Method for preparing (R)-1, 4-dichloro-5-(methyl-d3)-6, 7-dihydro-5H-cyclopenta [d] pyridazine
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- HAISCO PHARMACEUTICAL GROUP CO LTD
- Filing Date
- 2024-09-11
- Publication Date
- 2026-04-17
AI Technical Summary
The existing methods have problems of low production efficiency, high cost and long production cycle in the preparation of optically pure (R)-1,4-dichloro-5-(methyl-d3)-6,7-dihydro-5H-cyclopentene[d]pyridazine.
By using optically active organic acids to form diastereomeric complexes with different solubility with the target compound, crystallization separation is performed, and the optically active purity of the compound is gradually improved until it reaches an ee value of 99.5% or higher.
The high optical purity preparation of the compound is achieved, which reduces production costs, shortens the production cycle, and improves the preparation efficiency, and is suitable for large-scale industrial production.
Smart Images
Figure CN121889375A_ABST
Abstract
Description
A method for preparing (R)-1,4-dichloro-5-(methyl-d3)-6,7-dihydro-5H-cyclopenta[d]pyridazine Technical Field
[0001] The present invention relates to a method for preparing optical isomers, in particular to a method for preparing (R)-1,4-dichloro-5-(methyl-d3)-6,7-dihydro-5H-cyclopenta[d]pyridazine, and belongs to the field of organic synthesis. Background Art
[0002] Classic familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder characterized by markedly elevated serum low-density lipoprotein cholesterol (LDL-C) levels and skin / tendon xanthomas, which can lead to premature cardiovascular disease. FH is commonly divided into heterozygous familial hypercholesterolemia (HeFH) and the rarer homozygous familial hypercholesterolemia (HoFH). The prevalence of HeFH is estimated to be as high as 0.2%-0.48%. FH is typically caused by inactivating mutations in the LDL receptor (LDLR). Statins are the preferred treatment option, not only lowering LDL-C levels but also improving prognosis in FH patients. Patients who do not respond well to statins or experience adverse reactions can be treated with the cholesterol absorption inhibitor ezetimibe. For patients who fail to achieve satisfactory results despite these treatments, PCSK9 inhibitors can be added. Although there are treatments for HeFH, many patients (up to 40% of HeFH patients) still cannot achieve target cholesterol (LDL-C) levels after these treatments, and the accumulation of cholesterol in their bodies becomes a lifelong burden.
[0003] Thyroid hormone receptors are divided into two subtypes: α and β. Thyroid hormones bind to the β subtype receptor and promote cholesterol metabolism. Consequently, a variety of thyroid hormone analogs or thyroxine-mimetic drugs that selectively activate the β subtype have been developed in recent years. Clinical results show that MGL-3196, an oral agonist developed by Madrigal, can significantly lower LDL-C levels in patients and improve metabolic syndrome (such as insulin resistance and dyslipidemia) and fatty liver disease (including lipotoxicity and inflammation).
[0004] Compound patent WO2019240938A1 discloses an R-configured compound of formula (IV) having THRβ binding activity, wherein the compound of formula (I) can be used as a key intermediate for synthesizing compound of formula (IV).
[0005] Therefore, a method for preparing an optically pure isomer of the compound of formula (IV) in the R configuration is needed.
[0006] The method for preparing the optically pure isomer of the R-configured compound of formula (IV) is based on the preparation of the intermediate compound (R)-1,4-dichloro-5-(methyl-d3)-6,7-dihydro-5H-cyclopenta[d]pyridazine, namely formula (I).
[0007] WO2019240938A1, CN111484481A, CN114057701A, and WO2022099060A2 do not separate the corresponding isomer mixture of formula (I). They all only involve the use of SFC chiral preparative columns to separate and prepare products containing fragments of formula (I). However, this method has defects such as low preparation efficiency, high cost, and long production cycle. Therefore, it is necessary to provide an industrial application method for preparing compound formula (I).
[0008] Summary of the Invention
[0009] The present invention provides a process that can be easily used on an industrial level to prepare the compound (R)-2-(3,5-dichloro-4-((7-(methyl-d3)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile compound of formula (IV) with a high optical purity that makes it useful for pharmaceutical purposes.
[0010] The solution provided by the present invention is based on the inventors' observation that certain optically active organic acids can form diastereomeric complexes with enantiomers of formula (I) in a reaction medium with different solubilities, which allows their separation by crystallization. When a mixture of these diastereomeric complexes is crystallized in a reaction medium or in a suitable solvent, due to their different solubilities, the resulting crystals are enriched in diastereomeric complexes of enantiomers of formula (I), which are useful as intermediate compounds for the preparation of formula (IV). The separation and purification of the diastereomeric complexes and their subsequent release yield the aforementioned intermediates of high optical purity.
[0011] The method of the present invention can obtain the intermediate compound of formula (I) by continuous recrystallization or resuspension of the corresponding diastereomeric complex, and its ee value has an optical purity similar to or higher than 99%, preferably higher than 99.5%.
[0012] The present invention provides a method for preparing a compound represented by formula (I), comprising using an optically active form of dibenzoyltartaric acid or a hydrate of its optically active form as a chiral reagent to participate in the reaction and performing optical isomer resolution on an isomer mixture represented by formula (A):
[0013] In some embodiments, the chiral reagent is L-dibenzoyltartaric acid or a hydrate thereof.
[0014] In some embodiments, the chiral reagent is D-dibenzoyltartaric acid or a hydrate thereof.
[0015] In some embodiments, the preparation method comprises:
[0016] 1) reacting a chiral reagent with a mixture of enantiomers of formula (A) to obtain a compound of formula (II);
[0017] 2) treating the compound of formula (II) with an alkali to obtain the compound of formula (I); or treating the compound of formula (II) with an alkali and extracting with an organic solvent to obtain the compound of formula (I);
[0018] wherein the chiral reagent is selected from L-dibenzoyltartaric acid or a hydrate thereof;
[0019] The base is selected from sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, and ammonia water;
[0020] The organic solvent used in the extraction is selected from methyl tert-butyl ether, ethyl acetate, isopropyl acetate, dichloromethane, 2-methyltetrahydrofuran, and toluene;
[0021] In some embodiments, the preparation method comprises:
[0022] 1) reacting a chiral reagent with the enantiomeric mixture of formula (A) to obtain a compound of formula (III);
[0023] 2) treating the compound of formula (III) with an alkali to obtain the compound of formula (I); or treating the compound of formula (III) with an alkali and extracting with an organic solvent to obtain the compound of formula (I);
[0024] wherein the chiral reagent is selected from D-dibenzoyltartaric acid or a hydrate thereof;
[0025] The base is selected from sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, and ammonia water;
[0026] The organic solvent used in the extraction is selected from methyl tert-butyl ether, ethyl acetate, isopropyl acetate, dichloromethane, 2-methyltetrahydrofuran, and toluene;
[0027] In some embodiments, the preparation method comprises:
[0028] 1) reacting D-dibenzoyltartaric acid or a hydrate thereof with a mixture of enantiomers of 1,4-dichloro-5-(methyl-d3)-6,7-dihydro-5H-cyclopenta[d]pyridazine to obtain a compound of formula (III);
[0029] 2) reacting the compound of formula (III) in 1) with L-dibenzoyltartaric acid or a hydrate thereof, and then treating with a base to obtain a compound of formula (I);
[0030] 3) Repeat step 2) to further obtain a compound of formula (I) with a higher ee value.
[0031] In some embodiments, the molar ratio of the enantiomeric mixture of formula (I) represented by formula (A) to optically active dibenzoyltartaric acid is 1:0.1-2.0, preferably 1:0.8-1.8.
[0032] In some embodiments, the reaction solvent used in the splitting is selected from at least one of n-pentane, n-hexane, cyclohexane, n-octane or isooctane, preferably isooctane.
[0033] In some embodiments, the method for preparing the enantiomers of Formula (I) is carried out by treating the enantiomer mixture of Formula (I) (Formula (A)) with D-dibenzoyltartaric acid or a hydrate thereof, L-dibenzoyltartaric acid or a hydrate thereof in a suitable solvent to perform optical resolution. The resulting complex can be recrystallized or resuspended as many times as necessary until the desired optical purity is achieved. Subsequently, the formed complex can be released with a base to obtain the free compound of Formula (I).
[0034] The precipitation and subsequent recrystallization or resuspension of these diastereomeric complexes can be carried out in a suitable solvent such as n-pentane, n-hexane, cyclohexane, n-octane, isooctane or a mixture thereof. In a specific embodiment, the solvent is isooctane.
[0035] The proportion of the optically active organic acid to be added may be about 0.1 to about 2.0 equivalents, preferably 0.8 to 1.8 equivalents, compared to the initial enantiomeric mixture of formula (I).
[0036] The present invention also aims to provide a complex of the intermediate compound of formula (I) and optically active L-dibenzoyltartaric acid or D-dibenzoyltartaric acid, which are the following structures (II) and (III), respectively.
[0037] In addition, the present invention also provides the use of the complexes of the above formula (II) and (III) as intermediates in the preparation of (R)-2-(3,5-dichloro-4-((7-(methyl-d3)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile.
[0038] The method of the present invention has the advantages of low price of reaction starting materials, simple post-processing operation, high yield, high chemical and chiral purity of products, and suitability for large-scale industrial production. DETAILED DESCRIPTION
[0039] Example 1
[0040] Reaction formula:
[0041] Formula (A) (which is a mixture of the compound of formula (I) and its enantiomers) (1.0 eq), 0.8 eq of dibenzoyl-D-tartaric acid, and isooctane (50V) were added to a reactor and the temperature was raised to 30°C and maintained for 2-3 hours, then continued to rise to 45°C and maintained overnight (a small sample of the mother liquor may be taken midway to control isomers). The reaction was then maintained at 45°C and filtered while hot. The filtrate was collected and concentrated under reduced pressure at 45°C to obtain formula (I) with a certain optical purity. The yield was 45.5% and the ee value was 60%.
[0042] Formula (I) of a certain optical purity, dibenzoyl-L-tartaric acid (1.5 eq), and isooctane (50 V) were added to a reactor and heated to 30°C for 2-3 hours, then continued to 45°C overnight. The filter cake was collected. MTBE (10 V) was added to the filter cake, stirred to dissolve, and then H2O (7 V) was added. The mixture was stirred and cooled to 5-15°C. 1N NaOH (2.05 eq) was added dropwise. After the addition was complete, the mixture was stirred for 0.5 hours, allowed to stand for separation, and the aqueous phase was discarded. The organic phase was washed once with 10% NaCl (4 V) solution, allowed to stand for separation, and concentrated to dryness under reduced pressure at 45°C to obtain Formula (I) of certain optical purity. The yield was 76.8% and the ee value was 90%.
[0043] The concentrated dry sample (1.0 eq), dibenzoyl-L-tartaric acid (1.8 eq), and isooctane (50 V) were added to a reactor and heated to 30°C for 2-3 hours, then to 45°C overnight. The mixture was then kept at 40°C and filtered to collect the filter cake. MTBE (10 V) was added to the filter cake, stirred to dissolve, and then H2O (7 V) was added. The mixture was stirred and cooled to 5-15°C. 1N NaOH (2.05 eq) was added dropwise. After the addition was complete, the mixture was stirred for 0.5 hours, allowed to stand for separation, and the aqueous phase was discarded. The organic phase was washed once with 10% NaCl (4 V) solution, allowed to stand for separation, and concentrated to dryness under reduced pressure at 45°C to yield compound (I). The yield was 79.2% and the ee value was 99.5%.
[0044] Example 2
[0045] Reaction formula:
[0046] A reaction kettle was charged with 500.25 kg of isooctane, 14.50 kg of the compound of formula (A) (which is a mixture of the compound of formula (I) and its enantiomers), and 21.17 kg of D-(+)-dibenzoyltartaric acid monohydrate. After the additions were complete, the reaction was maintained at 30±5°C (optimum temperature 28-30°C) for approximately 16 hours. After the reaction, the contents of the kettle were centrifuged while maintaining the temperature at 30±5°C. The filtrate was collected and the filter cake was washed with 33.35 kg of isooctane. The filtrate was concentrated to dryness under reduced pressure at 55±5°C. Compound (I) of certain optical purity was obtained with a yield of 47.8% and an ee value of 68%.
[0047] Formula (I) with a certain optical purity, dibenzoyl-L-tartaric acid (1.5 eq) and isooctane (50 V) were added to the reactor, the temperature was raised to react, and the temperature was kept at 30±5°C (optimum temperature 28-30°C) for about 16 hours, and the filter cake was collected by centrifugation.
[0048] Isooctane (5V) was added to the filter cake, stirred to dissolve, and then H2O (2.5V) was added. The mixture was stirred and cooled to 5-15°C. 1N NaOH (2.05eq) was added dropwise. After the addition was complete, the internal temperature was raised to 33±5°C, stirred, and allowed to stand for separation (stirring and standing for 30 minutes is recommended). The resulting aqueous phase was extracted again with 2.5V isooctane, and the organic phases were combined. The organic phases were washed once with 10% NaCl (4V) solution, allowed to stand for separation, and concentrated to dryness under reduced pressure at 45°C to obtain compound (I) with a certain optical purity. The yield was 77.4% and the ee value was 92%.
[0049] The above concentrated dry sample (1.0 eq), dibenzoyl-L-tartaric acid (1.8 eq), and isooctane (50 V) were added to the reactor, the temperature was raised to react, and the temperature was controlled at 30±5°C (optimal temperature 28-30°C) for about 16 hours; the mixture was filtered while keeping warm and the filter cake was collected.
[0050] MTBE (3.5V) was added to the filter cake, stirred to dissolve, and then H2O (2.4V) was added. The mixture was stirred and cooled to 5-15°C. 1N NaOH (2.05eq) was added dropwise. After the addition was complete, stirring was continued for 0.5h. The mixture was allowed to stand for separation, and the aqueous phase was discarded. The organic phase was washed once with 10% NaCl (4V) solution, allowed to stand for separation, and concentrated to dryness under reduced pressure at 45°C to obtain compound (I). The yield was 81.3%, and the ee value was 99.7%.
[0051] Test example:
[0052] During the research process of the present invention, the following screening was performed on the resolution reagents:
[0053] Weigh 35 samples (50 mg each), add 0.5 eq of resolving agent and 0.4 ml of solvent according to Table 1 to each sample, cycle the temperature between 20-50°C for 48 hours, and separate by filtration.
[0054] Table 1. Statistical table of screening results of resolving agents for compounds of formula (I)
[0055] Note: THF: tetrahydrofuran; hept: n-heptane; Acetone: acetone; H2O: water; ACN: acetonitrile.
[0056] As can be seen from Table 1 above, the best resolving agents are D-dibenzoyltartaric acid and L-dibenzoyltartaric acid, and the best resolving solvent is isooctane.
Claims
1. A method for preparing a compound of formula (I), comprising reacting a chiral reagent with formula (A), The chiral reagent is selected from the optically active form of dibenzoyltartaric acid or its hydrate; formula (A) is a mixture of the compound of formula (I) and its enantiomer.
2. The preparation method according to claim 1, wherein the chiral reagent is selected from L-dibenzoyltartaric acid or a hydrate thereof.
3. The preparation method according to claim 1, wherein the chiral reagent is selected from D-dibenzoyltartaric acid or a hydrate thereof.
4. The preparation method according to claim 1, comprising: 1) reacting a chiral reagent with the compound of formula (A) to obtain a compound of formula (II); 2) the compound of formula (II) is treated with alkali to obtain the compound of formula (I); or the compound of formula (II) is treated with alkali and extracted with an organic solvent to obtain the compound of formula (I); wherein the chiral reagent is selected from L-dibenzoyltartaric acid or a hydrate thereof; The alkali is selected from one or more of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, and ammonia water; The organic solvent used in the extraction is selected from one or more of methyl tert-butyl ether, ethyl acetate, isopropyl acetate, dichloromethane, 2-methyltetrahydrofuran, and toluene; 5. The preparation method according to claim 1, comprising: 1) reacting a chiral reagent with the compound of formula (A) to obtain a compound of formula (III); 2) the compound of formula (III) is treated with alkali to obtain the compound of formula (I); or the compound of formula (III) is treated with alkali and extracted with an organic solvent to obtain the compound of formula (I); wherein the chiral reagent is selected from D-dibenzoyltartaric acid or a hydrate thereof; The alkali is selected from one or more of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, and ammonia water; The organic solvent used in the extraction is selected from one or more of methyl tert-butyl ether, ethyl acetate, isopropyl acetate, dichloromethane, 2-methyltetrahydrofuran, and toluene; 6. The preparation method according to claim 1, comprising: 1) using a chiral reagent to react with the compound of formula (A) to obtain a compound of formula (III); 2) reacting the compound of formula (III) in 1) with L-dibenzoyltartaric acid or its hydrate, and then treating with alkali to obtain the compound of formula (I): 3) Optionally, repeat step 2) to further obtain a compound of formula (I) with a higher ee value, wherein the chiral reagent is selected from D-dibenzoyltartaric acid; 7. The preparation method according to claim 1, comprising: 1) using a chiral reagent to react with the compound of formula (A) to obtain a compound of formula (III); 2) reacting the compound of formula (III) in 1) with L-dibenzoyltartaric acid or its hydrate, and then treating with alkali to obtain the compound of formula (I): 3) Optionally, repeat step 2) to further obtain a compound of formula (I) with a higher ee value, wherein the chiral reagent is selected from D-dibenzoyltartaric acid hydrate; 8. The preparation method according to any one of claims 1 to 7, wherein the molar ratio of the enantiomeric mixture of formula (I) to the chiral reagent is 1:0.1-2.0, preferably 1:0.8-1.
8.
9. The preparation method according to any one of claims 1 to 8, wherein the solvent used in the reaction is selected from at least one of n-pentane, n-hexane, cyclohexane, n-octane or isooctane, preferably isooctane.
10. A complex as shown in formula (II) or formula (III):
11. Use of the complex according to claim 10 as an intermediate in the preparation of (R)-2-(3,5-dichloro-4-((7-(methyl-d3)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile.