JPS6272660A - Pyrrolidine derivative and salt thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R1 is H or lower alkyl; R2 is H, lower alkyl or acyl which may be substituted by halogen; R3 is halogen, lower alkyl or lower alkoxy) and salt thereof. EXAMPLE:cis-3-Acetylaminomethyl-4-chloropyrrolidine. USE:An intermediate for producing pyridonecarboxylic acid derivatives having antimicrobial activity. PREPARATION:A compound expressed by formula II (Z is -CH2N3 or -CN) or formula III (R'2 is acyl group) is reduced in the presence of a reducing agent, e.g. Pd-C or Raney Ni, in a solvent, e.g. THF or methanol, at 0-80 deg.C for 30 min-24hr while stirring. If R is a protecting group, it is removed from the resultant reaction product to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel pyrrolidine derivatives and their salts, which are valuable intermediates in the production of pyrido-7-carboxylic acid derivatives with excellent antibacterial activity.

The compound of the present invention is produced by the following general formula (where R+14 means a hydrogen atom or a lower alkyl group, R2 means a hydrogen atom, a lower alkyl group, or an acyl group optionally substituted with a halogen atom, and R means a halogen base, a lower alkyl group, or a lower alkoxy group) and a salt thereof.

In this specification, lower alkyl group and lower alkoxy μ mean alkyl μ and alkoxy group having 1 to 6 carbon atoms, and halogen atom means fluorine, H;
It means i or bromine. Moreover, the acyl group means an acyl group having 1 to 6 carbon atoms. Halogen 0
An example of an acyl group which may be substituted with a substituent is a formyl group.

Examples include an acetyl group, a propionyl group, a pivaloyl group, a monochloroacetyl group, a dichloroacetyl group, a trichloroacetyl group, a trifluoroacetyl group, and the like.

Examples of the salts of the compounds of the present invention include acetic acid and lactic acid.

Examples include salts with organic acids such as succinic acid, oxalic acid, and methanesulfonic acid, and salts with inorganic acids such as hydrochloric acid, phosphoric acid, and sulfuric acid.

Since the compound of the present invention has an asymmetric carbon atom on the pyrrolidine ring, it exists as an optically active compound. Therefore, these optically active substances are included in the compounds of the present invention.

Furthermore, some of the compounds of the present invention have multiple asymmetric carbon atoms on the pyrrolidine ring, which exist as different stereoisomers.

These stereoisomers and mixtures thereof are also included in the compounds of the present invention.

The method for producing the compound of the present invention will be explained below.

(Emperor) The compound of the present invention in which R2 is a hydrogen atom or a lower alkyl group in the general formula [1] has the following general formula (wherein, Z means -CH2N3 or -CN, and R is a hydrogen atom or a protective group). and R3 is the same as above) or a compound represented by the following general formula (wherein R2 means an acyl group and R, Rt and R3 are the same as above) It can be produced by reducing [■] and, when R is a protecting group, removing the protecting group by a conventional method.

In this reaction, the raw material compound is mixed in a solvent in the presence of a reducing agent from 0 to
This can be carried out by stirring at 80°C for 30 minutes to 24 hours.

As the reducing agent, hydrogen, lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, etc. are used, for example, in the presence of a catalyst such as palladium carbon, Raney nickel, or platinum oxide.

The solvent may be appropriately selected depending on the raw material compound, the reducing agent used, etc., and examples include ether, tetrahydrofuran, toluene, methanol, ethanol, and vinegar.

Water etc. are used.

The raw material compound [■] can be produced by the method described in Reference Examples or a method analogous thereto.

The raw material compound [m] can be produced by reaction (3) described later.

(2) In the general formula [1], the compound of the present invention in which R3 is a halogen [child] may be expressed by the following general formula (where R, R1,
R2 is the same as above, and it can be produced by replacing the hydroxyl group of the compound [■] with a halogen atom, and when R is a protecting group, removing the protecting group by a conventional method.

In this reaction, the compound of formula [IV] and a halogenating agent (for example, thionyl chloride, phosphorus trichloride, phosphorus tribromide, hexafluoropropene-diethylamine diethylaminosulfa trifluoride, etc.) are mixed in a solvent or in the absence of a solvent. ~1
This can be carried out by reacting at 50°C for 20 minutes to 5 hours. Examples of solvents include ether, dichloromethane, and chloroform.

Be/ze/, toluene, etc. are used.

Starting compound [IV] can be produced by the method described in Reference Examples or a method analogous thereto.

(3) In the general formula [I], the compound of the present invention in which R2 is an acyl group is represented by the following general formula R' (wherein R1 means a protecting group, and RI and R3 are the same as above) It can be produced by acylating compound [V] and then removing the protecting group by a conventional method.

This reaction can be carried out by reacting the compound of formula [V] with an acylating agent at 0 to 150°C for 10 minutes to 12 hours in a solvent or without a solvent. Examples of the acylating agent include commonly used acylating agents such as acid anhydrides such as acetic anhydride and trifluoroacetic anhydride, and acid chlorides 9 such as acetyl chloride. As a solvent, chloroform, acetone, tetrahydrofuran, acetonitrile, toluene,
Pyridine.

Water 2 grade is used. This reaction may also be carried out in the presence of an acid acceptor such as caustic alkali, alkali carbonate, alkali bicarbonate, triethylamine, pyridine, or the like.

Raw material compound [V] can be produced by the reaction (11 or 2) described above.

The protecting groups used in each of the above reactions may be appropriately selected depending on the reaction conditions, and for example, protecting groups commonly used in the chemistry of β-lactam antibiotics, peptides, or nucleic acids are used.

The compound of the present invention produced in this way is isolated and purified according to conventional methods, and depending on the conditions, it can be obtained in the form of a salt or a free base, but these can be interconverted depending on the purpose. A compound of the present invention is prepared in the following form.

The compounds CI thus obtained are all new compounds and are valuable as intermediates for the production of pyrido-l carboxylic acid derivatives having excellent antibacterial activity.

Taking the 1,8-naphthyridine derivative of the compound of the present invention as an example, the production of the pyridonecarboxylic acid derivative is illustrated as follows.

According to this reaction formula, the compound [■] of the present invention is added to the compound [■].
VI] to obtain an ester of formula [■], which is further hydrolyzed to give carboxylic acid [■]! You can make two.

The compound of formula [■] obtained here has extremely excellent antibacterial activity and is a valuable compound as an antibacterial agent, especially as an injectable antibacterial agent.

Next, the method for producing the compound of the present invention will be explained with reference to Examples and Reference Examples.

Reference example 1 (1)! = Be/Gi-3-hydroxy-4-hydroxymethylpyrrolidine 110g, ) ethylamine 5
A solution of 0.9 g of methanesulfonyl chloride G in chloroform (00 ml) was added dropwise to a mixture of 3.7 g of methanesulfonyl chloride G and 11 of chloroform while stirring under water cooling at 3 to 6°C. 1
After stirring for an hour, saturated aqueous sodium bicarbonate solution 2001
Add '' to separate the chloroform layer. The chloroform layer was extracted with a 10% acetic acid aqueous solution, and the aqueous layer was diluted with 50% 6
After making alkaline with gamma soda water + 8 liquids, extract with chloroform. After drying, the solvent was distilled off to obtain 81 g of 1-benzyl-3-hydroxy-4-methylsulfonyloxymethylpyrrolisif as an oil.

Summer R spectrum (liquid!Z) cs-': 3370
', 1'350° 1170° Mass spectrum m/z: 285 (M"),
208°190, 91° NMR spectrum (CDCl3) δ: 3.0 (31-
1°s, 5O2CH3), 7.32(5H,
s, CeHs).

■ Add 50 g of the above compound to 200 g of dimethylformamide.
1 and add 22.8g of sodium azide to 12
Heat and stir at 0 to 130°C for 2.5 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ether. The ether layer was washed with water, dried and concentrated to give 3-azidomethyl-1
-30 g of benzyl-4-hydroxypyrrolidine are obtained as an oil.

IR spectrum (liquid film) am-': 3350.21
00. +450°12 (15.

Mass spectrum m/z: 232 (M”),
175°158, 91° NMR spectrum (CDCl3) δ: 3.30 (2
H, d, J"7H2, Cl2N3), 3.58 (2H.

S, Ct12Ph), 7.31 (51-1, S
, Calls).

(3) 8.0 g of the above compound is dissolved in chloroform 601, and thionyl chloride IO, Og is added dropwise while stirring.

The reaction mixture is heated under reflux for 2.5 hours and then concentrated under reduced pressure. Water and ethyl acetate were added to the residue, and the pH was adjusted to 9.0 or higher with a 40% aqueous solution of caustic soda, and the organic layer was separated. After drying, the solvent was distilled off, and the residue was separated and purified by column chromatography. Azidomethyl-1-benzyl-4
- 0.9 g of trans isomer and 4.6 g of cis isomer of chloropyrrolidine are obtained as oils.

Trans form: IR spectrum (liquid YX) cs-':
2800°2100, 740.700° Mass spectrum m/z: 250 (M”),
158.9+.

NMR spectrum (CDCl3) δ: 3. [i[i
(2H,s, CH2Ph), 4.05 (L
H, m, Ca-H), 7.34 (5H, S
, CaHs).

Cis form: IR spectrum (liquid film) cs-': 28
80°2300.740,700°'7X-x vector m/z: 250 (M”)
, 158.91° NMR spectrum (CDC13) δ
: 3.72 (2H,s, CH2Ph), 4.5(
I H, m, Ca-〇), 7.34 (5H, s,
CeHs).

Example 1 0) Dissolve 113.0 ml of a 70% toluene solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene/151, and add cis-3 to this while cooling with water.
A solution of 7.2 g of azidomethyl-1-benzyl-4-chloropyrrolidine in Toluev (15 ml) was added dropwise and stirred at room temperature for 2 hours. Ice water was added to the reaction mixture, and then made alkaline with a 20% aqueous solution of caustic soda, followed by toluene. The layers are separated and dried and concentrated to give cis-3-aminomethyl-1-benzyl-4-chloropyrrolidine as an oil.

Similarly, trans-3-aminomethyl-1-benzyl-4-chloropyrrolidine is obtained from trans-3-azidomethyl-1-benzyl-4-chloropyrrolidine/.

■ Dissolve the above compound (cis form) in 5o1 of toluene,
Add ice water and 20% caustic soda aqueous solution to this.
After setting I to 9.0 or more, 5.9 g of anhydrous vinegar fi is added. After 30 minutes, separate the Ia layer and extract with 2N hydrochloric acid.

After making the aqueous layer alkaline with 40% caustic soda aqueous solution,
Extract with ethyl acetate. After drying the ethyl acetate solution, it was condensed under reduced pressure to obtain 75.8 g of cis-3-acetylamide/methyl-1-pe/zi-4-ri-alopyrrolidi as an oil.

Summer R spectrum (liquid film) cm-': 3300.1G
50.700゜Mass spectrum m/z: 2GG
(M”), 158.91°NMR spectrum (C
DCl3) δ: 3.13 (21-1°s, Hz
Ph), 4.1 (lH,m, C4-H).

7.3 (58*S, C5Hs).

Similarly, from the above compound (trans form), trans-
3-acetylaminomethyl-1-benzyl-4-chlorovirolidi/ is obtained as an oil.

IR spectrum (liquid film) cm-': 3300.1
85j), 700° mass spectrum m/z: 2
00 (M”), 158.91° NMR spectrum (CDCl3) δ: 3.71 (211.

s, CH2Ph), 4.48 (IH,
m, C4-1-1).

7.33 (5H, s, CeHs).

(3) Add 17.7 g of the above compound (cis form) to 5 ml of acetic acid.
01, add 4001 g of 5% palladium-carbon, and hydrogenolyze under a hydrogen stream. After acetic acid is distilled off under reduced pressure, acetonitrile is added and left to stand. The precipitated crystals are collected by filtration to obtain 7 g of cis-3-acetylaminomethyl-4-chloropyrrolidine acetate.

m, p, 130-137°C.

Similarly, trans-3-acetylaminomethyl-4-chloropyrrolidine is obtained from the above compound (trans form).

Reference Example 2 64 g of hexafluoropropene-diethylamine is added to a solution of 32 g of 3-azidomethyl-1-benzyl-4-hydroxypyrrolidine in chloroform (300 ml), and heated under reflux for 2 hours while stirring. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, and extracted with 15% hydrochloric acid.

The aqueous layer is made alkaline with a 20% aqueous sodium hydroxide solution while cooling, and extracted with ethyl acetate.

The extract was dried and concentrated, and the residue (29 g) was separated and purified by column chromatography to obtain the following compound as an oil.

Trans-3-azidomethyl-1-benzyl-4-fluoropyrrolidine: 3.5 g IR spectrum (liquid film) Country: 2 00.1450.
127G.

Mass spectrum m/z: 234 (M”),
177,91°NMR spectrum (CDCl!l)
δ-: 3.04 (2H.

s, CH2Ph), 4.5.5.2 (IH,
br, Ca-H), 7.30(5H,s, C
aHs).

Cis-3-azidomethyl-■-be/giru-4-fluoropyrrolidine: 3. Og IR spectrum (liquid film) cs-': 2100.14
50. +270° mass spectrum m/z: 234
(M”), 17?, 91° NMR spectrum (
CDC1a) δ: 3.88 (21-1°s, CH2
1'h), 4.75.5.45 (I H, br,
Ca-H), 7.30(5H,s, CeHs
).

Mixture of cis and trans isomers: 7.3g Example 2 (1) Trans-3 obtained from 3.1g of trans-〇-azidomethyl-1-benzyl-4-fluoropyrrolisiph in the same manner as in Example 1 (1) -aminomethyl-1-
Benzyl-4-fluoropyrrolidine and acetic anhydride 71 are reacted in the same manner as in Example 1 (2) to obtain 2.2 g of trans-3-acetylaminomethyl-1-benzyl-4-fluoropyrrolidine as an oil.

IR spectrum (liquid film) cm-': 3270.1B
50.1550°vsll 2 vector m/z: 2
50 (M”), 158.91° NMR spectrum (CDCl3) δ: 1.96 (3H.

s, C0CH5), 3. Gl(2H,s,CH2Ph)
.

4.52.5.22 (I H, br, Ca-H)
, 7.30 (5H,s, CaHs).

Similarly, cis-3-azidomethyl-1-benzyl-
From 4-fluoropyrrolidine, cis-3-acetylaminomethyl-! -Be/Gi-4-fluoropyrrolidine is obtained as an oil.

IR spectrum (liquid film) cs-': 3270.10
50.1550°Mass spectrum m/z: 250
(M”), 158.91°NMR spectrum (
CDCl3) δ: 1.98 (311°s, C0
CHa), 3.613(2H,s, CH*P
h) +4.75, 5.48 (I H, br, C4-H
), 7.31 (5H.

s, C5Hs).

(2) In the same manner as in Example 2, cis- and trans-3-acetylaminomethyl-4-fluoropyrrolidine is obtained from cis- and trans-3-acetylaminomethyl-1-be/di-4-fluoropyrrolidine.

Reference Example 3 (1) 145 g of trimethylsulfoquinium iodide was mixed with 60 g of dimethyl sulfoxide while stirring under a nitrogen stream.
01 and add 25g of 639A sodium hydride to this.
Add in 15 minutes. After 10 minutes, the reaction solution was purified with 105 g of 1-benzyl-3-oxopyrrolisif in dimethyl sulfoxide (100 ml) tB solution over 10 minutes, and then 700 ml of toluene was added. Add water 6001. Separate the toluene layer, dry and concentrate under reduced pressure. The residue was distilled under reduced pressure, and 5
-Benzyl-1-oxal 5-azaspiro[2,4]hebutane 78 g are obtained.

b, P, 130-135°C 73.5-■11g.

1R spectrum (liquid film) cm-': 2980.28
00. H2O.

700° mass spectrum m/z: 189 (M”), 1
59.91゜■ The above compound Bog was heated to 70°C while stirring with water cooling.
% fluoride water cord-Viridin in 10 minutes. After 5 hours, the reaction solution was poured into 400ml of ice water and made alkaline by adding 12,100ml of 30% caustic soda in water. The precipitate was filtered off and the filtrate was extracted with chloroform. The extract was dried and concentrated to obtain l-benzyl-3-fluoro-3.
-Mixture of hydroxymethylpyrrolidine and 1-benzyl-3-fluoromethyl-3-hydroxypyrrolidine 05
get g. This mixture was mixed with 14.4 g of acetic anhydride in pyridine.
Acetylation is performed to obtain 08 g of an oil.

This is separated and purified by column chromatography to obtain 38 g of 3-acetyloxymethyl-1-benzyl-3-fluoropyrrolisif. Methanol 1001 to this compound
Add 100 ml of lθ% caustic solution and heat under reflux for 10 minutes. After adding 1001 parts of water and 300 parts of chloroform to the reaction solution, the chloroform layer was concentrated. The residue was distilled under reduced pressure to obtain 18.0 g of l-be/gi-3-fluoro-3-hydroxymethylpyrrolidine.

b, p, 133-137℃/1 Seal ■l1gIR
Spectrum (liquid film) cs-': 3350.1050
．． 700° mass spectrum m/z: 209 (M”
), 132.91° (3) 2.6 g of the above compound
Add 1.20 g of triethylamine to the chloroform (2011) EFI solution under water cooling (!: l 9 y y.

Add 1.2 g of sulfonyl chloride and stir for 16 hours.

Add 201 g of water to the reaction solution, separate the chloroform layer, dry and concentrate, and separate and purify the residue by column chromatography to obtain 3.2 g of ■-Be/True 3-fluoro 3-methylsulfonyloxymethylpyrrolidine as an oil. obtain.

IR spectrum (liquid film) cm-': 1350.12
70.700°Mass spectrum m/z: 287
(M”), 192.91°NMR spectrum (C
DC1a > δ: 3.05 (3H.

s,'5OzCH3), 3.05(2H,s
, Cl-12Ph).

(4) 3.1 g of the above compound, 1.1 g of sodium azide.
4g.

A mixture of dimethylformamide 301 and 120 to 130
Stir at ℃ for 3 hours. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. After pouring 20 l of water and 20 l of chloroform into the residue for 7 min, the chloroform layer was dried and concentrated. The residue was separated and purified by column chromatography to obtain 3-azidomethyl-1-
2.0 g of benzyl-3-fluoropyrrolisif are obtained as an oil.

IR spectrum (liquid film) α”: 1350.1270.
700° mass spectrum m/z: 287 (M”
), 210.91° NMR spectrum (CDCl
5) δ: 3.05 (3H.

s, 5O2CH3), 3.05(2H,s
, ChzPh).

7.30 (5H, s, C5Hs).

Example 3 (1) 70% toluene solution of 2.0 g of 3-azidomethyl-1-benzyl-3-fluoropyrrolidine and sodium bis(2-methoxyethoxy)aluminum hydride 2
Using 0-1, reaction treatment was carried out in the same manner as in Example 1 (1),
3-aminomethyl-1-benzyl-3-fluoropyrrolidine is obtained.

(2) After the above compound and 1.1 g of acetic anhydride were reacted in the same manner as in Example 1■, they were separated and purified by column chromatography, and 3-acetylamitumedel-1-benzyl-
1 g of 3-fluoropyrrolidine+ was obtained as an oil.

Iris R spectrum (liquid film) as-': 3150.16
50.1550°700°Mass spectrum m/z: 250 (M”),
230.91°NMRX hex)/k (CDCIs)
6: J, 18 (3H.

s, C0CH! l), 3.06(2H,s
, CH2Ph).

7.30 (5H, 'A, CaHs).

(3) 3.7 g of the above compound and alcohol (80 ml)
>Add 300 g of 5% palladium-carbon to the solution and hydrogenolyze it at 50-60°C under a hydrogen stream. Filter off the catalyst 1
:? The solvent i was distilled off to give 3-acetylaminomethyl-3-
2.3 g of fluoropyrrolisifu are obtained.

m, 9.122-125°C.

Reference Example 4 Trans-3-azidomethyl-1-benzyl-4-hydroxymethyl di:, ;lQg was added to 50% of tetrahydrofuran.
1 and 2.1 g of 60% sodium hydride under water cooling.
and 7.3 g of methyl iodide. After stirring for 2 hours,
Water was added and extracted with ether. After distilling off the ether, the residue was separated and purified by column chromatography to obtain trans-3
4.7 g of -azidomethyl-1-beacyl/-4-methoxypyrrolidine are obtained as an oil.

IR spectrum (liquid 112) cm-': 230
0°Mass spectrum m/z: 240 (M”)
, 158° NMR spectrum (CDC1a) δ:
3.30 (3II.

s, 0CH3), 3.00(2H,s, C
H2Ph) +7.28 (5H, s, CeHs)
.

Example 4 (dish) trans-3-azidomethyl-1-benzyl-4
-4.7 g of methoxypyrrolidine and sodium bis(2-
Trans-3-aminomethyl-1-benzyl-
4-Methoxypyrrolidine is obtained.

(2) The above compound and 5.6 g of acetic anhydride were added in Example 1 (
2), trans-3-acetylaminomethyl-1-be/gi-4-methoxypyrrolidine 4
．． 4 g are obtained as an oil.

IR spectrum (liquid film) cs-': 3300°Mass spectrum m/z: 2 (+2 (M"), 1
71.158°NMR spectrum (CDCl3) δ:
1.98 (3H.

s, C0C) Seal 3), 3.28 (3H,
s, 0CH3).

3.00 (2Ii, s, C)IzPh), 7
．． 25 (5H.

s, CaHs) (3) In the same manner as in Example 2, trans-3-acetylaminomethyl-4-methoxypyrrolidine is obtained from trans-3-acetylaminomethyl-1-benzyl-4-methoxypyrrolidine.

Reference example 5 (J)N-(2-cyanoethyl)be/zylamine 32g
was dissolved in 120 ml of acetonitrile, 32 g of sodium carbonate and ethyl chloroacetate were added thereto, and the mixture was heated under reflux for 13 hours with stirring. After filtering off the insoluble matter, the solvent is distilled off, and 200 ml of toluene and water are added to the residue.

The toluene layer was separated, washed with 10% acetic acid aqueous solution, dried, and the solvent was distilled off to give N-ethoxycarbonylmethyl-N-(
41 g of 2-cyanoethyl)benzylamine are obtained.

(2) Dissolve 28 g of the above compound in 200 ml of toluene and dropwise add a 28% methanol solution of sodium ethoxide a281 at room temperature. Heat at 70° C. for 1 hour and then cool. Take 4 precipitated crystals, wash with toluene, and give 1-
20 g of sodium salt of Be/Giro-3-cyano-4-oxopyrrolidine are obtained.

m, 9.207-210°C (decomposition) IR spectrum (KIlr) cm-': 2170
．． 1500° (3) 100g of the above compound and 150g of water
■To the mixture of 1 at 12 to 15°C, add 1Nz7 sodium aqueous solution (JOOml) containing sodium boron hydride IO[
Add. A mixed solution of 5611 acetic acid and 20011 water was added dropwise and extracted with chloroform.

After drying and concentrating the extract, the residue was left in inpropyl alcohol for 17 hours. The precipitated crystals were removed, the 4 liquid was concentrated, and trans-1-benzyl-4-hydroxy-3-
750 g of cyanopyrrolidi are obtained as an oil. (Quartz crystal contains about 10% of crystals.) IR spectrum (liquid G)
CI+-': 3430, 2240, 700.

-PX- x vector rr1/z: 202 (M”)
, 91. 42-(4) The above compound 5 (1 g was mixed with alcohol 1501 and 12% alcoholic ammonia 10
Catalytic reduction is carried out in 0 ml using Raney nickel 131 as a catalyst. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the trans-
48 g of 3-aminomethyl-1-benzyl-4-hydroxypyrrolidine are obtained as an oil.

2 oxalate: m. p. 107 ~ 1℃.

Example 5 (1) - Thionyl chloride 531 and rjoform 300
1 and trans-3-7minomethyl-1-
A solution of 50 g of benzyl-4-hydroxypyrrolidine in chloroform (200 ml) is added dropwise at 80°C. After heating and refluxing for about 3.5 hours while stirring, the reaction solution was reduced to about half its volume, and 200 ml of water was added dropwise thereto. Separate the water layer and 50%
Make alkaline with aqueous caustic soda solution and extract with ethyl acetate. The t[Il eluate was dried and concentrated to give cis-3-aminomethyl-1-benzyl-4-chloroapyridine 4FN.
get r.

The crystal is made into a 7-udate salt in a mixed solvent of dioxane and water,
Recrystallize to give cis-3-aminomethyl-1-benzyl-
74 g of 4-chloropyrrolidine dioxalate are obtained.

m, p, 150-159°C.

(2) Cis-3-aminomethyl-1-benzyl-4-
Chloropyrrolidine dioxalate ia, eg is suspended in water, an aqueous solution containing 12 g of caustic potassium is added thereto, and the mixture is extracted with chloroform. After drying the extract, 4.4 g of acetic anhydride is added. The reaction solution is extracted with 10% hydrochloric acid, the extract is made alkaline with 40% aqueous sodium hydroxide solution, and then extracted with chloroform.

The chloroform solution is dried and concentrated to obtain 7.7 g of cis-3-acetylaminomethyl-1-benzyl-4-chloropyrrolidine. The crystal was the same as that obtained in Example 1(2).

(31 10 g of cis-3-aminomethyl-1-benzyl-4-chloropyrrolidine dioxalate is suspended in water [101] and hydrolyzed with GO'C using palladium on carbon. The catalyst is removed by filtration. After concentration, alcohol is added. The precipitated crystals are collected by filtration to obtain 5.6 g of cis-3-aminomethyl-4-chloropyrrolidine dioxalate.

m, 9.199-201°C (decomposed) NMR spectrum (DMSO-do) δ: 4.95
(IH, bs, C4-H) - Reference example 6 (1) N-(2-cyanoethyl)benzylamine 40
g,) 56 g of ethylamine, 3001 g of acetonitrile
746 g of chloroacetate and acetonitrile (8
0 ml) solution dropwise. After the dropwise addition, the mixture was heated under reflux for 6 hours, and the precipitate was filtered off. After evaporation of the solvent, the residue is dissolved in chloroform and extracted with IN hydrochloric acid. The hydrochloric acid layer is made alkaline with a 20% aqueous sodium hydroxide solution and extracted with chloroform. After drying, the solvent was distilled off to give N-acetonyl-N-(
30 g of 2-cyanoethyl)benzylamine are obtained as an oil.

IR spectrum (liquid film) am-': 2250.17
10.740°mass spectrum m/z: 21G (
M”), +97.91°NMR spectrum (CDC
l3) δ: 2.10 (3H,s, C0CH
5).

(2) To a solution of 9.0 g of the above compound in methanol (150 ml) was added 0.9 g of sodium boron hydride, and the mixture was heated overnight. The solvent was distilled off, chloroform and water were added,
Dry the chloroform layer for a minute. The solvent was distilled off, and the residue was separated and purified by column chromatography to obtain 7.3 g of N-(2-cyanoethyl')-N-(2-hydroxypropyl)benzylamine as an oil.

Mass spectrum m/z: 218 (M”), 1
73.91°NMR spectrum (CDCl3) δ:1
．． 12 (3H, d, J=7Hz, CH-CH
a), 7.30 (5H, S, Ca1(s)
.

(3) 27.5 g of the above compound in chloroform (30
Add 30 g of thionyl chloride dropwise to the d3 solution and heat under reflux for 1 hour. After cooling, add ice water, make alkaline with 50% caustic soda aqueous solution, and separate the chloroform layer. After drying, chloroform was distilled off to obtain N-(2-chloropropyl)-2
-24 g of cyanoethylbenzylamine are obtained as an oil.

IR spectrum (liquid 112) cs-': 225
0.1450.740°mass spectrum m/z:
230 (M”), 190.91° NMR spectrum (CDCl3) δ: 1.50 (31 (.

d, J=7Hz,,C)■-CHa),
3.70 (2H.

s, CH2Ph), 7.30(5H,s,
C5)(s).

(4) Dimethyl sulfoxide 1001 and toluene 2
Dissolve 10g of potassium t-butoxide in the mixture of 00■1, and add 20g of the above compound in toluene (300ml).
After adding the solution dropwise, set it up overnight. Add water to separate the toluene layer, wash with water, and dry. The solvent is distilled off, and the residue is separated and purified by column chromatography to obtain the following compound as an oil.

trans-1-be/gi-3-thia/-4-methylpyrrolidine: 3.13g IR spectrum (liquid film) cm-': 2240. +
450.700°Mass spectrum m/z: 200
(M+), 133.91°NMR spectrum (C
DCl3) δ: 1.15 (3H, d, J=OH
z, , CH-CH3) , 3.00 (21-㽽, s, CH2Ph), 7
．． 30 (5H,s, CoHs).

cis-1-benzyl 3-cyano-4-methylpyrrolidiy
: 1. Og IR spectrum (liquid 112) cs-': 2240.
1450.700°Mass spectrum m/z: 200
(M”), 133.91°NMR spectrum (C
DCl3)δ: 1.21 (3H.

d, J”GHz, ,Cl-CHl)
, 3.00 (2H.

s-, CI*Ph), 7.30 (5H,s,
CaHs).

Mixture of trans isomer and cis isomer: 11 g Example 6 (凰) 1.0 g of cis-1-benzyl-3-cyano-4-methylpyrrolidine was hydrolyzed using 11 alpha nickel as a catalyst. 4 catalysts
After removal, the solvent was distilled off to give cis-3-aminomethyl-1
-benzyl-4-methylpyrrolidine is obtained as an oil.

Vortex-like, trans-1-benzyl-3-cyano-4
-Methylpyrrolidine to trans-3-aminomethyl-
1-benzyl-4-methylpyrrolidine is obtained.

(2) Dissolve the above compound (cis form) in 201 ml of chloroform and add 0.71 ml of acetic anhydride. After 1 hour, 10% aqueous sodium hydroxide solution was added to separate the chloroform layer, and the dried chloroform was distilled off to obtain 1.2 g of cis-3-acedelaminomethyl-1-benzyl-4-methylpyrrolidine as an oil. .

IR spectrum (liquid H) cs-': 3300,
I (+50, +550.

700.

Mass spectrum m/z: 240 (M”)
, 174, 91.

NMR spectrum (CDCl3) δ: 0.95 (3
1(.

d, J=THz. 7CH-CH3), 1.
'94 (3H, s.

COCH3), 7.25 (5H, s
, CoHs).

Similarly, trans-3-acetylaminomethyl-1-benzyl-4-methylpyrrolidine is obtained as an oil from the above compound (trans form).

IR spectrum (liquid film) cm-': 3300, +
050, 1550.

700.

Mass spectrum m/z: 240 (M”),
+59. 91.

NMR spectrum (CDC13) δ: 1.05
(3 1-1.

d, J=O)Iz,nCll-CI+),
1.95 (3H, s.

COCH3), 7.28 (5 1-1, s
, CeHs).

(3) In the same manner as in Example 2, cis- and tra/
Cis- and trans-3-acetylaminomethyl-1-be/di-4-methylpyrrolidine give cis- and trans-3-acetylamino-7methyl-4-methylpyrrolidi/.

Example 7 (1) Cis-3-azidomethyl-1-benzyl-4
-4.5 g of fluoropyrrolidine was added to sodium bis(2-
Methoxyethoxy)aluminum hydride was added dropwise to a mixture of 35ml of 70% toluene tB solution and 50ml of toluene under water cooling. After being left at room temperature for 2 days, ice water and 20% caustic soda aqueous solution 31 are added thereto. The toluene layer is separated, dried and condensed to obtain 5 g of cis-3-aminomethyl-1-benzyl-4-fluoropyrrolidine as an oil.

■ 201 parts of 100% formic acid is water-cooled, and 12 parts of acetic anhydride is added to this.
Add 1. Add 5 g of the above compound to this mixture and add about 1
Stir for an hour. Concentrate under reduced pressure, make alkaline by adding saturated aqueous sodium carbonate solution, and extract with chloroform. The extract was dried and concentrated to give cis-1-benzyl-4
-Fluoro-3-formylaminomethylpyrrolisif 4g
get.

IR spectrum (liquid film) am-': 3300.
1070, 700.

Mass spectrum m/z: 236 (M”),
158. 9+.

NMR spectrum (CDC13) δ: 3.65
(2 II.

s. HzPh), 5.12 (IH,brd.J=56
Ht).

7, 30 (5H, 'J, CoHs)
.

(3) Dissolve 4 g of the above compound in 201 g of toluene.

70% toluene solution of sodium bis(2-methoxyethoxy)aluminum hydride 301 and toluene 301
Cool the mixture with water, and add the above solution dropwise to it. After standing overnight at room temperature, ice water and 20% aqueous sodium hydroxide solution were added, the toluene layer was separated, dried and concentrated to obtain cis-1-benzyl-4-fluoro-3-methylaminomethylpyrrolidine as an oil.

(4) Dissolve the above compound in 50 1 carbonate of toluene, add 81 parts of trifluoroacetic anhydride while cooling with water, and leave to stand for about 1 hour. The reaction solution was washed with a saturated aqueous sodium bicarbonate solution, the solvent was distilled off under reduced pressure, and the residue was separated and purified by column chromatography to obtain cis-1-be/zi-4-fluoro-3-(N-)IJ fluoroacetyl. ) 2.4 g of methylaminomethylpyrrolidine are obtained as urafushimono.

IR spectrum (liquid film) cs-': 1090.11
90.700°Mass Spectrum m/z: 31B C
M”), 241.91° NMR spectrum (CDC
l3) δ: 3.15 (3H.

br, N-C1h), 3.08 (2H,s
, CHgPh).

7.30 (5H, s, CaHs).

6) In the same manner as in Example 2, cis-1-benzyl-4
-Fluoro-3-(N-)lifluoroacetyl)methylaminomethylpyrrolidine to cis-4-fluoro-3-
, (N-)lifluoroacetyl)methylaminomethylpyrrolidine is obtained.

Example 8 (1) 3-acetylaminomethyl-1-benzyl-4
-3.0 g of fluoropyrrolidine and sodium bis(2-
Using 0% toluene solution 301 of (methoxyethoxy)aluminum hydridonor, reaction treatment was carried out in the same manner as in Example 7 (3) to obtain cis-1-benzyl-3-ethylaminomethyl-4-fluoropyrrolidine.

(2) Using the above compound and trifluoroacetic anhydride 01, cis-1-be/gi-4-
72.4 g of fluoro-3-(N-)lifluoroacetyl)ethylaminomethylvirolidium are obtained.

IR spectrum (liquid film) am-': 1090.1+
40° mass spectrum m/z: 332 (M+)
, 255.91° NMR spectrum (CDCl3
) δ・: 5.10 (IH,br d, J:GO
H2,C4-H), 7.33 (5H,S,
CoHs).

(3) In the same manner as in Example 2, cis-4-fluoro-
3-(N-trifluoroacetyl)ethylaminomethylpyrrolidine is obtained.

Reference Example 7 (1) From 3.5 g of cis-3-acetylaminomethyl-1-benzyl-4-chloropyrrolidine, Example 1 (
Cis-3-acetylaminomethyl-4-chloropyrrolidine obtained in the same manner as in 3) is dissolved in acetonitrile 501. To this, 7-chloro-1-cyclopropyl-6-
3.3 g of ethyl fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate and 81 g of triethylamine were added, and the mixture was heated under reflux for 1 hour. - After standing at room temperature overnight, collect the precipitated crystals as d2. The crystals are dissolved in a mixture of water and chloroform at a ratio of 1/2 g, shaken, the chloroform layer is separated, dried, and the chloroform is distilled off. The residue was recrystallized from acetonitrile to give 7-(cis-3-acetylami/methyl-4-chloro-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-
4.6 g of ethyl oxo-1,8-naphthyridi/-3-carboxylate are obtained.

m, 9.213-214°C.

(2) Add 20% hydrochloric acid 2θ 1 to 2.0 g of this compound and heat under reflux for 2 hours. Hydrochloric acid is distilled off under reduced pressure, and ethanol is added to the residue. The precipitated crystals were collected by filtration to give 7-(cis-3-aminomethyl-4-chloro-1=pyrrolidinyl)-17cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine- 1.55 g of 3-carboxylic hydrochloride are obtained. m, 9.243
~248°C (decomposed).

(3) Dissolve 1.0 g of this compound in water, add saturated aqueous sodium bicarbonate solution to adjust the pH to 7.5 to 8.0, and cool. The crystals were collected by filtration and recrystallized from a chloroform-methanol mixture to give 7-(cis-3-aminomethyl-
4-Chloro-1-pyrrolidinyl)-1-cyclopyl-6-fluoroC1-1,4-dihydro-4-oxo-1
, 0.7 g of 8-naphthyridine-3-carboxylic acid are obtained.

m, 9.174-177°C.

Similarly, the following compounds are obtained.

Reference example 8 trans-3-acetylaminomethyl-4-chloro-1
- The following compounds are obtained from pyrrolidine.

(1) 7-() Lance-3-acetylamide/methyl-4
-chloro-1-pyrrolidinyl)-1-cyclopropyl-
6-Fluoro-1,4-dihydro-4=oxo-1,8
-Ethyl naphthyridine-3-carboxylate, m, p,
203-206°C.

(2) 7-()U/su-3-ami/methyl-4-chloro-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3 -Carboxylic acid.

m, p, 222-224°C (decomposition).

Reference example 9 cis-3-acetylaminomethyl-4-fluoro-1-
The following compound is obtained from pyrrolidine.

(1) 7-(cis-3-acetylamide/methyl-4-
Fluo (1-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,
Ethyl 8-naphthyridine-3-carboxylate, m, p
, 179-181°C0(2) 7-(cis-3-aminomethyl-4-fluoro-1-pyrrolidinyl)-1-
cyclopropyl-6-fluoro-1,4-dihydro-4
-Oxo-1,8-naphthyridine-3-carboxylic hydrochloride.

m, P, 284-286°C (decomposed).

(3) 7-(cis-3-aminomethyl-4-fluoro-
(1)-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.

m, 9.217-218°C.

Reference example lO trans-3-acetylaminomethyl-4-fluoro-
The following compound is obtained from 1-pyrrolidi/.

(1) 7-(trans-3-acedelaminomethyl-
4-fluoro-1-pyrrolidinyl)-1-cycloprobyl-6-fluoro-1,4-dihydro-4-oxo-1
, ethyl 8-naphthyridine-3-carboxylate, m,
9.211-213°C.

■ 7-(trans-3-aminomethyl-4-fluoro-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-okine-1,8-naphthyridine-3-carboxylic hydrochloride , m, p, 209
~272°C (decomposed).

Reference Example 11 The following compound is obtained from 3-acetyl-1-minomethyl-3-fluoro-1-pyrrolidine.

(J) 7-(3-acetylaminomethyl-3-fluoro-1-pyrrolidinyl)-1-cyclopropyl-6-2luoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl.

m, 9.214-215°C.

■ 7-(3-aminomethyl-3-fluoro-l-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,
4-dihydro-4-oxo-1,8-naphthyridine-3
-Carboxylic hydrochloride.

m, p, 272-279°C.

(3) 7-(3-aminomethyl-3-fluoro-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1
,4-dihydro-4-oxo-1,8-naphthyridine-
3-carboxylic acid.

m, I), 229-232°C.

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, R_1 means a hydrogen atom or a lower alkyl group, R_2 is substituted with a hydrogen atom, a lower alkyl group, or a halogen atom. means a good acyl group, R_3
means a halogen atom, a lower alkyl group or a lower alkoxy group. ) Pyrrolidine derivatives and salts thereof.