A process for the manufacture of (2s,3s,4s,5r,6s)-3,4,5-trihydroxy-6-(((4ar,10ar)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2h-pyran-2-carboxylic acid and intermediate thereof

A technology of iminoethoxy and triacetate used in the manufacture of (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4AR,10AR) -7-Hydroxy-1-propyl-1,2,3,4,4A,5,10,10A-octahydrobenzo[G]quinolin-6-yl)oxy)tetrahydro-2H-pyran - Field of 2-formic acid and its intermediates, capable of solving unsatisfied problems

Active Publication Date: 2021-12-03
H LUNDBECK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] Despite long standing interest in this field, there is clearly still an unmet need for the development of highly effective, well tolerated and orally active drugs for the treatment of PD

Method used

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  • A process for the manufacture of (2s,3s,4s,5r,6s)-3,4,5-trihydroxy-6-(((4ar,10ar)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2h-pyran-2-carboxylic acid and intermediate thereof
  • A process for the manufacture of (2s,3s,4s,5r,6s)-3,4,5-trihydroxy-6-(((4ar,10ar)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2h-pyran-2-carboxylic acid and intermediate thereof
  • A process for the manufacture of (2s,3s,4s,5r,6s)-3,4,5-trihydroxy-6-(((4ar,10ar)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2h-pyran-2-carboxylic acid and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0262] Preparation of compounds of formula (Id) and intermediates

[0263] NMR method

[0264] QNMR (600MHz):

[0265]

[0266]

[0267] LC-MS method

[0268] Method A: LC-MS run on a Waters Aquity UPLC-MS consisting of: Waters Aquity including column manager, binary solvent manager, sample organizer, PDA detector (operating at 254nM), ELS detection detector and a TQ-MS equipped with an APPI source operating in positive ion mode.

[0269] LC-conditions: the column is Acquity UPLC BEH C18 1.7μm; 2.1x150mm, at 60°C at 0.6ml / min by water + 0.05% trifluoroacetic acid (A) and acetonitrile / water (95:5) + 0.05% trifluoroacetic acid Binary gradient operation composed of fluoroacetic acid.

[0270] gradient (linear):

[0271] 0.00min 10%B

[0272] 3.00min 100%B

[0273] 3.60min 10%B

[0274] Total runtime: 3.6 minutes

[0275] Method B: LC-MS was run on an Agilent 1260 HPLC consisting of column components, binary pump, Hip sample, and a single Q-MS equipped with an E...

example 1

[0305] Example 1: Preparation of Compound (A2) (Step 1)

[0306] Example 1a:

[0307] 15g (50.4mmol, 1 equivalent) of the HCl salt of compound (I), 450ml of dry dichloromethane, 40.4ml (232mmol) of N,N-diisopropylethylamine (DIPEA) and 20.5 ml (96 mmol, 1.9 equivalents) of triisopropylsilyl chloride. The mixture was stirred at 20°C-25°C under an inert atmosphere. After 48 h, the reaction mixture was cooled to 0-5 °C and saturated NH 4 Cl solution (300ml). The mixture was stirred for 10 minutes, and then the phases were separated. The organic layer was washed with deionized water (2 × 150ml) in Na 2 SO 4 Drying and evaporation gave compound (A2) (27.8 g). Used directly in the next step (Example 2a).

[0308] LC-MS (Method A): retention time (RT) = 2.71 min, [M+H] + = 418.2 m / z.

[0309] Example 1b:

[0310] In a 3 L three-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen, place the HCl salt of compound (I) (68 g, 228 mmol), dichloro...

example 2

[0313] Example 2: Preparation of Compound (A3) (Step 2)

[0314] Example 2a:

[0315] Equipped with CaCl 2 A 500ml three-necked flask with a tube was charged with compound (A2) (8.7g, 21mmol), anhydrous dichloromethane (260mL) and (2S, 3S, 4S, 5R, 6R)-2-(methoxycarbonyl)- 6-(2,2,2-Trichloro-1-iminoethoxy)tetrahydro-2H-pyran-3,4,5-triyltriacetate (20 g, 42 mmol). The solution was cooled to 0-5 °C and boron trifluoride diethyl ether (5.2 mL, 42 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. Pour the reaction mixture into ice-cold saturated NaHCO 3 solution (770mL). After stirring for 10 minutes, the phases were separated and the aqueous phase was extracted with dichloromethane (235 mL). The combined organic phases were dissolved in Na 2 SO 4 Drying and evaporation to dryness gave 27.9 g of crude product as an oil.

[0316] The crude material was purified by normal phase silica gel column chromatography to afford comp...

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Abstract

The present invention relates to a process for manufacturing (2S,3S,4S,5R,6S)-3,4,5- trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a- octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid with the formula (Id) below and pharmaceutically acceptable salts thereof. The compound of formula (Id) is a prodrug of a catecholamine for use in treatment of neurodegenerative diseases and disorders such as Parkinson's Disease. The invention also relates to a new intermediate of said process.

Description

technical field [0001] The present invention relates to compounds (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(((4aR,10aR )-7-Hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyridine furan-2-carboxylic acid method. The invention also relates to novel intermediates of said process and methods of making said intermediates. Background technique [0002] Parkinson's disease (PD) is a common neurodegenerative disorder that becomes more prevalent with age and affects an estimated seven to ten million people worldwide. Parkinson's disease is a multifaceted disease characterized by both motor and non-motor symptoms. Motor symptoms include resting tremor (tremor), bradykinesia / akinesia (slowness and difficulty of movement), muscle rigidity, postural instability, and gait disturbance; nonmotor symptoms include neuropsychiatric disorders (eg, depression, psychotic symptoms , anxiety, apathy, mild cognitive impairment, and dementia) as well as autonomic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H1/00C07H15/26A61P25/16A61P25/00A61P25/14A61P25/28A61P25/18A61P25/30A61P25/24A61P3/04A61P15/10A61P15/00A61P35/00A61P13/12A61P9/12A61K31/706
CPCC07H1/00C07H15/26A61P25/16A61P25/00A61P25/14A61P25/28A61P25/18A61P25/30A61P25/24A61P3/04A61P15/10A61P15/00A61P35/00A61P13/12A61P9/12C07H15/02C07H17/02A61K31/706
Inventor M·祖尔M·F·贾科布森L·克韦尔诺
Owner H LUNDBECK AS
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