CN111004236A

CN111004236A - Dynamic kinetic resolution method of WXFL10203614 intermediate

Info

Publication number: CN111004236A
Application number: CN201911316935.XA
Authority: CN
Inventors: 王庆林; 王涛; 王彬彬; 游本加; 张莹; 李晓明
Original assignee: Zhuohe Pharmaceutical Group Co Ltd
Current assignee: Zhuohe Pharmaceutical Group Co Ltd
Priority date: 2019-12-19
Filing date: 2019-12-19
Publication date: 2020-04-14
Anticipated expiration: 2039-12-19
Also published as: CN111004236B

Abstract

The invention discloses a dynamic kinetic resolution method of a WXFL10203614 intermediate. Mixing [7- (methylamino) -5,6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-2-yl ] methanol and ethyl acetate with Novozym435, filtering, dissolving, concentrating, separating by silica gel column chromatography to obtain (R) -7-acetamido-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridine-2-hydroxyacetate; (R) -7-acetamido-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-2-glycolate is mixed with an acid reagent to give the (7R) -7- (methylamino) -5,6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-2-yl ] methanol. The method has high product yield and high chiral purity.

Description

Dynamic kinetic resolution method of WXFL10203614 intermediate

FIELD

The invention relates to the field of pharmaceutical chemistry, in particular to a dynamic kinetic resolution method of a WXFL10203614 intermediate.

Background

JAK kinases (Janus kinases) are a family of intracellular non-receptor tyrosine kinases that play important roles in cytokine receptor signaling pathways through interactions with Signal Transducers and Activator of Transcription (STATs). The JAK/STAT signaling pathway is associated with the pathogenesis of a variety of inflammatory diseases, such as Rheumatoid Arthritis (RA). In recent years, JAK inhibitors for the treatment of RA have attracted considerable attention from the pharmaceutical industry.

WXFL10203614 is a new generation of JAK inhibitors with complete intellectual property rights in the company, has already obtained clinical lots, and is now undergoing RA clinical trials.

WXFL10203614

[ (7R) -7- (methylamino) -5,6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-2-yl ] methanol is an important intermediate for the synthesis of WXFL10203614, and the reported route is to firstly carry out chemical resolution on a precursor compound for synthesizing the compound and then synthesize the intermediate by a chiral precursor, wherein the synthesis process may cause certain racemization; and the intermediate synthesized thereafter is chiral tertiary amine, which has great difficulty in resolution.

SUMMARY

The present disclosure relates to a method for dynamic kinetic resolution of a WXFL10203614 intermediate, comprising:

mixing [7- (methylamino) -5,6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-2-yl ] methanol and ethyl acetate with Novozym435, filtering, dissolving, concentrating, separating by silica gel column chromatography to obtain (R) -7-acetamido-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridine-2-hydroxyacetate; and

mixing the (R) -7-acetamido-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridine-2-hydroxyacetate with an acid reagent to obtain the (7R) -7- (methylamino) -5,6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-2-yl ] methanol.

Detailed description of the invention

In the following description, certain specific details are included to provide a thorough understanding of various disclosed embodiments. One skilled in the relevant art will recognize, however, that the embodiments can be practiced without one or more of the specific details, or with other methods, components, materials, and so forth.

Unless otherwise required by the disclosure, throughout the specification and the appended claims, the words "comprise", "comprising", and "have" are to be construed in an open, inclusive sense, i.e., "including but not limited to".

Reference throughout the specification to "one embodiment," "an embodiment," "in another embodiment," or "in certain embodiments" means that a particular reference element, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment, and furthermore, particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.

Definition of

In the present disclosure, the term "dynamic kinetic resolution" is a process combining enzyme catalysis (kinetic resolution of the racemate) with metal catalysis (catalysis of the racemization of S).

The term "racemate" is an equimolar mixture of a chiral molecule (see chirality) and its enantiomers with optical activity (see optical isomers).

In the present disclosure, the term "Novozym 435" is a lipase derived from B-lipase, prepared by submerged fermentation with a genetically modified Aspergillus oryzae microorganism and absorption on a macroporous resin.

In the present disclosure, the term "separation principle of silica gel chromatography" is to separate substances according to their different adsorption forces on silica gel, and in general, substances with relatively high polarity are easily adsorbed by silica gel, substances with relatively low polarity are not easily adsorbed by silica gel, and the whole chromatography process is adsorption, desorption, re-adsorption and re-desorption.

In the present disclosure, the term "elution" refers to the process in which, in an elution chromatography operation, a mobile phase carries the component to be measured forward in and out of a chromatography column, the flow phase used being referred to as the eluent.

In the present disclosure, the term "optically active" refers to two enantiomers of a chiral molecule, each of which rotates plane-polarized light to an angle that is the same in value but opposite in direction. The enantiomeric composition of a compound sample can be described in terms of "enantiomeric excess" or "e.e.%. It represents the excess of one enantiomer over the other, usually expressed as a percentage.

In the present disclosure, the term "recrystallization" is a method of separating components of a mixture from each other by using their solubility in a certain solvent or their solubility at different temperatures in the same solvent.

Detailed Description

The reaction formula is as follows:

in certain embodiments, "(7R) -7- (methylamino) -5,6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-2-yl ] methanol" is provided by stanford pharmaceutical limited.

In certain embodiments, the acid agent is selected from hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, or mixtures thereof.

In certain embodiments, the acid agent is selected from hydrochloric acid.

In certain embodiments, the silica gel column separation eluent is selected from dichloromethane/methanol, ethyl acetate/cyclohexane, chloroform/ethanol or mixtures thereof.

In certain embodiments, the silica gel column chromatography eluent is selected from ethyl acetate/cyclohexane.

In certain embodiments, the volume ratio of ethyl acetate to cyclohexane is 1: 3.

In certain embodiments, (R) -7-acetamido-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridine-2-hydroxyacetate is combined with concentrated hydrochloric acid by reflux reaction.

In certain embodiments, the reflux time is from 0 to 40 hours.

In certain embodiments, the reflux time is from 2 to 10 hours.

In certain embodiments, the reflux time is 4 hours.

In certain embodiments, the reflux temperature is from 0 to 100 ℃.

In certain embodiments, the reflux temperature is 40 ℃.

In certain embodiments, the reflux reaction is followed by extraction.

In certain embodiments, the extractant is selected from dichloromethane, acetone, tetrahydrofuran, water, or mixtures thereof.

In certain embodiments, the extractant is selected from dichloromethane.

In certain embodiments, a recrystallization step after extraction is also included.

In certain embodiments, the recrystallization is performed using isopropanol, methanol, ethanol, acetone, or a mixture thereof.

In certain embodiments, recrystallization is performed using a mixture of isopropanol and water.

In certain embodiments, the volume ratio of isopropanol to water is 4: 1.

Example 1

1. Intermediate 1

10g of racemate are added into 300ml of ethyl acetate, 60g of Novozym435 is added continuously, the mixture is reacted for 96 hours at room temperature in a shaking flask (180r/min) under the protection of nitrogen, the reaction is stopped, the Novozym435 is removed by filtration, the reaction solution is concentrated and separated by a silica gel column, and an eluent is ethyl acetate/cyclohexane (1/3), so that 4.2g of white solid is obtained.

2. [ (7R) -7- (methylamino) -5,6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-2-yl ] methanol

2g of (R) -7-acetamido-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridine-2-hydroxyacetate was added to 20ml of concentrated hydrochloric acid, reacted for 4 hours, naturally cooled to room temperature, neutralized with 2M sodium hydroxide, extracted with dichloromethane 3 times, the organic layers were combined and washed with water, dried over anhydrous magnesium sulfate, dichloromethane was removed under reduced pressure, and the residue was recrystallized from isopropanol/water (4/1) to give 1.1g of a white solid with an ee value of 99.5%.

From the foregoing it will be appreciated that, although specific embodiments of the disclosure have been described herein for purposes of illustration, various modifications or improvements may be made by those skilled in the art without departing from the spirit and scope of the disclosure, and that such modifications or improvements are intended to be within the scope of the appended claims.

Claims

1. A method for dynamic kinetic resolution of a WXFL10203614 intermediate comprising:

2. The dynamic kinetic resolution method of claim 1, wherein said acid agent is selected from hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid or mixtures thereof, preferably the acid agent is selected from hydrochloric acid.

3. The dynamic kinetic resolution method of claim 1 or 2, wherein the silica gel column separation eluent is selected from dichloromethane/methanol, ethyl acetate/cyclohexane, chloroform/ethanol or mixtures thereof, preferably the silica gel column chromatography eluent is selected from ethyl acetate/cyclohexane, more preferably the volume ratio of ethyl acetate to cyclohexane is 1: 3.

4. The dynamic kinetic resolution method according to any one of claims 1 to 3, wherein said (R) -7-acetamido-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridine-2-hydroxyacetate is mixed with concentrated hydrochloric acid by reflux reaction for 0 to 40 hours, preferably for 2 to 10 hours, more preferably for 4 hours; the reflux temperature is 0 to 100 ℃, preferably 40 ℃.

5. The dynamic kinetic resolution method of claim 4, wherein said refluxing reaction is followed by extraction with an extractant selected from the group consisting of dichloromethane, acetone, tetrahydrofuran, water or mixtures thereof, preferably with an extractant selected from the group consisting of dichloromethane.

6. The dynamic kinetic resolution method of any one of claims 4 or 5, further comprising a recrystallization step after extraction, preferably using isopropanol, methanol, ethanol, acetone or a mixture thereof, more preferably using a mixture of isopropanol and water, preferably at a volume ratio of isopropanol to water of 4: 1.