JPH0714905B2 - Novel method for producing 2-aminopentanoic acid compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel method for producing a 2-aminopentanoic acid compound useful as a medicine, particularly as an immunosuppressant.

[Conventional technology]

Japanese Patent Application Laid-Open No. 1-104087 discloses that an immunosuppressive substance is produced from a microorganism belonging to the genus Isaria, and that the immunosuppressive substance is myriocin (hereinafter referred to as ISP-I).
It is also disclosed). This myriocin (ISP-I) is the formula It is known to have an antifungal effect, for example from US Pat. No. 3,928,572.

Regarding immunosuppressive agents of ISP-I and related derivatives, international application PCT / JP88 / 00933 and a novel derivative have been applied for a patent in Japanese Patent Application No. 1-176914. Among them, in the latter patent application, a formula having an immunosuppressive activity equal to or higher than that of ISP-I is used. Compounds represented by are disclosed.

[Problems to be Solved by the Invention]

According to Japanese Patent Application No. 1-176914, the compound of formula (b) is a γ-lactone obtained by treating the compound of formula (a) with acetic anhydride in pyridine and having nitrogen and oxygen atoms protected by acetyl groups. The compound was subjected to reduction of the carbonyl group with sodium borohydride in the presence of dry ice, and the resulting hydroxy compound was reacted with 1,1'-thiocarbonyldiimidazole, followed by tributyltin hydride and 2,2'-azo. Radical reduction with (isobutyronitrile), and the fact that it is manufactured by finally subjecting it to an alkaline hydrolysis reaction,
Has been described.

However, since the method has a long process and the yield of individual steps is not high, it is easier to obtain a 2-aminopentanoic acid compound containing a compound of formula (b) at the 5-position with an alkenyl group. A new manufacturing method was needed.

[Means for Solving the Problems]

In order to solve the above-mentioned problems, the inventors of the present invention have conducted diligent research, and have found that the target product can be easily obtained by applying the Clemmensen reduction reaction, and have completed the method of the present invention.

That is, the present invention has the general formula (In the formula, R ¹ represents an alkyl group or an alkenyl group having a carbonyl group in the chain.) A γ-lactone compound which is a compound protected by an acetyl group and subjected to a Clemmensen reduction reaction. , A general formula characterized by being subjected to a γ-lactone ring opening reaction and / or a deacetylation group reaction if necessary (In the formula, R ² represents an alkyl group or an alkenyl group.) The 2-aminopentanoic acid compound represented by γ
-A novel method for producing a lactone compound or a compound protected by an acetyl group.

In the above definition, the alkyl group or alkenyl group having a carbonyl group in the chain of R ¹ is (Here, each symbol of a to j represents 0 or an integer of 1 to 20.). Further, as the alkyl group or alkenyl group for R ² , in the substituents exemplified for R ¹ ,
The carbonyl group corresponds to the group reduced to methylene.

The object compound (I) of the present invention includes metal salt compounds or acid addition salt compounds, hydrates or other solvates, and further includes individual optical isomers, diastereoisomers and racemates. To be done.

In carrying out the method of the present invention, preferably the formula (a)
The starting material is preferably a γ-lactone compound obtained by treating ISP-I represented by the formula (1) with acetic anhydride in pyridine and having nitrogen and oxygen atoms protected by acetyl groups.

The Clemmensen reduction reaction is known per se, using a powder of zinc or zinc amalgam and hydrochloric acid of the general formula (II) in an inert solvent (benzene, toluene, xylene, methanol, ethanol, etc.) for the reaction. By reacting with a lactone compound in which nitrogen and oxygen atoms are protected by an acetyl group, a compound in which a carbonyl group is once reduced to a methylene group is obtained. It is preferable to use acetic anhydride saturated with hydrogen chloride gas instead of hydrochloric acid. The reaction proceeds at room temperature or with heating for about 5 to 30 hours.

If necessary, the obtained compound is subjected to an alkaline hydrolysis reaction by a conventional method to obtain the desired compound of the general formula (I).

The target product can be isolated and purified by extraction, silica gel chromatography, fractional distillation, recrystallization, etc.

[Action]

As in the present invention, the compound of the general formula (I) useful as an immunosuppressant can be easily produced by carrying out the Klemensen reduction reaction.

〔Example〕

Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.

Reference example 1 To 8.10 g of ISP-I, 65 ml of pyridine was added at room temperature, and 70 ml of acetic anhydride was added with vigorous stirring. Continue stirring for about 1 hour,
After ISP-I was completely dissolved, stirring was stopped and the mixture was left overnight. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed successively with 1N hydrochloric acid, 5% sodium hydrogen carbonate and saturated aqueous sodium chloride solution, and the organic layer was dried. The oily residue (10.08 g) obtained by distilling off the solvent was separated with a silica gel column (300 g) using ethyl acetate: hexane = 7: 3 as a developing solvent. 900-170
The 0 ml eluate was combined and concentrated under reduced pressure to obtain the desired ISP-I-
19.29 g was obtained as a colorless transparent oily substance (yield 91.4%).

IRν _max (CHCl ₃ ) (cm ^-1 ): 2930,1760,1690,1380,1220 ¹ H-NMR (200MHz, in CDCl ₃ , Ref: TMS), δ: 6.05 (1H, b
rs, -NHAc), 5.79 (1H, d, J = 4.4Hz, 3-H), 5.57 (1H, d
tt-like, J = 15.4,6.3Hz, 7-H), 5.38 (1H, dt.t-like, J
= 15.4,6.4Hz, 6-H), 4.72 (1H, ddd, J = 7.6,5.1,4.6Hz, 4
-H), 4.51 (2H, s, 21-H ₂ ), 2.5 to 2.2 (2H, m, 5-Hz), 2.38
(4H, t, J = 7.5Hz, 13-, 15-H ₂ ), 2.10 (3H, s, -Ac), 2.05
(3H, s, -Ac), 2.03 (3H, s, -Ac), 2.1 to 1.9 (2H, m, 8-
H ₂ ), 1.55 (4H, qui., J = 6.8Hz, 12,16-H ₂ ), 1.27 (12H, b
_{. rs, 9~11,17~19-H 2)} , 0.88 (3H, t, J = 6.5Hz, 20-H 3) 13 C-NMR (100MHz, in CDCl 3, Ref: TMS), δ: 211.37 (S,
14-C), 172.32 (s,> C = O), 170.08, (s,> C = O),
169.27 (s,> C = O), 168.75 (s,> C = O), 135.04
(D, 6-C), 123.16 (d, 7-C), 81.62 (d, 4-C), 72.01 (d,
3-C), 62.75 (t, 21-C), 62.73 (s, 2-C), 42.85,42,77
(Each t, 13,15-C), 32.46,32.20,31.63 (each t, 5-, 8-
18-C), 29.11,29.00,28.97,28.91,23.91,23.85 (each
t, 9 ~ 12,16,17-C), 22.76 (q, -COMe), 22.50 (t, 19-
C), 20.55 (q, -COMe), 20.31 (q, -COMe), 14.00 (q, 20-
C) EI-MS m / z: 509,491,382,348,279,129,43HR EI-MS: C ₂₇ H ₄₃
As NO ₈ , calculated value: 509.2990, measured value: 509.2998 Example 1 ISP-I-1 7.804g saturated hydrogen chloride-acetic anhydride solution (156ml)
To the above, about 29.5 g of activated zinc dust was added little by little while slowly stirring with cooling with a sodium chloride-ice bath.
After the addition was completed, stirring was continued for 1.5 hours under cooling. The reaction solution was filtered with a cotton plug and transferred to ice water, and the residual zinc dust was washed with ethyl acetate. The reaction mixture was extracted with shaking using a washed ethyl acetate layer, and the aqueous layer was extracted again with ethyl acetate. The ethyl acetate layers were combined, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a pale yellow oily residue (about 7 g). This was immediately purified and separated on a silica gel column (140 g) using ethyl acetate: hexane = 7: 3 as a developing solvent to obtain ISP-I-13γ6.204 g as a colorless transparent oily substance. (Yield 81.7%) IRν _max (CHCl ₃ ) (cm ⁻¹ ): 1780,1755,1685,1500,1030 ^1- NMR (200MHz, in CDCl ₃ , Ref: TMS) δ: 5.99 (1H, br.
s.,-NH), 5.79 (1H, d, J = 4.4Hz, 3-H), 5.58 (1H, dt.tl
ike, J = 15.3,6.6Hz, 7-H), 5.39 (1H, dt, t-like, J = 15.
3,7.1Hz, 6-H), 4.71 (1H, ddd, J = 7.1,5.6,4.4Hz, 4-H),
4.52 (2H, br.s., 21-H ₂ ), 2.39 (2H, m, 5-H ₂ ), 2.10 (3H,
s, -Ac), 2.05 (3H, s, -Ac), 2.03 (3H, s, -Ac), 2.01 (2
H, m, 8-H ₂ ), 1.26 (22H, br.s., 9〜19-H ₂ ), 0.88 (3H, t, J
= 6.4Hz, 20-H ₃ ) ¹³ C-NMR (50MHz, in CDCl ₃ , Ref: TMS) δ: 172.44 (s,>
C = O), 170.17 (s,> C = O), 169.42 (s,> C =
O), 168.89 (s,> C = O), 135,29 (d, 6-C), 122.96
(D, 7-C), 81.66 (d, 4-C), 71.93 (d, 3-C), 62.73 (t, 2
1-C), 62.64 (s, 2-C), 32.57,32.18,31.91 (each t, 5-,
8-, 18-C), 29.68,29.68,29.68,29.68,29.68,29.51,29.3
6,29.21,29.21 (each t, 9 ~ 17-C), 22.77 (q, -CO M
e ), 22.70 (t, 19-C), 20.58 (q, -CO Me ), 20.34 (q, -CO M
e ), 14.11 (q, 20-C) EI-MS m / z: 495,436,376,334,265,151,129,43 HREI-MS: C ₂₇ H ₄₅ NO ₇ , calculated: 495.31975, found:
495.31864 3.102 g of ISP-I-13γ was dissolved in 150 ml of methanol, 37.6 ml of a 1N sodium hydroxide aqueous solution was added, and the mixture was heated and cooled overnight under a nitrogen stream. The reaction solution was neutralized with 1N hydrochloric acid, and the precipitated colorless substance was collected by absorption filtration. The precipitate obtained here was thoroughly washed with water, further washed once with methanol water (1: 1), and dried under reduced pressure to obtain 2.018 g of ISP-I-13 (yield 83.2%). Melting point 186 ℃ IR
ν _max (KBr) (cm ^-1 ): 3400,3200,1660,1565,1525,1465 ¹ H-NMR (200MHz, in CD ₃ OD, Ref: TMS) δ: 5.54 (1H, dt, t-
like, J = 15.4,5.9Hz, 7-H), 5.38 (1H, dt.t-like, J = 15.
4,6.1Hz, 6-H), 4.00 (1H, d, J = 11.0Hz, 21-H), 3.86 (1
H, d, J = 11.0Hz, 21-H), 3.83 (1H, br.t., J = 7.3Hz, 4-
H), 3.78 (1H, br.s., 3-H), 2.26 (2H, br.t., J = 6.8Hz, 5
-H ₂ ), 2.00 (2H, m, 8-H ₂ ), 1.28 (22H, br.s., 9〜19-
H ₂ ), 0.90 (3H, t, J = 6.5Hz, 20-H ₃ ) FAB-MS m / z: 388,104,57,45,29 Elemental analysis value C ₂₁ H ₄₁ NO ₅ calculated value C: 65.08, H: 10.66, N: 3.61 Measured value C: 64.78, H: 10.91, N: 3.61

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display area C07D 307/33

Claims (1)

[Claims] 1. A general formula (In the formula, R ¹ represents an alkyl group or an alkenyl group having a carbonyl group in the chain.) A γ-lactone compound which is a compound protected by an acetyl group and subjected to a Clemmensen reduction reaction. , A general formula characterized by being subjected to a γ-lactone ring opening reaction and / or a deacetylation group reaction if necessary (In the formula, R ² represents an alkyl group or an alkenyl group.) The 2-aminopentanoic acid compound represented by γ
-A novel method for producing lactone compounds or compounds protected by an acetyl group.