CN117843529A - Resolution method of ozagrel hydrochloride intermediate and preparation method of ozagrel hydrochloride - Google Patents

Resolution method of ozagrel hydrochloride intermediate and preparation method of ozagrel hydrochloride Download PDF

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CN117843529A
CN117843529A CN202410012471.8A CN202410012471A CN117843529A CN 117843529 A CN117843529 A CN 117843529A CN 202410012471 A CN202410012471 A CN 202410012471A CN 117843529 A CN117843529 A CN 117843529A
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yaz
indene
dihydro
hydroxyethyl
carbonitrile
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王志强
崔子珺
张文腾
曹力敏
谌宗永
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Beijing Sunshine Nuohe Pharmaceutical Research Co ltd
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Beijing Sunshine Nuohe Pharmaceutical Research Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/32—Separation; Purification; Stabilisation; Use of additives
    • C07C253/34—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

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Abstract

The application discloses a resolution method of an ozagrel hydrochloride intermediate, which sequentially comprises the following steps: pretreatment procedure: mixing 1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile racemate with an organic solvent, and heating and refluxing to obtain a reflux liquid; crystallization process: adding a resolving agent into the reflux liquid for salt forming reaction, stirring, and primarily crystallizing, wherein the resolving agent is selected from one of S-binaphthol phosphate, tartaric acid, dibenzoyl tartaric acid and di-p-methylbenzoyl tartaric acid; post-treatment procedure: cooling, filtering and drying to obtain (S) -1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile salt; salt decomposition procedure: the acid salt is converted into (S) -1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile. The resolution method of the ozagrel hydrochloride intermediate provided by the invention has the advantages that the chiral purity and ee value of the resolved chiral substance of the target obtained by resolution are extremely high, the yield is greatly improved, and the method is suitable for large-scale industrial production.

Description

Resolution method of ozagrel hydrochloride intermediate and preparation method of ozagrel hydrochloride
Technical Field
The application belongs to the technical field of pharmaceutical chemistry synthesis, and particularly relates to a resolution method of an ozagrel hydrochloride intermediate and application of the resolution method.
Background
Ozagrel hydrochloride (hereinafter sometimes abbreviated as "YAZ"), english name ozanimod hydrochloride, molecular formula: C 23 H 25 ClN 4 O 3 The molecular weight is 440.93, the CAS number is 1306760-87-1, and the structural formula is:
the ozagrel hydrochloride is prepared from Ruieputos (Receptos Inc) of biological pharmaceutical company in the United states, and has the trade name of Zeposia, and can be used for treating ulcerative colitis, and compound remission type multiple sclerosis.
Patent CN102762100B reports the preparation method of ozagrel hydrochloride. This patent reports that 4-cyano-1-indanone is obtained by a cyanation reaction using zinc cyanide as a reagent, starting from 4-bromo-indanone. Condensing the intermediate with (R) - (+) -2-methyl-2-propylsulfinamide to generate an imine intermediate, then utilizing the chirality of the sulfonamide to perform induction control, hydrolyzing sulfinyl to obtain chiral amino derivatives under the condition of strong acid, then obtaining the next intermediate through upper protecting group and nucleophilic substitution reaction, obtaining Schiff base intermediate through sodium hydride, and finally obtaining the final product through condensation and deprotection (the route is shown as formula 1):
disadvantages of this route include: the whole reaction steps are longer, and the production period of the product is long; the reagent zinc cyanide used in the first step is extremely toxic and has great harm to human body; the second step of reaction conditions are anhydrous and oxygen-free, and simultaneously, the chiral center is reduced at ultralow temperature, so that the requirements on process operation and equipment are high; sodium hydride is used in the sixth step, the reaction safety is poor, and explosion is easy to occur; finally, the chiral purity of the product prepared by the method is not high, and the total yield is low.
The patent CN108727291A of Ningbo Ainuo medical science and technology Co., ltd takes 4-cyano-1-indenone as a raw material and takes asymmetric reduction reaction with aminoethanol in the presence of a catalyst to prepare (S) -1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile. It was also reported that 1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile racemate could also be obtained by condensation with aminoethanol by reduction with a reducing agent (borohydride, lithium aluminum hydride or hydrogen), and the compound (S) -1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile was obtained by chiral acid (wherein the chiral resolving agent, i.e., chiral acid, was D-mandelic acid, D-tartaric acid, D-camphorsulfonic acid, D-lactic acid, D-malic acid, D-glutamic acid, diacetone-L-gulonic acid, and example 2 specifically discloses that the purity (relative substance) of the compound of formula III obtained "after resolution was 99%, yield was 35%". Then, protecting the amino group and the hydroxyl group by adopting acetone fork to obtain (S) -1- (2, 2-dimethyl oxadiazole-3-yl) -2, 3-dihydro-1H-indene-4-carbonitrile; then carrying out an amidoxime reaction with hydroxylamine hydrochloride to obtain a compound (S) -1- (2, 2-dimethyl oxadiazole-3-yl) -N-hydroxy-1H-indene-4-amidoxime, then carrying out a condensation reaction on the compound (S) -1- (2, 2-dimethyl oxadiazole-3-yl) -N-hydroxy-1H-indene-4-amidoxime and the compound 3-cyano-4-isopropoxybenzoic acid to obtain an intermediate, and finally carrying out ring opening deprotection to obtain a final product (the route is shown as the following formula 2):
advantages of this route include: shortens the synthetic steps (only 5-6 steps of reactions) of Ozanimod and reduces the production period of the product; the total yield and quality of the product are improved; the reaction conditions in the route are mild, so that anhydrous and anaerobic operation steps are avoided, and the requirements of equipment and operation are reduced; the production process is environment-friendly, safe and reliable, and is suitable for industrial production. However, the disadvantage is that the chiral purity of chiral resolution is also generally low.
Patent IN201741031729 reports that starting from 4-cyano-1-indanone, 4-cyano-1-indenol is obtained by reduction with sodium borohydride, then 1-chloro-2, 3-dihydro-1H-indene-4-carbonitrile is obtained by substitution with thionyl chloride, then 1-chloro-2, 3-dihydro-1H-indene-4-carbonitrile and ethanolamine are subjected to substitution to obtain 1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile racemate, then 1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile racemate is subjected to chiral acid resolution to obtain (S) -1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile (wherein the mentioned chiral acids include tartaric acid, dibenzoyltartaric acid, di-p-methylbenzoyl tartaric acid, camphorsulfonic acid, glutamic acid, malic acid, pyro acid and mandelic acid, then (S) -1-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile racemate is obtained by condensation of the formula (S) -1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-indene-4-carbonitrile, the final protection of which is obtained by condensation reaction of (see the following the scheme:
advantages of this route include: shortens the synthetic steps (only 5-6 steps of reactions) of Ozanimod and reduces the production period of the product; the total yield and quality of the product are improved; the reaction conditions in the route are mild, so that anhydrous and anaerobic operation steps are avoided, and the requirements of equipment and operation are reduced; the production process is environment-friendly, safe and reliable, and is suitable for industrial production. Disadvantages of this route include: when the substitution reaction is performed using a chlorinated intermediate after substitution with thionyl chloride and ethanolamine, it is difficult to control the end point of the reaction, impurities of di-substituted ethanolamine are generated, it is difficult to control the purity of the intermediate, the yield and chiral purity of the obtained chiral product are not high (wherein, example-2 d discloses that the chiral purity of the obtained target product by HPLC is "89.62%), and the product is derived until the final product. Therefore, the control of the final product is difficult.
The above patents all mention resolution of the 1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile racemate by chiral acids, but these resolution are not efficient.
Disclosure of Invention
In view of the problems existing in the prior art, the invention provides a resolution method of an ozagrel hydrochloride intermediate and application thereof. The method carries out chiral resolution by using a specific resolution method, has good safety and low resolution cost, and the purity (ee value, optical purity) of the target resolution chiral substance is extremely high, and simultaneously, the yield is greatly improved, so that the method is suitable for large-scale industrial production.
1. The invention relates to a resolution method of an ozagrel hydrochloride intermediate, which sequentially comprises the following steps:
pretreatment procedure: mixing 1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile racemate shown in the following chemical formula 1 with an organic solvent, and heating and refluxing to obtain a reflux liquid;
crystallization process: adding a resolving agent into the reflux liquid for salifying reaction, stirring, and primarily crystallizing, wherein the resolving agent is selected from one of S-binaphthol phosphate, tartaric acid, dibenzoyl tartaric acid and di-p-methylbenzoyl tartaric acid;
post-treatment procedure: cooling, filtering and drying to obtain (S) -1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile salt shown in the following chemical formula 2, wherein M represents acid radical ions of acid selected from S-binaphthol phosphate, tartaric acid, dibenzoyl tartaric acid and di-p-methylbenzoyl tartaric acid;
salt decomposition procedure: the (S) -1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile acid salt described above was converted to the following chemistry
(S) -1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile represented by formula 3.
2. The resolution method according to the above 1, wherein the resolving agent is S-binaphthol phosphate.
3. The resolution method according to 1 or 2, wherein the organic solvent is at least one selected from the group consisting of methanol, ethanol, isopropanol, acetonitrile, acetone and tetrahydrofuran.
4. The resolution method according to the above 1 to 3, wherein the liquid-solid ratio (ml/g) of the organic solvent to the 1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile racemate is 3 to 100:1, further 5 to 55:1, further 10 to 50:1.
5. The resolution method according to 1 to 3, wherein the molar equivalent ratio of the resolving agent to the 1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile racemate is 0.10 to 1.00:1, further 0.3 to 0.75:1, further 0.3 to 0.5:1.
6. The method for resolution according to 1 to 3, wherein the heat-retaining time of the reflow in the pretreatment step is 10min to 10h, and further 0.5h to 5h.
7. The resolution method according to 1 to 3, wherein in the crystallization step, after the primary crystallization, the system is cooled to-30 to 30 ℃ while stirring for 2 to 5 hours, and secondary crystallization is performed.
8. The resolution method according to the above 7, wherein the crystallization temperature of the secondary crystallization is-10℃to-5 ℃.
9. The resolution method according to the above 1 to 3, wherein the drying temperature in the post-treatment step is 30℃to 80 ℃.
10. A process for preparing ozagrel hydrochloride, which comprises the steps of resolving 1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile as shown in the following chemical formula 1 into (S) -1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile as shown in the following chemical formula 3, wherein resolving agent used for resolving is resolving agent of 1-9.
Specifically:
the invention relates to a 1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile racemate with the following structure:
the racemate of the above chemical formula (1) has two structures, namely, an S configuration (chemical formula (3), (S) -1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile, hereinafter abbreviated as "S configuration YAZ-1") and an R configuration (chemical formula (4), (R) -1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile, hereinafter abbreviated as "R configuration YAZ-1"):
the technical scheme of the invention is as follows: the invention provides a resolution method of an ozagrel hydrochloride intermediate, wherein 1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile racemate (hereinafter referred to as 'YAZ-1') and a resolving agent are subjected to a salt forming reaction, then crystallization is carried out at a certain temperature to obtain S configuration YAZ-1 salt, and then the S configuration YAZ-1 salt is converted into a target resolution chiral substance, namely S configuration YAZ-1 through the reaction.
As a specific mixing mode of the YAZ-1 and the resolving agent, YAZ-1 is preferably pretreated in advance and then subjected to a salt forming reaction with the resolving agent.
Preferably, the pretreatment step is to add YAZ-1 to the organic solvent in advance and then to heat and reflux the mixture.
The ratio of the organic solvent to YAZ-1 (in terms of "ml/g") is 3 to 100:1, more preferably 5 to 55:1, still more preferably 10 to 50:1, and specifically, for example, 3:1, 5:1, 10:1, 15:1, 20:1, 30:1, 40:1, 50:1, 55:1, 60:1, 80:1, 90:1, 100:1, etc., but is not limited thereto. When the liquid-solid ratio is too large, the yield of the obtained S-configuration YAZ-1 salt tends to be reduced, and when the liquid-solid ratio is too small, the S-configuration content obtained by resolution tends to be relatively less, but the R-configuration content is increased.
Examples of the organic solvent include, but are not limited to, methanol, ethanol, isopropanol, acetonitrile, acetone, and tetrahydrofuran, and methanol, ethanol, and isopropanol are preferable.
The temperature of the heating and refluxing is usually 50 to 70 ℃, preferably 50 to 65 ℃, more preferably 60 to 65 ℃, but is not limited thereto.
As one specific embodiment of the pretreatment step, there may be mentioned, but not limited to, stirring 100ml of methanol with YAZ-110.00g, heating to 50-70℃and refluxing for 0.5-5 hours until the system is clear and orange-yellow clear liquid.
After the pretreatment of YAZ-1 described above, a resolving agent was added to the solution.
The type of the resolving agent may be one selected from the group consisting of S-binaphthol phosphate, tartaric acid, dibenzoyltartaric acid, and di-p-methylbenzotrartaric acid, but is not limited thereto, and S-binaphthol phosphate and tartaric acid are preferable, and S-binaphthol phosphate is more preferable, from the viewpoint of achieving both chiral purity, ee value, and yield.
The molar equivalent ratio of the resolving agent to YAZ-1 to be added is usually 0.10 to 1.00:1, more preferably 0.3 to 0.75:1, still more preferably 0.3 to 0.5:1, and specifically, for example, 0.10:1, 0.20:1, 0.30:1, 0.40:1, 0.50:1, 0.60:1, 0.70:1, 0.80:1, 0.90:1, and 1.00:1, but is not limited thereto, and the molar equivalent ratio is too small, the salt formation is insufficient, the yield is too low, and the molar equivalent ratio is too large, with the result that chiral purity and ee value are greatly reduced.
After adding a resolving agent such as S-binaphthol phosphate or the like to the system, preliminary crystallization is performed in advance, that is, the system gradually precipitates a large amount of off-white solid, and the system is preferably kept warm and stirred.
The heat-retaining time in the crystallization step is usually 10min to 10h, more preferably 10min to 5h, still more preferably 0.5h to 5h, and specifically, for example: 10min, 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h. If the holding time is too short, complete salt formation is not possible, resulting in an excessively low yield.
After the stirring, the system can be subjected to cooling treatment and secondary stirring, so that secondary crystallization is realized.
The crystallization temperature range of the above-mentioned cooling is usually, but not limited to, 30℃to-30℃and preferably-15℃to-5℃and more preferably-10℃to-5 ℃.
The time for the secondary crystallization is usually 30min to 10 hours, preferably 1 to 10 hours, more preferably 2 to 5 hours, and most preferably 2 hours, but is not limited thereto.
As one specific embodiment of the crystallization process, there may be mentioned, but not limited to, slowly cooling the system to-10 to-5 ℃ (crystallization temperature), stirring and crystallizing for 2 hours, filtering, and collecting the cake after the pretreatment step.
After the crystallization process, a post-treatment process is performed.
The S-configuration YAZ-1 salt is obtained by the post-treatment process, the S-configuration YAZ-1 salt is a salt obtained by reacting the S-configuration YAZ-1 with a resolving agent, and when the resolving agent selects an acid, the salt formed is a salt of YAZ-1 with the acid, and the salt is represented by the following chemical formula (2):
(wherein M represents an acid ion selected from the group consisting of S-binaphthol phosphate, tartaric acid, dibenzoyl tartaric acid, and di-p-methylbenzoyl tartaric acid, but is not limited thereto)
As a specific salt, for example, when the above resolving agent uses S-binaphthol phosphate, the S-configuration YAZ-1 salt is "S-configuration YAZ-1S-binaphthol phosphate", when the above resolving agent uses tartaric acid, the S-configuration YAZ-1 salt is "S-configuration YAZ-1 tartrate", and when the above resolving agent uses dibenzoyltartaric acid, the S-configuration YAZ-1 salt is "S-configuration YAZ-1 dibenzoyltartrate", and is not limited to any form exemplified in the present invention as long as it can form a salt with S-configuration YAZ-1 acid.
As a specific embodiment of the post-treatment step, there is mentioned a method in which the cake is rinsed and dried to obtain the final product.
The washing method is not limited to this, and examples of the organic solvent include methanol and ethanol.
The drying method includes air-drying to a constant weight at a drying temperature of 30 to 80 ℃, preferably 30 to 50 ℃, more preferably 50 ℃.
After (S) -1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile acid salt was obtained in the above-mentioned work-up step, the (S) -1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile acid salt was converted into the following chemical by the above-mentioned salt decomposition step
(S) -1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile of formula 3:
as a specific transformation mode in the above-mentioned salt decomposition step, any mode is not limited as long as the salt can be transformed into the target S configuration YAZ-1, and specifically, for example, the obtained YAZ-1 salt is subjected to Boc protection with Boc anhydride to obtain YAZ-2; YAZ-2 and hydroxylamine hydrochloride undergo amidoxime reaction to obtain YAZ-3; YAZ-3 and 3-cyano-4-isopropoxy benzoic acid undergo a condensation reaction to obtain YAZ-4; YAZ-4 and hydrogen chloride in methanol undergo a simultaneous salt formation reaction with Boc deprotection to give YAZ, but are not limited to this.
The main resolution route of the resolution method of the present invention is, for example, specifically as follows:
in addition, the invention also relates to a preparation method of ozagrel hydrochloride, which comprises the step of splitting YAZ-1 into an S configuration YAZ-1 and an R configuration YAZ-1, wherein the splitting agent used for splitting is the splitting agent used in the invention. The method has the advantages of good safety, low resolution cost, extremely high chiral purity and ee value of the target resolution chiral substance, greatly improved yield and suitability for large-scale industrial production.
Drawings
FIG. 1 shows a high performance liquid chromatogram of the YAZ-1 salt of example 1.
FIG. 2 shows a high performance liquid chromatography-related substance detection spectrum of YAZ-1 salt of example 1.
FIG. 3 shows a liquid mass (LC-MS) diagram of YAZ-1 of example 1.
Detailed Description
Technical solutions in the embodiments of the present application will be clearly described below with reference to the drawings in the embodiments of the present application, and it is apparent that the described embodiments are some embodiments of the present application, but not all embodiments. All other embodiments obtained by a person of ordinary skill in the art based on the embodiments in the present application are within the scope of the protection of the present application.
Example 1:
preparation of YAZ-1 salts
100ml of methanol and 110.00g of YAZ are added into a 250ml three-necked flask, stirred, heated to reflux and kept for 5 hours, the system is clear and presents orange-yellow clear liquid, 0.50eq of S-binaphthol phosphate is added into the three-necked flask, a large amount of off-white solid YAZ-1 salt is separated out from the system along with the stirring process, and then the temperature is kept for 5 hours. Slowly cooling to-5 ℃, stirring and crystallizing for 2 hours, filtering, collecting a filter cake, leaching the filter cake with 30ml of methanol, and then drying at the blast air of 40 ℃ to obtain 10.62g of total off-white solid YAZ-1 salt.
The yield was calculated by the following method:
[ yield ]
The yield was calculated as follows:
yield (%) = (m YAZ-1 salt ×MW YAZ-1 )/(m YAZ-1 ×MW YAZ-1 salt )
Wherein the method comprises the steps of
“m YAZ-1 salt "means the mass of YAZ-1 salt
“MW YAZ-1 "means the molecular weight of YAZ-1
“m YAZ-1 "means the charging quality of YAZ-1
“MW YAZ-1 salt "means the molecular weight of YAZ-1 salt
Preparation of S configuration YAZ-1
To a 250ml three-necked flask, 150ml of ethyl acetate and 10.00g of YAZ-1 salt were added and stirred, 100ml of a 2N aqueous sodium hydroxide solution was added and stirred for 2 hours, the stirring was stopped, and the upper organic phase was collected by separating. The organic phase was concentrated to dryness under vacuum-0.10 MPa at 40℃to give S configuration YAZ-1.
Wherein, the chiral purity and ee value of the S configuration YAZ-1 are obtained by the following method:
[ chiral purity ]
Chiral purity detection for S configuration YAZ-1 was determined by high performance liquid chromatography:
enantiomers: high performance liquid chromatography (according to the general rule of four parts of the year of the Chinese pharmacopoeia 2020)
Solvent: methanol-absolute ethanol (10:90)
Test solution: taking a proper amount of the product, adding a solvent for ultrasonic dissolution and diluting to prepare a solution containing about 2.0mg of the product in each 1ml of the product, and taking the solution as a test sample solution.
Control solution: a proper amount of the sample solution was precisely measured, and the solution was quantitatively diluted with a solvent to prepare a control solution containing about 10. Mu.g per 1 ml.
System applicability solution: appropriate amounts of R-configuration YAZ-1 and S-configuration YAZ-1 were precisely weighed, dissolved by ultrasonic with a solvent, and diluted to prepare a mixed solution containing about 3. Mu.g of R-configuration YAZ-1 and 2. Mu.g of S-configuration YAZ-1 per 1ml as a system-suitable solution.
Chromatographic conditions: cellulose-3, 5-dichlorophenyl carbamate linked silica gel was used as a filler (recommended: DALCEL CHIRPAK IC, 4.6X250 mm,5 μm or column with comparable performance); n-hexane-absolute ethyl alcohol-diethylamine (90:10:0.1) is used as a mobile phase A, and absolute ethyl alcohol is used as a mobile phase B; gradient elution was performed according to the following table; the flow rate is 1.0ml per minute; the column temperature is 30 ℃; the detection wavelength is 215nm; the sample volume was 20. Mu.l.
System applicability requirements: in a 20-mu l chromatogram of the system-applicable solution, the peak order of each component is in sequence of S configuration YAZ-1 and R configuration YAZ-1.
[ ee value ]
The ee value is calculated as follows:
ee (%) = (S configuration YAZ-1-R configuration YAZ-1)/(S configuration YAZ-1+r configuration YAZ-1)) ×100%
Thus, the "chiral purity", "ee value" and "yield" of S configuration YAZ-1 obtained in example 1 are shown in Table 1 below.
In addition, FIG. 1 shows a High Performance Liquid Chromatography (HPLC) chromatogram of YAZ-1 salt of example 1, which is a High Performance Liquid Chromatography (HPLC) chromatogram isomer detection chart, wherein the S-configuration product is 98.693%, the R-configuration isomer is 1.307%, i.e., chiral purity is 98.693%, and ee value is 97.39% as seen from the "peak table" of FIG. 1; FIG. 2 shows a high performance liquid chromatography-related substance detection spectrum of YAZ-1 salt of example 1, wherein the main component accounts for about 99.801% and the other maximum unknown single impurity is 0.052% as seen from the "peak table" of FIG. 2; FIG. 3 shows an LC-MS diagram of "YAZ-1" of example 1, and it is revealed from FIG. 3 that YAZ-1 has a molecular weight of 202.26 and a molecular ion peak M+1 peak of 203.
In addition, the detailed preparation process of the final product YAZ finished product is as follows:
preparation of YAZ-2
Adding THF, water and S-shaped YAZ-1 salt into a three-mouth bottle, stirring, gradually dissolving the system, presenting orange clear liquid, adding sodium hydroxide aqueous solution, adding Boc anhydride, heating to 20-30 ℃, and stirring for 6-8.0 h. After the completion of the reaction, ethyl acetate was added thereto for extraction, the upper organic phase was collected, dried by adding anhydrous sodium sulfate to the organic phase, then filtered, and concentrated at 30 to 35℃to give (S) -tert-butyl- [ (4-cyano-2, 3-dihydro-1H-inden-1-yl) -2-hydroxyethyl ] carbamate (abbreviated as "YAZ-2") as an oil.
Preparation of YAZ-3
Adding absolute ethyl alcohol into a three-mouth bottle, adding hydroxylamine hydrochloride and triethylamine, stirring for 1.0h at 20-35 ℃, adding YAZ-2 into the three-mouth bottle, heating to 80-85 ℃, gradually dissolving the system, presenting yellow clear liquid, and stirring for 3.0-4.0 h. The reaction solution was then concentrated to dryness to obtain a pale yellow solid, methylene chloride and water were then added to the pale yellow solid to separate out an organic phase, the organic phase was washed with water, then the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phase was collected and concentrated to dryness to obtain (S) -tert-butyl- [ (4-cyano-2, 3-dihydro-1H-inden-1-yl) -2-hydroxyethyl ] carbamate (abbreviated as "YAZ-3") as a foamed white solid.
Preparation of YAZ-4
DMF is added into a three-necked flask, EDCI.HCl and HOBt are added into the flask, stirring is carried out for 3.0H to 5.0H, the mixture is subjected to YAZ-SM-B to be basically completely converted into an acid compound, YAZ-3 is then added into the flask, the mixture is stirred for 2.0H at 25 to 35 ℃, the mixture is subjected to complete conversion into a chain intermediate (transition state), the mixture is heated to 110 to 120 ℃ and stirred for 6.0H to 8.0H at a fixed time, the mixture is subjected to complete conversion into YAZ-4, the mixture is cooled to room temperature, ethyl acetate and saturated sodium bicarbonate aqueous solution are added into the mixture, the mixture is stirred for 10min, an upper organic phase is separated, the mixture is dried by anhydrous sodium sulfate and concentrated to be dried at 40 to 50 ℃ to obtain oily substance (S) -tert-butyl- [ [4- [5- (3-cyano-4-isopropoxyphenyl) -1,2, 4-oxadiazol ] -3-yl ] -2, 3-dihydro-1H-1-hydroxyethyl ] -2-indene (35-4-hydroxyethyl) carbamate) which is called as an oil product of YAZ'.
Preparation of YAZ
Adding methanol into a three-mouth bottle, adding YAZ-4, clarifying the system, adding a methanol solution of hydrogen chloride into the system, stirring for 3.0h at 50-60 ℃, gradually precipitating off-white solid along with the stirring process, cooling to room temperature, gradually precipitating a large amount of solid, then cooling to 0-10 ℃, stirring for 1.0h, filtering, and collecting a filter cake to obtain off-white solid, namely YAZ finished product.
Example 2:
a three-necked flask of 250ml was charged with 150ml of methanol under the same reaction conditions as in example 1 except that the temperature keeping time in the crystallization step was 2 hours, to obtain 9.25g of a total off-white solid YAZ-1 salt, and the "chiral purity", "ee value" and "yield" of YAZ-1 in S configuration obtained in example 2 were measured by the same measurement method as described above, as shown in Table 1 below.
Example 3:
the "chiral purity", "ee value" and "yield" of the S configuration YAZ-1 obtained in example 3 were determined by the same measurement method as described above, see Table 1 below, except that 200ml of methanol was added to a 250ml three-necked flask under the same reaction conditions as in example 2, to obtain 6.80g of a total off-white solid YAZ-1 salt.
Example 4:
the "chiral purity", "ee value" and "yield" of the S configuration YAZ-1 obtained in example 4 were determined by the same measurement method as described above, see Table 1 below, except that 500ml of methanol was added to a 250ml three-necked flask under the same reaction conditions as in example 2, to obtain 5.44g of a total off-white solid YAZ-1 salt.
Example 5:
the "chiral purity", "ee value" and "yield" of the S configuration YAZ-1 obtained in example 5 were measured by the same measurement method as described above, and are shown in Table 1 below, except that the heat-insulating time in the crystallization step was 2 hours, the temperature of the lowered crystallization was-10 ℃, and the reaction conditions were the same as in example 1, except that 10.34g of the total off-white solid YAZ-1 salt was obtained.
Example 6:
the "chiral purity", "ee value" and "yield" of the S configuration YAZ-1 obtained in example 6 were measured by the same measurement method as described above, with the exception that the crystallization temperature in the crystallization step was-5℃and the other reaction conditions were the same as in example 5, to obtain 11.43g of a total off-white solid YAZ-1 salt, and are shown in Table 1 below.
Example 7:
the chiral purity, ee value and yield of S-configuration YAZ-1 obtained in example 7 were measured by the same measurement method as described above, with the exception that the molar equivalent ratio of the resolving agent to YAZ-1 in the crystallization step was 0.3, and the conditions of the other reactions were the same as in example 6, to obtain 5.44g of a total off-white solid YAZ-1 salt, as shown in Table 1 below.
Example 8:
the "chiral purity", "ee value" and "yield" of the S configuration YAZ-1 obtained in example 8 were measured by the same measurement method as described above, with the exception that the heat-retaining time in the crystallization step was 1h, and the other reaction conditions were the same as in example 6, to obtain 10.89g of a total off-white solid YAZ-1 salt, and are shown in Table 1 below.
Example 9:
the "chiral purity", "ee value" and "yield" of the S configuration YAZ-1 obtained in example 9 were measured by the same measurement method as described above, and are shown in Table 1 below, except that the heat-retaining time in the crystallization step was 0.5h, and the reaction conditions were the same as in example 6, to obtain 10.89g of a total off-white solid YAZ-1 salt.
Comparative example 1:
the "chiral purity", "ee value" and "yield" of S configuration YAZ-1 obtained in comparative example 1 were determined by the same measurement method as described above with the exception that 13.07g of the total off-white solid YAZ-1 salt was obtained in the same manner as in example 6 except that 50ml of methanol was added to a 250ml three-necked flask, and are shown in Table 1 below.
Comparative example 2:
the "chiral purity", "ee value" and "yield" of S configuration YAZ-1 obtained in comparative example 2 were determined by the same measurement method as described above, see Table 1 below, except that 30ml of methanol was added to a 250ml three-necked flask under the same reaction conditions as in example 6, to obtain 14.15g of a total off-white solid YAZ-1 salt.
Comparative example 3:
the "chiral purity", "ee value" and "yield" of S configuration YAZ-1 obtained in comparative example 3 were determined by the same measurement method as described above, see Table 1 below, except that 20ml of methanol was added to a 250ml three-necked flask under the same reaction conditions as in example 6 to obtain 16.33g of a total off-white solid YAZ-1 salt.
Comparative example 4:
the "chiral purity", "ee value" and "yield" of S configuration YAZ-1 obtained in comparative example 4 were determined by the same measurement method as described above, see Table 1 below, except that 10ml of methanol was added to a 250ml three-necked flask under the same reaction conditions as in example 6, to obtain 17.69g of a total off-white solid YAZ-1 salt.
Comparative example 5:
the "chiral purity", "ee value" and "yield" of S configuration YAZ-1 obtained in comparative example 5 were determined by the same measurement method as described above, see Table 1 below, except that 550ml of methanol was added to a 250ml three-necked flask under the same reaction conditions as in example 6, to obtain 2.18g of a total off-white solid YAZ-1 salt.
Comparative example 6:
the chiral purity, ee value and yield of S-configuration YAZ-1 obtained in comparative example 6 were measured by the same measurement method as described above, and are shown in Table 1 below, except that the molar equivalent ratio of the resolving agent to YAZ-1 in the crystallization step was 0.75, and the reaction conditions were the same as in example 6, to obtain 10.89g of a total off-white solid YAZ-1 salt.
Comparative example 7:
the chiral purity, ee value and yield of S-configuration YAZ-1 obtained in comparative example 7 were measured by the same measurement method as described above, with the exception that the molar equivalent ratio of the resolving agent to YAZ-1 in the crystallization step was 1.0, and the reaction conditions were the same as in example 6, to obtain 13.61g of a total off-white solid YAZ-1 salt, as shown in Table 1 below.
Comparative example 8:
the chiral purity, ee value and yield of S-configuration YAZ-1 obtained in comparative example 8 were measured by the same measurement method as described above, and are shown in Table 1 below, except that the molar equivalent ratio of the resolving agent to YAZ-1 in the crystallization step was 1.5, and the reaction conditions were the same as in example 6, to give 15.52g of a total off-white solid YAZ-1 salt.
Comparative example 9:
the chiral purity, ee value and yield of S-configuration YAZ-1 obtained in comparative example 9 were measured by the same measurement method as described above, and are shown in Table 1 below, except that the molar equivalent ratio of the resolving agent to YAZ-1 in the crystallization step was 2.0, and the reaction conditions were the same as in example 6, to give 16.88g of a total off-white solid YAZ-1 salt.
Comparative example 10:
the "chiral purity", "ee value" and "yield" of the S configuration YAZ-1 obtained in comparative example 10 were measured by the same measurement method as described above, and are shown in Table 1 below, except that D-acetylmandelic acid was used as the resolving agent in the crystallization step, and the reaction conditions were the same as in example 6, to obtain 8.98g of a total off-white solid YAZ-1 salt.
Comparative example 11:
the "chiral purity", "ee value" and "yield" of S configuration YAZ-1 obtained in comparative example 11 were determined by the same measurement method as described above, see Table 1 below, except that camphorsulfonic acid was used as the resolving agent in the crystallization step, and the reaction conditions were the same as in example 6, to obtain 8.17g of a total off-white solid YAZ-1 salt.
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TABLE 1
From Table 1, it is apparent that the present invention has been examined, in particular, for the liquid-solid ratio of the solvent to YAZ-1, the type of the resolving agent, the ratio of the resolving agent to YAZ-1, etc. in the whole process, wherein the "chiral purity" and "ee value" of S-configuration YAZ-1 of examples 1 to 7 are 90 or more, excellent resolving effect is exhibited, and the "yield" of S-configuration YAZ-1 of these examples is 20% or more, and the yield is high. As is clear from the comparative examples, the amounts of solvents in comparative examples 1 to 4 do not satisfy the scope of the present invention, and the "chiral purity" and "ee value" of the S configuration YAZ-1 obtained are low, and the "chiral purity" and "ee value" of the S configuration YAZ-1 obtained in comparative example 5 are very low, although they are high, the yields are only "8%"; the resolving agent equivalent of comparative examples 6 to 9 does not satisfy the scope of the present invention, and at this time, although the yield of the obtained S configuration YAZ-1 is still acceptable, the "chiral purity" and "ee value" of the obtained S configuration YAZ-1 are low; comparative example 10 and comparative example 11 attempted to replace "S-binaphthol phosphate" of the present invention with the resolving agents "D-acetylmandelic acid" and "camphorsulfonic acid", but the "chiral purity" and "ee value" were both low, and the resolving effect was extremely unsatisfactory. In addition, although these comparative examples showed a higher "yield" value, the resolution was incomplete because of the lower chiral purity value corresponding to these comparative examples, and the resulting product contained more R-configuration YAZ-1, which was responsible for the higher yield value.
The resolution method of the ozagrel hydrochloride intermediate provided by the invention has the advantages that the chiral purity and ee value of the target resolution chiral substance obtained by resolution are extremely high, the yield is greatly improved, and the method is suitable for large-scale industrial production.
The embodiments of the present application have been described above with reference to the accompanying drawings, but the present application is not limited to the above-described embodiments, which are merely illustrative and not restrictive, and many forms may be made by those of ordinary skill in the art without departing from the spirit of the present application and the scope of the claims, which are also within the protection of the present application.

Claims (10)

1. The splitting method of the ozagrel hydrochloride intermediate is characterized by comprising the following steps of:
pretreatment procedure: mixing 1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile racemate shown in the following chemical formula 1 with an organic solvent, and heating and refluxing to obtain a reflux liquid;
crystallization process: adding a resolving agent into the reflux liquid for salt forming reaction, stirring, and primarily crystallizing, wherein the resolving agent is selected from one of S-binaphthol phosphate, tartaric acid, dibenzoyl tartaric acid and di-p-methylbenzoyl tartaric acid;
post-treatment procedure: cooling, filtering and drying to obtain (S) -1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile salt shown in the following chemical formula 2, wherein M represents acid radical ions of acid selected from S-binaphthol phosphate, tartaric acid, dibenzoyl tartaric acid and di-p-methylbenzoyl tartaric acid;
salt decomposition procedure: the above (S) -1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile acid salt is converted into (S) -1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile shown in the following chemical formula 3,
2. the resolution method according to claim 1, wherein the resolving agent is S-binaphthol phosphate.
3. The resolution method according to claim 1 or 2, wherein the organic solvent is at least one selected from the group consisting of methanol, ethanol, isopropanol, acetonitrile, acetone, and tetrahydrofuran.
4. A resolution process according to any one of claims 1 to 3, wherein the liquid to solid ratio (ml/g) of the organic solvent to the 1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile racemate is 3 to 100:1, further 5 to 55:1, further 10 to 55:1, still further 10 to 50:1.
5. A resolution process according to any one of claims 1 to 3 wherein the molar equivalent ratio of resolving agent to the 1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile racemate is from 0.10 to 1.00:1, further from 0.3 to 0.75:1, further from 0.3 to 0.5:1.
6. The resolution method according to any one of claims 1 to 3, wherein the heat-retaining time of the reflow in the pretreatment step is 10min to 10h, and further 0.5h to 5h.
7. The resolution method according to any one of claims 1 to 3, wherein in the crystallization step, after the primary crystallization, the system is cooled to-30 to 30 ℃ while stirring for 2 to 5 hours to perform secondary crystallization.
8. The resolution method according to claim 7, wherein the crystallization temperature of the secondary crystallization is-10 ℃ to-5 ℃.
9. A resolution method according to any one of claims 1 to 3, wherein in the post-treatment step, the drying temperature is 30 ℃ to 80 ℃.
10. A process for preparing ozagrel hydrochloride, which comprises the steps of resolving a racemate of 1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile represented by the following chemical formula 1 into (S) -1- [ (2-hydroxyethyl) amino ] -2, 3-dihydro-1H-indene-4-carbonitrile represented by the following chemical formula 3, wherein the resolving agent used for resolving is the resolving agent according to any one of claims 1 to 9.
CN202410012471.8A 2024-01-04 2024-01-04 Resolution method of ozagrel hydrochloride intermediate and preparation method of ozagrel hydrochloride Pending CN117843529A (en)

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