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Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde

A kind of CH2R1, methyl tert-butyl ether technology, applied in the direction of organic chemistry methods, chemical instruments and methods, preparation of organic compounds, etc.

Pending Publication Date: 2019-01-04
GLOBAL BLOOD THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Therefore, the scale-up of fabrication and isolation may require substantial efforts to achieve these goals

Method used

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  • Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde
  • Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde
  • Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde

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Experimental program
Comparison scheme
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Embodiment approach

[0074] (a) In embodiment (a), the method of the first aspect further comprises formylation of a compound having formula (4):

[0075]

[0076] where each R is -CH(CH 2 R 1 )-OR 2 (where R 1 is hydrogen or alkyl and R 2 is alkyl) or R is tetrahydropyran-2-yl optionally substituted with one, two or three alkyl groups to provide compounds of formula (2).

[0077]

[0078] In a first subembodiment of embodiment (a), each R is the same. In a second subembodiment, the tetrahydropyran-2-yl moiety is unsubstituted. In a third sub-embodiment of embodiment (a), the tetrahydropyran-2-yl moiety is substituted with one, two or three alkyl groups.

[0079] (b) In embodiment (b), the method of embodiment (a) also includes compound (5):

[0080]

[0081] with the formula CHR 1 = CHOR 2 of vinyl ethers (where R 1 is hydrogen or alkyl, and R 2 is an alkyl group) or 3,4-dihydro-2H-pyran optionally substituted by one, two or three alkyl groups,

[0082] Reaction in the presen...

Embodiment 1

[0112] Synthesis of 2,6-Dihydroxybenzaldehyde (Compound (1))

[0113]

[0114] step 1:

[0115] Under the protection of an inert gas, tetrahydrofuran (700 mL) was added to resorcinol (170 g, 1.54 mol, 1 eq), then pyridinium tosylate (3.9 g, 15.4 mmol, 0.01 eq), THF (65 mL), And the reaction mixture was cooled to 0°C-5°C. Ethyl vinyl ether (444 mL, 4.63 mol, 3.0 equiv) was added over 1-1.5 h while maintaining the temperature 3 , while maintaining the reaction solution below 20 °C. separate phases. The organic phase was washed once with 425 mL of water and once with 425 mL of 12.5% ​​NaCl solution and evaporated, azeotroped with THF to give bis-EOE-protected resorcinol (401.2 g, 1.55 mol, 102% uncorrected).

[0116] Step 2:

[0117] Bis-EOE-protected resorcinol (390 g, actual: 398.6 g = 1.53 mol, 1 equiv, corrected for 100% conversion) was added to a 6 L glass vessel under inert gas protection, and THF (1170 mL) was added. The reaction mixture was cooled to -10°C to -5°...

Embodiment 1A

[0123] Alternative Synthesis of 2,6-Dihydroxybenzaldehyde Compound (1)

[0124]

[0125] step 1:

[0126] In a suitable reactor under nitrogen, tetrahydrofuran (207 L) was added to resorcinol (46 kg, 0.42 kmol, 1 equiv), followed by pyridinium tosylate (1.05 kg, 4.2 mol, 0.01 equiv), and The reaction mixture was cooled to 0°C-5°C. Ethyl vinyl ether (90.4 kg, 120.5 L, 125 kmol, 3.0 equiv) was added over 1-1.5 h while maintaining the temperature 3 aqueous solution while maintaining the reaction solution below 20°C. separate phases. The organic phase was washed once with 115 L of water and once with 125.2 kg of 12.5% ​​NaCl solution. The organic layer was dried by azeotropic distillation with THF to a water content value of <0.05% by weight to give bis-EOE-protected resorcinol (106.2 kg, 0.42 kmol) as a solution in THF. An advantage over previously reported protection procedures is that the bis-EOE-protected resorcinol product does not need to be isolated as a pure product...

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Abstract

Disclosed herein are processes for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H- pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde (also referred to herein as Compound (I)) and intermediates used in such processes. Compound (I) binds to hemoglobin and increases it oxygen affinity and hence can be useful for the treatment of diseases such as sickle cell disease.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application No. 62 / 335,583, filed May 12, 2016, which is hereby incorporated by reference in its entirety and for all purposes. technical field [0003] Disclosed herein is the synthesis of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde (compound (I)). methods and intermediates useful in such methods. Compound (I) binds to hemoglobin and increases its oxygen affinity, and thus is useful in the treatment of diseases such as sickle cell disease. Background technique [0004] Compound (I) is disclosed in Example 17 of International Publication No. WO 2013 / 102142. Compound (I) binds to hemoglobin and increases its oxygen affinity, and thus is useful in the treatment of diseases such as sickle cell disease. [0005] Often, for a compound to be suitable as a therapeutic agent or part of a therapeutic agent, the synthesis of the comp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/44C07D231/02C07D401/04
CPCC07C45/65C07C47/575C07D401/04C07B2200/13C07C47/56C07C47/565A61K31/4439
Inventor 李喆N·古兹邵意阳J·科库兹M·佛雷泽G·P·伊安妮库罗斯廖亮
Owner GLOBAL BLOOD THERAPEUTICS
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