated value (X): C, 64,13; H, 5,71 Actual value (X): C, 64, oz; H, 5,57°'
H-NMR (CDC1, -TMS) δppm: 1.3
0-1.66 (m, 4H).

1.69-1.87 (m, 1B), 1.96-2.
13 (m, IH), 2.60 (br.

s, 2H), 3.04(dABq, Apart,
2.8.12.1Hz.

IH), 3.13 (dABq, Bpart, J
=3.8. 12, IHz, 11).

5.84 (s, IH), 7.33-7.58 (
m, SR>.

[α] M=-st, st0.6° (MaOH,C
=2.005%).

) Production of ester n 2-D (blank below) Crude compound II obtained in the same manner as the first step of Example 1
2-De2 (43 g) in methylene chloride solution (60 m
1) was cooled to 0°C, anisole (18ml) and trifluoroacetic acid (50ml) were added, and the mixture was stirred for 1 hour.
After concentrating the reaction solution, ethyl acetate and 5% aqueous sodium hydrogen carbonate solution are added. The aqueous layer is separated, washed with ethyl acetate, and made acidic by adding 2N hydrochloric acid. Extracted with ethyl acetate,
The crude product compound is obtained by washing with saturated saline, then drying and concentrating (product ratio, 112-D: I2'-
D74:26 (by HPLC)), which was recrystallized from ethyl acetate to obtain the pure target compound ([2-D)
(13.37 g, yield 47%), melting point: 169
~171℃.

Elemental analysis (as C8tHIO・) Calculated value (X): C, 64,55; H, 5,10 Actual value (1): C, 64,46; H, 5, 12°I
R(CI(C1l): 3500-2400.173
4.1438.1375°1342, 1256.116
8.1146.1072゜'H-NMR (CDC1*-
TMS) & ppm: 1.36 (ABq, Apar
t.

J=7.2Hz; IH), 1.51(ABq,
Bpart, J=7.2Hz, IH).

3.15 (br, s, 2H), 3.43 (dA
Bq, Apart, J=2.9°10.4Hz,
IH), 3.53 (dABq, Bpart, J=
3.1.10.4Hz, IH), 5.86(s
, 2H), 6.14-6.33(m, 2H
).

7.32-7.62 (m, 5H).

[12] Amase-t5q, s*t, o° (MeOH, C=
1.993%).

The reaction conditions for obtaining the target compound (II-D) or (II-L) shown in Table 1 in the same manner as in Example 1 or 2 are also shown in Table 1.

(Left below) Preparation of 01 Edel Ester 2-L Crude 1[2-Li2 (30.6 mg, 70 mm)
ol) in 160+nl of acetonitrile, added 35.9ml (70mmolX 6 ) of concentrated hydrochloric acid, stirred at room temperature for 16 hours, adjusted to pH 4 with 4N NaOH aqueous solution,
This is made alkaline by adding an aqueous solution of Na HCOs under water cooling, and washed with ethyl acetate. The organic layer is 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 was recrystallized from ethyl acetate to form the compound (T12-t
, ) tl, tzg (yield: 50.2%). Melting point =
168-170℃.

IR, 'HNMR(CDC1,) is I[-1-D(al
)same as.

[α]ss''=+160.5*1.O' (MeOH,
C=2.002 Shown below.

Example 1 from 10.5 g (62 o1) of compound 1-3 on Tuesday (blank below)
, compound (I[3
-D) and (I[3°'-D) are obtained.

(I3-D): (II3'-D)-73: 27(H
PLC) From this mixture, (I3-D), 7.1 (yield: 35.8%) and ([3'-D) 1.5 g (
Yield near.

6%) were isolated by recrystallization.

Compound (I3-D) Melting point: 175-177°C Elemental analysis (as C+ s Hr * Ov) Calculated value (
X): C, 59,99; H, 5,04 actual value m:
C,59,85; H,5,04'H-NMR (CD
, OD, IMS) δppm: 1.55-1.88 (
m, 4H).

3.13 (ABq, Apart, Ko; 9.6H
z, IM), 3.19 (ABq, Bpar
t, J=9.6Hz, 1B), 4.83-4.9
0 (m, 2H), 5.85 (s.

IH), 7.35-7.65 (m, 5H) IR (N
ujol)l/mix: 3480-2200.173
3.1712°1659, 1229.1220.118
5; 1011.969.936.766°735, 6
96cm-' [α] o (11,9±1.5@<MeOH, C=1
．． 013%, 23℃) Compound (113'-D) Melting point: 133-135℃ Elemental analysis CC, mH1aOt・o, sHm O) Calculated value (X): C, 58, 35: H, 5, 21
Actual value (X): C, 58, 33: H, 5, 48I
H-NMR (CD, OD, MS) ε ppm: 1
．． 55-1.90 (m, 4H).

3.12 (ABq, Apart, J=9.6Hz,
IH), 3.22 (ABq, Bpart,
J=9.6Hz, IH), 4.75-4.9
0 (m, 28), 5.74 (s.

IH), 7.35-7.65 (a+, 5B) IR (
Nujol) νwax: 3680-2200. 17
33. 1710 (sh).

1230.1177.1044.994,925,81
9.724cm-'C(1] o -92,0*L,3
° (MaOH, C=1.OL4χ, 23°C) (blank below) Tue 1111 (1st step) Toester 1 [4-D under nitrogen atmosphere, D-mandelic acid benzyl ester (24
, 23g, 100mmol) in THF (480mL
), cooled to -78°C, and dissolved n-BuLi (
Add 3-[(tert-
butyldimethylsilyl)oxy]glutaric anhydride (I
-4) (24.44 g, 100 mmol) in THFm solution (100 mL) is added. After stirring at -78°C for 2 hours,
Treat with IN hydrochloric acid and extract with ethyl acetate. After washing with water and saline and concentrating, a mixture of compound 14-Del and by-product I[4'-Del is obtained. ((I4
-Del): (I[4'-Del)-5: 1 ('
)I NMR)) Rf-0,29 (Rooform:methanol-10=1
) 'H-NMR (CDC1,, TMS) & ppm: 0
．． 03(s, 3H), 0.05(s, 3H),
0.82 (s, 9H), 2.61-2.68 (m,
4H), 4.53-4.63 (m, IH), 5
．． 10 (ABq, Apart, J=12.5Hz.

LH>, 5.17 (ABq, Bpart, J=1
2.5Hz, LH), 5.98(s, 114>
.

7.17 to 7.48 (m, 10H) (Hereafter the margin) (Second step) Crude products M 4-Del and If 4 obtained in the first step
'-D rainbow mixture in ethyl acetate solution (500 mL)
% palladium on carbon (1,00 g) was added, and after stirring at room temperature under normal pressure and hydrogen atmosphere for 1 hour, the catalyst was removed by filtration.
Concentration gives the crude product l±'. The target compound (
I[4-D) is isolated (22.53 g, yield: 57
%), melting point: 141-142°C.

Elemental analysis (as cI*Hsaots i) Calculated value (X
): C, 57, 55i H, 7, 12 actual value (%)
: C,57,39;H,7,08IR(KBr)ν
maxH3700~2400.1735.1712゜1
253, 1188.1167, 1080.980.83
2cm-''H-NMR (CDC1,, IMS)-δp
pm: 0.04<s, 3H), 0.05(s,
3H), 0.82 (s, 91), 2.53-2.
84 (m, 4H), 4.53-4.66 (m, I
H), 5.95 (s, IH), 7.38-7.4
9(m, 5) [α ko D” -70,2*
1.1” (CHCIs, c=t, oosx.

23.5°C) Rf=0.82 (ethyl acetate: acetic acid: water tan 30:1:
(Left space below) 11 Examples 2 (Method for producing arylacetic acid derivatives) Production of D-mandel benzyl ester D-mandelic acid (85,
1g, 559 mmol), benzyl alcohol (65
ml, 628 mmol) and p-toluenesulfonic acid (1,01 g, 5.35 mmol) in benzene (70 mmol).
After refluxing in 0ml) for 6.5 hours, it is washed with water and concentrated. Recrystallization from ether gives the title compound at 123.5K.

Yield 91%, melting point 103.5-105°C.

Elemental analysis (as C+ m HI-Os) Calculated value (X)
: C, 74, 36; H, 5, 82 actual measurement value (X)
: C,74,53;H,5,90'H-NMR (CD
C1, -IMS) l; ppm: 3.44 (d,
, C5,6Hz.

IH), 5.14 (ABq, Apart, J=1
2.3Hz, IH), 5.22(d.

J=5.6Hz, IH), 5.24(ABq, B
part, J=12.3Hz, IH) 7.15~7
．． 50 (m, 101).

[α] 'j = -55,7±1.0°(CI(C1s
, C=1. OQ3χ).

D-7under # (15.3g, 100mmol),
4-methoxybenzyl alcohol (15.2g, 11Q
mmol) and p-toluenesulfonic acid (0°197
g, 1.01m5aol) to benzene (300m
1) After refluxing for 7 hours, the reaction solution was washed four times with water and concentrated.

The obtained crude product was subjected to silica gel column chromatography, purified with toluene/ethyl acetate, and purified with ether/ethyl acetate.
Recrystallization from petroleum ether yields the title compound at 6.58
g get. Yield: 24%, melting point 70.5-73.5°C0 Elemental analysis (as C+ s Hr * Oa) Calculated value (
X): C, 70, 58; H, 5, 92 actual value (1
): C,70,55+H,6,00゜'H-NM
R(CDC1,-TMS) S ppm: 3.80
(s, 3H), 5.05 (ABq, Apart,
J=11.8Hz, IH), 5.19(s, I
H).

5.19 (ABq, Bpart, 11.8Hz,
IH), 6.84 (d.

J=8.7Hz, 21(), 7.17(d, J=
8.7Hz, 21), 7.30-7, 45 (set 5H
).

Cα]'1=-36,0*0.8" (CHCIs,
C=1.017%)-D-mandel-4-nitrobenzyl ester in DMF (300ml), D-7underic acid (15°2 g, 100mmol), 4-nitrobenzyl bromide (2L, S g, 100ml)
mol) and triethylamine (14.0 ml, 10
Add 0 mmol) and stir at room temperature for 8 hours. Add water to the reaction solution, extract with ethyl acetate, wash with dilute hydrochloric acid and water,
Recrystallization from ether/petroleum ether yields 19.6 g of the title compound. Yield 6B%, melting point 143-145°C.

Elemental analysis (as C1s Hls N O*) Calculated value (
%): C, 62,72i H, 4, 56:N, 4.
88 Actual value (%): C, 62, 76i) 1.4.
61; L4.99°'H-NMR (CDC1,-TM
S) δppm: 3.2fr3.52(br, s.

LH), 5.25 (ABq, Apart, J=1
3.5) 1z, IH), 5.28(s.

LH), 5.32 (ABq, Bpart, J=1
3.5Hz, IH), 7.27(d.

J=8.4Hz, 28), 7.34~7.48(b
r, s, 5H), 8.14 (d.

J=8.4Hz, 2H) [α]! =-40,0*0.8' (CHC1$,
C=0.995
a + mol) in ethyl acid (200 ml),
Diphenyldiazomethane (38,9
g, 164 mmol). After confirming the completion of the reaction by TLC, concentrate. Recrystallization from ether/petroleum ether gives 47.7 g of the title compound. Yield 91%, melting point 91-91.5°C.

Elemental analysis (CacHt*, as Os) Calculated value (X)
: C, 79, 22; H, 5, 71 actual measurement value (X):
C,79,44i H,5,67゜'H-NMR (C
DCIA-TMS) δppm: 3.47 (d, J
=5.31(z.

IH), 5.28 (d, J=5.3Hz, IH)
, 6.87(s, IH), 6.87-7.46(
sa, 15H).

[(Zl'o = -57,4*1.0°(CHCl,
, C=1.023%).

L-mandelic acid benzhydryl ester was reacted in the same manner as in the production of D-mandelic acid benzhydryl ester, and L-mandelic acid (30.4 g, 200 mmo
1), ethyl acetate (200 ml) and diphenyldiazomethane (38.9 g, 200 fins o1) to obtain 54.7 g (172 mmol) of the title compound. Yield 86
%, melting point 91°5-92.0°C.

[:alV = +55.7 * 0.9@(CHC
l,, C=1.013%>.

Aryl acetic acid monoesters (1-D
) or (If-L), a pure dicarboxylic acid monoester (■) having any desired configuration can be obtained by the simple reaction shown below.

Heating in the presence of a metal salt of the alcohol (such as NaOMe).

A reaction process diagram using compound (I[1-D) or (Ill-L) is shown below.

(In the formula, R represents alkyl) (1) After dialkyl esterification under neutral to acidic conditions (such as a methylating agent such as a catalytic amount of p-toluenesulfonic acid in diazomethane or methanol), hydrogenation The arylacetic acid derivative moiety is removed by decomposition.

■In a suitable alcohol (methanol etc.), Part 11 [1
-t2 Reference Example 2 Using (I[1-D) as a raw material, compound (11
11-t) was obtained. Yield 94%, melting point 59-60°C0
Elemental analysis (as C+eH+aOa) Calculated value (X): C,60,58i H,7,13 Actual value (X): C,60,66i H,7,08'H
-NMR (CDCIs-TMS) & ppm: 1.2
0-1.74 (m, 6H).

2.59(br, s, LH>, 2.69(br,
s, 18), 2.79 (d.

J=5.4Hz, IH), 3.27(dd, J:
3.8.5.4Hz, IH).

3.69(s, 38) [αkoy = +38.4±0.4@(MaOH
, C=2.002%> Using (It-L) as a raw material, compound (1111-t2) was obtained by method (2). Yield 78%,
Melting point 59-60°C.

[α] Amase-38, 31, 4° (MaOH, C=2.0
13%>.

(Left below) Reference Example 3 (+)-(I) useful as thromboxane receptor antagonist
R,2S,3S,4S)-(5Z)-7-[3-[
:(7!Nylsulfonyl)aminocobicyclo[2,2,
1] hept-2-yl]heptenoic acid (hereinafter referred to as (+)-3
-14s) was prepared from compound (I[
[1-tl).

(In the formula, Et is ethyl, 2 is benzyloxycarbonyl, and FCC is pyridinium chloride chromate.) The compound (A) thus obtained is described in the literature (J.

Mad, Chew, 31(9), 1847-18
54 (198 g)), and (+)-8-145 was obtained by the method described in the literature.

Patent applicant: Shionogi & Co., Ltd.

Claims (2)

[Claims] (1) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, R^1 is hydrogen or optionally substituted C_
1-C_2 represents alkyl or phenyl or may be taken together to form C_2-C_■ alkylene, C_2 or C_4-C_■ alkenylene or bicyclo ring, R^2 represents hydrogen or methyl, R^3
represents hydrogen, optionally substituted alkyl, or optionally substituted aralkyl, and X represents a single bond or CH
_2, C=O, N-R^4, O, S, CHNR^4, C
HCH_3, CHAr or CHOR^5 (however,
is a single bond or CH_2, C=O, N-R^4, O or S, R^1 and R^2 are hydrogen or methyl at the same time), and R^4 is hydrogen or amino an optically active arylacetic acid monoester represented by the following formula: a protecting group, R^5 represents a hydrogen or hydroxy protecting group, and Ar represents an optionally substituted aryl. (2) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) An acid anhydride with σ symmetry represented by (in the formula, R^1, R^2 and X have the same meanings as above) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, M^1 is hydrogen or a metal atom, R^3 and A
A formula characterized by reacting an (R)- or (S)-arylacetic acid derivative represented by (r has the same meaning as above): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula , R^1, R^2, R^3, Ar and X have the same meanings as above).