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Processes and intermediates useful to make antifolates

A solvent and compound technology, applied in the field of synthetic organic chemistry, can solve problems such as difficulty in obtaining pure compound of general formula XIV, difficulty in separation, etc.

Inactive Publication Date: 2005-08-10
ELI LILLY & CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] If carried out by the Larock method, a mixture of desired and unwanted products is obtained, these components are extremely difficult to separate, and it is difficult to obtain pure compounds of general formula XIV

Method used

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  • Processes and intermediates useful to make antifolates
  • Processes and intermediates useful to make antifolates
  • Processes and intermediates useful to make antifolates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] 4-(4-Methoxyphenyl)butyraldehyde

[0094] Deloxan used below  THP Type 2 resin was pretreated by mixing with isopropanol (2.0 vol, 20 ml) and washing with ethyl acetate (4.0 vol, 40 ml). Filter the organic layer / resin slurry before subsequent use.

[0095] Methyl 4-bromobenzoate (60.0 g, 279.0 mmol), lithium acetate dihydrate (31.31 g, 306.9 mmol), lithium chloride (35.48 g, 837 mmol) and tetrabutylammonium chloride (41.22 g, 131.49 mmol) Add to dimethylformamide (698ml). The resulting solution was degassed by bubbling nitrogen. 3-Buten-1-ol (24.19g, 28.81ml, 334.81mmol) and palladium acetate (1.57g, 6.98mmol) were added and the reaction mixture was heated and stirred at 65°C for about 10 hours. Completion of the reaction was indicated by HPLC monitoring of consumption of starting material (less than 0.4% methyl 4-bromobenzoate remaining) (reverse phase, 60% acetonitrile: 2.5% acetic acid buffer). The reaction mixture was cooled to 25°-30°C, water (700ml) and ethy...

Embodiment 2

[0099] 1-Hydroxy-4-(4-methoxyphenyl)butanesulfonic acid sodium salt

[0100]The ethyl acetate extract of Example 1 was concentrated in vacuo at about 37°C to 3.6 vol (8.7 ml). Alcohol 3A (3 vol, 7.2 ml) and water (0.63 vol, 1.51 ml) were added, followed by sodium bisulfite (1.04 g, 10.03 mmol). The reaction mixture was stirred for about 8 hours. After 10 minutes, the sulfonic acid started to crystallize. through 1 H NMR analysis of the filtrate of the reaction mixture verified the completion of the reaction. The resulting white slurry was filtered to afford the title compound (2.78 g, 8.98 mmol) as a white crystalline solid in about 80% yield. The filter cake was washed with ethanol (1.8 vol) and dried under vacuum at 40°C. Isomer impurities were not detected by NMR.

[0101] 1 H-NMR: (d 6 -DMSO) δ7.86(d, J=8.27Hz, 2H), 7.32(d, J=8.27Hz, 2H), 5.33(d, J=2.3Hz, 1H), 3.84(m, 1H), 3.81( s, 3H), 2.63(m, 2H), 1.75(m, 1H), 1.73(m, 1H), 1.61(m, 1H), 1.48(m, 1H).

[0102] 13...

Embodiment 3

[0105] 1-Hydroxy-2-bromo-4-(4-methoxyphenyl)butyraldehyde

[0106] To a 50 ml round bottom flask equipped with magnetic stirring was added 4-(4-oxobutyl)methyl benzoate sodium bisulfite adduct (3.10 g, 10 mmol), acetonitrile (14 ml) and trimethylchlorosilane ( 3.6ml, 28mmol). Nitrogen was sparged for 5 minutes, then the mixture was heated at 60° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was bright yellow at this point. The mixture was cooled to 5°C and bromine (0.5ml, 9.7mmol) was added. Within 1 minute, the bromine brown color disappeared. The solution was bright yellow and the visible solid was colorless. The mixture was removed from the cooling bath and stirred for an additional 2 hours. Water (14ml) and sodium bisulfite (0.14g) were added to quench the remaining bromine and the resulting mixture was stirred for 1 hour. The mixture was partitioned between dichloromethane (14ml) and a further 7ml of water. The organic phase was separated and strip...

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Abstract

The present application relates to a series of novel sulfonic acid metal cation salts of formula which are useful intermediates to prepare antifolate 5-substituted pyrrolo[2,3-d]pyrimidines. The present invention also relates to a novel process for preparing the sulfonic acid metal cation salts and to a novel process for preparing aldehydes of formula from the corresponding sulfonic acid metal cation salts.

Description

[0001] Pursuant to 37 C.F.R.1.53(b)(2)(ii), this application claims the benefit of U.S. Application 60 / 093039, filed September 26, 1997, which is an extension of U.S. Application 08 / 938385, filed September 26, 1997 transform. field of invention [0002] The present invention relates to synthetic organic chemistry. In particular, the present invention relates to processes for the preparation of intermediates useful in the synthesis of valuable antifolate compounds. Background of the invention [0003] Known compounds having antifolate activity are all recognized as chemotherapeutic agents for the treatment of cancer. Recently, a series of 5-substituted pyrrolo[2,3-d]pyrimidine compounds of general formula XVI and pharmaceutically acceptable salts thereof have been disclosed as antifolates or intermediates for the manufacture of antifolates, for example US.5416211 (U.S.' 211), [0004] [0005] where R is NHC * H(CO 2 R 1 )CH 2 CH ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/519A61P35/00C07C67/313C07C67/317C07C69/76C07C69/767C07C231/12C07C235/84C07C309/24C07C323/56C07C323/60C07D487/04
CPCC07C69/76C07D487/04C07C309/24Y02P20/55A61P35/00C07C229/06
Inventor D·P·谢尔B·J·斯莱特里C·J·巴尼特
Owner ELI LILLY & CO
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