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N-methyl-homocysteines and their use as well as process for their production

A technology of methyl and ylmethyloxycarbonyl, which is applied to N-methyl-homocysteine ​​and its application and preparation fields, can solve the problem that the yield is only 22% and the like

Inactive Publication Date: 2007-03-14
CIS BIO INT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the Friedinger method, the reaction of Fmoc-L-methionine with formaldehyde to form the oxazolidinone yielded 88%, but the reduction to Fmoc-N-methyl-L-methionine with triethylsilane remained stable even after 5 days. Not complete, and the yield is only 22% (J.Org.Chem.1983, 48, 77-81)

Method used

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  • N-methyl-homocysteines and their use as well as process for their production
  • N-methyl-homocysteines and their use as well as process for their production
  • N-methyl-homocysteines and their use as well as process for their production

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] a) N-(tert-oxycarbonyl)- A mixture of L-methionine (0.4mol), 100g of paraformaldehyde (3.3mol), 200g of anhydrous magnesium sulfate (1.7mol) and 4g of p-toluenesulfonic acid (0.02mol) in 1L of toluene was heated for 3 hours to 90 ℃. After cooling to 20°C, 800 ml of a saturated sodium bicarbonate solution was added thereto while cooling with ice. It was filtered and the residue was washed with 400 ml of ethyl acetate. The organic phase is extracted with 300 ml of water, dried over sodium sulfate and evaporated to dryness in vacuo. The crude product was dissolved in 150 ml of hexane / ethyl acetate 1:3, then filtered on silica gel and washed again with 500 ml of hexane / ethyl acetate 1:3. Evaporation to dryness in vacuo gave 85.3 g (0.33 mmol, 83% of theory) of a yellow oil.

[0028] Calculated: C 50.56 H 7.33 N 5.36 S 12.27

[0029] Found: C 50.38 H 7.24 N 5.43 S 12.10

[0030] IR: 2980, 2920, 1800, 1715, 1390, 1170, 1050

[0031] NMR (CDCl 3 ): 1.5(9H), 2.1(3H), 2....

Embodiment 2

[0056] Using N-(tertoxycarbonyl)-D-methionine in place of N-(tertoxycarbonyl)-L-methionine as described above, the enantiomeric compound of the title compound of Example 1d can be obtained similarly.

[0057] a) tert-butyl-(R)-4-[2-(methylsulfanyl)ethyl)]-5-oxooxazolidinone-3-carboxylate

[0058] Calculated: C 50.56 H 7.33 N 5.36 S 12.27

[0059] Found: C 50.30 H 7.51 N 5.50 S 12.41

[0060] IR: 2980, 2920, 1800, 1715, 1390, 1175, 1050

[0061] NMR (CDCl 3 ): 1.5(9H), 2.08(3H), 2.15-2.35(2H), 2.5-2.68(2H), 4.33(1H), 5.21(1H), 5.48(1H)

[0062] MS(EI): m / z 261, 205, 188, 116, 100, 57

[0063] b) N-methyl-D-methionine

[0064] Calculated: C 44.15 H 8.03 N 8.58 S 19.64

[0065] Found: C 43.98 H 7.81 N 8.70 S 19.82

[0066] IR: 3430, 3010, 2920, 2830, 2420, 1630, 1580, 1395

[0067] NMR (D 2 O): 2.13(3H), 2.12-2.22(2H), 2.55-2.68(2H), 2.74(3H), 3.68-3.73(1H)

[0068] MS(EI): m / z 163, 145, 118, 88, 70, 61

[0069] CD (water): 200nm, Δε 1.87

[0070] c) N-methyl-S-trityl...

Embodiment 3

[0083] N-Benzyloxycarbonyl-N-methyl-S-trityl-L-homocysteine

[0084] 16.6 g (0.042 mol) of N-methyl-S-trityl-L-homocysteine ​​(the title compound of Example 1c) were suspended in 90 ml of water and 100 ml of THF, then 12.58 g of (0.12 mol) of sodium carbonate. At 10° C., a solution of 10.97 g (0.044 mol) of N-benzyloxycarbonyloxysuccinimide in 50 ml THF is added dropwise and stirred at 10° C. for a further 3 hours. It is then mixed with 80 ml of water and 130 ml of ethyl acetate, stirred at room temperature for 10 minutes, and then brought to pH 4 with citric acid. The organic phase was washed twice with 100 ml of water and once with 100 ml of common salt solution. The aqueous phase was then extracted once more with 100 ml of ethyl acetate. The combined organic phases are evaporated to dryness in a vacuum; the residue is chromatographed on silica gel (mobile solvent: dichloromethane / acetone 6:4). This gave 22.08 g (87% of theory) of the product as a solid colorless foam. ...

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Abstract

Disclosed is the synthesis of N-methyl-homocystines and the use thereof.

Description

technical field [0001] The present invention relates to the subject-matter characterized in the claims, namely, N-methyl-homocysteine ​​of the general formulas I and II, their use and processes for their preparation. Background technique [0002] N-Methyl-amino acids are useful intermediates in synthetic chemistry. Major medicinal chemistry uses such ingredients very frequently, since many highly potent and selective drugs contain N-methyl-amino acids. [0003] Optically active N-methyl-amino acids are all naturally individual compounds (e.g. N-methyl-tryptophan; Liebigs Ann. Chem. 1935, 520, 31-34), but are also found as a component of many natural bioactive substances. Components such as dolastatin (G.R.Pettit et al., J.Org.Chem. 1990, 55, 2989-2990; Tetrahedron 1993, 41, 9151-9170) or didemnins (K.L.Rinehart et al., J.Nat.Prod. .1988, 51, 1-21; J Am. Chem. Soc. 1987, 109, 6846-6848; J. Am. Chem. Soc. 1995, 117, 3734-3748). Other examples are jasplakinolide (J.Org.Chem....

Claims

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Application Information

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IPC IPC(8): C07C229/12C07C323/56A61K38/12C07CC07C319/20C07C323/58C07C323/59C07K7/54C07K7/64
CPCC07K7/06C07K7/52C07C319/20C07K7/64Y02P20/55C07C323/58C07C323/59C07C323/56
Inventor 马克·维卢恩约翰内斯·普拉策克埃克哈德·奥托奥尔林·彼得罗夫克劳迪娅·博尔姆迪尔克·欣茨格雷戈尔·曼约翰·利斯特-詹姆斯戴维·M·威尔逊
Owner CIS BIO INT
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