JPH03109355A - Production of 2,2,5,5-tetramethylcyclopentane carboxylic acid derivative and intermediate thereof - Google Patents

Abstract

PURPOSE:To industrially advantageously obtain the subject compound composing principal part of artificial sweetener by using novel cyclopentane dicarboxylic acid derivative as a starting substance and treating with alkali metal persulfate in the presence of silver ion catalyst or cobalt salt. CONSTITUTION:A novel 2,2,5,5-tetramethylcyclopentane-3-carboxy-1-carboxylate expressed by formula I (R is lower alkyl, aralkyl or aryl) is subjected to decarboxylation by treating with alkali metal persulfate in the presence of silver ion catalyst or cobalt salt to afford 2,2,5,5-tetramethylcyclopentane carboxylic acid derivative expressed by formula II. Novel compound expressed by formula I is obtained as one of novel compound expressed by formula V (R<1>is H, lower alkyl, aralkyl or aryl) from a compound expressed by formula II through novel compound expressed by formula IV (X is halogen).

Description

Detailed Description of the Invention: 2,2.5.5-Tetramethylcyclopentane
-N'-(2,2,5,5-tetramethylcyclopentanecarbonyl) = (R) -2,2,5.5-tetramethylcyclopentanecarboxylic acid, which is the main component of 1,1-diaminoethane This invention relates to methods for producing derivatives and intermediates thereof.

Conventional technology 2, 2.5. Conventional methods for producing 5-tetramethylcyclopentanecarboxylic acid include (a) a method in which cyclopentanone is tetramethylated and then one carbon chain is extended by Wittig reaction (Japanese Patent Application Laid-open No. 59-231050)
, (b) A method of obtaining 2.2.5.5-tetramethylcyclopentanone by methylsulfinyl methylenation, hydrolysis and oxidation at the ei position (JP-A-61-200
940) and (C) 2,5-dichloro-2,
A method in which 5-dimethylhexane and 1,1-dichloroethylene are reacted, followed by alkali treatment to produce chloroacetylene, and then cyclized in formic acid (0to^353461
3) is known. However, in methods (a) and et al., it is necessary to use 2.2.5.5-tetramethylcyclopentanone, which is difficult to obtain, and to generate a carbon-carbon bond for a carbonyl group with large steric hindrance. It is difficult to In method (C), the synthetic intermediate chloroacetylene is unstable and is not suitable for large-scale synthesis.

Problems to be Solved by the Invention The known methods are not necessarily sufficient as industrial production methods, and it is desired to develop a more advantageous production method.

The object of the present invention is to provide a method for manufacturing IM that can produce 2.2.5.5-tetramethylcyclopentanone derivatives at low cost and industrially, and an intermediate therefor.

Means for Solving the Problems The present invention provides a method for producing a 2,2,5,5-tetramethylcyclopentanecarboxylic acid derivative represented by formula (I) (wherein R represents lower alkyl, aralkyl or aryl). 2, 2 represented by the formula (I[[) (wherein, X represents a halogen and R has the same meaning as above), which is a method and an intermediate for its production.
．． 6.6-Tetramethyl-3-halo 4-cyclohexanone-1-carboxylic acid derivative and formula (rV) tart-butyl, pentyl, hexyl, etc., aralkyl is benzyl, phenethyl, benzhydryl, etc., aryl is phenyl, naphthyl etc., respectively. Also,
Halogen means chlorine, bromine, and iodine atoms.

The cyclopentanecarboxylic acid derivative represented by the general formula (1) related to the present invention can be produced by the following steps.

(wherein, R1 represents hydrogen, lower alkyl, aralkyl or aryl, and R has the same meaning as above) 2
, 2.5.5-tetramethylcyclopentane-1,3
-Relates to dicarboxylic acid derivatives.

In the definition of each layer, lower alkyl is straight or branched and has 1 to 6 carbon atoms, such as methyl, ethyl, propyl,
Isopropyl, butyl, COROOR (In the formula, Rla represents a group other than hydrogen in the definition of R' above, and R and X have the same meanings as above) [First step] This step Formula (III
) 2,2.6.6-tetramethyl-3-halo-4-cyclohexanone-1-carboxylic acid ester is obtained. The substance represented by formula (n), which is the raw material for this step, is a known substance and can be easily prepared manually in two steps using acetoacetate and mesityl oxide as starting materials [J, Med, Chem, 17, 1262 ( 19
74)].

In halogenation, chlorination, bromination and iodination are effectively carried out.

As the chlorinating agent, common chlorinating agents such as sulfuryl chloride, chlorine gas, and cyafryl chloride can be effectively used.

Brominating agents include bromine, N-bromosuccinimide,
Conventional brominating agents such as pyridinium hydropromide barbromide are used. As an iodinating agent, I 1-C
aO type, N-iodosuccinimide, etc. are used.

This reaction may be carried out in a solvent, and examples of the solvent include carbon tetrachloride, chloroform, l, 2
-Dichloroethane, methylene chloride, acetic acid, propionic acid, tetrahydrofuran, dioxane, etc. may be mentioned. The reaction temperature is appropriately selected depending on the reaction reagents, reaction solvent, etc., but it is preferably carried out at room temperature to the boiling point of the solvent for several hours.

[Second Step] In this step, the 2,2,2,6,6-tetramethyl-3-halo-4-cyclohexanone-1-carboxylic acid ester represented by the formula (I[I) is treated with a base to obtain the formula (rVa
) 2,2.5.5-tetramethylcyclopentane-1,3-dicarboxylic acid ester is obtained. This reaction is the so-called Favorski reaction.
ii) It is treated with a base under the reaction conditions. Suitable bases to be used include alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium isopropoxide, potassium methoxide, potassium ethoxide, and potassium isopropoxide, alkali metal phenylmethoxides, and alkali metal phenoxides. be. As a reaction solvent, alcoholic solvents such as methanol, ethanol, and isopropanol, diethyl ether,
Ethers such as tetrahydrofuran and 1,2-dimethoxyethane are preferably used. Reaction temperature is room temperature to 120℃
The reaction is carried out at a temperature within the range of 0.degree. C., but it is preferably carried out by heating under reflux for several hours at the boiling point of the solvent.

[Third Step] In this step, 2, 2.
5゜By selectively hydrolyzing 5-tetramethylcyclopentane-1,3-dicarboxylic acid ester, 2,2.5.5-tetramethylcyclopentane-3-carboxy- represented by general formula (IVb) 1-carboxylic acid ester is obtained.

For hydrolysis, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, etc. can be used. Tetrahydrofuran, methanol, ethanol, and mixtures of these and water can be used as solvents. Although the reaction can be carried out at room temperature, in order to speed up the reaction, it is preferable to heat and reflux at the boiling point of the solvent for several hours.

Furthermore, when the Fapolski reaction of the compound represented by the general formula (I[r) is carried out using an aqueous solution of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, the compound (rVb) is given at once and hydrolyzed. It is unnecessary and convenient. In the reaction, 5 to 10% aqueous alkali metal hydroxide solution is added to the compound represented by formula (III) at a rate of 2 to 3
The objective can be achieved by adjusting the amount to be equivalent and heating under reflux for several hours.

[Fourth step] This step is represented by the general formula (rvb) 2, 2.5.5
-tetramethylcyclopentane-3-carboxy-1-
The carboxylic acid ester is decarboxylated to obtain the 2,2,5,5-tetramethylcyclopentane-1-carboxylic acid ester represented by the general formula (1). This reaction is carried out with an alkali metal persulfate in the presence of a silver ion catalyst or a cobalt salt. As a silver ion catalyst, silver nitrate,
Silver compounds such as acetic acid and silver carbonate are used. Silver ions may be present in an amount of 0.5 to 5 mol%, preferably 1 to 2 mol%. Further, as the cobalt salt, cobalt salts such as cobalt nitrate, cobalt chloride, cobalt oxalate, and cobalt sulfate are used.

Cobalt salt should be used in an amount of 0.5 to 1.5 molar equivalents, but 1
Molar equivalents are preferred. Examples of alkali metal persulfates include persulfate, potassium persulfate, and potassium persulfate. The reaction is carried out in the presence of a solvent. The solvent used is a mixture of water and acetonitrile or acetone. The alkali metal persulfate is used in an amount of 1 to 4 equivalents, preferably 2 to 3 equivalents. The reaction is carried out under heating under reflux for several hours.

The intermediate and target compound in the above production method are:
It can be isolated and purified by purification methods commonly used in organic synthetic chemistry, such as ρ-filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. Moreover, the intermediate can also be subjected to the next reaction without being particularly purified.

Compound (I) thus obtained is 2.2.5.5-tetramethylcyclopentanecarboxylic acid (BP-A-01
28654> (see Reference Example 2).

Hereinafter, the present invention will be explained in detail with reference to Reference Examples and Examples.

Reference example 1 coocm)l,
C0 mouth C2Hs(If) Iodide 14(I) 340■(1,7
9 mmol> was suspended in a mixed solvent of ether 15- and tetrahydrofuran 15-, and cooled to -30°C to obtain 14.311 Il! of methylmagnesium bromide (1,83M ether solution). and 1.5 m of hexamethylphosphoramide and 5.0 m of ethyl 2.6.6-trimethyl-2-cyclohexen-4-one-1-carboxylate.
g (23.8 mmo+) dissolved in ether 25- was added and stirred for 1 hour.

A saturated ammonium chloride aqueous solution was added, and the mixture was extracted with ether and dried, and then the solvent was distilled off under reduced pressure. Silica gel column chromatography (n-hexane/ether = lO/1-
→ 4/1) and purified with 2.2.6° ethyl 6-tetramethyl-4-cyclohexanone-1-carboxylate 3.5
68 g (15.8 mmol, yield 66%) was obtained.

NMR(CDCj!,)δ: 1.11(s, 12
H), 1.3Ht, 3H, J=7Hz), 2.1
2(d, 2H, J=1311z), 2.49(s, I
H), 2.60(d,2)1,13Hz), 4.2
1(q, 2H, J=7Hz) Example 1 COOC, H5CO CJs (II) (I[I) 2,2,6.6-tetramethyl-4-cyclohexanone-1-carvone under argon atmosphere Ethyl acid 500 mg (
2.21 mmol) was dissolved in 5-methylene chloride, 89.5 m (2.21 mmol) of methanol and 195 m (2.43 mmol) of sulfuryl chloride were added in this order at room temperature, and the mixture was heated under reflux for 2 hours. The reaction solution was returned to room temperature, saturated aqueous carbonate solution was added, and extracted with ether. After drying, the solvent was distilled off under reduced pressure. Silica gel column chromatography (n-hexane/ether =
20/1) to give 3-chloro-2,2,6,6-
Ethyl tetramethyl-4-cyclohexanone-1-carboxylate 421 mg (1,62 mmol, yield 73%)
I got it.

NMR(CDCl3)δ;l,09(s,3H)
, 1.14 (s, 311).

1.15 (s, 3H), 1.24 (s, 3H), 1
．． 32 (t, 3H, J='1lz).

2.50 (d, LH), 2.69 (s, IH), 2
．． 78(d,l)1.13flz).

4.21(q, 2H, J=7Hz>, 4.87(s,
LH) Example 2 0OCJs (III) (rV a ) Under an argon atmosphere, 21 mg of sodium ethoxide was suspended in 0.4-ether, and 3-chloro-2,2,6,
Ethyl 6-tetramethyl-4-cyclohexanone-1-carboxylate 81 tag (OJ11mmo+) was dissolved in 0.2 ml of ether and added. After heating under reflux for 3 hours,
Water was added until the salt was dissolved, and the mixture was extracted with ether. After drying, the solvent was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (n-hexane/ether-8
/l) to give 2.2.5.5-tetramethyl-1,
58 mg (0.21 mmol, yield 69%, isomer ratio ^/B = 2/1) of an isomer mixture of diethyl 3-cyclopentanedicarboxylate was obtained.

Isomer A: NMR (CDCj!,)δ; 1.07(s, 3H
), 1.15 (s, 3H).

L, 17(s, 3) 1), 1.25-1.31(m,
9H), 1.65 (dd, ltl.

J42.8.6.8)1z), 1.92(dd, l
)I, J=12.8.11.6tlz).

2,39(s, LH), 2.83(dd, IH,
J=11.6.6.8Hz).

4.06-4.22 (m, 4H) Isomer B: NMR (CDCj! 3) δ; 1.10 (s, 3)
1), 1. lHs, 3H).

1.18(s, 3t(), 1.25~1.31(+
m, 911), 1.72 (dd, 1tl.

J=13.4.7°3Hz), 2.16(dd,
IH, J = 13.3.12.6flz).

2,33(s, IH), 2.52(dd, 1)
1. J=12.6.7.3Hz).

4.06-4.22 (m, 4H) Example 3 (IVa) (rVb)2,
2.5.5-Tetramethyl-1,3-cyclopentanedicarboxylate diethyl 765 mg (2,83 mmol
), 3 m methanol solution of barium hydroxide (0,
4 mol/f) and stirred at 70° C. for 3 hours and then at room temperature overnight. Methanol was removed under reduced pressure, 4N hydrochloric acid was added to the residue, and the mixture was extracted with ether. After drying, the solvent was distilled off under reduced pressure and subjected to silica gel column chromatography (n
-Hexane/ether = 10/1 → 3/1) with W4I
! 384 mg (1
, 59m+nol, yield 56%) was converted into an isomer mixture (^/
B=1/2).

Isomer A: NMR (C11s>δ: 1.15(s,
6H), 1.17 (s, 3fl).

1.27(s, 3H), 1.27(t, 3H, J=
7.2Hz), 1.68(dd.

IH, J=12.9.6.8Hz), 1.9Hdd,
IH, J=12.9.11.6Hz), 2.40(s
, LH), 2.90 (dd, E, J=11.6.6.
8Hz), 4.12 (dq, ltl, J=10.8.
7.2Hz>, 4.15(dq.

IH, J = 10.8.7.2 Hz) Isomer B: NMR (CDtJ,) δ: 1.11 (s
, 3tl), 1.17(s, 3H).

1.19 (s, 3H), 1.27 (s, 3H), 1
．． 27(t, 3H, J=7.111z), 1.76(
dd, LH, J=13.4.7JHz), 2.13(
dd.

LH, J=13.4.12.6)1z), 2.36(
s, 1) I), 2.58 (dd.

LH, J=12.6.7.3Hz), 4.11 (d
q, Iff, J=10.8.7.1tlz), 4
．． 16 (dq, ill, J=10.8.7.E
z)(III) Ethyl 3-chloro-2,2,6,6-tetramethyl-4-cyclohexanone-1-carboxylate 100■(0,3
84 mmol) in 5% potassium hydroxide aqueous solution 0.86
g1:! ! The mixture became cloudy and heated under reflux for 4 hours. After the solution became homogeneous, it was returned to room temperature, acidified (pH 2 to 3) by adding 1N aqueous hydrochloric acid solution, and extracted with ether. After drying, the solvent was distilled off under reduced pressure and purified by silica gel column chromatography (n-hexane/ether-10/1-3/l) to give 3-ethoxycarbonyl-2,2,4,4-tetra Methylcyclopentanecarboxylic acid 71 n (0,
293mmo+, yield 76%) was converted into an isomer mixture (^/B
=5/1).

Isomer A: NMR (CDCf,) δ; 1.15 (s, 6H),
1.17 (s, 3H).

1.27 (s, 3H), 1.27 (t, 3H, J=7
．． 2Hz), 1.68 (ddIH, J=12.9,6
．． 8Hz), 1.91 (dd, IH, J=12.9.
11.6Hz), 2.40 (s, IH), 2.90
(dd, LH, J=11.6.6.8Hz).

4, 12 (dq, IH, J=10.8.7.2)lz
), 4.15 (dq, lfl, J=10, 8.7
．． 2flz) Isomer B: NMR (CD(J,)δ; 1.IHs, 3) 1)
, 1.17 (s, 3H).

1.19 (s, 3tl), 1.27 (s, 3) 1),
1.27 (t, 3LJ=7.1Hz), 1.76 (
dd, 1N, J=13.4, 7.3Hz), 2.13
(dd.

IH, J=13.4, 12.6flz), 2J6(s
, IH), 2.58 (dd.

IH, J=12.6.7.311z), 4.11(d
q, LH, J=lO, 8, 7, 1Hz), 4.16
(dq, IH, J = 10.8.7.1Hz) Example 5 (rVb) (1) Under an argon atmosphere, 160 mg of 3-ethoxycarbonyl-2,2,4,4-tetramethylcyclopentanecarboxylic acid (
0,661 mmo+) and silver nitrate 2.25 mg (0,0
13 mmol) was heated to reflux in a mixed solvent of acetonitrile:water-3:1, and persulfate was added. 6.4 m of IJium aqueous solution (containing 350 mg of 90% sodium persulfate)
was slowly dripped. After further heating under reflux for 5 minutes, the mixture was returned to room temperature, extracted with ether, dried, and the solvent was distilled off under reduced pressure. Purified by silica gel column chromatography (n-hexane/ether = 50/l), 2.2.5.5
-Ethyl tetramethylcyclopentanecarboxylate 70■
(OJ54 mmol, yield 53%) was obtained.

NMR (COCj!,) δ; 1.10 (s, 6)
1), 1.12 (s, 6H).

1, 26 (t, 3H, J='/, 11Hz),
1.46-1.64 (+++, 4H).

2. 19(s, l1l), 4. lHq, 2
H, J = 7.1 IHz) Example 6 Under argon atmosphere, 3-ethoxycarbonyl 2, 2.4
．． 50 g of 4-tetramethylcyclopentanecarboxylic acid
(0,207 mmol) and cobalt nitrate hole hydrate 60
．． 1 mg (0,207n++nol) was heated under reflux in a mixed solvent 4- of acetonitrile:water=3=1, and 2.0 m of an aqueous sodium persulfate solution (containing 90% sodium persulfate 109+ag) was slowly added dropwise. After further heating under reflux for 5 minutes, the mixture was returned to room temperature, extracted with ether, dried, and the solvent was distilled off under reduced pressure.

Silica gel column chromatography (n-hexane/
Purified with ether = 50/1) to 2.2.5°5-
Ethyl tetramethylcyclopentanecarboxylate 13 m
g (0,0657 mmol yield 32%) was obtained.

Reference Example 2 (1) Dityl 2,2.5.5-tetramethylcyclopentanecarboxylate l Oag (0,051 mmol) was dissolved in 0.25 methanol and 0.1 N potassium hydroxide was added.
26- was added and heated at 80°C for 1 day. p with 1N hydrochloric acid
Ether extraction was carried out in H2-3, and after drying, the solvent was distilled off under reduced pressure. Silica gel column chromatography (n
- Hexane/ether = 5/l) to purify with 2.2.5
．． 5-tetramethylcyclopentanecarboxylic acid 6 ta
g (0,035+mmol, yield 70%) was obtained.

NMR (CDC1,) δ; 1.15 (s, 12
H), 1.43-1.66 (m.

4)1), 2.28(s, 1)l), 8. (1
8 (bs, 1) 1) Effect of the invention According to the present invention, 2, which constitutes the main part of the artificial sweetener,
An industrially advantageous method for producing 2.5.5-tetramethylcyclopentanecarboxylic acid is provided.

Claims (3)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R represents lower alkyl, aralkyl or aryl). Formulas characterized by treatment with metal persulfates ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ 2, 2, 5 represented by (in the formula, R has the same meaning as above)
, 5-tetramethylcyclopentanecarboxylic acid derivative manufacturing method. (2) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ 2,2,6,6-tetramethyl-3-halo represented by -4-cyclohexanone-1-carboxylic acid ester. (3) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 represents hydrogen, lower alkyl, aralkyl, or aryl, and R has the same meaning as above) 2, 2, 5 , 5-tetramethylcyclopentanedicarboxylic acid derivative.