JPH02233651A - P-toluensulfonic acid salt of n-(2,2,5,5-tetramethylcyclo-pentanecarbonyl)-(s)-1,1-diaminoethane - Google Patents

Abstract

NEW MATERIAL:N-(2,2,5,5-tetramethylcyclopentanecarbonyl)-(S)-1,1-diaminoeth- ane p-toluenesulfonic acid salt expressed by formula. USE:A synthetic intermediate for sweeteners. PREPARATION:The objective compound of formula can be produced by subjecting free N-(2,2,5,5-tetramethylcyclopentanecarbonyl)-(S)-1,1-diamino-ethane to Hofmann degradation reaction, extracting the obtained liquid with an organic solvent, adding p-toluene-sulfonic acid to the extract and crystallizing the objec tive compound from the mixture. The extraction solvent is preferably hydrocarbons such as n-hexane, toluene and benzene and especially preferably ethyl acetate. The compound of formula is useful for the synthesis of N-(L- aspartyl)-N'-(2,2,5,5-tetramethylcyclopentanecarbonyl)-(R)-1,1-diamino ethane.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to N-(L-aspartyl) having a sweetening effect.
-N' - (2.2,5-tetramethylcyclopenkunyl)- (R) - N- (2.2.5 ，
5-Tetramethynorecyclobentanane (S) -1.1-') p-}luenesulfonate of aminoethane.

PRIOR ART Free N-(2.2.5.5-tetramethylcyclopentanyl)-(S)-1.1-diaminoethane is prepared from N-(2,2,5,5- It is reported in JP-A-61-200951 that tetramethylcyclobenzene-L-alanine amide can be obtained by reaction with iodobenzene diacetate. A method by Hofmann decomposition using acid soda is disclosed in 11087/07312, but the p-toluenesulfonate salt of this compound is not known.

Problems to be Solved by the Invention Free N-(2.2.5.
5-Tetramethylcyclopentane (S)
-1.1-diaminoethane does not necessarily have good stability in organic solvents, as described below. This poor stability is a factor that leads to a decrease in product yield or quality during unit operations such as extraction, concentration, and phosphorus filtration, or during large-scale synthesis, which takes a long time.

From the standpoint of industrial production methods, compounds with even higher purity and better stability are desired.

Means for Solving the Problems According to the present invention, a highly pure and stable synthetic intermediate N-
(2.2.5.5-tetramethylcyclopentanetricarbonyl)-(S)-1.1-diaminoethane p-toluenesulfonate salt is provided.

Free N-(2.2.5.5-tetramethylcyclopenkylcarbonyl)-(S)-1. 1-') Aminoethane can be obtained by the method described in JP-A-61-200951 or WO 87/07312, etc., but is particularly preferably obtained by the inexpensive Hofmann decomposition reaction.

The compound of the present invention can be obtained by adding 1)-}luenesulfonic acid to an organic solvent extract of the above reaction solution and causing crystallization.

Organic solvents used for extraction include hydrocarbons such as n-hexane, toluene, and benzene, diethyl ether,
Ethers such as diisopropyl 1-f, tert-butyl methyl ether, esters such as methyl acetate, ethyl acetate, proyl acetate, butyl acetate, and halogenated hydrocarbons such as carbon tetrachloride, chloroform, methylene chloride, etc. Examples include protic organic solvents, and ethyl acetate is particularly preferably used.

p-}luenesulfonic acid is the starting material N-(2.2,
5.5-Tetramethylcyclopenkylbenyl)-L
- 0.5 to 2.0 equivalents to alaninamide,
Preferably 0.7 to 1.2 equivalents are added at -70 to 50°C, preferably -10 to 10°C, and 3 equivalents are added at -10 to 10°C.
It can be obtained as a crystalline or amorphous powder by aging under stirring for ~24 hours. For crystallization, p-}luenesulfonic acid may be added directly to the reaction extract, or if necessary, an extract dried with a dehydrating agent such as anhydrous magnesium sulfate, anhydrous sodium sulfate, or molequinylar sieves may be used. good. In addition, p-}luenesulfonic acid is usually used as a permanent product, and the solution after addition may be crystallized as it is, but if desired, it may be concentrated under reduced pressure to about 2/3 to 1/4 for crystallization. You can also do it. The precipitated compound can be separated and obtained by conventional operations such as centrifugation, F filtration, washing, and drying.

The obtained compound of the present invention contains doluene, ethyl ether,
It can be used as an educt in the next reaction in the presence of one equivalent or more of a base in an aprotic organic solvent such as tetrahydrofuran, acetonitrile, chloroform, methylene chloride, dichloroethane, or ethyl acetate. Examples of the base include tertiary organic amines such as N-methylmorpholine, triethylamine, and diisopropylethylamine.

In addition, in carrying out the process, in order to avoid the presence of an excessive free form over a long period of time, preferably the base is gradually added dropwise in the presence of a reactive derivative such as a mixed acid anhydride of the compound of the present invention and the corresponding carboxylic acid. The reaction can be carried out advantageously by carrying out the reaction at the same time.

In addition, from N-(2.2.5.5-tetramethylcyclopentanecarbonyl)-(S)-1.1-diaminoethane to N-(L-aspartyl)-N'-(2.2.
5. 5-tetramethylcyclopenkylbenyl
-(R)-1,1-diaminoethane can be prepared by a known method (JP-A No. 61-200940; No. 61-200951).
Publications, etc.).

Next, the free form of N-(2,-2.5.5-tetramethylcyclobenzene carbonyl)-(S)-1,1-diaminoethane and the organic solvent of I)-}luenesulfonate were added. The test example shows the results of examining the stability in the medium.

Test Example The ethyl acetate extract obtained in the same manner as in step 8 of the example described later was divided into four parts, and an equivalent amount of p-}luenesulfonic acid monohydrate was added to the two samples.

While maintaining a constant temperature, sample 1-1 at a certain time, and add 0.1% diphenylmethane-methanol solution 1-
was added and mixed. 4g of it was subjected to high performance liquid chromatography [Column: Nucleosil 7cgφ4.6
X25QIIuo; Elution solvent: 0. 0 5 MK
82PO. /CH3CN= 1/ 1 (V/V)1
)+17. 0;Flow rate: l ml! /min; detection: UV 220 mm), and the residual rate was determined using diphenylmethane as an internal standard.

The results are shown in Table 1. However, salt and free in the table are N
-(2.2.5. 5-tetramethylcyclobenzenecarbonyl)- (S)- represents the p-}luenesulfonate salt and the educt of 1-diaminoethane, respectively.

Table 1 (Salt) (Free) (Salt) (Free) 93.9 85.6 98.4 75.2 94.7 99.8 61.2 From Table 1, p-}luene at any temperature. It can be seen that the sulfonate has superior stability compared to the free form.

Aspects of the present invention will be explained below using Examples and Reference Examples.

Example N- (2.2.5.5-tetramethylcyclopenkyl)-L-alaninamide 1 2. 0 2
g (50 mmol), acetonitrile 251n1 and 1.5N sodium hydroxide 50mi! 43 ml of 1.78N sodium hypobromite was added dropwise over about 10 minutes while cooling with water. After stirring for 1 hour under water cooling, the pH was adjusted to 3.0 with 6N hydrochloric acid, and after 30 minutes, the pH was adjusted to 10.0 with 10N sodium hydroxide. The reaction solution was diluted with 75-ethyl acetate.
After extraction, the organic layers were combined and dried over anhydrous magnesium sulfate, and then the magnesium sulfate was separated from each other (Step A).

To the organic layer, p-}luenesulfonic acid l hydrate (
50 mmol] was added thereto, and crystallization was performed overnight under water cooling. The precipitated crystals were collected, washed with 50 ml of ethyl acetate, and dried in vacuum to give N-(2.2,5.5-tetramethylcyclopentanyl)-(S)-1-aminoethyl-
1-Ammonium p-toluenesulfone}13.5
g (yield 70%) was obtained.

When the amine content was measured by non-aqueous titration method, the purity was 9.
It was 9.6% or more.

Elemental analysis (%): C+sH32NzOaSCHNS Calculated value 7 59.34 8,39 7.2
8 8.34 Actual value: 59.16 8.
21? ．． 13 8.47 [α] 2” = +38
．． 4° (C=0.5.methanol) 1515.
1210. 1150NMR(300M}Iz,
DMSO-d,): δ1.03 (s. 3H).
1.05 (s, 3H). 1.07 (s. 6H)
, 1.37 (d, J=6.45Hz, 3H).
2.09 (s. LH). 2.3Hs. 3H).
4.9Hguint,, J=6.45Hz. IH)
．． 7.15 (d, J=7.92Hz, 2}1).
7.53 (d, J=7.92Hz, 2H) Reference example 1. N-pendyloxycarbonyl-aspartic acid
β-pendyl ester 1 0. After dissolving 0 kg (28 mol) in tetrahydrofuran 651, the solution was cooled and stirred with ice and salt. Then N-methylmorpholine2. 8 3
A solution prepared by diluting 2.5 kg of tetrahydrofuran with 2.51 kg of tetrahydrofuran was added dropwise, and then added to the incubator.3.
A solution prepared by diluting 83 kg (28 mol) with 2.52 ml of tetrahydrofuran was added dropwise while keeping the internal temperature below 10°C, and the mixture was stirred for 30 minutes at an internal temperature of below 10°C. Thereafter, it was obtained in the same manner as in the example. 8.30 kg (22 mol) of N-(2.2.5.5tetramethylcyclobenzenetricarbonyl)-(S)-1-aminoethyl-1-ammonium p-toluenesulfonate was slowly added. A solution diluted with 2.2 kg of N-methylmorpholine and 2.51 kg of lahydrofuran was added dropwise while keeping the internal temperature below 5°C, and stirred at the same temperature for 2 hours. After the reaction was completed,
Water 1 4. 5 j! was added and concentrated under reduced pressure to remove the organic solvent. 4.5 liters of methylene chloride and 3.01 liters of water were added to the residue, stirred, and then separated. The obtained methylene chloride layer was washed with a 5% aqueous citric acid solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.

The crude product was recrystallized from ethyl acetate to give N-(N-penzyloxycarbonyl-β-benzyl-aspartyl)-N'-(2.2.5.5-tetramethylcyclopentane-carbonyl)-(R ) -1. 9.53 kg (yield: 80%) of 1-diaminoethane was obtained.

After concentrating the mother liquor under reduced pressure, the same recrystallization operation is performed to further reduce the
．． 87 kg (yield: 7.3%) of secondary crystals were obtained.Including the primary crystals, a total of 0.3 kg (yield: 87.3%) of the target compound was obtained.

The structure of the obtained target compound was confirmed by the fact that the physicochemical data such as IR and NMR coincided with that of the standard product.

Incidentally, the total yield from N-(2.2.5.5-tetramethylcyclopenkylcarbonyl)-L-alaninamide was 61%.

Reference example 2. The ethyl acetate solution obtained in the same manner as in Step A of the Example was concentrated under reduced pressure, and the obtained oily substance was vacuum-dried for 3 hours.
- (2.2.5.5-tetramethylcyclopenkylcarbonyl) - (S) -1. Oil containing 1-cyaminoethane 1 0. 93 g was obtained. The purity was determined to be 61% by non-aqueous titration.

N-penzyloxycarbonyl-asbarthyl-β-benzyl ester 1 in the same manner as in Reference Example 1 8. 3
By reacting with the mixed acid anhydride prepared from 2.
2,5. 5-tetramethylcyclopentane(R)-1. 1-cyaminoethane 14.9
g (yield 86.0%) was obtained.

The total yield from N-(2.2.5.5-tetramethylcyclopenkylbenyl)-L-alaninamide is 5
It was 4%.

Reference example 3. N- (N-penzyloxycarbonyl-β-benzyl-aspartyl') -N' - (2.2.5.
5-tetramethylcyclopenkylbenyl》(R)-
1.1-diaminoethane5. 52 g was dissolved in a mixed solvent of 50 mg of methanol and 20 mA' of water, and 10
% palladium-add 1.1g of carbon catalyst to 15kg/cr
Catalytic reduction was carried out under 1 hydrogen pressure at room temperature for 5 hours. After the reaction, the catalyst was separated, the P solution was concentrated under reduced pressure, and the residue was poured into 20af of water.
Crystallized from N-(L-aspartyl)-N'-
(2,2,5.5-tetramethylcyclopentane-carbonyl')-(R)-1.1-diaminoethane 2.2
6 g (yield: 69%) was obtained.

The structure of the obtained target compound was confirmed by the fact that the physicochemical data such as IR and NMR coincided with that of the standard product.

Effect of the invention The present invention provides salts of useful intermediates for sweeteners.

Patent applicant (102) Kyowa Hakko Kogyo Co., Ltd. Procedural amendment (voluntary)

Claims (1)

[Claims] p of N-(2,2,5,3-tetramethylcyclopentanecarbonyl)-(S)-1,1-diaminoethane represented by the formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ -Toluenesulfonate.