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Melphalan intermediate and preparation method thereof

An intermediate and system technology, applied in the field of compound synthesis, can solve problems such as inability to overcome immune evasion, and achieve the effects of improving stereoselectivity, mild reaction conditions and high yield

Inactive Publication Date: 2019-07-23
CHIRAL QUEST (SUZHOU) CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the past, immunotherapeutic regimens were often designed to mainly stimulate tumor-specific host immune responses, but were unable to overcome the key mechanism of immune evasion caused by tumors, which has become the main limitation of the regimen

Method used

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  • Melphalan intermediate and preparation method thereof
  • Melphalan intermediate and preparation method thereof
  • Melphalan intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] A kind of preparation method of Melphalan intermediate is as follows:

[0045] Step 1:

[0046]

[0047] In a 2L round bottom flask, 165.3g of p-nitrobenzaldehyde was added to 2L of methylene chloride, and 321.2g of methyl 2-acetamido-2-(dimethoxyphosphoryl)acetate was added. Add 237.4g DBU dropwise at 0°C. After the dropwise addition, monitor the reaction for about 2 hours until the raw material disappears. Add 900 mL of 5% sulfuric acid aqueous solution dropwise, filter, and rinse the filter cake with 450 mL of water. Collect the filter cake. After the filter cake was dried, 298.3 g of a yellow solid was obtained, which was the target product. Yield 98.2%, purity 98.1%.

[0048] 1H NMR (400MHz, CDCl3): δ=8.23(d,2H), 7.57(d,2H), 7.42(d,2H), 3.92(s,2H), 2.16(s,3H).

[0049] MS+: 265.1

[0050] Step 2:

[0051]

[0052] In a 2000 mL hydrogenation kettle, 237.9 g of the substrate compound 2 and 145 mg of Rh(ScRp-DuanPhos) (NBD) BF4 were added to 1200 mL of me...

Embodiment 2

[0108] A kind of preparation method of Melphalan intermediate is as follows:

[0109] Step 1:

[0110]

[0111] In a 2L round bottom flask, 181.2g of p-nitrobenzaldehyde was added to 2L of methylene chloride, and 344.4g of methyl 2-acetamido-2-(dimethoxyphosphoryl)acetate was added. Add 237.4g of DBU dropwise at 3°C. After the dropwise addition, monitor the reaction for about 2 hours until the raw material disappears. Add 900 mL of 5% sulfuric acid aqueous solution dropwise, filter, and rinse the filter cake with 450 mL of water. Collect the filter cake. After the filter cake was dried, 311.7 g of a yellow solid was obtained, which was the target product. Yield 98.8%, purity 98.9%.

[0112] 1H NMR (400MHz, CDCl3): δ=8.23(d,2H),7.57(d,2H),7.42(d,2H),3.92(s,2H),2.16(s,3H).

[0113] MS+: 265.1

[0114] Step 2:

[0115]

[0116] In a 2000 mL hydrogenation kettle, 237.9 g of the substrate and 145 mg of Rh(ScRp-DuanPhos)(NBD)BF4 were added to 1200 mL of methanol. Under...

Embodiment 3

[0172] A kind of preparation method of Melphalan intermediate is as follows:

[0173] Step 1:

[0174]

[0175] In a 2L round bottom flask, 190.5g of p-nitrobenzaldehyde was added to 2L of methylene chloride, and 344.4g of methyl 2-acetamido-2-(dimethoxyphosphoryl)acetate was added. 237.4g of DBU was added dropwise at 5°C. After the dropwise addition, the reaction was monitored for about 2 hours until the raw material disappeared. Add 900 mL of 5% sulfuric acid aqueous solution dropwise, filter, and rinse the filter cake with 450 mL of water. Collect the filter cake. After the filter cake was dried, 317.5 g of a yellow solid was obtained, which was the target product, compound 2. Yield 98.9%, purity 99.2%.

[0176] 1H NMR (400MHz, CDCl3): δ=8.23(d,2H),7.57(d,2H),7.42(d,2H),3.92(s,2H),2.16(s,3H).

[0177] MS+: 265.1

[0178] Step 2:

[0179]

[0180] In a 2000 mL hydrogenation kettle, 241.2 g of the substrate and 145 mg of Rh(ScRp-DuanPhos) (NBD) BF4 were added to ...

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Abstract

The invention discloses a Melphalan intermediate and a preparation method thereof. The Melphalan intermediate is prepared by acidifying a compound p-nitrobenzaldehyde under the action of methanol, a hydrochloric acid solvent, etc. The preparation method has a route with mild reaction conditions, is higher than an existing preparation method in yield, is economical and effective, and is suitable for large-scale industrial production. The synthesis route is as shown in the description.

Description

technical field [0001] The invention relates to the technical field of compound synthesis, in particular to a Melphalan intermediate and a preparation method thereof. Background technique [0002] Melphalan (Melphalan) is an anti-tumor western medicine, which has obvious curative effect on multiple myeloma, and is also suitable for ovarian cancer; Levosarcomolysin. [0003] On October 27, 2017, the list of carcinogens released by the International Agency for Research on Cancer of the World Health Organization was initially compiled for reference. list. [0004] In the past, immunotherapy programs were often designed to mainly stimulate tumor-specific host immune responses, and the inability to overcome the key mechanism of immune evasion caused by tumors has become the main limitation of the program. Among the many defined mechanisms for diminishing anti-tumor immune responses, T regulatory cells (Treg), myeloid-derived suppressor cells, and tolerizing dendritic cells (DC...

Claims

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Application Information

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IPC IPC(8): C07C227/16C07C229/42C07C227/18C07C229/34C07C231/12C07C233/48C07D209/48
CPCC07B2200/07C07C227/16C07C227/18C07C229/42C07C231/12C07D209/48C07C229/34C07C233/48
Inventor 陈翀吴生文李文革吴磊
Owner CHIRAL QUEST (SUZHOU) CO LTD
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