JPH03112962A - New hydroxypyrrolidine compound, intermediate for production thereof and production thereof - Google Patents

Abstract

NEW MATERIAL:Hydroxypyrrolidine compounds represented by formula I (Ar is substituted or non-substituted aryl; Z is protecting group for amino group or H; * is optically active carbon). EXAMPLE:2-Methoxyphenylmethyl-4-hydroxy-N-benzyloxycarbonylpyrrolidine. USE:An intermediate for production of an antibiotics anisomycin and derivatives thereof. The antibiotics anisomycin is effective for remedy of diseases due to parthenenogenone protozoa and for protection of damages due to fungi such as powdery mildew of a vegetable, e.g. a bean. PREPARATION:The objective compound of formula I is obtained by directly hydrolyzing the acyloxy group of a new acyloxypyrrolidine compound of formula II (Ar' is substituted or non-substituted aryl) or by protecting the amino group of a new compound of formula II, preparing a new N-substituted pyrrolidine compound of formula III and then hydrolyzing the acyloxy group of thereof.

Description

[Detailed Description of the Invention] [Industrial Application Fields] The present invention is applicable to the treatment of diseases caused by parthenogenetic protozoa,
It is a useful reaction intermediate for producing the antibiotic anisomycin and its derivatives, which are useful for controlling fungal damage such as powdery mildew on plants such as legumes (wherein, Ar is a substituted or unsubstituted aryl group Z The present invention relates to novel hydroxypyrrolidine compounds, intermediates for their production, and methods for their production.

[Prior art and problem to be solved B] The above hydroxypyrrolidine compound [XXI 3] is obtained by dehydrating it to form No. (wherein Ar is a substituted or unsubstituted aryl group, Z is a protecting group for an amino group, The optically active 3,4-dehydropyrrolidine compound represented by * means each optically active carbon is obtained, and if necessary, the N-protecting group is removed to further obtain an N-free compound.

Regarding the production of the optically active compound represented by the general formula [1], as shown in the following reaction route 1, a method using D-tyrosine as a starting material (Tetrahedron Le
tt,,29.4419. L98fl, S, Jegham, B, C, Das (B, C
, Das )) are known.

(Left below) Reaction route 1 (n) [M] ↓ (In each of the above formulas, r is 4-methoxyphenyl, is -butyloxycarbonyl, and Me is, however, in this reaction route, the intermediate [V] is racemic) Therefore, the final product, optically active compound [
1] had a problem in optical purity. Also, in this method, Ar
is limited to 4-methoxyphenyl, and a homolog of the above compound CI] has not yet been developed.

In view of the above circumstances, an object of the present invention is to provide a novel hydroxypyrrolidine compound [XXI] useful in producing anisomycin and its homologues, and a method for producing the same.

The present invention also provides the hydroxypyrrolidine compound [1'X
It is an object of the present invention to provide novel N-substituted coloridine compounds and novel acyloxypyrrolidine compounds that are useful intermediates for the production of [I], and methods for producing them.

[Means for Solving the Problems] The hydroxypyrrolidine compound according to the present invention has the following formula:
Ar represents a substituted or unsubstituted aryl group, Z represents a protecting group for an amino group or a hydrogen atom, and * represents an optically active carbon.

In addition, the N-substituted pyrrolidine compound [XXI and the acyloxypyrrolidine compound [X
XI has a chemical structure represented by ↓, and (in each of the above formulas, Ar and Ar- are the same or different substituted or unsubstituted aryl group, Z is a protecting group for an amino group, and * means an optically active carbon, respectively. ) have the chemical structures shown below.

In order to produce the above hydroxypyrrolidine compound [XXI], the acyloxy group of the acyloxypyrrolidine compound represented by the following formulas is directly hydrolyzed, or the amino group of the acyloxypyrrolidine compound [XIII (wherein, Ar5Z and * have the same meanings as defined above, and Ar" means a substituted or unsubstituted aryl group, respectively), and then the same compound [acyloxy of XXI Hydrolyze groups.

Acyloxypyrrolidine compound [X
To produce III, a benzamide compound represented by the general formula (wherein A', Ar- and * have the same meanings as defined above) is mixed with bromine, iodine chloride, iodine, HBr3 salt of pyridine, N - treatment with a cyclizing reagent selected from the group consisting of bromosuccinimides.

To produce the benzamide compound [X■ used in the above method, an allylamine compound represented by the general formula % (in each of the above formulas, Ar, Ar' and book have the same meaning as defined above) and Xl means a halogen atom).

To prepare the allylamine compound [X■] used in the above method, (wherein Ar and * have the same meanings as defined above, and Y is NHCOzt-Bu.

NHCO2Bn (Bn means benzyl group BnO
NCO2Bn.

o -C6H4 (CO) 2 N% NC(C6H4)3, HCONH.

p-Me (C6Ha)S02NH or CsH
s S02 NH) is treated with a base, or in the above general formula, Y is N
, the nitrogen-containing compound [x■] is subjected to a hydrogenation reaction.

To produce the nitrogen-containing compound [XVI] used in the above method, an allyl alcohol compound represented by the general formula R202
Diazocarboxylic acid dialkyl represented by CN -N C02R2 and general formula P(R'), (In each of the above formulas, Ar and * have the same meanings as defined above, R2 is an alkyl group, R3 is an aryl group or an alkyl group), or CCb React with HsO)2PON3.

To produce the allyl alcohol compound [KV] used in the above method, an epoxypropane compound represented by the general formula is reacted with lithium acetylide to produce the epoxypropane compound represented by the general formula (in each of the above formulas, Ar and * are the same as those defined above). ethynyl alcohol, which has a meaning), and partially reduces it.

Hydroxypyrrolidine compound according to the present invention [XXl ]
By dehydrating this, the optically active 3, represented by the following formula, is obtained: A 4-dehydropyrrolidine compound is obtained, and if necessary, the N-protecting group is removed to further obtain an N-free compound.

Hydroxypyrrolidine compound CXXI according to the present invention]
To obtain compound [11] by dehydrating (1) hydroxypyrrolidine compound [XXl], carbon disulfide and a compound represented by the general formula RIX2 are reacted, (in each of the above formulas, Ar, Z and * are has the same meaning as defined above, R1 is an alkyl group or an aralkyl group,
N2 means a halogen atom or a sulfonyloxy group, and Yo means 0C32R1).
A method of subjecting XX[] to an elimination reaction, (11) A method of acid-treating a hydroxypyrrolidine compound [:XXl ], (
111) There is a method in which the hydroxyl group of the hydroxypyrrolidine compound [Xrl] is substituted with a halogen, a p-toluenesulfonic acid ester group, or an acetyloxy group, and the resulting compound is subjected to an elimination reaction.

The method for preparing the l-aryl-2,3-epoxypropane compound [X], which is the starting material for the method of the present invention, is shown in Reaction Route 2, and the hydroxypyrrolidine compound [1:XI] according to the present invention described above, as well as the optical A method for producing the active 3,4-dehydropyrrolidine compound is shown in Reaction Route 3.

(Left space below) pcs k] X-penzyloxyallyloxy [■a] The definition of each compound shown in will be explained in the reaction order of the above reaction route 3.

The aryl group A of the epoxypropane compound [X] includes unsubstituted aryl groups such as phenyl, naphthyl, indolyl, and biphenyl, and halogen atoms such as fluorine, chlorine, bromine, and iodine in the aromatic ring, and methyl, ethyl, and propyl. , alkyl groups having 1 to 4 carbon atoms such as isopropyl and butyl, alkoxy groups having 1 to 4 carbon atoms such as methoxy and ethoxy, aralkyloxy groups such as benzyloxy, cyano groups, and substituents such as trifluoromethyl groups. Examples include substituted aryl groups such as phenyl, naphthyl, indolyl, and biphenyl.Also, the same compound [X]
* indicates optically active carbon.

Allyl alcohol compound [XV] to nitrogen-containing compound [X
Examples of the alkyl group of the dialkyl diazocarboxylate R20□CN-NCO2R2 used in the reaction to obtain Examples of the R3 group in (R3) include aryl groups such as phenyl and alkyl groups such as n-butyl.

Amidation reagent Ar'CO for allylamine compound [X■]
The aryl group Ar'' in Alkyl groups having 1 to 4 carbon atoms such as, alkoxy groups having 1 to 4 carbon atoms such as methoxy and ethoxy,
Examples include substituted aryl groups such as phenyl and naphthyl having substituents such as cyano group, nitro group, acetyl group, and benzoyl group. Furthermore, examples of the halogen X1 in the amidation reagent include chlorine, bromine, and the like.

Protecting reagents used for carbamate or amidation for protecting the amino group of the acyloxypyrrolidine compound [rlK] include alkyl chlorocarbonates such as ethyl chlorocarbonate, benzyl chlorocarbonate, t-butyl chlorocarbonate, aralkyl chlorocarbonates, Examples include halogenated acetyl, acetic anhydride, halogenated benzoyl, and benzoic anhydride. Therefore, Z as a protecting group for an amino group is an easily removable substituent such as an oxycarbonyl group such as benzyloxycarbonyl or t-butyloxycarbonyl, or an acyl group such as acetyl or benzoyl.

When Y' of the xanthate compound [HI] is 0C32R1, examples of R' include alkyl groups such as methyl and ethyl, and aralkyl groups such as benzyl.

Next, the conditions for each reaction in the above reaction routes 2 and 3 will be explained in order of reaction.

(A) First, the production of the epoxypropane compound [X], which is the starting material for the method of the present invention, will be explained according to the reaction route 2 above.

In the 2,3-epoxypropane derivative [■], which is the starting material for reaction route 2, Sulfonyloxy groups such as luenesulfonyloxy and 3-nitrobenzenesulfonyloxy,
Indicates easily removable substituents such as aralkyloxy groups such as benzyloxy, diphenylmethyloxy, and trityloxy, and allyloxy groups.

First, a 2,3-epoxypropane derivative [■] was mixed with a monovalent copper salt in an inert solvent at a low temperature of 00°C to -10°C.
．． 005 to 2.0 molar equivalents. Examples of inert solvents include hexane,
Hydrocarbons such as pentane, heptane and toluene, ethers, ethers such as tetrahydrofuran and ethylene glycol dimethyl ether, or mixed solvents thereof are used. As the copper salt, Cu2 (CN) 2, Cu212, etc. can be used. As the aryllithium, those having an aryl group (Ar) as defined above are appropriately selected and used. Usually a lithium cu-plate reagent is used. In this case, (1) when substituent X of compound [■] is a halogen, halohydrin [■1] is obtained from compound [■1], and (il) X is a sulfonyloxy group such as toluenesulfonyloxy. In some cases, the epoxypropane compound [X] is obtained from the compound [Wbl, and (III) when X is aralkyloxy, allyloxy, etc., the compound [IKb] is obtained from the compound [11c].

In method (1), the halohydrin [■1] is reacted with a base in a polar solvent, or the compound [■
1] with a base, the above compound [X
] can be obtained. As bases, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc. are used; as polar solvents, water, methanol, acetone, ether, etc. are used; as nonpolar solvents, hexane, ether, dichloromethane, etc. are used. etc. are used.

In the method (ili), the protective group is removed from the compound [Wbl by a known method, for example, hydrogenolysis using a palladium catalyst or acid decomposition accompanied by isomerization of an olefin, and the compound [Wbl is converted into diol [x1], This was further acetalized with benzaldehyde in the presence of an acid catalyst such as luenesulfonic acid using a method developed by the present inventors, namely, 1)-) to form a compound [III], which was then treated with bromine or N-bromosuccinimide. The benzoyl ester of bromohydrin can be obtained using the above-described method, and this can be further treated with a base to obtain the epoxypropane compound [X] (see Synthesls. 1985, 503). Here, as the base, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc. are used.

(B) Next, the production of the hydroxypyrrolidine compound [XXl 2 ] according to the present invention will be explained in more detail according to the above reaction route 3.

a) First, the epoxypropane compound [Xl produced through reaction route 2 is reacted with lithium acetylide in an inert solvent to obtain an ethynyl alcohol compound [Iff]. As lithium acetylide, a commercially available ethylenediamine complex of lithium acetylide is used, or one prepared by introducing acetylene gas into an inert solvent of a lithiation reagent such as butyllithium or phenyllithium is used. The inert solvent is appropriately selected from ethers such as ether, tetrahydrofuran and dioxane, hydrocarbons such as toluene and hexane, aprotic polar solvents such as dimethyl sulfoxide and hexamethylphosphoamide, and mixtures thereof. Lithium acetylide is used in an amount of 1 to 5 molar equivalents relative to the epoxypropane compound [Xl, and is reacted with the same compound [Xl] at a temperature range of -70°C to 80°C.

b) Ethynyl alcohol compound [IN] is partially reduced to obtain allyl alcohol compound [XV].

This partial reduction can be achieved by carrying out the reaction in a solvent such as acetone, methanol, chloroform, ethyl acetate, or acetic acid in a hydrogen atmosphere of 1 to 5 atmospheres using a Lindlar catalyst.

C) Mitsunobu reaction (formerly t) of allyl alcohol compound [MY]
Sunobu et al. A nitrogen-containing compound [XXl] whose configuration is inverted from that of the alcohol compound [XV] is obtained. As the compound YH reacted with the allyl alcohol compound [rV], a compound having the group Y as defined above is appropriately used. However, nitrogen-containing compounds where Y is N [XVI
To obtain I, CCb Hs O)2 PONs are used instead of YH. The Mitsunobu reaction can be achieved by reacting the allyl alcohol compound [XV] as a substrate with 1 to 5 molar equivalents of YH or (C6H,0)2PON, dialkyl diazocarboxylate, and tertiary phosphine, respectively. . Here, as the dialkyl diazocarboxylate, those having an alkyl group R2 as defined above are appropriately used, and as the tertiary phosphine, those having a group R3 as defined above are appropriately used. As the reaction solvent, ethers such as ether, tetrahydrofuran, dioxane, and diethylene glycol dimethyl ether can be used. The reaction temperature ranges from 8°C to room temperature.

d) Nitrogen-containing compound [XVII is treated with a base such as potassium hydroxide, sodium hydroxide, or hydrazine to obtain an allylamine compound [X■]. However, nitrogen-containing compounds [X'
When Y in VII is N, a nitrogen-containing compound [XVII is made into an allylamine compound [Xl] by a hydrogenation reaction using palladium, platinum, etc.

e) an allylamine compound [Xl] with an amidation reagent represented by the general formula % (wherein Ar' has the meaning defined above and Xl means a halogen atom such as chlorine or bromine); The reaction is carried out to form a benzamide compound [Xl].

r) benzamide compound [Xl] is treated with a cyclizing reagent in a water-containing solvent such as a water-acetrinitrile mixed solvent,
The acyloxypyrrolidine compound [XXl is obtained as a mixture of epimers at the C-4 position. As the cyclization reagent, an appropriate one is selected from those defined above. When using iodine as the cyclization reagent, 1 to 3 equivalents of iodine are reacted with the benzamide compound [XvA].

g) Acyloxypyrrolidine compound [The acyloxy group of XXl is directly hydrolyzed or the same compound [1'ff
The amino group of 1 is reacted with a compound represented by the general formula ZH in the presence of a base to obtain an N-substituted pyrrolidine compound [XXl, which is then hydrolyzed to give a hydroxypyrrolidine compound [XXl 1]. As the compound represented by the general formula ZH, those having Z as defined above are used as appropriate.

As the base, inorganic bases such as sodium carbonate, potassium carbonate, potassium hydroxide, and sodium hydroxide, and organic bases such as triethylamine and pyridine are used as appropriate.

Hydrolysis of the benzoyl group of the N-substituted pyrrolidine compound [XXI is carried out in the presence of a base such as sodium hydroxide or potassium hydroxide.

(C) h) The thus obtained hydroxypyrrolidine compound [Xrl ] of the present invention is dehydrated to yield a dehydropyrrolidine compound [1]. Methods for dehydrating hydroxypyrrolidine compound [Hl] include (1) converting the same compound [XXl] to a xanthate compound [XXI] and then subjecting the same compound [XXI] to an elimination reaction; (If) hydroxypyrrolidine Compound [XXl 1
(111) Hydroxypyrrolidine compound [
A method of converting the hydroxyl group of XXI 1 into a halogen atom such as chlorine, bromine, or iodine, a p-toluenesulfonic acid ester group, an acetyloxy group, etc., and then subjecting the obtained compound to an elimination reaction in the presence of a base, etc. There is.

As an example, the method (1) via the xanthate compound [XXI] will be explained in more detail. Hydroxypyrrolidine compound [XXI] is reacted with carbon disulfide in the presence of an inorganic base such as sodium hydroxide or potassium hydroxide to form a dithiocarboxylic acid salt, which has the general formula RIX2 (
In the formula, R1 has the same meaning as defined above, X2 is chlorine,
Xanthate Compound [XXI] is obtained. When this xanthate compound [XXI] is heated and refluxed in a high boiling point solvent such as]0-dichlorobenzenenitrobenzene, mesitylene, or xylene, the 3,4-dehydropyrrolidine compound [1
1 (Z is a group other than hydrogen among those defined above) and 4.
A mixture of 5-dehydropyrrolidine compounds [XXI] is obtained. In this reaction, for example, when a xanthate compound [111] in which 2 is a benzyloxycarbonyl group and R1 is a methyl group is heated under reflux with ]0-dichlorobenzene, the compound CI] and the compound [XH] are separated at a ratio of 8.2:1. obtained as a mixture of 3.4-Dehydropyrrolidine compound [I] can be separated from the mixture by chromatography using silica gel or the like.

[) 3.4-Dehydropyrrolidine compound [I] itself is a useful intermediate for manisomycin synthesis, but if necessary, it can be treated by a method known per se, such as alkaline hydrolysis or hydrogenolysis using palladium. 3.
Protecting group 2 of 4-dehydropyrrolidine compound [1] is removed to obtain N-free 3,4-dehydropyrrolidine [:XX
ff].

Compounds obtained intermediately through the above series of reactions are usually isolated and then used in the next step, but isolation is not necessarily required.

[Effects of the Invention] Since the present invention is configured as described above, unlike the conventional method described at the beginning of this book, the problem that the intermediate is easily racemized and the optical purity of the final product, the optically active compound, is low can be avoided. A highly pure optically active substance can be produced without any generation. Further, according to the present invention, the general formula [
Various homologs belonging to the hydroxypyrrolidine compound represented by
, various homologues belonging to the 4-dehydropyrrolidine compound can be obtained.

(The following is a blank space) [Examples] In order to illustrate the technical features of the present invention, some examples and reference examples are listed below. However, these do not limit the present invention.

In these Examples and Reference Examples, specific compounds belonging to the compound groups indicated by Roman numerals [1] to [XXff] in the above explanation are indicated by Arabic numerals [1] to [24] corresponding to the above Roman numerals. . Moreover, all percentages indicating percentages indicate weight 96.

First, S-(
+)-1-(4-methoxyphenyl)-2,3-epoxypropane [10] will be described as a reference example.

Reference Example I R-1-benzyloxy-2,3-epoxypropane [
8c] Synthesis of the above [10] a) A solution of 4-bromoanisole 3.03 (24.2 mM) in 10 moles of tetrahydrofuran was heated at -78°C under an argon stream.
Cool to 14% n-butyllithium 15% hexane solution
．． 8 (23,11 nM) was added dropwise, and the mixture was stirred for 30 minutes to carry out the reaction. This reaction solution was added using a cask to a 10-layer suspension of cupric cyanide and 0.3 g (11.5+M) of tetrahydrofuran at -78 DEG C., and stirred for an additional 30 minutes at the same temperature.

A suspension of lithium cuplate reagent was thus prepared.

Separately, using R-(-)-epichlorohydrin [8a] with high optical purity obtained by the method described in JP-A-61-132196 as a raw material, R-(-
)-1-benzyloxy-2,3-epoxypropane [
8c (9696ee) was synthesized.

A suspension of the above lithium cuplate reagent was added at -78°C.
A solution of R-(-)-benzyloxy-2,3 epoxypropane [8 cl 1.20 g (7.3 mM) in tetrahydrofuran was added dropwise, and the mixture was stirred at the same temperature for 3 hours, and then further heated at -25°C. Stirred for 1 hour. Extraction was performed by adding 20 parts of saturated brine and 100 w1 of ether to the reaction solution, and the ether layer was washed with 20111 parts of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography using 120 g of silica gel, and ether:hexane-1=2
A colorless oily S-(+)- was obtained from the solvent fraction of
Alcohol [9bl 1.97 g (yield 98%)
I got it.

[cr]” :+7.0 (C-3,11,
MeOH) NMR (CDC/3) δ: 1.80 (IH
,d.

J = 4.5 Hz, disappears at D20), 2.75 (2
H.

d, 6.3 Hz), 3.20-3.60 (2H
, m), 3°80 (3H, s), 3.90-4.1
0 (IH, m), 4°55 (2H, s), 6
．． 70-7.20 (4H, m), 7°33 (
5H,S) I R(neat) cm-': 3450.162
0.1520,1240M5ll1e :273
(M+1), 121 (100%).

b) S-(+)-alcohol C9bl 1.75 g (
20% palladium hydroxide 50B supported on activated carbon was added to a methanol 301111 solution of 6°45 d), and the solution was stirred for 16 hours under an atmosphere of 1 atmosphere of hydrogen gas. After the reaction solution was filtered through Celite, the solvent was distilled off under reduced pressure and S-
Diol [1111.19 g (yield 99%) was obtained.

This was recrystallized from a mixture of ethanol and hexane to obtain plate crystals.

mp: 74-75°C NMR (CDC/3) δ: 2.30 (2H, br
s.

disappeared at D20), 2.85 (2H, d, J
-6,4Hz), 3.25-4.0 (3H,m
), 3.70 (3H.

s), 8.80 (2H, d, J=8.8 Hz), 7.
10 (2H, d, J=8.6 Hz) I R (neat) am-': 3400.161
0.1510.1240゜M5 tale:
182 (M”), 121 (100%
).

S-diol [11 L, 17 g (8,41 M) in benzene solution at 10 degrees Celsius and benzaldehyde 0.85111
(8,4a+M) and 30 mg (2M%) of p-1 sulfonic acid hydrate were added, a Digi-Stark apparatus was attached to the reactor, and the mixture was heated under reflux for 5 hours.

Ether 50/12/ was added to the reaction solution for extraction,
The ether layer was washed successively with saturated aqueous sodium bicarbonate solution 20/II/ and saturated brine 2011+2/, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure, and the resulting residue was subjected to column chromatography using 70 g of silica gel.
Acetal [12] 1°65 g (yield 95.5
%) was obtained.

N~IR(CDC/i)δ: 2.85-3.25
(2H.

m), 3.75 (3H, s), 3. BO-4,60(3
H.

m), 5.70 (0,8H,s), 5.95
(0,4H,s)6.80(2H,d, J =8
．． 8 Hz), 7.10 (2H1 d.

-8,B Hz) 7.30-7.50 (5H.

m) IR(neat) C11-': 1B20
,1520.1250M5 l1le: 27
0 (M”), 149 (100%)
.

d) To a solution of 1.31 g (4,85 layers M) of acetal [12] in carbon tetrachloride 15,712/solution, 917 mg (5,01 IIM) of N-bromoconolyric acid imide was added, and the mixture was stirred at room temperature for 20 hours. The resulting precipitate was filtered through Celite, and the filtrate was washed successively with 10 layers of saturated sodium bicarbonate solution and 10 layers of saturated brine, and dried over anhydrous magnesium sulfate.

The solvent was then distilled off under reduced pressure to give S- as a yellow oil.
Bromobenzoate [13] 1.87 g of crude product was obtained.

This crude product was dissolved in 10 methanol, 850 mg of potassium carbonate (8 and 15 layers M) was added thereto, stirred at room temperature for 5 hours, and most of the solvent was distilled off under reduced pressure. Ether 30I111 was added to this residue for extraction, and the ether layer was washed with saturated brine and dried over anhydrous magnesium sulfate.

Then, the solvent was distilled off under reduced pressure, and the residue was dissolved in 50 g of silica gel.
S-(+)- was subjected to column chromatography using a solvent of ether:hexane-1:9.
1546 mg (yield: 81.2%) of 1-(4-methoxyphenyl)-2,3-epoxypropane C10 was obtained.

[α] 28D, + 1. Q.

(C=1.0.CHC/ ] ) NMR (CD
C/3) δ: 2.50 (IH, dd J
-2,44,4,11IllHz), 2.70-2
．． 85 (2H.

m), 3.0-3.20 (I H, m), 3
．． 80 (3H.

s), 6.80 (2H, d, J = 8.55
Hz), 7.10 (2H, d, 8.55Hz) I R(neat) cm-': 1610.151
5.1240M5 tale: 1B4 (M”
), 121 (100%).

Reference example 2 [10] from S-<+>-ebichlorohydrin [8a]
Synthesis of 4-bromoanisole 1.25111 (10n+M) in tetrahydrofuran 5a solution under argon atmosphere -78
A 15% n-butyl lithium solution in hexane (6.1 degrees Celsius (9.51 M)) was added dropwise at a temperature of .degree. C., and the mixture was stirred for 20 minutes.

The resulting pale yellow solution was heated to -78°C with cupric cyanide (488°C).
mg (5a+M) of tetrahydrofuran 10/7i
/ Add to the suspension using a cask and stir the mixture at the same temperature for 30 minutes.
After stirring for 0 minutes, the mixture was stirred at -45°C for 20 minutes. A suspension of lithium cuplate reagent was thus prepared.

A tetrahydrofuran solution containing 463 mg (5 mM) of S-(+)-epichlorohydrin [8a] with high optical purity obtained by the method described in JP-A-62-6697 was added dropwise to this suspension, and the solution was allowed to cool to room temperature. After returning, 2.5
Stir for hours. Then, saturated ammonium chloride aqueous solution 10
I112/ and ether 30 IM were added to perform extraction, and the ether layer was washed successively with 10 parts of saturated sodium bicarbonate solution and 10 parts of saturated brine, and then dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure to obtain 1.38 g of crude S-(+)-chlorohydrin [9a1. This was dissolved in tetrahydrofuran 15IrIl, and powdered sodium hydroxide was obtained.
800 I1g (15IIIM) were added and the solution was stirred for 11 hours at room temperature. Next, extraction was performed by adding 50 IIll of ether, and the ether layer was washed with saturated brine until the washings became neutral, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. ether:hexane-1:
From fractions with 10 solvents, S-(+)-1-
(4-Methoxyphenyl)-2,3-epoxypropane [10 colo 09 mg (yield 74%) was obtained.

Next, examples of the present invention will be shown.

Example 1 S-(+)-1-(4-methoxyphenyl)-2,3-
Epoxypropane [10] 610 mg (3,7
2mM) of dimethyl sulfoxide 5 was added to the solution at 90w/
v% Noritium acetylide/ethylenediamine complex 52
After gradual addition of 0B (5, LII+M), the mixture was stirred for 1 hour at room temperature.

After carefully adding 3M of saturated saline, 507M of ether
The ether layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography using 35 g of silica gel, and ether:hexane-1:3
578 mg (yield: 82%) of R-(+)-ethynyl alcohol [14] was obtained from the solvent fraction.

[α] 23: +3.84° (C”1.04. CHCI' i ) NMR (CD
C/3) δ: 2.00 (IH, brs)
, 2.05 (IH, t, J-2,6Hz)
, 2.35 (2H, d d, J = 2.4
4.5.4 Hz), 2.80 (2H, m)
, 3.80 (3H,s), 3.80 -
4.10 (IH, m), 6.80 (2H, d,
J-8,5Hz), 7.10 (2H,d
, J=8.55Hz) I R(neat)cg-': 3450.33
00.2150.1615,15MS l1lle
: 190 (M”).

121 (too%).

Example 2 R-(+)-ethynyl alcohol [14 pieces 405ig
Lindlar catalyst (5% palladium-calcium carbonate poisoned with lead) 6B was added to the solution of ethyl acetate (2.13 mM) and the mixture was stirred for 1 hour at room temperature under a hydrogen atmosphere. The reaction solution was filtered through Celite, the filtrate was distilled off under reduced pressure, and the residue was subjected to column chromatography using 12 g of silica gel. 383 erg (94%) was obtained.

[α] 22: -u, t.

(C-1,08,CHC/,) NMR (CDC/i) δ: 1.85
(IH, brs), 2.0-2.40 (2
H, m), 2.45 -2°90 (2H, m),
3.80 (3H, s), 3.70-4.00
(IH, m), 5.00 -5.30 (2
H, m) 5.80 -8.10 (LH, m),
8.80 (2H.

d, J -8,55Hz), 7.10
(2H, d, J-8, 55Hz) IR(neat)am-': 3400.18
10.152G, 1240M5 tile: 1
92 (M”), 121 (100%).

Example 3 R-(-)-7su/Izfurcol [15] 2.0
3g (10,6d),) Riphenylphosphine 3.33g (12,7mM) and Phthalimide 1
．． A mixture of 87g (12.7mM) of tetrahydrofuran solution was cooled to 20°C, and diisopropylazodicarboxylic acid ester 2.5/# (1
2,7o+M) was added dropwise over 20 minutes, and then 1
Stirring was performed for 2 hours. The reaction solution was returned to room temperature, 20 g of silica gel was added, and the solvent was distilled off under reduced pressure. The remaining powdery residue was subjected to column chromatography using 100 g of silica gel, and the phthalimide derivative of allylamine S-(+)-[1812, 89 g (yield: 8
5%).

[α Ko 26D: +147.7 @(C
-1,01,CHC/3) NMR (CDC/3) δ: 2.40-3.
50 (4H, m), 3.71 (3H, m)
, 4.304.70 (I H, m) , 4.7
0-5.15 (2H, m).

5.50-6.00 (IH, m), 8.8
0 (2H, d.

J-8,5! , Hz), 7.10 (2H,d
, J -8,55Hz), 7.55-7.
80 (4H, m)IR(neat) cm-”
: 178G, 1710.1B20.1520.14M
S m/e: 321 (M”),
174 (100%).

Example 4 Phthalimide derivative of allylamine S-(+)[1B1
2.83 g (8,8ff1M) of ethanol 10
0.66 g of hydrazine monohydrate (13,
2+uM) was added thereto, and the mixture was heated under reflux for 5 hours. The solvent was evaporated under reduced pressure, chloroform was added, filtered through Celite, and the filtrate was evaporated under reduced pressure and distilled with Kugelol to give colorless oily S-(+)allylamine [17] 1.5
7 g (yield 93%) was obtained.

b p: 140℃10.8io+Hg[α]”
: + 23.1° (C-1,07, CHC/3) NMR (CDC/3) δ: 1.50 (2H,
brs), 1.80-3.15 (5H, m)
, 3.80 (3H, s) , 5.00-5.2
0 (2H, m), 5.80-8.10 (IH, m
), 8.80 (2H, d, J=8.55
Hz), 7.10 Hz).

Example 5 (2H2 d.

8.55 S-(+)-allylamine [171500B (2,6
Triethylamine 0.44Ill (3.1mM) and benzoyl chloride 0J4IIII (2,88IIM) at 0°C in a dichloromethane 210 layer solution of 2+aM)
was added and stirred for 1 hour. After returning the reaction solution to room temperature, dichloromethane 10. @' was added, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 880 mg of 5-(-)-benzamide [18] as colorless needles. Recrystallization was performed with a mixture of ethanol and hexane to obtain 800 mg (yield: 9496) of pure S-[18].

mp: 110 112℃ [α]”: -6,86@ (C=0.38.CHC/3) NMR (CD
C/s) δ: 2.10-2.50 (
2H.

m), 2.90 (2H, d, J=6.6 Hz)
, 3.79 (3H, s), 4.20 - 4
．． 60 (IH, m).

5.00-5.20 (2H, m), 5.60-6
．． 15 (2Hm), 6.80 (2H, d, J=
8.55 Hz), 7,LO(2H,d,
J -8,55Hz), 7.35-7゜55 (
3H, m), 7.60-7.80 (2H, m
)IR(neat)Qll-': 3310.
2920.1630゜Example 6 S-(-)-benzamide [18 pieces 120a+g (
acetonitrile:water-1:1 (0.41mM)
V/V) 61111 solution with 310 mg of iodine (1,
23 mM) was added thereto, and the mixture was stirred at room temperature for 3 days. A saturated aqueous sodium bicarbonate solution and 5% aqueous sodium sulfite solution were added to the reaction solution, and after confirming that the color of iodine had disappeared, dichloromethane 2C1' was added to perform extraction.

The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified with 5 g of silica gel.
The 2-
114 mg (yield 90%) of methoxyphenylmethyl-4-benzoyloxypyrrolidine [19] was obtained.

NMR (CD C13) δ: 1.50-2.55 (
3H.

m, IH disappeared at D20), 2.80 (2H, t.

J -7,1Hz), 2.90-3.70 (3H
, m), 5゜30-5.60 (L H, m),
6.80 (2H, d, J = 8.55Hz),
7.10 (2H, d, J = 8.55Hz)
.

7.30-7.70 (3H, m), 7.90-8
．． 10 (2H.

m) IR(neat)co+-': 3350,1
710,1270. 1240゜Example 7 Triethylamine 0゜277 was added to a solution of 9011g (1.25mM) of pyrrolidine [19] in dichloromethane at 0°C.
72/ (1,63mM), benzyl chlorocarbonate 0.
21 layers (1.5d) were added and stirred at room temperature for 12 hours. After distilling off most of the solvent under reduced pressure, 50ffi/ of ether was added to the residue for extraction. The ether layer was washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. After distillation, 82 gIIg of carbamate, ie, 2-methoxyphenylmethyl-4-benzoyloxy-N-penzyloxyluponylpyrrolidine [20], was obtained as a crude product.

Example 8 The above carbamate [201828 mg of the crude product was dissolved in 10 layers of methanol, and 190 a+g of potassium carbonate was dissolved in 10 layers of methanol.
(1, HtsM ) was added and stirred at room temperature for 2 hours. Then, most of the solvent was distilled off under reduced pressure, leaving 30! Extraction was performed by adding Il. The ether layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using 12 g of silica gel.
: From the fraction with the solvent of
13881 g (yield 91%) was obtained.

NMR (CD C/3) δ: 1.80-2.00
(4H.

m), 2.50-3.70 (4H, m), 3
．． 80 (3H.

s), 3.90-4.50 (2H, m),
5.20 (2H.

br s), 8.80 (2H, m), 7.1
0 (2H, br d) 7.35 (5H, s) I R (neat): 3400.1B90.15
15c11-' Reference Example 3 Hydroxycarbamate [2111481g (0°43+eM) in benzene 311Il solution with 14g 1g of tetrabutylammonium hydrogen sulfate
(0-4311M) and carbon disulfide 34IIll (0
, 56IIM) and stirred for 10 minutes, one layer of aqueous sodium hydroxide solution was added to 50, and stirring was continued for 25 minutes at room temperature. After forming the dithiocarboxylate in this way, iodomethane 33II! 1 (0.52 layer M) was added and vigorously stirred for 3 hours. Add ether 30111 to the reaction solution
The ether layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue 190B was subjected to column chromatography using 8 g of silica gel, and ether:hexane-1:
Xanthate [22] from the solvent fraction of 2
182 mg (yield 90%) was obtained.

NMR (CDC/3) δ:2. Q −2,30<
2H.

m), 2.50 (2H, s), 2.65 (IH
,s).

2.65-3.50 (4H, m), 3.80 (3
H,s).

4.00-4.45 (L H, m), 5.20
(2H, m).

5.80-5.80 (0.88H, m), 5.8
0-6.10 (0.33H, m), 5.70-7
．． 20 (4H, m), 7.40 (5H, s) I R(neat)am-': 50.1200. Llooo.

Reference Example 4 1700.1605, 1520, 1410.12 Bovine Santate [22 pieces 123mg (0,2611M) 0
- A 10-layer solution of dichlorobenzene was heated at 200°C for 1.5 hours. Then, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.
-2-methoxyphenylmethyl-N-benzyloxycarbonyl-3,4-dehydropyrrolidine [1] 59.5
mg (86%).

mp: 49-50°C (recrystallized from a mixture of ether + hexane) [α] 26: -190,4° (C-1,0, CHCl3) NMR (CDC/3) δ: 2.80
-3.30 (2H.

m), 3.77 (3H,s), 3.80
-3.90 (2H.

m), 4.05-4.30 (I H, m),
4.60-4.90 (IH, m), 5.20 (
2H, m), 5.70 (2H.

m), 6.75-7. LO (4H, m), 7.
40 (5H.

S) I R(neat) c+a-' two 1700
．． 1800.1510,1410M5 ale
: 323 (M”), 121 (10
0%).

Reference example 5 R-(-)-N-benzyloxycarbonyl-3,4~
Dehydropyrrolidine [1] 117mg (0°38I
1-0 g (25IIIM) of sodium hydroxide was added to the ethylene glycol 3III solution of IM), and the mixture was heated and stirred at 120°C for 14 hours. Extraction was performed by adding methylene chloride, and the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using 5 g of silica gel, and R-(-)-2-methoxyphenylmethyl-3,4-dehydro Pyrrolidine C24] 72mg
(yield 89%).

[α]” Knee 101.2' (C-1,44, Tetrahydrofuran) 1 Literature value [α] Knee 89.3
'(C-1,26, tetrahydrofuran) (Te
trahedron Lett, 29,4419.
1988) NMR (CDC/3) δ: 2
．． 15 (I H, br s.

Disappeared at D20 > , 2.44 (2H, d, J −
e, g Hz), 2.80-2.95 (2H, m
), 3.79 (2H.

s), 4.00-4.35 (IH, m)
, 5.85-5.95 (2H, m), 8.80 (2
H, d, J-8, 55Hz) 7.10 (2H, d,
J = 8.55Hz) I R(neat)a
m-': 3300. 1B10. 1515. 1
240. 1180.

The NMR and IR spectral values were consistent with literature values.

that's all

Claims (10)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [XX I] (In the formula, Ar is a substituted or unsubstituted aryl group, Z is a protecting group for an amino group or a hydrogen atom, * is an optically active carbon A hydroxypyrrolidine compound represented by (2) The hydroxypyrrolidine compound [X
In producing the acyloxypyrrolidine compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. Protected with a protective agent, the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [XX] (In each of the above formulas, Ar, Z and * have the same meanings as in claim 1, and Ar' is substituted or A method characterized by obtaining an N-substituted pyrrolidine compound represented by (respectively meaning an unsubstituted aryl group), and then hydrolyzing the acyloxy group of the compound [XX]. (3) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [XX] (In the formula, Ar and Ar' are the same or different substituted or unsubstituted aryl groups, Z is a protecting group for an amino group, * is an optical An N-substituted pyrrolidine compound represented by: (4) N-substituted pyrrolidine compound according to claim 3 [XX
] of the acyloxypyrrolidine compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [XIX] (wherein Ar, Ar' and * have the same meanings as in claim 3) A method characterized by protecting an amino group with a protecting reagent. (5) General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [XIX] (In the formula, Ar and Ar' are the same or different substituted or unsubstituted aryl groups, * means optically active carbon, respectively) Acyloxypyrrolidine compounds shown. (6) The acyloxypyrrolidine compound according to claim 5 [
XIX], a benzamide compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [XVIII] (wherein Ar, Ar' and * have the same meanings as in claim 5) A method characterized by treatment with a cyclizing reagent selected from the group consisting of bromine, iodine chloride, iodine, HBr_3 salt of pyridine, and N-bromosuccinimide. (7) In the method according to claim 6, when producing the benzamide compound [XVIII], an allylamine compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [XVII] is converted into the general formula Ar'COX^1 or Ar'CO_2COAr' (in each of the above formulas, Ar, Ar'
and * have the same meaning as in claim 6, and X^1 means a halogen atom). (8) In the method according to claim 7, when producing the allylamine compound [XVII], the general formula ▲ has a mathematical formula, a chemical formula, a table, etc. ▼ [XVI] (wherein, Ar and * are the same as those in claim 7). have the same meaning, Y is NHCO_2t-Bu, NHCO_2Bn(B
n means benzyl group), BnONCO_2Bn, o-C_6H_4(CO)_2N, NC(C_6H_4)_3, HCONH, p-Me(C_6H_4)SO_2NH or C_6H
_5SO_2NH) is treated with a base, or a nitrogen-containing compound [XV
A method characterized by subjecting [I] to a hydrogenation reaction. (9) In the method according to claim 8, the nitrogen-containing compound [X
VI], the allyl alcohol compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [XV]
A dialkyl diazocarboxylate represented by _2CN=NCO_2R^2 and the general formula P(R^3)_3 (in each of the above formulas, Ar and * have the same meanings as in claim 8, and R^2 is an alkyl group , R^
3 means an aryl group or an alkyl group, respectively)
In the presence of a tertiary phosphine compound represented by the general formula YH
(Y means a group other than N_3 among the groups of claim 8) or (C_6H_5O)_2PON_3. (10) In claim 9, in producing the allyl alcohol compound [XV], an epoxypropane compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [X] is reacted with lithium acetylide, and the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [XIV] (In each of the above formulas, Ar and * have the same meanings as in claim 9) ethynyl alcohol, which is characterized by being partially reduced. how to.