JPH0672143B2 - Method for producing oxamate compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention has the general formula (I) (Wherein, R ₁ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or a phenyl group, a R ₂ is a lower alkyl group or a phenyl group, R ₃ represents a hydrogen atom or a lower alkyl group. However, as R ₁ R ₂ may combine with each other to form a ring), and is a compound that is expected to be used as an intermediate for oxamate drugs having various physiological activities. The compound has the general formula (II) (In the formula, R ₁ , R ₂ and R ₃ have the same meanings as described above), the amino alcohol represented by
It can be easily produced by reacting with carbon monoxide in the presence of a copper salt and oxygen.

In the amino alcohol represented by the general formula (II) which is a raw material in this reaction, the substituent R ₁ is specifically a hydrogen atom, methyl, ethyl, propyro, butyl, hexyl, ethylene, allyl, butene, hexene, phenyl, etc. Are preferred, and a hydrogen atom or a lower alkyl group is preferred. Further, as R ₂ , specifically, the same lower alkyl group as described above or a phenyl group, preferably a lower alkyl group, and as R ₃ , specifically, a hydrogen atom or the same lower alkyl group as described above is exemplified, and R ₁ and R ₂ may combine with each other to form a 4-membered ring, a 5-membered ring, a 6-membered ring or the like containing a nitrogen atom.

In this reaction, a divalent palladium-based catalyst is used as the catalyst, and various conventionally known ones can be applied as the palladium-based catalyst. PdX ₂ (X: a halogen atom such as chlorine or bromine, Pd (OAc) ₂ or a complex thereof such as PdCl ₂ (MeCN) ₂ or PdCl ₂ (PEt ₃ ) ₂ is preferably used.

The amount of such a catalyst used is usually 0.1 to 20 mol%, preferably 1 to 10 mol%, based on the starting amino alcohol.

Further, in this reaction, coexistence of a copper salt is essential, and as the copper salt, a copper halide (for example, CuI, CuCl, CuCl ₂ , CuB
r, CuBr _2), copper oxide (e.g., Cu ₂ O, CuO), copper sulfate (e.g. _{Cu (SO 4) 2, CuSO} 4) but are exemplified, copper halide is preferably used. Such a copper salt is usually used in an equivalent amount or more with respect to the palladium-based catalyst, and the upper limit thereof is not particularly limited, but is generally 20 due to reasons such as economic efficiency.
Up to twice the equivalent.

Theoretically, carbon monoxide is required to be twice equivalent to the raw material amino alcohol, but in general, an excess amount is needed,
And the reaction is carried out under a pressure of 5 to 200 kg / cm ² , preferably 20 to 100 kg / cm ² .

Oxygen is used in the range of ² to ²⁰ kg / cm ² , preferably 3 to 15 kg / cm ² as the partial pressure in the reaction system.

The reaction is usually carried out in a solvent, and the solvent is not particularly limited as long as it is inert to the reaction, but acetonitrile and lower alcohols (for example, methanol, ethanol, butanol, amyl alcohol) are preferably used.

In this reaction, it is effective, but not necessary, to use a dehydrating agent such as trimethoxymethane.

The reaction temperature may be in the range of 0 to 100 ° C, but the reaction does not need to be extremely high because the reaction proceeds sufficiently even at room temperature.

Thus, according to the above reaction, the double carbonylation easily proceeds from the aminoalcohol represented by the general formula (II) in one step to obtain the desired oxamate compound represented by the general formula (I) in a good yield. The oxamate compound thus obtained is expected to be used in many cases as an intermediate for oxamate drugs having various physiological activities.

Hereinafter, the present invention will be described with reference to examples.

Example 1 2 ml of acetonitrile, 1.0 mmol of N-methylethanolamine, 0.05 mmol of dichloropalladium-acetonitrile complex and 0.25 mmol of cuprous iodide in a 10 ml autoclave.
The CO pressure of 40 kg / cm ² , O ₂ pressure of 5 kg /
Enclose to cm ² and stir at room temperature for 20 hours.

After completion of the reaction, the reaction system was returned to clean pressure, the catalyst was removed by filtration, and the filtrate was subjected to column chromatography with methylene chloride-ether to remove 4-methylmorpholine-2,3-dione.
0.78 mmol (yield 78% of amino alcohol) was obtained. This was recrystallized from benzene.

mp: 90-91 ℃ IR (KBr): 1750 (S, C = O), 1686 (S, C = O), 1352
(M), 1190 (m) , 1056 (w) cm -1 1 H-NMR (CDCl 3): δ3.13 (S, 3H, -CH 3), 3.70 (t, J =
_{7.0Hz, 2H, N-CH 2} -), 4.51 (t, J = 7.0Hz, 2H-O-CH
₂ −) Example 2 A 10 ml autoclave was charged with 2 ml of methanol, 1.0 mmol of N-butylethanolamine, 0.1 mmol of dichloropalladium-acetonitrile complex and 0.5 mmol of cuprous chloride, and CO pressure of generalized carbon and oxygen was 80 kg / cm. ^2. Enclose it so that the O ₂ pressure is 5 kg / cm ² and stir at room temperature for 20 hours.

After completion of the reaction, post-treatment was carried out in the same manner as in Example 1 to obtain 0.86 mmol (rate 86%) of 4-butylmorpholine-2,3-dione, which was recrystallized from ether.

mp: 62.5-63 ℃ IR (KBr): 2970 (w), 1754 ((S, C = O), 1682 (S, C =
O), 1482 (w), 1454 (w), 1360 (m), 1180 (m), 1
^{06 (w) cm -1 1 H} -NMR (CDCl 3): δ0.73~1.90 (m, 7H, CH 2 2 C
_{H 3), 3.57 (q,} J = 6.9Hz, 2H, N-CH 2 -), 3.65 (t, J = 5.2
_{Hz, 2H, -N-CH 2} ), 4.51 (t, J = 5.2Hz, 2H, O-CH 2 -) Example 3 10 ml capacity autoclave acetonitrile 2 ml, N-ethyl ethanolamine 1.0 mmol, jaw of palladium - Acetonitrile complex 0.05 mmol and cuprous iodide 0.5 mmol
The CO pressure is 80 kg / cm ² , O ₂ pressure is 5 kg / c.
Enclose to m ² and stir at 40 ° C. for 2 hours.

Thereafter, post-treatment was carried out in the same manner as in Example 1 to obtain 4-ethylmorpholine-2,3-dione (0.86 mmol, yield 86%). It was recrystallized from ether.

mp: 70 ~ 70.5 ℃ IR (KBr): 1754 (S, C = O), 1682 (S, C = O), 1488
(W), 1444 (w), 1368 (m), 1314 (w), 1178
(M), 1058 (w) cm -1 1 H-NMR (CDCl 3): δ1.21 (t, J = 7.4Hz, 3H, -CH 3), 3.
54 (J = 7.4Hz, 2H, N−CH ₂ −), 3.67 (t, J = 5.8Hz, 2H, N
_{-CH 2 -), 4.51 (t} , J = 5.3Hz, 2H, O-CH 2 -) in place of Example 4 N-methylethanolamine using 2-hydroxymethyl pyrrolidine, a CO pressure of 80 kg / cm ² Hexahydro-1H- was reacted and worked up in the same manner as in Example 1 except that
Pyrrolo [2,1-C] [1.4] -oxazine-3,4-dione
0.64 mmol (yield 64%) was obtained.

This was recrystallized from a benzene-hexane mixed solvent.

mp: 135〜137 ℃ IR (KBr): 1756 (S, C = O), 1688 (S, C = O), 1450
(M), 1396 (w), 1362 (w), 1192 (m), 1048
(W), 1002 (w) cm -1 1 H-NMR (CDCl 3): δ1.36~2.38 (m, 4H, -CH 2 -), 2.9
9~3.74 (m, 2H, N- CH 2 -), 3.92~4.60 (m, 3H, O-CH
_{2 -, N-CH 2 -} ) mass ^{spectrum: m / e155 (M +)} , 111 (M + -CO 2) Example 5 10 ml volumes autoclave acetonitrile 2 ml, 2-hydroxymethyl piperidine 1.0 mmol, palladium acetate 0.1mm
ol and 0.5 mmol cuprous iodide were charged, CO pressure 80 kg / c
The mixture was stirred at m ² and O ₂ pressure of 5 kg / cm ² and 50 ° C. for 20 hours. Thereafter, the same treatment as in Example 1 was carried out to obtain octahydropyridino [2,1-
C] [1.4] Oxazine-3,4-dione 0.76 mmol (yield 76
%) Was obtained.

This was recrystallized from benzene-ether to give crystals having m.p. 68-69 ° C.

IR (KBr): 3960 (w), 3880 (w), 1760 (S, C = O), 16
86 (S, C = O), 1440 (m), 1396 (w), 1352 (m), 129
6 (w), 1208 (m ), 1092 (w), 1044 (m) cm -1 1 H-NMR (CDCl 3): δ1.16~2.17 (m, 6H, -CH 2 -), 2.5
0~3.07 (m, 1H, N- CH -), 3.43~3.99 (1H, N-CH 2 -),
4.01~4.67 (m, 3H, O- CH 2 -, N-CH 2 -) mass ^{spectrum: m / e169 (M +)} , 141 (M + -CO) 125 (M + -
CO ₂ )

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display area C07D 498/04

Claims (1)

[Claims] 1. A general formula (Wherein, R ₁ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or a phenyl group, a R ₂ is a lower alkyl group or a phenyl group, R ₃ represents a hydrogen atom or a lower alkyl group. However, as R ₁ R ₂ may combine with each other to form a ring.) An amino alcohol represented by
General formula characterized by reacting with carbon monoxide in the presence of copper salt and oxygen (Wherein R ₁ , R ₂ and R ₃ have the same meanings as described above).