JPH0812670A - New pyrrolidine derivative - Google Patents

Abstract

PURPOSE:To obtain a new derivative, having antagonistic actions on thromboxane A2 (TXA2) and inhibiting actions on synthesis of the TXA2 and capable of providing an intermediate for producing a compound effectively used in preventing and treating thrombotic diseases, allergic diseases, nephritis, peptic ulcer and migraine, etc. CONSTITUTION:This derivative is expressed formula I [A is a 1-6C alkyl; B is a (substituted)phenyl or a (substituted)naphthyl; (S) is S-configuration], e.g. (2S,4S)-2-methoxycarbonyl-4-(4-nitrophenyl-sulfonyloxy)-1-(3-pyridylme thyl) pyrrolidine. The derivative is obtained by reacting trans-hydroxy-L-proline methyl ester hydrochloride with 3-(methanesulfonyloxymethyl)pyridine in the presence of a base, providing a compound of formula II, then reacting the resultant compound with methanesulfonyl chloride, affording a compound of formula III, subsequently hydrolyzing the prepared compound of formula III with sodium hydroxide, carrying out the intramolecular cyclizing reaction, providing a compound of formula IV, then reacting the resultant compound with a lower alcohol in the presence of anhydrous potassium carbonate, affording a compound of formula V and subsequently reacting the formed compound of formula V with a compound of the formula, B-SO2Cl in the presence of a base.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel pyrrolidine derivative useful as an intermediate for the production of pharmaceuticals.

More specifically, the present invention has a thromboxane A ₂ (TXA ₂ ) antagonistic action and a TXA ₂ synthesis inhibitory action, and has thrombotic diseases, allergic diseases such as asthma, nephritis, peptic ulcers, and migraine. , Diabetic neuropathy, diabetic angiopathy, restenosis after percutaneous transluminal coronary angioplasty, adult respiratory distress syndrome, shock, liver injury, cerebrovascular spasm after subarachnoid hemorrhage, hypertension, arteriosclerosis, cancer Formula useful as a prophylactic and / or therapeutic agent for metastasis, thrombus formation in extracorporeal circulation, thrombus formation in transplantation, conjunctivitis, etc.

[0003]

[Chemical 6]

(5Z) -6- [represented by (5Z) -6- [in the formula, the arrangement of carbon atoms with (S) indicates the S configuration and the arrangement of carbon atoms with (R) indicates the R configuration) (2S, 4R)-
4- (4-chlorophenylsulfonylamino) -1-
A general formula useful as an intermediate for the production of (3-pyridylmethyl) -2-pyrrolidinyl] -5-hexenoic acid and salts thereof

[0005]

[Chemical 7]

(A in the formula is a linear or branched alkyl group having 1 to 6 carbon atoms, B is a phenyl group which may have one or more substituents, or a naphthyl group,
The configuration of the carbon atom with (S) indicates the S configuration) (2S, 4S) -2-alkoxycarbonyl-4-
Allylsulfonyloxy-1- (3-pyridylmethyl)
The present invention relates to a pyrrolidine derivative.

[0007]

2. Description of the Related Art There are several known methods for producing a pyrrolidine derivative represented by the above formula (I) (JP-A-2-152960), but the production of the production intermediate used is complicated and complicated. It is not always satisfactory because it requires a long process, and there is a risky process such as the use of sodium azide in the process.

[0008]

DISCLOSURE OF THE INVENTION The present invention provides a pyrrolidine derivative represented by the above formula (I), which has a thromboxane A ₂ (TXA ₂ ) antagonistic action and a TXA ₂ synthesis inhibitory action and is useful as a drug. Moreover, it is to provide a useful intermediate for production, which can produce a product having a high optical purity in a high yield.

[0009]

Means for Solving the Problems The present inventors have conducted extensive studies to efficiently produce the pyrrolidine derivative represented by the above formula (I), and as a result, the compound represented by the above general formula (II) (2S , 4S) -2-Alkoxycarbonyl-4-allylsulfonyloxy-1- (3-pyridylmethyl) pyrrolidine derivative is used to produce the pyrrolidine derivative represented by the formula (I) very easily and in high yield. The inventors have found that they can be achieved and have completed the present invention.

The pyrrolidine derivative represented by the general formula (II) of the present invention can be produced, for example, as follows.

That is, trans-hydroxy-L-proline methyl ester hydrochloride is reacted with 3- (methanesulfonyloxymethyl) pyridine in the presence of a basic substance to give a compound of the formula

[0012]

Embedded image

Trans-4-hydroxy-1-represented by (S and R in the formula have the same meanings as described above)
(3-pyridylmethyl) -L-proline methyl ester was prepared and then reacted with methanesulfonyl chloride in the presence of a basic substance to give a compound of the formula

[0014]

[Chemical 9]

(2S, 4R) -2-methoxycarbonyl-4-methylsulfonyloxy-1- (3-pyridylmethyl) represented by the formula (S) and (R) have the same meanings as described above. ) Pyrrolidine is produced and then hydrolyzed in the presence of sodium hydroxide, and then the configuration at the 4-position of the compound represented by the formula (IV) is selectively inverted by an intramolecular ring closure reaction.

[0016]

[Chemical 10]

((S) in the formula has the same meaning as above)
To produce (1S, 4S) -5- (3-pyridylmethyl) -2-oxa-5-azabicyclo [2,2,1] heptan-3-one. Then, by reacting with a lower alcohol in the presence of anhydrous potassium carbonate, the compound of the general formula

[0018]

[Chemical 11]

A (2S, 4S) -2-alkoxycarbonyl-4-hydroxy-1- (3-pyridylmethyl) pyrrolidine derivative represented by the formula (A and (S) have the same meanings as described above) Manufactured, and in the presence of a basic substance,

[0020]

[Chemical 12]

It can be produced by reacting with an allylsulfonyl chloride derivative represented by the formula (B in the formula has the same meaning as described above).

The (2S, 4S) -2-alkoxycarbonyl-4-allylsulfonyloxy-1- (3-pyridylmethyl) pyrrolidine derivative represented by the above general formula (II) of the present invention is very easily 4- Substitution reaction with chlorophenyl sulfonamide alkali metal salt

[0023]

[Chemical 13]

(2S, 4R) -2-alkoxycarbonyl-4- (4-chlorophenylsulfonylamino) -1 represented by the formula (A, (S) and (R) have the same meanings as described above). It is converted into a-(3-pyridylmethyl) pyrrolidine derivative in high yield and stereoselectively.

The above-mentioned general formula (VI
The pyrrolidine derivative represented by II) is reduced with sodium borohydride in the presence of, for example, lithium chloride to give a compound of the formula

[0026]

Embedded image

(2S, 4R) -4- (4-chlorophenylsulfonylamino) -2-hydroxymethyl-1- (denoted by (S) and (R) in the formula have the same meanings as described above.) After conversion to 3-pyridylmethyl) pyrrolidine, it is then oxidized, for example with a dimethylsulfoxide-sulfur trioxide pyridine complex,

[0028]

[Chemical 15]

(2S, 4R) -4- (4-chlorophenylsulfonylamino) -2-formyl-1-represented by (wherein (S) and (R) have the same meanings as described above)
After conversion to (3-pyridylmethyl) pyrrolidine, a (4-carboxybutyl) triphenylphosphonium salt is reacted in the presence of a basic substance to represent (5Z) -6-[(2S , 4R) -4- (4-Chlorophenylsulfonylamino) -1- (3-pyridylmethyl) -2-pyrrolidinyl] -5-hexenoic acid in high yield,
It can be manufactured with high purity.

Thus, the pyrrolidine derivative represented by the above general formula (II) is represented by the above formula (I) (5
Z) -6-[(2S, 4R) -4- (4-chlorophenylsulfonylamino) -1- (3-pyridylmethyl)-
It is a very useful compound as a production intermediate of 2-pyrrolidinyl] -5-hexenoic acid.

In the pyrrolidine derivative represented by the general formula (II) of the present invention, when B is a phenyl group,
The phenyl group may or may not have a substituent, and when the substituent is present, the kind of the substituent, the substitution position and the number of the substituents are not particularly limited. Examples of such a substituent include a nitro group, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, a linear or branched alkoxy group having 1 to 6 carbon atoms, and a straight chain having 1 to 6 carbon atoms. Examples thereof include a chain-like or branched alkyl group, a protected hydroxyl group, and an alkoxycarbonyl group.

In the pyrrolidine derivative represented by the general formula (II) of the present invention, preferred compounds are:
(2S, 4S) -2-Methoxycarbonyl-4- (4-
Nitrophenylsulfonyloxy) -1- (3-pyridylmethyl) pyrrolidine, (2S, 4S) -2-methoxycarbonyl-4- (3-nitrophenylsulfonyloxy) -1- (3-pyridylmethyl) pyrrolidine, (2
S, 4S) -2-Methoxycarbonyl-4- (2-nitrophenylsulfonyloxy) -1- (3-pyridylmethyl) pyrrolidine, (2S, 4S) -4- (4-chlorophenylsulfonyloxy) -2-methoxy Carbonyl-1- (3-pyridylmethyl) pyrrolidine, (2S, 4
S) -4- (4-Bromophenylsulfonyloxy)-
2-methoxycarbonyl-1- (3-pyridylmethyl)
Pyrrolidine, (2S, 4S) -4- (4-methylphenylsulfonyloxy) -2-methoxycarbonyl-1-
(3-pyridylmethyl) pyrrolidine, (2S, 4S)-
2-Methoxycarbonyl-4- (4-methoxyphenylsulfonyloxy) -1- (3-pyridylmethyl) pyrrolidine, (2S, 4S) -4- (3,4-dichlorophenylsulfonyloxy) -2-methoxycarbonyl-1
-(3-pyridylmethyl) pyrrolidine, (2S, 4S)
-4- (2,5-dichlorophenylsulfonyloxy)
2-Methoxycarbonyl-1- (3-pyridylmethyl) pyrrolidine, (2S, 4S) -2-methoxycarbonyl-4-phenylsulfonyloxy-1- (3-pyridylmethyl) pyrrolidine, (2S, 4S) -2 -Methoxycarbonyl-4- (β-naphthylsulfonyloxy)
-1- (3-Pyridylmethyl) pyrrolidine may be mentioned.

In the pyrrolidine derivative represented by the general formula (II) of the present invention, (2S, 4S) -2-methoxycarbonyl-4- is particularly preferable.
(4-Nitrophenylsulfonyloxy) -1- (3-
Pyridylmethyl) pyrrolidine, (2S, 4S) -4-
(4-Chlorophenylsulfonyloxy) -2-methoxycarbonyl-1- (3-pyridylmethyl) pyrrolidine may be mentioned.

[0034]

By using the compound represented by the general formula (II) of the present invention as a production intermediate, it has a thromboxane A ₂ (TXA ₂ ) antagonistic action and a TXA ₂ synthesis inhibitory action, and The pyrrolidine derivative represented by the above formula (I) useful as the above can be easily produced with high optical purity and high yield. In addition, the pyrrolidine derivative represented by the general formula (II) of the present invention can be easily produced in a short process with a high yield and can be produced without using a dangerous reagent. Therefore, the general formula (I
The above formula (I) using a compound represented by I) as a production intermediate
The method for producing a pyrrolidine derivative represented by is a very useful method as an industrial production method.

[0035]

EXAMPLES The contents of the present invention will be described in more detail with reference to the following reference examples and examples. In addition, the melting points of the compounds in each Reference Example and Examples are all uncorrected.

Reference Example 1 (2S, 4R) -2-Methoxycarbonyl-4-methylsulfonyloxy-1- (3-pyridylmethyl) pyrrolidine 3-pyridinemethanol 6.30 g (57.7 mmo)
l), triethylamine 9.65 ml (69.2 mmo)
1) was added to 100 ml of ethyl acetate, and a solution of 6.94 g (60.6 mmol) of methanesulfonyl chloride in 10 ml of ethyl acetate was cooled (-13 ° C to 0 ° C) at 20 ° C.
Dropped in minutes. After 10 minutes of dropping, trans-4-hydroxy-L-proline methyl ester hydrochloride 10.0 g (55 mmol) and triethylamine 30 m were kept ice-cooled.
l (215 mmol) each at once and added at room temperature to 1
Stir for 5 hours. To the reaction solution, 8.60 g (75.1 mmol) of methanesulfonyl chloride in ethyl acetate 10 was added.
The solution of ml was added dropwise over 20 minutes under cooling (-13 ° C to 0 ° C), and the mixture was stirred for 1 hour under cooling. After completion of mesylation, the reaction solution was 1N hydrochloric acid 50ml, 30ml, 30m
Extract 3 times with 1. Sodium bicarbonate was added to the aqueous layer while paying attention to foaming, and the pH was adjusted to 7-8, and then ethyl acetate 50
It extracted 3 times with ml, 40 ml, and 40 ml. Next, the organic layer was washed with 20 ml of saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure (2S, 4R) -2.
-Methoxycarbonyl-4-methylsulfonyloxy-
1- (3-pyridylmethyl) pyrrolidine 14.7 g (8
5%) as an oil.

[0037]

Reference Example 2 (1S, 4S) -5- (3-Pyridylmethyl) -2-oxa-5-azabicyclo [2,2,1] heptane-3-
On (2S, 4R) -2-methoxycarbonyl-4-methylsulfonyloxy-1- (3-pyridylmethyl) pyrrolidine (247.0 g, 0.786 mol) was dissolved in 200 ml of acetonitrile, and 2N aqueous sodium hydroxide solution was stirred at room temperature. 400 ml (0.80 mol) was added and stirred for 2 hours. After toluene was added to the reaction solution, water in the reflux solution was removed using a dehydration tube, and heated under reflux until no water was confirmed. The insoluble matter was filtered, and the insoluble matter was washed with ethyl acetate. The filtrate and washings were combined, the solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give (1S, 4S) -5- (3-pyridylmethyl) -2-oxa-5-azabicyclo [ 2,2,1] Heptane-3-
Obtained 105.6 g (70.6%) of on.

[0039] Melting point: 78 to 82 ° C

Reference Example 3 (2S, 4S) -4-Hydroxy-2-methoxycarbonyl-1- (3-pyridylmethyl) pyrrolidine (1S, 4S) -5- (3-pyridylmethyl) -2-oxa-5 -Azabicyclo [2,2,1] heptane-3-
On 105.6 g (0.555 mol) of methanol 1
Dissolve in 00 ml, 3.1 g of anhydrous potassium carbonate (0.0
(22 mol) was added and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and 200 ml of water and 5 methylene chloride were added to the residue.
00 ml was added, and the mixture was dissolved and separated, and the aqueous layer was extracted twice with 200 ml of methylene chloride. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and treated with activated carbon. The solvent was distilled off under reduced pressure (2S, 4S) -4
110.4 g (84%) of -hydroxy-2-methoxycarbonyl-1- (3-pyridylmethyl) pyrrolidine was obtained as an oil.

[0041]

Reference Example 4 (2S, 4S) -4-Hydroxy-2-methoxycarbonyl-1- (3-pyridylmethyl) pyrrolidine (2S, 4R) -2-Methoxycarbonyl-4-methylsulfonyloxy-1- ( 37.6 g (120 mmol) of 3-pyridylmethyl) pyrrolidine was added to acetonitrile 5
It was dissolved in 0 ml, and 64 ml (128 mmol) of 2N aqueous sodium hydroxide solution was added with stirring at room temperature, and the mixture was stirred for 30 minutes. After completion of the hydrolysis, 300 ml of benzene was added to the reaction solution, and water in the reflux solution was removed using a dehydration tube, and the mixture was heated under reflux until no water was confirmed. The solvent was distilled off under reduced pressure, 100 ml of dry methanol and 0.83 g (6 mmol) of anhydrous potassium carbonate were added to the residue, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, saturated saline and chloroform were added to dissolve the solution, and the solution was separated, and the aqueous layer was extracted with chloroform. The organic layers were combined, washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 22.2 g (78%) of (2S, 4S) -4-hydroxy-2-methoxycarbonyl-1- (3-pyridylmethyl) pyrrolidine as a pale yellow oil. The instrumental analysis result of this product was the same as that obtained in Reference Example 3.

Example 1 (2S, 4S) -2-Methoxycarbonyl-4- (4-
Nitrophenylsulfonyloxy) -1- (3-pyridylmethyl) pyrrolidine (2S, 4S) -4-hydroxy-2-methoxycarbonyl-1- (3-pyridylmethyl) pyrrolidine 3.00
g (12.7 mmol) was dissolved in 20 ml of dry methylene chloride, and 2.09 ml (15.0 mm) of triethylamine was dissolved.
was added and 3.33 g (15.0 mmol) of 4-nitrophenylsulfonyl chloride was added under ice-cooling stirring.
After stirring at room temperature for 4 hours, the reaction solution was washed with an aqueous sodium hydrogen carbonate solution and water. The organic layer was extracted 5 times with 1N hydrochloric acid, the aqueous layers were combined, washed with methylene chloride, adjusted to pH 7-8 with sodium hydrogen carbonate, and extracted with methylene chloride. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and treated with activated carbon, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-hexane to give (2S, 4S) -2-methoxycarbonyl-4-.
(4-Nitrophenylsulfonyloxy) -1- (3-
4.01 g (75%) of pyridylmethyl) pyrrolidine was obtained as pale red crystals.

[0044] Melting point: 117-118 ° C

Example 2 (2S, 4S) -2-Methoxycarbonyl-4- (4-
Nitrophenylsulfonyloxy) -1- (3-pyridylmethyl) pyrrolidine (2S, 4S) -4-hydroxy-2-methoxycarbonyl-1- (3-pyridylmethyl) pyrrolidine 110.
4 g (0.47 mol) was dissolved in 500 ml of pyridine, and 155.4 g (0.70 mol) of 4-nitrophenylsulfonyl chloride was added under stirring with ice cooling. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. Ice water was added to the residue to precipitate crystals, and 88 g of sodium hydrogen carbonate was further added.
(1.05 mol) was added to sufficiently precipitate crystals,
The precipitated crystals were collected by filtration and washed with cold water. The obtained crystals were dissolved in 1000 ml of methylene chloride, the organic layer was dried over anhydrous magnesium sulfate and treated with activated carbon. The solvent was distilled off under reduced pressure, and (2S, 4S) -2-methoxycarbonyl-4-
(4-Nitrophenylsulfonyloxy) -1- (3-
172.3 g (87.4) of pyridylmethyl) pyrrolidine
%) Was obtained as crystals. The instrumental analysis result of this product was the same as that obtained in Example 1.

Example 3 (2S, 4S) -2-Methoxycarbonyl-4- (3-
Nitrophenylsulfonyloxy) -1- (3-pyridylmethyl) pyrrolidine 3 instead of 4-nitrophenylsulfonyl chloride
The above compound was obtained as an oily substance in the same manner as in Example 1 using -nitrophenylsulfonyl chloride.

[0047]

Example 4 (2S, 4S) -2-Methoxycarbonyl-4- (2-
Nitrophenylsulfonyloxy) -1- (3-pyridylmethyl) pyrrolidine 2 instead of 4-nitrophenylsulfonyl chloride
The above compound was obtained as an oily substance in the same manner as in Example 1 using -nitrophenylsulfonyl chloride.

[0049]

Example 5 (2S, 4S) -4- (4-Chlorophenylsulfonyloxy) -2-methoxycarbonyl-1- (3-pyridylmethyl) pyrrolidine (2S, 4S) -4-hydroxy-2-methoxycarbonyl -1- (3-pyridylmethyl) pyrrolidine 3.89
g (16.4 mmol) was dissolved in 5 ml of pyridine, and 5.21 g (24.7 mmol) of 4-chlorophenylsulfonyl chloride was added under stirring with ice cooling. After stirring at room temperature for 1 hour, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and treated with activated carbon. The solvent was distilled off under reduced pressure,
The obtained crystals were recrystallized from ethyl acetate-hexane,
5.31 g (79%) of (2S, 4S) -4- (4-chlorophenylsulfonyloxy) -2-methoxycarbonyl-1- (3-pyridylmethyl) pyrrolidine was obtained as crystals.

[0051] Melting point: 58 to 61 ° C

Example 6 (2S, 4S) -4- (4-Bromophenylsulfonyloxy) -2-methoxycarbonyl-1- (3-pyridylmethyl) pyrrolidine 4-chlorophenylsulfonyl chloride instead of 4
The above compound was obtained as an oil in the same manner as in Example 5 by using -bromophenylsulfonyl chloride.

[0053]

Example 7 (2S, 4S) -4- (4-Methylphenylsulfonyloxy) -2-methoxycarbonyl-1- (3-pyridylmethyl) pyrrolidine 4-chlorophenylsulfonyl chloride instead of 4
The above compound was obtained as an oil in the same manner as in Example 5 by using -methylphenylsulfonyl chloride.

[0055]

Example 8 (2S, 4S) -2-Methoxycarbonyl-4- (4-
Methoxyphenylsulfonyloxy) -1- (3-pyridylmethyl) pyrrolidine 4 instead of 4-chlorophenylsulfonyl chloride
The above compound was obtained as an oil in the same manner as in Example 5 by using -methoxyphenylsulfonyl chloride.

[0057]

Example 9 (2S, 4S) -4- (3,4-dichlorophenylsulfonyloxy) -2-methoxycarbonyl-1- (3-
The above compound was obtained as an oil in the same manner as in Example 5 except that 3,4-dichlorophenylsulfonyl chloride was used instead of pyridylmethyl) pyrrolidine 4-chlorophenylsulfonyl chloride.

[0059]

Example 10 (2S, 4S) -4- (2,5-dichlorophenylsulfonyloxy) -2-methoxycarbonyl-1- (3-
Pyridylmethyl) pyrrolidine 2,5-Dichlorophenylsulfonyl chloride was used instead of 4-chlorophenylsulfonyl chloride to give the above compound as an oil in the same manner as in Example 5.

[0061]

Example 11 (2S, 4S) -2-Methoxycarbonyl-4-phenylsulfonyloxy-1- (3-pyridylmethyl) pyrrolidine Example 5 using phenylsulfonyl chloride instead of 4-chlorophenylsulfonyl chloride. The above compound was obtained as an oil in the same manner as.

[0063]

Example 12 (2S, 4S) -2-Methoxycarbonyl-4- (β-
Naphthylsulfonyloxy-1- (3-pyridylmethyl) pyrrolidine 4-β instead of 4-chlorophenylsulfonyl chloride
Using naphthylsulfonyl chloride, the above compound was obtained as an oil in the same manner as in Example 5.

[0065]

Reference Example 5 (2S, 4R) -4- (4-chlorophenylsulfonylamino) -2-methoxycarbonyl-1- (3-pyridylmethyl) pyrrolidine (2S, 4S) -2-methoxycarbonyl-4- ( 4-
Nitrophenylsulfonyloxy) -1- (3-pyridylmethyl) pyrrolidine 1.00 g (2.37 mmo)
l) and 1.02 g (4.77 mmol) of 4-chlorophenylsulfonamide sodium salt were suspended in 5 ml of dry dimethyl sulfoxide, and the mixture was stirred at room temperature overnight. The reaction solution became a homogeneous solution as the reaction proceeded. After completion of the reaction, 1N hydrochloric acid and ethyl acetate were added to the reaction solution for liquid separation, and the organic layer was further extracted twice with 1N hydrochloric acid. The aqueous layers were combined, washed with ethyl acetate, adjusted to pH 7-8 with sodium hydrogen carbonate, and extracted 3 times with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. After treatment with activated carbon, the mixture was concentrated under reduced pressure to obtain 0.91 g of an oily substance. Recrystallize from ethyl acetate-hexane to give (2S, 4
R) -4- (4-chlorophenylsulfonylamino)-
2-methoxycarbonyl-1- (3-pyridylmethyl)
0.77 g (79%) of pyrrolidine was obtained as yellow crystals.

[0067] Melting point: 112-115 ° C

Reference Example 6 (2S, 4R) -4- (4-chlorophenylsulfonylamino) -2-methoxycarbonyl-1- (3-pyridylmethyl) pyrrolidine (2S, 4S) -4- (4-chlorophenylsulfonyloxy) ) -2-Methoxycarbonyl-1- (3-pyridylmethyl) pyrrolidine 5.32 g (12.9 mmo)
l) and 4.15 g (19.4 mmol) of 4-chlorophenylsulfonamide sodium salt were suspended in 20 ml of dry dimethyl sulfoxide, and the suspension was stirred at 60 ° C. for 6 hours. After completion of the reaction, 1N hydrochloric acid and ethyl acetate were added to the reaction solution for liquid separation, and the organic layer was further extracted twice with 1N hydrochloric acid. The aqueous layers were combined, washed with ethyl acetate, adjusted to pH 7-8 with sodium hydrogen carbonate, and extracted 3 times with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. After treatment with activated carbon, concentration under reduced pressure gave 4.12 g of an oily substance. Recrystallize from ethyl acetate-hexane to give (2
3.55 g (67%) of S, 4R) -4- (4-chlorophenylsulfonylamino) -2-methoxycarbonyl-1- (3-pyridylmethyl) pyrrolidine was obtained as yellow crystals. The instrumental analysis result of this product was the same as that obtained in Reference Example 5.

Reference Example 7 (2S, 4R) -4- (4-chlorophenylsulfonylamino) -2-hydroxymethyl-1- (3-pyridylmethyl) pyrrolidine (2S, 4R) -4- (4-chlorophenylsulfonylamino) ) -2-Methoxycarbonyl-1- (3-pyridylmethyl) pyrrolidine (1.64 g, 4.0 mmol) in a tetrahydrofuran solution, lithium chloride (510 mg)
(12.0 mmol), sodium borohydride 455
mg (12.0 mmol) was added, and 20 ml of ethanol was added under ice cooling. The reaction solution was stirred overnight while gradually returning to room temperature. After adding 30 ml of 1N hydrochloric acid to the reaction solution and stirring for 1 hour, the reaction solution was concentrated. The residue was dissolved in ethyl acetate, extracted twice with 1N hydrochloric acid, and the aqueous layers were combined and washed once with ethyl acetate. The pH of the aqueous layer was adjusted to 8 with saturated aqueous sodium hydrogen carbonate solution, and then adjusted to 2 with ethyl acetate.
Extracted times. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. Ethanol was added to the residue to dissolve it, about 0.3 g of activated carbon was added, and the mixture was stirred at a bath temperature of 50 ° C. for 10 minutes. After removing the activated carbon by filtration, the filtrate was concentrated. After the residue was dissolved in a small amount of ethanol, water was added to inoculate seed crystals and left overnight. The precipitated crystals were collected by filtration and dried, and (2S, 4R) -4- (4-chlorophenylsulfonylamino) -2-hydroxymethyl-1-
1.3 g (3-pyridylmethyl) pyrrolidine (87
%) Was obtained.

[0070] Melting point: 126.5 to 127 ° C

Reference Example 8 (2S, 4R) -4- (4-chlorophenylsulfonylamino) -2-formyl-1- (3-pyridylmethyl)
Pyrrolidine (2S, 4R) -4- (4-chlorophenylsulfonylamino) -2-hydroxymethyl-1- (3-pyridylmethyl) pyrrolidine 3.304 g (8.65 mmol)
Was dissolved in 30 ml of dry methylene chloride and 6.0 ml of dry dimethyl sulfoxide, and triethylamine 3.61 was added.
After adding ml (25.9 mmol), 4.13 g (25.9 mmol) of sulfur trioxide pyridine complex was added under stirring with ice cooling. After reacting for 30 minutes at room temperature, add methylene chloride to 1
It was extracted with normal hydrochloric acid. The aqueous layer was washed with methylene chloride, adjusted to pH 8 with sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give (2S, 4R) -4.
-(4-chlorophenylsulfonylamino) -2-formyl-1- (3-pyridylmethyl) pyrrolidine 2.95
5 g (90%) was obtained as an amorphous.

[0072]

Reference Example 9 (5Z) -6-[(2S, 4R) -4- (4-chlorophenylsulfonylamino) -1- (3-pyridylmethyl) -2-pyrrolidinyl] -5-hexenoic acid (4- 2.18 g (4.92 mmol) of (carboxybutyl) triphenylphosphonium bromide and 1.50 g (13.4 mmol) of potassium t-butoxy were suspended in 15 ml of dry tetrahydrofuran, stirred at 45 ° C. for 30 minutes, and then cooled under ice-cooling 2 to 2. (2S, 4R) -4- (4-
Chlorophenylsulfonylamino) -2-formyl-1
-(3-pyridylmethyl) pyrrolidine 919 mg (2.
A solution of 42 mmol) in 5 ml of dry tetrahydrofuran was added, and the mixture was reacted at room temperature for 2 hours. To the reaction solution was added 30 ml of methylene chloride, 30 ml of 1N hydrochloric acid, 20 ml,
Extract with 20 ml and combine the aqueous layers with 20 ml of methylene chloride.
After washing with, the pH was adjusted to 5 with a 5N aqueous sodium hydroxide solution, and the mixture was extracted 3 times with 20 ml of ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure,
(5Z) -6-[(2S, 4R) -4- (4-chlorophenylsulfonylamino) -1- (3-pyridylmethyl) -2-pyrrolidinyl] -5-hexenoic acid 933 mg
(83%) was obtained as an oil.

[0074]

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yuko Oda 2027-11, Akimori, Misato-mura, Minamiazumi-gun, Nagano Maison Misato NAONAO Building No. 203

Claims (5)

[Claims] 1. A compound of the general formula (A in the formula is a linear or branched alkyl group having 1 to 6 carbon atoms, B is a phenyl group which may have one or more substituents, or a naphthyl group, (S) The arrangement of carbon atoms marked with indicates the S configuration). 2. A general formula: (A in the formula is a linear or branched alkyl group having 1 to 6 carbon atoms, R ¹ is a nitro group, a halogen atom, a linear or branched alkoxy group having 1 to 6 carbon atoms,
A linear or branched alkyl group having 1 to 6 carbon atoms, n is an integer of 0 to 2, and the arrangement of carbon atoms with (S) indicates the S arrangement). 1. The pyrrolidine derivative according to 1. 3. A general formula: (A in the formula is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, R ² is a nitro group or a chlorine atom, and the carbon atom with (S) has the S configuration. ] The pyrrolidine derivative of Claim 2 represented by these. 4. A compound of the general formula (A in the formula is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and the arrangement of the carbon atom with (S) is S
The pyrrolidine derivative according to claim 3, which is represented by 5. A general formula: (A in the formula is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and the arrangement of the carbon atom with (S) is S
The pyrrolidine derivative according to claim 3, which is represented by